CN118619931A - Aryl or heteroaryl derivative inhibitor, preparation method and application thereof - Google Patents
Aryl or heteroaryl derivative inhibitor, preparation method and application thereof Download PDFInfo
- Publication number
- CN118619931A CN118619931A CN202410269362.4A CN202410269362A CN118619931A CN 118619931 A CN118619931 A CN 118619931A CN 202410269362 A CN202410269362 A CN 202410269362A CN 118619931 A CN118619931 A CN 118619931A
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- Prior art keywords
- alkoxy
- alkyl
- deuterated
- alkylene
- cycloalkyl
- Prior art date
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- 125000003118 aryl group Chemical group 0.000 title claims abstract description 328
- 239000003112 inhibitor Substances 0.000 title claims abstract description 6
- 238000002360 preparation method Methods 0.000 title claims abstract description 5
- 125000001072 heteroaryl group Chemical group 0.000 title abstract description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 34
- 208000023275 Autoimmune disease Diseases 0.000 claims abstract description 5
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract 3
- 125000003545 alkoxy group Chemical group 0.000 claims description 813
- 125000000217 alkyl group Chemical group 0.000 claims description 714
- -1 amino, hydroxyl Chemical group 0.000 claims description 485
- 125000000623 heterocyclic group Chemical group 0.000 claims description 482
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 433
- 125000004737 (C1-C6) haloalkoxy group Chemical group 0.000 claims description 421
- 125000006577 C1-C6 hydroxyalkyl group Chemical group 0.000 claims description 421
- 125000001313 C5-C10 heteroaryl group Chemical group 0.000 claims description 413
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 391
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 382
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 382
- 229910052736 halogen Inorganic materials 0.000 claims description 294
- 150000002367 halogens Chemical group 0.000 claims description 294
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical group [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 claims description 293
- 229910052805 deuterium Inorganic materials 0.000 claims description 293
- 229910052739 hydrogen Inorganic materials 0.000 claims description 284
- 239000001257 hydrogen Substances 0.000 claims description 284
- 150000002431 hydrogen Chemical group 0.000 claims description 282
- 125000002947 alkylene group Chemical group 0.000 claims description 236
- 125000000041 C6-C10 aryl group Chemical group 0.000 claims description 159
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 150
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 141
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 127
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 104
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 104
- 125000004043 oxo group Chemical group O=* 0.000 claims description 104
- 125000000446 sulfanediyl group Chemical group *S* 0.000 claims description 104
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims description 65
- 125000004438 haloalkoxy group Chemical group 0.000 claims description 60
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 60
- 125000006583 (C1-C3) haloalkyl group Chemical group 0.000 claims description 56
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 54
- 125000004450 alkenylene group Chemical group 0.000 claims description 52
- 125000004419 alkynylene group Chemical group 0.000 claims description 52
- 125000003342 alkenyl group Chemical group 0.000 claims description 42
- 125000000304 alkynyl group Chemical group 0.000 claims description 42
- 102000013691 Interleukin-17 Human genes 0.000 claims description 17
- 108050003558 Interleukin-17 Proteins 0.000 claims description 17
- 150000003839 salts Chemical class 0.000 claims description 15
- 201000004681 Psoriasis Diseases 0.000 claims description 7
- 239000003814 drug Substances 0.000 claims description 5
- 229940079593 drug Drugs 0.000 claims description 5
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 claims description 3
- 206010002556 Ankylosing Spondylitis Diseases 0.000 claims description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- 206010015278 Erythrodermic psoriasis Diseases 0.000 claims 1
- 201000001263 Psoriatic Arthritis Diseases 0.000 claims 1
- 208000036824 Psoriatic arthropathy Diseases 0.000 claims 1
- 206010037575 Pustular psoriasis Diseases 0.000 claims 1
- 206010046851 Uveitis Diseases 0.000 claims 1
- 239000003085 diluting agent Substances 0.000 claims 1
- 239000003937 drug carrier Substances 0.000 claims 1
- 206010018797 guttate psoriasis Diseases 0.000 claims 1
- 201000007162 hidradenitis suppurativa Diseases 0.000 claims 1
- 208000015181 infectious disease Diseases 0.000 claims 1
- 230000002458 infectious effect Effects 0.000 claims 1
- 239000000546 pharmaceutical excipient Substances 0.000 claims 1
- 206010039073 rheumatoid arthritis Diseases 0.000 claims 1
- 201000005671 spondyloarthropathy Diseases 0.000 claims 1
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 description 11
- 125000006656 (C2-C4) alkenyl group Chemical group 0.000 description 11
- 125000006650 (C2-C4) alkynyl group Chemical group 0.000 description 11
- 125000006274 (C1-C3)alkoxy group Chemical group 0.000 description 10
- 101000998146 Homo sapiens Interleukin-17A Proteins 0.000 description 4
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- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical group C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- 229960002751 imiquimod Drugs 0.000 description 2
- DOUYETYNHWVLEO-UHFFFAOYSA-N imiquimod Chemical compound C1=CC=CC2=C3N(CC(C)C)C=NC3=C(N)N=C21 DOUYETYNHWVLEO-UHFFFAOYSA-N 0.000 description 2
- 208000027866 inflammatory disease Diseases 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 210000000581 natural killer T-cell Anatomy 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 2
- MZOFCQQQCNRIBI-VMXHOPILSA-N (3s)-4-[[(2s)-1-[[(2s)-1-[[(1s)-1-carboxy-2-hydroxyethyl]amino]-4-methyl-1-oxopentan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-3-[[2-[[(2s)-2,6-diaminohexanoyl]amino]acetyl]amino]-4-oxobutanoic acid Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@@H](N)CCCCN MZOFCQQQCNRIBI-VMXHOPILSA-N 0.000 description 1
- 125000006704 (C5-C6) cycloalkyl group Chemical group 0.000 description 1
- UOCLXMDMGBRAIB-UHFFFAOYSA-N 1,1,1-trichloroethane Chemical compound CC(Cl)(Cl)Cl UOCLXMDMGBRAIB-UHFFFAOYSA-N 0.000 description 1
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- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical group FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
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- 102100033096 Interleukin-17D Human genes 0.000 description 1
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- 108090001005 Interleukin-6 Proteins 0.000 description 1
- 102000004889 Interleukin-6 Human genes 0.000 description 1
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- 102000043136 MAP kinase family Human genes 0.000 description 1
- 108091054455 MAP kinase family Proteins 0.000 description 1
- 102000000380 Matrix Metalloproteinase 1 Human genes 0.000 description 1
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- 108010000684 Matrix Metalloproteinases Proteins 0.000 description 1
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- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 1
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- 230000001580 bacterial effect Effects 0.000 description 1
- 208000022362 bacterial infectious disease Diseases 0.000 description 1
- 229950002853 bimekizumab Drugs 0.000 description 1
- 230000027455 binding Effects 0.000 description 1
- 230000031018 biological processes and functions Effects 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 229960003735 brodalumab Drugs 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 230000007783 downstream signaling Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 210000002919 epithelial cell Anatomy 0.000 description 1
- 239000011737 fluorine Chemical group 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 230000014509 gene expression Effects 0.000 description 1
- 210000002443 helper t lymphocyte Anatomy 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 229960005435 ixekizumab Drugs 0.000 description 1
- 238000011813 knockout mouse model Methods 0.000 description 1
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
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- 210000004927 skin cell Anatomy 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 230000002103 transcriptional effect Effects 0.000 description 1
- 230000037314 wound repair Effects 0.000 description 1
Classifications
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- 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
- C07D405/02—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 two hetero rings
- C07D405/12—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 two hetero rings linked by a chain containing hetero atoms as chain links
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C271/06—Esters of carbamic acids
- C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
- C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C271/22—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
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- C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
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- C07C271/32—Esters of carbamic acids having oxygen atoms of carbamate groups bound to carbon atoms of rings other than six-membered aromatic rings
- C07C271/34—Esters of carbamic acids having oxygen atoms of carbamate groups bound to carbon atoms of rings other than six-membered aromatic rings with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
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- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/72—Nitrogen atoms
- C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
- C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
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- C07D261/08—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
- C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
- C07D265/30—1,4-Oxazines; Hydrogenated 1,4-oxazines not condensed with other rings
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
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- C07D307/04—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D307/10—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D307/14—Radicals substituted by nitrogen atoms not forming part of a nitro radical
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- 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
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- C07D401/12—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 two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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Abstract
本发明涉及芳基或杂芳基类衍生物抑制剂、其制备方法和应用。特别地，本发明涉及化合物、其制备方法及含有该化合物的药物组合物，及其作为抑制剂在治疗自身免疫性疾病的用途。The present invention relates to an aryl or heteroaryl derivative inhibitor, a preparation method and application thereof, and in particular, to a compound, a preparation method thereof, a pharmaceutical composition containing the compound, and the use of the compound as an inhibitor in treating autoimmune diseases.
Description
技术领域Technical Field
本发明属于药物合成领域，具体涉及一种芳基或杂芳基类衍生物抑制剂及其制备方法和应用。The invention belongs to the field of drug synthesis, and specifically relates to an aryl or heteroaryl derivative inhibitor and a preparation method and application thereof.
背景技术Background Art
人IL-17(白细胞介素17，Interleukin 17)是一大类促炎性细胞因子。人IL-17共包含6位家族成员：IL-17A(也称为CTLA-8)，IL-17B，IL-17C，IL-17D，IL-17E(也称为IL-25)和IL-17F。人IL-17受体家族共包含5位家族成员：IL-17RA，IL-17RB，IL-17RC，IL-17RD，IL-17RE。人IL-17通过与异源二聚体IL-17受体结合，启动下游信号通路。Human IL-17 (interleukin 17) is a large class of proinflammatory cytokines. Human IL-17 contains 6 family members: IL-17A (also known as CTLA-8), IL-17B, IL-17C, IL-17D, IL-17E (also known as IL-25) and IL-17F. The human IL-17 receptor family contains 5 family members: IL-17RA, IL-17RB, IL-17RC, IL-17RD, IL-17RE. Human IL-17 activates downstream signaling pathways by binding to the heterodimeric IL-17 receptor.
IL-17A是研究最多的细胞因子。IL-17A由多种细胞产生，比如Th17(辅助型T细胞17)，Tc17(杀伤型T细胞17)，NKT(自然杀伤T细胞)，γδT(γδT细胞)，epithelial cell(上皮细胞)等。IL-17通过与皮肤细胞等的IL-17受体结合，激活Act1(TRAF3 interactingprotein 2)依赖的MAPK和NF-κb信号通路，从转录水平提高多种细胞因子(如IL-6，TNF-α，G-CSF，GM-CSF等)、趋化因子(如CXCL1，CXCL2，CXCL5，CXCL8，CXCL10等)、抗菌肽(如Defensin，MUCSAC，S100A7等)以及基质金属蛋白酶(如MMP1等)的表达水平。IL-17A参与调控多种重要生物学过程，比如细菌真菌感染、伤口修复、促进炎症等。IL-17A is the most studied cytokine. IL-17A is produced by a variety of cells, such as Th17 (helper T cell 17), Tc17 (killer T cell 17), NKT (natural killer T cell), γδT (γδT cell), epithelial cell, etc. IL-17 binds to the IL-17 receptor of skin cells, activates the Act1 (TRAF3 interacting protein 2)-dependent MAPK and NF-κb signaling pathways, and increases the expression levels of a variety of cytokines (such as IL-6, TNF-α, G-CSF, GM-CSF, etc.), chemokines (such as CXCL1, CXCL2, CXCL5, CXCL8, CXCL10, etc.), antimicrobial peptides (such as Defensin, MUCSAC, S100A7, etc.) and matrix metalloproteinases (such as MMP1, etc.) at the transcriptional level. IL-17A participates in the regulation of a variety of important biological processes, such as bacterial and fungal infections, wound repair, and the promotion of inflammation.
IL-17A通路在自身免疫/炎性疾病中也扮演了重要的角色。临床前研究表明，IL-23或IL-17RA敲除小鼠对imiquimod(IMQ，咪喹莫特)诱导的银屑病抵抗；IL-17单抗可有效抑制IMQ或IL-23诱导的银屑病相关评分。IL-17相关治疗性抗体(Secukinumab，Ixekizumab，Brodalumab，Bimekizumab等)也获批用于治疗银屑病、强直性脊柱炎等疾病，临床疗效优异，毒副作用轻微可控。The IL-17A pathway also plays an important role in autoimmune/inflammatory diseases. Preclinical studies have shown that IL-23 or IL-17RA knockout mice are resistant to imiquimod (IMQ)-induced psoriasis; IL-17 monoclonal antibodies can effectively inhibit IMQ- or IL-23-induced psoriasis-related scores. IL-17-related therapeutic antibodies (Secukinumab, Ixekizumab, Brodalumab, Bimekizumab, etc.) have also been approved for the treatment of psoriasis, ankylosing spondylitis and other diseases, with excellent clinical efficacy and mild and controllable toxic side effects.
尽管如此，IL-17相关治疗性抗体成本高昂，且需要皮下或静脉注射，对于需长期给药的自身免疫/炎性疾病病人而言可及性较低、便捷性较差。开发高活性口服IL-17小分子抑制剂可以极大地提高病人的用药可及性及便捷性，具有极高的临床和商业价值。Despite this, IL-17-related therapeutic antibodies are expensive and require subcutaneous or intravenous injections, which are less accessible and convenient for patients with autoimmune/inflammatory diseases who require long-term medication. The development of highly active oral IL-17 small molecule inhibitors can greatly improve the accessibility and convenience of medication for patients, and has extremely high clinical and commercial value.
发明内容Summary of the invention
本发明的目的在于提供一种如通式(I)所示的化合物、其立体异构体或其药学上可接受的盐：The object of the present invention is to provide a compound represented by general formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof:
其中，in,
环A选自5-6元杂芳基；Ring A is selected from 5-6 membered heteroaryl;
M1选自-NH-、-CH2-、-S-、-O-、-CO-、-SO-或-SO2-；M 1 is selected from -NH-, -CH 2 -, -S-, -O-, -CO-, -SO- or -SO 2 -;
M2选自-NH-、-CH2-、-S-、-O-、-CO-、-SO-或-SO2-；M 2 is selected from -NH-, -CH 2 -, -S-, -O-, -CO-, -SO- or -SO 2 -;
M3选自-NH-、-CH2-、-S-、-O-、-CO-、-SO-或-SO2-；M 3 is selected from -NH-, -CH 2 -, -S-, -O-, -CO-, -SO- or -SO 2 -;
L1选自键、-O-、-S-、-NH-、-CO-、-CONH-、C1-3亚烷基、C2-4亚烯基、C2-4亚炔基、-O-C1-3亚烷基-、-COC1-3亚烷基-、-S-C1-3亚烷基-、-C1-3亚烷基-NH-、-C1-3亚烷基-C(O)NH-、-C1-3亚烷基-NHC(O)-、-C1-3亚烷基-S(O)r1-、-C1-3亚烷基-NHS(O)r2-或-C1-3亚烷基-S(O)r3NH-；所述的-NH-、-CONH-、C1-3亚烷基、C2-4亚烯基、C2-4亚炔基、-O-C1-3亚烷基-、-COC1-3亚烷基-、-S-C1-3亚烷基-、-C1-3亚烷基-NH-、-C1-3亚烷基-C(O)NH-、-C1-3亚烷基-NHC(O)-、-C1-3亚烷基-S(O)r1-、-C1-3亚烷基-NHS(O)r2-或-C1-3亚烷基-S(O)r3NH-任选地被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-3烷基、C2-4烯基、C2-4炔基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3氘代烷氧基、C1-3卤代烷氧基、C1-3羟烷基、C3-6环烷基、3-6元杂环基、C6-10芳基、5-6元杂芳基中的一个或多个取代； L1 is selected from a bond, -O-, -S-, -NH-, -CO-, -CONH-, C1-3 alkylene, C2-4 alkenylene, C2-4 alkynylene, -OC1-3 alkylene-, -COC1-3 alkylene-, -SC1-3 alkylene-, -C1-3 alkylene-NH-, -C1-3 alkylene-C(O)NH-, -C1-3 alkylene-NHC(O)-, -C1-3 alkylene-S(O)r1- , -C1-3 alkylene-NHS(O) r2- or -C1-3 alkylene-S(O) r3NH- ; said -NH-, -CONH-, C1-3 alkylene, C2-4 alkenylene, C2-4 alkynylene, -OC1-3 alkylene-, -COC1-3 alkylene-, -SC1-3 alkylene-, -C1-3 alkylene-NH-, -C1-3 alkylene-C(O)NH-, -C1-3 alkylene-NHC(O)-, -C1-3 alkylene-S(O) r1- , -C1-3 alkylene-NHS(O)r2- or -C1-3 alkylene -S(O)r3NH- -C 1-3 alkylene-, -C 1-3 alkylene-NH-, -C 1-3 alkylene-C(O)NH-, -C 1-3 alkylene-NHC(O)-, -C 1-3 alkylene-S(O) r1 -, -C 1-3 alkylene-NHS(O) r2 -, or -C 1-3 alkylene-S(O) r3 NH- is optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, 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, C 1-3 deuterated alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 2-4 One or more of 6-10- membered aryl and 5-6-membered heteroaryl are substituted;
L2选自键、-O-、-S-、-NH-、-CO-、-CONH-、C1-3亚烷基、C2-4亚烯基、C2-4亚炔基、-O-C1-3亚烷基-、-COC1-3亚烷基-、-S-C1-3亚烷基-、-C1-3亚烷基-NH-、-C1-3亚烷基-C(O)NH-、-C1-3亚烷基-NHC(O)-、-C1-3亚烷基-S(O)r4-、-C1-3亚烷基-NHS(O)r5-或-C1-3亚烷基-S(O)r6NH-；所述的-NH-、-CONH-、C1-3亚烷基、C2-4亚烯基、C2-4亚炔基、-O-C1-3亚烷基-、-COC1-3亚烷基-、-S-C1-3亚烷基-、-C1-3亚烷基-NH-、-C1-3亚烷基-C(O)NH-、-C1-3亚烷基-NHC(O)-、-C1-3亚烷基-S(O)r1-、-C1-3亚烷基-NHS(O)r2-或-C1-3亚烷基-S(O)r3NH-任选地被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-3烷基、C2-4烯基、C2-4炔基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3氘代烷氧基、C1-3卤代烷氧基、C1-3羟烷基、C3-6环烷基、3-6元杂环基、C6-10芳基、5-6元杂芳基中的一个或多个取代； L2 is selected from a bond, -O-, -S-, -NH-, -CO-, -CONH-, C1-3 alkylene, C2-4 alkenylene, C2-4 alkynylene, -OC1-3 alkylene-, -COC1-3 alkylene-, -SC1-3 alkylene-, -C1-3 alkylene-NH-, -C1-3 alkylene-C(O)NH-, -C1-3 alkylene-NHC(O)-, -C1-3 alkylene-S(O)r4-, -C1-3 alkylene-NHS(O) r5- or -C1-3 alkylene-S(O) r6NH- ; said -NH-, -CONH-, C1-3 alkylene, C2-4 alkenylene, C2-4 alkynylene, -OC1-3 alkylene-, -COC1-3 alkylene-, -SC1-3 alkylene-, -C1-3 alkylene-NH-, -C1-3 alkylene-C(O)NH-, -C1-3 alkylene-NHC(O)-, -C1-3 alkylene-S(O) r4- , -C1-3 alkylene-NHS(O)r5- or -C1-3 alkylene -S(O)r6NH- -C 1-3 alkylene-, -C 1-3 alkylene-NH-, -C 1-3 alkylene-C(O)NH-, -C 1-3 alkylene-NHC(O)-, -C 1-3 alkylene-S(O) r1 -, -C 1-3 alkylene-NHS(O) r2 -, or -C 1-3 alkylene-S(O) r3 NH- is optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, 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, C 1-3 deuterated alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 2-4 One or more of 6-10- membered aryl and 5-6-membered heteroaryl are substituted;
R1独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基、5-10元杂芳基、-(CH2)m1ORa1、-(CH2)m2C(O)Ra2、-(CH2)m3NHC(O)Ra3、-(CH2)m4C(O)NHRa4、-(CH2)m5NRa5Ra6、-(CH2)m6S(O)m7Ra7、-(CH2)m8S(O)2NHRa8、-(CH2)m9NHS(O)2Ra9，所述的氨基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基任选地可以进一步被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代； R1 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, -( CH2 ) m1ORa1 , -( CH2 ) m2C ( O)Ra2, -(CH2)m3NHC(O)Ra3, -(CH2)m4C ( O ) NHRa4 , - ( CH2 )m5NRa5Ra6 , - ( CH2 ) m6 S(O) m7Ra7 , -( CH2 ) m8S (O) 2NHRa8 , -( CH2 ) m9NHS (O) 2Ra9 , the amino, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl or 5-10 membered heteroaryl may be further optionally substituted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl or 5-10 membered heteroaryl. substituted by one or more of C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl;
R2-1和R2-2各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基、5-10元杂芳基、-(CH2)n1ORb1、-(CH2)n2C(O)Rb2、-(CH2)n3NHC(O)Rb3、-(CH2)n4C(O)NHRb4、-(CH2)n5NRb5Rb6、-(CH2)n6S(O)n7Rb7、-(CH2)n8S(O)2NHRb8、-(CH2)n9NHS(O)2Rb9，所述的氨基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基任选地可以进一步被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代；R 2-1 and R 2-2 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy , C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, -(CH 2 ) n1 OR b1 , -(CH 2 ) n2 C(O)R b2 , -(CH 2 ) n3 NHC(O)R b3 , -(CH 2 ) n4 C(O)NHR b4 , -(CH 2 ) n5 NR b5 R b6 wherein 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 , C 1-6 deuterated alkoxy, C 1-6 haloalkoxy , C 1-6 hydroxyalkyl , C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl may be further substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 alkyl , C 2-6 alkenyl, C 2-6 alkynyl , C The group is substituted by one or more of C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl;
R3各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基、5-10元杂芳基、-(CH2)o1ORc1、-(CH2)o2C(O)Rc2、-(CH2)o3NHC(O)Rc3、-(CH2)o4C(O)NHRc4、-(CH2)o5NRc5Rc6、-(CH2)o6S(O)o7Rc7、-(CH2)o8S(O)2NHRc8、-(CH2)o9NHS(O)2Rc9，所述的氨基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基任选地可以进一步被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代； R3 is each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl , C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, -( CH2 ) o1ORc1 , -( CH2 ) o2C (O ) Rc2, -(CH2) o3NHC(O)Rc3 , -( CH2 ) o4C ( O ) NHRc4 , -( CH2 ) o5NRc5Rc6 , -( CH2 ) o6 S(O) o7Rc7 , -( CH2 ) o8S (O) 2NHRc8 , -( CH2 ) o9NHS (O) 2Rc9 , the amino , C1-6 alkyl, C2-6 alkenyl , C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy , C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl , 3-8 membered heterocyclyl , C6-10 aryl or 5-10 membered heteroaryl may be further optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 substituted by one or more of C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl;
R4各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基、5-10元杂芳基、-(CH2)p1ORd1、-(CH2)p2C(O)Rd2、-(CH2)p3NHC(O)Rd3、-(CH2)p4C(O)NHRd4、-(CH2)p5NRd5Rd6、-(CH2)p6S(O)p7Rd7、-(CH2)p8S(O)2NHRd8、-(CH2)p9NHS(O)2Rd9、-(CH2)p10S(＝O)(＝NH)Rd10，所述的氨基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基任选地可以进一步被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代； R4 is each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl , C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, -( CH2 ) p1ORd1 , -( CH2 ) p2C (O) Rd2 , -(CH2)p3NHC(O)Rd3, -(CH2)p4C ( O ) NHRd4 , - ( CH2 ) p5NRd5Rd6 , -(CH wherein 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl , C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl group may be further substituted with hydrogen, deuterium, halogen , amino, hydroxyl, cyano, nitro, oxo, thio, 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl , C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl. The alkyl group may be substituted by one or more of C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl;
R4-1选自氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基、5-10元杂芳基、-(CH2)p1ORd1、-(CH2)p2C(O)Rd2、-(CH2)p3NHC(O)Rd3、-(CH2)p4C(O)NHRd4、-(CH2)p5NRd5Rd6、-(CH2)p6S(O)p7Rd7、-(CH2)p8S(O)2NHRd8、-(CH2)p9NHS(O)2Rd9、-(CH2)p10S(＝O)(＝NH)Rd10，所述的氨基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基任选地可以进一步被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代；R 4-1 is selected from deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, -(CH 2 ) p1 OR d1 , -(CH 2 ) p2 C(O)R d2 , -(CH 2 ) p3 NHC(O)R d3 , -(CH 2 ) p4 C(O)NHR d4 , -(CH 2 ) p5 NR d5 R d6 , -(CH 2 wherein 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl , C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl group may be further substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl , C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl. The alkyl group may be substituted by one or more of C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl;
Ra1、Ra2、Ra3、Ra4、Ra5、Ra6、Ra7、Ra8和Ra9各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基、5-10元杂芳基，所述的氨基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基任选地可以进一步被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代； Ra1 , Ra2 , Ra3 , Ra4 , Ra5 , Ra6 , Ra7 , Ra8 and Ra9 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, and the amino, C1-6 alkyl , C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl , C1-6 alkoxy , C C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl may be further optionally substituted with one or more of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl , 3-8 membered heterocyclyl , C 6-10 aryl and 5-10 membered heteroaryl;
Rb1、Rb2、Rb3、Rb4、Rb5、Rb6、Rb7、Rb8和Rb9各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基、5-10元杂芳基，所述的氨基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基任选地可以进一步被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代；R b1 , R b2 , R b3 , R b4 , R b5 , R b6 , R b7 , R b8 and R b9 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, said 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 , C C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl may be further optionally substituted with one or more of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl , 3-8 membered heterocyclyl , C 6-10 aryl and 5-10 membered heteroaryl;
Rc1、Rc2、Rc3、Rc4、Rc5、Rc6、Rc7、Rc8和Rc9各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基、5-10元杂芳基，所述的氨基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基任选地可以进一步被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代；R c1 , R c2 , R c3 , R c4 , R c5 , R c6 , R c7 , R c8 and R c9 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, said 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 , C C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl may be further optionally substituted with one or more of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl , 3-8 membered heterocyclyl , C 6-10 aryl and 5-10 membered heteroaryl;
Rd1、Rd2、Rd3、Rd4、Rd5、Rd6、Rd7、Rd8、Rd9和Rd10各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基、5-10元杂芳基，所述的氨基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基任选地可以进一步被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代； Rd1 , Rd2 , Rd3, Rd4 , Rd5 , Rd6 , Rd7 , Rd8 , Rd9 and Rd10 are each independently selected from hydrogen, deuterium , halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, wherein the amino, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy , C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl may be further optionally substituted with one or more of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl;
x为0、1、2、3、4或5；x is 0, 1, 2, 3, 4, or 5;
y为0、1、2、3、4或5；y is 0, 1, 2, 3, 4, or 5;
m1、m2、m3、m4、m5、m6、m8、m9各自独立地选自0、1、2、3、4、5或6；m1, m2, m3, m4, m5, m6, m8, m9 are each independently selected from 0, 1, 2, 3, 4, 5 or 6;
n1、n2、n3、n4、n5、n6、n8、n9各自独立地选自0、1、2、3、4、5或6；n1, n2, n3, n4, n5, n6, n8, n9 are each independently selected from 0, 1, 2, 3, 4, 5 or 6;
o1、o2、o3、o4、o5、o6、o8、o9各自独立地选自0、1、2、3、4、5或6；o1, o2, o3, o4, o5, o6, o8, o9 are each independently selected from 0, 1, 2, 3, 4, 5 or 6;
p1、p2、p3、p4、p5、p6、p8、p9、p10各自独立地选自0、1、2、3、4、5或6；p1, p2, p3, p4, p5, p6, p8, p9, p10 are each independently selected from 0, 1, 2, 3, 4, 5 or 6;
r1、r2、r3、r4、r5、r6各自独立地选自0、1或2；r1, r2, r3, r4, r5, r6 are each independently selected from 0, 1 or 2;
m7、n7、o7、p7各自独立地选自0、1、2或3。m7, n7, o7, p7 are each independently selected from 0, 1, 2 or 3.
在本发明的某些实施方案中，所述的化合物如式(I-1)所示：In certain embodiments of the present invention, the compound is as shown in formula (I-1):
其中，in,
M4选自-N-或-CH-； M4 is selected from -N- or -CH-;
M5选自-N-或-CH-； M5 is selected from -N- or -CH-;
M6选自-N-或-CH-； M6 is selected from -N- or -CH-;
M7选自-N-或-CH-； M7 is selected from -N- or -CH-;
M1-M2-M3选自-CH2OCH2-、-NHCONH-、-CH2CONH-、-OCONH-、-NHCOCH2-、-CH2SO2CH2-或-CH2CH2CH2-；M 1 -M 2 -M 3 is selected from -CH 2 OCH 2 -, -NHCONH-, -CH 2 CONH-, -OCONH-, -NHCOCH 2 -, -CH 2 SO 2 CH 2 - or -CH 2 CH 2 CH2- ;
L1选自键、-O-、-S-、-NH-、-CO-、-CONH-、C1-3亚烷基、C2-4亚烯基、C2-4亚炔基、-O-C1-3亚烷基-、-COC1-3亚烷基-、-S-C1-3亚烷基-、-C1-3亚烷基-NH-、-C1-3亚烷基-C(O)NH-、-C1-3亚烷基-NHC(O)-、-C1-3亚烷基-S(O)r1-、-C1-3亚烷基-NHS(O)r2-或-C1-3亚烷基-S(O)r3NH-；所述的-NH-、-CONH-、C1-3亚烷基、C2-4亚烯基、C2-4亚炔基、-O-C1-3亚烷基-、-COC1-3亚烷基-、-S-C1-3亚烷基-、-C1-3亚烷基-NH-、-C1-3亚烷基-C(O)NH-、-C1-3亚烷基-NHC(O)-、-C1-3亚烷基-S(O)r1-、-C1-3亚烷基-NHS(O)r2-或-C1-3亚烷基-S(O)r3NH-任选地被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-3烷基、C2-4烯基、C2-4炔基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3氘代烷氧基、C1-3卤代烷氧基、C1-3羟烷基、C3-6环烷基、3-6元杂环基、C6-10芳基、5-6元杂芳基中的一个或多个取代； L1 is selected from a bond, -O-, -S-, -NH-, -CO-, -CONH-, C1-3 alkylene, C2-4 alkenylene, C2-4 alkynylene, -OC1-3 alkylene-, -COC1-3 alkylene-, -SC1-3 alkylene-, -C1-3 alkylene-NH-, -C1-3 alkylene-C(O)NH-, -C1-3 alkylene-NHC(O)-, -C1-3 alkylene-S(O)r1- , -C1-3 alkylene-NHS(O) r2- or -C1-3 alkylene-S(O) r3NH- ; said -NH-, -CONH-, C1-3 alkylene, C2-4 alkenylene, C2-4 alkynylene, -OC1-3 alkylene-, -COC1-3 alkylene-, -SC1-3 alkylene-, -C1-3 alkylene-NH-, -C1-3 alkylene-C(O)NH-, -C1-3 alkylene-NHC(O)-, -C1-3 alkylene-S(O) r1- , -C1-3 alkylene-NHS(O)r2- or -C1-3 alkylene -S(O)r3NH- -C 1-3 alkylene-, -C 1-3 alkylene-NH-, -C 1-3 alkylene-C(O)NH-, -C 1-3 alkylene-NHC(O)-, -C 1-3 alkylene-S(O) r1 -, -C 1-3 alkylene-NHS(O) r2 -, or -C 1-3 alkylene-S(O) r3 NH- is optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, 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, C 1-3 deuterated alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 2-4 One or more of 6-10- membered aryl and 5-6-membered heteroaryl are substituted;
L2选自键、-O-、-S-、-NH-、-CO-、-CONH-、C1-3亚烷基、C2-4亚烯基、C2-4亚炔基、-O-C1-3亚烷基-、-COC1-3亚烷基-、-S-C1-3亚烷基-、-C1-3亚烷基-NH-、-C1-3亚烷基-C(O)NH-、-C1-3亚烷基-NHC(O)-、-C1-3亚烷基-S(O)r4-、-C1-3亚烷基-NHS(O)r5-或-C1-3亚烷基-S(O)r6NH-；所述的-NH-、-CONH-、C1-3亚烷基、C2-4亚烯基、C2-4亚炔基、-O-C1-3亚烷基-、-COC1-3亚烷基-、-S-C1-3亚烷基-、-C1-3亚烷基-NH-、-C1-3亚烷基-C(O)NH-、-C1-3亚烷基-NHC(O)-、-C1-3亚烷基-S(O)r1-、-C1-3亚烷基-NHS(O)r2-或-C1-3亚烷基-S(O)r3NH-任选地被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-3烷基、C2-4烯基、C2-4炔基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3氘代烷氧基、C1-3卤代烷氧基、C1-3羟烷基、C3-6环烷基、3-6元杂环基、C6-10芳基、5-6元杂芳基中的一个或多个取代； L2 is selected from a bond, -O-, -S-, -NH-, -CO-, -CONH-, C1-3 alkylene, C2-4 alkenylene, C2-4 alkynylene, -OC1-3 alkylene-, -COC1-3 alkylene-, -SC1-3 alkylene-, -C1-3 alkylene-NH-, -C1-3 alkylene-C(O)NH-, -C1-3 alkylene-NHC(O)-, -C1-3 alkylene-S(O)r4-, -C1-3 alkylene-NHS(O) r5- or -C1-3 alkylene-S(O) r6NH- ; said -NH-, -CONH-, C1-3 alkylene, C2-4 alkenylene, C2-4 alkynylene, -OC1-3 alkylene-, -COC1-3 alkylene-, -SC1-3 alkylene-, -C1-3 alkylene-NH-, -C1-3 alkylene-C(O)NH-, -C1-3 alkylene-NHC(O)-, -C1-3 alkylene-S(O) r4- , -C1-3 alkylene-NHS(O)r5- or -C1-3 alkylene -S(O)r6NH- -C 1-3 alkylene-, -C 1-3 alkylene-NH-, -C 1-3 alkylene-C(O)NH-, -C 1-3 alkylene-NHC(O)-, -C 1-3 alkylene-S(O) r1 -, -C 1-3 alkylene-NHS(O) r2 -, or -C 1-3 alkylene-S(O) r3 NH- is optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, 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, C 1-3 deuterated alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 2-4 One or more of 6-10- membered aryl and 5-6-membered heteroaryl are substituted;
R1独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基、5-10元杂芳基、-(CH2)m1ORa1、-(CH2)m2C(O)Ra2、-(CH2)m3NHC(O)Ra3、-(CH2)m4C(O)NHRa4、-(CH2)m5NRa5Ra6、-(CH2)m6S(O)m7Ra7、-(CH2)m8S(O)2NHRa8、-(CH2)m9NHS(O)2Ra9，所述的氨基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基任选地可以进一步被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代； R1 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, -( CH2 ) m1ORa1 , -( CH2 ) m2C ( O)Ra2, -(CH2)m3NHC(O)Ra3, -(CH2)m4C ( O ) NHRa4 , - ( CH2 )m5NRa5Ra6 , - ( CH2 ) m6 S(O) m7Ra7 , -( CH2 ) m8S (O) 2NHRa8 , -( CH2 ) m9NHS (O) 2Ra9 , the amino, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl or 5-10 membered heteroaryl may be further optionally substituted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl or 5-10 membered heteroaryl. substituted by one or more of C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl;
R2-1选自氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基、5-10元杂芳基、-(CH2)n1ORb1、-(CH2)n2C(O)Rb2、-(CH2)n3NHC(O)Rb3、-(CH2)n4C(O)NHRb4、-(CH2)n5NRb5Rb6、-(CH2)n6S(O)n7Rb7、-(CH2)n8S(O)2NHRb8、-(CH2)n9NHS(O)2Rb9，所述的氨基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基任选地可以进一步被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代；R 2-1 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, -(CH 2 ) n1 OR b1 , -(CH 2 ) n2 C(O)R b2 , -(CH 2 ) n3 NHC(O)R b3 , -(CH 2 ) n4 C(O)NHR b4 , -(CH 2 ) n5 NR b5 R b6 , -(CH 2 ) n6 S(O) n7Rb7 , -( CH2 ) n8S (O) 2NHRb8 , -( CH2 ) n9NHS (O) 2Rb9 , the amino, C1-6 alkyl, C2-6 alkenyl , C2-6 alkynyl, C1-6 deuterated alkyl , C1-6 haloalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl or 5-10 membered heteroaryl may be further optionally substituted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl or 5-10 membered heteroaryl. substituted by one or more of C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl;
R3各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基、5-10元杂芳基、-(CH2)o1ORc1、-(CH2)o2C(O)Rc2、-(CH2)o3NHC(O)Rc3、-(CH2)o4C(O)NHRc4、-(CH2)o5NRc5Rc6、-(CH2)o6S(O)o7Rc7、-(CH2)o8S(O)2NHRc8、-(CH2)o9NHS(O)2Rc9，所述的氨基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基任选地可以进一步被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代； R3 is each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl , C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, -( CH2 ) o1ORc1 , -( CH2 ) o2C (O ) Rc2, -(CH2) o3NHC(O)Rc3 , -( CH2 ) o4C ( O ) NHRc4 , -( CH2 ) o5NRc5Rc6 , -( CH2 ) o6 S(O) o7Rc7 , -( CH2 ) o8S (O) 2NHRc8 , -( CH2 ) o9NHS (O) 2Rc9 , the amino, C1-6 alkyl, C2-6 alkenyl , C2-6 alkynyl, C1-6 deuterated alkyl , C1-6 haloalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl or 5-10 membered heteroaryl may be further optionally substituted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl or 5-10 membered heteroaryl. substituted by one or more of C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl;
R4各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基、5-10元杂芳基、-(CH2)p1ORd1、-(CH2)p2C(O)Rd2、-(CH2)p3NHC(O)Rd3、-(CH2)p4C(O)NHRd4、-(CH2)p5NRd5Rd6、-(CH2)p6S(O)p7Rd7、-(CH2)p8S(O)2NHRd8、-(CH2)p9NHS(O)2Rd9、-(CH2)p10S(＝O)(＝NH)Rd10，所述的氨基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基任选地可以进一步被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代； R4 is each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl , C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, -( CH2 ) p1ORd1 , -( CH2 ) p2C (O) Rd2 , -(CH2)p3NHC(O)Rd3, -(CH2)p4C ( O ) NHRd4 , - ( CH2 ) p5NRd5Rd6 , -(CH wherein 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl , C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl group may be further substituted with hydrogen, deuterium, halogen , amino, hydroxyl, cyano, nitro, oxo, thio, 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl , C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl. The alkyl group may be substituted by one or more of C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl;
R4-1选自氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基、5-10元杂芳基、-(CH2)p1ORd1、-(CH2)p2C(O)Rd2、-(CH2)p3NHC(O)Rd3、-(CH2)p4C(O)NHRd4、-(CH2)p5NRd5Rd6、-(CH2)p6S(O)p7Rd7、-(CH2)p8S(O)2NHRd8、-(CH2)p9NHS(O)2Rd9、-(CH2)p10S(＝O)(＝NH)Rd10，所述的氨基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基任选地可以进一步被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代；R 4-1 is selected from deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, -(CH 2 ) p1 OR d1 , -(CH 2 ) p2 C(O)R d2 , -(CH 2 ) p3 NHC(O)R d3 , -(CH 2 ) p4 C(O)NHR d4 , -(CH 2 ) p5 NR d5 R d6 , -(CH 2 wherein 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl , C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl group may be further substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl , C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl. The alkyl group may be substituted by one or more of C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl;
Ra1、Ra2、Ra3、Ra4、Ra5、Ra6、Ra7、Ra8和Ra9各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基、5-10元杂芳基，所述的氨基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基任选地可以进一步被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代； Ra1 , Ra2 , Ra3 , Ra4 , Ra5 , Ra6 , Ra7 , Ra8 and Ra9 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, and the amino, C1-6 alkyl , C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl , C1-6 alkoxy , C C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl may be further optionally substituted with one or more of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl , 3-8 membered heterocyclyl , C 6-10 aryl and 5-10 membered heteroaryl;
Rb1、Rb2、Rb3、Rb4、Rb5、Rb6、Rb7、Rb8和Rb9各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基、5-10元杂芳基，所述的氨基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基任选地可以进一步被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代；R b1 , R b2 , R b3 , R b4 , R b5 , R b6 , R b7 , R b8 and R b9 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, said 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 , C C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl may be further optionally substituted with one or more of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl , 3-8 membered heterocyclyl , C 6-10 aryl and 5-10 membered heteroaryl;
Rc1、Rc2、Rc3、Rc4、Rc5、Rc6、Rc7、Rc8和Rc9各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基、5-10元杂芳基，所述的氨基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基任选地可以进一步被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代；R c1 , R c2 , R c3 , R c4 , R c5 , R c6 , R c7 , R c8 and R c9 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, said 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 , C C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl may be further optionally substituted with one or more of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl , 3-8 membered heterocyclyl , C 6-10 aryl and 5-10 membered heteroaryl;
Rd1、Rd2、Rd3、Rd4、Rd5、Rd6、Rd7、Rd8、Rd9和Rd10各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基、5-10元杂芳基，所述的氨基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基任选地可以进一步被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代； Rd1 , Rd2 , Rd3, Rd4 , Rd5 , Rd6 , Rd7 , Rd8 , Rd9 and Rd10 are each independently selected from hydrogen, deuterium , halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, wherein the amino, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy , C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl may be further optionally substituted with one or more of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl;
x为0、1、2、3、4或5；x is 0, 1, 2, 3, 4, or 5;
y为0、1、2、3、4或5；y is 0, 1, 2, 3, 4, or 5;
m1、m2、m3、m4、m5、m6、m8、m9各自独立地选自0、1、2、3、4、5或6；m1, m2, m3, m4, m5, m6, m8, m9 are each independently selected from 0, 1, 2, 3, 4, 5 or 6;
n1、n2、n3、n4、n5、n6、n8、n9各自独立地选自0、1、2、3、4、5或6；n1, n2, n3, n4, n5, n6, n8, n9 are each independently selected from 0, 1, 2, 3, 4, 5 or 6;
o1、o2、o3、o4、o5、o6、o8、o9各自独立地选自0、1、2、3、4、5或6；o1, o2, o3, o4, o5, o6, o8, o9 are each independently selected from 0, 1, 2, 3, 4, 5 or 6;
p1、p2、p3、p4、p5、p6、p8、p9、p10各自独立地选自0、1、2、3、4、5或6；p1, p2, p3, p4, p5, p6, p8, p9, p10 are each independently selected from 0, 1, 2, 3, 4, 5 or 6;
r1、r2、r3、r4、r5、r6各自独立地选自0、1或2；r1, r2, r3, r4, r5, r6 are each independently selected from 0, 1 or 2;
m7、n7、o7、p7各自独立地选自0、1、2或3。m7, n7, o7, p7 are each independently selected from 0, 1, 2 or 3.
在本发明的某些实施方案中，所述的化合物如式(I-1-1)所示：In certain embodiments of the present invention, the compound is as shown in formula (I-1-1):
其中，in,
M4为-CH-，M5为-CH-，M6为-CH-，M7为-CH-； M4 is -CH-, M5 is -CH-, M6 is -CH-, and M7 is -CH-;
或M4为-N-，M5为-CH-，M6为-CH-，M7为-CH-；or M4 is -N-, M5 is -CH-, M6 is -CH-, and M7 is -CH-;
或M4为-CH-，M5为-CH-，M6为-N-，M7为-CH-；or M4 is -CH-, M5 is -CH-, M6 is -N-, and M7 is -CH-;
或M4为-N-，M5为-CH-，M6为-CH-，M7为-N-；or M4 is -N-, M5 is -CH-, M6 is -CH-, and M7 is -N-;
L1选自键、-O-、-S-、-NH-、-CO-、-CONH-、C1-3亚烷基、C2-4亚烯基、C2-4亚炔基、-O-C1-3亚烷基-、-COC1-3亚烷基-、-S-C1-3亚烷基-、-C1-3亚烷基-NH-、-C1-3亚烷基-C(O)NH-、-C1-3亚烷基-NHC(O)-、-C1-3亚烷基-S(O)r1-、-C1-3亚烷基-NHS(O)r2-或-C1-3亚烷基-S(O)r3NH-；所述的-NH-、-CONH-、C1-3亚烷基、C2-4亚烯基、C2-4亚炔基、-O-C1-3亚烷基-、-COC1-3亚烷基-、-S-C1-3亚烷基-、-C1-3亚烷基-NH-、-C1-3亚烷基-C(O)NH-、-C1-3亚烷基-NHC(O)-、-C1-3亚烷基-S(O)r1-、-C1-3亚烷基-NHS(O)r2-或-C1-3亚烷基-S(O)r3NH-任选地被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-3烷基、C2-4烯基、C2-4炔基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3氘代烷氧基、C1-3卤代烷氧基、C1-3羟烷基、C3-6环烷基、3-6元杂环基、C6-10芳基、5-6元杂芳基中的一个或多个取代； L1 is selected from a bond, -O-, -S-, -NH-, -CO-, -CONH-, C1-3 alkylene, C2-4 alkenylene, C2-4 alkynylene, -OC1-3 alkylene-, -COC1-3 alkylene-, -SC1-3 alkylene-, -C1-3 alkylene-NH-, -C1-3 alkylene-C(O)NH-, -C1-3 alkylene-NHC(O)-, -C1-3 alkylene-S(O)r1- , -C1-3 alkylene-NHS(O) r2- or -C1-3 alkylene-S(O) r3NH- ; said -NH-, -CONH-, C1-3 alkylene, C2-4 alkenylene, C2-4 alkynylene, -OC1-3 alkylene-, -COC1-3 alkylene-, -SC1-3 alkylene-, -C1-3 alkylene-NH-, -C1-3 alkylene-C(O)NH-, -C1-3 alkylene-NHC(O)-, -C1-3 alkylene-S(O) r1- , -C1-3 alkylene-NHS(O)r2- or -C1-3 alkylene -S(O)r3NH- -C 1-3 alkylene-, -C 1-3 alkylene-NH-, -C 1-3 alkylene-C(O)NH-, -C 1-3 alkylene-NHC(O)-, -C 1-3 alkylene-S(O) r1 -, -C 1-3 alkylene-NHS(O) r2 -, or -C 1-3 alkylene-S(O) r3 NH- is optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, 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, C 1-3 deuterated alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 2-4 One or more of 6-10- membered aryl and 5-6-membered heteroaryl are substituted;
L2选自键、-O-、-S-、-NH-、-CO-、-CONH-、C1-3亚烷基、C2-4亚烯基、C2-4亚炔基、-O-C1-3亚烷基-、-COC1-3亚烷基-、-S-C1-3亚烷基-、-C1-3亚烷基-NH-、-C1-3亚烷基-C(O)NH-、-C1-3亚烷基-NHC(O)-、-C1-3亚烷基-S(O)r4-、-C1-3亚烷基-NHS(O)r5-或-C1-3亚烷基-S(O)r6NH-；所述的-NH-、-CONH-、C1-3亚烷基、C2-4亚烯基、C2-4亚炔基、-O-C1-3亚烷基-、-COC1-3亚烷基-、-S-C1-3亚烷基-、-C1-3亚烷基-NH-、-C1-3亚烷基-C(O)NH-、-C1-3亚烷基-NHC(O)-、-C1-3亚烷基-S(O)r1-、-C1-3亚烷基-NHS(O)r2-或-C1-3亚烷基-S(O)r3NH-任选地被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-3烷基、C2-4烯基、C2-4炔基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3氘代烷氧基、C1-3卤代烷氧基、C1-3羟烷基、C3-6环烷基、3-6元杂环基、C6-10芳基、5-6元杂芳基中的一个或多个取代； L2 is selected from a bond, -O-, -S-, -NH-, -CO-, -CONH-, C1-3 alkylene, C2-4 alkenylene, C2-4 alkynylene, -OC1-3 alkylene-, -COC1-3 alkylene-, -SC1-3 alkylene-, -C1-3 alkylene-NH-, -C1-3 alkylene-C(O)NH-, -C1-3 alkylene-NHC(O)-, -C1-3 alkylene-S(O)r4-, -C1-3 alkylene-NHS(O) r5- or -C1-3 alkylene-S(O) r6NH- ; said -NH-, -CONH-, C1-3 alkylene, C2-4 alkenylene, C2-4 alkynylene, -OC1-3 alkylene-, -COC1-3 alkylene-, -SC1-3 alkylene-, -C1-3 alkylene-NH-, -C1-3 alkylene-C(O)NH-, -C1-3 alkylene-NHC(O)-, -C1-3 alkylene-S(O) r4- , -C1-3 alkylene-NHS(O)r5- or -C1-3 alkylene -S(O)r6NH- -C 1-3 alkylene-, -C 1-3 alkylene-NH-, -C 1-3 alkylene-C(O)NH-, -C 1-3 alkylene-NHC(O)-, -C 1-3 alkylene-S(O) r1 -, -C 1-3 alkylene-NHS(O) r2 -, or -C 1-3 alkylene-S(O) r3 NH- is optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, 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, C 1-3 deuterated alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 2-4 One or more of 6-10- membered aryl and 5-6-membered heteroaryl are substituted;
R2-1选自氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基、5-10元杂芳基、-(CH2)n1ORb1、-(CH2)n2C(O)Rb2、-(CH2)n3NHC(O)Rb3、-(CH2)n4C(O)NHRb4、-(CH2)n5NRb5Rb6、-(CH2)n6S(O)n7Rb7、-(CH2)n8S(O)2NHRb8、-(CH2)n9NHS(O)2Rb9，所述的氨基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基任选地可以进一步被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代；R 2-1 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, -(CH 2 ) n1 OR b1 , -(CH 2 ) n2 C(O)R b2 , -(CH 2 ) n3 NHC(O)R b3 , -(CH 2 ) n4 C(O)NHR b4 , -(CH 2 ) n5 NR b5 R b6 , -(CH 2 ) n6 S(O) n7Rb7 , -( CH2 ) n8S (O) 2NHRb8 , -( CH2 ) n9NHS (O) 2Rb9 , the amino, C1-6 alkyl, C2-6 alkenyl , C2-6 alkynyl, C1-6 deuterated alkyl , C1-6 haloalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl or 5-10 membered heteroaryl may be further optionally substituted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl or 5-10 membered heteroaryl. substituted by one or more of C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl;
R3各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基、5-10元杂芳基、-(CH2)o1ORc1、-(CH2)o2C(O)Rc2、-(CH2)o3NHC(O)Rc3、-(CH2)o4C(O)NHRc4、-(CH2)o5NRc5Rc6、-(CH2)o6S(O)o7Rc7、-(CH2)o8S(O)2NHRc8、-(CH2)o9NHS(O)2Rc9，所述的氨基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基任选地可以进一步被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代； R3 is each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl , C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, -( CH2 ) o1ORc1 , -( CH2 ) o2C (O)Rc2, - (CH2) o3NHC(O)Rc3 , -( CH2 ) o4C ( O ) NHRc4 , -( CH2 ) o5NRc5Rc6 , -( CH2 ) o6 S(O) o7Rc7 , -( CH2 ) o8S (O) 2NHRc8 , -( CH2 ) o9NHS (O) 2Rc9 , the amino, C1-6 alkyl, C2-6 alkenyl , C2-6 alkynyl, C1-6 deuterated alkyl , C1-6 haloalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl or 5-10 membered heteroaryl may be further optionally substituted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl or 5-10 membered heteroaryl. substituted by one or more of C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl;
R4各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基、5-10元杂芳基、-(CH2)p1ORd1、-(CH2)p2C(O)Rd2、-(CH2)p3NHC(O)Rd3、-(CH2)p4C(O)NHRd4、-(CH2)p5NRd5Rd6、-(CH2)p6S(O)p7Rd7、-(CH2)p8S(O)2NHRd8、-(CH2)p9NHS(O)2Rd9、-(CH2)p10S(＝O)(＝NH)Rd10，所述的氨基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基任选地可以进一步被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代； R4 is each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl , C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, -( CH2 ) p1ORd1 , -( CH2 ) p2C (O) Rd2 , -(CH2)p3NHC(O)Rd3, -(CH2)p4C ( O ) NHRd4 , - ( CH2 ) p5NRd5Rd6 , -(CH wherein 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl , C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl group may be further substituted with hydrogen, deuterium, halogen , amino, hydroxyl, cyano, nitro, oxo, thio, 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl , C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl. The alkyl group may be substituted by one or more of C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl;
R4-1选自氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基、5-10元杂芳基、-(CH2)p1ORd1、-(CH2)p2C(O)Rd2、-(CH2)p3NHC(O)Rd3、-(CH2)p4C(O)NHRd4、-(CH2)p5NRd5Rd6、-(CH2)p6S(O)p7Rd7、-(CH2)p8S(O)2NHRd8、-(CH2)p9NHS(O)2Rd9、-(CH2)p10S(＝O)(＝NH)Rd10，所述的氨基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基任选地可以进一步被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代；R 4-1 is selected from deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, -(CH 2 ) p1 OR d1 , -(CH 2 ) p2 C(O)R d2 , -(CH 2 ) p3 NHC(O)R d3 , -(CH 2 ) p4 C(O)NHR d4 , -(CH 2 ) p5 NR d5 R d6 , -(CH 2 wherein 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl , C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl group may be further substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl , C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl. The alkyl group may be substituted by one or more of C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl;
R5各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基；R 5 is each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy , C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl;
Rb1、Rb2、Rb3、Rb4、Rb5、Rb6、Rb7、Rb8和Rb9各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基、5-10元杂芳基，所述的氨基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基任选地可以进一步被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代；R b1 , R b2 , R b3 , R b4 , R b5 , R b6 , R b7 , R b8 and R b9 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, said 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 , C C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl may be further optionally substituted with one or more of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl , 3-8 membered heterocyclyl , C 6-10 aryl and 5-10 membered heteroaryl;
Rc1、Rc2、Rc3、Rc4、Rc5、Rc6、Rc7、Rc8和Rc9各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基、5-10元杂芳基，所述的氨基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基任选地可以进一步被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代；R c1 , R c2 , R c3 , R c4 , R c5 , R c6 , R c7 , R c8 and R c9 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, said 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 , C C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl may be further optionally substituted with one or more of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl , 3-8 membered heterocyclyl , C 6-10 aryl and 5-10 membered heteroaryl;
Rd1、Rd2、Rd3、Rd4、Rd5、Rd6、Rd7、Rd8、Rd9和Rd10各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基、5-10元杂芳基，所述的氨基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基任选地可以进一步被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代； Rd1 , Rd2 , Rd3, Rd4 , Rd5 , Rd6 , Rd7 , Rd8 , Rd9 and Rd10 are each independently selected from hydrogen, deuterium , halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, wherein the amino, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy , C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl may be further optionally substituted with one or more of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl;
x为0、1、2、3、4或5；x is 0, 1, 2, 3, 4, or 5;
y为0、1、2、3、4或5；y is 0, 1, 2, 3, 4, or 5;
z为0、1、2或3；z is 0, 1, 2, or 3;
n1、n2、n3、n4、n5、n6、n8、n9各自独立地选自0、1、2、3、4、5或6；n1, n2, n3, n4, n5, n6, n8, n9 are each independently selected from 0, 1, 2, 3, 4, 5 or 6;
o1、o2、o3、o4、o5、o6、o8、o9各自独立地选自0、1、2、3、4、5或6；o1, o2, o3, o4, o5, o6, o8, o9 are each independently selected from 0, 1, 2, 3, 4, 5 or 6;
p1、p2、p3、p4、p5、p6、p8、p9、p10各自独立地选自0、1、2、3、4、5或6；p1, p2, p3, p4, p5, p6, p8, p9, p10 are each independently selected from 0, 1, 2, 3, 4, 5 or 6;
r1、r2、r3、r4、r5、r6各自独立地选自0、1或2；r1, r2, r3, r4, r5, r6 are each independently selected from 0, 1 or 2;
n7、o7、p7各自独立地选自0、1、2或3n7, o7, p7 are each independently selected from 0, 1, 2 or 3
在本发明的某些实施方案中，所述的化合物如式(I-1-2)所示：In certain embodiments of the present invention, the compound is as shown in formula (I-1-2):
其中，in,
M4为-CH-，M5为-CH-，M6为-CH-，M7为-CH-； M4 is -CH-, M5 is -CH-, M6 is -CH-, and M7 is -CH-;
或M4为-N-，M5为-CH-，M6为-CH-，M7为-CH-；or M4 is -N-, M5 is -CH-, M6 is -CH-, and M7 is -CH-;
或M4为-CH-，M5为-CH-，M6为-N-，M7为-CH-；or M4 is -CH-, M5 is -CH-, M6 is -N-, and M7 is -CH-;
或M4为-N-，M5为-CH-，M6为-CH-，M7为-N-。Or M4 is -N-, M5 is -CH-, M6 is -CH-, and M7 is -N-.
L1选自键、-O-、-S-、-NH-、-CO-、-CONH-、C1-3亚烷基、C2-4亚烯基、C2-4亚炔基、-O-C1-3亚烷基-、-COC1-3亚烷基-、-S-C1-3亚烷基-、-C1-3亚烷基-NH-、-C1-3亚烷基-C(O)NH-、-C1-3亚烷基-NHC(O)-、-C1-3亚烷基-S(O)r1-、-C1-3亚烷基-NHS(O)r2-或-C1-3亚烷基-S(O)r3NH-；所述的-NH-、-CONH-、C1-3亚烷基、C2-4亚烯基、C2-4亚炔基、-O-C1-3亚烷基-、-COC1-3亚烷基-、-S-C1-3亚烷基-、-C1-3亚烷基-NH-、-C1-3亚烷基-C(O)NH-、-C1-3亚烷基-NHC(O)-、-C1-3亚烷基-S(O)r1-、-C1-3亚烷基-NHS(O)r2-或-C1-3亚烷基-S(O)r3NH-任选地被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-3烷基、C2-4烯基、C2-4炔基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3氘代烷氧基、C1-3卤代烷氧基、C1-3羟烷基、C3-6环烷基、3-6元杂环基、C6-10芳基、5-6元杂芳基中的一个或多个取代； L1 is selected from a bond, -O-, -S-, -NH-, -CO-, -CONH-, C1-3 alkylene, C2-4 alkenylene, C2-4 alkynylene, -OC1-3 alkylene-, -COC1-3 alkylene-, -SC1-3 alkylene-, -C1-3 alkylene-NH-, -C1-3 alkylene-C(O)NH-, -C1-3 alkylene-NHC(O)-, -C1-3 alkylene-S(O)r1- , -C1-3 alkylene-NHS(O) r2- or -C1-3 alkylene-S(O) r3NH- ; said -NH-, -CONH-, C1-3 alkylene, C2-4 alkenylene, C2-4 alkynylene, -OC1-3 alkylene-, -COC1-3 alkylene-, -SC1-3 alkylene-, -C1-3 alkylene-NH-, -C1-3 alkylene-C(O)NH-, -C1-3 alkylene-NHC(O)-, -C1-3 alkylene-S(O) r1- , -C1-3 alkylene-NHS(O)r2- or -C1-3 alkylene -S(O)r3NH- -C 1-3 alkylene-, -C 1-3 alkylene-NH-, -C 1-3 alkylene-C(O)NH-, -C 1-3 alkylene-NHC(O)-, -C 1-3 alkylene-S(O) r1 -, -C 1-3 alkylene-NHS(O) r2 -, or -C 1-3 alkylene-S(O) r3 NH- is optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, 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, C 1-3 deuterated alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 2-4 One or more of 6-10- membered aryl and 5-6-membered heteroaryl are substituted;
L2选自键、-O-、-S-、-NH-、-CO-、-CONH-、C1-3亚烷基、C2-4亚烯基、C2-4亚炔基、-O-C1-3亚烷基-、-COC1-3亚烷基-、-S-C1-3亚烷基-、-C1-3亚烷基-NH-、-C1-3亚烷基-C(O)NH-、-C1-3亚烷基-NHC(O)-、-C1-3亚烷基-S(O)r4-、-C1-3亚烷基-NHS(O)r5-或-C1-3亚烷基-S(O)r6NH-；所述的-NH-、-CONH-、C1-3亚烷基、C2-4亚烯基、C2-4亚炔基、-O-C1-3亚烷基-、-COC1-3亚烷基-、-S-C1-3亚烷基-、-C1-3亚烷基-NH-、-C1-3亚烷基-C(O)NH-、-C1-3亚烷基-NHC(O)-、-C1-3亚烷基-S(O)r1-、-C1-3亚烷基-NHS(O)r2-或-C1-3亚烷基-S(O)r3NH-任选地被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-3烷基、C2-4烯基、C2-4炔基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3氘代烷氧基、C1-3卤代烷氧基、C1-3羟烷基、C3-6环烷基、3-6元杂环基、C6-10芳基、5-6元杂芳基中的一个或多个取代； L2 is selected from a bond, -O-, -S-, -NH-, -CO-, -CONH-, C1-3 alkylene, C2-4 alkenylene, C2-4 alkynylene, -OC1-3 alkylene-, -COC1-3 alkylene-, -SC1-3 alkylene-, -C1-3 alkylene-NH-, -C1-3 alkylene-C(O)NH-, -C1-3 alkylene-NHC(O)-, -C1-3 alkylene-S(O)r4-, -C1-3 alkylene-NHS(O) r5- or -C1-3 alkylene-S(O) r6NH- ; said -NH-, -CONH-, C1-3 alkylene, C2-4 alkenylene, C2-4 alkynylene, -OC1-3 alkylene-, -COC1-3 alkylene-, -SC1-3 alkylene-, -C1-3 alkylene-NH-, -C1-3 alkylene-C(O)NH-, -C1-3 alkylene-NHC(O)-, -C1-3 alkylene-S(O) r4- , -C1-3 alkylene-NHS(O)r5- or -C1-3 alkylene -S(O)r6NH- -C 1-3 alkylene-, -C 1-3 alkylene-NH-, -C 1-3 alkylene-C(O)NH-, -C 1-3 alkylene-NHC(O)-, -C 1-3 alkylene-S(O) r1 -, -C 1-3 alkylene-NHS(O) r2 -, or -C 1-3 alkylene-S(O) r3 NH- is optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, 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, C 1-3 deuterated alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 2-4 One or more of 6-10- membered aryl and 5-6-membered heteroaryl are substituted;
R1独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基、5-10元杂芳基、-(CH2)m1ORa1、-(CH2)m2C(O)Ra2、-(CH2)m3NHC(O)Ra3、-(CH2)m4C(O)NHRa4、-(CH2)m5NRa5Ra6、-(CH2)m6S(O)m7Ra7、-(CH2)m8S(O)2NHRa8、-(CH2)m9NHS(O)2Ra9，所述的氨基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基任选地可以进一步被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代； R1 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, -( CH2 ) m1ORa1 , -( CH2 ) m2C ( O)Ra2, -(CH2)m3NHC(O)Ra3, -(CH2)m4C ( O ) NHRa4 , - ( CH2 )m5NRa5Ra6 , - ( CH2 ) m6 S(O) m7Ra7 , -( CH2 ) m8S (O) 2NHRa8 , -( CH2 ) m9NHS (O) 2Ra9 , the amino, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl or 5-10 membered heteroaryl may be further optionally substituted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl or 5-10 membered heteroaryl. substituted by one or more of C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl;
R3各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基、5-10元杂芳基、-(CH2)o1ORc1、-(CH2)o2C(O)Rc2、-(CH2)o3NHC(O)Rc3、-(CH2)o4C(O)NHRc4、-(CH2)o5NRc5Rc6、-(CH2)o6S(O)o7Rc7、-(CH2)o8S(O)2NHRc8、-(CH2)o9NHS(O)2Rc9，所述的氨基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基任选地可以进一步被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代； R3 is each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl , C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, -( CH2 ) o1ORc1 , -( CH2 ) o2C (O ) Rc2, -(CH2) o3NHC(O)Rc3 , -( CH2 ) o4C ( O ) NHRc4 , -( CH2 ) o5NRc5Rc6 , -( CH2 ) o6 S(O) o7Rc7 , -( CH2 ) o8S (O) 2NHRc8 , -( CH2 ) o9NHS (O) 2Rc9 , the amino, C1-6 alkyl, C2-6 alkenyl , C2-6 alkynyl, C1-6 deuterated alkyl , C1-6 haloalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl or 5-10 membered heteroaryl may be further optionally substituted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl or 5-10 membered heteroaryl. substituted by one or more of C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl;
R4各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基、5-10元杂芳基、-(CH2)p1ORd1、-(CH2)p2C(O)Rd2、-(CH2)p3NHC(O)Rd3、-(CH2)p4C(O)NHRd4、-(CH2)p5NRd5Rd6、-(CH2)p6S(O)p7Rd7、-(CH2)p8S(O)2NHRd8、-(CH2)p9NHS(O)2Rd9、-(CH2)p10S(＝O)(＝NH)Rd10，所述的氨基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基任选地可以进一步被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代； R4 is each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl , C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, -( CH2 ) p1ORd1 , -( CH2 ) p2C (O) Rd2 , -(CH2)p3NHC(O)Rd3, -(CH2)p4C ( O ) NHRd4 , - ( CH2 ) p5NRd5Rd6 , -(CH wherein 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl , C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl group may be further substituted with hydrogen, deuterium, halogen , amino, hydroxyl, cyano, nitro, oxo, thio, 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl , C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl. The alkyl group may be substituted by one or more of C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl;
R4-1选自氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基、5-10元杂芳基、-(CH2)p1ORd1、-(CH2)p2C(O)Rd2、-(CH2)p3NHC(O)Rd3、-(CH2)p4C(O)NHRd4、-(CH2)p5NRd5Rd6、-(CH2)p6S(O)p7Rd7、-(CH2)p8S(O)2NHRd8、-(CH2)p9NHS(O)2Rd9、-(CH2)p10S(＝O)(＝NH)Rd10，所述的氨基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基任选地可以进一步被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代；R 4-1 is selected from deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, -(CH 2 ) p1 OR d1 , -(CH 2 ) p2 C(O)R d2 , -(CH 2 ) p3 NHC(O)R d3 , -(CH 2 ) p4 C(O)NHR d4 , -(CH 2 ) p5 NR d5 R d6 , -(CH 2 wherein 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl , C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl group may be further substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl , C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl. The alkyl group may be substituted by one or more of C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl;
Ra1、Ra2、Ra3、Ra4、Ra5、Ra6、Ra7、Ra8和Ra9各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基、5-10元杂芳基，所述的氨基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基任选地可以进一步被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代； Ra1 , Ra2 , Ra3 , Ra4 , Ra5 , Ra6 , Ra7 , Ra8 and Ra9 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, and the amino, C1-6 alkyl , C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl , C1-6 alkoxy , C C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl may be further optionally substituted with one or more of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl , 3-8 membered heterocyclyl , C 6-10 aryl and 5-10 membered heteroaryl;
Rc1、Rc2、Rc3、Rc4、Rc5、Rc6、Rc7、Rc8和Rc9各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基、5-10元杂芳基，所述的氨基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基任选地可以进一步被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代；R c1 , R c2 , R c3 , R c4 , R c5 , R c6 , R c7 , R c8 and R c9 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, said 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 , C C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl may be further optionally substituted with one or more of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl , 3-8 membered heterocyclyl , C 6-10 aryl and 5-10 membered heteroaryl;
Rd1、Rd2、Rd3、Rd4、Rd5、Rd6、Rd7、Rd8、Rd9和Rd10各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基、5-10元杂芳基，所述的氨基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基任选地可以进一步被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代； Rd1 , Rd2 , Rd3, Rd4 , Rd5 , Rd6 , Rd7 , Rd8 , Rd9 and Rd10 are each independently selected from hydrogen, deuterium , halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, wherein the amino, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy , C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl may be further optionally substituted with one or more of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl;
x为0、1、2、3、4或5；x is 0, 1, 2, 3, 4, or 5;
y为0、1、2、3、4或5；y is 0, 1, 2, 3, 4, or 5;
m1、m2、m3、m4、m5、m6、m8、m9各自独立地选自0、1、2、3、4、5或6；m1, m2, m3, m4, m5, m6, m8, m9 are each independently selected from 0, 1, 2, 3, 4, 5 or 6;
o1、o2、o3、o4、o5、o6、o8、o9各自独立地选自0、1、2、3、4、5或6；o1, o2, o3, o4, o5, o6, o8, o9 are each independently selected from 0, 1, 2, 3, 4, 5 or 6;
p1、p2、p3、p4、p5、p6、p8、p9、p10各自独立地选自0、1、2、3、4、5或6；p1, p2, p3, p4, p5, p6, p8, p9, p10 are each independently selected from 0, 1, 2, 3, 4, 5 or 6;
r1、r2、r3、r4、r5、r6各自独立地选自0、1或2；r1, r2, r3, r4, r5, r6 are each independently selected from 0, 1 or 2;
m7、o7、p7各自独立地选自0、1、2或3。m7, o7, p7 are each independently selected from 0, 1, 2 or 3.
在本发明的某些实施方案中，所述的化合物如式(I-1-3)所示：In certain embodiments of the present invention, the compound is as shown in formula (I-1-3):
其中，in,
M4为-CH-，M5为-CH-，M6为-CH-，M7为-CH-； M4 is -CH-, M5 is -CH-, M6 is -CH-, and M7 is -CH-;
或M4为-N-，M5为-CH-，M6为-CH-，M7为-CH-；or M4 is -N-, M5 is -CH-, M6 is -CH-, and M7 is -CH-;
或M4为-CH-，M5为-CH-，M6为-N-，M7为-CH-；or M4 is -CH-, M5 is -CH-, M6 is -N-, and M7 is -CH-;
或M4为-N-，M5为-CH-，M6为-CH-，M7为-N-；or M4 is -N-, M5 is -CH-, M6 is -CH-, and M7 is -N-;
M1-M2-M3选自-CH2OCH2-、-NHCONH-、-CH2CONH-、-OCONH-、-NHCOCH2-、-CH2SO2CH2-或-CH2CH2CH2-；M 1 -M 2 -M 3 is selected from -CH 2 OCH 2 -, -NHCONH-, -CH 2 CONH-, -OCONH-, -NHCOCH 2 -, -CH 2 SO 2 CH 2 - or -CH 2 CH 2 CH2- ;
L1选自键、-O-、-S-、-NH-、-CO-、-CONH-、C1-3亚烷基、C2-4亚烯基、C2-4亚炔基、-O-C1-3亚烷基-、-COC1-3亚烷基-、-S-C1-3亚烷基-、-C1-3亚烷基-NH-、-C1-3亚烷基-C(O)NH-、-C1-3亚烷基-NHC(O)-、-C1-3亚烷基-S(O)r1-、-C1-3亚烷基-NHS(O)r2-或-C1-3亚烷基-S(O)r3NH-；所述的-NH-、-CONH-、C1-3亚烷基、C2-4亚烯基、C2-4亚炔基、-O-C1-3亚烷基-、-COC1-3亚烷基-、-S-C1-3亚烷基-、-C1-3亚烷基-NH-、-C1-3亚烷基-C(O)NH-、-C1-3亚烷基-NHC(O)-、-C1-3亚烷基-S(O)r1-、-C1-3亚烷基-NHS(O)r2-或-C1-3亚烷基-S(O)r3NH-任选地被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-3烷基、C2-4烯基、C2-4炔基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3氘代烷氧基、C1-3卤代烷氧基、C1-3羟烷基、C3-6环烷基、3-6元杂环基、C6-10芳基、5-6元杂芳基中的一个或多个取代； L1 is selected from a bond, -O-, -S-, -NH-, -CO-, -CONH-, C1-3 alkylene, C2-4 alkenylene, C2-4 alkynylene, -OC1-3 alkylene-, -COC1-3 alkylene-, -SC1-3 alkylene-, -C1-3 alkylene-NH-, -C1-3 alkylene-C(O)NH-, -C1-3 alkylene-NHC(O)-, -C1-3 alkylene-S(O)r1- , -C1-3 alkylene-NHS(O) r2- or -C1-3 alkylene-S(O) r3NH- ; said -NH-, -CONH-, C1-3 alkylene, C2-4 alkenylene, C2-4 alkynylene, -OC1-3 alkylene-, -COC1-3 alkylene-, -SC1-3 alkylene-, -C1-3 alkylene-NH-, -C1-3 alkylene-C(O)NH-, -C1-3 alkylene-NHC(O)-, -C1-3 alkylene-S(O) r1- , -C1-3 alkylene-NHS(O)r2- or -C1-3 alkylene -S(O)r3NH- -C 1-3 alkylene-, -C 1-3 alkylene-NH-, -C 1-3 alkylene-C(O)NH-, -C 1-3 alkylene-NHC(O)-, -C 1-3 alkylene-S(O) r1 -, -C 1-3 alkylene-NHS(O) r2 -, or -C 1-3 alkylene-S(O) r3 NH- is optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, 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, C 1-3 deuterated alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 2-4 One or more of 6-10- membered aryl and 5-6-membered heteroaryl are substituted;
L2选自键、-O-、-S-、-NH-、-CO-、-CONH-、C1-3亚烷基、C2-4亚烯基、C2-4亚炔基、-O-C1-3亚烷基-、-COC1-3亚烷基-、-S-C1-3亚烷基-、-C1-3亚烷基-NH-、-C1-3亚烷基-C(O)NH-、-C1-3亚烷基-NHC(O)-、-C1-3亚烷基-S(O)r4-、-C1-3亚烷基-NHS(O)r5-或-C1-3亚烷基-S(O)r6NH-；所述的-NH-、-CONH-、C1-3亚烷基、C2-4亚烯基、C2-4亚炔基、-O-C1-3亚烷基-、-COC1-3亚烷基-、-S-C1-3亚烷基-、-C1-3亚烷基-NH-、-C1-3亚烷基-C(O)NH-、-C1-3亚烷基-NHC(O)-、-C1-3亚烷基-S(O)r1-、-C1-3亚烷基-NHS(O)r2-或-C1-3亚烷基-S(O)r3NH-任选地被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-3烷基、C2-4烯基、C2-4炔基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3氘代烷氧基、C1-3卤代烷氧基、C1-3羟烷基、C3-6环烷基、3-6元杂环基、C6-10芳基、5-6元杂芳基中的一个或多个取代； L2 is selected from a bond, -O-, -S-, -NH-, -CO-, -CONH-, C1-3 alkylene, C2-4 alkenylene, C2-4 alkynylene, -OC1-3 alkylene-, -COC1-3 alkylene-, -SC1-3 alkylene-, -C1-3 alkylene-NH-, -C1-3 alkylene-C(O)NH-, -C1-3 alkylene-NHC(O)-, -C1-3 alkylene-S(O)r4-, -C1-3 alkylene-NHS(O) r5- or -C1-3 alkylene-S(O) r6NH- ; said -NH-, -CONH-, C1-3 alkylene, C2-4 alkenylene, C2-4 alkynylene, -OC1-3 alkylene-, -COC1-3 alkylene-, -SC1-3 alkylene-, -C1-3 alkylene-NH-, -C1-3 alkylene-C(O)NH-, -C1-3 alkylene-NHC(O)-, -C1-3 alkylene-S(O) r4- , -C1-3 alkylene-NHS(O)r5- or -C1-3 alkylene -S(O)r6NH- -C 1-3 alkylene-, -C 1-3 alkylene-NH-, -C 1-3 alkylene-C(O)NH-, -C 1-3 alkylene-NHC(O)-, -C 1-3 alkylene-S(O) r1 -, -C 1-3 alkylene-NHS(O) r2 -, or -C 1-3 alkylene-S(O) r3 NH- is optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, 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, C 1-3 deuterated alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 2-4 One or more of 6-10- membered aryl and 5-6-membered heteroaryl are substituted;
R3各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基、5-10元杂芳基、-(CH2)o1ORc1、-(CH2)o2C(O)Rc2、-(CH2)o3NHC(O)Rc3、-(CH2)o4C(O)NHRc4、-(CH2)o5NRc5Rc6、-(CH2)o6S(O)o7Rc7、-(CH2)o8S(O)2NHRc8、-(CH2)o9NHS(O)2Rc9，所述的氨基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基任选地可以进一步被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代； R3 is each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl , C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, -( CH2 ) o1ORc1 , -( CH2 ) o2C (O)Rc2, - (CH2) o3NHC(O)Rc3 , -( CH2 ) o4C ( O ) NHRc4 , -( CH2 ) o5NRc5Rc6 , -( CH2 ) o6 S(O) o7Rc7 , -( CH2 ) o8S (O) 2NHRc8 , -( CH2 ) o9NHS (O) 2Rc9 , the amino, C1-6 alkyl, C2-6 alkenyl , C2-6 alkynyl, C1-6 deuterated alkyl , C1-6 haloalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl or 5-10 membered heteroaryl may be further optionally substituted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl or 5-10 membered heteroaryl. substituted by one or more of C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl;
R4各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基、5-10元杂芳基、-(CH2)p1ORd1、-(CH2)p2C(O)Rd2、-(CH2)p3NHC(O)Rd3、-(CH2)p4C(O)NHRd4、-(CH2)p5NRd5Rd6、-(CH2)p6S(O)p7Rd7、-(CH2)p8S(O)2NHRd8、-(CH2)p9NHS(O)2Rd9、-(CH2)p10S(＝O)(＝NH)Rd10，所述的氨基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基任选地可以进一步被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代； R4 is each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl , C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, -( CH2 ) p1ORd1 , -( CH2 ) p2C (O) Rd2 , -(CH2)p3NHC(O)Rd3, -(CH2)p4C ( O ) NHRd4 , - ( CH2 ) p5NRd5Rd6 , -(CH wherein 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl , C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl group may be further substituted with hydrogen, deuterium, halogen , amino, hydroxyl, cyano, nitro, oxo, thio, 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl , C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl. The alkyl group may be substituted by one or more of C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl;
R4-1选自氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基、5-10元杂芳基、-(CH2)p1ORd1、-(CH2)p2C(O)Rd2、-(CH2)p3NHC(O)Rd3、-(CH2)p4C(O)NHRd4、-(CH2)p5NRd5Rd6、-(CH2)p6S(O)p7Rd7、-(CH2)p8S(O)2NHRd8、-(CH2)p9NHS(O)2Rd9、-(CH2)p10S(＝O)(＝NH)Rd10，所述的氨基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基任选地可以进一步被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代；R 4-1 is selected from deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, -(CH 2 ) p1 OR d1 , -(CH 2 ) p2 C(O)R d2 , -(CH 2 ) p3 NHC(O)R d3 , -(CH 2 ) p4 C(O)NHR d4 , -(CH 2 ) p5 NR d5 R d6 , -(CH 2 wherein 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl , C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl group may be further substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl , C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl. The alkyl group may be substituted by one or more of C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl;
R5各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基；R 5 is each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy , C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl;
Rc1、Rc2、Rc3、Rc4、Rc5、Rc6、Rc7、Rc8和Rc9各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基、5-10元杂芳基，所述的氨基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基任选地可以进一步被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代；R c1 , R c2 , R c3 , R c4 , R c5 , R c6 , R c7 , R c8 and R c9 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, said 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 , C C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl may be further optionally substituted with one or more of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl , 3-8 membered heterocyclyl , C 6-10 aryl and 5-10 membered heteroaryl;
Rd1、Rd2、Rd3、Rd4、Rd5、Rd6、Rd7、Rd8、Rd9和Rd10各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基、5-10元杂芳基，所述的氨基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基任选地可以进一步被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代； Rd1 , Rd2 , Rd3, Rd4 , Rd5 , Rd6 , Rd7 , Rd8 , Rd9 and Rd10 are each independently selected from hydrogen, deuterium , halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, wherein the amino, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy , C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl may be further optionally substituted with one or more of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl;
x为0、1、2、3、4或5；x is 0, 1, 2, 3, 4, or 5;
y为0、1、2、3、4或5；y is 0, 1, 2, 3, 4, or 5;
z为0、1、2或3；z is 0, 1, 2, or 3;
o1、o2、o3、o4、o5、o6、o8、o9各自独立地选自0、1、2、3、4、5或6；o1, o2, o3, o4, o5, o6, o8, o9 are each independently selected from 0, 1, 2, 3, 4, 5 or 6;
p1、p2、p3、p4、p5、p6、p8、p9、p10各自独立地选自0、1、2、3、4、5或6；p1, p2, p3, p4, p5, p6, p8, p9, p10 are each independently selected from 0, 1, 2, 3, 4, 5 or 6;
r1、r2、r3、r4、r5、r6各自独立地选自0、1或2；r1, r2, r3, r4, r5, r6 are each independently selected from 0, 1 or 2;
o7、p7各自独立地选自0、1、2或3。o7 and p7 are each independently selected from 0, 1, 2 or 3.
本发明还提供了一种如通式(II)所示的化合物、其立体异构体或其药学上可接受的盐：The present invention also provides a compound represented by general formula (II), a stereoisomer thereof or a pharmaceutically acceptable salt thereof:
环B为C3-8环烷基、5-6元杂芳基或3-8元杂环基；Ring B is C 3-8 cycloalkyl, 5-6 membered heteroaryl or 3-8 membered heterocyclyl;
M4为-CH-，M5为-CH-，M6为-CH-，M7为-CH-； M4 is -CH-, M5 is -CH-, M6 is -CH-, and M7 is -CH-;
或M4为-N-，M5为-CH-，M6为-CH-，M7为-CH-；or M4 is -N-, M5 is -CH-, M6 is -CH-, and M7 is -CH-;
或M4为-CH-，M5为-CH-，M6为-N-，M7为-CH-；or M4 is -CH-, M5 is -CH-, M6 is -N-, and M7 is -CH-;
或M4为-N-，M5为-CH-，M6为-CH-，M7为-N-；or M4 is -N-, M5 is -CH-, M6 is -CH-, and M7 is -N-;
L1选自键、-O-、-S-、-NH-、-CO-、-CONH-、C1-3亚烷基、C2-4亚烯基、C2-4亚炔基、-O-C1-3亚烷基-、-COC1-3亚烷基-、-S-C1-3亚烷基-、-C1-3亚烷基-NH-、-C1-3亚烷基-C(O)NH-、-C1-3亚烷基-NHC(O)-、-C1-3亚烷基-S(O)r1-、-C1-3亚烷基-NHS(O)r2-或-C1-3亚烷基-S(O)r3NH-；所述的-NH-、-CONH-、C1-3亚烷基、C2-4亚烯基、C2-4亚炔基、-O-C1-3亚烷基-、-COC1-3亚烷基-、-S-C1-3亚烷基-、-C1-3亚烷基-NH-、-C1-3亚烷基-C(O)NH-、-C1-3亚烷基-NHC(O)-、-C1-3亚烷基-S(O)r1-、-C1-3亚烷基-NHS(O)r2-或-C1-3亚烷基-S(O)r3NH-任选地被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-3烷基、C2-4烯基、C2-4炔基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3氘代烷氧基、C1-3卤代烷氧基、C1-3羟烷基、C3-6环烷基、3-6元杂环基、C6-10芳基、5-6元杂芳基中的一个或多个取代； L1 is selected from a bond, -O-, -S-, -NH-, -CO-, -CONH-, C1-3 alkylene, C2-4 alkenylene, C2-4 alkynylene, -OC1-3 alkylene-, -COC1-3 alkylene-, -SC1-3 alkylene-, -C1-3 alkylene-NH-, -C1-3 alkylene-C(O)NH-, -C1-3 alkylene-NHC(O)-, -C1-3 alkylene-S(O)r1- , -C1-3 alkylene-NHS(O) r2- or -C1-3 alkylene-S(O) r3NH- ; said -NH-, -CONH-, C1-3 alkylene, C2-4 alkenylene, C2-4 alkynylene, -OC1-3 alkylene-, -COC1-3 alkylene-, -SC1-3 alkylene-, -C1-3 alkylene-NH-, -C1-3 alkylene-C(O)NH-, -C1-3 alkylene-NHC(O)-, -C1-3 alkylene-S(O) r1- , -C1-3 alkylene-NHS(O)r2- or -C1-3 alkylene -S(O)r3NH- -C 1-3 alkylene-, -C 1-3 alkylene-NH-, -C 1-3 alkylene-C(O)NH-, -C 1-3 alkylene-NHC(O)-, -C 1-3 alkylene-S(O) r1 -, -C 1-3 alkylene-NHS(O) r2 -, or -C 1-3 alkylene-S(O) r3 NH- is optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, 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, C 1-3 deuterated alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 2-4 One or more of 6-10- membered aryl and 5-6-membered heteroaryl are substituted;
L2选自键、-O-、-S-、-NH-、-CO-、-CONH-、C1-3亚烷基、C2-4亚烯基、C2-4亚炔基、-O-C1-3亚烷基-、-COC1-3亚烷基-、-S-C1-3亚烷基-、-C1-3亚烷基-NH-、-C1-3亚烷基-C(O)NH-、-C1-3亚烷基-NHC(O)-、-C1-3亚烷基-S(O)r4-、-C1-3亚烷基-NHS(O)r5-或-C1-3亚烷基-S(O)r6NH-；所述的-NH-、-CONH-、C1-3亚烷基、C2-4亚烯基、C2-4亚炔基、-O-C1-3亚烷基-、-COC1-3亚烷基-、-S-C1-3亚烷基-、-C1-3亚烷基-NH-、-C1-3亚烷基-C(O)NH-、-C1-3亚烷基-NHC(O)-、-C1-3亚烷基-S(O)r1-、-C1-3亚烷基-NHS(O)r2-或-C1-3亚烷基-S(O)r3NH-任选地被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-3烷基、C2-4烯基、C2-4炔基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3氘代烷氧基、C1-3卤代烷氧基、C1-3羟烷基、C3-6环烷基、3-6元杂环基、C6-10芳基、5-6元杂芳基中的一个或多个取代； L2 is selected from a bond, -O-, -S-, -NH-, -CO-, -CONH-, C1-3 alkylene, C2-4 alkenylene, C2-4 alkynylene, -OC1-3 alkylene-, -COC1-3 alkylene-, -SC1-3 alkylene-, -C1-3 alkylene-NH-, -C1-3 alkylene-C(O)NH-, -C1-3 alkylene-NHC(O)-, -C1-3 alkylene-S(O)r4-, -C1-3 alkylene-NHS(O) r5- or -C1-3 alkylene-S(O) r6NH- ; said -NH-, -CONH-, C1-3 alkylene, C2-4 alkenylene, C2-4 alkynylene, -OC1-3 alkylene-, -COC1-3 alkylene-, -SC1-3 alkylene-, -C1-3 alkylene-NH-, -C1-3 alkylene-C(O)NH-, -C1-3 alkylene-NHC(O)-, -C1-3 alkylene-S(O) r4- , -C1-3 alkylene-NHS(O)r5- or -C1-3 alkylene -S(O)r6NH- -C 1-3 alkylene-, -C 1-3 alkylene-NH-, -C 1-3 alkylene-C(O)NH-, -C 1-3 alkylene-NHC(O)-, -C 1-3 alkylene-S(O) r1 -, -C 1-3 alkylene-NHS(O) r2 -, or -C 1-3 alkylene-S(O) r3 NH- is optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, 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, C 1-3 deuterated alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 2-4 One or more of 6-10- membered aryl and 5-6-membered heteroaryl are substituted;
R3各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基、5-10元杂芳基、-(CH2)o1ORc1、-(CH2)o2C(O)Rc2、-(CH2)o3NHC(O)Rc3、-(CH2)o4C(O)NHRc4、-(CH2)o5NRc5Rc6、-(CH2)o6S(O)o7Rc7、-(CH2)o8S(O)2NHRc8、-(CH2)o9NHS(O)2Rc9，所述的氨基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基任选地可以进一步被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代； R3 is each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl , C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, -( CH2 ) o1ORc1 , -( CH2 ) o2C (O ) Rc2, -(CH2) o3NHC(O)Rc3 , -( CH2 ) o4C ( O ) NHRc4 , -( CH2 ) o5NRc5Rc6 , -( CH2 ) o6 S(O) o7Rc7 , -( CH2 ) o8S (O) 2NHRc8 , -( CH2 ) o9NHS (O) 2Rc9 , the amino, C1-6 alkyl, C2-6 alkenyl , C2-6 alkynyl, C1-6 deuterated alkyl , C1-6 haloalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl or 5-10 membered heteroaryl may be further optionally substituted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl or 5-10 membered heteroaryl. substituted by one or more of C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl;
R4各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基、5-10元杂芳基、-(CH2)p1ORd1、-(CH2)p2C(O)Rd2、-(CH2)p3NHC(O)Rd3、-(CH2)p4C(O)NHRd4、-(CH2)p5NRd5Rd6、-(CH2)p6S(O)p7Rd7、-(CH2)p8S(O)2NHRd8、-(CH2)p9NHS(O)2Rd9、-(CH2)p10S(＝O)(＝NH)Rd10，所述的氨基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基任选地可以进一步被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代； R4 is each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl , C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, -( CH2 ) p1ORd1 , -( CH2 ) p2C (O) Rd2 , -(CH2)p3NHC(O)Rd3, -(CH2)p4C ( O ) NHRd4 , - ( CH2 ) p5NRd5Rd6 , -(CH wherein 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl , C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl group may be further substituted with hydrogen, deuterium, halogen , amino, hydroxyl, cyano, nitro, oxo, thio, 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl , C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl. The alkyl group may be substituted by one or more of C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl;
R4-1选自氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基、5-10元杂芳基、-(CH2)p1ORd1、-(CH2)p2C(O)Rd2、-(CH2)p3NHC(O)Rd3、-(CH2)p4C(O)NHRd4、-(CH2)p5NRd5Rd6、-(CH2)p6S(O)p7Rd7、-(CH2)p8S(O)2NHRd8、-(CH2)p9NHS(O)2Rd9、-(CH2)p10S(＝O)(＝NH)Rd10，所述的氨基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基任选地可以进一步被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代；R 4-1 is selected from deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, -(CH 2 ) p1 OR d1 , -(CH 2 ) p2 C(O)R d2 , -(CH 2 ) p3 NHC(O)R d3 , -(CH 2 ) p4 C(O)NHR d4 , -(CH 2 ) p5 NR d5 R d6 , -(CH 2 wherein 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl , C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl group may be further substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl , C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl. The alkyl group may be substituted by one or more of C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl;
R5各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基；R 5 is each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy , C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl;
Rc1、Rc2、Rc3、Rc4、Rc5、Rc6、Rc7、Rc8和Rc9各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基、5-10元杂芳基，所述的氨基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基任选地可以进一步被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代；R c1 , R c2 , R c3 , R c4 , R c5 , R c6 , R c7 , R c8 and R c9 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, said 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 , C C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl may be further optionally substituted with one or more of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl , 3-8 membered heterocyclyl , C 6-10 aryl and 5-10 membered heteroaryl;
Rd1、Rd2、Rd3、Rd4、Rd5、Rd6、Rd7、Rd8、Rd9和Rd10各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基、5-10元杂芳基，所述的氨基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基任选地可以进一步被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代； Rd1 , Rd2 , Rd3, Rd4 , Rd5 , Rd6 , Rd7 , Rd8 , Rd9 and Rd10 are each independently selected from hydrogen, deuterium , halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, wherein the amino, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy , C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl may be further optionally substituted with one or more of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl;
x为0、1、2、3、4或5；x is 0, 1, 2, 3, 4, or 5;
y为0、1、2、3、4或5；y is 0, 1, 2, 3, 4, or 5;
z为0、1、2或3；z is 0, 1, 2, or 3;
o1、o2、o3、o4、o5、o6、o8、o9各自独立地选自0、1、2、3、4、5或6；o1, o2, o3, o4, o5, o6, o8, o9 are each independently selected from 0, 1, 2, 3, 4, 5 or 6;
p1、p2、p3、p4、p5、p6、p8、p9、p10各自独立地选自0、1、2、3、4、5或6；p1, p2, p3, p4, p5, p6, p8, p9, p10 are each independently selected from 0, 1, 2, 3, 4, 5 or 6;
r1、r2、r3、r4、r5、r6各自独立地选自0、1或2；r1, r2, r3, r4, r5, r6 are each independently selected from 0, 1 or 2;
o7、p7各自独立地选自0、1、2或3。o7 and p7 are each independently selected from 0, 1, 2 or 3.
在本发明的某些实施方案中，所述的环B选自C5-6环烷基、5-6元杂芳基或5-6元杂环基；优选地，环B选自 In certain embodiments of the present invention, the ring B is selected from C 5-6 cycloalkyl, 5-6 membered heteroaryl or 5-6 membered heterocyclyl; preferably, the ring B is selected from
在本发明的某些实施方案中，L1选自键、-O-或-CF2-。In certain embodiments of the present invention, L 1 is selected from a bond, -O- or -CF 2 -.
在本发明的某些实施方案中，L2选自键、-NH-、-CH2-、-CH2CO-或-S-。In certain embodiments of the present invention, L2 is selected from a bond, -NH-, -CH2- , -CH2CO- , or -S-.
在本发明的某些实施方案中，R1独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-3烷基、C2-4烯基、C2-4炔基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3氘代烷氧基、C1-3卤代烷氧基、C1-3羟烷基、C3-6环烷基、3-6元杂环基、C6-10芳基、5-6元杂芳基、-(CH2)m1ORa1、-(CH2)m2C(O)Ra2、-(CH2)m3NHC(O)Ra3、-(CH2)m4C(O)NHRa4、-(CH2)m5NRa5Ra6、-(CH2)m6S(O)m7Ra7、-(CH2)m8S(O)2NHRa8、-(CH2)m9NHS(O)2Ra9，所述的氨基、C1-3烷基、C2-4烯基、C2-4炔基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3氘代烷氧基、C1-3卤代烷氧基、C1-3羟烷基、C3-6环烷基、3-6元杂环基、C6-10芳基或5-6元杂芳基任选地可以进一步被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-3烷基、C2-4烯基、C2-4炔基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3氘代烷氧基、C1-3卤代烷氧基、C1-3羟烷基、C3-6环烷基、3-6元杂环基、C6-10芳基和5-6元杂芳基中的一个或多个取代。In certain embodiments of the present invention, R 1 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, 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, C 1-3 deuterated alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-10 aryl, 5-6 membered heteroaryl, -(CH 2 ) m1 OR a1 , -(CH 2 ) m2 C(O)R a2 , -(CH 2 ) m3 NHC(O)R a3 , -(CH 2 ) m4 C(O)NHR a4 , -(CH 2 ) m5 NR a5 R a6 , -(CH 2 wherein the amino, 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, C 1-3 deuterated alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl , C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-10 aryl or 5-6 membered heteroaryl may be further substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, 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, C 1-3 deuterated alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-10 aryl or 5-6 membered heteroaryl. The group may be substituted by one or more of C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 deuterated alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-10 aryl and 5-6 membered heteroaryl.
在本发明的某些实施方案中，Ra1、Ra2、Ra3、Ra4、Ra5、Ra6、Ra7、Ra8和Ra9各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-3烷基、C2-4烯基、C2-4炔基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3氘代烷氧基、C1-3卤代烷氧基、C1-3羟烷基、C3-6环烷基、3-6元杂环基、C6-10芳基、5-6元杂芳基，所述的氨基、C1-3烷基、C2-4烯基、C2-4炔基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3氘代烷氧基、C1-3卤代烷氧基、C1-3羟烷基、C3-6环烷基、3-6元杂环基、C6-10芳基或5-6元杂芳基任选地可以进一步被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-3烷基、C2-4烯基、C2-4炔基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3氘代烷氧基、C1-3卤代烷氧基、C1-3羟烷基、C3-6环烷基、3-6元杂环基、C6-10芳基和5-6元杂芳基中的一个或多个取代。In certain embodiments of the present invention, Ra1 , Ra2 , Ra3 , Ra4 , Ra5 , Ra6 , Ra7 , Ra8 and Ra9 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C1-3 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-3 deuterated alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 deuterated alkoxy, C1-3 haloalkoxy, C1-3 hydroxyalkyl, C3-6 cycloalkyl, 3-6 membered heterocyclyl, C6-10 aryl, 5-6 membered heteroaryl, wherein the amino, C1-3 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-3 deuterated alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 deuterated alkoxy, C1-3 haloalkoxy, C1-3 hydroxyalkyl, C3-6 cycloalkyl, 3-6 membered heterocyclyl, C6-10 aryl, 5-6 membered heteroaryl The C 1-3 alkoxy, C 1-3 deuterated alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-10 aryl or 5-6 membered heteroaryl may optionally be further substituted with one or more of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, 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, C 1-3 deuterated alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl , C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-10 aryl and 5-6 membered heteroaryl.
在本发明的某些实施方案中，R1选自环丙基、 In certain embodiments of the present invention, R is selected from Cyclopropyl,
在本发明的某些实施方案中，R2-1和R2-2各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-3烷基、C2-4烯基、C2-4炔基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3氘代烷氧基、C1-3卤代烷氧基、C1-3羟烷基、C3-6环烷基、3-6元杂环基、C6-10芳基、5-6元杂芳基、-(CH2)n1ORb1、-(CH2)n2C(O)Rb2、-(CH2)n3NHC(O)Rb3、-(CH2)n4C(O)NHRb4、-(CH2)n5NRb5Rb6、-(CH2)n6S(O)n7Rb7、-(CH2)n8S(O)2NHRb8、-(CH2)n9NHS(O)2Rb9，所述的氨基、C1-3烷基、C2-4烯基、C2-4炔基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3氘代烷氧基、C1-3卤代烷氧基、C1-3羟烷基、C3-6环烷基、3-6元杂环基、C6-10芳基或5-6元杂芳基任选地可以进一步被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-3烷基、C2-4烯基、C2-4炔基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3氘代烷氧基、C1-3卤代烷氧基、C1-3羟烷基、C3-6环烷基、3-6元杂环基、C6-10芳基和5-6元杂芳基中的一个或多个取代。In certain embodiments of the present invention, R 2-1 and R 2-2 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, 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, C 1-3 deuterated alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-10 aryl, 5-6 membered heteroaryl, -(CH 2 ) n1 OR b1 , -(CH 2 ) n2 C(O)R b2 , -(CH 2 ) n3 NHC(O)R b3 , -(CH 2 ) n4 C(O)NHR b4 , -(CH 2 ) n5 NR b5 R b6 , -( CH2 ) n6S (O) n7Rb7 , -( CH2 ) n8S (O) 2NHRb8 , -( CH2 ) n9NHS (O) 2Rb9 , the amino, C1-3 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-3 deuterated alkyl, C1-3 haloalkyl , C1-3 alkoxy, C1-3 deuterated alkoxy, C1-3 haloalkoxy, C1-3 hydroxyalkyl, C3-6 cycloalkyl, 3-6 membered heterocyclyl, C6-10 aryl or 5-6 membered heteroaryl may be further optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C1-3 alkyl, C2-4 alkenyl, C2-4 alkynyl, C The group may be substituted by one or more of C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 deuterated alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-10 aryl and 5-6 membered heteroaryl.
在本发明的某些实施方案中，Rb1、Rb2、Rb3、Rb4、Rb5、Rb6、Rb7、Rb8和Rb9各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-3烷基、C2-4烯基、C2-4炔基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3氘代烷氧基、C1-3卤代烷氧基、C1-3羟烷基、C3-6环烷基、3-6元杂环基、C6-10芳基、5-6元杂芳基，所述的氨基、C1-3烷基、C2-4烯基、C2-4炔基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3氘代烷氧基、C1-3卤代烷氧基、C1-3羟烷基、C3-6环烷基、3-6元杂环基、C6-10芳基或5-6元杂芳基任选地可以进一步被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-3烷基、C2-4烯基、C2-4炔基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3氘代烷氧基、C1-3卤代烷氧基、C1-3羟烷基、C3-6环烷基、3-6元杂环基、C6-10芳基和5-6元杂芳基中的一个或多个取代。In certain embodiments of the present invention, R b1 , R b2 , R b3 , R b4 , R b5 , R b6 , R b7 , R b8 and R b9 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, 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, C 1-3 deuterated alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-10 aryl, 5-6 membered heteroaryl, wherein the amino, 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, C 1-3 deuterated alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-10 aryl, 5-6 membered heteroaryl The C 1-3 alkoxy, C 1-3 deuterated alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-10 aryl or 5-6 membered heteroaryl may optionally be further substituted with one or more of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, 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, C 1-3 deuterated alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl , C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-10 aryl and 5-6 membered heteroaryl.
在本发明的某些实施方案中，R2-1选自 In certain embodiments of the present invention, R 2-1 is selected from
在本发明的某些实施方案中，R2-2选自氢。In certain embodiments of the present invention, R 2-2 is selected from hydrogen.
在本发明的某些实施方案中，R3各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-3烷基、C2-4烯基、C2-4炔基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3氘代烷氧基、C1-3卤代烷氧基、C1-3羟烷基、C3-6环烷基、3-6元杂环基、C6-10芳基、5-6元杂芳基、-(CH2)o1ORc1、-(CH2)o2C(O)Rc2、-(CH2)o3NHC(O)Rc3、-(CH2)o4C(O)NHRc4、-(CH2)o5NRc5Rc6、-(CH2)o6S(O)o7Rc7、-(CH2)o8S(O)2NHRc8、-(CH2)o9NHS(O)2Rc9，所述的氨基、C1-3烷基、C2-4烯基、C2-4炔基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3氘代烷氧基、C1-3卤代烷氧基、C1-3羟烷基、C3-6环烷基、3-6元杂环基、C6-10芳基或5-6元杂芳基任选地可以进一步被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-3烷基、C2-4烯基、C2-4炔基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3氘代烷氧基、C1-3卤代烷氧基、C1-3羟烷基、C3-6环烷基、3-6元杂环基、C6-10芳基和5-6元杂芳基中的一个或多个取代。In certain embodiments of the present invention, R3 is each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C1-3 alkyl, C2-4 alkenyl, C2-4 alkynyl , C1-3 deuterated alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 deuterated alkoxy, C1-3 haloalkoxy, C1-3 hydroxyalkyl, C3-6 cycloalkyl, 3-6 membered heterocyclyl, C6-10 aryl, 5-6 membered heteroaryl, -( CH2 ) 01ORc1 , -( CH2 ) 02C (O) Rc2 , -( CH2 ) 03NHC (O) Rc3 , - ( CH2 ) 04C (O) NHRc4 , -( CH2 ) 05NRc5Rc6 , -( CH2 ) 05 wherein the amino, 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, C 1-3 deuterated alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl , C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-10 aryl or 5-6 membered heteroaryl may be further substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, 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, C 1-3 deuterated alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-10 aryl or 5-6 membered heteroaryl. The group may be substituted by one or more of C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 deuterated alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-10 aryl and 5-6 membered heteroaryl.
在本发明的某些实施方案中，Rc1、Rc2、Rc3、Rc4、Rc5、Rc6、Rc7、Rc8和Rc9各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-3烷基、C2-4烯基、C2-4炔基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3氘代烷氧基、C1-3卤代烷氧基、C1-3羟烷基、C3-6环烷基、3-6元杂环基、C6-10芳基、5-6元杂芳基，所述的氨基、C1-3烷基、C2-4烯基、C2-4炔基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3氘代烷氧基、C1-3卤代烷氧基、C1-3羟烷基、C3-6环烷基、3-6元杂环基、C6-10芳基或5-6元杂芳基任选地可以进一步被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-3烷基、C2-4烯基、C2-4炔基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3氘代烷氧基、C1-3卤代烷氧基、C1-3羟烷基、C3-6环烷基、3-6元杂环基、C6-10芳基和5-6元杂芳基中的一个或多个取代。In certain embodiments of the present invention, Rc1 , Rc2 , Rc3 , Rc4 , Rc5 , Rc6 , Rc7 , Rc8 and Rc9 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C1-3 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-3 deuterated alkyl, C1-3 haloalkyl, C1-3 alkoxy , C1-3 deuterated alkoxy, C1-3 haloalkoxy, C1-3 hydroxyalkyl, C3-6 cycloalkyl, 3-6 membered heterocyclyl, C6-10 aryl, 5-6 membered heteroaryl, wherein the amino, C1-3 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-3 deuterated alkyl, C1-3 haloalkyl, C1-3 The C 1-3 alkoxy, C 1-3 deuterated alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-10 aryl or 5-6 membered heteroaryl may optionally be further substituted with one or more of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, 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, C 1-3 deuterated alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl , C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-10 aryl and 5-6 membered heteroaryl.
在本发明的某些实施方案中，R3各自独立地选自氢、氟、甲基、三氟甲基、甲氧基或三氟甲氧基。In certain embodiments of the present invention, each R 3 is independently selected from hydrogen, fluoro, methyl, trifluoromethyl, methoxy or trifluoromethoxy.
在本发明的某些实施方案中，R4各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-3烷基、C2-4烯基、C2-4炔基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3氘代烷氧基、C1-3卤代烷氧基、C1-3羟烷基、C3-8环烷基、3-6元杂环基、C6-10芳基、5-6元杂芳基、-(CH2)p1ORd1、-(CH2)p2C(O)Rd2、-(CH2)p3NHC(O)Rd3、-(CH2)p4C(O)NHRd4、-(CH2)p5NRd5Rd6、-(CH2)p6S(O)p7Rd7、-(CH2)p8S(O)2NHRd8、-(CH2)p9NHS(O)2Rd9、-(CH2)p10S(＝O)(＝NH)Rd10，所述的氨基、C1-3烷基、C2-4烯基、C2-4炔基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3氘代烷氧基、C1-3卤代烷氧基、C1-3羟烷基、C3-8环烷基、3-6元杂环基、C6-10芳基或5-6元杂芳基任选地可以进一步被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-3烷基、C2-4烯基、C2-4炔基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3氘代烷氧基、C1-3卤代烷氧基、C1-3羟烷基、C3-6环烷基、3-6元杂环基、C6-10芳基和5-6元杂芳基中的一个或多个取代。In certain embodiments of the invention, R4 is each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C1-3 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-3 deuterated alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 deuterated alkoxy, C1-3 haloalkoxy, C1-3 hydroxyalkyl, C3-8 cycloalkyl, 3-6 membered heterocyclyl, C6-10 aryl, 5-6 membered heteroaryl, -(CH2)p1ORd1 , - ( CH2 ) p2C (O) Rd2 , -( CH2 ) p3NHC (O) Rd3 , -( CH2 ) p4C (O) NHRd4 , -( CH2 ) p5NRd5Rd6 wherein the amino, 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, C 1-3 deuterated alkoxy, C 1-3 haloalkoxy , C 1-3 hydroxyalkyl , C 3-8 cycloalkyl, 3-6 membered heterocyclyl, C 6-10 aryl or 5-6 membered heteroaryl group may be further substituted with hydrogen , deuterium, halogen , amino, hydroxyl , cyano, nitro , oxo, thioxo, C 1-3 alkoxy, C 1-3 deuterated alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 3-8 cycloalkyl, 3-6 membered heterocyclyl, C 6-10 aryl or 5-6 membered heteroaryl group may be further substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C The group may be substituted by one or more of 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, C 1-3 deuterated alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-10 aryl and 5-6 membered heteroaryl.
在本发明的某些实施方案中，R4-1选自氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-3烷基、C2-4烯基、C2-4炔基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3氘代烷氧基、C1-3卤代烷氧基、C1-3羟烷基、C3-8环烷基、3-6元杂环基、C6-10芳基、5-6元杂芳基、-(CH2)p1ORd1、-(CH2)p2C(O)Rd2、-(CH2)p3NHC(O)Rd3、-(CH2)p4C(O)NHRd4、-(CH2)p5NRd5Rd6、-(CH2)p6S(O)p7Rd7、-(CH2)p8S(O)2NHRd8、-(CH2)p9NHS(O)2Rd9、-(CH2)p10S(＝O)(＝NH)Rd10，所述的氨基、C1-3烷基、C2-4烯基、C2-4炔基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3氘代烷氧基、C1-3卤代烷氧基、C1-3羟烷基、C3-8环烷基、3-6元杂环基、C6-10芳基或5-6元杂芳基任选地可以进一步被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-3烷基、C2-4烯基、C2-4炔基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3氘代烷氧基、C1-3卤代烷氧基、C1-3羟烷基、C3-6环烷基、3-6元杂环基、C6-10芳基和5-6元杂芳基中的一个或多个取代。In certain embodiments of the present invention, R 4-1 is selected from deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, 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, C 1-3 deuterated alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 3-8 cycloalkyl , 3-6 membered heterocyclyl , C 6-10 aryl, 5-6 membered heteroaryl, -(CH 2 ) p1 OR d1 , -(CH 2 ) p2 C(O)R d2 , -(CH 2 ) p3 NHC(O)R d3 , -(CH 2 ) p4 C(O)NHR d4 , -(CH 2 ) p5 NR d5 R d6 wherein the amino, 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, C 1-3 deuterated alkoxy, C 1-3 haloalkoxy , C 1-3 hydroxyalkyl , C 3-8 cycloalkyl, 3-6 membered heterocyclyl, C 6-10 aryl or 5-6 membered heteroaryl group may be further substituted with hydrogen , deuterium, halogen , amino, hydroxyl , cyano, nitro , oxo, thioxo, C 1-3 alkoxy, C 1-3 deuterated alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 3-8 cycloalkyl, 3-6 membered heterocyclyl, C 6-10 aryl or 5-6 membered heteroaryl group may be further substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C The group may be substituted by one or more of 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, C 1-3 deuterated alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-10 aryl and 5-6 membered heteroaryl.
在本发明的某些实施方案中，Rd1、Rd2、Rd3、Rd4、Rd5、Rd6、Rd7、Rd8、Rd9和Rd10各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-3烷基、C2-4烯基、C2-4炔基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3氘代烷氧基、C1-3卤代烷氧基、C1-3羟烷基、C3-6环烷基、3-6元杂环基、C6-10芳基、5-6元杂芳基，所述的氨基、C1-3烷基、C2-4烯基、C2-4炔基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3氘代烷氧基、C1-3卤代烷氧基、C1-3羟烷基、C3-6环烷基、3-6元杂环基、C6-10芳基或5-6元杂芳基任选地可以进一步被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-3烷基、C2-4烯基、C2-4炔基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3氘代烷氧基、C1-3卤代烷氧基、C1-3羟烷基、C3-6环烷基、3-6元杂环基、C6-10芳基和5-6元杂芳基中的一个或多个取代。In certain embodiments of the invention, Rd1 , Rd2 , Rd3 , Rd4 , Rd5 , Rd6 , Rd7 , Rd8 , Rd9 and Rd10 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C1-3 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-3 deuterated alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 deuterated alkoxy, C1-3 haloalkoxy, C1-3 hydroxyalkyl, C3-6 cycloalkyl, 3-6 membered heterocyclyl, C6-10 aryl, 5-6 membered heteroaryl, wherein the amino, C1-3 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-3 deuterated alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 deuterated alkoxy, C1-3 haloalkoxy, C1-3 hydroxyalkyl, C3-6 cycloalkyl, 3-6 membered heterocyclyl, C6-10 aryl, 5-6 membered heteroaryl The C1-3 haloalkyl, C1-3 alkoxy, C1-3 deuterated alkoxy, C1-3 haloalkoxy, C1-3 hydroxyalkyl, C3-6 cycloalkyl, 3-6 membered heterocyclyl, C6-10 aryl or 5-6 membered heteroaryl may optionally be further substituted with one or more of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C1-3 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-3 deuterated alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 deuterated alkoxy, C1-3 haloalkoxy, C1-3 hydroxyalkyl, C3-6 cycloalkyl, 3-6 membered heterocyclyl, C6-10 aryl and 5-6 membered heteroaryl.
在本发明的某些实施方案中，R4-1选自CH＝CF2、一氟甲基、二氟甲基、三氟甲基、三氟甲氧基、 -SO2CH3、-COOH、-COOCH3、-CH2CF3、-CON(CH3)2、 -COCH3、 In certain embodiments of the present invention, R 4-1 is selected from CH=CF 2 , monofluoromethyl, difluoromethyl, trifluoromethyl, Trifluoromethoxy, -SO 2 CH 3 , -COOH, -COOCH 3 , -CH 2 CF 3 , -CON(CH 3 ) 2 , -COCH 3 ,
在本发明的某些实施方案中，R4选自氢、氟、甲基、氨基、羟基、 In certain embodiments of the present invention, R4 is selected from hydrogen, fluorine, methyl, amino, hydroxyl,
在本发明的某些实施方案中，R5各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-3烷基、C2-4烯基、C2-4炔基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3氘代烷氧基、C1-3卤代烷氧基、C1-3羟烷基、C3-6环烷基、3-6元杂环基、C6-10芳基和5-6元杂芳基中的一个或多个取代。In certain embodiments of the present invention, R 5 is each independently selected from one or more of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, 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, C 1-3 deuterated alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-10 aryl and 5-6 membered heteroaryl.
在本发明的某些实施方案中，R5各自独立地选自异丙基。In certain embodiments of the present invention, each R 5 is independently selected from isopropyl.
本发明还提供了一种式(I-A)所示的化合物The present invention also provides a compound represented by formula (I-A)
其中，M4、M5、M6、M7、L2、R3、R4、R4-1、x和y的定义如上所述。在某些实施方式中，所述化合物选自wherein M 4 , M 5 , M 6 , M 7 , L 2 , R 3 , R 4 , R 4-1 , x and y are as defined above. In certain embodiments, the compound is selected from
本发明还提供一种式(I-1-2)所示化合物的制备方法，包括如下步骤The present invention also provides a method for preparing the compound represented by formula (I-1-2), comprising the following steps:
在有机溶剂中，催化剂存在下，式(I-A)化合物与式(I-B)化合物发生反应，得到式(I-1-2)化合物；In an organic solvent, in the presence of a catalyst, the compound of formula (I-A) reacts with the compound of formula (I-B) to obtain a compound of formula (I-1-2);
其中，PG选自卤素、OH、OC1-6烷基；优选，OCH3；Wherein, PG is selected from halogen, OH, OC 1-6 alkyl; preferably, OCH 3 ;
M4、M5、M6、M7、L1、L2、R1、R3、R4、R4-1、x和y的定义如上所述。 M4 , M5 , M6 , M7 , L1 , L2 , R1 , R3 , R4 , R4-1 , x and y are as defined above.
在本发明某些实施方案中，所示催化剂选自CDI、HATU、二(三甲基硅基)氨基锂。In certain embodiments of the present invention, the catalyst is selected from CDI, HATU, lithium bis(trimethylsilyl)amide.
本发明还提供了一种如通式(I')所示的化合物、其立体异构体或其药学上可接受的盐：The present invention also provides a compound represented by general formula (I'), a stereoisomer thereof or a pharmaceutically acceptable salt thereof:
其中：in:
M'1选自N或CH； M'1 is selected from N or CH;
L'1选自键、-O-、-S-、-NH-、-CO-、-CONH-、C1-3亚烷基、C2-4亚烯基、C2-4亚炔基、-O-C1-3亚烷基-、-S-C1-3亚烷基-、-C1-3亚烷基-NH-、-C1-3亚烷基-C(O)NH-、-C1-3亚烷基-NHC(O)-、-C1-3亚烷基-S(O)r1-、-C1-3亚烷基-NHS(O)r2-或-C1-3亚烷基-S(O)r3NH-；所述的-NH-、-CONH-、C1-3亚烷基、C2-4亚烯基、C2-4亚炔基、-O-C1-3亚烷基-、-S-C1-3亚烷基-、-C1-3亚烷基-NH-、-C1-3亚烷基-C(O)NH-、-C1-3亚烷基-NHC(O)-、-C1-3亚烷基-S(O)r1-、-C1-3亚烷基-NHS(O)r2-或-C1-3亚烷基-S(O)r3NH-任选地被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-3烷基、C2-4烯基、C2-4炔基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3氘代烷氧基、C1-3卤代烷氧基、C1-3羟烷基、C3-6环烷基、3-6元杂环基、C6-10芳基、5-6元杂芳基中的一个或多个取代；L' 1 is selected from a bond, -O-, -S-, -NH-, -CO-, -CONH-, C 1-3 alkylene, C 2-4 alkenylene, C 2-4 alkynylene, -OC 1-3 alkylene-, -SC 1-3 alkylene-, -C 1-3 alkylene-NH-, -C 1-3 alkylene-C(O)NH-, -C 1-3 alkylene-NHC(O)-, -C 1-3 alkylene-S(O) r1 -, -C 1-3 alkylene-NHS(O) r2 - or -C 1-3 alkylene-S(O) r3 NH-; said -NH-, -CONH-, C 1-3 alkylene, C 2-4 alkenylene, C 2-4 alkynylene , -OC 1-3 alkylene-, -SC 1-3 alkylene-, -C 1-3 alkylene - NH- , -C -C 1-3 alkylene-C(O)NH-, -C 1-3 alkylene-NHC(O)-, -C 1-3 alkylene-S(O) r1 -, -C 1-3 alkylene-NHS(O) r2 -, or -C 1-3 alkylene-S(O) r3 NH- is optionally substituted with one or more of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, 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, C 1-3 deuterated alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl , C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-10 aryl, or 5-6 membered heteroaryl;
R'1独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基、5-10元杂芳基、-(CH2)m1ORa1、-(CH2)m2C(O)Ra2、-(CH2)m3NHC(O)Ra3、-(CH2)m4C(O)NHRa4、-(CH2)m5NRa5Ra6、-(CH2)m6S(O)m7Ra7、-(CH2)m8S(O)2NHRa8、-(CH2)m9NHS(O)2Ra9，所述的氨基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基任选地可以进一步被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代； R'1 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy , C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl , 3-8 membered heterocyclyl , C6-10 aryl, 5-10 membered heteroaryl, -( CH2 ) m1ORa1 , -( CH2 ) m2C ( O)Ra2, -(CH2)m3NHC(O)Ra3, -(CH2)m4C ( O ) NHRa4 , - ( CH2 ) m5NRa5Ra6 , -( CH2 ) m6 S(O) m7Ra7 , -( CH2 ) m8S (O) 2NHRa8 , -( CH2 ) m9NHS (O) 2Ra9 , the amino, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl or 5-10 membered heteroaryl may be further optionally substituted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl or 5-10 membered heteroaryl. substituted by one or more of C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl;
R'2-1和R'2-2各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基、5-10元杂芳基、-(CH2)n1ORb1、-(CH2)n2C(O)Rb2、-(CH2)n3NHC(O)Rb3、-(CH2)n4C(O)NHRb4、-(CH2)n5NRb5Rb6、-(CH2)n6S(O)n7Rb7、-(CH2)n8S(O)2NHRb8、-(CH2)n9NHS(O)2Rb9，所述的氨基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基任选地可以进一步被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代； R'2-1 and R'2-2 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl , C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, -( CH2 ) n1ORb1 , -( CH2 ) n2C (O) Rb2 , -( CH2 ) n3NHC (O) Rb3 , - ( CH2 ) n4C (O) NHRb4 , -( CH2 ) n5NRb5Rb6 wherein 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 , C 1-6 deuterated alkoxy, C 1-6 haloalkoxy , C 1-6 hydroxyalkyl , C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl may be further substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 alkyl , C 2-6 alkenyl, C 2-6 alkynyl , C The group is substituted by one or more of C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl;
R'3各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基、5-10元杂芳基、-(CH2)o1ORc1、-(CH2)o2C(O)Rc2、-(CH2)o3NHC(O)Rc3、-(CH2)o4C(O)NHRc4、-(CH2)o5NRc5Rc6、-(CH2)o6S(O)o7Rc7、-(CH2)o8S(O)2NHRc8、-(CH2)o9NHS(O)2Rc9，所述的氨基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基任选地可以进一步被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代；R' 3 is each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, -(CH 2 ) o1 OR c1 , -(CH 2 ) o2 C(O)R c2 , -(CH 2 ) o3 NHC(O)R c3 , -(CH 2 ) o4 C(O)NHR c4 , -(CH 2 ) o5 NR c5 R c6 , -(CH 2 ) o5 o6 S(O) o7 R c7 , -(CH 2 ) o8 S(O) 2 NHR c8 , -(CH 2 ) o9 NHS(O) 2 R c9 , 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl may be further optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl. substituted by one or more of C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl;
R'4-1、R'4-2、R'4-3、R'4-4和R'4-5各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基、5-10元杂芳基、-(CH2)p1ORd1、-(CH2)p2C(O)Rd2、-(CH2)p3NHC(O)Rd3、-(CH2)p4C(O)NHRd4、-(CH2)p5NRd5Rd6、-(CH2)p6S(O)p7Rd7、-(CH2)p8S(O)2NHRd8、-(CH2)p9NHS(O)2Rd9，所述的氨基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基任选地可以进一步被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代； R'4-1 , R'4-2 , R'4-3 , R'4-4 and R'4-5 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, -( CH2 ) p1ORd1 , -( CH2 ) p2C (O) Rd2 , -( CH2 ) p3NHC (O) Rd3 , - ( CH2 ) p4 C(O) NHRd4 , -( CH2 ) p5NRd5Rd6 , -( CH2 ) p6S (O) p7Rd7 , -( CH2 ) p8S (O) 2NHRd8 , - ( CH2 ) p9NHS (O) 2Rd9 , wherein the amino, C1-6 alkyl, C2-6 alkenyl , C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl or 5-10 membered heteroaryl may be further optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C1-6 alkoxy, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl or 5-10 membered heteroaryl. The alkyl group may be substituted by one or more of C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl and 5-10 membered heteroaryl;
或者，R'4-3和R'4-5连接形成3-8元杂环基，所述的3-8元杂环基任选地被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代；Alternatively, R'4-3 and R'4-5 are linked to form a 3-8 membered heterocyclic group, wherein the 3-8 membered heterocyclic group is optionally substituted by one or more of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclic group, C6-10 aryl and 5-10 membered heteroaryl;
Ra1、Ra2、Ra3、Ra4、Ra5、Ra6、Ra7、Ra8和Ra9各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基、5-10元杂芳基，所述的氨基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基任选地可以进一步被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代； Ra1 , Ra2 , Ra3 , Ra4 , Ra5 , Ra6 , Ra7 , Ra8 and Ra9 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, and the amino, C1-6 alkyl , C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl , C1-6 alkoxy , C C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl may be further optionally substituted with one or more of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl , 3-8 membered heterocyclyl , C 6-10 aryl and 5-10 membered heteroaryl;
Rb1、Rb2、Rb3、Rb4、Rb5、Rb6、Rb7、Rb8和Rb9各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基、5-10元杂芳基，所述的氨基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基任选地可以进一步被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代；R b1 , R b2 , R b3 , R b4 , R b5 , R b6 , R b7 , R b8 and R b9 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, said 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 , C C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl may be further optionally substituted with one or more of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl , 3-8 membered heterocyclyl , C 6-10 aryl and 5-10 membered heteroaryl;
Rc1、Rc2、Rc3、Rc4、Rc5、Rc6、Rc7、Rc8和Rc9各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基、5-10元杂芳基，所述的氨基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基任选地可以进一步被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代；R c1 , R c2 , R c3 , R c4 , R c5 , R c6 , R c7 , R c8 and R c9 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, said 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 , C C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl may be further optionally substituted with one or more of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl , 3-8 membered heterocyclyl , C 6-10 aryl and 5-10 membered heteroaryl;
Rd1、Rd2、Rd3、Rd4、Rd5、Rd6、Rd7、Rd8和Rd9各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基、5-10元杂芳基，所述的氨基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基任选地可以进一步被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代； Rd1 , Rd2 , Rd3, Rd4 , Rd5 , Rd6 , Rd7 , Rd8 and Rd9 are each independently selected from hydrogen, deuterium, halogen, amino , hydroxyl, cyano, nitro, oxo, thioxo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, said amino, C1-6 alkyl, C2-6 alkenyl , C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl may be further substituted with one or more of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl , 3-8 membered heterocyclyl , C 6-10 aryl and 5-10 membered heteroaryl;
z'为0、1、2、3或4；z' is 0, 1, 2, 3 or 4;
m1、m2、m3、m4、m5、m6、m8、m9各自独立地选自0、1、2、3、4、5或6；m1, m2, m3, m4, m5, m6, m8, m9 are each independently selected from 0, 1, 2, 3, 4, 5 or 6;
n1、n2、n3、n4、n5、n6、n8、n9各自独立地选自0、1、2、3、4、5或6；n1, n2, n3, n4, n5, n6, n8, n9 are each independently selected from 0, 1, 2, 3, 4, 5 or 6;
o1、o2、o3、o4、o5、o6、o8、o9各自独立地选自0、1、2、3、4、5或6；o1, o2, o3, o4, o5, o6, o8, o9 are each independently selected from 0, 1, 2, 3, 4, 5 or 6;
p1、p2、p3、p4、p5、p6、p8、p9各自独立地选自0、1、2、3、4、5或6；p1, p2, p3, p4, p5, p6, p8, p9 are each independently selected from 0, 1, 2, 3, 4, 5 or 6;
r1、r2、r3各自独立地选自0、1或2；r1, r2, r3 are each independently selected from 0, 1 or 2;
m7、n7、o7、p7各自独立地选自0、1、2或3。m7, n7, o7, p7 are each independently selected from 0, 1, 2 or 3.
在本发明的某些实施方案中，所述的式(I')所示化合物如式(I'-1)所示：In certain embodiments of the present invention, the compound represented by formula (I') is represented by formula (I'-1):
在本发明的某些实施方案中，所述的式(I')所示化合物如式(I'-2)所示：In certain embodiments of the present invention, the compound represented by formula (I') is represented by formula (I'-2):
其中：in:
环B'为3-8元杂环基；Ring B' is a 3-8 membered heterocyclic group;
R'4-7独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基；R' 4-7 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy , C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl;
x'为0、1、2、3或4。x' is 0, 1, 2, 3, or 4.
本发明还提供了一种如通式(II')所示的化合物、其立体异构体或其药学上可接受的盐：The present invention also provides a compound represented by general formula (II'), a stereoisomer thereof or a pharmaceutically acceptable salt thereof:
其中：in:
环A'选自C6-10芳基或5-10元杂芳基；Ring A' is selected from C 6-10 aryl or 5-10 membered heteroaryl;
L'1选自键、-O-、-S-、-NH-、-CO-、-CONH-、C1-3亚烷基、C2-4亚烯基、C2-4亚炔基、-O-C1-3亚烷基-、-S-C1-3亚烷基-、-C1-3亚烷基-NH-、-C1-3亚烷基-C(O)NH-、-C1-3亚烷基-NHC(O)-、-C1-3亚烷基-S(O)r1-、-C1-3亚烷基-NHS(O)r2-或-C1-3亚烷基-S(O)r3NH-；所述的-NH-、-CONH-、C1-3亚烷基、C2-4亚烯基、C2-4亚炔基、-O-C1-3亚烷基-、-S-C1-3亚烷基-、-C1-3亚烷基-NH-、-C1-3亚烷基-C(O)NH-、-C1-3亚烷基-NHC(O)-、-C1-3亚烷基-S(O)r1-、-C1-3亚烷基-NHS(O)r2-或-C1-3亚烷基-S(O)r3NH-任选地被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-3烷基、C2-4烯基、C2-4炔基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3氘代烷氧基、C1-3卤代烷氧基、C1-3羟烷基、C3-6环烷基、3-6元杂环基、C6-10芳基、5-6元杂芳基中的一个或多个取代；L' 1 is selected from a bond, -O-, -S-, -NH-, -CO-, -CONH-, C 1-3 alkylene, C 2-4 alkenylene, C 2-4 alkynylene, -OC 1-3 alkylene-, -SC 1-3 alkylene-, -C 1-3 alkylene-NH-, -C 1-3 alkylene-C(O)NH-, -C 1-3 alkylene-NHC(O)-, -C 1-3 alkylene-S(O) r1 -, -C 1-3 alkylene-NHS(O) r2 - or -C 1-3 alkylene-S(O) r3 NH-; said -NH-, -CONH-, C 1-3 alkylene, C 2-4 alkenylene, C 2-4 alkynylene , -OC 1-3 alkylene-, -SC 1-3 alkylene-, -C 1-3 alkylene - NH- , -C -C 1-3 alkylene-C(O)NH-, -C 1-3 alkylene-NHC(O)-, -C 1-3 alkylene-S(O) r1 -, -C 1-3 alkylene-NHS(O) r2 -, or -C 1-3 alkylene-S(O) r3 NH- is optionally substituted with one or more of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, 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, C 1-3 deuterated alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl , C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-10 aryl, or 5-6 membered heteroaryl;
R'1独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基、5-10元杂芳基、-(CH2)m1ORa1、-(CH2)m2C(O)Ra2、-(CH2)m3NHC(O)Ra3、-(CH2)m4C(O)NHRa4、-(CH2)m5NRa5Ra6、-(CH2)m6S(O)m7Ra7、-(CH2)m8S(O)2NHRa8、-(CH2)m9NHS(O)2Ra9，所述的氨基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基任选地可以进一步被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代； R'1 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy , C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl , 3-8 membered heterocyclyl , C6-10 aryl, 5-10 membered heteroaryl, -( CH2 ) m1ORa1 , -( CH2 ) m2C ( O)Ra2, -(CH2)m3NHC(O)Ra3, -(CH2)m4C ( O ) NHRa4 , - ( CH2 ) m5NRa5Ra6 , -( CH2 ) m6 S(O) m7Ra7 , -( CH2 ) m8S (O) 2NHRa8 , -( CH2 ) m9NHS (O) 2Ra9 , the amino, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl or 5-10 membered heteroaryl may be further optionally substituted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl or 5-10 membered heteroaryl. substituted by one or more of C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl;
R'3各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基、5-10元杂芳基、-(CH2)o1ORc1、-(CH2)o2C(O)Rc2、-(CH2)o3NHC(O)Rc3、-(CH2)o4C(O)NHRc4、-(CH2)o5NRc5Rc6、-(CH2)o6S(O)o7Rc7、-(CH2)o8S(O)2NHRc8、-(CH2)o9NHS(O)2Rc9，所述的氨基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基任选地可以进一步被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代；R' 3 is each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, -(CH 2 ) o1 OR c1 , -(CH 2 ) o2 C(O)R c2 , -(CH 2 ) o3 NHC(O)R c3 , -(CH 2 ) o4 C(O)NHR c4 , -(CH 2 ) o5 NR c5 R c6 , -(CH 2 ) o5 o6 S(O) o7 R c7 , -(CH 2 ) o8 S(O) 2 NHR c8 , -(CH 2 ) o9 NHS(O) 2 R c9 , 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl may be further optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl. substituted by one or more of C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl;
R'4-1、R'4-2、R'4-3、R'4-4和R'4-5各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基、5-10元杂芳基、-(CH2)p1ORd1、-(CH2)p2C(O)Rd2、-(CH2)p3NHC(O)Rd3、-(CH2)p4C(O)NHRd4、-(CH2)p5NRd5Rd6、-(CH2)p6S(O)p7Rd7、-(CH2)p8S(O)2NHRd8、-(CH2)p9NHS(O)2Rd9，所述的氨基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基任选地可以进一步被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代； R'4-1 , R'4-2 , R'4-3 , R'4-4 and R'4-5 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, -( CH2 ) p1ORd1 , -( CH2 ) p2C (O) Rd2 , -( CH2 ) p3NHC (O) Rd3 , - ( CH2 ) p4 C(O) NHRd4 , -( CH2 ) p5NRd5Rd6 , -( CH2 ) p6S (O) p7Rd7 , -( CH2 ) p8S (O) 2NHRd8 , - ( CH2 ) p9NHS (O) 2Rd9 , wherein the amino, C1-6 alkyl, C2-6 alkenyl , C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl or 5-10 membered heteroaryl may be further optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C1-6 alkoxy, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl or 5-10 membered heteroaryl. The alkyl group may be substituted by one or more of C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl and 5-10 membered heteroaryl;
或者，R'4-3和R'4-5连接形成3-8元杂环基，所述的3-8元杂环基任选地被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代；Alternatively, R'4-3 and R'4-5 are linked to form a 3-8 membered heterocyclic group, wherein the 3-8 membered heterocyclic group is optionally substituted by one or more of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclic group, C6-10 aryl and 5-10 membered heteroaryl;
Ra1、Ra2、Ra3、Ra4、Ra5、Ra6、Ra7、Ra8和Ra9各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基、5-10元杂芳基，所述的氨基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基任选地可以进一步被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代； Ra1 , Ra2 , Ra3 , Ra4 , Ra5 , Ra6 , Ra7 , Ra8 and Ra9 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, and the amino, C1-6 alkyl , C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl , C1-6 alkoxy , C C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl may be further optionally substituted with one or more of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl , 3-8 membered heterocyclyl , C 6-10 aryl and 5-10 membered heteroaryl;
Rc1、Rc2、Rc3、Rc4、Rc5、Rc6、Rc7、Rc8和Rc9各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基、5-10元杂芳基，所述的氨基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基任选地可以进一步被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代；R c1 , R c2 , R c3 , R c4 , R c5 , R c6 , R c7 , R c8 and R c9 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, said 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 , C C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl may be further optionally substituted with one or more of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl , 3-8 membered heterocyclyl , C 6-10 aryl and 5-10 membered heteroaryl;
Rd1、Rd2、Rd3、Rd4、Rd5、Rd6、Rd7、Rd8和Rd9各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基、5-10元杂芳基，所述的氨基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基任选地可以进一步被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代； Rd1 , Rd2 , Rd3, Rd4 , Rd5 , Rd6 , Rd7 , Rd8 and Rd9 are each independently selected from hydrogen, deuterium, halogen, amino , hydroxyl, cyano, nitro, oxo, thioxo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, said amino, C1-6 alkyl, C2-6 alkenyl , C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl may be further substituted with one or more of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl , 3-8 membered heterocyclyl , C 6-10 aryl and 5-10 membered heteroaryl;
z'为0、1、2、3或4；z' is 0, 1, 2, 3 or 4;
m1、m2、m3、m4、m5、m6、m8、m9各自独立地选自0、1、2、3、4、5或6；m1, m2, m3, m4, m5, m6, m8, m9 are each independently selected from 0, 1, 2, 3, 4, 5 or 6;
o1、o2、o3、o4、o5、o6、o8、o9各自独立地选自0、1、2、3、4、5或6；o1, o2, o3, o4, o5, o6, o8, o9 are each independently selected from 0, 1, 2, 3, 4, 5 or 6;
p1、p2、p3、p4、p5、p6、p8、p9各自独立地选自0、1、2、3、4、5或6；p1, p2, p3, p4, p5, p6, p8, p9 are each independently selected from 0, 1, 2, 3, 4, 5 or 6;
r1、r2、r3各自独立地选自0、1或2；r1, r2, r3 are each independently selected from 0, 1 or 2;
m7、o7、p7各自独立地选自0、1、2或3。m7, o7, p7 are each independently selected from 0, 1, 2 or 3.
在本发明的某些实施方案中，所述的式(II')所示的化合物如式(II'-1)所示：In certain embodiments of the present invention, the compound represented by formula (II') is represented by formula (II'-1):
在本发明的某些实施方案中，所述的式(II')所示的化合物如式(II'-2)所示：In certain embodiments of the present invention, the compound represented by formula (II') is represented by formula (II'-2):
其中：in:
环B'为3-8元杂环基；Ring B' is a 3-8 membered heterocyclic group;
R'4-7独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基；R' 4-7 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy , C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl;
x'为0、1、2、3或4。x' is 0, 1, 2, 3, or 4.
本发明还提供了一种如通式(III')所示的化合物、其立体异构体或其药学上可接受的盐：The present invention also provides a compound represented by the general formula (III'), a stereoisomer thereof or a pharmaceutically acceptable salt thereof:
其中：in:
M'1选自N或CH； M'1 is selected from N or CH;
L'1选自键、-O-、-S-、-NH-、-CO-、-CONH-、C1-3亚烷基、C2-4亚烯基、C2-4亚炔基、-O-C1-3亚烷基-、-S-C1-3亚烷基-、-C1-3亚烷基-NH-、-C1-3亚烷基-C(O)NH-、-C1-3亚烷基-NHC(O)-、-C1-3亚烷基-S(O)r1-、-C1-3亚烷基-NHS(O)r2-或-C1-3亚烷基-S(O)r3NH-；所述的-NH-、-CONH-、C1-3亚烷基、C2-4亚烯基、C2-4亚炔基、-O-C1-3亚烷基-、-S-C1-3亚烷基-、-C1-3亚烷基-NH-、-C1-3亚烷基-C(O)NH-、-C1-3亚烷基-NHC(O)-、-C1-3亚烷基-S(O)r1-、-C1-3亚烷基-NHS(O)r2-或-C1-3亚烷基-S(O)r3NH-任选地被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-3烷基、C2-4烯基、C2-4炔基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3氘代烷氧基、C1-3卤代烷氧基、C1-3羟烷基、C3-6环烷基、3-6元杂环基、C6-10芳基、5-6元杂芳基中的一个或多个取代；L' 1 is selected from a bond, -O-, -S-, -NH-, -CO-, -CONH-, C 1-3 alkylene, C 2-4 alkenylene, C 2-4 alkynylene, -OC 1-3 alkylene-, -SC 1-3 alkylene-, -C 1-3 alkylene-NH-, -C 1-3 alkylene-C(O)NH-, -C 1-3 alkylene-NHC(O)-, -C 1-3 alkylene-S(O) r1 -, -C 1-3 alkylene-NHS(O) r2 - or -C 1-3 alkylene-S(O) r3 NH-; said -NH-, -CONH-, C 1-3 alkylene, C 2-4 alkenylene, C 2-4 alkynylene , -OC 1-3 alkylene-, -SC 1-3 alkylene-, -C 1-3 alkylene - NH- , -C -C 1-3 alkylene-C(O)NH-, -C 1-3 alkylene-NHC(O)-, -C 1-3 alkylene-S(O) r1 -, -C 1-3 alkylene-NHS(O) r2 -, or -C 1-3 alkylene-S(O) r3 NH- is optionally substituted with one or more of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, 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, C 1-3 deuterated alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl , C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-10 aryl, or 5-6 membered heteroaryl;
R'1独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基、5-10元杂芳基、-(CH2)m1ORa1、-(CH2)m2C(O)Ra2、-(CH2)m3NHC(O)Ra3、-(CH2)m4C(O)NHRa4、-(CH2)m5NRa5Ra6、-(CH2)m6S(O)m7Ra7、-(CH2)m8S(O)2NHRa8、-(CH2)m9NHS(O)2Ra9，所述的氨基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基任选地可以进一步被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代； R'1 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy , C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl , 3-8 membered heterocyclyl , C6-10 aryl, 5-10 membered heteroaryl, -( CH2 ) m1ORa1 , -( CH2 ) m2C ( O)Ra2, -(CH2)m3NHC(O)Ra3, -(CH2)m4C ( O ) NHRa4 , - ( CH2 ) m5NRa5Ra6 , -( CH2 ) m6 S(O) m7Ra7 , -( CH2 ) m8S (O) 2NHRa8 , -( CH2 ) m9NHS (O) 2Ra9 , the amino, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl or 5-10 membered heteroaryl may be further optionally substituted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl or 5-10 membered heteroaryl. substituted by one or more of C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl;
R'3各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基、5-10元杂芳基、-(CH2)o1ORc1、-(CH2)o2C(O)Rc2、-(CH2)o3NHC(O)Rc3、-(CH2)o4C(O)NHRc4、-(CH2)o5NRc5Rc6、-(CH2)o6S(O)o7Rc7、-(CH2)o8S(O)2NHRc8、-(CH2)o9NHS(O)2Rc9，所述的氨基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基任选地可以进一步被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代；R' 3 is each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, -(CH 2 ) o1 OR c1 , -(CH 2 ) o2 C(O)R c2 , -(CH 2 ) o3 NHC(O)R c3 , -(CH 2 ) o4 C(O)NHR c4 , -(CH 2 ) o5 NR c5 R c6 , -(CH 2 ) o5 o6 S(O) o7 R c7 , -(CH 2 ) o8 S(O) 2 NHR c8 , -(CH 2 ) o9 NHS(O) 2 R c9 , 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl may be further optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl. substituted by one or more of C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl;
R'4-1、R'4-2、R'4-3、R'4-4、R'4-5和R'4-6各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基、5-10元杂芳基、-(CH2)p1ORd1、-(CH2)p2C(O)Rd2、-(CH2)p3NHC(O)Rd3、-(CH2)p4C(O)NHRd4、-(CH2)p5NRd5Rd6、-(CH2)p6S(O)p7Rd7、-(CH2)p8S(O)2NHRd8、-(CH2)p9NHS(O)2Rd9，所述的氨基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基任选地可以进一步被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代； R'4-1 , R'4-2 , R'4-3 , R'4-4 , R'4-5 and R'4-6 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl , C1-6 haloalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, -( CH2 ) p1ORd1 , -( CH2 ) p2C ( O) Rd2 , -( CH2 ) p3NHC (O) Rd3 d4 , -( CH2 ) p5NRd5Rd6 , -( CH2 ) p6S ( O ) p7Rd7 , -( CH2 ) p8S (O) 2NHRd8 , -( CH2 ) p9NHS ( O ) 2Rd9 , wherein the amino, C1-6 alkyl , C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl , C1-6 haloalkyl , C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl , 3-8 membered heterocyclyl , C The 6-10 membered aryl or 5-10 membered heteroaryl may be further optionally substituted with one or more of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl;
或者，R'4-3和R'4-5连接形成3-8元杂环基，所述的3-8元杂环基任选地被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代；Alternatively, R'4-3 and R'4-5 are linked to form a 3-8 membered heterocyclic group, wherein the 3-8 membered heterocyclic group is optionally substituted by one or more of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclic group, C6-10 aryl and 5-10 membered heteroaryl;
Ra1、Ra2、Ra3、Ra4、Ra5、Ra6、Ra7、Ra8和Ra9各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基、5-10元杂芳基，所述的氨基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基任选地可以进一步被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代； Ra1 , Ra2 , Ra3 , Ra4 , Ra5 , Ra6 , Ra7 , Ra8 and Ra9 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, and the amino, C1-6 alkyl , C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl , C1-6 alkoxy , C C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl may be further optionally substituted with one or more of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl , 3-8 membered heterocyclyl , C 6-10 aryl and 5-10 membered heteroaryl;
Rc1、Rc2、Rc3、Rc4、Rc5、Rc6、Rc7、Rc8和Rc9各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基、5-10元杂芳基，所述的氨基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基任选地可以进一步被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代；R c1 , R c2 , R c3 , R c4 , R c5 , R c6 , R c7 , R c8 and R c9 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, said 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 , C C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl may be further optionally substituted with one or more of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl , 3-8 membered heterocyclyl , C 6-10 aryl and 5-10 membered heteroaryl;
Rd1、Rd2、Rd3、Rd4、Rd5、Rd6、Rd7、Rd8和Rd9各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基、5-10元杂芳基，所述的氨基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基任选地可以进一步被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代； Rd1 , Rd2 , Rd3, Rd4 , Rd5 , Rd6 , Rd7 , Rd8 and Rd9 are each independently selected from hydrogen, deuterium, halogen, amino , hydroxyl, cyano, nitro, oxo, thioxo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, said amino, C1-6 alkyl, C2-6 alkenyl , C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl may be further substituted with one or more of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl , 3-8 membered heterocyclyl , C 6-10 aryl and 5-10 membered heteroaryl;
z'为0、1、2、3或4；z' is 0, 1, 2, 3 or 4;
m1、m2、m3、m4、m5、m6、m8、m9各自独立地选自0、1、2、3、4、5或6；m1, m2, m3, m4, m5, m6, m8, m9 are each independently selected from 0, 1, 2, 3, 4, 5 or 6;
o1、o2、o3、o4、o5、o6、o8、o9各自独立地选自0、1、2、3、4、5或6；o1, o2, o3, o4, o5, o6, o8, o9 are each independently selected from 0, 1, 2, 3, 4, 5 or 6;
p1、p2、p3、p4、p5、p6、p8、p9各自独立地选自0、1、2、3、4、5或6；p1, p2, p3, p4, p5, p6, p8, p9 are each independently selected from 0, 1, 2, 3, 4, 5 or 6;
r1、r2、r3各自独立地选自0、1或2；r1, r2, r3 are each independently selected from 0, 1 or 2;
m7、o7、p7各自独立地选自0、1、2或3。m7, o7, p7 are each independently selected from 0, 1, 2 or 3.
在本发明的某些实施方案中，所述的式(III')所示化合物如式(III'-1)所示：In certain embodiments of the present invention, the compound represented by formula (III') is represented by formula (III'-1):
在本发明的某些实施方案中，所述的式(III')所示化合物如式(III'-2)或所示：In certain embodiments of the present invention, the compound represented by formula (III') is represented by formula (III'-2) or:
其中：in:
环B'为3-8元杂环基；Ring B' is a 3-8 membered heterocyclic group;
R'4-7独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基；R' 4-7 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy , C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl;
x'为0、1、2、3或4。x' is 0, 1, 2, 3, or 4.
本发明还提供了一种如通式(IV')所示的化合物、其立体异构体或其药学上可接受的盐：The present invention also provides a compound represented by the general formula (IV'), a stereoisomer thereof or a pharmaceutically acceptable salt thereof:
其中：in:
环A'选自C6-10芳基或5-10元杂芳基；Ring A' is selected from C 6-10 aryl or 5-10 membered heteroaryl;
L'1选自键、-O-、-S-、-NH-、-CO-、-CONH-、C1-3亚烷基、C2-4亚烯基、C2-4亚炔基、-O-C1-3亚烷基-、-S-C1-3亚烷基-、-C1-3亚烷基-NH-、-C1-3亚烷基-C(O)NH-、-C1-3亚烷基-NHC(O)-、-C1-3亚烷基-S(O)r1-、-C1-3亚烷基-NHS(O)r2-或-C1-3亚烷基-S(O)r3NH-；所述的-NH-、-CONH-、C1-3亚烷基、C2-4亚烯基、C2-4亚炔基、-O-C1-3亚烷基-、-S-C1-3亚烷基-、-C1-3亚烷基-NH-、-C1-3亚烷基-C(O)NH-、-C1-3亚烷基-NHC(O)-、-C1-3亚烷基-S(O)r1-、-C1-3亚烷基-NHS(O)r2-或-C1-3亚烷基-S(O)r3NH-任选地被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-3烷基、C2-4烯基、C2-4炔基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3氘代烷氧基、C1-3卤代烷氧基、C1-3羟烷基、C3-6环烷基、3-6元杂环基、C6-10芳基、5-6元杂芳基中的一个或多个取代；L' 1 is selected from a bond, -O-, -S-, -NH-, -CO-, -CONH-, C 1-3 alkylene, C 2-4 alkenylene, C 2-4 alkynylene, -OC 1-3 alkylene-, -SC 1-3 alkylene-, -C 1-3 alkylene-NH-, -C 1-3 alkylene-C(O)NH-, -C 1-3 alkylene-NHC(O)-, -C 1-3 alkylene-S(O) r1 -, -C 1-3 alkylene-NHS(O) r2 - or -C 1-3 alkylene-S(O) r3 NH-; said -NH-, -CONH-, C 1-3 alkylene, C 2-4 alkenylene, C 2-4 alkynylene , -OC 1-3 alkylene-, -SC 1-3 alkylene-, -C 1-3 alkylene - NH- , -C -C 1-3 alkylene-C(O)NH-, -C 1-3 alkylene-NHC(O)-, -C 1-3 alkylene-S(O) r1 -, -C 1-3 alkylene-NHS(O) r2 -, or -C 1-3 alkylene-S(O) r3 NH- is optionally substituted with one or more of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, 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, C 1-3 deuterated alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl , C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-10 aryl, or 5-6 membered heteroaryl;
R'2-1和R'2-2各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基、5-10元杂芳基、-(CH2)n1ORb1、-(CH2)n2C(O)Rb2、-(CH2)n3NHC(O)Rb3、-(CH2)n4C(O)NHRb4、-(CH2)n5NRb5Rb6、-(CH2)n6S(O)n7Rb7、-(CH2)n8S(O)2NHRb8、-(CH2)n9NHS(O)2Rb9，所述的氨基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基任选地可以进一步被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代； R'2-1 and R'2-2 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl , C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, -( CH2 ) n1ORb1 , -( CH2 ) n2C (O) Rb2 , -( CH2 ) n3NHC (O) Rb3 , - ( CH2 ) n4C (O) NHRb4 , -( CH2 ) n5NRb5Rb6 wherein 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 , C 1-6 deuterated alkoxy, C 1-6 haloalkoxy , C 1-6 hydroxyalkyl , C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl may be further substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 alkyl , C 2-6 alkenyl, C 2-6 alkynyl , C The group is substituted by one or more of C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl;
R'3各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基、5-10元杂芳基、-(CH2)o1ORc1、-(CH2)o2C(O)Rc2、-(CH2)o3NHC(O)Rc3、-(CH2)o4C(O)NHRc4、-(CH2)o5NRc5Rc6、-(CH2)o6S(O)o7Rc7、-(CH2)o8S(O)2NHRc8、-(CH2)o9NHS(O)2Rc9，所述的氨基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基任选地可以进一步被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代；R' 3 is each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, -(CH 2 ) o1 OR c1 , -(CH 2 ) o2 C(O)R c2 , -(CH 2 ) o3 NHC(O)R c3 , -(CH 2 ) o4 C(O)NHR c4 , -(CH 2 ) o5 NR c5 R c6 , -(CH 2 ) o5 o6 S(O) o7 R c7 , -(CH 2 ) o8 S(O) 2 NHR c8 , -(CH 2 ) o9 NHS(O) 2 R c9 , 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl may be further optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl. substituted by one or more of C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl;
R'4-1、R'4-2、R'4-3、R'4-4和R'4-5各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基、5-10元杂芳基、-(CH2)p1ORd1、-(CH2)p2C(O)Rd2、-(CH2)p3NHC(O)Rd3、-(CH2)p4C(O)NHRd4、-(CH2)p5NRd5Rd6、-(CH2)p6S(O)p7Rd7、-(CH2)p8S(O)2NHRd8、-(CH2)p9NHS(O)2Rd9，所述的氨基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基任选地可以进一步被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代； R'4-1 , R'4-2 , R'4-3 , R'4-4 and R'4-5 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, -( CH2 ) p1ORd1 , -( CH2 ) p2C (O) Rd2 , -( CH2 ) p3NHC (O) Rd3 , - ( CH2 ) p4 C(O) NHRd4 , -( CH2 ) p5NRd5Rd6 , -( CH2 ) p6S ( O ) p7Rd7 , -( CH2 ) p8S (O) 2NHRd8 , -( CH2 ) p9NHS (O) 2Rd9 , wherein the amino, C1-6 alkyl, C2-6 alkenyl , C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy , C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl or 5-10 membered heteroaryl may be further optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl or 5-10 membered heteroaryl. The alkyl group may be substituted by one or more of C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl and 5-10 membered heteroaryl;
或者，R'4-3和R'4-5连接形成3-8元杂环基，所述的3-8元杂环基任选地被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代；Alternatively, R'4-3 and R'4-5 are linked to form a 3-8 membered heterocyclic group, wherein the 3-8 membered heterocyclic group is optionally substituted by one or more of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclic group, C6-10 aryl and 5-10 membered heteroaryl;
Rb1、Rb2、Rb3、Rb4、Rb5、Rb6、Rb7、Rb8和Rb9各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基、5-10元杂芳基，所述的氨基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基任选地可以进一步被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代；R b1 , R b2 , R b3 , R b4 , R b5 , R b6 , R b7 , R b8 and R b9 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, said 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 , C C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl may be further optionally substituted with one or more of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl , 3-8 membered heterocyclyl , C 6-10 aryl and 5-10 membered heteroaryl;
Rc1、Rc2、Rc3、Rc4、Rc5、Rc6、Rc7、Rc8和Rc9各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基、5-10元杂芳基，所述的氨基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基任选地可以进一步被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代；R c1 , R c2 , R c3 , R c4 , R c5 , R c6 , R c7 , R c8 and R c9 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, said 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 , C C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl may be further optionally substituted with one or more of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl , 3-8 membered heterocyclyl , C 6-10 aryl and 5-10 membered heteroaryl;
Rd1、Rd2、Rd3、Rd4、Rd5、Rd6、Rd7、Rd8和Rd9各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基、5-10元杂芳基，所述的氨基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基任选地可以进一步被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代； Rd1 , Rd2 , Rd3, Rd4 , Rd5 , Rd6 , Rd7 , Rd8 and Rd9 are each independently selected from hydrogen, deuterium, halogen, amino , hydroxyl, cyano, nitro, oxo, thioxo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, said amino, C1-6 alkyl, C2-6 alkenyl , C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl may be further substituted with one or more of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl , 3-8 membered heterocyclyl , C 6-10 aryl and 5-10 membered heteroaryl;
z'为0、1、2、3或4；z' is 0, 1, 2, 3 or 4;
n1、n2、n3、n4、n5、n6、n8、n9各自独立地选自0、1、2、3、4、5或6；n1, n2, n3, n4, n5, n6, n8, n9 are each independently selected from 0, 1, 2, 3, 4, 5 or 6;
o1、o2、o3、o4、o5、o6、o8、o9各自独立地选自0、1、2、3、4、5或6；o1, o2, o3, o4, o5, o6, o8, o9 are each independently selected from 0, 1, 2, 3, 4, 5 or 6;
p1、p2、p3、p4、p5、p6、p8、p9各自独立地选自0、1、2、3、4、5或6；p1, p2, p3, p4, p5, p6, p8, p9 are each independently selected from 0, 1, 2, 3, 4, 5 or 6;
r1、r2、r3各自独立地选自0、1或2；r1, r2, r3 are each independently selected from 0, 1 or 2;
n7、o7、p7各自独立地选自0、1、2或3。n7, o7, p7 are each independently selected from 0, 1, 2 or 3.
在本发明的某些实施方案中，所述的式(IV')所示的化合物如式(IV'-1)所示：In certain embodiments of the present invention, the compound represented by formula (IV') is represented by formula (IV'-1):
在本发明的某些实施方案中，所述的式(IV')所示的化合物如式(IV'-2)所示：In certain embodiments of the present invention, the compound represented by formula (IV') is represented by formula (IV'-2):
其中：in:
环B'为3-8元杂环基；Ring B' is a 3-8 membered heterocyclic group;
R'4-7独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基；R' 4-7 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy , C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl;
x'为0、1、2、3或4。x' is 0, 1, 2, 3, or 4.
本发明还提供了一种如通式(V')所示的化合物、其立体异构体或其药学上可接受的盐：The present invention also provides a compound represented by general formula (V'), a stereoisomer thereof or a pharmaceutically acceptable salt thereof:
其中：in:
环A'选自C6-10芳基或5-10元杂芳基；Ring A' is selected from C 6-10 aryl or 5-10 membered heteroaryl;
L'1选自键、-O-、-S-、-NH-、-CO-、-CONH-、C1-3亚烷基、C2-4亚烯基、C2-4亚炔基、-O-C1-3亚烷基-、-S-C1-3亚烷基-、-C1-3亚烷基-NH-、-C1-3亚烷基-C(O)NH-、-C1-3亚烷基-NHC(O)-、-C1-3亚烷基-S(O)r1-、-C1-3亚烷基-NHS(O)r2-或-C1-3亚烷基-S(O)r3NH-；所述的-NH-、-CONH-、C1-3亚烷基、C2-4亚烯基、C2-4亚炔基、-O-C1-3亚烷基-、-S-C1-3亚烷基-、-C1-3亚烷基-NH-、-C1-3亚烷基-C(O)NH-、-C1-3亚烷基-NHC(O)-、-C1-3亚烷基-S(O)r1-、-C1-3亚烷基-NHS(O)r2-或-C1-3亚烷基-S(O)r3NH-任选地被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-3烷基、C2-4烯基、C2-4炔基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3氘代烷氧基、C1-3卤代烷氧基、C1-3羟烷基、C3-6环烷基、3-6元杂环基、C6-10芳基、5-6元杂芳基中的一个或多个取代；L' 1 is selected from a bond, -O-, -S-, -NH-, -CO-, -CONH-, C 1-3 alkylene, C 2-4 alkenylene, C 2-4 alkynylene, -OC 1-3 alkylene-, -SC 1-3 alkylene-, -C 1-3 alkylene-NH-, -C 1-3 alkylene-C(O)NH-, -C 1-3 alkylene-NHC(O)-, -C 1-3 alkylene-S(O) r1 -, -C 1-3 alkylene-NHS(O) r2 - or -C 1-3 alkylene-S(O) r3 NH-; said -NH-, -CONH-, C 1-3 alkylene, C 2-4 alkenylene, C 2-4 alkynylene , -OC 1-3 alkylene-, -SC 1-3 alkylene-, -C 1-3 alkylene - NH- , -C -C 1-3 alkylene-C(O)NH-, -C 1-3 alkylene-NHC(O)-, -C 1-3 alkylene-S(O) r1 -, -C 1-3 alkylene-NHS(O) r2 -, or -C 1-3 alkylene-S(O) r3 NH- is optionally substituted with one or more of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, 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, C 1-3 deuterated alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl , C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-10 aryl, or 5-6 membered heteroaryl;
R'3各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基、5-10元杂芳基、-(CH2)o1ORc1、-(CH2)o2C(O)Rc2、-(CH2)o3NHC(O)Rc3、-(CH2)o4C(O)NHRc4、-(CH2)o5NRc5Rc6、-(CH2)o6S(O)o7Rc7、-(CH2)o8S(O)2NHRc8、-(CH2)o9NHS(O)2Rc9，所述的氨基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基任选地可以进一步被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代；R' 3 is each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, -(CH 2 ) o1 OR c1 , -(CH 2 ) o2 C(O)R c2 , -(CH 2 ) o3 NHC(O)R c3 , -(CH 2 ) o4 C(O)NHR c4 , -(CH 2 ) o5 NR c5 R c6 , -(CH 2 ) o5 o6 S(O) o7 R c7 , -(CH 2 ) o8 S(O) 2 NHR c8 , -(CH 2 ) o9 NHS(O) 2 R c9 , 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl may be further optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl. substituted by one or more of C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl;
R'4-1、R'4-2、R'4-3、R'4-4、R'4-5和R'4-6各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基、5-10元杂芳基、-(CH2)p1ORd1、-(CH2)p2C(O)Rd2、-(CH2)p3NHC(O)Rd3、-(CH2)p4C(O)NHRd4、-(CH2)p5NRd5Rd6、-(CH2)p6S(O)p7Rd7、-(CH2)p8S(O)2NHRd8、-(CH2)p9NHS(O)2Rd9，所述的氨基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基任选地可以进一步被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代； R'4-1 , R'4-2 , R'4-3 , R'4-4 , R'4-5 and R'4-6 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl , C1-6 haloalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, -( CH2 ) p1ORd1 , -( CH2 ) p2C ( O) Rd2 , -( CH2 ) p3NHC (O) Rd3 d4 , -( CH2 ) p5NRd5Rd6 , -( CH2 ) p6S ( O ) p7Rd7 , -( CH2 ) p8S (O) 2NHRd8 , -( CH2 ) p9NHS ( O ) 2Rd9 , wherein the amino, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl , C1-6 haloalkyl , C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl , 3-8 membered heterocyclyl , C The 6-10 membered aryl or 5-10 membered heteroaryl may be further optionally substituted with one or more of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl;
或者，R'4-3和R'4-5连接形成3-8元杂环基，所述的3-8元杂环基任选地被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代；Alternatively, R'4-3 and R'4-5 are linked to form a 3-8 membered heterocyclic group, wherein the 3-8 membered heterocyclic group is optionally substituted by one or more of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclic group, C6-10 aryl and 5-10 membered heteroaryl;
Rc1、Rc2、Rc3、Rc4、Rc5、Rc6、Rc7、Rc8和Rc9各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基、5-10元杂芳基，所述的氨基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基任选地可以进一步被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代；R c1 , R c2 , R c3 , R c4 , R c5 , R c6 , R c7 , R c8 and R c9 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, said 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 , C C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl may be further optionally substituted with one or more of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl , 3-8 membered heterocyclyl , C 6-10 aryl and 5-10 membered heteroaryl;
Rd1、Rd2、Rd3、Rd4、Rd5、Rd6、Rd7、Rd8和Rd9各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基、5-10元杂芳基，所述的氨基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基任选地可以进一步被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代； Rd1 , Rd2 , Rd3, Rd4 , Rd5 , Rd6 , Rd7 , Rd8 and Rd9 are each independently selected from hydrogen, deuterium, halogen, amino , hydroxyl, cyano, nitro, oxo, thioxo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, said amino, C1-6 alkyl, C2-6 alkenyl , C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl may be further substituted with one or more of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl , 3-8 membered heterocyclyl , C 6-10 aryl and 5-10 membered heteroaryl;
z'为0、1、2、3或4；z' is 0, 1, 2, 3 or 4;
o1、o2、o3、o4、o5、o6、o8、o9各自独立地选自0、1、2、3、4、5或6；o1, o2, o3, o4, o5, o6, o8, o9 are each independently selected from 0, 1, 2, 3, 4, 5 or 6;
p1、p2、p3、p4、p5、p6、p8、p9各自独立地选自0、1、2、3、4、5或6；p1, p2, p3, p4, p5, p6, p8, p9 are each independently selected from 0, 1, 2, 3, 4, 5 or 6;
r1、r2、r3各自独立地选自0、1或2；r1, r2, r3 are each independently selected from 0, 1 or 2;
o7、p7各自独立地选自0、1、2或3。o7 and p7 are each independently selected from 0, 1, 2 or 3.
在本发明的某些实施方案中，所述的式(V')所示的化合物如式(V'-1)所示：In certain embodiments of the present invention, the compound represented by formula (V') is represented by formula (V'-1):
在本发明的某些实施方案中，所述的式(V')所示的化合物如式(V'-2)所示：In certain embodiments of the present invention, the compound represented by formula (V') is represented by formula (V'-2):
其中：in:
环B'为3-8元杂环基；Ring B' is a 3-8 membered heterocyclic group;
R'4-7独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基；R' 4-7 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy , C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl;
x'为0、1、2、3或4。x' is 0, 1, 2, 3, or 4.
本发明还提供了一种如通式(VI')所示的化合物、其立体异构体或其药学上可接受的盐：The present invention also provides a compound represented by the general formula (VI'), a stereoisomer thereof or a pharmaceutically acceptable salt thereof:
其中：in:
M'1选自N或CH； M'1 is selected from N or CH;
L'1选自键、-O-、-S-、-NH-、-CO-、-CONH-、C1-3亚烷基、C2-4亚烯基、C2-4亚炔基、-O-C1-3亚烷基-、-S-C1-3亚烷基-、-C1-3亚烷基-NH-、-C1-3亚烷基-C(O)NH-、-C1-3亚烷基-NHC(O)-、-C1-3亚烷基-S(O)r1-、-C1-3亚烷基-NHS(O)r2-或-C1-3亚烷基-S(O)r3NH-；所述的-NH-、-CONH-、C1-3亚烷基、C2-4亚烯基、C2-4亚炔基、-O-C1-3亚烷基-、-S-C1-3亚烷基-、-C1-3亚烷基-NH-、-C1-3亚烷基-C(O)NH-、-C1-3亚烷基-NHC(O)-、-C1-3亚烷基-S(O)r1-、-C1-3亚烷基-NHS(O)r2-或-C1-3亚烷基-S(O)r3NH-任选地被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-3烷基、C2-4烯基、C2-4炔基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3氘代烷氧基、C1-3卤代烷氧基、C1-3羟烷基、C3-6环烷基、3-6元杂环基、C6-10芳基、5-6元杂芳基中的一个或多个取代；L' 1 is selected from a bond, -O-, -S-, -NH-, -CO-, -CONH-, C 1-3 alkylene, C 2-4 alkenylene, C 2-4 alkynylene, -OC 1-3 alkylene-, -SC 1-3 alkylene-, -C 1-3 alkylene-NH-, -C 1-3 alkylene-C(O)NH-, -C 1-3 alkylene-NHC(O)-, -C 1-3 alkylene-S(O) r1 -, -C 1-3 alkylene-NHS(O) r2 - or -C 1-3 alkylene-S(O) r3 NH-; said -NH-, -CONH-, C 1-3 alkylene, C 2-4 alkenylene, C 2-4 alkynylene , -OC 1-3 alkylene-, -SC 1-3 alkylene-, -C 1-3 alkylene - NH- , -C -C 1-3 alkylene-C(O)NH-, -C 1-3 alkylene-NHC(O)-, -C 1-3 alkylene-S(O) r1 -, -C 1-3 alkylene-NHS(O) r2 -, or -C 1-3 alkylene-S(O) r3 NH- is optionally substituted with one or more of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, 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, C 1-3 deuterated alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl , C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-10 aryl, or 5-6 membered heteroaryl;
R'2-1和R'2-2各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基、5-10元杂芳基、-(CH2)n1ORb1、-(CH2)n2C(O)Rb2、-(CH2)n3NHC(O)Rb3、-(CH2)n4C(O)NHRb4、-(CH2)n5NRb5Rb6、-(CH2)n6S(O)n7Rb7、-(CH2)n8S(O)2NHRb8、-(CH2)n9NHS(O)2Rb9，所述的氨基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基任选地可以进一步被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代； R'2-1 and R'2-2 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl , C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, -( CH2 ) n1ORb1 , -( CH2 ) n2C (O) Rb2 , -( CH2 ) n3NHC (O) Rb3 , - ( CH2 ) n4C (O) NHRb4 , -( CH2 ) n5NRb5Rb6 wherein 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 , C 1-6 deuterated alkoxy, C 1-6 haloalkoxy , C 1-6 hydroxyalkyl , C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl may be further substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 alkyl , C 2-6 alkenyl, C 2-6 alkynyl , C The group may be substituted by one or more of C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl;
R'3各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基、5-10元杂芳基、-(CH2)o1ORc1、-(CH2)o2C(O)Rc2、-(CH2)o3NHC(O)Rc3、-(CH2)o4C(O)NHRc4、-(CH2)o5NRc5Rc6、-(CH2)o6S(O)o7Rc7、-(CH2)o8S(O)2NHRc8、-(CH2)o9NHS(O)2Rc9，所述的氨基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基任选地可以进一步被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代；R' 3 is each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, -(CH 2 ) o1 OR c1 , -(CH 2 ) o2 C(O)R c2 , -(CH 2 ) o3 NHC(O)R c3 , -(CH 2 ) o4 C(O)NHR c4 , -(CH 2 ) o5 NR c5 R c6 , -(CH 2 ) o5 o6 S(O) o7 R c7 , -(CH 2 ) o8 S(O) 2 NHR c8 , -(CH 2 ) o9 NHS(O) 2 R c9 , 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl may be further optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl. substituted by one or more of C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl;
R'4-1、R'4-2、R'4-3、R'4-4、R'4-5和R'4-6各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基、5-10元杂芳基、-(CH2)p1ORd1、-(CH2)p2C(O)Rd2、-(CH2)p3NHC(O)Rd3、-(CH2)p4C(O)NHRd4、-(CH2)p5NRd5Rd6、-(CH2)p6S(O)p7Rd7、-(CH2)p8S(O)2NHRd8、-(CH2)p9NHS(O)2Rd9，所述的氨基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基任选地可以进一步被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代； R'4-1 , R'4-2 , R'4-3 , R'4-4 , R'4-5 and R'4-6 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl , C1-6 haloalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, -( CH2 ) p1ORd1 , -( CH2 ) p2C ( O) Rd2 , -( CH2 ) p3NHC (O) Rd3 d4 , -( CH2 ) p5NRd5Rd6 , -( CH2 ) p6S ( O ) p7Rd7 , -( CH2 ) p8S (O) 2NHRd8 , -( CH2 ) p9NHS ( O ) 2Rd9 , the amino, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl , C1-6 deuterated alkyl, C1-6 haloalkyl , C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl , C3-8 cycloalkyl , 3-8 membered heterocyclyl , C The 6-10 membered aryl or 5-10 membered heteroaryl may be further optionally substituted with one or more of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl;
或者，R'4-3和R'4-5连接形成3-8元杂环基，所述的3-8元杂环基任选地被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代；Alternatively, R'4-3 and R'4-5 are linked to form a 3-8 membered heterocyclic group, wherein the 3-8 membered heterocyclic group is optionally substituted by one or more of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclic group, C6-10 aryl and 5-10 membered heteroaryl;
Rb1、Rb2、Rb3、Rb4、Rb5、Rb6、Rb7、Rb8和Rb9各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基、5-10元杂芳基，所述的氨基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基任选地可以进一步被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代；R b1 , R b2 , R b3 , R b4 , R b5 , R b6 , R b7 , R b8 and R b9 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, said 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 , C C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl may be further optionally substituted with one or more of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl , 3-8 membered heterocyclyl , C 6-10 aryl and 5-10 membered heteroaryl;
Rc1、Rc2、Rc3、Rc4、Rc5、Rc6、Rc7、Rc8和Rc9各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基、5-10元杂芳基，所述的氨基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基任选地可以进一步被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代；R c1 , R c2 , R c3 , R c4 , R c5 , R c6 , R c7 , R c8 and R c9 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, said 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 , C C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl may be further optionally substituted with one or more of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl , 3-8 membered heterocyclyl , C 6-10 aryl and 5-10 membered heteroaryl;
Rd1、Rd2、Rd3、Rd4、Rd5、Rd6、Rd7、Rd8和Rd9各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基、5-10元杂芳基，所述的氨基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基任选地可以进一步被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代； Rd1 , Rd2 , Rd3, Rd4 , Rd5 , Rd6 , Rd7 , Rd8 and Rd9 are each independently selected from hydrogen, deuterium, halogen, amino , hydroxyl, cyano, nitro, oxo, thioxo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, said amino, C1-6 alkyl, C2-6 alkenyl , C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl may be further substituted with one or more of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl , 3-8 membered heterocyclyl , C 6-10 aryl and 5-10 membered heteroaryl;
z'为0、1、2、3或4；z' is 0, 1, 2, 3 or 4;
n1、n2、n3、n4、n5、n6、n8、n9各自独立地选自0、1、2、3、4、5或6；n1, n2, n3, n4, n5, n6, n8, n9 are each independently selected from 0, 1, 2, 3, 4, 5 or 6;
o1、o2、o3、o4、o5、o6、o8、o9各自独立地选自0、1、2、3、4、5或6；o1, o2, o3, o4, o5, o6, o8, o9 are each independently selected from 0, 1, 2, 3, 4, 5 or 6;
p1、p2、p3、p4、p5、p6、p8、p9各自独立地选自0、1、2、3、4、5或6；p1, p2, p3, p4, p5, p6, p8, p9 are each independently selected from 0, 1, 2, 3, 4, 5 or 6;
r1、r2、r3各自独立地选自0、1或2；r1, r2, r3 are each independently selected from 0, 1 or 2;
n7、o7、p7各自独立地选自0、1、2或3。n7, o7, p7 are each independently selected from 0, 1, 2 or 3.
在本发明的某些实施方案中，所述的式(VI')所示的化合物如式(VI'-1)所示：In certain embodiments of the present invention, the compound represented by formula (VI') is represented by formula (VI'-1):
在本发明的某些实施方案中，所述的式(VI')所示的化合物如式(VI'-2)所示：In certain embodiments of the present invention, the compound represented by formula (VI') is represented by formula (VI'-2):
其中：in:
环B'为3-8元杂环基；Ring B' is a 3-8 membered heterocyclic group;
R'4-7独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基；R' 4-7 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy , C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl;
x'为0、1、2、3或4。x' is 0, 1, 2, 3, or 4.
在本发明的某些实施方案中，环A'为苯基或5-6元杂芳基；优选为苯基或吡啶基。In certain embodiments of the present invention, ring A' is phenyl or 5-6 membered heteroaryl; preferably phenyl or pyridyl.
在本发明的某些实施方案中，环B'为3-8元杂环基；优选为5-6元杂环基；更优选为 In certain embodiments of the present invention, ring B' is a 3-8 membered heterocyclyl; preferably a 5-6 membered heterocyclyl; more preferably
在本发明的某些实施方案中，L'1选自键、-O-或-CH2O-。In certain embodiments of the present invention, L' 1 is selected from a bond, -O- or -CH2O- .
在本发明的某些实施方案中，R'1独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-3烷基、C2-4烯基、C2-4炔基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3氘代烷氧基、C1-3卤代烷氧基、C1-3羟烷基、C3-6环烷基、3-6元杂环基、C6-10芳基、5-6元杂芳基、-(CH2)m1ORa1、-(CH2)m2C(O)Ra2、-(CH2)m3NHC(O)Ra3、-(CH2)m4C(O)NHRa4、-(CH2)m5NRa5Ra6、-(CH2)m6S(O)m7Ra7、-(CH2)m8S(O)2NHRa8、-(CH2)m9NHS(O)2Ra9，所述的氨基、C1-3烷基、C2-4烯基、C2-4炔基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3氘代烷氧基、C1-3卤代烷氧基、C1-3羟烷基、C3-6环烷基、3-6元杂环基、C6-10芳基或5-6元杂芳基任选地可以进一步被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-3烷基、C2-4烯基、C2-4炔基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3氘代烷氧基、C1-3卤代烷氧基、C1-3羟烷基、C3-6环烷基、3-6元杂环基、C6-10芳基和5-6元杂芳基中的一个或多个取代。In certain embodiments of the present invention, R'1 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C1-3 alkyl, C2-4 alkenyl, C2-4 alkynyl , C1-3 deuterated alkyl, C1-3 haloalkyl, C1-3 alkoxy , C1-3 deuterated alkoxy, C1-3 haloalkoxy, C1-3 hydroxyalkyl, C3-6 cycloalkyl, 3-6 membered heterocyclyl, C6-10 aryl , 5-6 membered heteroaryl , -( CH2 ) m1ORa1 , -( CH2 ) m2C (O) Ra2 , -( CH2 ) m3NHC (O) Ra3 , -( CH2 ) m4C (O ) NHRa4 , -( CH2 ) m5NRa5Ra6 , -( CH2 )m6 wherein the amino, 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, C 1-3 deuterated alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl , C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-10 aryl or 5-6 membered heteroaryl may be further substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, 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, C 1-3 deuterated alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-10 aryl or 5-6 membered heteroaryl. The group may be substituted by one or more of C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 deuterated alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-10 aryl and 5-6 membered heteroaryl.
在本发明的某些实施方案中，Ra1、Ra2、Ra3、Ra4、Ra5、Ra6、Ra7、Ra8和Ra9各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-3烷基、C2-4烯基、C2-4炔基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3氘代烷氧基、C1-3卤代烷氧基、C1-3羟烷基、C3-6环烷基、3-6元杂环基、C6-10芳基、5-6元杂芳基，所述的氨基、C1-3烷基、C2-4烯基、C2-4炔基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3氘代烷氧基、C1-3卤代烷氧基、C1-3羟烷基、C3-6环烷基、3-6元杂环基、C6-10芳基或5-6元杂芳基任选地可以进一步被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-3烷基、C2-4烯基、C2-4炔基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3氘代烷氧基、C1-3卤代烷氧基、C1-3羟烷基、C3-6环烷基、3-6元杂环基、C6-10芳基和5-6元杂芳基中的一个或多个取代。In certain embodiments of the present invention, Ra1 , Ra2 , Ra3 , Ra4 , Ra5 , Ra6 , Ra7 , Ra8 and Ra9 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C1-3 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-3 deuterated alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 deuterated alkoxy, C1-3 haloalkoxy, C1-3 hydroxyalkyl, C3-6 cycloalkyl, 3-6 membered heterocyclyl, C6-10 aryl, 5-6 membered heteroaryl, wherein the amino, C1-3 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-3 deuterated alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 deuterated alkoxy, C1-3 haloalkoxy, C1-3 hydroxyalkyl, C3-6 cycloalkyl, 3-6 membered heterocyclyl, C6-10 aryl, 5-6 membered heteroaryl The C 1-3 alkoxy, C 1-3 deuterated alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-10 aryl or 5-6 membered heteroaryl may optionally be further substituted with one or more of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, 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, C 1-3 deuterated alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl , C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-10 aryl and 5-6 membered heteroaryl.
在本发明的某些实施方案中，R'1选自环丙基、异丙基、 In certain embodiments of the present invention, R'1 is selected from cyclopropyl, isopropyl,
在本发明的某些实施方案中，R'2-1和R'2-2各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-3烷基、C2-4烯基、C2-4炔基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3氘代烷氧基、C1-3卤代烷氧基、C1-3羟烷基、C3-6环烷基、3-6元杂环基、C6-10芳基、5-6元杂芳基、-(CH2)n1ORb1、-(CH2)n2C(O)Rb2、-(CH2)n3NHC(O)Rb3、-(CH2)n4C(O)NHRb4、-(CH2)n5NRb5Rb6、-(CH2)n6S(O)n7Rb7、-(CH2)n8S(O)2NHRb8、-(CH2)n9NHS(O)2Rb9，所述的氨基、C1-3烷基、C2-4烯基、C2-4炔基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3氘代烷氧基、C1-3卤代烷氧基、C1-3羟烷基、C3-6环烷基、3-6元杂环基、C6-10芳基或5-6元杂芳基任选地可以进一步被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-3烷基、C2-4烯基、C2-4炔基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3氘代烷氧基、C1-3卤代烷氧基、C1-3羟烷基、C3-6环烷基、3-6元杂环基、C6-10芳基和5-6元杂芳基中的一个或多个取代。In certain embodiments of the present invention, R'2-1 and R'2-2 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C1-3 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-3 deuterated alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 deuterated alkoxy, C1-3 haloalkoxy, C1-3 hydroxyalkyl, C3-6 cycloalkyl, 3-6 membered heterocyclyl, C6-10 aryl, 5-6 membered heteroaryl, -( CH2 ) n1ORb1 , -( CH2 ) n2C (O) Rb2 , -( CH2 ) n3NHC (O) Rb3 , - ( CH2) n4C (O) NHRb4 , -( CH2 ) n5NRb5 R b6 , -(CH 2 ) n6 S(O) n7 R b7 , -(CH 2 ) n8 S(O) 2 NHR b8 , -(CH 2 ) n9 NHS(O) 2 R b9 , the amino, 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, C 1-3 deuterated alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-10 aryl or 5-6 membered heteroaryl may be further optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C The group may be substituted by one or more of C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 deuterated alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-10 aryl and 5-6 membered heteroaryl.
在本发明的某些实施方案中，Rb1、Rb2、Rb3、Rb4、Rb5、Rb6、Rb7、Rb8和Rb9各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-3烷基、C2-4烯基、C2-4炔基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3氘代烷氧基、C1-3卤代烷氧基、C1-3羟烷基、C3-6环烷基、3-6元杂环基、C6-10芳基、5-6元杂芳基，所述的氨基、C1-3烷基、C2-4烯基、C2-4炔基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3氘代烷氧基、C1-3卤代烷氧基、C1-3羟烷基、C3-6环烷基、3-6元杂环基、C6-10芳基或5-6元杂芳基任选地可以进一步被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-3烷基、C2-4烯基、C2-4炔基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3氘代烷氧基、C1-3卤代烷氧基、C1-3羟烷基、C3-6环烷基、3-6元杂环基、C6-10芳基和5-6元杂芳基中的一个或多个取代。In certain embodiments of the present invention, R b1 , R b2 , R b3 , R b4 , R b5 , R b6 , R b7 , R b8 and R b9 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, 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, C 1-3 deuterated alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-10 aryl, 5-6 membered heteroaryl, wherein the amino, 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, C 1-3 deuterated alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-10 aryl, 5-6 membered heteroaryl The C 1-3 alkoxy, C 1-3 deuterated alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-10 aryl or 5-6 membered heteroaryl may optionally be further substituted with one or more of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, 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, C 1-3 deuterated alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl , C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-10 aryl and 5-6 membered heteroaryl.
在本发明的某些实施方案中，R'2-1选自 In certain embodiments of the present invention, R'2-1 is selected from
在本发明的某些实施方案中，R'2-2选自氢。In certain embodiments of the present invention, R'2-2 is selected from hydrogen.
在本发明的某些实施方案中，R'3各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-3烷基、C2-4烯基、C2-4炔基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3氘代烷氧基、C1-3卤代烷氧基、C1-3羟烷基、C3-6环烷基、3-6元杂环基、C6-10芳基、5-6元杂芳基、-(CH2)o1ORc1、-(CH2)o2C(O)Rc2、-(CH2)o3NHC(O)Rc3、-(CH2)o4C(O)NHRc4、-(CH2)o5NRc5Rc6、-(CH2)o6S(O)o7Rc7、-(CH2)o8S(O)2NHRc8、-(CH2)o9NHS(O)2Rc9，所述的氨基、C1-3烷基、C2-4烯基、C2-4炔基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3氘代烷氧基、C1-3卤代烷氧基、C1-3羟烷基、C3-6环烷基、3-6元杂环基、C6-10芳基或5-6元杂芳基任选地可以进一步被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-3烷基、C2-4烯基、C2-4炔基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3氘代烷氧基、C1-3卤代烷氧基、C1-3羟烷基、C3-6环烷基、3-6元杂环基、C6-10芳基和5-6元杂芳基中的一个或多个取代。In certain embodiments of the present invention, R'3 is each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C1-3 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-3 deuterated alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 deuterated alkoxy , C1-3 haloalkoxy, C1-3 hydroxyalkyl, C3-6 cycloalkyl, 3-6 membered heterocyclyl, C6-10 aryl, 5-6 membered heteroaryl, -( CH2 ) o1ORc1 , -( CH2 ) o2C(O)Rc2 , -( CH2 ) o3NHC (O) Rc3 , - ( CH2 ) o4C (O) NHRc4 , -( CH2 ) o5NRc5Rc6 , -(CH wherein the amino , 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, C 1-3 deuterated alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-10 aryl or 5-6 membered heteroaryl may be further substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, 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, C 1-3 deuterated alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-10 aryl or 5-6 membered heteroaryl. The group may be substituted by one or more of C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 deuterated alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-10 aryl and 5-6 membered heteroaryl.
在本发明的某些实施方案中，Rc1、Rc2、Rc3、Rc4、Rc5、Rc6、Rc7、Rc8和Rc9各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-3烷基、C2-4烯基、C2-4炔基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3氘代烷氧基、C1-3卤代烷氧基、C1-3羟烷基、C3-6环烷基、3-6元杂环基、C6-10芳基、5-6元杂芳基，所述的氨基、C1-3烷基、C2-4烯基、C2-4炔基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3氘代烷氧基、C1-3卤代烷氧基、C1-3羟烷基、C3-6环烷基、3-6元杂环基、C6-10芳基或5-6元杂芳基任选地可以进一步被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-3烷基、C2-4烯基、C2-4炔基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3氘代烷氧基、C1-3卤代烷氧基、C1-3羟烷基、C3-6环烷基、3-6元杂环基、C6-10芳基和5-6元杂芳基中的一个或多个取代。In certain embodiments of the present invention, Rc1 , Rc2 , Rc3 , Rc4 , Rc5 , Rc6 , Rc7 , Rc8 and Rc9 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C1-3 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-3 deuterated alkyl, C1-3 haloalkyl, C1-3 alkoxy , C1-3 deuterated alkoxy, C1-3 haloalkoxy, C1-3 hydroxyalkyl, C3-6 cycloalkyl, 3-6 membered heterocyclyl, C6-10 aryl, 5-6 membered heteroaryl, wherein the amino, C1-3 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-3 deuterated alkyl, C1-3 haloalkyl, C1-3 The C 1-3 alkoxy, C 1-3 deuterated alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-10 aryl or 5-6 membered heteroaryl may optionally be further substituted with one or more of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, 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, C 1-3 deuterated alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl , C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-10 aryl and 5-6 membered heteroaryl.
在本发明的某些实施方案中，R'3各自独立地选自氟、甲基、甲氧基、三氟甲氧基或三氟甲基。In certain embodiments of the present invention, R'3 is each independently selected from fluoro, methyl, methoxy, trifluoromethoxy or trifluoromethyl.
在本发明的某些实施方案中，R'4-1、R'4-2、R'4-3、R'4-4、R'4-5、R'4-6或R'4-7各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-3烷基、C2-4烯基、C2-4炔基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3氘代烷氧基、C1-3卤代烷氧基、C1-3羟烷基、C3-8环烷基、3-6元杂环基、C6-10芳基、5-6元杂芳基、-(CH2)p1ORd1、-(CH2)p2C(O)Rd2、-(CH2)p3NHC(O)Rd3、-(CH2)p4C(O)NHRd4、-(CH2)p5NRd5Rd6、-(CH2)p6S(O)p7Rd7、-(CH2)p8S(O)2NHRd8、-(CH2)p9NHS(O)2Rd9、-(CH2)p10S(＝O)(＝NH)Rd10，所述的氨基、C1-3烷基、C2-4烯基、C2-4炔基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3氘代烷氧基、C1-3卤代烷氧基、C1-3羟烷基、C3-8环烷基、3-6元杂环基、C6-10芳基或5-6元杂芳基任选地可以进一步被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-3烷基、C2-4烯基、C2-4炔基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3氘代烷氧基、C1-3卤代烷氧基、C1-3羟烷基、C3-6环烷基、3-6元杂环基、C6-10芳基和5-6元杂芳基中的一个或多个取代。In certain embodiments of the invention, R'4-1 , R'4-2 , R'4-3 , R'4-4 , R'4-5 , R'4-6 or R'4-7 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C1-3 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-3 deuterated alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 deuterated alkoxy, C1-3 haloalkoxy, C1-3 hydroxyalkyl, C3-8 cycloalkyl, 3-6 membered heterocyclyl, C6-10 aryl, 5-6 membered heteroaryl , -( CH2 ) p1ORd1 , -( CH2 ) p2C (O) Rd2 , -( CH2 ) p3 NHC(O) Rd3 , -( CH2 ) p4 , C(O) NHRd4 , -( CH2 ) p5 , NRd5Rd6 , -( CH2 ) p6 , S(O) p7Rd7 , -( CH2 ) p8 , S (O) 2NHRd8 , -( CH2 ) p9 , NHS(O) 2Rd9 , -( CH2 ) p10 , S(=O)(=NH) Rd10 , wherein the amino, C1-3 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-3 deuterated alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 deuterated alkoxy, C1-3 haloalkoxy, C1-3 hydroxyalkyl, C3-8 cycloalkyl, 3-6 membered heterocyclyl, C The 6-10 membered aryl or 5-6 membered heteroaryl may optionally be further substituted with one or more of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, 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, C 1-3 deuterated alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-10 aryl and 5-6 membered heteroaryl.
在本发明的某些实施方案中，Rd1、Rd2、Rd3、Rd4、Rd5、Rd6、Rd7、Rd8、Rd9和Rd10各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-3烷基、C2-4烯基、C2-4炔基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3氘代烷氧基、C1-3卤代烷氧基、C1-3羟烷基、C3-6环烷基、3-6元杂环基、C6-10芳基、5-6元杂芳基，所述的氨基、C1-3烷基、C2-4烯基、C2-4炔基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3氘代烷氧基、C1-3卤代烷氧基、C1-3羟烷基、C3-6环烷基、3-6元杂环基、C6-10芳基或5-6元杂芳基任选地可以进一步被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-3烷基、C2-4烯基、C2-4炔基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3氘代烷氧基、C1-3卤代烷氧基、C1-3羟烷基、C3-6环烷基、3-6元杂环基、C6-10芳基和5-6元杂芳基中的一个或多个取代。In certain embodiments of the invention, Rd1 , Rd2 , Rd3 , Rd4 , Rd5 , Rd6 , Rd7 , Rd8 , Rd9 and Rd10 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C1-3 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-3 deuterated alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 deuterated alkoxy, C1-3 haloalkoxy, C1-3 hydroxyalkyl, C3-6 cycloalkyl, 3-6 membered heterocyclyl, C6-10 aryl, 5-6 membered heteroaryl, wherein the amino, C1-3 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-3 deuterated alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 deuterated alkoxy, C1-3 haloalkoxy, C1-3 hydroxyalkyl, C3-6 cycloalkyl, 3-6 membered heterocyclyl, C6-10 aryl, 5-6 membered heteroaryl The C1-3 haloalkyl, C1-3 alkoxy, C1-3 deuterated alkoxy, C1-3 haloalkoxy, C1-3 hydroxyalkyl, C3-6 cycloalkyl, 3-6 membered heterocyclyl, C6-10 aryl or 5-6 membered heteroaryl may be further substituted with one or more of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C1-3 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-3 deuterated alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 deuterated alkoxy, C1-3 haloalkoxy, C1-3 hydroxyalkyl, C3-6 cycloalkyl, 3-6 membered heterocyclyl, C6-10 aryl and 5-6 membered heteroaryl.
在本发明的某些实施方案中，R'4-1独立地选自甲基、 In certain embodiments of the present invention, R'4-1 is independently selected from methyl,
在本发明的某些实施方案中，R'4-2独立地选自氢。In certain embodiments of the present invention, R'4-2 is independently selected from hydrogen.
在本发明的某些实施方案中，R'4-3独立地选自甲基或-CD3。In certain embodiments of the present invention, R'4-3 is independently selected from methyl or -CD3 .
在本发明的某些实施方案中，R'4-4独立地选自氢。In certain embodiments of the present invention, R'4-4 is independently selected from hydrogen.
在本发明的某些实施方案中，R'4-5独立地选自氢。In certain embodiments of the present invention, R'4-5 is independently selected from hydrogen.
在本发明的某些实施方案中，R'4-3和R'4-5连接形成 In certain embodiments of the present invention, R'4-3 and R'4-5 are linked to form
在本发明的某些实施方案中，R'4-6独立地选自三氟甲基。In certain embodiments of the present invention, R'4-6 is independently selected from trifluoromethyl.
在本发明的某些实施方案中，R'4-7独立地选自氢、甲基或氟。In certain embodiments of the present invention, R'4-7 is independently selected from hydrogen, methyl or fluoro.
本发明还提供了一种如通式(I”)所示的化合物、其立体异构体或其药学上可接受的盐：The present invention also provides a compound represented by general formula (I"), a stereoisomer thereof or a pharmaceutically acceptable salt thereof:
其中，in,
M1”选自N或CR3-3”；M 1 ” is selected from N or CR 3-3 ”;
L1”选自键、-O-、-S-、-NH-、-CO-、-CONH-、C1-3亚烷基、C2-4亚烯基、C2-4亚炔基、-O-C1-3亚烷基-、-S-C1-3亚烷基-、-C1-3亚烷基-NH-、-C1-3亚烷基-C(O)NH-、-C1-3亚烷基-NHC(O)-、-C1-3亚烷基-S(O)r1-、-C1-3亚烷基-NHS(O)r2-或-C1-3亚烷基-S(O)r3NH-；所述的-NH-、-CONH-、C1-3亚烷基、C2-4亚烯基、C2-4亚炔基、-O-C1-3亚烷基-、-S-C1-3亚烷基-、-C1-3亚烷基-NH-、-C1-3亚烷基-C(O)NH-、-C1-3亚烷基-NHC(O)-、-C1-3亚烷基-S(O)r1-、-C1-3亚烷基-NHS(O)r2-或-C1-3亚烷基-S(O)r3NH-任选地被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-3烷基、C2-4烯基、C2-4炔基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3氘代烷氧基、C1-3卤代烷氧基、C1-3羟烷基、C3-6环烷基、3-6元杂环基、C6-10芳基、5-6元杂芳基中的一个或多个取代；L 1 "is selected from a bond, -O-, -S-, -NH-, -CO-, -CONH-, C 1-3 alkylene, C 2-4 alkenylene, C 2-4 alkynylene, -OC 1-3 alkylene-, -SC 1-3 alkylene-, -C 1-3 alkylene-NH-, -C 1-3 alkylene-C(O)NH-, -C 1-3 alkylene-NHC(O)-, -C 1-3 alkylene-S(O) r1 -, -C 1-3 alkylene-NHS(O) r2 - or -C 1-3 alkylene-S(O) r3 NH-; said -NH-, -CONH-, C 1-3 alkylene, C 2-4 alkenylene, C 2-4 alkynylene, -OC 1-3 alkylene-, -SC 1-3 alkylene-, -C 1-3 alkylene - NH-, -C -C 1-3 alkylene-C(O)NH-, -C 1-3 alkylene-NHC(O)-, -C 1-3 alkylene-S(O) r1 -, -C 1-3 alkylene-NHS(O) r2 -, or -C 1-3 alkylene-S(O) r3 NH- is optionally substituted with one or more of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, 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, C 1-3 deuterated alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl , C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-10 aryl, or 5-6 membered heteroaryl;
R1”独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基、5-10元杂芳基、-(CH2)m1ORa1、-(CH2)m2C(O)Ra2、-(CH2)m3NHC(O)Ra3、-(CH2)m4C(O)NHRa4、-(CH2)m5NRa5Ra6、-(CH2)m6S(O)m7Ra7、-(CH2)m8S(O)2NHRa8、-(CH2)m9NHS(O)2Ra9，所述的氨基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基任选地可以进一步被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代；R 1 "is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, -(CH 2 ) m1 OR a1 , -(CH 2 ) m2 C(O)R a2 , -(CH 2 ) m3 NHC(O)R a3 , -(CH 2 ) m4 C(O)NHR a4 , -(CH 2 ) m5 NR a5 R a6 , -(CH 2 ) m5 m6 S(O) m7 R a7 , -(CH 2 ) m8 S(O) 2 NHR a8 , -(CH 2 ) m9 NHS(O) 2 R a9 , wherein 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl may be further optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl. substituted by one or more of C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl;
R2-1”和R2-2”各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基、5-10元杂芳基、-(CH2)n1ORb1、-(CH2)n2C(O)Rb2、-(CH2)n3NHC(O)Rb3、-(CH2)n4C(O)NHRb4、-(CH2)n5NRb5Rb6、-(CH2)n6S(O)n7Rb7、-(CH2)n8S(O)2NHRb8、-(CH2)n9NHS(O)2Rb9，所述的氨基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基任选地可以进一步被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代；R 2-1 ″ and R 2-2 ″ are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl , 3-8 membered heterocyclyl , C 6-10 aryl, 5-10 membered heteroaryl, -(CH 2 ) n1 OR b1 , -(CH 2 ) n2 C(O)R b2 , -(CH 2 ) n3 NHC(O)R b3 , -(CH 2 ) n4 C(O)NHR b4 , -(CH 2 ) n5 NR b5 R b6 , -( CH2 ) n6S (O) n7Rb7 , -( CH2 ) n8S (O) 2NHRb8 , -( CH2 ) n9NHS (O) 2Rb9 , the amino, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl , C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl or 5-10 membered heteroaryl may be further optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C The group may be substituted by one or more of C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl;
R3-1”和R3-2”各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基、5-10元杂芳基、-(CH2)o1ORc1、-(CH2)o2C(O)Rc2、-(CH2)o3NHC(O)Rc3、-(CH2)o4C(O)NHRc4、-(CH2)o5NRc5Rc6、-(CH2)o6S(O)o7Rc7、-(CH2)o8S(O)2NHRc8、-(CH2)o9NHS(O)2Rc9，所述的氨基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基任选地可以进一步被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代；R 3-1 " and R 3-2 " are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl , 3-8 membered heterocyclyl , C 6-10 aryl, 5-10 membered heteroaryl, -(CH 2 ) o1 OR c1 , -(CH 2 ) o2 C(O)R c2 , -(CH 2 ) o3 NHC(O)R c3 , -(CH 2 ) o4 C(O)NHR c4 , -(CH 2 ) o5 NR c5 R c6 , -( CH2 ) o6S (O) o7Rc7 , -( CH2 ) o8S (O) 2NHRc8 , -( CH2 ) o9NHS (O) 2Rc9 , the amino, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl , C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl or 5-10 membered heteroaryl may be further optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C The group may be substituted by one or more of C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl;
R3-3”选自氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基、5-10元杂芳基、-(CH2)o1ORc1、-(CH2)o2C(O)Rc2、-(CH2)o3NHC(O)Rc3、-(CH2)o4C(O)NHRc4、-(CH2)o5NRc5Rc6、-(CH2)o6S(O)o7Rc7、-(CH2)o8S(O)2NHRc8、-(CH2)o9NHS(O)2Rc9，所述的氨基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基任选地可以进一步被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代；R 3-3 "is selected from deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, -(CH 2 ) o1 OR c1 , -(CH 2 ) o2 C(O)R c2 , -(CH 2 ) o3 NHC(O)R c3 , -(CH 2 ) o4 C(O)NHR c4 , -( CH 2 ) o5 NR c5 R c6 , -(CH 2 ) o6 S(O) o7Rc7 , -( CH2 ) o8S (O) 2NHRc8 , -( CH2 ) o9NHS (O) 2Rc9 , the amino, C1-6 alkyl, C2-6 alkenyl , C2-6 alkynyl, C1-6 deuterated alkyl , C1-6 haloalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl or 5-10 membered heteroaryl may be further optionally substituted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl or 5-10 membered heteroaryl. substituted by one or more of C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl;
R4-1”和R4-2”各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基、5-10元杂芳基、-(CHRd10)p1ORd1、-(CHRd10)p2C(O)Rd2、-(CHRd10)p3NHC(O)Rd3、-(CHRd10)p4C(O)NHRd4、-(CHRd10)p5NRd5Rd6、-(CHRd10)p6S(O)p7Rd7、-(CHRd10)p8S(O)2NHRd8、-(CHRd10)p9NHS(O)2Rd9，所述的氨基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基任选地可以进一步被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代；R 4-1 ″ and R 4-2 ″ are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl , 3-8 membered heterocyclyl , C 6-10 aryl, 5-10 membered heteroaryl, -(CHR d10 ) p1 OR d1 , -(CHR d10 ) p2 C(O)R d2 , -(CHR d10 ) p3 NHC(O)R d3 , -(CHR d10 ) p4 C(O)NHR d4 d10 , -(CHR d10 ) p5 NR d5 R d6 , -(CHR d10 ) p6 S(O) p7 R d7 , -(CHR d10 ) p8 S(O) 2 NHR d8 , -(CHR d10 ) p9 NHS(O) 2 R d9 , 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl , C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C The 6-10 membered aryl or 5-10 membered heteroaryl may be further optionally substituted with one or more of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl;
优选地，R4-1”和R4-2”各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基、5-10元杂芳基、-(CH2)p1ORd1、-(CH2)p2C(O)Rd2、-(CH2)p3NHC(O)Rd3、-(CH2)p4C(O)NHRd4、-(CH2)p5NRd5Rd6、-(CH2)p6S(O)p7Rd7、-(CH2)p8S(O)2NHRd8、-(CH2)p9NHS(O)2Rd9，所述的氨基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基任选地可以进一步被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代；Preferably, R 4-1 "and R 4-2 "are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl , 3-8 membered heterocyclyl , C 6-10 aryl, 5-10 membered heteroaryl, -(CH 2 ) p1 OR d1 , -(CH 2 ) p2 C(O)R d2 , -(CH 2 ) p3 NHC(O)R d3 , -(CH 2 ) p4 C(O)NHR d4 , -(CH 2 ) p4 p5 NR d5 R d6 , -(CH 2 ) p6 S(O) p7 R d7 , -(CH 2 ) p8 S(O) 2 NHR d8 , -(CH 2 ) p9 NHS(O) 2 R d9 , 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl may be further optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C 1-6 alkyl, C 2-6 alkenyl, C The alkyl group may be substituted by one or more of C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl , C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl;
R5”选自氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基、5-10元杂芳基、-(CH2)q1ORe1、-(CH2)q2C(O)Re2、-(CH2)q3NHC(O)Re3、-(CH2)q4C(O)NHRe4、-(CH2)q5NRe5Re6、-(CH2)q6S(O)q7Re7、-(CH2)q8S(O)2NHRe8、-(CH2)q9NHS(O)2Re9，所述的氨基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基任选地可以进一步被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代；R 5 ″ is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, -(CH 2 ) q1 OR e1 , -(CH 2 ) q2 C(O)R e2 , -(CH 2 ) q3 NHC(O)R e3 , -(CH 2 ) q4 C(O)NHR e4 , -(CH 2 ) q5 NR e5 R e6 , -(CH 2 wherein 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl may be further substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl. substituted by one or more of C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl;
Ra1、Ra2、Ra3、Ra4、Ra5、Ra6、Ra7、Ra8和Ra9各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基、5-10元杂芳基，所述的氨基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基任选地可以进一步被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代； Ra1 , Ra2 , Ra3 , Ra4 , Ra5 , Ra6 , Ra7 , Ra8 and Ra9 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, and the amino, C1-6 alkyl , C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl , C1-6 alkoxy , C C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl may be further optionally substituted with one or more of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl , 3-8 membered heterocyclyl , C 6-10 aryl and 5-10 membered heteroaryl;
Rb1、Rb2、Rb3、Rb4、Rb5、Rb6、Rb7、Rb8和Rb9各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基、5-10元杂芳基，所述的氨基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基任选地可以进一步被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代；R b1 , R b2 , R b3 , R b4 , R b5 , R b6 , R b7 , R b8 and R b9 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, said 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 , C C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl may be further optionally substituted with one or more of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl , 3-8 membered heterocyclyl , C 6-10 aryl and 5-10 membered heteroaryl;
Rc1、Rc2、Rc3、Rc4、Rc5、Rc6、Rc7、Rc8和Rc9各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基、5-10元杂芳基，所述的氨基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基任选地可以进一步被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代；R c1 , R c2 , R c3 , R c4 , R c5 , R c6 , R c7 , R c8 and R c9 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, said 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 , C C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl may be further optionally substituted with one or more of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl , 3-8 membered heterocyclyl , C 6-10 aryl and 5-10 membered heteroaryl;
Rd1、Rd2、Rd3、Rd4、Rd5、Rd6、Rd7、Rd8、Rd9和Rd10各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基、5-10元杂芳基，所述的氨基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基任选地可以进一步被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代； Rd1 , Rd2 , Rd3, Rd4 , Rd5 , Rd6 , Rd7 , Rd8 , Rd9 and Rd10 are each independently selected from hydrogen, deuterium , halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, wherein the amino, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy , C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl may be further optionally substituted with one or more of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl;
Re1、Re2、Re3、Re4、Re5、Re6、Re7、Re8和Re9各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基、5-10元杂芳基，所述的氨基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基任选地可以进一步被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代； Re1 , Re2 , Re3 , Re4 , Re5 , Re6 , Re7 , Re8 and Re9 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, said amino , C1-6 alkyl , C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl , C1-6 alkoxy , C C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl may be further optionally substituted with one or more of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl , 3-8 membered heterocyclyl , C 6-10 aryl and 5-10 membered heteroaryl;
x”为0、1、2、3、4或5；x” is 0, 1, 2, 3, 4, or 5;
m1、m2、m3、m4、m5、m6、m8、m9各自独立地选自0、1、2、3、4、5或6；m1, m2, m3, m4, m5, m6, m8, m9 are each independently selected from 0, 1, 2, 3, 4, 5 or 6;
n1、n2、n3、n4、n5、n6、n8、n9各自独立地选自0、1、2、3、4、5或6；n1, n2, n3, n4, n5, n6, n8, n9 are each independently selected from 0, 1, 2, 3, 4, 5 or 6;
o1、o2、o3、o4、o5、o6、o8、o9各自独立地选自0、1、2、3、4、5或6；o1, o2, o3, o4, o5, o6, o8, o9 are each independently selected from 0, 1, 2, 3, 4, 5 or 6;
p1、p2、p3、p4、p5、p6、p8、p9各自独立地选自0、1、2、3、4、5或6；p1, p2, p3, p4, p5, p6, p8, p9 are each independently selected from 0, 1, 2, 3, 4, 5 or 6;
q1、q2、q3、q4、q5、q6、q8、q9各自独立地选自0、1、2、3、4、5或6；q1, q2, q3, q4, q5, q6, q8, q9 are each independently selected from 0, 1, 2, 3, 4, 5 or 6;
r1、r2、r3各自独立地选自0、1或2；r1, r2, r3 are each independently selected from 0, 1 or 2;
m7、n7、o7、p7、q7各自独立地选自0、1、2或3。m7, n7, o7, p7, q7 are each independently selected from 0, 1, 2 or 3.
在本发明的某些实施方案中，所述的化合物如式(I”-1)所示：In certain embodiments of the present invention, the compound is as shown in formula (I"-1):
在本发明的某些实施方案中，所述的化合物如式(I”-2)所示：In certain embodiments of the present invention, the compound is as shown in formula (I"-2):
本发明还提供了一种如通式(II”)所示的化合物、其立体异构体或其药学上可接受的盐：The present invention also provides a compound represented by general formula (II"), a stereoisomer thereof or a pharmaceutically acceptable salt thereof:
其中，in,
M2”选自N、CH或CR3-3”；M 2 ″ is selected from N, CH or CR 3-3 ″;
L1”选自键、-O-、-S-、-NH-、-CO-、-CONH-、C1-3亚烷基、C2-4亚烯基、C2-4亚炔基、-O-C1-3亚烷基-、-S-C1-3亚烷基-、-C1-3亚烷基-NH-、-C1-3亚烷基-C(O)NH-、-C1-3亚烷基-NHC(O)-、-C1-3亚烷基-S(O)r1-、-C1-3亚烷基-NHS(O)r2-或-C1-3亚烷基-S(O)r3NH-；所述的-NH-、-CONH-、C1-3亚烷基、C2-4亚烯基、C2-4亚炔基、-O-C1-3亚烷基-、-S-C1-3亚烷基-、-C1-3亚烷基-NH-、-C1-3亚烷基-C(O)NH-、-C1-3亚烷基-NHC(O)-、-C1-3亚烷基-S(O)r1-、-C1-3亚烷基-NHS(O)r2-或-C1-3亚烷基-S(O)r3NH-任选地被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-3烷基、C2-4烯基、C2-4炔基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3氘代烷氧基、C1-3卤代烷氧基、C1-3羟烷基、C3-6环烷基、3-6元杂环基、C6-10芳基、5-6元杂芳基中的一个或多个取代；L 1 "is selected from a bond, -O-, -S-, -NH-, -CO-, -CONH-, C 1-3 alkylene, C 2-4 alkenylene, C 2-4 alkynylene, -OC 1-3 alkylene-, -SC 1-3 alkylene-, -C 1-3 alkylene-NH-, -C 1-3 alkylene-C(O)NH-, -C 1-3 alkylene-NHC(O)-, -C 1-3 alkylene-S(O) r1 -, -C 1-3 alkylene-NHS(O) r2 - or -C 1-3 alkylene-S(O) r3 NH-; said -NH-, -CONH-, C 1-3 alkylene, C 2-4 alkenylene, C 2-4 alkynylene, -OC 1-3 alkylene-, -SC 1-3 alkylene-, -C 1-3 alkylene - NH-, -C -C 1-3 alkylene-C(O)NH-, -C 1-3 alkylene-NHC(O)-, -C 1-3 alkylene-S(O) r1 -, -C 1-3 alkylene-NHS(O) r2 -, or -C 1-3 alkylene-S(O) r3 NH- is optionally substituted with one or more of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, 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, C 1-3 deuterated alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl , C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-10 aryl, or 5-6 membered heteroaryl;
R1”和R1-1”各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基、5-10元杂芳基、-(CH2)m1ORa1、-(CH2)m2C(O)Ra2、-(CH2)m3NHC(O)Ra3、-(CH2)m4C(O)NHRa4、-(CH2)m5NRa5Ra6、-(CH2)m6S(O)m7Ra7、-(CH2)m8S(O)2NHRa8、-(CH2)m9NHS(O)2Ra9，所述的氨基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基任选地可以进一步被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代；R 1 " and R 1-1 " are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl , 3-8 membered heterocyclyl , C 6-10 aryl, 5-10 membered heteroaryl, -(CH 2 ) m1 OR a1 , -(CH 2 ) m2 C(O)R a2 , -(CH 2 ) m3 NHC(O)R a3 , -(CH 2 ) m4 C(O)NHR a4 , -(CH 2 ) m5 NR a5 R a6 wherein 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy , C 1-6 hydroxyalkyl , C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl may be further substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 alkyl , C 2-6 alkenyl, C 2-6 alkynyl , C The group may be substituted by one or more of C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl;
R2-1”和R2-2”各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基、5-10元杂芳基、-(CH2)n1ORb1、-(CH2)n2C(O)Rb2、-(CH2)n3NHC(O)Rb3、-(CH2)n4C(O)NHRb4、-(CH2)n5NRb5Rb6、-(CH2)n6S(O)n7Rb7、-(CH2)n8S(O)2NHRb8、-(CH2)n9NHS(O)2Rb9，所述的氨基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基任选地可以进一步被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代；R 2-1 ″ and R 2-2 ″ are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl , 3-8 membered heterocyclyl , C 6-10 aryl, 5-10 membered heteroaryl, -(CH 2 ) n1 OR b1 , -(CH 2 ) n2 C(O)R b2 , -(CH 2 ) n3 NHC(O)R b3 , -(CH 2 ) n4 C(O)NHR b4 , -(CH 2 ) n5 NR b5 R b6 , -( CH2 ) n6S (O) n7Rb7 , -( CH2 ) n8S (O) 2NHRb8 , -( CH2 ) n9NHS (O) 2Rb9 , the amino, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl , C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl or 5-10 membered heteroaryl may be further optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C The group is substituted by one or more of C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl;
R3-1”和R3-2”各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基、5-10元杂芳基、-(CH2)o1ORc1、-(CH2)o2C(O)Rc2、-(CH2)o3NHC(O)Rc3、-(CH2)o4C(O)NHRc4、-(CH2)o5NRc5Rc6、-(CH2)o6S(O)o7Rc7、-(CH2)o8S(O)2NHRc8、-(CH2)o9NHS(O)2Rc9，所述的氨基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基任选地可以进一步被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代；R 3-1 " and R 3-2 " are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl , 3-8 membered heterocyclyl , C 6-10 aryl, 5-10 membered heteroaryl, -(CH 2 ) o1 OR c1 , -(CH 2 ) o2 C(O)R c2 , -(CH 2 ) o3 NHC(O)R c3 , -(CH 2 ) o4 C(O)NHR c4 , -(CH 2 ) o5 NR c5 R c6 , -( CH2 ) o6S (O) o7Rc7 , -( CH2 ) o8S (O) 2NHRc8 , -( CH2 ) o9NHS (O) 2Rc9 , the amino, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl , C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl or 5-10 membered heteroaryl may be further optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C The group may be substituted by one or more of C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl;
R3-3”选自氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基、5-10元杂芳基、-(CH2)o1ORc1、-(CH2)o2C(O)Rc2、-(CH2)o3NHC(O)Rc3、-(CH2)o4C(O)NHRc4、-(CH2)o5NRc5Rc6、-(CH2)o6S(O)o7Rc7、-(CH2)o8S(O)2NHRc8、-(CH2)o9NHS(O)2Rc9，所述的氨基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基任选地可以进一步被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代；R 3-3 "is selected from deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, -(CH 2 ) o1 OR c1 , -(CH 2 ) o2 C(O)R c2 , -(CH 2 ) o3 NHC(O)R c3 , -(CH 2 ) o4 C(O)NHR c4 , -( CH 2 ) o5 NR c5 R c6 , -(CH 2 ) o6 S(O) o7Rc7 , -( CH2 ) o8S (O) 2NHRc8 , -( CH2 ) o9NHS (O) 2Rc9 , the amino, C1-6 alkyl, C2-6 alkenyl , C2-6 alkynyl, C1-6 deuterated alkyl , C1-6 haloalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl or 5-10 membered heteroaryl may be further optionally substituted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl or 5-10 membered heteroaryl. substituted by one or more of C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl;
R4-1”和R4-2”各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基、5-10元杂芳基、-(CHRd10)p1ORd1、-(CHRd10)p2C(O)Rd2、-(CHRd10)p3NHC(O)Rd3、-(CHRd10)p4C(O)NHRd4、-(CHRd10)p5NRd5Rd6、-(CHRd10)p6S(O)p7Rd7、-(CHRd10)p8S(O)2NHRd8、-(CHRd10)p9NHS(O)2Rd9，所述的氨基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基任选地可以进一步被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代；R 4-1 ″ and R 4-2 ″ are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl , 3-8 membered heterocyclyl , C 6-10 aryl, 5-10 membered heteroaryl, -(CHR d10 ) p1 OR d1 , -(CHR d10 ) p2 C(O)R d2 , -(CHR d10 ) p3 NHC(O)R d3 , -(CHR d10 ) p4 C(O)NHR d4 d10 , -(CHR d10 ) p5 NR d5 R d6 , -(CHR d10 ) p6 S(O) p7 R d7 , -(CHR d10 ) p8 S(O) 2 NHR d8 , -(CHR d10 ) p9 NHS(O) 2 R d9 , 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl , C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C The 6-10 membered aryl or 5-10 membered heteroaryl may be further optionally substituted with one or more of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl;
优选地，R4-1”和R4-2”各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基、5-10元杂芳基、-(CH2)p1ORd1、-(CH2)p2C(O)Rd2、-(CH2)p3NHC(O)Rd3、-(CH2)p4C(O)NHRd4、-(CH2)p5NRd5Rd6、-(CH2)p6S(O)p7Rd7、-(CH2)p8S(O)2NHRd8、-(CH2)p9NHS(O)2Rd9，所述的氨基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基任选地可以进一步被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代；Preferably, R 4-1 "and R 4-2 "are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl , 3-8 membered heterocyclyl , C 6-10 aryl, 5-10 membered heteroaryl, -(CH 2 ) p1 OR d1 , -(CH 2 ) p2 C(O)R d2 , -(CH 2 ) p3 NHC(O)R d3 , -(CH 2 ) p4 C(O)NHR d4 , -(CH 2 ) p4 p5 NR d5 R d6 , -(CH 2 ) p6 S(O) p7 R d7 , -(CH 2 ) p8 S(O) 2 NHR d8 , -(CH 2 ) p9 NHS(O) 2 R d9 , 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl may be further optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C 1-6 alkyl, C 2-6 alkenyl, C The alkyl group may be substituted by one or more of C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl , C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl;
R5”选自氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基、5-10元杂芳基、-(CH2)q1ORe1、-(CH2)q2C(O)Re2、-(CH2)q3NHC(O)Re3、-(CH2)q4C(O)NHRe4、-(CH2)q5NRe5Re6、-(CH2)q6S(O)q7Re7、-(CH2)q8S(O)2NHRe8、-(CH2)q9NHS(O)2Re9，所述的氨基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基任选地可以进一步被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代；R 5 ″ is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, -(CH 2 ) q1 OR e1 , -(CH 2 ) q2 C(O)R e2 , -(CH 2 ) q3 NHC(O)R e3 , -(CH 2 ) q4 C(O)NHR e4 , -(CH 2 ) q5 NR e5 R e6 , -(CH 2 wherein 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl may be further substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl. substituted by one or more of C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl;
Ra1、Ra2、Ra3、Ra4、Ra5、Ra6、Ra7、Ra8和Ra9各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基、5-10元杂芳基，所述的氨基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基任选地可以进一步被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代； Ra1 , Ra2 , Ra3 , Ra4 , Ra5 , Ra6 , Ra7 , Ra8 and Ra9 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, and the amino, C1-6 alkyl , C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl , C1-6 alkoxy , C C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl may be further optionally substituted with one or more of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl , 3-8 membered heterocyclyl , C 6-10 aryl and 5-10 membered heteroaryl;
Rb1、Rb2、Rb3、Rb4、Rb5、Rb6、Rb7、Rb8和Rb9各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基、5-10元杂芳基，所述的氨基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基任选地可以进一步被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代；R b1 , R b2 , R b3 , R b4 , R b5 , R b6 , R b7 , R b8 and R b9 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, said 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 , C C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl may be further optionally substituted with one or more of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl , 3-8 membered heterocyclyl , C 6-10 aryl and 5-10 membered heteroaryl;
Rc1、Rc2、Rc3、Rc4、Rc5、Rc6、Rc7、Rc8和Rc9各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基、5-10元杂芳基，所述的氨基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基任选地可以进一步被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代；R c1 , R c2 , R c3 , R c4 , R c5 , R c6 , R c7 , R c8 and R c9 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, said 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 , C C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl may be further optionally substituted with one or more of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl , 3-8 membered heterocyclyl , C 6-10 aryl and 5-10 membered heteroaryl;
Rd1、Rd2、Rd3、Rd4、Rd5、Rd6、Rd7、Rd8、Rd9和Rd10各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基、5-10元杂芳基，所述的氨基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基任选地可以进一步被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代； Rd1 , Rd2 , Rd3, Rd4 , Rd5 , Rd6 , Rd7 , Rd8 , Rd9 and Rd10 are each independently selected from hydrogen, deuterium , halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, wherein the amino, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy , C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl may be further optionally substituted with one or more of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl;
Re1、Re2、Re3、Re4、Re5、Re6、Re7、Re8和Re9各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基、5-10元杂芳基，所述的氨基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基任选地可以进一步被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代； Re1 , Re2 , Re3 , Re4 , Re5 , Re6 , Re7 , Re8 and Re9 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, said amino , C1-6 alkyl , C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl , C1-6 alkoxy , C C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl may be further optionally substituted with one or more of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl , 3-8 membered heterocyclyl , C 6-10 aryl and 5-10 membered heteroaryl;
n”为1、2、3、4或5；n” is 1, 2, 3, 4 or 5;
x”为0、1、2、3、4或5；x” is 0, 1, 2, 3, 4, or 5;
y”为0、1、2、3、4或5；y” is 0, 1, 2, 3, 4, or 5;
m1、m2、m3、m4、m5、m6、m8、m9各自独立地选自0、1、2、3、4、5或6；m1, m2, m3, m4, m5, m6, m8, m9 are each independently selected from 0, 1, 2, 3, 4, 5 or 6;
n1、n2、n3、n4、n5、n6、n8、n9各自独立地选自0、1、2、3、4、5或6；n1, n2, n3, n4, n5, n6, n8, n9 are each independently selected from 0, 1, 2, 3, 4, 5 or 6;
o1、o2、o3、o4、o5、o6、o8、o9各自独立地选自0、1、2、3、4、5或6；o1, o2, o3, o4, o5, o6, o8, o9 are each independently selected from 0, 1, 2, 3, 4, 5 or 6;
p1、p2、p3、p4、p5、p6、p8、p9各自独立地选自0、1、2、3、4、5或6；p1, p2, p3, p4, p5, p6, p8, p9 are each independently selected from 0, 1, 2, 3, 4, 5 or 6;
q1、q2、q3、q4、q5、q6、q8、q9各自独立地选自0、1、2、3、4、5或6；q1, q2, q3, q4, q5, q6, q8, q9 are each independently selected from 0, 1, 2, 3, 4, 5 or 6;
r1、r2、r3各自独立地选自0、1或2；r1, r2, r3 are each independently selected from 0, 1 or 2;
m7、n7、o7、p7、q7各自独立地选自0、1、2或3。m7, n7, o7, p7, q7 are each independently selected from 0, 1, 2 or 3.
在本发明的某些实施方案中，所述的式(II”)所示化合物如式(II”-1)所示：In certain embodiments of the present invention, the compound represented by formula (II") is represented by formula (II"-1):
本发明还提供了一种如通式(III”)所示的化合物、其立体异构体或其药学上可接受的盐：The present invention also provides a compound represented by the general formula (III"), a stereoisomer thereof or a pharmaceutically acceptable salt thereof:
其中，in,
M2”选自N、CH或CR3-3”；优选为N或CR3-3”；M 2 ″ is selected from N, CH or CR 3-3 ″; preferably N or CR 3-3 ″;
L1”选自键、-O-、-S-、-NH-、-CO-、-CONH-、C1-3亚烷基、C2-4亚烯基、C2-4亚炔基、-O-C1-3亚烷基-、-S-C1-3亚烷基-、-C1-3亚烷基-NH-、-C1-3亚烷基-C(O)NH-、-C1-3亚烷基-NHC(O)-、-C1-3亚烷基-S(O)r1-、-C1-3亚烷基-NHS(O)r2-或-C1-3亚烷基-S(O)r3NH-；所述的-NH-、-CONH-、C1-3亚烷基、C2-4亚烯基、C2-4亚炔基、-O-C1-3亚烷基-、-S-C1-3亚烷基-、-C1-3亚烷基-NH-、-C1-3亚烷基-C(O)NH-、-C1-3亚烷基-NHC(O)-、-C1-3亚烷基-S(O)r1-、-C1-3亚烷基-NHS(O)r2-或-C1-3亚烷基-S(O)r3NH-任选地被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-3烷基、C2-4烯基、C2-4炔基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3氘代烷氧基、C1-3卤代烷氧基、C1-3羟烷基、C3-6环烷基、3-6元杂环基、C6-10芳基、5-6元杂芳基中的一个或多个取代；优选地，L1选自-O-、-S-、-NH-、-CO-、-CONH-、C1-3亚烷基、C2-4亚烯基、C2-4亚炔基、-O-C1-3亚烷基-、-S-C1-3亚烷基-、-C1-3亚烷基-NH-、-C1-3亚烷基-C(O)NH-、-C1-3亚烷基-NHC(O)-、-C1-3亚烷基-S(O)r1-、-C1-3亚烷基-NHS(O)r2-或-C1-3亚烷基-S(O)r3NH-；所述的-NH-、-CONH-、C1-3亚烷基、C2-4亚烯基、C2-4亚炔基、-O-C1-3亚烷基-、-S-C1-3亚烷基-、-C1-3亚烷基-NH-、-C1-3亚烷基-C(O)NH-、-C1-3亚烷基-NHC(O)-、-C1-3亚烷基-S(O)r1-、-C1-3亚烷基-NHS(O)r2-或-C1-3亚烷基-S(O)r3NH-任选地被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-3烷基、C2-4烯基、C2-4炔基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3氘代烷氧基、C1-3卤代烷氧基、C1-3羟烷基、C3-6环烷基、3-6元杂环基、C6-10芳基、5-6元杂芳基中的一个或多个取代；L 1 "is selected from a bond, -O-, -S-, -NH-, -CO-, -CONH-, C 1-3 alkylene, C 2-4 alkenylene, C 2-4 alkynylene, -OC 1-3 alkylene-, -SC 1-3 alkylene-, -C 1-3 alkylene-NH-, -C 1-3 alkylene-C(O)NH-, -C 1-3 alkylene-NHC(O)-, -C 1-3 alkylene-S(O) r1 -, -C 1-3 alkylene-NHS(O) r2 - or -C 1-3 alkylene-S(O) r3 NH-; said -NH-, -CONH-, C 1-3 alkylene, C 2-4 alkenylene, C 2-4 alkynylene, -OC 1-3 alkylene-, -SC 1-3 alkylene-, -C 1-3 alkylene - NH-, -C -C 1-3 alkylene-C(O)NH-, -C 1-3 alkylene-NHC(O)-, -C 1-3 alkylene-S(O) r1 -, -C 1-3 alkylene-NHS(O) r2 - or -C 1-3 alkylene-S(O) r3 NH- is optionally substituted with one or more of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, 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, C 1-3 deuterated alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl , C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-10 aryl, 5-6 membered heteroaryl; preferably, L 1 is selected from -O-, -S-, -NH-, -CO-, -CONH-, C 1-3 alkylene, C 2-4 alkenylene, C 2-4 alkynylene, -OC 1-3 alkylene-, -SC 1-3 alkylene-, -C 1-3 alkylene-NH-, -C 1-3 alkylene-C(O)NH-, -C 1-3 alkylene-NHC(O)-, -C 1-3 alkylene-S(O) r1 -, -C 1-3 alkylene-NHS(O) r2 - or -C 1-3 alkylene-S(O) r3 NH-; said -NH-, -CONH-, C 1-3 alkylene, C 2-4 alkenylene, C 2-4 alkynylene , -OC 1-3 alkylene-, -SC 1-3 alkylene-, -C 1-3 alkylene - NH- , -C -C 1-3 alkylene-C(O)NH-, -C 1-3 alkylene-NHC(O)-, -C 1-3 alkylene-S(O) r1 -, -C 1-3 alkylene-NHS(O) r2 -, or -C 1-3 alkylene-S(O) r3 NH- is optionally substituted with one or more of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, 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, C 1-3 deuterated alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl , C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-10 aryl, or 5-6 membered heteroaryl;
R1”独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基、5-10元杂芳基、-(CH2)m1ORa1、-(CH2)m2C(O)Ra2、-(CH2)m3NHC(O)Ra3、-(CH2)m4C(O)NHRa4、-(CH2)m5NRa5Ra6、-(CH2)m6S(O)m7Ra7、-(CH2)m8S(O)2NHRa8、-(CH2)m9NHS(O)2Ra9，所述的氨基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基任选地可以进一步被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代；R 1 "is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, -(CH 2 ) m1 OR a1 , -(CH 2 ) m2 C(O)R a2 , -(CH 2 ) m3 NHC(O)R a3 , -(CH 2 ) m4 C(O)NHR a4 , -(CH 2 ) m5 NR a5 R a6 , -(CH 2 ) m5 m6 S(O) m7 R a7 , -(CH 2 ) m8 S(O) 2 NHR a8 , -(CH 2 ) m9 NHS(O) 2 R a9 , wherein 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl may be further optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl. substituted by one or more of C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl;
或者，其中两个R1”连接形成C3-8环烷基或3-8元杂环基，所述的C3-8环烷基和3-8元杂环基任选地可以进一步被一个或多个R1-1”取代；Alternatively, two R 1 " are linked to form a C 3-8 cycloalkyl group or a 3-8 membered heterocyclic group, and the C 3-8 cycloalkyl group and the 3-8 membered heterocyclic group may be further substituted by one or more R 1-1 ";
R1-1”独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基、5-10元杂芳基、-(CH2)m1ORa1、-(CH2)m2C(O)Ra2、-(CH2)m3NHC(O)Ra3、-(CH2)m4C(O)NHRa4、-(CH2)m5NRa5Ra6、-(CH2)m6S(O)m7Ra7、-(CH2)m8S(O)2NHRa8、-(CH2)m9NHS(O)2Ra9，所述的氨基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基任选地可以进一步被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代；R 1-1 "is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, -(CH 2 ) m1 OR a1 , -(CH 2 ) m2 C(O)R a2 , -(CH 2 ) m3 NHC(O)R a3 , -(CH 2 ) m4 C(O)NHR a4 , -(CH 2 ) m5 NR a5 R a6 , -(CH 2 wherein 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl may be further substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl. substituted by one or more of C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl;
R2-1”和R2-2”各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基、5-10元杂芳基、-(CH2)n1ORb1、-(CH2)n2C(O)Rb2、-(CH2)n3NHC(O)Rb3、-(CH2)n4C(O)NHRb4、-(CH2)n5NRb5Rb6、-(CH2)n6S(O)n7Rb7、-(CH2)n8S(O)2NHRb8、-(CH2)n9NHS(O)2Rb9，所述的氨基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基任选地可以进一步被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代；R 2-1 ″ and R 2-2 ″ are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl , 3-8 membered heterocyclyl , C 6-10 aryl, 5-10 membered heteroaryl, -(CH 2 ) n1 OR b1 , -(CH 2 ) n2 C(O)R b2 , -(CH 2 ) n3 NHC(O)R b3 , -(CH 2 ) n4 C(O)NHR b4 , -(CH 2 ) n5 NR b5 R b6 , -( CH2 ) n6S (O) n7Rb7 , -( CH2 ) n8S (O) 2NHRb8 , -( CH2 ) n9NHS (O) 2Rb9 , the amino, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl , C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl or 5-10 membered heteroaryl may be further optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C The group is substituted by one or more of C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl;
R3-1”和R3-2”各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基、5-10元杂芳基、-(CH2)o1ORc1、-(CH2)o2C(O)Rc2、-(CH2)o3NHC(O)Rc3、-(CH2)o4C(O)NHRc4、-(CH2)o5NRc5Rc6、-(CH2)o6S(O)o7Rc7、-(CH2)o8S(O)2NHRc8、-(CH2)o9NHS(O)2Rc9，所述的氨基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基任选地可以进一步被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代；R 3-1 " and R 3-2 " are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl , 3-8 membered heterocyclyl , C 6-10 aryl, 5-10 membered heteroaryl, -(CH 2 ) o1 OR c1 , -(CH 2 ) o2 C(O)R c2 , -(CH 2 ) o3 NHC(O)R c3 , -(CH 2 ) o4 C(O)NHR c4 , -(CH 2 ) o5 NR c5 R c6 , -( CH2 ) o6S (O) o7Rc7 , -( CH2 ) o8S (O) 2NHRc8 , -( CH2 ) o9NHS (O) 2Rc9 , the amino, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl , C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl or 5-10 membered heteroaryl may be further optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C The group may be substituted by one or more of C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl;
R3-3”选自氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基、5-10元杂芳基、-(CH2)o1ORc1、-(CH2)o2C(O)Rc2、-(CH2)o3NHC(O)Rc3、-(CH2)o4C(O)NHRc4、-(CH2)o5NRc5Rc6、-(CH2)o6S(O)o7Rc7、-(CH2)o8S(O)2NHRc8、-(CH2)o9NHS(O)2Rc9，所述的氨基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基任选地可以进一步被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代；R 3-3 "is selected from deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, -(CH 2 ) o1 OR c1 , -(CH 2 ) o2 C(O)R c2 , -(CH 2 ) o3 NHC(O)R c3 , -(CH 2 ) o4 C(O)NHR c4 , -( CH 2 ) o5 NR c5 R c6 , -(CH 2 ) o6 S(O) o7Rc7 , -( CH2 ) o8S (O) 2NHRc8 , -( CH2 ) o9NHS (O) 2Rc9 , the amino, C1-6 alkyl, C2-6 alkenyl , C2-6 alkynyl, C1-6 deuterated alkyl , C1-6 haloalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl or 5-10 membered heteroaryl may be further optionally substituted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl or 5-10 membered heteroaryl. substituted by one or more of C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl;
R4-1”和R4-2”各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基、5-10元杂芳基、-(CHRd10)p1ORd1、-(CHRd10)p2C(O)Rd2、-(CHRd10)p3NHC(O)Rd3、-(CHRd10)p4C(O)NHRd4、-(CHRd10)p5NRd5Rd6、-(CHRd10)p6S(O)p7Rd7、-(CHRd10)p8S(O)2NHRd8、-(CHRd10)p9NHS(O)2Rd9，所述的氨基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基任选地可以进一步被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代；R 4-1 ″ and R 4-2 ″ are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl , 3-8 membered heterocyclyl , C 6-10 aryl, 5-10 membered heteroaryl, -(CHR d10 ) p1 OR d1 , -(CHR d10 ) p2 C(O)R d2 , -(CHR d10 ) p3 NHC(O)R d3 , -(CHR d10 ) p4 C(O)NHR d4 d10 , -(CHR d10 ) p5 NR d5 R d6 , -(CHR d10 ) p6 S(O) p7 R d7 , -(CHR d10 ) p8 S(O) 2 NHR d8 , -(CHR d10 ) p9 NHS(O) 2 R d9 , 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl , C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C The 6-10 membered aryl or 5-10 membered heteroaryl may be further optionally substituted with one or more of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl;
优选地，R4-1”和R4-2”各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基、5-10元杂芳基、-(CH2)p1ORd1、-(CH2)p2C(O)Rd2、-(CH2)p3NHC(O)Rd3、-(CH2)p4C(O)NHRd4、-(CH2)p5NRd5Rd6、-(CH2)p6S(O)p7Rd7、-(CH2)p8S(O)2NHRd8、-(CH2)p9NHS(O)2Rd9，所述的氨基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基任选地可以进一步被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代；Preferably, R 4-1 "and R 4-2 "are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl , 3-8 membered heterocyclyl , C 6-10 aryl, 5-10 membered heteroaryl, -(CH 2 ) p1 OR d1 , -(CH 2 ) p2 C(O)R d2 , -(CH 2 ) p3 NHC(O)R d3 , -(CH 2 ) p4 C(O)NHR d4 , -(CH 2 ) p4 p5 NR d5 R d6 , -(CH 2 ) p6 S(O) p7 R d7 , -(CH 2 ) p8 S(O) 2 NHR d8 , -(CH 2 ) p9 NHS(O) 2 R d9 , 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl may be further optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C 1-6 alkyl, C 2-6 alkenyl, C The alkyl group may be substituted by one or more of C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl , C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl;
R5”选自氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基、5-10元杂芳基、-(CH2)q1ORe1、-(CH2)q2C(O)Re2、-(CH2)q3NHC(O)Re3、-(CH2)q4C(O)NHRe4、-(CH2)q5NRe5Re6、-(CH2)q6S(O)q7Re7、-(CH2)q8S(O)2NHRe8、-(CH2)q9NHS(O)2Re9，所述的氨基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基任选地可以进一步被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代；R 5 ″ is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, -(CH 2 ) q1 OR e1 , -(CH 2 ) q2 C(O)R e2 , -(CH 2 ) q3 NHC(O)R e3 , -(CH 2 ) q4 C(O)NHR e4 , -(CH 2 ) q5 NR e5 R e6 , -(CH 2 wherein 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl may be further substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl. substituted by one or more of C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl;
Ra1、Ra2、Ra3、Ra4、Ra5、Ra6、Ra7、Ra8和Ra9各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基、5-10元杂芳基，所述的氨基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基任选地可以进一步被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代； Ra1 , Ra2 , Ra3 , Ra4 , Ra5 , Ra6 , Ra7 , Ra8 and Ra9 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, and the amino, C1-6 alkyl , C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl , C1-6 alkoxy , C C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl may be further optionally substituted with one or more of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl , 3-8 membered heterocyclyl , C 6-10 aryl and 5-10 membered heteroaryl;
Rb1、Rb2、Rb3、Rb4、Rb5、Rb6、Rb7、Rb8和Rb9各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基、5-10元杂芳基，所述的氨基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基任选地可以进一步被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代；R b1 , R b2 , R b3 , R b4 , R b5 , R b6 , R b7 , R b8 and R b9 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, said 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 , C C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl may be further optionally substituted with one or more of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl , 3-8 membered heterocyclyl , C 6-10 aryl and 5-10 membered heteroaryl;
Rc1、Rc2、Rc3、Rc4、Rc5、Rc6、Rc7、Rc8和Rc9各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基、5-10元杂芳基，所述的氨基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基任选地可以进一步被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代；R c1 , R c2 , R c3 , R c4 , R c5 , R c6 , R c7 , R c8 and R c9 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, said 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 , C C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl may be further optionally substituted with one or more of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl , 3-8 membered heterocyclyl , C 6-10 aryl and 5-10 membered heteroaryl;
Rd1、Rd2、Rd3、Rd4、Rd5、Rd6、Rd7、Rd8、Rd9和Rd10各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基、5-10元杂芳基，所述的氨基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基任选地可以进一步被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代； Rd1 , Rd2 , Rd3, Rd4 , Rd5 , Rd6 , Rd7 , Rd8 , Rd9 and Rd10 are each independently selected from hydrogen, deuterium , halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, wherein the amino, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy , C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl may be further optionally substituted with one or more of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl;
Re1、Re2、Re3、Re4、Re5、Re6、Re7、Re8和Re9各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基、5-10元杂芳基，所述的氨基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基任选地可以进一步被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代； Re1 , Re2 , Re3 , Re4 , Re5 , Re6 , Re7 , Re8 and Re9 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, said amino , C1-6 alkyl , C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl , C1-6 alkoxy , C C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl may be further optionally substituted with one or more of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl , 3-8 membered heterocyclyl , C 6-10 aryl and 5-10 membered heteroaryl;
m”为1、2、3、4或5；m” is 1, 2, 3, 4 or 5;
x”为0、1、2、3、4或5；x” is 0, 1, 2, 3, 4, or 5;
m1、m2、m3、m4、m5、m6、m8、m9各自独立地选自0、1、2、3、4、5或6；m1, m2, m3, m4, m5, m6, m8, m9 are each independently selected from 0, 1, 2, 3, 4, 5 or 6;
n1、n2、n3、n4、n5、n6、n8、n9各自独立地选自0、1、2、3、4、5或6；n1, n2, n3, n4, n5, n6, n8, n9 are each independently selected from 0, 1, 2, 3, 4, 5 or 6;
o1、o2、o3、o4、o5、o6、o8、o9各自独立地选自0、1、2、3、4、5或6；o1, o2, o3, o4, o5, o6, o8, o9 are each independently selected from 0, 1, 2, 3, 4, 5 or 6;
p1、p2、p3、p4、p5、p6、p8、p9各自独立地选自0、1、2、3、4、5或6；p1, p2, p3, p4, p5, p6, p8, p9 are each independently selected from 0, 1, 2, 3, 4, 5 or 6;
q1、q2、q3、q4、q5、q6、q8、q9各自独立地选自0、1、2、3、4、5或6；q1, q2, q3, q4, q5, q6, q8, q9 are each independently selected from 0, 1, 2, 3, 4, 5 or 6;
r1、r2、r3各自独立地选自0、1或2；r1, r2, r3 are each independently selected from 0, 1 or 2;
m7、n7、o7、p7、q7各自独立地选自0、1、2或3。m7, n7, o7, p7, q7 are each independently selected from 0, 1, 2 or 3.
在本发明的某些实施方案中，所述的式(III”)所示化合物如式(III”-1)所示：In certain embodiments of the present invention, the compound represented by formula (III") is represented by formula (III"-1):
其中，in,
R1”独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基、5-10元杂芳基、-(CH2)m1ORa1、-(CH2)m2C(O)Ra2、-(CH2)m3NHC(O)Ra3、-(CH2)m4C(O)NHRa4、-(CH2)m5NRa5Ra6、-(CH2)m6S(O)m7Ra7、-(CH2)m8S(O)2NHRa8、-(CH2)m9NHS(O)2Ra9，所述的氨基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基任选地可以进一步被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代。R 1 "is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, -(CH 2 ) m1 OR a1 , -(CH 2 ) m2 C(O)R a2 , -(CH 2 ) m3 NHC(O)R a3 , -(CH 2 ) m4 C(O)NHR a4 , -(CH 2 ) m5 NR a5 R a6 , -(CH 2 ) m5 m6 S(O) m7 R a7 , -(CH 2 ) m8 S(O) 2 NHR a8 , -(CH 2 ) m9 NHS(O) 2 R a9 , wherein 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl may be further optionally substituted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl. The group may be substituted by one or more of C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl.
在本发明的某些实施方案中，所述的式(III”)所示化合物如式(III”-2)所示：In certain embodiments of the present invention, the compound represented by formula (III") is represented by formula (III"-2):
其中，in,
R1”独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基、5-10元杂芳基、-(CH2)m1ORa1、-(CH2)m2C(O)Ra2、-(CH2)m3NHC(O)Ra3、-(CH2)m4C(O)NHRa4、-(CH2)m5NRa5Ra6、-(CH2)m6S(O)m7Ra7、-(CH2)m8S(O)2NHRa8、-(CH2)m9NHS(O)2Ra9，所述的氨基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基任选地可以进一步被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代。R 1 "is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, -(CH 2 ) m1 OR a1 , -(CH 2 ) m2 C(O)R a2 , -(CH 2 ) m3 NHC(O)R a3 , -(CH 2 ) m4 C(O)NHR a4 , -(CH 2 ) m5 NR a5 R a6 , -(CH 2 ) m5 m6 S(O) m7 R a7 , -(CH 2 ) m8 S(O) 2 NHR a8 , -(CH 2 ) m9 NHS(O) 2 R a9 , wherein 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl may be further optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl. The group may be substituted by one or more of C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl.
在本发明的某些实施方案中，所述的式(III”)所示化合物如式(III”-3)所示：In certain embodiments of the present invention, the compound represented by formula (III") is represented by formula (III"-3):
其中，in,
R1”独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基、5-10元杂芳基、-(CH2)m1ORa1、-(CH2)m2C(O)Ra2、-(CH2)m3NHC(O)Ra3、-(CH2)m4C(O)NHRa4、-(CH2)m5NRa5Ra6、-(CH2)m6S(O)m7Ra7、-(CH2)m8S(O)2NHRa8、-(CH2)m9NHS(O)2Ra9，所述的氨基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基任选地可以进一步被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代；R 1 "is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, -(CH 2 ) m1 OR a1 , -(CH 2 ) m2 C(O)R a2 , -(CH 2 ) m3 NHC(O)R a3 , -(CH 2 ) m4 C(O)NHR a4 , -(CH 2 ) m5 NR a5 R a6 , -(CH 2 ) m5 m6 S(O) m7 R a7 , -(CH 2 ) m8 S(O) 2 NHR a8 , -(CH 2 ) m9 NHS(O) 2 R a9 , wherein 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl may be further optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl. substituted by one or more of C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl;
R1-1”独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基、5-10元杂芳基、-(CH2)m1ORa1、-(CH2)m2C(O)Ra2、-(CH2)m3NHC(O)Ra3、-(CH2)m4C(O)NHRa4、-(CH2)m5NRa5Ra6、-(CH2)m6S(O)m7Ra7、-(CH2)m8S(O)2NHRa8、-(CH2)m9NHS(O)2Ra9，所述的氨基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基任选地可以进一步被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代；R 1-1 "is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, -(CH 2 ) m1 OR a1 , -(CH 2 ) m2 C(O)R a2 , -(CH 2 ) m3 NHC(O)R a3 , -(CH 2 ) m4 C(O)NHR a4 , -(CH 2 ) m5 NR a5 R a6 , -(CH 2 wherein 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl may be further substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl. substituted by one or more of C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl;
y”为0、1、2、3或4。y" is 0, 1, 2, 3, or 4.
本发明还提供了一种如通式(IV”)所示的化合物、其立体异构体或其药学上可接受的盐：The present invention also provides a compound represented by the general formula (IV"), a stereoisomer thereof or a pharmaceutically acceptable salt thereof:
其中，in,
M2”选自N、CH或CR3-3”；M 2 ″ is selected from N, CH or CR 3-3 ″;
M3”选自N或CH；M 3 ″ is selected from N or CH;
L1”选自键、-O-、-S-、-NH-、-CO-、-CONH-、C1-3亚烷基、C2-4亚烯基、C2-4亚炔基、-O-C1-3亚烷基-、-S-C1-3亚烷基-、-C1-3亚烷基-NH-、-C1-3亚烷基-C(O)NH-、-C1-3亚烷基-NHC(O)-、-C1-3亚烷基-S(O)r1-、-C1-3亚烷基-NHS(O)r2-或-C1-3亚烷基-S(O)r3NH-；所述的-NH-、-CONH-、C1-3亚烷基、C2-4亚烯基、C2-4亚炔基、-O-C1-3亚烷基-、-S-C1-3亚烷基-、-C1-3亚烷基-NH-、-C1-3亚烷基-C(O)NH-、-C1-3亚烷基-NHC(O)-、-C1-3亚烷基-S(O)r1-、-C1-3亚烷基-NHS(O)r2-或-C1-3亚烷基-S(O)r3NH-任选地被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-3烷基、C2-4烯基、C2-4炔基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3氘代烷氧基、C1-3卤代烷氧基、C1-3羟烷基、C3-6环烷基、3-6元杂环基、C6-10芳基、5-6元杂芳基中的一个或多个取代；L 1 "is selected from a bond, -O-, -S-, -NH-, -CO-, -CONH-, C 1-3 alkylene, C 2-4 alkenylene, C 2-4 alkynylene, -OC 1-3 alkylene-, -SC 1-3 alkylene-, -C 1-3 alkylene-NH-, -C 1-3 alkylene-C(O)NH-, -C 1-3 alkylene-NHC(O)-, -C 1-3 alkylene-S(O) r1 -, -C 1-3 alkylene-NHS(O) r2 - or -C 1-3 alkylene-S(O) r3 NH-; said -NH-, -CONH-, C 1-3 alkylene, C 2-4 alkenylene, C 2-4 alkynylene, -OC 1-3 alkylene-, -SC 1-3 alkylene-, -C 1-3 alkylene - NH-, -C -C 1-3 alkylene-C(O)NH-, -C 1-3 alkylene-NHC(O)-, -C 1-3 alkylene-S(O) r1 -, -C 1-3 alkylene-NHS(O) r2 -, or -C 1-3 alkylene-S(O) r3 NH- is optionally substituted with one or more of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, 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, C 1-3 deuterated alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl , C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-10 aryl, or 5-6 membered heteroaryl;
R1”独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基、5-10元杂芳基、-(CH2)m1ORa1、-(CH2)m2C(O)Ra2、-(CH2)m3NHC(O)Ra3、-(CH2)m4C(O)NHRa4、-(CH2)m5NRa5Ra6、-(CH2)m6S(O)m7Ra7、-(CH2)m8S(O)2NHRa8、-(CH2)m9NHS(O)2Ra9，所述的氨基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基任选地可以进一步被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代；R 1 "is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, -(CH 2 ) m1 OR a1 , -(CH 2 ) m2 C(O)R a2 , -(CH 2 ) m3 NHC(O)R a3 , -(CH 2 ) m4 C(O)NHR a4 , -(CH 2 ) m5 NR a5 R a6 , -(CH 2 ) m5 m6 S(O) m7 R a7 , -(CH 2 ) m8 S(O) 2 NHR a8 , -(CH 2 ) m9 NHS(O) 2 R a9 , wherein 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl may be further optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl. substituted by one or more of C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl;
或者，其中两个R1”连接形成C3-8环烷基或3-8元杂环基，所述的C3-8环烷基和3-8元杂环基任选地可以进一步被一个或多个R1-1”取代；Alternatively, two R 1 " are linked to form a C 3-8 cycloalkyl group or a 3-8 membered heterocyclic group, and the C 3-8 cycloalkyl group and the 3-8 membered heterocyclic group may be further substituted by one or more R 1-1 ";
R1-1”独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基、5-10元杂芳基、-(CH2)m1ORa1、-(CH2)m2C(O)Ra2、-(CH2)m3NHC(O)Ra3、-(CH2)m4C(O)NHRa4、-(CH2)m5NRa5Ra6、-(CH2)m6S(O)m7Ra7、-(CH2)m8S(O)2NHRa8、-(CH2)m9NHS(O)2Ra9，所述的氨基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基任选地可以进一步被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代；R 1-1 "is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, -(CH 2 ) m1 OR a1 , -(CH 2 ) m2 C(O)R a2 , -(CH 2 ) m3 NHC(O)R a3 , -(CH 2 ) m4 C(O)NHR a4 , -(CH 2 ) m5 NR a5 R a6 , -(CH 2 wherein 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl may be further substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl. substituted by one or more of C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl;
R2-1”和R2-2”各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基、5-10元杂芳基、-(CH2)n1ORb1、-(CH2)n2C(O)Rb2、-(CH2)n3NHC(O)Rb3、-(CH2)n4C(O)NHRb4、-(CH2)n5NRb5Rb6、-(CH2)n6S(O)n7Rb7、-(CH2)n8S(O)2NHRb8、-(CH2)n9NHS(O)2Rb9，所述的氨基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基任选地可以进一步被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代；R 2-1 ″ and R 2-2 ″ are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl , 3-8 membered heterocyclyl , C 6-10 aryl, 5-10 membered heteroaryl, -(CH 2 ) n1 OR b1 , -(CH 2 ) n2 C(O)R b2 , -(CH 2 ) n3 NHC(O)R b3 , -(CH 2 ) n4 C(O)NHR b4 , -(CH 2 ) n5 NR b5 R b6 , -( CH2 ) n6S (O) n7Rb7 , -( CH2 ) n8S (O) 2NHRb8 , -( CH2 ) n9NHS (O) 2Rb9 , the amino, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl , C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl or 5-10 membered heteroaryl may be further optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C The group may be substituted by one or more of C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl;
R3-1”和R3-2”各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基、5-10元杂芳基、-(CH2)o1ORc1、-(CH2)o2C(O)Rc2、-(CH2)o3NHC(O)Rc3、-(CH2)o4C(O)NHRc4、-(CH2)o5NRc5Rc6、-(CH2)o6S(O)o7Rc7、-(CH2)o8S(O)2NHRc8、-(CH2)o9NHS(O)2Rc9，所述的氨基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基任选地可以进一步被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代；R 3-1 " and R 3-2 " are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl , 3-8 membered heterocyclyl , C 6-10 aryl, 5-10 membered heteroaryl, -(CH 2 ) o1 OR c1 , -(CH 2 ) o2 C(O)R c2 , -(CH 2 ) o3 NHC(O)R c3 , -(CH 2 ) o4 C(O)NHR c4 , -(CH 2 ) o5 NR c5 R c6 , -( CH2 ) o6S (O) o7Rc7 , -( CH2 ) o8S (O) 2NHRc8 , -( CH2 ) o9NHS (O) 2Rc9 , the amino, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl , C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl or 5-10 membered heteroaryl may be further optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C The group may be substituted by one or more of C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl;
R3-3”选自氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基、5-10元杂芳基、-(CH2)o1ORc1、-(CH2)o2C(O)Rc2、-(CH2)o3NHC(O)Rc3、-(CH2)o4C(O)NHRc4、-(CH2)o5NRc5Rc6、-(CH2)o6S(O)o7Rc7、-(CH2)o8S(O)2NHRc8、-(CH2)o9NHS(O)2Rc9，所述的氨基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基任选地可以进一步被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代；R 3-3 "is selected from deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, -(CH 2 ) o1 OR c1 , -(CH 2 ) o2 C(O)R c2 , -(CH 2 ) o3 NHC(O)R c3 , -(CH 2 ) o4 C(O)NHR c4 , -( CH 2 ) o5 NR c5 R c6 , -(CH 2 ) o6 S(O) o7Rc7 , -( CH2 ) o8S (O) 2NHRc8 , -( CH2 ) o9NHS (O) 2Rc9 , the amino, C1-6 alkyl, C2-6 alkenyl , C2-6 alkynyl, C1-6 deuterated alkyl , C1-6 haloalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl or 5-10 membered heteroaryl may be further optionally substituted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl or 5-10 membered heteroaryl. substituted by one or more of C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl;
R4-1”和R4-2”各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基、5-10元杂芳基、-(CHRd10)p1ORd1、-(CHRd10)p2C(O)Rd2、-(CHRd10)p3NHC(O)Rd3、-(CHRd10)p4C(O)NHRd4、-(CHRd10)p5NRd5Rd6、-(CHRd10)p6S(O)p7Rd7、-(CHRd10)p8S(O)2NHRd8、-(CHRd10)p9NHS(O)2Rd9，所述的氨基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基任选地可以进一步被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代；R 4-1 ″ and R 4-2 ″ are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl , 3-8 membered heterocyclyl , C 6-10 aryl, 5-10 membered heteroaryl, -(CHR d10 ) p1 OR d1 , -(CHR d10 ) p2 C(O)R d2 , -(CHR d10 ) p3 NHC(O)R d3 , -(CHR d10 ) p4 C(O)NHR d4 d10 , -(CHR d10 ) p5 NR d5 R d6 , -(CHR d10 ) p6 S(O) p7 R d7 , -(CHR d10 ) p8 S(O) 2 NHR d8 , -(CHR d10 ) p9 NHS(O) 2 R d9 , 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl , C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C The 6-10 membered aryl or 5-10 membered heteroaryl may be further optionally substituted with one or more of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl;
优选地，R4-1”和R4-2”各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基、5-10元杂芳基、-(CH2)p1ORd1、-(CH2)p2C(O)Rd2、-(CH2)p3NHC(O)Rd3、-(CH2)p4C(O)NHRd4、-(CH2)p5NRd5Rd6、-(CH2)p6S(O)p7Rd7、-(CH2)p8S(O)2NHRd8、-(CH2)p9NHS(O)2Rd9，所述的氨基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基任选地可以进一步被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代；Preferably, R 4-1 "and R 4-2 "are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl , 3-8 membered heterocyclyl , C 6-10 aryl, 5-10 membered heteroaryl, -(CH 2 ) p1 OR d1 , -(CH 2 ) p2 C(O)R d2 , -(CH 2 ) p3 NHC(O)R d3 , -(CH 2 ) p4 C(O)NHR d4 , -(CH 2 ) p4 p5 NR d5 R d6 , -(CH 2 ) p6 S(O) p7 R d7 , -(CH 2 ) p8 S(O) 2 NHR d8 , -(CH 2 ) p9 NHS(O) 2 R d9 , 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl may be further optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C 1-6 alkyl, C 2-6 alkenyl, C The alkyl group may be substituted by one or more of C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl , C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl;
R5”选自氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基、5-10元杂芳基、-(CH2)q1ORe1、-(CH2)q2C(O)Re2、-(CH2)q3NHC(O)Re3、-(CH2)q4C(O)NHRe4、-(CH2)q5NRe5Re6、-(CH2)q6S(O)q7Re7、-(CH2)q8S(O)2NHRe8、-(CH2)q9NHS(O)2Re9，所述的氨基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基任选地可以进一步被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代；R 5 ″ is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, -(CH 2 ) q1 OR e1 , -(CH 2 ) q2 C(O)R e2 , -(CH 2 ) q3 NHC(O)R e3 , -(CH 2 ) q4 C(O)NHR e4 , -(CH 2 ) q5 NR e5 R e6 , -(CH 2 wherein 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl may be further substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl. substituted by one or more of C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl;
Ra1、Ra2、Ra3、Ra4、Ra5、Ra6、Ra7、Ra8和Ra9各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基、5-10元杂芳基，所述的氨基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基任选地可以进一步被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代； Ra1 , Ra2 , Ra3 , Ra4 , Ra5 , Ra6 , Ra7 , Ra8 and Ra9 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, and the amino, C1-6 alkyl , C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl , C1-6 alkoxy , C C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl may be further optionally substituted with one or more of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl , 3-8 membered heterocyclyl , C 6-10 aryl and 5-10 membered heteroaryl;
Rb1、Rb2、Rb3、Rb4、Rb5、Rb6、Rb7、Rb8和Rb9各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基、5-10元杂芳基，所述的氨基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基任选地可以进一步被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代；R b1 , R b2 , R b3 , R b4 , R b5 , R b6 , R b7 , R b8 and R b9 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, said 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 , C C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl may be further optionally substituted with one or more of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl , 3-8 membered heterocyclyl , C 6-10 aryl and 5-10 membered heteroaryl;
Rc1、Rc2、Rc3、Rc4、Rc5、Rc6、Rc7、Rc8和Rc9各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基、5-10元杂芳基，所述的氨基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基任选地可以进一步被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代；R c1 , R c2 , R c3 , R c4 , R c5 , R c6 , R c7 , R c8 and R c9 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, said 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 , C C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl may be further optionally substituted with one or more of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl , 3-8 membered heterocyclyl , C 6-10 aryl and 5-10 membered heteroaryl;
Rd1、Rd2、Rd3、Rd4、Rd5、Rd6、Rd7、Rd8、Rd9和Rd10各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基、5-10元杂芳基，所述的氨基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基任选地可以进一步被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代； Rd1 , Rd2 , Rd3, Rd4 , Rd5 , Rd6 , Rd7 , Rd8 , Rd9 and Rd10 are each independently selected from hydrogen, deuterium , halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, wherein the amino, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy , C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl may be further optionally substituted with one or more of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl;
Re1、Re2、Re3、Re4、Re5、Re6、Re7、Re8和Re9各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基、5-10元杂芳基，所述的氨基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基任选地可以进一步被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代； Re1 , Re2 , Re3 , Re4 , Re5 , Re6 , Re7 , Re8 and Re9 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, said amino , C1-6 alkyl , C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl , C1-6 alkoxy , C C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl may be further optionally substituted with one or more of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl , 3-8 membered heterocyclyl , C 6-10 aryl and 5-10 membered heteroaryl;
m”为1、2、3、4或5；m” is 1, 2, 3, 4 or 5;
x”为0、1、2、3、4或5；x” is 0, 1, 2, 3, 4, or 5;
m1、m2、m3、m4、m5、m6、m8、m9各自独立地选自0、1、2、3、4、5或6；m1, m2, m3, m4, m5, m6, m8, m9 are each independently selected from 0, 1, 2, 3, 4, 5 or 6;
n1、n2、n3、n4、n5、n6、n8、n9各自独立地选自0、1、2、3、4、5或6；n1, n2, n3, n4, n5, n6, n8, n9 are each independently selected from 0, 1, 2, 3, 4, 5 or 6;
o1、o2、o3、o4、o5、o6、o8、o9各自独立地选自0、1、2、3、4、5或6；o1, o2, o3, o4, o5, o6, o8, o9 are each independently selected from 0, 1, 2, 3, 4, 5 or 6;
p1、p2、p3、p4、p5、p6、p8、p9各自独立地选自0、1、2、3、4、5或6；p1, p2, p3, p4, p5, p6, p8, p9 are each independently selected from 0, 1, 2, 3, 4, 5 or 6;
q1、q2、q3、q4、q5、q6、q8、q9各自独立地选自0、1、2、3、4、5或6；q1, q2, q3, q4, q5, q6, q8, q9 are each independently selected from 0, 1, 2, 3, 4, 5 or 6;
r1、r2、r3各自独立地选自0、1或2；r1, r2, r3 are each independently selected from 0, 1 or 2;
m7、n7、o7、p7、q7各自独立地选自0、1、2或3。m7, n7, o7, p7, q7 are each independently selected from 0, 1, 2 or 3.
在本发明的某些实施方案中，所述如通式(IV”)所示的化合物如通式(IV”-1)所示：In certain embodiments of the present invention, the compound represented by the general formula (IV") is represented by the general formula (IV"-1):
本发明还提供了一种如通式(V”)所示的化合物、其立体异构体或其药学上可接受的盐：The present invention also provides a compound represented by general formula (V"), a stereoisomer thereof or a pharmaceutically acceptable salt thereof:
M2”选自N、CH或CR3-3”；M 2 ″ is selected from N, CH or CR 3-3 ″;
环A”选自C6-10芳基或5-10元杂芳基；Ring A" is selected from C 6-10 aryl or 5-10 membered heteroaryl;
R1”独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基、5-10元杂芳基、-(CH2)m1ORa1、-(CH2)m2C(O)Ra2、-(CH2)m3NHC(O)Ra3、-(CH2)m4C(O)NHRa4、-(CH2)m5NRa5Ra6、-(CH2)m6S(O)m7Ra7、-(CH2)m8S(O)2NHRa8、-(CH2)m9NHS(O)2Ra9，所述的氨基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基任选地可以进一步被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代；R 1 "is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, -(CH 2 ) m1 OR a1 , -(CH 2 ) m2 C(O)R a2 , -(CH 2 ) m3 NHC(O)R a3 , -(CH 2 ) m4 C(O)NHR a4 , -(CH 2 ) m5 NR a5 R a6 , -(CH 2 ) m5 m6 S(O) m7 R a7 , -(CH 2 ) m8 S(O) 2 NHR a8 , -(CH 2 ) m9 NHS(O) 2 R a9 , wherein 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl may be further optionally substituted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl. substituted by one or more of C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl;
R2-1”和R2-2”各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基、5-10元杂芳基、-(CH2)n1ORb1、-(CH2)n2C(O)Rb2、-(CH2)n3NHC(O)Rb3、-(CH2)n4C(O)NHRb4、-(CH2)n5NRb5Rb6、-(CH2)n6S(O)n7Rb7、-(CH2)n8S(O)2NHRb8、-(CH2)n9NHS(O)2Rb9，所述的氨基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基任选地可以进一步被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代；R 2-1 ″ and R 2-2 ″ are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl , 3-8 membered heterocyclyl , C 6-10 aryl, 5-10 membered heteroaryl, -(CH 2 ) n1 OR b1 , -(CH 2 ) n2 C(O)R b2 , -(CH 2 ) n3 NHC(O)R b3 , -(CH 2 ) n4 C(O)NHR b4 , -(CH 2 ) n5 NR b5 R b6 , -( CH2 ) n6S (O) n7Rb7 , -( CH2 ) n8S (O) 2NHRb8 , -( CH2 ) n9NHS (O) 2Rb9 , the amino, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl , C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl or 5-10 membered heteroaryl may be further optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C The group may be substituted by one or more of C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl;
R3-1”和R3-2”各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基、5-10元杂芳基、-(CH2)o1ORc1、-(CH2)o2C(O)Rc2、-(CH2)o3NHC(O)Rc3、-(CH2)o4C(O)NHRc4、-(CH2)o5NRc5Rc6、-(CH2)o6S(O)o7Rc7、-(CH2)o8S(O)2NHRc8、-(CH2)o9NHS(O)2Rc9，所述的氨基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基任选地可以进一步被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代；R 3-1 " and R 3-2 " are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl , 3-8 membered heterocyclyl , C 6-10 aryl, 5-10 membered heteroaryl, -(CH 2 ) o1 OR c1 , -(CH 2 ) o2 C(O)R c2 , -(CH 2 ) o3 NHC(O)R c3 , -(CH 2 ) o4 C(O)NHR c4 , -(CH 2 ) o5 NR c5 R c6 , -( CH2 ) o6S (O) o7Rc7 , -( CH2 ) o8S (O) 2NHRc8 , -( CH2 ) o9NHS (O) 2Rc9 , the amino, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl , C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl or 5-10 membered heteroaryl may be further optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C The group may be substituted by one or more of C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl;
R3-3”选自氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基、5-10元杂芳基、-(CH2)o1ORc1、-(CH2)o2C(O)Rc2、-(CH2)o3NHC(O)Rc3、-(CH2)o4C(O)NHRc4、-(CH2)o5NRc5Rc6、-(CH2)o6S(O)o7Rc7、-(CH2)o8S(O)2NHRc8、-(CH2)o9NHS(O)2Rc9，所述的氨基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基任选地可以进一步被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代；R 3-3 "is selected from deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, -(CH 2 ) o1 OR c1 , -(CH 2 ) o2 C(O)R c2 , -(CH 2 ) o3 NHC(O)R c3 , -(CH 2 ) o4 C(O)NHR c4 , -( CH 2 ) o5 NR c5 R c6 , -(CH 2 ) o6 S(O) o7Rc7 , -( CH2 ) o8S (O) 2NHRc8 , -( CH2 ) o9NHS (O) 2Rc9 , the amino, C1-6 alkyl, C2-6 alkenyl , C2-6 alkynyl, C1-6 deuterated alkyl , C1-6 haloalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl or 5-10 membered heteroaryl may be further optionally substituted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl or 5-10 membered heteroaryl. substituted by one or more of C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl;
R4-1”和R4-2”各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基、5-10元杂芳基、-(CHRd10)p1ORd1、-(CHRd10)p2C(O)Rd2、-(CHRd10)p3NHC(O)Rd3、-(CHRd10)p4C(O)NHRd4、-(CHRd10)p5NRd5Rd6、-(CHRd10)p6S(O)p7Rd7、-(CHRd10)p8S(O)2NHRd8、-(CHRd10)p9NHS(O)2Rd9，所述的氨基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基任选地可以进一步被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代；R 4-1 ″ and R 4-2 ″ are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl , 3-8 membered heterocyclyl , C 6-10 aryl, 5-10 membered heteroaryl, -(CHR d10 ) p1 OR d1 , -(CHR d10 ) p2 C(O)R d2 , -(CHR d10 ) p3 NHC(O)R d3 , -(CHR d10 ) p4 C(O)NHR d4 d10 , -(CHR d10 ) p5 NR d5 R d6 , -(CHR d10 ) p6 S(O) p7 R d7 , -(CHR d10 ) p8 S(O) 2 NHR d8 , -(CHR d10 ) p9 NHS(O) 2 R d9 , 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl , C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C The 6-10 membered aryl or 5-10 membered heteroaryl may be further optionally substituted with one or more of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl;
R5”选自氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基、5-10元杂芳基、-(CH2)q1ORe1、-(CH2)q2C(O)Re2、-(CH2)q3NHC(O)Re3、-(CH2)q4C(O)NHRe4、-(CH2)q5NRe5Re6、-(CH2)q6S(O)q7Re7、-(CH2)q8S(O)2NHRe8、-(CH2)q9NHS(O)2Re9，所述的氨基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基任选地可以进一步被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代；R 5 ″ is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, -(CH 2 ) q1 OR e1 , -(CH 2 ) q2 C(O)R e2 , -(CH 2 ) q3 NHC(O)R e3 , -(CH 2 ) q4 C(O)NHR e4 , -(CH 2 ) q5 NR e5 R e6 , -(CH 2 wherein 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl may be further substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl. substituted by one or more of C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl;
Ra1、Ra2、Ra3、Ra4、Ra5、Ra6、Ra7、Ra8和Ra9各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基、5-10元杂芳基，所述的氨基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基任选地可以进一步被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代； Ra1 , Ra2 , Ra3 , Ra4 , Ra5 , Ra6 , Ra7 , Ra8 and Ra9 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, and the amino, C1-6 alkyl , C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl , C1-6 alkoxy , C C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl may be further optionally substituted with one or more of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl , 3-8 membered heterocyclyl , C 6-10 aryl and 5-10 membered heteroaryl;
Rb1、Rb2、Rb3、Rb4、Rb5、Rb6、Rb7、Rb8和Rb9各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基、5-10元杂芳基，所述的氨基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基任选地可以进一步被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代；R b1 , R b2 , R b3 , R b4 , R b5 , R b6 , R b7 , R b8 and R b9 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, said 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 , C C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl may be further optionally substituted with one or more of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl , 3-8 membered heterocyclyl , C 6-10 aryl and 5-10 membered heteroaryl;
Rc1、Rc2、Rc3、Rc4、Rc5、Rc6、Rc7、Rc8和Rc9各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基、5-10元杂芳基，所述的氨基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基任选地可以进一步被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代；R c1 , R c2 , R c3 , R c4 , R c5 , R c6 , R c7 , R c8 and R c9 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, said 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 , C C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl may be further optionally substituted with one or more of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl , 3-8 membered heterocyclyl , C 6-10 aryl and 5-10 membered heteroaryl;
Rd1、Rd2、Rd3、Rd4、Rd5、Rd6、Rd7、Rd8、Rd9和Rd10各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基、5-10元杂芳基，所述的氨基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基任选地可以进一步被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代； Rd1 , Rd2 , Rd3, Rd4 , Rd5 , Rd6 , Rd7 , Rd8 , Rd9 and Rd10 are each independently selected from hydrogen, deuterium , halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, wherein the amino, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy , C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl may be further optionally substituted with one or more of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl;
Re1、Re2、Re3、Re4、Re5、Re6、Re7、Re8和Re9各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基、5-10元杂芳基，所述的氨基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基任选地可以进一步被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代； Re1 , Re2 , Re3 , Re4 , Re5 , Re6 , Re7 , Re8 and Re9 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, said amino , C1-6 alkyl , C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl , C1-6 alkoxy , C C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl may be further optionally substituted with one or more of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl , 3-8 membered heterocyclyl , C 6-10 aryl and 5-10 membered heteroaryl;
n”为1、2、3、4或5；n” is 1, 2, 3, 4 or 5;
x”为0、1、2、3、4或5；x” is 0, 1, 2, 3, 4, or 5;
y”为0、1、2、3、4或5；y” is 0, 1, 2, 3, 4, or 5;
m1、m2、m3、m4、m5、m6、m8、m9各自独立地选自0、1、2、3、4、5或6；m1, m2, m3, m4, m5, m6, m8, m9 are each independently selected from 0, 1, 2, 3, 4, 5 or 6;
n1、n2、n3、n4、n5、n6、n8、n9各自独立地选自0、1、2、3、4、5或6；n1, n2, n3, n4, n5, n6, n8, n9 are each independently selected from 0, 1, 2, 3, 4, 5 or 6;
o1、o2、o3、o4、o5、o6、o8、o9各自独立地选自0、1、2、3、4、5或6；o1, o2, o3, o4, o5, o6, o8, o9 are each independently selected from 0, 1, 2, 3, 4, 5 or 6;
p1、p2、p3、p4、p5、p6、p8、p9各自独立地选自0、1、2、3、4、5或6；p1, p2, p3, p4, p5, p6, p8, p9 are each independently selected from 0, 1, 2, 3, 4, 5 or 6;
q1、q2、q3、q4、q5、q6、q8、q9各自独立地选自0、1、2、3、4、5或6；q1, q2, q3, q4, q5, q6, q8, q9 are each independently selected from 0, 1, 2, 3, 4, 5 or 6;
r1、r2、r3各自独立地选自0、1或2；r1, r2, r3 are each independently selected from 0, 1 or 2;
m7、n7、o7、p7、q7各自独立地选自0、1、2或3。m7, n7, o7, p7, q7 are each independently selected from 0, 1, 2 or 3.
在本发明的某些实施方案，所述的式(V”)所示化合物如式(V”-1)或式(V”-2)所示：In certain embodiments of the present invention, the compound represented by formula (V") is represented by formula (V"-1) or formula (V"-2):
在本发明的某些实施方案，所述的式(V”-1)或式(V”-2)所示化合物如式(V”-1-1)或式(V”-2-1)所示：In certain embodiments of the present invention, the compound represented by formula (V"-1) or formula (V"-2) is as represented by formula (V"-1-1) or formula (V"-2-1):
在本发明的某些实施方案，环A”选自5-10元杂芳基，优选为5-6元杂芳基，更优选为5元杂芳基，进一步优选为 In certain embodiments of the present invention, ring A" is selected from 5-10 membered heteroaryl, preferably 5-6 membered heteroaryl, more preferably 5 membered heteroaryl, and further preferably
在本发明的某些实施方案中，L1”选自-O-、-CH2O-或-CF2-。In certain embodiments of the present invention, L 1 ″ is selected from —O—, —CH 2 O—, or —CF 2 —.
在本发明的某些实施方案中，L1”选自键、-O-、-CH2O-或-CF2-。In certain embodiments of the present invention, L 1 ″ is selected from a bond, —O—, —CH 2 O—, or —CF 2 —.
在本发明的某些实施方案中，L1”选自键。In certain embodiments of the present invention, L 1 ″ is selected from a bond.
在本发明的某些实施方案中，R1”独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-3烷基、C2-4烯基、C2-4炔基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3氘代烷氧基、C1-3卤代烷氧基、C1-3羟烷基、C3-6环烷基、3-6元杂环基、C6-10芳基、5-6元杂芳基、-(CH2)m1ORa1、-(CH2)m2C(O)Ra2、-(CH2)m3NHC(O)Ra3、-(CH2)m4C(O)NHRa4、-(CH2)m5NRa5Ra6、-(CH2)m6S(O)m7Ra7、-(CH2)m8S(O)2NHRa8、-(CH2)m9NHS(O)2Ra9，所述的氨基、C1-3烷基、C2-4烯基、C2-4炔基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3氘代烷氧基、C1-3卤代烷氧基、C1-3羟烷基、C3-6环烷基、3-6元杂环基、C6-10芳基或5-6元杂芳基任选地可以进一步被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-3烷基、C2-4烯基、C2-4炔基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3氘代烷氧基、C1-3卤代烷氧基、C1-3羟烷基、C3-6环烷基、3-6元杂环基、C6-10芳基和5-6元杂芳基中的一个或多个取代。In certain embodiments of the present invention, R 1 "is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, 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, C 1-3 deuterated alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-10 aryl, 5-6 membered heteroaryl, -(CH 2 ) m1 OR a1 , -(CH 2 ) m2 C(O)R a2 , -(CH 2 ) m3 NHC(O)R a3 , -(CH 2 ) m4 C(O)NHR a4 , -(CH 2 ) m5 NR a5 R a6 , -(CH 2 ) m5 wherein the amino, 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, C 1-3 deuterated alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-10 aryl or 5-6 membered heteroaryl may be further substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, 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, C 1-3 deuterated alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-10 aryl or 5-6 membered heteroaryl. The group may be substituted by one or more of C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 deuterated alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-10 aryl and 5-6 membered heteroaryl.
在本发明的某些实施方案中，Ra1、Ra2、Ra3、Ra4、Ra5、Ra6、Ra7、Ra8和Ra9各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-3烷基、C2-4烯基、C2-4炔基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3氘代烷氧基、C1-3卤代烷氧基、C1-3羟烷基、C3-6环烷基、3-6元杂环基、C6-10芳基、5-6元杂芳基，所述的氨基、C1-3烷基、C2-4烯基、C2-4炔基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3氘代烷氧基、C1-3卤代烷氧基、C1-3羟烷基、C3-6环烷基、3-6元杂环基、C6-10芳基或5-6元杂芳基任选地可以进一步被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-3烷基、C2-4烯基、C2-4炔基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3氘代烷氧基、C1-3卤代烷氧基、C1-3羟烷基、C3-6环烷基、3-6元杂环基、C6-10芳基和5-6元杂芳基中的一个或多个取代。In certain embodiments of the present invention, Ra1 , Ra2 , Ra3 , Ra4 , Ra5 , Ra6 , Ra7 , Ra8 and Ra9 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C1-3 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-3 deuterated alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 deuterated alkoxy, C1-3 haloalkoxy, C1-3 hydroxyalkyl, C3-6 cycloalkyl, 3-6 membered heterocyclyl, C6-10 aryl, 5-6 membered heteroaryl, wherein the amino, C1-3 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-3 deuterated alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 deuterated alkoxy, C1-3 haloalkoxy, C1-3 hydroxyalkyl, C3-6 cycloalkyl, 3-6 membered heterocyclyl, C6-10 aryl, 5-6 membered heteroaryl The C 1-3 alkoxy, C 1-3 deuterated alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-10 aryl or 5-6 membered heteroaryl may optionally be further substituted with one or more of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, 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, C 1-3 deuterated alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl , C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-10 aryl and 5-6 membered heteroaryl.
在本发明的某些实施方案中，R1”独立地为三氟甲基、氟、氯或氘。In certain embodiments of the present invention, R 1 ″ is independently trifluoromethyl, fluorine, chlorine, or deuterium.
在本发明的某些实施方案中，R1”独立地为三氟甲基、氟或氘。In certain embodiments of the invention, R 1 ″ is independently trifluoromethyl, fluorine or deuterium.
在本发明的某些实施方案中，R1”为三氟甲基。In certain embodiments of the present invention, R 1 ″ is trifluoromethyl.
在本发明的某些实施方案中，R1-1”独立地为氟。In certain embodiments of the present invention, R 1-1 ″ is independently fluorine.
在本发明的某些实施方案中，R2-1”和R2-2”各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-3烷基、C2-4烯基、C2-4炔基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3氘代烷氧基、C1-3卤代烷氧基、C1-3羟烷基、C3-6环烷基、3-6元杂环基、C6-10芳基、5-6元杂芳基、-(CH2)n1ORb1、-(CH2)n2C(O)Rb2、-(CH2)n3NHC(O)Rb3、-(CH2)n4C(O)NHRb4、-(CH2)n5NRb5Rb6、-(CH2)n6S(O)n7Rb7、-(CH2)n8S(O)2NHRb8、-(CH2)n9NHS(O)2Rb9，所述的氨基、C1-3烷基、C2-4烯基、C2-4炔基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3氘代烷氧基、C1-3卤代烷氧基、C1-3羟烷基、C3-6环烷基、3-6元杂环基、C6-10芳基或5-6元杂芳基任选地可以进一步被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-3烷基、C2-4烯基、C2-4炔基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3氘代烷氧基、C1-3卤代烷氧基、C1-3羟烷基、C3-6环烷基、3-6元杂环基、C6-10芳基和5-6元杂芳基中的一个或多个取代。In certain embodiments of the present invention, R 2-1 "and R 2-2 "are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, 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, C 1-3 deuterated alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl , C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-10 aryl, 5-6 membered heteroaryl, -(CH 2 ) n1 OR b1 , -(CH 2 ) n2 C(O)R b2 , -(CH 2 ) n3 NHC(O)R b3 , -(CH 2 ) n4 C(O)NHR b4 , -(CH 2 ) n5 NR b1, -(CH 2 ) n6 wherein the amino, 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 , C 1-3 deuterated alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl , C 3-6 cycloalkyl , 3-6 membered heterocyclyl, C 6-10 aryl or 5-6 membered heteroaryl group may be further substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-3 alkyl , C 2-4 alkenyl, C 2-4 alkynyl , C The group may be substituted by one or more of C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 deuterated alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-10 aryl and 5-6 membered heteroaryl.
在本发明的某些实施方案中，Rb1、Rb2、Rb3、Rb4、Rb5、Rb6、Rb7、Rb8和Rb9各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-3烷基、C2-4烯基、C2-4炔基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3氘代烷氧基、C1-3卤代烷氧基、C1-3羟烷基、C3-6环烷基、3-6元杂环基、C6-10芳基、5-6元杂芳基，所述的氨基、C1-3烷基、C2-4烯基、C2-4炔基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3氘代烷氧基、C1-3卤代烷氧基、C1-3羟烷基、C3-6环烷基、3-6元杂环基、C6-10芳基或5-6元杂芳基任选地可以进一步被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-3烷基、C2-4烯基、C2-4炔基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3氘代烷氧基、C1-3卤代烷氧基、C1-3羟烷基、C3-6环烷基、3-6元杂环基、C6-10芳基和5-6元杂芳基中的一个或多个取代。In certain embodiments of the present invention, R b1 , R b2 , R b3 , R b4 , R b5 , R b6 , R b7 , R b8 and R b9 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, 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, C 1-3 deuterated alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-10 aryl, 5-6 membered heteroaryl, wherein the amino, 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, C 1-3 deuterated alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-10 aryl, 5-6 membered heteroaryl The C 1-3 alkoxy, C 1-3 deuterated alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-10 aryl or 5-6 membered heteroaryl may optionally be further substituted with one or more of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, 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, C 1-3 deuterated alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl , C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-10 aryl and 5-6 membered heteroaryl.
在本发明的某些实施方案中，R2-1”选自氢、甲基、二氟甲基、环丙基、In certain embodiments of the present invention, R 2-1 ″ is selected from Hydrogen, methyl, difluoromethyl, cyclopropyl,
在本发明的某些实施方案中，R2-1”选自氢、甲基、二氟甲基、环丙基、 In certain embodiments of the present invention, R 2-1 ″ is selected from Hydrogen, methyl, difluoromethyl, cyclopropyl,
在本发明的某些实施方案中，R2-1”选自氢、甲基、环丙基、 In certain embodiments of the present invention, R 2-1 ″ is selected from Hydrogen, methyl, cyclopropyl,
在本发明的某些实施方案中，R2-2”选自氢。In certain embodiments of the present invention, R 2-2 ″ is selected from hydrogen.
在本发明的某些实施方案中，R3-1”和R3-2”各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-3烷基、C2-4烯基、C2-4炔基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3氘代烷氧基、C1-3卤代烷氧基、C1-3羟烷基、C3-6环烷基、3-6元杂环基、C6-10芳基、5-6元杂芳基、-(CH2)o1ORc1、-(CH2)o2C(O)Rc2、-(CH2)o3NHC(O)Rc3、-(CH2)o4C(O)NHRc4、-(CH2)o5NRc5Rc6、-(CH2)o6S(O)o7Rc7、-(CH2)o8S(O)2NHRc8、-(CH2)o9NHS(O)2Rc9，所述的氨基、C1-3烷基、C2-4烯基、C2-4炔基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3氘代烷氧基、C1-3卤代烷氧基、C1-3羟烷基、C3-6环烷基、3-6元杂环基、C6-10芳基或5-6元杂芳基任选地可以进一步被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-3烷基、C2-4烯基、C2-4炔基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3氘代烷氧基、C1-3卤代烷氧基、C1-3羟烷基、C3-6环烷基、3-6元杂环基、C6-10芳基和5-6元杂芳基中的一个或多个取代。In certain embodiments of the present invention, R 3-1 "and R 3-2 "are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, 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, C 1-3 deuterated alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl , C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-10 aryl, 5-6 membered heteroaryl, -(CH 2 ) o1 OR c1 , -(CH 2 ) o2 C(O)R c2 , -(CH 2 ) o3 NHC(O)R c3 , -(CH 2 ) o4 C(O)NHR c4, -(CH 2 ) o5 NR c1 , -(CH 2 ) o6 c5 R c6 , -(CH 2 ) o6 S(O) o7 R c7 , -(CH 2 ) o8 S(O) 2 NHR c8 , -(CH 2 ) o9 NHS(O) 2 R c9 , the amino, 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, C 1-3 deuterated alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl , C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-10 aryl or 5-6 membered heteroaryl may be further optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C The group may be substituted by one or more of C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 deuterated alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-10 aryl and 5-6 membered heteroaryl.
在本发明的某些实施方案中，R3-3”选自氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-3烷基、C2-4烯基、C2-4炔基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3氘代烷氧基、C1-3卤代烷氧基、C1-3羟烷基、C3-6环烷基、3-6元杂环基、C6-10芳基、5-6元杂芳基、-(CH2)o1ORc1、-(CH2)o2C(O)Rc2、-(CH2)o3NHC(O)Rc3、-(CH2)o4C(O)NHRc4、-(CH2)o5NRc5Rc6、-(CH2)o6S(O)o7Rc7、-(CH2)o8S(O)2NHRc8、-(CH2)o9NHS(O)2Rc9，所述的氨基、C1-3烷基、C2-4烯基、C2-4炔基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3氘代烷氧基、C1-3卤代烷氧基、C1-3羟烷基、C3-6环烷基、3-6元杂环基、C6-10芳基或5-6元杂芳基任选地可以进一步被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-3烷基、C2-4烯基、C2-4炔基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3氘代烷氧基、C1-3卤代烷氧基、C1-3羟烷基、C3-6环烷基、3-6元杂环基、C6-10芳基和5-6元杂芳基中的一个或多个取代。In certain embodiments of the present invention, R 3-3 "is selected from deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, 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, C 1-3 deuterated alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-10 aryl, 5-6 membered heteroaryl, -(CH 2 ) o1 OR c1 , -(CH 2 ) o2 C(O)R c2 , -(CH 2 ) o3 NHC(O)R c3 , -(CH 2 ) o4 C(O)NHR c4 , -(CH 2 ) o5 NR c5 R c6 , -(CH 2 wherein the amino, 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, C 1-3 deuterated alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl , C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-10 aryl or 5-6 membered heteroaryl may be further substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, 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, C 1-3 deuterated alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-10 aryl or 5-6 membered heteroaryl. The group may be substituted by one or more of C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 deuterated alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-10 aryl and 5-6 membered heteroaryl.
在本发明的某些实施方案中，Rc1、Rc2、Rc3、Rc4、Rc5、Rc6、Rc7、Rc8和Rc9各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-3烷基、C2-4烯基、C2-4炔基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3氘代烷氧基、C1-3卤代烷氧基、C1-3羟烷基、C3-6环烷基、3-6元杂环基、C6-10芳基、5-6元杂芳基，所述的氨基、C1-3烷基、C2-4烯基、C2-4炔基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3氘代烷氧基、C1-3卤代烷氧基、C1-3羟烷基、C3-6环烷基、3-6元杂环基、C6-10芳基或5-6元杂芳基任选地可以进一步被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-3烷基、C2-4烯基、C2-4炔基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3氘代烷氧基、C1-3卤代烷氧基、C1-3羟烷基、C3-6环烷基、3-6元杂环基、C6-10芳基和5-6元杂芳基中的一个或多个取代。In certain embodiments of the present invention, Rc1 , Rc2 , Rc3 , Rc4 , Rc5 , Rc6 , Rc7 , Rc8 and Rc9 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C1-3 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-3 deuterated alkyl, C1-3 haloalkyl, C1-3 alkoxy , C1-3 deuterated alkoxy, C1-3 haloalkoxy, C1-3 hydroxyalkyl, C3-6 cycloalkyl, 3-6 membered heterocyclyl, C6-10 aryl, 5-6 membered heteroaryl, wherein the amino, C1-3 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-3 deuterated alkyl, C1-3 haloalkyl, C1-3 The C 1-3 alkoxy, C 1-3 deuterated alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-10 aryl or 5-6 membered heteroaryl may optionally be further substituted with one or more of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, 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, C 1-3 deuterated alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl , C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-10 aryl and 5-6 membered heteroaryl.
在本发明的某些实施方案中，R3-1”和R3-2”各自独立地为氢。In certain embodiments of the present invention, R 3-1 ″ and R 3-2 ″ are each independently hydrogen.
在本发明的某些实施方案中，R3-3”选自氟。In certain embodiments of the present invention, R 3-3 ″ is selected from fluorine.
在本发明的某些实施方案中，R4-1”和R4-2”各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基、5-10元杂芳基、-(CHRd10)p1ORd1、-(CHRd10)p2C(O)Rd2、-(CHRd10)p3NHC(O)Rd3、-(CHRd10)p4C(O)NHRd4、-(CHRd10)p5NRd5Rd6、-(CHRd10)p6S(O)p7Rd7、-(CHRd10)p8S(O)2NHRd8、-(CHRd10)p9NHS(O)2Rd9，所述的氨基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基任选地可以进一步被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代。In certain embodiments of the present invention, R 4-1 "and R 4-2 "are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, -(CHR d10 ) p1 OR d1 , -(CHR d10 ) p2 C(O)R d2 , -(CHR d10 ) p3 NHC(O)R d3 , -(CHR d10 ) p4 C(O)NHR d4 , -(CHR d10 ) p5 NR d5 R d6 , -(CHR d10 ) p6 S(O) p7 R d7 , -(CHR d10 ) p8 S(O) 2 NHR d8 , -(CHR d10 ) p9 NHS(O) 2 R d9 , 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, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C The 6-10 membered aryl or 5-10 membered heteroaryl may optionally be further substituted with one or more of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, 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 , C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl.
在本发明的某些实施方案中，R4-1”和R4-2”各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-3烷基、C2-4烯基、C2-4炔基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3氘代烷氧基、C1-3卤代烷氧基、C1-3羟烷基、C3-8环烷基、3-6元杂环基、C6-10芳基、5-6元杂芳基、-(CH2)p1ORd1、-(CH2)p2C(O)Rd2、-(CH2)p3NHC(O)Rd3、-(CH2)p4C(O)NHRd4、-(CH2)p5NRd5Rd6、-(CH2)p6S(O)p7Rd7、-(CH2)p8S(O)2NHRd8、-(CH2)p9NHS(O)2Rd9，所述的氨基、C1-3烷基、C2-4烯基、C2-4炔基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3氘代烷氧基、C1-3卤代烷氧基、C1-3羟烷基、C3-8环烷基、3-6元杂环基、C6-10芳基或5-6元杂芳基任选地可以进一步被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-3烷基、C2-4烯基、C2-4炔基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3氘代烷氧基、C1-3卤代烷氧基、C1-3羟烷基、C3-6环烷基、3-6元杂环基、C6-10芳基和5-6元杂芳基中的一个或多个取代。In certain embodiments of the present invention, R4-1 " and R4-2 " are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C1-3 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-3 deuterated alkyl, C1-3 haloalkyl, C1-3 alkoxy , C1-3 deuterated alkoxy, C1-3 haloalkoxy, C1-3 hydroxyalkyl, C3-8 cycloalkyl, 3-6 membered heterocyclyl, C6-10 aryl, 5-6 membered heteroaryl, -( CH2 ) p1ORd1 , -( CH2 ) p2C (O) Rd2 , -( CH2 ) p3NHC (O) Rd3 , -( CH2 ) p4C (O) NHRd4 , -( CH2 ) p5 NR d5 R d6 , -(CH 2 ) p6 S(O) p7 R d7 , -(CH 2 ) p8 S(O) 2 NHR d8 , -(CH 2 ) p9 NHS(O) 2 R d9 , the amino, 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, C 1-3 deuterated alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 3-8 cycloalkyl, 3-6 membered heterocyclyl, C 6-10 aryl or 5-6 membered heteroaryl may be further optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C 1-3 alkyl, C 2-4 alkenyl, C The group may be substituted by one or more of C 2-4 alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 deuterated alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl , C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-10 aryl and 5-6 membered heteroaryl.
在本发明的某些实施方案中，Rd1、Rd2、Rd3、Rd4、Rd5、Rd6、Rd7、Rd8、Rd9和Rd10各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-3烷基、C2-4烯基、C2-4炔基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3氘代烷氧基、C1-3卤代烷氧基、C1-3羟烷基、C3-6环烷基、3-6元杂环基、C6-10芳基、5-6元杂芳基，所述的氨基、C1-3烷基、C2-4烯基、C2-4炔基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3氘代烷氧基、C1-3卤代烷氧基、C1-3羟烷基、C3-6环烷基、3-6元杂环基、C6-10芳基或5-6元杂芳基任选地可以进一步被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-3烷基、C2-4烯基、C2-4炔基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3氘代烷氧基、C1-3卤代烷氧基、C1-3羟烷基、C3-6环烷基、3-6元杂环基、C6-10芳基和5-6元杂芳基中的一个或多个取代。In certain embodiments of the invention, Rd1 , Rd2 , Rd3 , Rd4 , Rd5 , Rd6 , Rd7 , Rd8 , Rd9 and Rd10 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C1-3 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-3 deuterated alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 deuterated alkoxy, C1-3 haloalkoxy, C1-3 hydroxyalkyl, C3-6 cycloalkyl, 3-6 membered heterocyclyl, C6-10 aryl, 5-6 membered heteroaryl, wherein the amino, C1-3 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-3 deuterated alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 deuterated alkoxy, C1-3 haloalkoxy, C1-3 hydroxyalkyl, C3-6 cycloalkyl, 3-6 membered heterocyclyl, C6-10 aryl, 5-6 membered heteroaryl The C1-3 haloalkyl, C1-3 alkoxy, C1-3 deuterated alkoxy, C1-3 haloalkoxy, C1-3 hydroxyalkyl, C3-6 cycloalkyl, 3-6 membered heterocyclyl, C6-10 aryl or 5-6 membered heteroaryl may optionally be further substituted with one or more of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C1-3 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-3 deuterated alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 deuterated alkoxy, C1-3 haloalkoxy, C1-3 hydroxyalkyl, C3-6 cycloalkyl, 3-6 membered heterocyclyl, C6-10 aryl and 5-6 membered heteroaryl.
在本发明的某些实施方案中，R4-1”选自 In certain embodiments of the present invention, R 4-1 ″ is selected from
在本发明的某些实施方案中，R4-1”选自 In certain embodiments of the present invention, R 4-1 ″ is selected from
在本发明的某些实施方案中，R4-1”选自 In certain embodiments of the present invention, R 4-1 ″ is selected from
在本发明的某些实施方案中，R4-1”选自 In certain embodiments of the present invention, R 4-1 ″ is selected from
在本发明的某些实施方案中，R4-2”选自氢。In certain embodiments of the present invention, R 4-2 ″ is selected from hydrogen.
在本发明的某些实施方案中，R5”选自氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-3烷基、C2-4烯基、C2-4炔基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3氘代烷氧基、C1-3卤代烷氧基、C1-3羟烷基、C3-6环烷基、3-6元杂环基、C6-10芳基、5-6元杂芳基、-(CH2)q1ORe1、-(CH2)q2C(O)Re2、-(CH2)q3NHC(O)Re3、-(CH2)q4C(O)NHRe4、-(CH2)q5NRe5Re6、-(CH2)q6S(O)q7Re7、-(CH2)q8S(O)2NHRe8、-(CH2)q9NHS(O)2Re9，所述的氨基、C1-3烷基、C2-4烯基、C2-4炔基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3氘代烷氧基、C1-3卤代烷氧基、C1-3羟烷基、C3-6环烷基、3-6元杂环基、C6-10芳基或5-6元杂芳基任选地可以进一步被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-3烷基、C2-4烯基、C2-4炔基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3氘代烷氧基、C1-3卤代烷氧基、C1-3羟烷基、C3-6环烷基、3-6元杂环基、C6-10芳基和5-6元杂芳基中的一个或多个取代。In certain embodiments of the present invention, R 5 ″ is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, 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, C 1-3 deuterated alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl , C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-10 aryl, 5-6 membered heteroaryl, -(CH 2 ) q1 OR e1 , -(CH 2 ) q2 C(O)R e2 , -(CH 2 ) q3 NHC(O)R e3 , -(CH 2 ) q4 C(O)NHR e4 , -(CH 2 ) q5 NR e5 R e6 wherein the amino, 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, C 1-3 deuterated alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl , C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-10 aryl or 5-6 membered heteroaryl may be further substituted with hydrogen, deuterium , halogen, amino , hydroxyl, cyano, nitro, oxo, thio, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl , C The group may be substituted by one or more of C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 deuterated alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-10 aryl and 5-6 membered heteroaryl.
在本发明的某些实施方案中，Re1、Re2、Re3、Re4、Re5、Re6、Re7、Re8和Re9各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-3烷基、C2-4烯基、C2-4炔基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3氘代烷氧基、C1-3卤代烷氧基、C1-3羟烷基、C3-6环烷基、3-6元杂环基、C6-10芳基、5-6元杂芳基，所述的氨基、C1-3烷基、C2-4烯基、C2-4炔基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3氘代烷氧基、C1-3卤代烷氧基、C1-3羟烷基、C3-6环烷基、3-6元杂环基、C6-10芳基或5-6元杂芳基任选地可以进一步被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-3烷基、C2-4烯基、C2-4炔基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3氘代烷氧基、C1-3卤代烷氧基、C1-3羟烷基、C3-6环烷基、3-6元杂环基、C6-10芳基和5-6元杂芳基中的一个或多个取代。In certain embodiments of the present invention, Re1 , Re2 , Re3 , Re4 , Re5 , Re6 , Re7 , Re8 and Re9 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C1-3 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-3 deuterated alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 deuterated alkoxy, C1-3 haloalkoxy, C1-3 hydroxyalkyl, C3-6 cycloalkyl, 3-6 membered heterocyclyl, C6-10 aryl, 5-6 membered heteroaryl, wherein the amino, C1-3 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-3 deuterated alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 deuterated alkoxy, C1-3 haloalkoxy, C1-3 hydroxyalkyl, C3-6 cycloalkyl, 3-6 membered heterocyclyl, C6-10 aryl, 5-6 membered heteroaryl The C 1-3 alkoxy, C 1-3 deuterated alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-10 aryl or 5-6 membered heteroaryl may optionally be further substituted with one or more of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, 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, C 1-3 deuterated alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl , C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-10 aryl and 5-6 membered heteroaryl.
在本发明的某些实施方案中，R5”选自5-6元杂芳基，所述的5-6元杂芳基任选地可以进一步被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-3烷基、C2-4烯基、C2-4炔基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3氘代烷氧基、C1-3卤代烷氧基、C1-3羟烷基、C3-6环烷基、3-6元杂环基、C6-10芳基和5-6元杂芳基中的一个或多个取代；In certain embodiments of the present invention, R 5 " is selected from 5-6 membered heteroaryl, which may be further optionally substituted by one or more of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, 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, C 1-3 deuterated alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-10 aryl and 5-6 membered heteroaryl;
更优选地，R5”选自所述的任选地可以进一步被氢、氘、卤素、氨基、羟基、氰基、硝基、氧代基、硫代基、C1-3烷基、C2-4烯基、C2-4炔基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3氘代烷氧基、C1-3卤代烷氧基、C1-3羟烷基、C3-6环烷基、3-6元杂环基、C6-10芳基和5-6元杂芳基中的一个或多个取代。More preferably, R 5 ″ is selected from The Optionally, it may be further substituted by one or more of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C1-3 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-3 deuterated alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 deuterated alkoxy, C1-3 haloalkoxy, C1-3 hydroxyalkyl, C3-6 cycloalkyl, 3-6 membered heterocyclyl, C6-10 aryl and 5-6 membered heteroaryl.
在本发明的某些实施方案中，R5”选自环丙基、异丙基、环丁基、 In certain embodiments of the present invention, R 5 " is selected from cyclopropyl, isopropyl, cyclobutyl,
在本发明的某些实施方案中，R5”选自甲基或异丙基。本发明还提供了一种药物组合物，其包括治疗有效剂量的所述化合物、其立体异构体或其药学上可接受的盐以及一种或多种药学上可接受的载体、稀释剂或赋形剂。In certain embodiments of the present invention, R 5 ″ is selected from methyl or isopropyl. The present invention also provides a pharmaceutical composition comprising a therapeutically effective dose of the compound, its stereoisomer or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers, diluents or excipients.
在本发明的某些实施方案中，所述化合物、其立体异构体或其药学上可接受盐，在组合物中所占的重量百分比为0.1％～95％，优选0.5％～85％，更优选1％～60％，进一步优选10％～50％，更进一步优选15-40％，更进一步优选20-30％，更进一步优选20-25％(以药物组合物总重计)。In certain embodiments of the present invention, the weight percentage of the compound, its stereoisomer or pharmaceutically acceptable salt thereof in the composition is 0.1% to 95%, preferably 0.5% to 85%, more preferably 1% to 60%, further preferably 10% to 50%, further preferably 15-40%, further preferably 20-30%, further preferably 20-25% (based on the total weight of the pharmaceutical composition).
在本发明的某些实施方案中，所述化合物、其立体异构体或其药学上可接受盐的给药剂量为1mg-1000mg，例如，1mg、5mg、10mg、20mg、30mg、40mg、50mg、60mg、70mg、80mg、90mg、100mg、150mg、200mg、250mg、300mg、350mg、400mg、450mg、500mg、550mg、600mg、650mg、700mg、750mg、800mg、850mg、900mg、950mg、1000mg(或者它们之间的任意整数)。In certain embodiments of the present invention, the compound, its stereoisomer or its pharmaceutically acceptable salt is administered in a dosage of 1 mg-1000 mg, for example, 1 mg, 5 mg, 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg (or any integer therebetween).
本发明进一步涉及所述化合物、其立体异构体或其药学上可接受的盐，或所述的药物组合物在制备IL-17抑制剂药物中的应用。所述的IL-17优选为IL-17A。The present invention further relates to the use of the compound, its stereoisomer or pharmaceutically acceptable salt, or the pharmaceutical composition in the preparation of IL-17 inhibitor drugs. The IL-17 is preferably IL-17A.
本发明进一步涉及所述化合物、其立体异构体或其药学上可接受的盐，或其药物组合物在制备治疗自身免疫性疾病药物中的应用，其中所述自身免疫性疾病优选选自银屑病、斑块状银屑病、点状银屑病、逆向银屑病、脓疱性银屑病、红皮病性银屑病、银屑病性关节炎、强直性脊柱炎、化脓性汗腺炎、类风湿性关节炎、掌跖银屑病、脊椎关节炎和非感染性葡萄膜炎。The present invention further relates to the use of the compound, its stereoisomer or pharmaceutically acceptable salt, or its pharmaceutical composition in the preparation of a drug for treating an autoimmune disease, wherein the autoimmune disease is preferably selected from psoriasis, plaque psoriasis, guttate psoriasis, inverse psoriasis, pustular psoriasis, erythrodermic psoriasis, psoriatic arthritis, ankylosing spondylitis, suppurative hidradenitis, rheumatoid arthritis, palmoplantar psoriasis, spondyloarthritis and non-infectious uveitis.
本发明还涉及一种治疗预防和/或治疗自身免疫性疾病的方法，其包括向患者施用治疗有效剂量的所述的化合物其立体异构体或其药学上可接受的盐，或其药物组合物。The present invention also relates to a method for preventing and/or treating autoimmune diseases, which comprises administering a therapeutically effective dose of the compound, its stereoisomer or its pharmaceutically acceptable salt, or its pharmaceutical composition to the patient.
在本发明的某些实施方案中，所述自身免疫性疾病选自银屑病、斑块状银屑病、点状银屑病、逆向银屑病、脓疱性银屑病、红皮病性银屑病、银屑病性关节炎、强直性脊柱炎、化脓性汗腺炎、类风湿性关节炎、掌跖银屑病、脊椎关节炎和非感染性葡萄膜炎。In certain embodiments of the invention, the autoimmune disease is selected from psoriasis, plaque psoriasis, guttate psoriasis, inverse psoriasis, pustular psoriasis, erythrodermic psoriasis, psoriatic arthritis, ankylosing spondylitis, hidradenitis suppurativa, rheumatoid arthritis, palmoplantar psoriasis, spondyloarthritis and non-infectious uveitis.
发明的详细说明Detailed description of the invention
除非有相反陈述，此处所用的所有技术和科学术语通常与本领域普通技术人员的一般理解具有相同的含义，具体而言，在说明书和权利要求书中使用的术语具有下述含义。Unless otherwise stated, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art. Specifically, the terms used in the specification and claims have the following meanings.
术语“烷基”指直链或支链的饱和脂肪族烃基团，所述烷基可任选地被一个或多个取代基取代。在特定的实施方式中，烷基是指具有1至20(C1-20)、1至15(C1-15)、1至12(C1-12)、1至10(C1-10)、1至8(C1-8)、1至6(C1-6)或1至3(C1-3)个碳原子的直链饱和烃基，或者具有3至20(C3-20)、3至15(C3-15)、3至12(C3-12)、3至10(C3-10)、3至8(C3-8)或3至6(C3-6)个碳原子的带支链饱和烃基。此处所用的直链C1-6烷基和带支链C3-6烷基基团也称为“低级烷基”。例如，C1-6烷基指具有1至6个碳原子的线性饱和单价烃基或者具有3至6个碳原子的带支链饱和单价烃基。在一个实施方式中，所述C1-6烷基含有1至6个(例如1个、2个、3个、4个、5个、6个)碳原子。非限制性实例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基、正庚基、2-甲基己基、3-甲基己基、4-甲基己基、5-甲基己基、2,3-二甲基戊基、2,4-二甲基戊基、2,2-二甲基戊基、3,3-二甲基戊基、2-乙基戊基、3-乙基戊基、正辛基、2,3-二甲基己基、2,4-二甲基己基、2,5-二甲基己基、2,2-二甲基己基、3,3-二甲基己基、4,4-二甲基己基、2-乙基己基、3-乙基己基、4-乙基己基、2-甲基-2-乙基戊基、2-甲基-3-乙基戊基、正壬基、2-甲基-2-乙基己基、2-甲基-3-乙基己基、2,2-二乙基戊基、正癸基、3,3-二乙基己基、2,2-二乙基己基及其各种支链异构体等。在一个实施方式中，该烷基是本文别处描述的任选地取代的烷基。The term "alkyl" refers to a straight or branched saturated aliphatic hydrocarbon group, which may be optionally substituted with one or more substituents. In a specific embodiment, the alkyl group refers to a straight chain saturated hydrocarbon group having 1 to 20 (C 1-20 ), 1 to 15 (C 1-15 ), 1 to 12 (C 1-12 ), 1 to 10 (C 1-10 ), 1 to 8 (C 1-8 ), 1 to 6 (C 1-6 ) or 1 to 3 (C 1-3 ) carbon atoms, or a branched saturated hydrocarbon group having 3 to 20 (C 3-20 ), 3 to 15 (C 3-15 ), 3 to 12 (C 3-12 ), 3 to 10 (C 3-10 ), 3 to 8 (C 3-8 ) or 3 to 6 (C 3-6 ) carbon atoms. As used herein, straight-chain C 1-6 alkyl and branched C 3-6 alkyl groups are also referred to as "lower alkyl". For example, C 1-6 alkyl refers to a linear saturated monovalent hydrocarbon group having 1 to 6 carbon atoms or a branched saturated monovalent hydrocarbon group having 3 to 6 carbon atoms. In one embodiment, the C 1-6 alkyl contains 1 to 6 (e.g., 1, 2, 3, 4, 5, 6) 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-methylhexyl, 5-methylhexyl, 2, 3-ethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl and various branched chain isomers thereof, and the like. In one embodiment, the alkyl group is an optionally substituted alkyl group described elsewhere herein.
术语“亚烷基”是指烷基的一个氢原子进一步被取代，其中“烷基”的定义同前所述。“亚烷基”的非限制性实例包括：亚甲基(-CH2-)、亚乙基(-(CH2)2-)、亚丙基(-(CH2)3-)或亚丁基(-(CH2)4-)。在一个实施方式中，该亚烷基是本文别处描述的任选地取代的烷基。The term "alkylene" refers to an alkyl group in which one hydrogen atom is further substituted, wherein "alkyl" is as defined above. Non-limiting examples of "alkylene" include: methylene ( -CH2- ), ethylene (-( CH2 ) 2- ), propylene (-( CH2 ) 3- ) or butylene (-( CH2 ) 4- ). In one embodiment, the alkylene is an optionally substituted alkyl group as described elsewhere herein.
术语“烯基”指直链或支链的不饱和脂肪族烃基团，其含有至少一个碳碳双键且碳碳双键可以位于烯基内的任何位置，所述烯基可任选地被一个或多个取代基所取代。在特定的实施方式中，烯基是具有2至20(C2-20)、2至15(C2-15)、2至12(C2-12)、2至10(C2-10)、2至8(C2-8)、2至6(C2-6)或2至4(C2-4)个碳原子的直链不饱和烃基，或者具有3至20(C3-20)、3至15(C3-15)、3至12(C3-12)、3至10(C3-10)、3至8(C3-8)或3至6(C3-6)个碳原子的带支链不饱和烃基。除非另行指明，此处所用的术语“烯基”同时包括了直链和带支链的烯基。例如，C2-6烯基指具有2至6个碳原子的直链不饱和烃基或者具有3至6个碳原子的带支链不饱和烃基。在一个实施方式中，所述C2-6烯基含有2至6个(例如2个、3个、4个、5个、6个)碳原子。烯基的非限制性实例包括： 本领域普通技术人员可以理解，术语“烯基”还可包括具有“顺式”和“反式”构型的基团，或者替代性地，“E”和“Z”构型的基团。在一个实施方式中，该烯基是本文别处描述的任选地取代的烯基。The term "alkenyl" refers to a straight or branched unsaturated aliphatic hydrocarbon group containing at least one carbon-carbon double bond and the carbon-carbon double bond may be located at any position within the alkenyl group, and the alkenyl group may be optionally substituted with one or more substituents. In certain embodiments, alkenyl is a straight chain unsaturated hydrocarbon group having 2 to 20 (C 2-20 ), 2 to 15 (C 2-15 ), 2 to 12 (C 2-12 ), 2 to 10 (C 2-10 ), 2 to 8 (C 2-8 ), 2 to 6 (C 2-6 ) or 2 to 4 (C 2-4 ) carbon atoms, or a branched unsaturated hydrocarbon group having 3 to 20 (C 3-20 ), 3 to 15 (C 3-15 ), 3 to 12 (C 3-12 ), 3 to 10 (C 3-10 ), 3 to 8 (C 3-8 ) or 3 to 6 (C 3-6 ) carbon atoms. Unless otherwise specified, the term "alkenyl" as used herein includes both straight chain and branched alkenyl groups. For example, C2-6 alkenyl refers to a straight chain unsaturated hydrocarbon group having 2 to 6 carbon atoms or a branched unsaturated hydrocarbon group having 3 to 6 carbon atoms. In one embodiment, the C2-6 alkenyl contains 2 to 6 (e.g., 2, 3, 4, 5, 6) carbon atoms. Non-limiting examples of alkenyl include: One of ordinary skill in the art will appreciate that the term "alkenyl" may also include groups having "cis" and "trans" configurations, or alternatively, groups having "E" and "Z" configurations. In one embodiment, the alkenyl is an optionally substituted alkenyl described elsewhere herein.
术语“炔基”指直链或支链不饱和脂肪族烃基团，其含有至少一个碳碳三键且碳碳三键可以位于炔基内的任何位置，所述炔基可任选地被一个或多个取代基所取代。在特定的实施方式中，炔基是具有2至20(C2-20)、2至15(C2-15)、2至12(C2-12)、2至10(C2-10)、2至8(C2-8)、2至6(C2-6)或2至4(C2-4)个碳原子的直链不饱和烃基，或者具有3至20(C3-20)、3至15(C3-15)、3至12(C3-12)、3至10(C3-10)、3至8(C3-8)或3至6(C3-6)个碳原子的带支链不饱和烃基。除非另行指明，此处所用的术语“炔基”同时包括了直链和带支链的炔基。例如，C2-6炔基指具有2至6个碳原子的直链不饱和烃基或者具有3至6个碳原子的带支链不饱和烃基。在一个实施方式中，所述C2-6炔基含有2至6个(例如2个、3个、4个、5个、6个)碳原子。炔基的非限制性实例包括： 在一个实施方式中，该炔基是本文别处描述的任选地取代的炔基。The term "alkynyl" refers to a straight or branched unsaturated aliphatic hydrocarbon group containing at least one carbon-carbon triple bond and the carbon-carbon triple bond can be located at any position within the alkynyl group, and the alkynyl group can be optionally substituted with one or more substituents. In a specific embodiment, the alkynyl group is a straight chain unsaturated hydrocarbon group having 2 to 20 (C 2-20 ), 2 to 15 (C 2-15 ), 2 to 12 (C 2-12 ), 2 to 10 (C 2-10 ), 2 to 8 (C 2-8 ), 2 to 6 (C 2-6 ) or 2 to 4 (C 2-4 ) carbon atoms, or a branched unsaturated hydrocarbon group having 3 to 20 (C 3-20 ), 3 to 15 (C 3-15 ), 3 to 12 (C 3-12 ), 3 to 10 (C 3-10 ), 3 to 8 (C 3-8 ) or 3 to 6 (C 3-6 ) carbon atoms. Unless otherwise indicated, the term "alkynyl" as used herein includes both straight-chain and branched alkynyl groups. For example, C2-6 alkynyl refers to a straight-chain unsaturated hydrocarbon group having 2 to 6 carbon atoms or a branched unsaturated hydrocarbon group having 3 to 6 carbon atoms. In one embodiment, the C2-6 alkynyl group contains 2 to 6 (e.g., 2, 3, 4, 5, 6) carbon atoms. Non-limiting examples of alkynyl groups include: In one embodiment, the alkynyl group is an optionally substituted alkynyl group described elsewhere herein.
术语“环烷基”指饱和或部分不饱和的脂肪烃单环、多环(两个及以上)环状基团，其可任选地被一个或多个取代基取代。在特定的实施方式中，环烷基环包含3至20(C3-20)、3至12(C3-12)、3至8(C3-8)或3至6(C3-6)个碳原子；在一个实施方式中，环烷基环包含6至14(C6-14)或7至10(C7-10)个碳原子；其可以含有一个或多个双键，但不具有完全共轭的π电子系统。单环环烷基的非限制性实例包括环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基、环庚三烯基或环辛基等；多环环烷基包括螺环烷基、稠环烷基和桥环烷基在一个实施方式中。在一个实施方式中，该环烷基是本文别处描述的任选地取代的环烷基或任选与杂环基、芳基或杂芳基稠合的环烷基，非限制性实例包括茚满基、四氢萘基、苯并环庚烷基等。The term "cycloalkyl" refers to a saturated or partially unsaturated aliphatic hydrocarbon monocyclic, polycyclic (two or more) cyclic group, which may be optionally substituted by one or more substituents. In a specific embodiment, the cycloalkyl ring contains 3 to 20 (C 3-20 ), 3 to 12 (C 3-12 ), 3 to 8 (C 3-8 ) or 3 to 6 (C 3-6 ) carbon atoms; in one embodiment, the cycloalkyl ring contains 6 to 14 (C 6-14 ) or 7 to 10 (C 7-10 ) carbon atoms; it may contain one or more double bonds, but does not have a completely conjugated π electron system. Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl or cyclooctyl, etc.; polycyclic cycloalkyls include spirocycloalkyl, fused cycloalkyl and bridged cycloalkyl in one embodiment. In one embodiment, the cycloalkyl is an optionally substituted cycloalkyl or a cycloalkyl optionally fused to a heterocyclyl, aryl or heteroaryl group as described elsewhere herein, non-limiting examples of which include indanyl, tetrahydronaphthyl, benzocycloheptanyl, and the like.
术语“螺环烷基”指单环之间共用一个碳原子(称螺原子)的脂肪烃多环基团，其可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。在特定的实施方式中，螺环烷基包含5至20(C5-20)、6至14(C6-14)或7至10(C7-10)(例如7个、8个、9个、10个)个碳原子。根据环与环之间共用螺原子的数目将螺环烷基分为单螺环烷基、双螺环烷基或多螺环烷基，在一个实施方式中为单螺环烷基和双螺环烷基。在一个实施方式中为4元/4元、3元/5元、4元/5元、4元/6元、5元/5元或5元/6元单螺环烷基。在一个实施方式中，该螺环烷基是本文别处描述的任选地取代的螺环烷基。螺环烷基的非限制性实例包括：The term "spirocycloalkyl" refers to an aliphatic hydrocarbon polycyclic group that shares a carbon atom (called a spiral atom) between monocyclic rings, which may contain one or more double bonds, but no ring has a completely conjugated π electron system. In a specific embodiment, the spirocycloalkyl comprises 5 to 20 (C 5-20 ), 6 to 14 (C 6-14 ) or 7 to 10 (C 7-10 ) (e.g., 7, 8, 9, 10) carbon atoms. According to the number of spiral atoms shared between rings, the spirocycloalkyl is divided into a single spiral cycloalkyl, a double spiral cycloalkyl or a multi-spirocycloalkyl, in one embodiment, a single spiral cycloalkyl and a double spiral cycloalkyl. In one embodiment, it is a 4 yuan/4 yuan, 3 yuan/5 yuan, 4 yuan/5 yuan, 4 yuan/6 yuan, 5 yuan/5 yuan or 5 yuan/6 yuan single spiral cycloalkyl. In one embodiment, the spirocycloalkyl is an optionally substituted spirocycloalkyl described elsewhere herein. Non-limiting examples of spirocycloalkyl include:
术语“稠环烷基”指系统中的每个环与体系中的其他环共享毗邻的一对碳原子的全碳多环基团，其中一个或多个环可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。在特定的实施方式中，稠环烷基包含5至20(C5-20)、6至14(C6-14)或7至10(C7-10)(例如7个、8个、9个、10个)个碳原子。根据组成环的数目可以分为双环、三环、四环或多环稠环烷基，在一个实施方式中为双环或三环，进一步在一个实施方式中为3元/5元、4元/5元、5元/5元或5元/6元双环烷基。在一个实施方式中，该稠环烷基是本文别处描述的任选地取代的稠环烷基或任选与杂环基、芳基或杂芳基稠合的稠环烷基。稠环烷基的非限制性实例包括：The term "fused cycloalkyl" refers to a full carbon polycyclic group in which each ring in the system shares a pair of adjacent carbon atoms with other rings in the system, wherein one or more rings may contain one or more double bonds, but no ring has a completely conjugated π electron system. In a specific embodiment, the fused cycloalkyl comprises 5 to 20 (C 5-20 ), 6 to 14 (C 6-14 ) or 7 to 10 (C 7-10 ) (e.g., 7, 8, 9, 10) carbon atoms. According to the number of constituent rings, it can be divided into a bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl, in one embodiment, a bicyclic or tricyclic, and further in one embodiment, a 3 yuan/5 yuan, 4 yuan/5 yuan, 5 yuan/5 yuan or 5 yuan/6 yuan bicyclic alkyl. In one embodiment, the fused cycloalkyl is an optionally substituted fused cycloalkyl described elsewhere herein or a fused cycloalkyl optionally fused to a heterocyclic radical, an aryl or a heteroaryl. Non-limiting examples of fused cycloalkyls include:
术语“桥环烷基”指任意两个环共用两个不直接连接的碳原子的全碳多环基团，其可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。在特定的实施方式中，桥环烷基包含5至20(C5-20)、6至14(C6-14)或7至10(C7-10)(例如7个、8个、9个、10个)个碳原子。根据组成环的数目可以分为双环、三环、四环或多环桥环烷基，优选双环或三环。在一个实施方式中，该桥环烷基是本文别处描述的任选地取代的桥环烷基。桥环烷基的非限制性实例包括：The term "bridged cycloalkyl" refers to a full carbon polycyclic group in which any two rings share two carbon atoms that are not directly connected, which may contain one or more double bonds, but no ring has a completely conjugated π electron system. In a specific embodiment, the bridged cycloalkyl contains 5 to 20 (C 5-20 ), 6 to 14 (C 6-14 ) or 7 to 10 (C 7-10 ) (e.g., 7, 8, 9, 10) carbon atoms. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl, preferably bicyclic or tricyclic. In one embodiment, the bridged cycloalkyl is an optionally substituted bridged cycloalkyl described elsewhere herein. Non-limiting examples of bridged cycloalkyl include:
术语“杂环基”指饱和或部分不饱和单环或多环环状烃基团，其中一个或多个环原子为选自氮、氧、硼、磷或硫的杂原子，其中该氮、磷或硫原子可被任选地氧化，氮原子可被任选地季铵化，环碳原子可任选地被氧取代，但不包括-O-O-、-O-S-的环部分，其余环原子为碳，其可以含有一个或多个双键，但不具有完全共轭的π电子系统。在特定实施方式中，杂环基包含3至20、3至12、3至8或3至6个环原子，其中1～4个是杂原子；在一个实施方式中，杂环基包含3至6、4至6、3至8、3至10、6至10或7至11个环原子；在一个实施方式中，杂环基包含3至8个(例如3个、4个、5个、6个、7个、8个)环原子。单环杂环基的非限制性实例包括四氢吡咯基、氮杂环丁烷基、氧杂环丁烷基、氧杂环己烷基、四氢呋喃基、四氢吡喃基、四氢噻吩基、二氢咪唑基、二氢呋喃基、二氢吡唑基、二氢吡咯基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、高哌嗪基和吡喃基等。多环杂环基包括螺杂环基、稠杂环基和桥杂环基。在一个实施方式中，所述的杂环基是本文别处描述的任选地取代的，或者通过环上的任意两个或者两个以上的原子与其他环烷基、杂环基、芳基和杂芳基进一步并环连接的杂环基。The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon group, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, boron, phosphorus or sulfur, wherein the nitrogen, phosphorus or sulfur atom may be optionally oxidized, the nitrogen atom may be optionally quaternized, the ring carbon atom may be optionally substituted by oxygen, but does not include the ring part of -O-O-, -O-S-, and the remaining ring atoms are carbon, which may contain one or more double bonds, but does not have a completely conjugated π electron system. In a specific embodiment, the heterocyclyl contains 3 to 20, 3 to 12, 3 to 8 or 3 to 6 ring atoms, of which 1 to 4 are heteroatoms; in one embodiment, the heterocyclyl contains 3 to 6, 4 to 6, 3 to 8, 3 to 10, 6 to 10 or 7 to 11 ring atoms; in one embodiment, the heterocyclyl contains 3 to 8 (e.g., 3, 4, 5, 6, 7, 8) ring atoms. The limiting examples of monocyclic heterocyclic radical include tetrahydropyrrolyl, azetidinyl, oxetanyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl and pyranyl etc..Polycyclic heterocyclic radical includes spiro heterocyclic radical, condensed heterocyclic radical and bridge heterocyclic radical.In one embodiment, the heterocyclic radical is the optionally substituted described elsewhere herein, or the heterocyclic radical further and ring-connected with other cycloalkyl, heterocyclic radical, aryl and heteroaryl by any two or more atoms on the ring.
术语“螺杂环基”指环之间共用一个原子(称螺原子)的多环杂环基团，其中一个或多个环原子为选自氮、氧、硼、磷或硫的杂原子，其余环原子为碳，其可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。在特定实施方式中，螺杂环基包含5至20或6至14个环原子；在一个实施方式中包含7至11个(例如7个、8个、9个、10个、11个)个环原子；根据环与环之间共用螺原子的数目将螺杂环基分为单螺杂环基、双螺杂环基或多螺杂环基；优选单螺杂环基和双螺杂环基；在一个实施方式中，螺杂环基为4元/4元、4元/5元、4元/6元、5元/5元或5元/6元单螺杂环基；在一个实施方式中，该螺杂环基是本文别处描述的任选地取代的螺杂环基；螺杂环基的非限制性实例包括：The term "spiroheterocyclyl" refers to a polycyclic heterocyclic group in which one atom (called a spiro atom) is shared between the rings, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, boron, phosphorus or sulfur, and the remaining ring atoms are carbon, which may contain one or more double bonds, but no ring has a completely conjugated π electron system. In a specific embodiment, the spiroheterocyclyl contains 5 to 20 or 6 to 14 ring atoms; in one embodiment, it contains 7 to 11 (e.g., 7, 8, 9, 10, 11) ring atoms; according to the number of spiro atoms shared between the rings, the spiroheterocyclyl is divided into a monospiroheterocyclyl, a bispiroheterocyclyl or a polyspiroheterocyclyl; preferably a monospiroheterocyclyl and a bispiroheterocyclyl; in one embodiment, the spiroheterocyclyl is a 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered monospiroheterocyclyl; in one embodiment, the spiroheterocyclyl is an optionally substituted spiroheterocyclyl described elsewhere herein; non-limiting examples of spiroheterocyclyls include:
术语“稠杂环基”指系统中的每个环与体系中的其他环共享毗邻的一对原子的多环杂环基团，一个或多个环可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统，其中一个或多个环原子为选自氮、氧、硼、磷或硫的杂原子，其余环原子为碳。在特定实施方式中，稠杂环基为包含5至20或6至14个环原子，在一个实施方式中包含7至10个(例如7个、8个、9个、10个)环原子；根据组成环的数目可以分为双环、三环、四环或多环稠杂环基；优选双环或三环；在一个实施方式中为5元/5元或5元/6元双环稠杂环基；在一个实施方式中，该稠杂环基是本文别处描述的任选地取代的，或可与环烷基、杂环基、芳基或杂芳基稠合的稠杂环基；稠杂环基的非限制性实例包括：The term "fused heterocyclic group" refers to a polycyclic heterocyclic group in which each ring in the system shares a pair of adjacent atoms with other rings in the system, one or more rings may contain one or more double bonds, but no ring has a completely conjugated π electron system, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, boron, phosphorus or sulfur, and the remaining ring atoms are carbon. In a specific embodiment, the fused heterocyclic group is a heterocyclic group containing 5 to 20 or 6 to 14 ring atoms, and in one embodiment contains 7 to 10 (e.g., 7, 8, 9, 10) ring atoms; according to the number of constituent rings, it can be divided into a bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic group; preferably a bicyclic or tricyclic group; in one embodiment, it is a 5-membered/5-membered or 5-membered/6-membered bicyclic fused heterocyclic group; in one embodiment, the fused heterocyclic group is a fused heterocyclic group described elsewhere herein that is optionally substituted or fused with a cycloalkyl, heterocyclic, aryl or heteroaryl group; non-limiting examples of fused heterocyclic groups include:
术语“桥杂环基”指任意两个环共用两个不直接连接的原子的多环杂环基团，其可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统，其中一个或多个环原子为选自氮、氧、硼、磷或硫的杂原子，其余环原子为碳。在特定的实施方式中，桥杂环基包含5至20或6至14个环原子；在一个实施方式中包含7至10个(例如7个、8个、9个、10个)环原子；根据组成环的数目可以分为双环、三环、四环或多环桥杂环基；优选双环、三环或四环；在一个实施方式中为双环或三环；在一个实施方式中，该桥杂环基是本文别处描述的任选地取代的桥杂环基；桥杂环基的非限制性实例包括：The term "bridged heterocyclic group" refers to a polycyclic heterocyclic group in which any two rings share two atoms that are not directly connected, which may contain one or more double bonds, but none of the rings has a completely conjugated π electron system, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, boron, phosphorus or sulfur, and the remaining ring atoms are carbon. In a specific embodiment, the bridged heterocyclic group contains 5 to 20 or 6 to 14 ring atoms; in one embodiment, it contains 7 to 10 (e.g., 7, 8, 9, 10) ring atoms; according to the number of constituent rings, it can be divided into a bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic group; preferably a bicyclic, tricyclic or tetracyclic group; in one embodiment, it is a bicyclic or tricyclic group; in one embodiment, the bridged heterocyclic group is an optionally substituted bridged heterocyclic group described elsewhere herein; non-limiting examples of bridged heterocyclic groups include:
术语“芳基”指至少含有一个具有共轭的π电子体系的全碳单环或稠合多环(也就是共享毗邻碳原子对的环)基团，其可任选地被一个或多个取代基取代。在特定的实施方式中，芳基包含6至20个、6至14个或6至10个环原子；在一个实施方式中，芳基可以进一步指双环、三环或四环的环系统，其中至少一个环是芳香族环，其他的环可以是饱和的、部分不饱和的碳环或包含一个或多个独立选自O、S和N的杂原子的环；在一个实施方式中，所述芳基选自苯并5-10元杂芳基、苯并3-10元环烷基或苯并3-10元杂环基。在一个实施方式中，所述芳基选自苯并5-6元杂芳基、苯并3-6元环烷基或苯并3-6元杂环基，其中杂环基为含1-3个氮原子、氧原子或硫原子的杂环基。其非限制性实例包括苯基、萘基、芴基、甘菊环基、蒽基、菲基、芘基、联苯基、三联苯基、二氢萘基、茚基、四氢萘基(萘满基)、 The term "aryl" refers to an all-carbon monocyclic or fused polycyclic (i.e., rings that share adjacent pairs of carbon atoms) group containing at least one conjugated π electron system, which may be optionally substituted by one or more substituents. In a particular embodiment, the aryl group contains 6 to 20, 6 to 14, or 6 to 10 ring atoms; in one embodiment, the aryl group may further refer to a bicyclic, tricyclic, or tetracyclic ring system, wherein at least one ring is an aromatic ring, and the other rings may be saturated, partially unsaturated carbon rings, or rings containing one or more heteroatoms independently selected from O, S, and N; in one embodiment, the aryl group is selected from a benzo 5-10 membered heteroaryl, a benzo 3-10 membered cycloalkyl, or a benzo 3-10 membered heterocyclyl. In one embodiment, the aryl group is selected from a benzo 5-6 membered heteroaryl, a benzo 3-6 membered cycloalkyl, or a benzo 3-6 membered heterocyclyl, wherein the heterocyclyl group is a heterocyclyl group containing 1-3 nitrogen atoms, oxygen atoms, or sulfur atoms. Non-limiting examples include phenyl, naphthyl, fluorenyl, azulenyl, anthracenyl, phenanthrenyl, pyrenyl, biphenyl, terphenyl, dihydronaphthyl, indenyl, tetrahydronaphthyl (tetralinyl),
术语“亚芳基”是指芳基的一个氢原子进一步被取代形成的二价芳基，其中，亚芳基是任选取代的或非取代的，芳基定义如上所述。The term "arylene group" refers to a divalent aromatic group formed by further replacing one hydrogen atom of an aromatic group, wherein the arylene group is optionally substituted or unsubstituted, and the aromatic group is as defined above.
术语“杂芳基”指包含至少一个芳香族环的任选地取代的单环、多环基团或环系统，其中该芳香族环具有一个或多个独立选自O、S和N的杂原子。在特定的实施方式中，杂芳基包含5至20个、5至15个或者5至10个环原子，其中1至4个为杂原子；在一个实施方式中，杂芳基包含5个或6个环原子；在特定的实施方式中，杂芳基可以进一步指双环、三环或四环状环，其中至少含有一个环是具有一个或多个独立选自O、S和N的杂原子的芳香族环，其他的环可以是饱和的、部分不饱和的碳环或包含一个或多个独立选自O、S和N的杂原子的环。在一个实施方式中，所述杂芳基选自杂芳基并6-10元芳基、杂芳基并3-10元环烷基或杂芳基并3-10元杂环基；进一步在一个实施方式中，所述杂芳基选自5元或6元杂芳基并6-10元芳基、5元或6元杂芳基并3-6元环烷基、5元或6元杂芳基并3-6元杂环基，其中杂环基为含1-3个氮原子、氧原子或硫原子的杂环基。其非限制性实例包括：呋喃基、咪唑基、异噻唑基、异噁唑基、噁二唑基、噁唑基、吡嗪基、吡唑基、哒嗪基、吡啶基、嘧啶基、吡咯基、噻二唑基、噻唑基、噻吩基、四唑基、三嗪基、三唑基、苯并呋喃基、苯并咪唑基、苯并异噁唑基、苯并吡喃基、苯并噻二唑基、苯并噻吩基、苯并苯硫基、苯并噻吩基、苯并三唑基、咪唑并吡啶基、咪唑并噻唑基、吲嗪基、吲哚基、吲唑基、异苯并呋喃基、异苯并噻吩基、异吲哚基、异喹啉基、萘啶基、噁唑并吡啶基、酞嗪基、蝶啶基、嘌呤基、吡啶并吡啶基、吡咯并吡啶基、喹啉基、喹喔啉基、喹唑啉基、噻二唑并嘧啶基、噻吩并吡啶基、吖啶基、苯并吲哚基、咔唑基、联苯并呋喃基、菲咯啉基、菲啶基、吩吡嗪基、吩嗪基、吩噻嗪基、吩噁嗪基、呫吨基、 The term "heteroaryl" refers to an optionally substituted monocyclic, polycyclic group or ring system containing at least one aromatic ring, wherein the aromatic ring has one or more heteroatoms independently selected from O, S and N. In specific embodiments, the heteroaryl group contains 5 to 20, 5 to 15 or 5 to 10 ring atoms, of which 1 to 4 are heteroatoms; in one embodiment, the heteroaryl group contains 5 or 6 ring atoms; in specific embodiments, the heteroaryl group may further refer to a bicyclic, tricyclic or tetracyclic ring, wherein at least one ring is an aromatic ring having one or more heteroatoms independently selected from O, S and N, and the other rings may be saturated, partially unsaturated carbocyclic rings or rings containing one or more heteroatoms independently selected from O, S and N. In one embodiment, the heteroaryl group is selected from heteroaryl and 6-10 membered aryl, heteroaryl and 3-10 membered cycloalkyl or heteroaryl and 3-10 membered heterocyclyl; further in one embodiment, the heteroaryl group is selected from 5- or 6-membered heteroaryl and 6-10 membered aryl, 5- or 6-membered heteroaryl and 3-6 membered cycloalkyl, 5- or 6-membered heteroaryl and 3-6 membered heterocyclyl, wherein the heterocyclyl is a heterocyclyl containing 1-3 nitrogen atoms, oxygen atoms or sulfur atoms. Non-limiting examples include furanyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, thiadiazolyl, thiazolyl, thienyl, tetrazolyl, triazinyl, triazolyl, benzofuranyl, benzimidazolyl, benzisoxazolyl, benzopyranyl, benzothiadiazolyl, benzothiophenyl, benzothiophenyl, benzotriazolyl, imidazopyridinyl, imidazothiazolyl , indolizinyl, indolyl, indazolyl, isobenzofuranyl, isobenzothiophenyl, isoindolyl, isoquinolyl, naphthyridinyl, oxazolopyridinyl, phthalazinyl, pteridinyl, purinyl, pyridopyridinyl, pyrrolopyridinyl, quinolyl, quinoxalinyl, quinazolinyl, thiadiazolopyrimidinyl, thienopyridinyl, acridinyl, benzindolyl, carbazolyl, bibenzofuranyl, phenanthrolinyl, phenanthridinyl, phenpyrazinyl, phenazinyl, phenothiazinyl, phenoxazinyl, xanthenyl,
术语“亚杂芳基”是指环烷基的一个氢原子进一步被取代形成的二价杂芳基，其中，亚杂芳基是任选取代的或非取代的，杂芳基定义如上所述。The term "heteroarylene" refers to a divalent heteroaryl group formed by further replacing one hydrogen atom of a cycloalkyl group, wherein the heteroarylene group is optionally substituted or unsubstituted, and the heteroaryl group is as defined above.
术语“杂烷基”指稳定的直链或支链，或者环状的烃基，或其组合，其由所示数量的碳原子和选自O、N、Si和S的一个或多个(在一个实施方式中为一至三个)杂原子组成，且其中氮和硫原子任选地被氧化，该氮杂原子可任选地被季铵化。在一个实施方式中，杂原子O、N和S可被放在杂烷基基团的任意内部位置。在一个实施方式中，杂原子Si可被放在杂烷基基团的任意位置(例如，内部或末端位置)，包括烷基基团与分子的剩余部分连接的位置。其非限制性实例包括：-CH2-CH2-O-CH3、-CH2-CH2-NH-CH3、-CH2-CH2-N(CH3)-CH3、-CH2-S-CH2-CH3、-CH2-CH2-S(O)-CH3、-CH2-CH2-S(O)2-CH3、-CH＝CH-O-CH3、-Si(CH3)3、-CH2-CH＝N-OCH3和-CH＝CH-N(CH3)-CH3。最多两个杂原子可以是连续的，例如，-CH2-NH-O-CH3和-CH2-O-Si(CH3)3。在特定的实施方式中，该杂烷基是本文别处描述的任选地取代的杂烷基。The term "heteroalkyl" refers to a stable straight or branched chain, or cyclic hydrocarbon group, or a combination thereof, consisting of the indicated number of carbon atoms and one or more (in one embodiment, one to three) heteroatoms selected from O, N, Si and S, and wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen heteroatom may be optionally quaternized. In one embodiment, the heteroatoms O, N and S may be placed at any interior position of the heteroalkyl group. In one embodiment, the heteroatom Si may be placed at any position (e.g., interior or terminal position) of the heteroalkyl group, including the position where the alkyl group is attached to the remainder of the molecule. Non-limiting examples thereof include: -CH2 - CH2 -O- CH3 , -CH2- CH2 -NH- CH3 , -CH2 - CH2 - N ( CH3 )-CH3 , -CH2 - S- CH2 -CH3, -CH2 - CH2 -S(O) -CH3 , -CH2 - CH2 -S(O) 2 - CH3 , -CH=CH- O -CH3, -Si( CH3 ) 3 , -CH2 -CH=N- OCH3 , and -CH=CH-N( CH3 ) -CH3 . Up to two heteroatoms may be consecutive, for example, -CH2 -NH-O- CH3 and -CH2 -O-Si( CH3 ) 3 . In a particular embodiment, the heteroalkyl group is an optionally substituted heteroalkyl group described elsewhere herein.
术语“烷氧基”指-O-(烷基)和-O-(非取代的环烷基)，其中烷基或环烷基的定义同前所述。烷氧基的非限制性实例包括：甲氧基、乙氧基、丙氧基、丁氧基、环丙氧基、环丁氧基、环戊氧基或环己氧基。在一个实施方式中，该烷氧基是本文别处描述的任选地取代的烷氧基。The term "alkoxy" refers to -O-(alkyl) and -O-(unsubstituted cycloalkyl), wherein alkyl or cycloalkyl are as defined above. Non-limiting examples of alkoxy include: methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy or cyclohexyloxy. In one embodiment, the alkoxy is an optionally substituted alkoxy described elsewhere herein.
术语“烷基酰基”指-C(O)-烷基，其中烷基的定义同前所述。The term "alkylacyl" refers to a -C(O)-alkyl group wherein alkyl is as previously defined.
术语“卤代烷基”指被一个或多个卤素取代的烷基，其中烷基的定义同前所述。所述卤代烷基非限制性实例包括：三氟甲基、-CH2CF3、 The term "haloalkyl" refers to an alkyl group substituted by one or more halogens, wherein the definition of alkyl is the same as above. Non-limiting examples of the haloalkyl group include: trifluoromethyl, -CH 2 CF 3 ,
术语“卤代烷氧基”指被一个或多个卤素取代的烷氧基，其中烷氧基的定义同前所述。The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogen groups, wherein alkoxy is as defined above.
术语“羟烷基”指被羟基取代的烷基，其中烷基的定义同前所述。The term "hydroxyalkyl" refers to an alkyl group substituted with a hydroxy group, wherein alkyl is as defined above.
术语“烷硫基”指-S-(烷基)和-S-(非取代的环烷基)，其中烷基或环烷基的定义同前所述。烷硫基的非限制性实例包括：甲硫基、乙硫基、丙硫基、丁硫基、环丙硫基、环丁硫基、环戊硫基或环己硫基。在一个实施方式中，该烷硫基是本文别处描述的任选地取代的烷硫基。The term "alkylthio" refers to -S-(alkyl) and -S-(unsubstituted cycloalkyl), wherein alkyl or cycloalkyl are as defined above. Non-limiting examples of alkylthio include: methylthio, ethylthio, propylthio, butylthio, cyclopropylthio, cyclobutylthio, cyclopentylthio or cyclohexylthio. In one embodiment, the alkylthio is an optionally substituted alkylthio described elsewhere herein.
术语“卤代烷硫基”指被一个或多个卤素取代的烷硫基，其中烷硫基的定义同前所述。The term "haloalkylthio" refers to an alkylthio group substituted by one or more halogens, wherein alkylthio is as defined above.
术语“烯基羰基”指-C(O)-(烯基)，其中烯基的定义同前所述。烯基羰基的非限制性实例包括：乙烯基羰基、丙烯基羰基或丁烯基羰基。在一个实施方式中，该烯基羰基是本文别处描述的任选地取代的烯基羰基。The term "alkenylcarbonyl" refers to -C(O)-(alkenyl), wherein alkenyl is as defined above. Non-limiting examples of alkenylcarbonyl include: vinylcarbonyl, propenylcarbonyl, or butenylcarbonyl. In one embodiment, the alkenylcarbonyl is an optionally substituted alkenylcarbonyl described elsewhere herein.
术语“氨基羰基”指NH2-C(O)-。The term "aminocarbonyl" refers to NH2 -C(O)-.
术语“烷基氨基羰基”指氨基羰基(NH2-C(O)-)上的两个氢中的一个或全部被烷基取代，其中烷基的定义同前所述。The term "alkylaminocarbonyl" refers to an aminocarbonyl ( NH2 -C(O)-) group in which one or both of the two hydrogen atoms are replaced by an alkyl group, wherein the alkyl group has the same definition as above.
术语“烷基氨基”指氨基上的两个氢中的一个或全部被烷基取代，其中烷基的定义同前所述。The term "alkylamino" refers to an amino group in which one or both of the two hydrogen atoms are replaced by an alkyl group, wherein the alkyl group has the same definition as above.
术语“羰基””指-C(O)-、-(CO)-或-C(＝O)-基团。所有的标记在说明书中可交换使用。The term "carbonyl" refers to a -C(O)-, -(CO)-, or -C(=O)- group. All notations are used interchangeably in the specification.
术语“羟基”指-OH基团。The term "hydroxy" refers to an -OH group.
术语“卤素”指氟、氯、溴或碘。The term "halogen" refers to fluorine, chlorine, bromine or iodine.
术语“氨基”指-NH2。The term "amino" refers to -NH2 .
术语“氰基”指-CN。The term "cyano" refers to -CN.
术语“硝基”指-NO2。The term "nitro" refers to -NO2 .
术语“羧基”指-C(O)OH。The term "carboxy" refers to -C(O)OH.
术语“乙酰基”指-C(O)CH3。The term "acetyl" refers to -C(O) CH3 .
术语“氧代”或“侧氧”指＝O。The term "oxo" or "oxo" refers to =0.
术语“巯基”指-SH。The term "thiol" refers to -SH.
术语“THF”指四氢呋喃。The term "THF" refers to tetrahydrofuran.
术语“EtOAc”指乙酸乙酯。The term "EtOAc" refers to ethyl acetate.
术语“MeOH”指甲醇。The term "MeOH" refers to methanol.
术语“DMF”指N、N-二甲基甲酰胺。The term "DMF" refers to N,N-dimethylformamide.
术语“DIPEA”指二异丙基乙胺。The term "DIPEA" refers to diisopropylethylamine.
术语“TFA”指三氟乙酸。The term "TFA" refers to trifluoroacetic acid.
术语“TEA”指三乙胺。The term "TEA" refers to triethylamine.
术语“MeCN”指乙腈。The term "MeCN" refers to acetonitrile.
术语“DMA”指N,N-二甲基乙酰胺。The term "DMA" refers to N,N-dimethylacetamide.
术语“Et2O”指乙醚。The term " Et2O " refers to diethyl ether.
术语“DCE”指1,2-二氯乙烷。The term "DCE" refers to 1,2-dichloroethane.
术语“DIPEA”指N，N-二异丙基乙胺。The term "DIPEA" refers to N,N-diisopropylethylamine.
术语“NBS”指N-溴代琥珀酰亚胺。The term "NBS" refers to N-bromosuccinimide.
术语“NIS”指N-碘代丁二酰亚胺。The term "NIS" refers to N-iodosuccinimide.
术语“Cbz-Cl”指氯甲酸苄酯。The term "Cbz-Cl" refers to benzyl chloroformate.
术语“Pd2(dba)3”指三(二亚苄基丙酮)二钯。The term "Pd 2 (dba) 3 " refers to tris(dibenzylideneacetone)dipalladium.
术语“Dppf”指1,1’-双二苯基膦二茂铁。The term "Dppf" refers to 1,1'-bis(diphenylphosphino)ferrocene.
术语“HATU”指2-(7-氧化苯并三氮唑)-N,N,N’,N’-四甲基脲六氟磷酸酯。The term "HATU" refers to 2-(7-oxybenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate.
术语“KHMDS”指六甲基二硅基胺基钾。The term "KHMDS" refers to potassium hexamethyldisilazide.
术语“LiHMDS”指双三甲基硅基胺基锂。The term "LiHMDS" refers to lithium bistrimethylsilylamide.
术语“MeLi”指甲基锂。The term "MeLi" refers to methyllithium.
术语“n-BuLi”指正丁基锂。The term "n-BuLi" refers to n-butyllithium.
术语“NaBH(OAc)3”指三乙酰氧基硼氢化钠。The term "NaBH(OAc) 3 " refers to sodium triacetoxyborohydride.
术语“氢”包括质子(1H)、氘(2H)、氚(3H)和/或其混合物。在特定的实施方式中，化合物中一个或多个被氢占据的位置可被氘和/或氚富集。该种同位素富集类似物可通过由商业来源获得的合适的同位素标记起始原料制备得到或者由已知的文献步骤制备得到。The term "hydrogen" includes protons ( 1H ), deuterium ( 2H ), tritium ( 3H ) and/or mixtures thereof. In certain embodiments, one or more positions occupied by hydrogen in the compound may be enriched with deuterium and/or tritium. Such isotopically enriched analogs may be prepared by appropriately isotopically labeled starting materials obtained from commercial sources or by known literature procedures.
所述烷基、亚烷基、烯基、炔基、环烷基、杂环基、芳基、亚芳基、杂芳基、亚杂芳基、杂烷基、烷氧基、烷硫基、羟烷基、烯基羰基、氨基羰基、烷基氨基羰基、烷基氨基、烷基酰基可以是取代的或非取代的，在一个实施方式中，取代基选自一个或多个以下基团：烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、烷基酰基、卤素、巯基、羟基、硝基、氰基、叠氮基、肟基、磷酸酯基、氧代基、硫代基、羧基、羧酸酯基、环烷基、杂环基、芳基、杂芳基、杂环烷氧基、环烷硫基或杂环烷硫基。The alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, arylene, heteroaryl, heteroarylene, heteroalkyl, alkoxy, alkylthio, hydroxyalkyl, alkenylcarbonyl, aminocarbonyl, alkylaminocarbonyl, alkylamino, and alkylacyl may be substituted or unsubstituted. In one embodiment, the substituent is selected from one or more of the following groups: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, alkylacyl, halogen, sulfhydryl, hydroxyl, nitro, cyano, azido, oxime, phosphate, oxo, thio, carboxyl, carboxylate, cycloalkyl, heterocyclyl, aryl, heteroaryl, heterocycloalkyloxy, cycloalkylthio, or heterocycloalkylthio.
“X选自A、B、或C”、“X选自A、B和C”、“X为A、B或C”、“X为A、B和C”等不同用语均表达了相同的意义，即表示X可以是A、B、C中的任意一种或几种。Different expressions such as “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” all express the same meaning, that is, X can be any one or more of A, B, C.
“任选”或“任选地”意味着随后所描述的事件或环境可以但不必发生，该说明包括该事件或环境发生或不发生的场合。例如，“任选被烷基取代的杂环基团”意味着烷基可以但不必须存在，该说明包括杂环基团被烷基取代的情形和杂环基团不被烷基取代的情形。"Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and the description includes instances where the event or circumstance occurs or does not occur. For example, "a heterocyclic group optionally substituted with an alkyl group" means that an alkyl group may but need not be present, and the description includes instances where the heterocyclic group is substituted with an alkyl group and instances where the heterocyclic group is not substituted with an alkyl group.
在本发明的各部分，描述了连接取代基。当该结构清楚地需要连接基团时，针对该基团所列举的马库什变量应理解为连接基团。例如，如果该结构需要连接基团并且针对该变量的马库什基团定义列举了“烷基”或“芳基”，则应该理解，该“烷基”或“芳基”分别代表连接的亚烷基基团或亚芳基基团。In various parts of the present invention, linking substituents are described. When the structure clearly requires a linking group, the Markush variable listed for that group should be understood as a linking group. For example, if the structure requires a linking group and the Markush group definition for that variable lists "alkyl" or "aryl", it should be understood that the "alkyl" or "aryl" represents an alkylene group or an arylene group, respectively, that is connected.
“取代的”是指特定原子上的任意一个或多个氢原子被取代基取代，只要特定原子的价态是正常的并且取代后的化合物是稳定的在一个实施方式中在一个实施方式中。当取代基为氧代(即＝O)时，意味着两个氢原子被取代。术语“任选被取代的”是指可以被取代，也可以不被取代，除非另有规定，取代基的种类和数目在化学上可以实现的基础上可以是任意的。不言而喻，取代基仅处在它们的可能的化学位置，本领域技术人员能够在不付出过多努力的情况下确定(通过实验或理论)可能或不可能的取代。例如，具有游离氢的氨基或羟基与具有不饱和(如烯属)键的碳原子结合时可能是不稳定的。"Substituted" means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, as long as the valence state of the particular atom is normal and the substituted compound is stable in one embodiment. In one embodiment. When the substituent is oxo (i.e., =O), it means that two hydrogen atoms are replaced. The term "optionally substituted" means that it may be substituted or not substituted, and unless otherwise specified, the type and number of the substituent may be arbitrary on the basis of chemical realization. It goes without saying that the substituent is only in their possible chemical position, and those skilled in the art can determine (by experiment or theory) possible or impossible substitution without paying too much effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom with an unsaturated (such as olefinic) bond.
除非有相反的陈述，在本说明书和权利要求书中的不定冠词“一个”和“一种”以及定冠词“该”包括复数和单数形式。In this specification and the claims, the indefinite articles "a" and "an" and the definite article "the" include plural as well as singular, unless stated to the contrary.
“药物组合物”表示含有一种或多种本文所述化合物或其生理学上/可药用的盐或前体药物与其他化学组分的混合物，以及其他组分例如生理学/可药用的载体和赋形剂。药物组合物的目的是促进对生物体的给药，利于活性成分的吸收进而发挥生物活性。"Pharmaceutical composition" means a mixture containing one or more compounds described herein or their physiologically/pharmaceutically acceptable salts or prodrugs and other chemical components, as well as other components such as physiologically/pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitate the absorption of the active ingredient, and thus exert biological activity.
“可药用盐”是指本发明化合物的盐，这类盐用于哺乳动物体内时具有安全性和有效性，且具有应有的生物活性。"Pharmaceutically acceptable salts" refer to salts of the compounds of the present invention, which are safe and effective when used in mammals and have the desired biological activity.
“立体异构体”包含了所有的对映异构/非对应异构/立体异构纯和对映异构/非对应异构/立体异构富集的本发明化合物。"Stereoisomers" encompass all enantiomerically/diastereomerically/stereomerically pure and enantiomerically/diastereomerically/stereomerically enriched forms of the compounds of the invention.
“立体异构纯”指一种包含某化合物的一种立体异构体而基本没有该化合物的另一立体异构体的组合物。例如，一种具有一个手性中心的化合物的立体异构纯组合物将基本没有该化合物的相对的对映异构体。一种具有两个手性中心的化合物的立体异构纯组合物将基本不含该化合物的其它非对映异构体。典型的立体异构纯化合物包含质量含量大于约80％的该化合物的一种立体异构体和质量含量少于约20％的该化合物另一立体异构体、质量含量大于约90％的该化合物的一种立体异构体和质量含量少于约10％的该化合物另一立体异构体、质量含量大于约95％的该化合物的一种立体异构体和质量含量少于约5％的该化合物另一立体异构体、质量含量大于约97％的该化合物的一种立体异构体和质量含量少于约3％的该化合物另一立体异构体或者质量含量大于约99％的该化合物的一种立体异构体和质量含量少于约1％的该化合物另一立体异构体。"Stereomerically pure" refers to a composition comprising one stereoisomer of a compound and being substantially free of another stereoisomer of the compound. For example, a stereomerically pure composition of a compound having one chiral center will be substantially free of the opposite enantiomer of the compound. A stereomerically pure composition of a compound having two chiral centers will be substantially free of other diastereomers of the compound. A typical stereoisomerically pure compound contains greater than about 80% by weight of one stereoisomer of the compound and less than about 20% by weight of another stereoisomer of the compound, greater than about 90% by weight of one stereoisomer of the compound and less than about 10% by weight of another stereoisomer of the compound, greater than about 95% by weight of one stereoisomer of the compound and less than about 5% by weight of another stereoisomer of the compound, greater than about 97% by weight of one stereoisomer of the compound and less than about 3% by weight of another stereoisomer of the compound, or greater than about 99% by weight of one stereoisomer of the compound and less than about 1% by weight of another stereoisomer of the compound.
“立体异构富集”指包含了质量含量大于约55％、质量含量大于约60％、质量含量大于约70％或质量含量大于约80％的某化合物的一种立体异构体的组合物。"Stereoisomerically enriched" refers to a composition comprising greater than about 55% by weight, greater than about 60% by weight, greater than about 70% by weight, or greater than about 80% by weight of one stereoisomer of a compound.
“对映异构纯”指一种具有一个手性中心的化合物的立体异构纯组合物。类似地，术语“对映异构富集”指一种具有一个手性中心的化合物的立体异构富集组合物。"Enantiomerically pure" refers to a stereomerically pure composition of a compound having one chiral center. Similarly, the term "enantiomerically enriched" refers to a stereomerically enriched composition of a compound having one chiral center.
“光学活性”和“对映异构活性”指一个分子组合，其具有不少于约50％、不少于约70％、不少于约80％、不少于约90％、不少于约91％、不少于约92％、不少于约93％、不少于约94％、不少于约95％、不少于约96％、不少于约97％、不少于约98％、不少于约99％、不少于约99.5％或不少于约99.8％的对映体过量或非对映体过量。在特定的实施方式中，该化合物包含了占外消旋物总重约95％或更多的所需对映体或非对映体和约5％或更少的次优选对映体或非对映体。"Optical activity" and "enantiomeric activity" refer to a combination of molecules having an enantiomeric or diastereomeric excess of not less than about 50%, not less than about 70%, not less than about 80%, not less than about 90%, not less than about 91%, not less than about 92%, not less than about 93%, not less than about 94%, not less than about 95%, not less than about 96%, not less than about 97%, not less than about 98%, not less than about 99%, not less than about 99.5%, or not less than about 99.8%. In certain embodiments, the compound comprises about 95% or more of the desired enantiomer or diastereomer and about 5% or less of the less preferred enantiomer or diastereomer, based on the total weight of the racemate.
在描述光学活性化合物时，前缀R和S被用于表示该分子相对于其手性中心的绝对构型。(+)和(-)被用于表示该化合物的光学旋转，即，经该光学活性化合物旋转的偏振光的平面的方向。前缀(-)表示该化合物是左旋的，即，该化合物将偏振光的平面向左或逆时针旋转。前缀(+)表示该化合物是右旋的，即，该化合物将偏振光的平面向右或顺时针旋转。然而，光学旋转的符号(+)和(-)与分子的绝对构型R和S无关。When describing an optically active compound, the prefixes R and S are used to denote the absolute configuration of the molecule with respect to its chiral center. (+) and (-) are used to denote the optical rotation of the compound, i.e., the direction of the plane of polarized light rotated by the optically active compound. The prefix (-) indicates that the compound is levorotatory, i.e., the compound rotates the plane of polarized light to the left or counterclockwise. The prefix (+) indicates that the compound is dextrorotatory, i.e., the compound rotates the plane of polarized light to the right or clockwise. However, the signs (+) and (-) of the optical rotation have nothing to do with the absolute configuration, R and S, of the molecule.
具体实施方式DETAILED DESCRIPTION
以下结合实施例进一步描述本发明，但这些实施例并非限制着本发明的范围。The present invention is further described below in conjunction with examples, but these examples are not intended to limit the scope of the present invention.
实施例Example
本发明的化合物结构是通过核磁共振(NMR)或/和液质联用色谱(LC-MS)来确定的。NMR化学位移(δ)以百万分之一(ppm)的单位给出。NMR的测定是用Bruker AVANCE-400核磁仪，测定溶剂为氘代二甲基亚砜(DMSO-d6)，氘代甲醇(CD3OD)和氘代氯仿(CDCl3)，内标为四甲基硅烷(TMS)。The structure of the compound of the present invention is determined by nuclear magnetic resonance (NMR) or/and liquid chromatography-mass spectrometry (LC-MS). The NMR chemical shift (δ) is given in parts per million (ppm). The NMR measurement is performed using a Bruker AVANCE-400 nuclear magnetic spectrometer, the measurement solvents are deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated methanol (CD 3 OD) and deuterated chloroform (CDCl 3 ), and the internal standard is tetramethylsilane (TMS).
液质联用色谱LC-MS的测定用Agilent 1200Infinity Series质谱仪。HPLC的测定使用安捷伦1200DAD高压液相色谱仪(Sunfire C18 150×4.6mm色谱柱)和Waters 2695-2996高压液相色谱仪(Gimini C18 150×4.6mm色谱柱)。Liquid chromatography-mass spectrometry (LC-MS) was performed using an Agilent 1200 Infinity Series mass spectrometer, and HPLC was performed using an Agilent 1200DAD high pressure liquid chromatograph (Sunfire C18 150×4.6 mm column) and a Waters 2695-2996 high pressure liquid chromatograph (Gimini C 18 150×4.6 mm column).
薄层层析硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板，TLC采用的规格是0.15mm～0.20mm，薄层层析分离纯化产品采用的规格是0.4mm～0.5mm。柱层析一般使用烟台黄海硅胶200～300目硅胶为载体。Thin layer chromatography silica gel plates use Yantai Huanghai HSGF254 or Qingdao GF254 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.
本发明实施例中的起始原料是已知的并且可以在市场上买到，或者可以采用或按照本领域已知的方法来合成。The starting materials in the examples of the present invention are known and can be purchased on the market, or can be synthesized by or according to methods known in the art.
在无特殊说明的情况下，本发明的所有反应均在连续的磁力搅拌下，在干燥氮气或氩气氛下进行，溶剂为干燥溶剂，反应温度单位为摄氏度。Unless otherwise specified, all reactions of the present invention are carried out under continuous magnetic stirring in a dry nitrogen or argon atmosphere, the solvent is a dry solvent, and the reaction temperature is in degrees Celsius.
实施例1AExample 1A
N-((S)-1,1-二环丙基-3-((4-((3R,4R)-4-(2,2-二氟乙烯基)四氢呋喃-3-基)-2-氟-5-甲基苯基)氨基)-3-羰基丙烷-2-基)-1-异丙基-1H-吡唑-5-甲酰胺N-((S)-1,1-dicyclopropyl-3-((4-((3R,4R)-4-(2,2-difluorovinyl)tetrahydrofuran-3-yl)-2-fluoro-5-methylphenyl)amino)-3-carbonylpropan-2-yl)-1-isopropyl-1H-pyrazole-5-carboxamide
合成路线：Synthesis route:
以下实施例参照上述的路线合成：The following examples are synthesized according to the above-mentioned route:
实施例414A还可以按照如下路线合成：Example 414A can also be synthesized according to the following route:
第一步：4-(((三氟甲基)磺酰)氧代)-2,5-二氢呋喃-3-羧酸甲酯的制备Step 1: Preparation of methyl 4-(((trifluoromethyl)sulfonyl)oxy)-2,5-dihydrofuran-3-carboxylate
室温下，将甲基4-羰基四氢呋喃-3-羧酸酯(5.2g,36.1mmol)溶于二氯甲烷(100mL)中，加入N,N-二异丙基乙胺(7.0g,54.2mmol)，冷却至-78℃，滴加三氟甲磺酸酐(12.2g,43.3mmol)，滴毕，逐渐升至室温继续搅拌2小时。加入水淬灭反应，用二氯甲烷萃取，合并有机相，依次用饱和碳酸氢钠溶液和饱和氯化钠溶液洗涤，无水硫酸钠干燥，过滤，减压浓缩标题化合物粗品，直接用于下一步反应。At room temperature, dissolve methyl 4-carbonyltetrahydrofuran-3-carboxylate (5.2 g, 36.1 mmol) in dichloromethane (100 mL), add N,N-diisopropylethylamine (7.0 g, 54.2 mmol), cool to -78 ° C, add trifluoromethanesulfonic anhydride (12.2 g, 43.3 mmol), gradually warm to room temperature and continue stirring for 2 hours. Add water to quench the reaction, extract with dichloromethane, combine the organic phases, wash with saturated sodium bicarbonate solution and saturated sodium chloride solution in turn, dry over anhydrous sodium sulfate, filter, concentrate the crude title compound under reduced pressure, and use it directly in the next reaction.
MS m/z(ESI):277.1[M+H]+.MS m/z(ESI):277.1[M+H] + .
第二步：4-(4-氨基-2-氟苯基)-2,5-二氢呋喃-3-羧酸甲酯的制备Step 2: Preparation of methyl 4-(4-amino-2-fluorophenyl)-2,5-dihydrofuran-3-carboxylate
室温下，将3-氟-4-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)苯胺(4.1g,17.4mmol)，甲基4-(((三氟甲基)磺酰)氧代)-2,5-二氢呋喃-3-羧酸甲酯(9.6g,34.8mmol)和碳酸钾(6.0g,43.5mmol)加入到二氧六环-水(40mL-10mL)的混合溶剂中，加入四三苯基膦钯(1.9g,1.7mmol)，氮气置换三次，升温至130℃搅拌10小时。冷却至室温，加水稀释，用乙酸乙酯萃取，有机相用饱和氯化钠溶液洗涤，无水硫酸钠干燥，过滤，浓缩，粗品经柱层析纯化得标题化合物(3.4g,83％)。At room temperature, 3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (4.1 g, 17.4 mmol), methyl 4-(((trifluoromethyl)sulfonyl)oxy)-2,5-dihydrofuran-3-carboxylate (9.6 g, 34.8 mmol) and potassium carbonate (6.0 g, 43.5 mmol) were added to a mixed solvent of dioxane-water (40 mL-10 mL), tetrakistriphenylphosphine palladium (1.9 g, 1.7 mmol) was added, nitrogen was replaced three times, the temperature was raised to 130°C and stirred for 10 hours. The mixture was cooled to room temperature, diluted with water, extracted with ethyl acetate, the organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by column chromatography to obtain the title compound (3.4 g, 83%).
MS m/z(ESI):238.1[M+H]+.MS m/z(ESI):238.1[M+H] + .
第三步：4-(4-((叔-丁氧基羰基)氨基)-2-氟苯基)-2,5-二氢呋喃-3-羧酸甲酯的制备Step 3: Preparation of methyl 4-(4-((tert-butoxycarbonyl)amino)-2-fluorophenyl)-2,5-dihydrofuran-3-carboxylate
室温下，将4-(4-氨基-2-氟苯基)-2,5-二氢呋喃-3-羧酸甲酯(3.4g,14.3mmol)溶于二碳酸二叔丁酯(30mL)中，升温至120℃搅拌5小时。冷却至室温，浓缩，粗品经柱层析纯化得标题化合物(2.1g,44％)。At room temperature, dissolve methyl 4-(4-amino-2-fluorophenyl)-2,5-dihydrofuran-3-carboxylate (3.4 g, 14.3 mmol) in di-tert-butyl dicarbonate (30 mL), heat to 120°C and stir for 5 hours. Cool to room temperature, concentrate, and purify the crude product by column chromatography to obtain the title compound (2.1 g, 44%).
MS m/z(ESI):338.1[M+H]+.MS m/z(ESI):338.1[M+H] + .
第四步：顺式-4-(4-((叔-丁氧基羰基)氨基)-2-氟苯基)四氢呋喃-3-羧酸甲酯的制备Step 4: Preparation of cis-4-(4-((tert-butoxycarbonyl)amino)-2-fluorophenyl)tetrahydrofuran-3-carboxylic acid methyl ester
室温下，4-(4-((叔-丁氧基羰基)氨基)-2-氟苯基)-2,5-二氢呋喃-3-羧酸甲酯(2.1g,6.2mmol)溶于甲醇(50mL)中，氮气置换三次，加入钯/碳(500mg)和氢氧化钯/碳(500mg)，氢气氛围下，升温至50℃搅拌5小时，冷却至室温。硅藻土过滤，滤液浓缩得标题化合物粗品，直接用于下一步反应。At room temperature, methyl 4-(4-((tert-butoxycarbonyl)amino)-2-fluorophenyl)-2,5-dihydrofuran-3-carboxylate (2.1 g, 6.2 mmol) was dissolved in methanol (50 mL), replaced with nitrogen three times, and palladium/carbon (500 mg) and palladium hydroxide/carbon (500 mg) were added. Under a hydrogen atmosphere, the temperature was raised to 50°C and stirred for 5 hours, and then cooled to room temperature. Filtered with diatomaceous earth, the filtrate was concentrated to obtain the crude title compound, which was directly used in the next step reaction.
MS m/z(ESI):340.1[M+H]+.MS m/z(ESI):340.1[M+H] + .
第五步：叔-丁基(3-氟-4-(顺式-4-(羟甲基)四氢呋喃-3-基)苯基)氨基甲酸酯的制备Step 5: Preparation of tert-butyl (3-fluoro-4-(cis-4-(hydroxymethyl)tetrahydrofuran-3-yl)phenyl)carbamate
将顺式-4-(4-((叔-丁氧基羰基)氨基)-2-氟苯基)四氢呋喃-3-羧酸甲酯(1.9g,5.6mmol)溶解于四氢呋喃-甲醇(30mL-2mL)中，冷却至0℃，分批次加入硼氢化锂(635mg,28.8mmol)，0℃搅拌反应5小时。减压浓缩除去大部分溶剂，加入水稀释，用二氯甲烷萃取，有机相用无水硫酸钠干燥，过滤，浓缩，粗品经柱层析纯化得标题化合物(1.6g，91％)。Dissolve cis-4-(4-((tert-butoxycarbonyl)amino)-2-fluorophenyl)tetrahydrofuran-3-carboxylic acid methyl ester (1.9 g, 5.6 mmol) in tetrahydrofuran-methanol (30 mL-2 mL), cool to 0°C, add lithium borohydride (635 mg, 28.8 mmol) in batches, and stir at 0°C for 5 hours. Concentrate under reduced pressure to remove most of the solvent, dilute with water, extract with dichloromethane, dry the organic phase with anhydrous sodium sulfate, filter, and concentrate. The crude product is purified by column chromatography to obtain the title compound (1.6 g, 91%).
MS m/z(ESI):312.1[M+H]+.MS m/z(ESI):312.1[M+H] + .
第六步：叔-丁基(3-氟-4-(顺式-4-甲酰基四氢呋喃-3-基)苯基)氨基甲酸酯的制备Step 6: Preparation of tert-butyl (3-fluoro-4-(cis-4-formyltetrahydrofuran-3-yl)phenyl)carbamate
将叔-丁基(3-氟-4-(顺式-4-(羟甲基)四氢呋喃-3-基)苯基)氨基甲酸酯(1.6g,5.1mmol)溶于乙酸乙酯(30mL)中，加入2-碘酰苯甲酸(2.8g,10.0mmol)，升温至80℃搅拌2小时，LCMS显示原料反应完全。冷却至室温，硅藻土过滤，滤液减压浓缩得标题化合物(1.3g，83％)。Dissolve tert-butyl (3-fluoro-4-(cis-4-(hydroxymethyl)tetrahydrofuran-3-yl)phenyl)carbamate (1.6 g, 5.1 mmol) in ethyl acetate (30 mL), add 2-iodobenzoic acid (2.8 g, 10.0 mmol), heat to 80°C and stir for 2 hours. LCMS shows that the raw material is completely reacted. Cool to room temperature, filter through celite, and concentrate the filtrate under reduced pressure to obtain the title compound (1.3 g, 83%).
MS m/z(ESI):310.1[M+H]+.MS m/z(ESI):310.1[M+H] + .
第七步：叔-丁基(3-氟-4-(反式-4-甲酰基四氢呋喃-3-基)苯基)氨基甲酸酯的制备Step 7: Preparation of tert-butyl (3-fluoro-4-(trans-4-formyltetrahydrofuran-3-yl)phenyl)carbamate
将叔-丁基(3-氟-4-(顺式-4-甲酰基四氢呋喃-3-基)苯基)氨基甲酸酯(880mg,2.8mmol)溶于二氯甲烷(10mL)中，冷却至0℃，加入1,8-二氮杂二环十一碳-7-烯(10滴)，0℃下，搅拌反应2小时，LCMS显示原料反应完全。加入水，用二氯甲烷萃取，合并有机相，用饱和食盐水和饱和氯化铵溶液洗涤，无水硫酸钠干燥，减压浓缩除去溶剂得标题化合物(630mg，72％)。Dissolve tert-butyl (3-fluoro-4-(cis-4-formyltetrahydrofuran-3-yl)phenyl)carbamate (880 mg, 2.8 mmol) in dichloromethane (10 mL), cool to 0°C, add 1,8-diazabicycloundec-7-ene (10 drops), stir at 0°C for 2 hours, LCMS shows that the raw material is completely reacted. Add water, extract with dichloromethane, combine the organic phases, wash with saturated brine and saturated ammonium chloride solution, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to remove the solvent to obtain the title compound (630 mg, 72%).
MS m/z(ESI):310.1[M+H]+.MS m/z(ESI):310.1[M+H] + .
第八步：叔-丁基(4-(顺式-4-(2,2-二氟乙烯基)四氢呋喃-3-基)-3-氟苯基)氨基甲酸酯的制备Step 8: Preparation of tert-butyl (4-(cis-4-(2,2-difluorovinyl)tetrahydrofuran-3-yl)-3-fluorophenyl)carbamate
将叔-丁基(3-氟-4-(反式-4-甲酰基四氢呋喃-3-基)苯基)氨基甲酸酯(630mg,2.0mmol)和三苯基膦(1.1g,4.2mmol)溶于N,N-二甲基甲酰胺(15mL)中，氮气置换三次，升温至100℃，滴加2-氯-2,2-二氟乙酸钠溶于N,N-二甲基甲酰胺(5mL)的溶液，滴毕，100℃下，搅拌1小时，LCMS显示原料反应完全。加乙酸乙酯稀释，用饱和食盐水洗涤，分离有机相，经无水硫酸钠干燥，过滤后减压浓缩有机溶剂，所得残余物经柱层析分离得标题化合物(240mg，35％)。Dissolve tert-butyl (3-fluoro-4-(trans-4-formyltetrahydrofuran-3-yl)phenyl)carbamate (630mg, 2.0mmol) and triphenylphosphine (1.1g, 4.2mmol) in N,N-dimethylformamide (15mL), replace with nitrogen three times, heat to 100℃, add dropwise a solution of 2-chloro-2,2-difluoroacetate sodium dissolved in N,N-dimethylformamide (5mL), stir at 100℃ for 1 hour, LCMS shows that the raw material reacts completely. Dilute with ethyl acetate, wash with saturated brine, separate the organic phase, dry over anhydrous sodium sulfate, filter, and concentrate the organic solvent under reduced pressure. The residue is separated by column chromatography to obtain the title compound (240mg, 35%).
MS m/z(ESI):344.1[M+H]+.MS m/z(ESI):344.1[M+H] + .
第九步：4-(顺式-4-(2,2-二氟乙烯基)四氢呋喃-3-基)-3-氟苯胺的制备Step 9: Preparation of 4-(cis-4-(2,2-difluorovinyl)tetrahydrofuran-3-yl)-3-fluoroaniline
将叔-丁基(4-(顺式-4-(2,2-二氟乙烯基)四氢呋喃-3-基)-3-氟苯基)氨基甲酸酯(240mg,0.7mmol)溶于4M盐酸二氧六环(8mL)中，室温搅拌1小时，LCMS显示原料反应完全。减压浓缩有机溶剂，得标题化合物盐酸盐(170mg，>99％)。Dissolve tert-butyl (4-(cis-4-(2,2-difluorovinyl)tetrahydrofuran-3-yl)-3-fluorophenyl)carbamate (240 mg, 0.7 mmol) in 4M hydrochloric acid dioxane (8 mL) and stir at room temperature for 1 hour. LCMS showed that the reaction of the raw material was complete. Concentrate the organic solvent under reduced pressure to obtain the title compound hydrochloride (170 mg, >99%).
MS m/z(ESI):244.1[M+H]+.MS m/z(ESI):244.1[M+H] + .
第十步：N-((S)-1,1-二环丙基-3-((4-((3R,4R)-4-(2,2-二氟乙烯基)四氢呋喃-3-基)-3-氟苯基)氨基)-3-羰基丙烷-2-基)-1-异丙基-1H-吡唑-5-甲酰胺的制备Step 10: Preparation of N-((S)-1,1-dicyclopropyl-3-((4-((3R,4R)-4-(2,2-difluorovinyl)tetrahydrofuran-3-yl)-3-fluorophenyl)amino)-3-carbonylpropane-2-yl)-1-isopropyl-1H-pyrazole-5-carboxamide
将(S)-3,3-二环丙基-2-(1-异丙基-1H-吡唑-5-碳杂草酰氨基<乙二酰氨基>)丙酸甲酯(32.0mg,0.1mmol)和4-(顺式-4-(2,2-二氟乙烯基)四氢呋喃-3-基)-3-氟苯胺(24.0mg,0.1mmol)溶于甲苯(2mL)中，冷却至-20℃，缓慢滴加二(三甲基硅基)氨基锂(0.35mL,0.35mmol,0.1M in四氢呋喃)，-20℃下，搅拌10小时，LCMS显示原料反应完全。减压浓缩有机溶剂，粗品经柱层析和手性拆分得标题化合物(37.8mg，71％)。(S)-3,3-dicyclopropyl-2-(1-isopropyl-1H-pyrazole-5-carbazylamino <oxalylamino>) propionic acid methyl ester (32.0 mg, 0.1 mmol) and 4-(cis-4-(2,2-difluorovinyl)tetrahydrofuran-3-yl)-3-fluoroaniline (24.0 mg, 0.1 mmol) were dissolved in toluene (2 mL), cooled to -20°C, and lithium bis(trimethylsilyl)amide (0.35 mL, 0.35 mmol, 0.1 M in tetrahydrofuran) was slowly added dropwise. Stirring was continued at -20°C for 10 hours. LCMS showed that the raw material was completely reacted. The organic solvent was concentrated under reduced pressure, and the crude product was separated by column chromatography and chiral separation to obtain the title compound (37.8 mg, 71%).
1H NMR(400MHz,DMSO-d6)δ10.39(s,1H),8.49(d,J＝8.6Hz,1H),7.63-7.55(m,1H),7.50(d,J＝1.8Hz,1H),7.39-7.28(m,2H),6.93(d,J＝2.0Hz,1H),5.46-5.36(m,1H),4.77(t,J＝8.2Hz,1H),4.70-4.56(m,1H),4.10(t,J＝8.0,2H),3.71(t,J＝8.6Hz,1H),3.53(t,J＝8.4Hz,1H),3.41-3.35(m,1H),3.17-3.07(m,1H),1.41-1.32(m,6H),0.93-0.85(m,1H),0.81-0.71(m,2H),0.49-0.43(m,1H),0.40-0.23(m,3H),0.24-0.16(m,3H),0.15-0.10(m,1H). 1 H NMR (400MHz, DMSO-d 6 ) δ10.39 (s, 1H), 8.49 (d, J = 8.6Hz, 1H), 7.63-7.55 (m, 1H), 7.50 (d, J = 1.8Hz, 1H),7.39-7.28(m,2H),6.93(d,J＝2.0Hz,1H),5.46-5.36(m,1H),4.77(t,J＝8.2Hz,1H),4.70-4.56(m ,1H),4.10(t,J＝8.0,2H),3.71( t,J＝8.6Hz,1H),3.53(t,J＝8.4Hz,1H),3.41-3.35(m,1H),3.17-3.07(m,1H),1.41-1.32(m,6H),0.93 -0.85(m,1H),0.81-0.71(m,2H),0.49-0.43(m,1H),0.40-0.23(m,3H),0.24-0.16(m,3H),0.15-0.10(m, 1H).
MS m/z(ESI):531.1[M+H]+.MS m/z(ESI):531.1[M+H] + .
实施例1'Embodiment 1
环丙基((2S)-1,1-二环丙基-3-((2-氟-5-甲基-4-(1-(甲基(2,2,2-三氟乙基)氨基)-1-氧代丙烷-2-基)苯基)氨基)-3-氧代丙烷-2-基)氨基甲酸酯Cyclopropyl ((2S)-1,1-dicyclopropyl-3-((2-fluoro-5-methyl-4-(1-(methyl(2,2,2-trifluoroethyl)amino)-1-oxopropan-2-yl)phenyl)amino)-3-oxopropan-2-yl)carbamate
MS m/z(ESI):528.2[M+H]+ MS m/z(ESI):528.2[M+H] +
合成路线：Synthesis route:
具体地，实施例1'还可以按照如下路线制备Specifically, Example 1' can also be prepared according to the following route
第一步：2-(5-氟-2-甲基苯基)乙酸甲酯的制备Step 1: Preparation of methyl 2-(5-fluoro-2-methylphenyl)acetate
室温下，2-(5-氟-2-甲基苯基)乙酰腈(10.0g,67.1mmol)溶于盐酸甲醇(100mL)中，升温至80℃搅拌16小时，LCMS显示原料反应完全。浓缩，加入饱和碳酸氢钠溶液，用乙酸乙酯萃取，有机相无水硫酸钠干燥，减压浓缩有机溶剂，得标题化合物(9.9g,81％)。At room temperature, 2-(5-fluoro-2-methylphenyl)acetonitrile (10.0 g, 67.1 mmol) was dissolved in hydrochloric acid methanol (100 mL), heated to 80°C and stirred for 16 hours. LCMS showed that the raw material was completely reacted. Concentrate, add saturated sodium bicarbonate solution, extract with ethyl acetate, dry the organic phase with anhydrous sodium sulfate, and concentrate the organic solvent under reduced pressure to obtain the title compound (9.9 g, 81%).
MS m/z(ESI):183.1[M+H]+.MS m/z(ESI):183.1[M+H] + .
第二步：2-(5-氟-2-甲基苯基)丙酸甲酯的制备Step 2: Preparation of methyl 2-(5-fluoro-2-methylphenyl)propionate
室温下，2-(5-氟-2-甲基苯基)乙酸酯(9.5g,52.2mmol)溶于N,N-二甲基甲酰胺(100mL)中，冷却至0℃，分批次加入氢化钠(2.5g,62.6mmol,60％分散于矿物油中)，0℃下，搅拌30分钟，滴加碘甲烷(6.7g,47.0mmol)，滴毕，逐渐升至室温搅拌2小时，LCMS显示原料反应完全。加入饱和氯化铵溶液，用乙酸乙酯萃取，有机相用饱和氯化钠溶液洗涤，无水硫酸钠干燥，浓缩，粗品柱层析纯化得标题化合物(6.3g,62％)。At room temperature, 2-(5-fluoro-2-methylphenyl)acetate (9.5 g, 52.2 mmol) was dissolved in N,N-dimethylformamide (100 mL), cooled to 0°C, sodium hydride (2.5 g, 62.6 mmol, 60% dispersed in mineral oil) was added in batches, stirred at 0°C for 30 minutes, iodomethane (6.7 g, 47.0 mmol) was added dropwise, and the temperature was gradually raised to room temperature and stirred for 2 hours. LCMS showed that the raw material was completely reacted. Saturated ammonium chloride solution was added, extracted with ethyl acetate, the organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by column chromatography to obtain the title compound (6.3 g, 62%).
MS m/z(ESI):197.1[M+H]+.MS m/z(ESI):197.1[M+H] + .
第三步：2-(5-氟-2-甲基苯基)丙酸的制备Step 3: Preparation of 2-(5-fluoro-2-methylphenyl)propionic acid
室温下，2-(5-氟-2-甲基苯基)丙酸甲酯(6.2g,31.6mmol)溶于甲醇(60mL)中，滴加氢氧化钠(2.5g,63.2mmol)溶于水(16mL)的溶液，滴毕，室温搅拌5小时，LCMS显示原料反应完全。浓缩，用1N盐酸调至pH3，用乙酸乙酯萃取，有机相用饱和氯化钠溶液洗涤，无水硫酸钠干燥，浓缩，得标题化合物(5.5g,95％)。At room temperature, methyl 2-(5-fluoro-2-methylphenyl)propionate (6.2 g, 31.6 mmol) was dissolved in methanol (60 mL), and a solution of sodium hydroxide (2.5 g, 63.2 mmol) dissolved in water (16 mL) was added dropwise. After the addition was completed, the mixture was stirred at room temperature for 5 hours. LCMS showed that the reaction of the raw material was complete. The mixture was concentrated, adjusted to pH 3 with 1N hydrochloric acid, extracted with ethyl acetate, and the organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to obtain the title compound (5.5 g, 95%).
MS m/z(ESI):183.1[M+H]+.MS m/z(ESI):183.1[M+H] + .
第四步：2-(5-氟-2-甲基-4-硝基苯基)丙酸的制备Step 4: Preparation of 2-(5-fluoro-2-methyl-4-nitrophenyl)propionic acid
室温下，将2-(5-氟-2-甲基苯基)丙酸(5.5g,30.2mmol)溶于硫酸(40mL)中，冷却至0℃，缓慢滴加70％的硝酸(4.7g,45.3mmol)，滴毕，0℃下，搅拌2小时，LCMS显示原料反应完全。将反应液滴加到冰水中，用乙酸乙酯萃取，有机相用饱和氯化钠溶液洗涤，无水硫酸钠干燥，浓缩，得标题化合物(6.8g,>99％)。At room temperature, 2-(5-fluoro-2-methylphenyl)propionic acid (5.5 g, 30.2 mmol) was dissolved in sulfuric acid (40 mL), cooled to 0°C, and 70% nitric acid (4.7 g, 45.3 mmol) was slowly added dropwise. After the addition was completed, the mixture was stirred at 0°C for 2 hours. LCMS showed that the reaction of the raw materials was complete. The reaction solution was added dropwise to ice water, extracted with ethyl acetate, and the organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to obtain the title compound (6.8 g, >99%).
MS m/z(ESI):228.1[M+H]+.MS m/z(ESI):228.1[M+H] + .
第五步：2-(5-氟-2-甲基-4-硝基苯基)-N-甲基-N-(2,2,2-三氟乙基)丙酰胺的制备Step 5: Preparation of 2-(5-fluoro-2-methyl-4-nitrophenyl)-N-methyl-N-(2,2,2-trifluoroethyl)propionamide
室温下，将2-(5-氟-2-甲基-4-硝基苯基)丙酸(6.8g,30.0mmol)和2,2,2-三氟-N-甲基乙烷-1-胺盐酸盐(8.9g,60.0mmol)溶解于吡啶(60mL)中，加入1-乙基-(3-二甲基氨基丙基)碳二亚胺盐酸盐(17.3g,90.0mmol)，室温搅拌反应12小时，LCMS显示原料反应完全。减压浓缩除去溶剂，加入水，用二氯甲烷萃取，有机相依次用饱和碳酸氢钠溶液和饱和氯化钠溶液洗涤，无水硫酸钠干燥，浓缩，粗品柱层析纯化得标题化合物(6.3g，65％)。At room temperature, 2-(5-fluoro-2-methyl-4-nitrophenyl)propionic acid (6.8 g, 30.0 mmol) and 2,2,2-trifluoro-N-methylethane-1-amine hydrochloride (8.9 g, 60.0 mmol) were dissolved in pyridine (60 mL), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (17.3 g, 90.0 mmol) was added, and the mixture was stirred at room temperature for 12 hours. LCMS showed that the raw materials were completely reacted. The solvent was removed by concentration under reduced pressure, water was added, and the mixture was extracted with dichloromethane. The organic phase was washed with saturated sodium bicarbonate solution and saturated sodium chloride solution in turn, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by column chromatography to obtain the title compound (6.3 g, 65%).
MS m/z(ESI):323.1[M+H]+.MS m/z(ESI):323.1[M+H] + .
第六步：2-(4-氨基-5-氟-2-甲基苯基)-N-甲基-N-(2,2,2-三氟乙基)丙酰胺的制备Step 6: Preparation of 2-(4-amino-5-fluoro-2-methylphenyl)-N-methyl-N-(2,2,2-trifluoroethyl)propionamide
将2-(5-氟-2-甲基-4-硝基苯基)-N-甲基-N-(2,2,2-三氟乙基)丙酰胺(6.3g,19.6mmol)溶于甲醇(50mL)中，加入钯/碳(600mg)，室温搅拌2小时，LCMS显示原料反应完全。硅藻土过滤，滤液浓缩，得标题化合物(5.1g,89％)。Dissolve 2-(5-fluoro-2-methyl-4-nitrophenyl)-N-methyl-N-(2,2,2-trifluoroethyl)propionamide (6.3 g, 19.6 mmol) in methanol (50 mL), add palladium/carbon (600 mg), stir at room temperature for 2 hours, LCMS shows that the raw material is completely reacted. Filter through celite, concentrate the filtrate to obtain the title compound (5.1 g, 89%).
MS m/z(ESI):293.1[M+H]+.MS m/z(ESI):293.1[M+H] + .
第七步：(2-甲氧基乙烯-1,1-二基)二环丙烷的制备Step 7: Preparation of (2-methoxyethylene-1,1-diyl)dicyclopropane
将乙氧甲酰基亚甲基三苯基膦(236g,0.68mol)溶于四氢呋喃(1000mL)中，冷却至0℃，滴加正丁基锂(272mL,0.68mol，2.5M的正己烷溶液)，0℃搅拌30分钟，滴加二环丙基甲酮(50g,0.45mol)，滴毕，升温至60℃搅拌反应16小时，TLC显示原料反应完全。加入饱和氯化铵溶液，用乙酸乙酯萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，浓缩除去溶剂，粗品柱层析纯化得标题化合物(48.4g，78％)。Dissolve ethoxyformylmethylenetriphenylphosphine (236g, 0.68mol) in tetrahydrofuran (1000mL), cool to 0℃, add n-butyllithium (272mL, 0.68mol, 2.5M n-hexane solution) dropwise, stir at 0℃ for 30 minutes, add dicyclopropyl ketone (50g, 0.45mol) dropwise, heat to 60℃ and stir for 16 hours, TLC shows that the raw material reacts completely. Add saturated ammonium chloride solution, extract with ethyl acetate, wash the organic phase with saturated brine, dry over anhydrous sodium sulfate, concentrate to remove the solvent, and purify the crude product by column chromatography to obtain the title compound (48.4g, 78%).
第八步：2,2-二环丙基乙醛的制备Step 8: Preparation of 2,2-dicyclopropylacetaldehyde
将(2-甲氧基乙烯-1,1-二基)二环丙烷(48.4g,0.35mol)溶于四氢呋喃(200mL)中，加入6N盐酸(200mL)，室温搅拌16小时，TLC显示原料反应完全。加入甲基叔丁基醚稀释，用饱和食盐水洗涤，分离有机相，经无水硫酸钠干燥，过滤后减压浓缩有机溶剂，得标题化合物(26.9g，62％)。Dissolve (2-methoxyethylene-1,1-diyl)dicyclopropane (48.4 g, 0.35 mol) in tetrahydrofuran (200 mL), add 6N hydrochloric acid (200 mL), stir at room temperature for 16 hours, TLC shows that the raw material is completely reacted. Add methyl tert-butyl ether to dilute, wash with saturated brine, separate the organic phase, dry over anhydrous sodium sulfate, filter and concentrate the organic solvent under reduced pressure to obtain the title compound (26.9 g, 62%).
第九步：(E)-N-(2,2-二环丙基亚乙基)-2-甲基丙烷-2-亚磺酰胺的制备Step 9: Preparation of (E)-N-(2,2-dicyclopropylethylidene)-2-methylpropane-2-sulfenamide
将2,2-二环丙基乙醛(25g,0.2mol)溶于二氯甲烷(100mL)中，加入2-甲基丙烷-2-亚磺酰胺(24.2g,0.2mol)和四异丙基氧钛(85.3g,0.3mol)，升温至45℃搅拌2小时，LCMS显示原料反应完全。加入水，过滤，用二氯甲烷萃取，有机相用无水硫酸钠干燥，浓缩，粗品柱层析纯化得标题化合物(32.2g，71％)。Dissolve 2,2-dicyclopropylacetaldehyde (25g, 0.2mol) in dichloromethane (100mL), add 2-methylpropane-2-sulfinamide (24.2g, 0.2mol) and tetraisopropyloxytitanium (85.3g, 0.3mol), heat to 45°C and stir for 2 hours. LCMS shows that the raw materials are completely reacted. Add water, filter, extract with dichloromethane, dry the organic phase with anhydrous sodium sulfate, concentrate, and purify the crude product by column chromatography to obtain the title compound (32.2g, 71%).
MS m/z(ESI):228.1[M+H]+.MS m/z(ESI):228.1[M+H] + .
第十步：N-(1-氰基-2,2-二环丙基乙基)-2-甲基丙烷-2-亚磺酰胺的制备Step 10: Preparation of N-(1-cyano-2,2-dicyclopropylethyl)-2-methylpropane-2-sulfenamide
将(E)-N-(2,2-二环丙基亚乙基)-2-甲基丙烷-2-亚磺酰胺(32.2g,0.14mol)溶于二氯甲烷(350mL)中，加入三甲基硅氰(27.7g,0.28mol)和氟化铯(6.4g,42mol)，室温搅拌16小时，LCMS显示原料反应完全。加入水，用二氯甲烷萃取，有机相用无水硫酸钠干燥，过滤，浓缩，粗品柱层析纯化得标题化合物(24.5g，69％)。Dissolve (E)-N-(2,2-dicyclopropylethylidene)-2-methylpropane-2-sulfenamide (32.2 g, 0.14 mol) in dichloromethane (350 mL), add trimethylsilyl cyanide (27.7 g, 0.28 mol) and cesium fluoride (6.4 g, 42 mol), stir at room temperature for 16 hours, LCMS shows that the raw material is completely reacted. Add water, extract with dichloromethane, dry the organic phase with anhydrous sodium sulfate, filter, concentrate, and purify the crude product by column chromatography to obtain the title compound (24.5 g, 69%).
MS m/z(ESI):255.1[M+H]+.MS m/z(ESI):255.1[M+H] + .
第十一步：2-氨基-3,3-二环丙基丙腈的制备Step 11: Preparation of 2-amino-3,3-dicyclopropylpropionitrile
将N-(1-氰基-2,2-二环丙基乙基)-2-甲基丙烷-2-亚磺酰胺(24.5g,96.5mmol)溶于二氯甲烷(200mL)中，冷却至0℃，加入4M盐酸甲醇(200mL)，室温搅拌6小时，LCMS显示原料反应完全。浓缩，得标题化合物(14.5g，>99％)。Dissolve N-(1-cyano-2,2-dicyclopropylethyl)-2-methylpropane-2-sulfinamide (24.5 g, 96.5 mmol) in dichloromethane (200 mL), cool to 0°C, add 4M methanolic hydrochloric acid (200 mL), stir at room temperature for 6 hours, LCMS shows that the raw material is completely reacted. Concentrate to obtain the title compound (14.5 g, >99%).
MS m/z(ESI):151.1[M+H]+.MS m/z(ESI):151.1[M+H] + .
第十二步：2-氨基-3,3-二环丙基丙酸的制备Step 12: Preparation of 2-amino-3,3-dicyclopropylpropionic acid
将2-氨基-3,3-二环丙基丙腈(14.5g,96.5mmol)溶于醋酸(20mL)中，加入6N盐酸(160mL,965.0mmol)，升温至125℃搅拌16小时，LCMS显示原料反应完全。过滤，滤液浓缩，得标题化合物(16.4g，>99％)。Dissolve 2-amino-3,3-dicyclopropylpropionitrile (14.5 g, 96.5 mmol) in acetic acid (20 mL), add 6N hydrochloric acid (160 mL, 965.0 mmol), heat to 125°C and stir for 16 hours. LCMS shows that the reaction of the raw material is complete. Filter and concentrate the filtrate to obtain the title compound (16.4 g, >99%).
MS m/z(ESI):170.1[M+H]+.MS m/z(ESI):170.1[M+H] + .
第十三步：2-((叔-丁氧基羰基)氨基)-3,3-二环丙基丙酸的制备Step 13: Preparation of 2-((tert-butoxycarbonyl)amino)-3,3-dicyclopropylpropionic acid
将2-氨基-3,3-二环丙基丙酸(16.4g,96.5mmol)溶于四氢呋喃/水(80mL/40mL)中，冷却至0℃，加入碳酸氢钠(40.5g,482.5mmol)和二碳酸二叔丁酯(31.6g,144.8mmol)，逐渐升至室温搅拌16小时，LCMS显示原料反应完全。过滤，滤液用甲基叔丁基醚萃取，水相用1N盐酸调pH-2，用乙酸乙酯萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，浓缩，得标题化合物(17.1g，66％)。Dissolve 2-amino-3,3-dicyclopropylpropionic acid (16.4 g, 96.5 mmol) in tetrahydrofuran/water (80 mL/40 mL), cool to 0°C, add sodium bicarbonate (40.5 g, 482.5 mmol) and di-tert-butyl dicarbonate (31.6 g, 144.8 mmol), gradually warm to room temperature and stir for 16 hours, LCMS shows that the raw material is completely reacted. Filter, extract the filtrate with methyl tert-butyl ether, adjust the pH of the aqueous phase to -2 with 1N hydrochloric acid, extract with ethyl acetate, wash the organic phase with saturated brine, dry over anhydrous sodium sulfate, and concentrate to obtain the title compound (17.1 g, 66%).
MS m/z(ESI):270.1[M+H]+.MS m/z(ESI):270.1[M+H] + .
第十四步：4-甲氧苄基(S)-2-((叔-丁氧基羰基)氨基)-3,3-二环丙基丙酸酯的制备Step 14: Preparation of 4-methoxybenzyl (S)-2-((tert-butoxycarbonyl)amino)-3,3-dicyclopropyl propionate
室温下，2-((叔-丁氧基羰基)氨基)-3,3-二环丙基丙酸(17.1g,63.6mmol)和对甲氧基苄醇(13.2g,95.4mmol)溶于乙腈(100mL)中，加入三乙胺(19.3g,190.8mmol)和2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(48.3g,127.2mmol)，室温搅拌16小时，LCMS显示原料反应完全。加入水，用乙酸乙酯萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，浓缩，粗品依次经过硅胶柱层析和手性柱拆分纯化得标题化合物(9.2g，37％)。At room temperature, 2-((tert-butoxycarbonyl)amino)-3,3-dicyclopropylpropionic acid (17.1 g, 63.6 mmol) and p-methoxybenzyl alcohol (13.2 g, 95.4 mmol) were dissolved in acetonitrile (100 mL), triethylamine (19.3 g, 190.8 mmol) and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (48.3 g, 127.2 mmol) were added, and stirred at room temperature for 16 hours. LCMS showed that the raw materials were completely reacted. Water was added, extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography and chiral column separation to obtain the title compound (9.2 g, 37%).
MS m/z(ESI):390.1[M+H]+.MS m/z(ESI):390.1[M+H] + .
第十五步：(S)-2-((叔-丁氧基羰基)氨基)-3,3-二环丙基丙酸的制备Step 15: Preparation of (S)-2-((tert-butoxycarbonyl)amino)-3,3-dicyclopropylpropionic acid
室温下，4-甲氧苄基(S)-2-((叔-丁氧基羰基)氨基)-3,3-二环丙基丙酸酯(9.2g,23.7mmol)溶于甲醇(100mL)中，氮气置换三次，加入钯碳(900mg)，氢气氛围下，室温搅拌5小时，LCMS显示原料反应完全。过滤，滤液浓缩得标题化合物(5.7g，90％)。At room temperature, 4-methoxybenzyl (S)-2-((tert-butoxycarbonyl)amino)-3,3-dicyclopropylpropanoate (9.2 g, 23.7 mmol) was dissolved in methanol (100 mL), replaced with nitrogen three times, palladium carbon (900 mg) was added, and stirred at room temperature for 5 hours under hydrogen atmosphere. LCMS showed that the raw material reacted completely. Filter and concentrate the filtrate to obtain the title compound (5.7 g, 90%).
MS m/z(ESI):270.1[M+H]+.MS m/z(ESI):270.1[M+H] + .
第十六步：叔-丁基((2S)-1,1-二环丙基-3-((2-氟-4-(1-(甲基(2,2,2-三氟乙基)氨基)-1-羰基丙烷-2-基)苯基)氨基)-3-羰基丙烷-2-基)氨基甲酸酯的制备Step 16: Preparation of tert-butyl ((2S)-1,1-dicyclopropyl-3-((2-fluoro-4-(1-(methyl(2,2,2-trifluoroethyl)amino)-1-carbonylpropane-2-yl)phenyl)amino)-3-carbonylpropane-2-yl)carbamate
室温下，将(S)-2-((叔-丁氧基羰基)氨基)-3,3-二环丙基丙酸(100mg,0.37mmol)和2-(4-氨基-5-氟-2-甲基苯基)-N-甲基-N-(2,2,2-三氟乙基)丙酰胺(102.8mg,0.37mmol)溶于N,N-二甲基甲酰胺(5mL)中，加入三乙胺(112.1mg,1.11mmol)和2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(281.2mg,0.74mmol)，室温搅拌16小时，LCMS显示原料反应完全。加入水，用乙酸乙酯萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，浓缩，粗品经柱层析纯化得标题化合物(112mg，57％)。At room temperature, (S)-2-((tert-butoxycarbonyl)amino)-3,3-dicyclopropylpropionic acid (100 mg, 0.37 mmol) and 2-(4-amino-5-fluoro-2-methylphenyl)-N-methyl-N-(2,2,2-trifluoroethyl)propionamide (102.8 mg, 0.37 mmol) were dissolved in N,N-dimethylformamide (5 mL), triethylamine (112.1 mg, 1.11 mmol) and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (281.2 mg, 0.74 mmol) were added, and stirred at room temperature for 16 hours. LCMS showed that the raw materials were completely reacted. Water was added, extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by column chromatography to obtain the title compound (112 mg, 57%).
MS m/z(ESI):530.1[M+H]+.MS m/z(ESI):530.1[M+H] + .
第十七步：(2S)-2-氨基-3,3-二环丙基-N-(2-氟-4-(1-(甲基(2,2,2-三氟乙基)氨基)-1-羰基丙烷-2-基)苯基)丙酰胺的制备Step 17: Preparation of (2S)-2-amino-3,3-dicyclopropyl-N-(2-fluoro-4-(1-(methyl(2,2,2-trifluoroethyl)amino)-1-carbonylpropane-2-yl)phenyl)propanamide
将叔-丁基((2S)-1,1-二环丙基-3-((2-氟-4-(1-(甲基(2,2,2-三氟乙基)氨基)-1-羰基丙烷-2-基)苯基)氨基)-3-羰基丙烷-2-基)氨基甲酸酯(111.6g,0.21mmol)溶于二氯甲烷(3mL)中，加入4M盐酸二氧六环(3mL)，室温搅拌1小时，LCMS显示原料反应完全。浓缩，得标题化合物盐酸盐，直接用于下一步反应。Dissolve tert-butyl ((2S)-1,1-dicyclopropyl-3-((2-fluoro-4-(1-(methyl(2,2,2-trifluoroethyl)amino)-1-carbonylpropane-2-yl)phenyl)amino)-3-carbonylpropane-2-yl)carbamate (111.6 g, 0.21 mmol) in dichloromethane (3 mL), add 4M hydrochloric acid dioxane (3 mL), stir at room temperature for 1 hour, LCMS shows that the raw material is completely reacted. Concentrate to obtain the title compound hydrochloride, which is directly used in the next step reaction.
MS m/z(ESI):430.1[M+H]+.MS m/z(ESI):430.1[M+H] + .
第十八步：环丙基((2S)-1,1-二环丙基-3-((2-氟-5-甲基-4-(1-(甲基(2,2,2-三氟乙基)氨基)-1-羰基丙烷-2-基)苯基)氨基)-3-羰基丙烷-2-基)氨基甲酸酯的制备Step 18: Preparation of cyclopropyl ((2S)-1,1-dicyclopropyl-3-((2-fluoro-5-methyl-4-(1-(methyl(2,2,2-trifluoroethyl)amino)-1-carbonylpropane-2-yl)phenyl)amino)-3-carbonylpropane-2-yl)carbamate
将(2S)-2-氨基-3,3-二环丙基-N-(2-氟-4-(1-(甲基(2,2,2-三氟乙基)氨基)-1-羰基丙烷-2-基)苯基)丙酰胺(85.8mg,0.2mmol)和三乙胺(40.4mg,0.4mmol)溶于二氯甲烷(3mL)中，冷却至0℃，滴加氯甲酸环丙酯(28.8mg,0.24mmol)，0℃下搅拌1小时，LCMS显示原料反应完全。加入水，用二氯甲烷萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，浓缩，粗品经HPLC分离纯化得标题化合物(40mg,38％)。Dissolve (2S)-2-amino-3,3-dicyclopropyl-N-(2-fluoro-4-(1-(methyl(2,2,2-trifluoroethyl)amino)-1-carbonylpropane-2-yl)phenyl)propanamide (85.8 mg, 0.2 mmol) and triethylamine (40.4 mg, 0.4 mmol) in dichloromethane (3 mL), cool to 0°C, add cyclopropyl chloroformate (28.8 mg, 0.24 mmol) dropwise, stir at 0°C for 1 hour, LCMS shows that the raw material reacts completely. Add water, extract with dichloromethane, wash the organic phase with saturated brine, dry over anhydrous sodium sulfate, concentrate, and separate and purify the crude product by HPLC to obtain the title compound (40 mg, 38%).
MS m/z(ESI):528.1[M+H]+.MS m/z(ESI):528.1[M+H] + .
以下实施例参照上述实施例1'的路线合成：The following examples are synthesized by referring to the route of Example 1' above:
实施例1”Example 1
环丙基((S)-(4，4-二氟环己基)(3-((S)-2-甲氧基-1-((S S)-2-氧代-4-(三氟甲基)咪唑啉-1-基)乙基)咪唑并[1,2-b][1,2,4]三嗪-6-基)甲基)氨基甲酸酯Cyclopropyl ((S)-(4,4-difluorocyclohexyl)(3-((S)-2-methoxy-1-((SS)-2-oxo-4-(trifluoromethyl)imidazolin-1-yl)ethyl)imidazo[1,2-b][1,2,4]triazin-6-yl)methyl)carbamate
MS m/z(ESI):562.2[M+H]+ MS m/z(ESI):562.2[M+H] +
合成路线：Synthesis route:
SchemeScheme
SchemeScheme
具体地，实施例1”还可以按照如下步骤合成Specifically, Example 1" can also be synthesized according to the following steps:
第一步：甲基2-(((苄氧基)羰基)氨基)-2-(4,4-二氟亚环己基)乙酸酯的制备Step 1: Preparation of methyl 2-(((benzyloxy)carbonyl)amino)-2-(4,4-difluorocyclohexylidene)acetate
将2-(((苄氧基)羰基)氨基)-2-(二甲氧基磷基)乙酸甲酯(441g,1.33mol)，溶于N-甲基吡咯烷酮(0.9L)中，冷却至15℃，加入DBU(183.5g,1.21mmol)，并于15℃搅拌反应0.5小时。加入4,4-二氟环己烷-1-酮(161g,1.2mol)的N-甲基吡咯烷酮溶液(340ml)，保持反应温度低于20℃。反应液于10-20℃搅拌反应12小时。反应液加入水，过滤得到白色固体，用石油醚洗涤。将白色固体溶于1,4-二氧六环(4L)和水(4L)的混合液中，过滤，石油醚洗涤，干燥得到标题化合物(366g，90％)。Methyl 2-(((benzyloxy)carbonyl)amino)-2-(dimethoxyphosphino)acetate (441 g, 1.33 mol) was dissolved in N-methylpyrrolidone (0.9 L), cooled to 15 ° C, DBU (183.5 g, 1.21 mmol) was added, and stirred at 15 ° C for 0.5 hours. A solution of 4,4-difluorocyclohexane-1-one (161 g, 1.2 mol) in N-methylpyrrolidone (340 ml) was added, and the reaction temperature was kept below 20 ° C. The reaction solution was stirred at 10-20 ° C for 12 hours. Water was added to the reaction solution, filtered to obtain a white solid, and washed with petroleum ether. The white solid was dissolved in a mixture of 1,4-dioxane (4 L) and water (4 L), filtered, washed with petroleum ether, and dried to obtain the title compound (366 g, 90%).
MS m/z(ESI):340.1[M+H]+.MS m/z(ESI):340.1[M+H] + .
第二步：2-(((苄氧基)羰基)氨基)-2-(4,4-二氟亚环己基)乙酸的制备Step 2: Preparation of 2-(((benzyloxy)carbonyl)amino)-2-(4,4-difluorocyclohexylidene)acetic acid
将甲基2-(((苄氧基)羰基)氨基)-2-(4,4-二氟亚环己基)乙酸酯(249g,0.735mol)溶解于四氢呋喃(0.75L)中，加入1.5M氢氧化钠溶液(0.75L)，反应液于25℃搅拌反应12小时，减压浓缩除去大部分四氢呋喃，水相用5N硫酸调节pH～1,用乙酸乙酯萃取，经无水硫酸钠干燥，过滤，减压浓缩有机溶剂得标题化合物(201g，84％)。Methyl 2-(((benzyloxy)carbonyl)amino)-2-(4,4-difluorocyclohexylidene)acetate (249 g, 0.735 mol) was dissolved in tetrahydrofuran (0.75 L), and 1.5 M sodium hydroxide solution (0.75 L) was added. The reaction solution was stirred at 25°C for 12 hours, and most of the tetrahydrofuran was removed by concentration under reduced pressure. The aqueous phase was adjusted to pH ~ 1 with 5N sulfuric acid, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and the organic solvent was concentrated under reduced pressure to obtain the title compound (201 g, 84%).
MS m/z(ESI):326.1[M+H]+.MS m/z(ESI):326.1[M+H] + .
第三步：(S)-2-(((苄氧基)羰基)氨基)-2-(4,4-二氟环己基)乙酸的制备Step 3: Preparation of (S)-2-(((Benzyloxy)carbonyl)amino)-2-(4,4-difluorocyclohexyl)acetic acid
重复以下步骤两次：在手套箱中将2-(((苄氧基)羰基)氨基)-2-(4,4-二氟亚环己基)乙酸(176g,0.54mol)加入含有甲醇(700mL)的高压釜中，15-20℃下用氮气饱和1小时。在手套箱中，加入Rh-COD-[(S)-Maxphos]-BF4(3.4g,5.38mmol)，然后鼓吹氢气三次。反应液继续于30℃和氢气压力(100psi)下搅拌反应22小时。将反应液浓缩得到黄色固体。将固体溶于水(3L)，加入2N氢氧化钠调节pH～13，用MTBE洗涤，分液，水相用5N盐酸调节pH～1，用乙酸乙酯萃取，经无水硫酸钠干燥，过滤后减压浓缩有机溶剂得到被铑污染的标题化合物粗品。Repeat the following steps twice: Add 2-(((benzyloxy)carbonyl)amino)-2-(4,4-difluorocyclohexylidene)acetic acid (176 g, 0.54 mol) to an autoclave containing methanol (700 mL) in a glove box and saturate with nitrogen for 1 hour at 15-20°C. Add Rh-COD-[(S)-Maxphos]-BF 4 (3.4 g, 5.38 mmol) in a glove box, and then blow hydrogen three times. The reaction solution continues to stir and react at 30°C and hydrogen pressure (100 psi) for 22 hours. Concentrate the reaction solution to obtain a yellow solid. Dissolve the solid in water (3 L), add 2N sodium hydroxide to adjust the pH to 13, wash with MTBE, separate the liquid, adjust the pH of the aqueous phase to 1 with 5N hydrochloric acid, extract with ethyl acetate, dry over anhydrous sodium sulfate, filter, and concentrate the organic solvent under reduced pressure to obtain the crude product of the title compound contaminated with rhodium.
重复以下步骤四次：将(S)-2-(((苄氧基)羰基)氨基)-2-(4,4-二氟环己基)乙酸粗品溶于乙酸乙酯(1.33L)中，15-20℃下加入聚缩硫醛多支烷基聚硫化丙基二氧化硅(31.25g)，反应液继续于25℃氮气保护下搅拌反应15小时。硅藻土过滤，减压浓缩有机溶剂得到标题化合物(159g,90％,98％ee)。Repeat the following steps four times: Dissolve the crude (S)-2-(((benzyloxy)carbonyl)amino)-2-(4,4-difluorocyclohexyl)acetic acid in ethyl acetate (1.33 L), add polythioacetal multi-branched alkyl polysulfide propyl silica (31.25 g) at 15-20°C, and continue stirring the reaction solution at 25°C under nitrogen protection for 15 hours. Filter through diatomaceous earth, and concentrate the organic solvent under reduced pressure to obtain the title compound (159 g, 90%, 98% ee).
MS m/z(ESI):328.1[M+H]+.MS m/z(ESI):328.1[M+H] + .
第四步：叔-丁基(S)-4-(((苄氧基)羰基)氨基)-4-(4,4-二氟环己基)-3-羰基丁酸酯的制备Step 4: Preparation of tert-butyl (S)-4-(((benzyloxy)carbonyl)amino)-4-(4,4-difluorocyclohexyl)-3-carbonylbutyrate
将(S)-2-(((苄氧基)羰基)氨基)-2-(4,4-二氟环己基)乙酸(7.5g,24mmol)和羰基二咪唑(7.8g,24mmol)溶解于四氢呋喃(200mL)中，25℃搅拌反应1.5小时，然后将上述反应液冷却到-78℃。(S)-2-(((Benzyloxy)carbonyl)amino)-2-(4,4-difluorocyclohexyl)acetic acid (7.5 g, 24 mmol) and carbonyldiimidazole (7.8 g, 24 mmol) were dissolved in tetrahydrofuran (200 mL), stirred at 25°C for 1.5 hours, and then the reaction solution was cooled to -78°C.
将二异丙基乙胺(14.5ml,103mmol)溶解于四氢呋喃(75mL)中，0℃加入2.5M正丁基锂(41ml,105mmol)，搅拌反应10分钟后，冷却到-78℃，加入乙酸叔丁酯(13.9g,103mmol)，搅拌反应1小时后，将此反应液加入到上面反应液中。搅拌反应1小时，用饱和氯化铵淬灭，用乙酸乙酯稀释，依次用饱和碳酸钠水溶液和饱和食盐水洗涤，分离有机相，用无水硫酸钠干燥，过滤后减压浓缩有机溶剂，所得残余物经柱层析分离得标题化合物(9.75g，95％)。Dissolve diisopropylethylamine (14.5ml, 103mmol) in tetrahydrofuran (75mL), add 2.5M n-butyllithium (41ml, 105mmol) at 0℃, stir and react for 10 minutes, cool to -78℃, add tert-butyl acetate (13.9g, 103mmol), stir and react for 1 hour, then add this reaction solution to the above reaction solution. Stir and react for 1 hour, quench with saturated ammonium chloride, dilute with ethyl acetate, wash with saturated sodium carbonate aqueous solution and saturated brine in sequence, separate the organic phase, dry with anhydrous sodium sulfate, filter and concentrate the organic solvent under reduced pressure, and separate the residue by column chromatography to obtain the title compound (9.75g, 95%).
MS m/z(ESI):426.2[M-H]+.MS m/z(ESI):426.2[MH] + .
第五步：苯甲基(S)-(3-溴-1-(4,4-二氟环己基)-2-羰基丙基)氨基甲酸酯的制备Step 5: Preparation of benzyl (S)-(3-bromo-1-(4,4-difluorocyclohexyl)-2-carbonylpropyl)carbamate
将叔-丁基(S)-4-(((苄氧基)羰基)氨基)-4-(4,4-二氟环己基)-3-羰基丁酸酯(9.75mg,22.9mmol)和2,6-二甲基吡啶(0.2ml,1.72mmol)溶于甲醇(40mL)中，加入NBS(4.0g,22.25mmol)，反应液于室温下搅拌2.5小时，反应液加入乙酸乙酯和50％的氯化铵溶液，分离有机相，用无水硫酸钠干燥，过滤后减压浓缩有机溶剂，残余物溶于甲苯(120ml)中，加入三氟乙酸(15ml)，80℃搅拌反应2小时。减压浓缩有机溶剂，所得残余物经柱层析分离得标题化合物(5.15g，56％)。Tert-butyl (S)-4-(((benzyloxy)carbonyl)amino)-4-(4,4-difluorocyclohexyl)-3-carbonylbutyrate (9.75 mg, 22.9 mmol) and 2,6-dimethylpyridine (0.2 ml, 1.72 mmol) were dissolved in methanol (40 mL), and NBS (4.0 g, 22.25 mmol) was added. The reaction solution was stirred at room temperature for 2.5 hours. Ethyl acetate and 50% ammonium chloride solution were added to the reaction solution, and the organic phase was separated and dried over anhydrous sodium sulfate. After filtration, the organic solvent was concentrated under reduced pressure. The residue was dissolved in toluene (120 ml), trifluoroacetic acid (15 ml) was added, and the reaction was stirred at 80°C for 2 hours. The organic solvent was concentrated under reduced pressure, and the residue was separated by column chromatography to obtain the title compound (5.15 g, 56%).
MS m/z(ESI):404.1[M+H]+.MS m/z(ESI):404.1[M+H] + .
第六步：2-苯基-4-(2,2,2-三氟乙酰基)噁唑-5(4H)-酮的制备Step 6: Preparation of 2-phenyl-4-(2,2,2-trifluoroacetyl)oxazol-5(4H)-one
将苯甲酰甘氨酸(100g,558mmol)溶于丙酮(500mL)中，0℃加入三氟乙酸酐(374g,1.78mol)，确保反应温度低于5℃。反应混合液0℃搅拌反应23小时。0℃加入水(500ml)淬灭，搅拌10分钟后，过滤，用水洗涤，真空干燥得标题化合物(126.7g，88％)。Dissolve benzoylglycine (100 g, 558 mmol) in acetone (500 mL), add trifluoroacetic anhydride (374 g, 1.78 mol) at 0°C, and ensure that the reaction temperature is below 5°C. Stir the reaction mixture at 0°C for 23 hours. Add water (500 ml) at 0°C to quench, stir for 10 minutes, filter, wash with water, and dry in vacuo to obtain the title compound (126.7 g, 88%).
MS m/z(ESI):258.0[M+H]+.MS m/z(ESI):258.0[M+H] + .
第七步：N-(3,3,3-三氟-2,2-二羟基丙基)苯酰胺的制备Step 7: Preparation of N-(3,3,3-trifluoro-2,2-dihydroxypropyl)benzamide
将2-苯基-4-(2,2,2-三氟乙酰基)噁唑-5(4H)-酮(126g,490mmol)溶于四氢呋喃(800mL)中，加水15分钟，保持反应液温度低于28℃，然后室温搅拌24小时。加入水(500mL)，加入5N氢氧化钠调节pH～7.5，用MTBE(250mL)萃取，饱和碳酸氢钠和饱和氯化钠洗涤，分离有机相，用无水硫酸钠干燥，过滤后减压浓缩有机溶剂得标题化合物(101.85g，83％)。Dissolve 2-phenyl-4-(2,2,2-trifluoroacetyl)oxazol-5(4H)-one (126 g, 490 mmol) in tetrahydrofuran (800 mL), add water for 15 minutes, keep the reaction solution temperature below 28°C, and then stir at room temperature for 24 hours. Add water (500 mL), add 5N sodium hydroxide to adjust the pH to 7.5, extract with MTBE (250 mL), wash with saturated sodium bicarbonate and saturated sodium chloride, separate the organic phase, dry with anhydrous sodium sulfate, filter, and concentrate the organic solvent under reduced pressure to obtain the title compound (101.85 g, 83%).
MS m/z(ESI):250.1[M+H]+.MS m/z(ESI):250.1[M+H] + .
第八步：(S,Z)-N-(3,3,3-三氟-2-((1-苯基乙基)氨基)丙-1-烯-1-基)苯酰胺的制备Step 8: Preparation of (S,Z)-N-(3,3,3-trifluoro-2-((1-phenylethyl)amino)prop-1-en-1-yl)benzamide
将N-(3,3,3-三氟-2,2-二羟基丙基)苯酰胺(101.5g,407.3mmol)溶于甲苯(1L)中，加入(1S)-1-苯基乙胺(60ml,465mmol)，105℃搅拌反应7.5小时，然后室温下搅拌16小时。反应液浓缩，所得残余物经柱层析分离得粗品(102g)。将粗品溶于乙醇(500mL)中，慢慢加入水直至溶液浑浊。加入晶种(100mg)。将浑浊液冷至10℃，加入水(25mL)，继续将溶液冷至5℃ 10分钟，使产品进一步结晶。过滤，固体用10％乙醇水溶液(200mL)洗涤，真空干燥得标题化合物(86g，63％)。Dissolve N-(3,3,3-trifluoro-2,2-dihydroxypropyl)benzamide (101.5g, 407.3mmol) in toluene (1L), add (1S)-1-phenylethylamine (60ml, 465mmol), stir at 105℃ for 7.5 hours, and then stir at room temperature for 16 hours. The reaction solution is concentrated, and the residue is separated by column chromatography to obtain a crude product (102g). The crude product is dissolved in ethanol (500mL), and water is slowly added until the solution is turbid. Add seed crystals (100mg). Cool the turbid solution to 10℃, add water (25mL), and continue to cool the solution to 5℃ for 10 minutes to further crystallize the product. Filter, wash the solid with 10% ethanol aqueous solution (200mL), and vacuum dry to obtain the title compound (86g, 63%).
MS m/z(ESI):335.1[M+H]+.MS m/z(ESI):335.1[M+H] + .
第九步：N-((S)-3,3,3-三氟-2-(((S)-1-苯基乙基)氨基)丙基)苯酰胺的制备Step 9: Preparation of N-((S)-3,3,3-trifluoro-2-(((S)-1-phenylethyl)amino)propyl)benzamide
重复以下步骤四次：在手套箱中的高压反应釜中加入(S,Z)-N-(3,3,3-三氟-2-((1-苯基乙基)氨基)丙-1-烯-1-基)苯酰胺(21.5g,64.3mmol)、Rh-COD-[(S)-Maxphos]-BF4(350mg,0.625mmol)和叔戊醇(200mL)。置换氢气三次，在氢气(150psi)下30℃反应20-31小时。在手套箱中将反应釜放空，再次加入Rh-COD-[(S)-Maxphos]-BF4(350mg,0.625mmol)。置换氢气三次，在氢气(150psi)下30℃反应0-43小时。将反应液转移到烧瓶中，减压浓缩，所得残余物经柱层析分离得半纯产物，此产物用正己烷重结晶两次得到标题化合物(16.7g，77％，96％ee)。Repeat the following steps four times: Add (S,Z)-N-(3,3,3-trifluoro-2-((1-phenylethyl)amino)prop-1-en-1-yl)benzamide (21.5 g, 64.3 mmol), Rh-COD-[(S)-Maxphos]-BF 4 (350 mg, 0.625 mmol) and tert-amyl alcohol (200 mL) to a high pressure reactor in a glove box. Replace the hydrogen three times and react at 30°C under hydrogen (150 psi) for 20-31 hours. Vent the reactor in the glove box and add Rh-COD-[(S)-Maxphos]-BF 4 (350 mg, 0.625 mmol) again. Replace the hydrogen three times and react at 30°C under hydrogen (150 psi) for 0-43 hours. The reaction solution was transferred to a flask and concentrated under reduced pressure. The residue was separated by column chromatography to obtain a semi-pure product, which was recrystallized twice from n-hexane to obtain the title compound (16.7 g, 77%, 96% ee).
MS m/z(ESI):337.1[M+H]+.MS m/z(ESI):337.1[M+H] + .
第十步：(S)-3,3,3-三氟丙烷-1,2-二胺二盐酸盐的制备Step 10: Preparation of (S)-3,3,3-trifluoropropane-1,2-diamine dihydrochloride
将N-((S)-3,3,3-三氟-2-(((S)-1-苯基乙基)氨基)丙基)苯酰胺(55g,163.5mmol)溶于1,4-二氧六环(100mL)和水(250mL)中，加入浓盐酸(12M,125ml)，反应液于95℃反应72小时。反应液冷却至22℃，并用甲苯(200mL×2)洗涤。水溶液旋转蒸发用正丁醇(300mL×3)共沸蒸馏。剩余的含有结晶固体的透明黄色母液用异丙醇稀释，并在10℃下冷却过夜。所得固体过滤，用异丙醇冲洗，并在50℃正空干燥箱中干燥1小时，得到标题化合物(31.75g，97％)。N-((S)-3,3,3-trifluoro-2-(((S)-1-phenylethyl)amino)propyl)benzamide (55g, 163.5mmol) was dissolved in 1,4-dioxane (100mL) and water (250mL), and concentrated hydrochloric acid (12M, 125ml) was added. The reaction solution was reacted at 95°C for 72 hours. The reaction solution was cooled to 22°C and washed with toluene (200mL×2). The aqueous solution was rotary evaporated and azeotropically distilled with n-butanol (300mL×3). The remaining transparent yellow mother liquor containing crystalline solids was diluted with isopropanol and cooled at 10°C overnight. The obtained solid was filtered, rinsed with isopropanol, and dried in a positive vacuum drying oven at 50°C for 1 hour to obtain the title compound (31.75g, 97%).
MS m/z(ESI):129.1[M+H]+.MS m/z(ESI):129.1[M+H] + .
第十一步：5-甲基-1,2,4-三嗪-3-胺的制备Step 11: Preparation of 5-methyl-1,2,4-triazine-3-amine
将5-甲基-3-甲磺酰-1,2,4-三嗪(5g,28.87mmol)溶于乙醇(40mL)和氨水(8mL)的混合溶剂中，封管，反应混合液加热至80℃搅拌反应12小时，冷却至室温。反应液用乙酸乙酯稀释，依次用饱和碳酸钠水溶液和饱和食盐水洗涤，分离有机相，用无水硫酸钠干燥，过滤后减压浓缩有机溶剂，所得残余物经柱层析分离得标题化合物(2.18g,69％)。Dissolve 5-methyl-3-methylsulfonyl-1,2,4-triazine (5 g, 28.87 mmol) in a mixed solvent of ethanol (40 mL) and ammonia water (8 mL), seal the tube, heat the reaction mixture to 80 ° C, stir and react for 12 hours, and cool to room temperature. Dilute the reaction solution with ethyl acetate, wash with saturated sodium carbonate aqueous solution and saturated brine in sequence, separate the organic phase, dry with anhydrous sodium sulfate, filter and concentrate the organic solvent under reduced pressure, and separate the residue by column chromatography to obtain the title compound (2.18 g, 69%).
MS m/z(ESI):111.1[M+H]+.MS m/z(ESI):111.1[M+H] + .
第十二步：N-(5-甲基-1,2,4-三嗪-3-基)特戊基酰胺的制备Step 12: Preparation of N-(5-methyl-1,2,4-triazine-3-yl)-tert-pentylamide
冰浴下，将5-甲基-1,2,4-三嗪-3-胺(6.1g,55.4mmol)溶于N-甲基吡咯烷酮(60mL)中，加入吡啶(8.76g,110.79mmol,8.93mL)和特戊酰氯(8.02g,66.47mmol)，恢复至室温反应12小时。反应液用乙酸乙酯稀释，依次用饱和碳酸钠水溶液和饱和食盐水洗涤，分离有机相，用无水硫酸钠干燥，过滤后减压浓缩有机溶剂，所得残余物经柱层析分离得标题化合物(8.2g,76％)。Under ice bath, 5-methyl-1,2,4-triazine-3-amine (6.1g, 55.4mmol) was dissolved in N-methylpyrrolidone (60mL), pyridine (8.76g, 110.79mmol, 8.93mL) and pivaloyl chloride (8.02g, 66.47mmol) were added, and the mixture was returned to room temperature for reaction for 12 hours. The reaction solution was diluted with ethyl acetate, washed with saturated sodium carbonate aqueous solution and saturated brine in sequence, the organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the organic solvent was concentrated under reduced pressure. The residue was separated by column chromatography to obtain the title compound (8.2g, 76%).
MS m/z(ESI):195.1[M+H]+.MS m/z(ESI):195.1[M+H] + .
第十三步：N-(5-(2-(二甲氨基)乙烯基)-1,2,4-三嗪-3-基)特戊基酰胺的制备Step 13: Preparation of N-(5-(2-(dimethylamino)vinyl)-1,2,4-triazine-3-yl)-t-pentylamide
将N-(5-甲基-1,2,4-三嗪-3-基)特戊基酰胺(11.5g,59.21mmol)溶于N,N-二甲基甲酰胺二甲基缩醛(100mL)和N,N-二甲基甲酰胺(20mL)的混合溶剂中，反应液加热至120℃搅拌反应6小时，冷却至室温搅拌12小时，反应液中析出大量固体，过滤，滤饼用石油醚洗涤，干燥，得到得标题化合物(9.9g,67％)。N-(5-methyl-1,2,4-triazine-3-yl)-t-pentylamide (11.5 g, 59.21 mmol) was dissolved in a mixed solvent of N,N-dimethylformamide dimethyl acetal (100 mL) and N,N-dimethylformamide (20 mL). The reaction solution was heated to 120°C and stirred for 6 hours. It was cooled to room temperature and stirred for 12 hours. A large amount of solid precipitated in the reaction solution. The solid was filtered, and the filter cake was washed with petroleum ether and dried to obtain the title compound (9.9 g, 67%).
MS m/z(ESI):250.2[M+H]+.MS m/z(ESI):250.2[M+H] + .
第十四步：N-(5-甲酰基-1,2,4-三嗪-3-基)特戊基酰胺的制备Step 14: Preparation of N-(5-formyl-1,2,4-triazine-3-yl)-t-pentylamide
将N-(5-(2-(二甲氨基)乙烯基)-1,2,4-三嗪-3-基)特戊基酰胺(14.8g,59.36mmol)溶于四氢呋喃(100mL)和水(20mL)的混合溶剂中，加入高碘酸钠(38.09g,178.09mmol)，反应液搅拌反应2小时。反应液用乙酸乙酯稀释，依次用饱和碳酸钠水溶液和饱和食盐水洗涤，分离有机相，用无水硫酸钠干燥，过滤后减压浓缩有机溶剂，所得残余物经柱层析分离得标题化合物(9.6g,77％)。N-(5-(2-(dimethylamino)vinyl)-1,2,4-triazine-3-yl)-t-pentylamide (14.8 g, 59.36 mmol) was dissolved in a mixed solvent of tetrahydrofuran (100 mL) and water (20 mL), sodium periodate (38.09 g, 178.09 mmol) was added, and the reaction solution was stirred for 2 hours. The reaction solution was diluted with ethyl acetate, washed with saturated sodium carbonate aqueous solution and saturated brine in sequence, the organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the organic solvent was concentrated under reduced pressure. The residue was separated by column chromatography to obtain the title compound (9.6 g, 77%).
MS m/z(ESI):209.1[M+H]+.MS m/z(ESI):209.1[M+H] + .
第十五步：N-(5-(1-羟基-2-甲氧基乙基)-1,2,4-三嗪-3-基)特戊基酰胺的制备Step 15: Preparation of N-(5-(1-hydroxy-2-methoxyethyl)-1,2,4-triazine-3-yl)-tert-pentylamide
冰浴氮气氛围下，将N-(5-甲酰基-1,2,4-三嗪-3-基)特戊基酰胺(18.3g,87.89mmol)溶于四氢呋喃(100mL)溶剂中，加入甲氧基甲基溴化镁的四氢呋喃溶液(2M,52.8mL,105.6mmol)，反应液搅拌反应2小时，恢复至室温。反应液用乙酸乙酯稀释，依次用饱和碳酸钠水溶液和饱和食盐水洗涤，分离有机相，用无水硫酸钠干燥，过滤后减压浓缩有机溶剂，所得残余物经柱层析分离得标题化合物(16.4g,73％)。Under an ice bath nitrogen atmosphere, N-(5-formyl-1,2,4-triazine-3-yl)-t-pentylamide (18.3 g, 87.89 mmol) was dissolved in tetrahydrofuran (100 mL) solvent, and a tetrahydrofuran solution of methoxymethylmagnesium bromide (2M, 52.8 mL, 105.6 mmol) was added. The reaction solution was stirred for 2 hours and returned to room temperature. The reaction solution was diluted with ethyl acetate, washed with saturated sodium carbonate aqueous solution and saturated brine in sequence, the organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the organic solvent was concentrated under reduced pressure. The residue was separated by column chromatography to obtain the title compound (16.4 g, 73%).
MS m/z(ESI):255.1[M+H]+.MS m/z(ESI):255.1[M+H] + .
第十六步：N-(5-(2-甲氧基乙酰基)-1,2,4-三嗪-3-基)特戊基酰胺的制备Step 16: Preparation of N-(5-(2-methoxyacetyl)-1,2,4-triazine-3-yl)-tert-pentylamide
冰浴下，将N-(5-(1-羟基-2-甲氧基乙基)-1,2,4-三嗪-3-基)特戊基酰胺(15.3g,60.23mmol)溶于二氯甲烷(100mL)溶剂中，加入戴斯-马丁氧化剂(30.62g,72.20mmol)，反应液搅拌反应1小时，恢复至室温。反应液用乙酸乙酯稀释，依次用饱和碳酸钠水溶液和饱和食盐水洗涤，分离有机相，用无水硫酸钠干燥，过滤后减压浓缩有机溶剂，所得残余物经柱层析分离得标题化合物(14.8g,98％)。Under ice bath, N-(5-(1-hydroxy-2-methoxyethyl)-1,2,4-triazine-3-yl)-t-pentylamide (15.3 g, 60.23 mmol) was dissolved in dichloromethane (100 mL) solvent, and Dess-Martin periodinane (30.62 g, 72.20 mmol) was added. The reaction solution was stirred for 1 hour and returned to room temperature. The reaction solution was diluted with ethyl acetate, washed with saturated sodium carbonate aqueous solution and saturated brine in sequence, the organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the organic solvent was concentrated under reduced pressure. The residue was separated by column chromatography to obtain the title compound (14.8 g, 98%).
MS m/z(ESI):253.1[M+H]+.MS m/z(ESI):253.1[M+H] + .
第十七步：N-(5-(1-(((S)-2-氨基-3,3,3-三氟丙基)氨基)-2-甲氧基乙基)-1,2,4-三嗪-3-基)特戊基酰胺的制备Step 17: Preparation of N-(5-(1-(((S)-2-amino-3,3,3-trifluoropropyl)amino)-2-methoxyethyl)-1,2,4-triazine-3-yl)-t-pentylamide
将N-(5-(2-甲氧基乙酰基)-1,2,4-三嗪-3-基)特戊基酰胺(13.8g,54.76mmol,)，(S)-3,3,3-三氟丙烷-1,2-二胺二盐酸盐(22g,109.48mmol)溶于异丙醇(100mL)中，加入二异丙基乙胺(34.22g,264.80mmol,46.12mL)，反应液加热至75℃搅拌反应2小时，冷却至室温搅拌12小时，减压除去溶剂，残余物溶解在甲醇(40mL)，再加入乙酸(5mL)和氰基硼氢化钠(4.16g,66.20mmol)，加热至40℃搅拌反应6小时。反应液用乙酸乙酯稀释，依次用饱和碳酸钠水溶液和饱和食盐水洗涤，分离有机相，用无水硫酸钠干燥，过滤后减压浓缩有机溶剂，所得残余物经柱层析分离得标题化合物(17.3g,72％)。N-(5-(2-methoxyacetyl)-1,2,4-triazine-3-yl)-t-pentylamide (13.8 g, 54.76 mmol), (S)-3,3,3-trifluoropropane-1,2-diamine dihydrochloride (22 g, 109.48 mmol) were dissolved in isopropanol (100 mL), and diisopropylethylamine (34.22 g, 264.80 mmol, 46.12 mL) was added. The reaction solution was heated to 75°C and stirred for 2 hours, cooled to room temperature and stirred for 12 hours, and the solvent was removed under reduced pressure. The residue was dissolved in methanol (40 mL), and acetic acid (5 mL) and sodium cyanoborohydride (4.16 g, 66.20 mmol) were added, and heated to 40°C and stirred for 6 hours. The reaction solution was diluted with ethyl acetate, washed with saturated aqueous sodium carbonate solution and saturated brine in sequence, the organic phase was separated, dried over anhydrous sodium sulfate, filtered and the organic solvent was concentrated under reduced pressure. The residue was separated by column chromatography to obtain the title compound (17.3 g, 72%).
MS m/z(ESI):365.2[M+H]+.MS m/z(ESI):365.2[M+H] + .
第十八步：N-(5-((S)-2-甲氧基-1-((S)-2-羰基-4-(三氟甲基)咪唑烷-1-基)乙基)-1,2,4-三嗪-3-基)特戊基酰胺的制备Step 18: Preparation of N-(5-((S)-2-methoxy-1-((S)-2-carbonyl-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)-1,2,4-triazine-3-yl)-t-pentylamide
将N-(5-(1-(((S)-2-氨基-3,3,3-三氟丙基)氨基)-2-甲氧基乙基)-1,2,4-三嗪-3-基)特戊基酰胺(9.8g,26.90mmol)溶于四氢呋喃(100mL)中，加入N,N'-羰基二咪唑(4.36g,26.90mmol)，反应液加热至40℃搅拌反应2小时，冷却至室温加入1M氢氧化钠水溶液(20mL)。反应液用乙酸乙酯稀释，依次用饱和碳酸钠水溶液和饱和食盐水洗涤，分离有机相，用无水硫酸钠干燥，过滤后减压浓缩有机溶剂，所得残余物经柱层析分离得标题化合物(8.8g,84％)。N-(5-(1-(((S)-2-amino-3,3,3-trifluoropropyl)amino)-2-methoxyethyl)-1,2,4-triazine-3-yl)-tert-pentylamide (9.8g, 26.90mmol) was dissolved in tetrahydrofuran (100mL), and N,N'-carbonyldiimidazole (4.36g, 26.90mmol) was added. The reaction solution was heated to 40°C and stirred for 2 hours. After cooling to room temperature, 1M sodium hydroxide aqueous solution (20mL) was added. The reaction solution was diluted with ethyl acetate, washed with saturated sodium carbonate aqueous solution and saturated brine in sequence, the organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the organic solvent was concentrated under reduced pressure. The residue was separated by column chromatography to obtain the title compound (8.8g, 84%).
MS m/z(ESI):391.2[M+H]+.MS m/z(ESI):391.2[M+H] + .
第十九步：(S)-1-((S)-1-(3-氨基-1,2,4-三嗪-5-基)-2-甲氧基乙基)-4-(三氟甲基)咪唑烷-2-酮的制备Step 19: Preparation of (S)-1-((S)-1-(3-amino-1,2,4-triazine-5-yl)-2-methoxyethyl)-4-(trifluoromethyl)imidazolidin-2-one
将N-(5-((S)-2-甲氧基-1-((S)-2-羰基-4-(三氟甲基)咪唑烷-1-基)乙基)-1,2,4-三嗪-3-基)特戊基酰胺(5.6g,14.35mmol)溶于二氧六环(20mL)和5M HCl(60mL)的混合溶剂中，反应液加热至105℃搅拌反应1小时，冷却至室温，加入1M氢氧化钠水溶液调节pH至中性。反应液用乙酸乙酯稀释，依次用饱和碳酸钠水溶液和饱和食盐水洗涤，分离有机相，用无水硫酸钠干燥，过滤后减压浓缩有机溶剂，所得残余物经柱层析得到标题化合物(3.7g,84％)。N-(5-((S)-2-methoxy-1-((S)-2-carbonyl-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)-1,2,4-triazine-3-yl)-t-pentylamide (5.6 g, 14.35 mmol) was dissolved in a mixed solvent of dioxane (20 mL) and 5M HCl (60 mL). The reaction solution was heated to 105°C and stirred for 1 hour. The mixture was cooled to room temperature and 1M sodium hydroxide aqueous solution was added to adjust the pH to neutral. The reaction solution was diluted with ethyl acetate, washed with saturated sodium carbonate aqueous solution and saturated brine in sequence, the organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the organic solvent was concentrated under reduced pressure. The residue was subjected to column chromatography to obtain the title compound (3.7 g, 84%).
MS m/z(ESI):307.1[M+H]+.MS m/z(ESI):307.1[M+H] + .
第二十步：苯甲基((S)-(4,4-二氟环己基)(3-((S)-2-甲氧基-1-((S)-2-羰基-4-(三氟甲基)咪唑烷-1-基)乙基)咪唑并[1,2-b][1,2,4]三嗪-6-基)甲基)氨基甲酸酯的制备Step 20: Preparation of benzyl ((S)-(4,4-difluorocyclohexyl)(3-((S)-2-methoxy-1-((S)-2-carbonyl-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)imidazo[1,2-b][1,2,4]triazin-6-yl)methyl)carbamate
将(S)-1-((S)-1-(3-氨基-1,2,4-三嗪-5-基)-2-甲氧基乙基)-4-(三氟甲基)咪唑烷-2-酮(800mg,2.61mmol)，苯甲基N-[(1S)-3-溴-1-(4,4-二氟环己基)-2-羰基-丙基]氨基甲酸酯(1.27g,3.13mmol)和碳酸氢钠(658.35mg,7.84mmol)溶于异丙醇(40mL)中，反应液加热至100℃搅拌反应12小时，冷却至室温。反应液用乙酸乙酯稀释，依次用饱和碳酸钠水溶液和饱和食盐水洗涤，分离有机相，用无水硫酸钠干燥，过滤后减压浓缩有机溶剂，所得残余物经柱层析得到标题化合物(0.78g,49％)。(S)-1-((S)-1-(3-amino-1,2,4-triazine-5-yl)-2-methoxyethyl)-4-(trifluoromethyl)imidazolidin-2-one (800 mg, 2.61 mmol), benzyl N-[(1S)-3-bromo-1-(4,4-difluorocyclohexyl)-2-carbonyl-propyl]carbamate (1.27 g, 3.13 mmol) and sodium bicarbonate (658.35 mg, 7.84 mmol) were dissolved in isopropanol (40 mL), the reaction solution was heated to 100°C and stirred for 12 hours, and then cooled to room temperature. The reaction solution was diluted with ethyl acetate, washed with saturated sodium carbonate aqueous solution and saturated brine in sequence, the organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the organic solvent was concentrated under reduced pressure. The residue was subjected to column chromatography to obtain the title compound (0.78 g, 49%).
MS m/z(ESI):612.2[M+H]+.MS m/z(ESI):612.2[M+H] + .
第二十一步：(S)-1-((S)-1-(6-((S)-氨基(4,4-二氟环己基)甲基)咪唑并[1,2-b][1,2,4]三嗪-3-基)-2-甲氧基乙基)-4-(三氟甲基)咪唑烷-2-酮的制备Step 21: Preparation of (S)-1-((S)-1-(6-((S)-amino(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b][1,2,4]triazine-3-yl)-2-methoxyethyl)-4-(trifluoromethyl)imidazolidin-2-one
将苯甲基((S)-(4,4-二氟环己基)(3-((S)-2-甲氧基-1-((S)-2-羰基-4-(三氟甲基)咪唑烷-1-基)乙基)咪唑并[1,2-b][1,2,4]三嗪-6-基)甲基)氨基甲酸酯(680mg,1.11mmol),10％钯碳(354.99mg,333.57μmol)溶于甲醇(20mL)中，置换氢气三次，反应液加热至40℃搅拌反应12小时，冷却至室温。反应液过滤除去钯碳，减压浓缩有机溶剂，得到标题化合物(0.49g,92％)。Benzyl ((S)-(4,4-difluorocyclohexyl)(3-((S)-2-methoxy-1-((S)-2-carbonyl-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)imidazo[1,2-b][1,2,4]triazin-6-yl)methyl)carbamate (680 mg, 1.11 mmol) and 10% palladium on carbon (354.99 mg, 333.57 μmol) were dissolved in methanol (20 mL), and hydrogen was replaced three times. The reaction solution was heated to 40°C and stirred for 12 hours, and then cooled to room temperature. The reaction solution was filtered to remove palladium on carbon, and the organic solvent was concentrated under reduced pressure to obtain the title compound (0.49 g, 92%).
MS m/z(ESI):478.2[M+H]+.MS m/z(ESI):478.2[M+H] + .
第二十二步：环丙基((S)-(4，4-二氟环己基)(3-((S)-2-甲氧基-1-((S)-2-氧代-4-(三氟甲基)咪唑啉-1-基)乙基)咪唑并[1,2-b][1,2,4]三嗪-6-基)甲基)氨基甲酸酯的制备Step 22: Preparation of cyclopropyl ((S)-(4,4-difluorocyclohexyl)(3-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolin-1-yl)ethyl)imidazo[1,2-b][1,2,4]triazin-6-yl)methyl)carbamate
冰浴下，将(S)-1-((S)-1-(6-((S)-氨基(4,4-二氟环己基)甲基)咪唑并[1,2-b][1,2,4]三嗪-3-基)-2-甲氧基乙基)-4-(三氟甲基)咪唑烷-2-酮(450mg,942.55μmol)和三乙胺(286.13mg,2.83mmol,394.39μL)溶于二氯甲烷(20mL)中，加入氯甲酸环丙酯(113.61mg,942.55μmol)，冰浴下搅拌0.5小时，恢复至室温。反应液用乙酸乙酯稀释，依次用饱和碳酸钠水溶液和饱和食盐水洗涤，分离有机相，用无水硫酸钠干燥，过滤后减压浓缩有机溶剂，所得残余物经柱层析分离得标题化合物(0.39g,74％)。Under ice bath, (S)-1-((S)-1-(6-((S)-amino(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b][1,2,4]triazin-3-yl)-2-methoxyethyl)-4-(trifluoromethyl)imidazolidin-2-one (450mg, 942.55μmol) and triethylamine (286.13mg, 2.83mmol, 394.39μL) were dissolved in dichloromethane (20mL), cyclopropyl chloroformate (113.61mg, 942.55μmol) was added, stirred under ice bath for 0.5 hours, and returned to room temperature. The reaction solution was diluted with ethyl acetate, washed with saturated sodium carbonate aqueous solution and saturated brine in sequence, the organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the organic solvent was concentrated under reduced pressure. The residue was separated by column chromatography to obtain the title compound (0.39g, 74%).
MS m/z(ESI):562.2[M+H]+.MS m/z(ESI):562.2[M+H] + .
以下实施例参照上述实施例1”的路线合成：The following examples are synthesized according to the route of Example 1 above:
生物学测试评价Biological test evaluation
以下结合测试例进一步描述解释本发明，但这些实施例并非意味着限制本发明的范围。The present invention is further described and explained below in conjunction with test examples, but these embodiments are not intended to limit the scope of the present invention.
测试例1、本发明化合物与人源IL-17受体对配体竞争性结合作用的测定1.实验目的：Test Example 1. Determination of the competitive binding effect between the compound of the present invention and human IL-17 receptor on ligand 1. Experimental purpose:
通过在体外条件下的竞争性ELISA将化合物对人源IL-17RA与IL-17A蛋白结合的阻断情况进行定量检测。The blocking effect of the compounds on the binding of human IL-17RA to IL-17A protein was quantitatively detected by competitive ELISA under in vitro conditions.
2.实验仪器和试剂：2. Experimental instruments and reagents:
2.1仪器：2.1 Instruments:
2.2试剂：2.2 Reagents:
3.实验方法：3. Experimental methods:
将0.0625μg/mL的IL-17A以100μL每孔在96孔板中4℃包被过夜。用每次300μL每孔的PBST洗板4次后，每孔再加入300μL的ELISABlocker封闭缓冲液，24℃封闭2h，以相同条件再次洗板。在每孔中加入80μL的含有1％BSA的PBS溶液和10μL的10×待测化合物溶液，混匀后室温孵育1h，再加入10μL的IL-17RA溶液，使终浓度为5nM，混匀后24℃孵育1h。阳性对照孔中加入无化合物的相应浓度和体积的DMSO溶液，阴性对照孔中加入无IL-17RA的1％BSA溶液。洗板4次后，加入100μL抗Fc标签HRP偶联抗体37℃孵育1h。洗板4次后，每孔加入100μL的TMB底物37℃避光孵育。显色完成后，每孔加入100μL的终止液终止反应，使用酶标仪分别在450nm和570nm波长下检测吸光值。0.0625 μg/mL IL-17A was coated in 96-well plates at 4°C overnight with 100 μL per well. After washing the plate 4 times with 300 μL per well of PBST, 300 μL of ELISABlocker blocking buffer was added to each well, blocked at 24°C for 2 hours, and the plate was washed again under the same conditions. 80 μL of PBS solution containing 1% BSA and 10 μL of 10× test compound solution were added to each well, mixed and incubated at room temperature for 1 hour, and then 10 μL of IL-17RA solution was added to make the final concentration 5 nM, mixed and incubated at 24°C for 1 hour. The corresponding concentration and volume of DMSO solution without compound was added to the positive control wells, and 1% BSA solution without IL-17RA was added to the negative control wells. After washing the plate 4 times, 100 μL of anti-Fc tag HRP-conjugated antibody was added and incubated at 37°C for 1 hour. After washing the plate 4 times, 100 μL of TMB substrate was added to each well and incubated at 37°C in the dark. After color development, 100 μL of stop solution was added to each well to terminate the reaction, and the absorbance was detected at 450 nm and 570 nm using an ELISA reader.
4.实验数据处理方法：4. Experimental data processing method:
1)抑制率(％)：将原始数据(OD450-OD570)按照以下公式进行计算，得到抑制率。1) Inhibition rate (%): The original data (OD450-OD570) was calculated according to the following formula to obtain the inhibition rate.
抑制率％＝[(阳性对照孔平均值–样品孔值)/(阳性对照孔平均值–阴性对照孔平均值)]×100，其中阳性对照孔为无化合物孔，阴性对照孔为无IL-17RA蛋白溶液孔。Inhibition rate % = [(average value of positive control wells - value of sample wells) / (average value of positive control wells - average value of negative control wells)] × 100, where the positive control wells are wells without compound, and the negative control wells are wells without IL-17RA protein solution.
2)曲线拟合：使用GraphPad Prism 8中的log(inhibitor)vs.response--Variable slope(four parameters)对化合物浓度及对应的抑制率进行拟合方程分析，拟合曲线并得出化合物IC50值。2) Curve fitting: Use log(inhibitor) vs.response--Variable slope(four parameters) in GraphPad Prism 8 to perform fitting equation analysis on compound concentration and corresponding inhibition rate, fit the curve and obtain the IC50 value of the compound.
拟合计算方程为Y＝Bottom+(Top-Bottom)/(1+10^((LogIC50-X)*HillSlope))5.实验结果与结论：The fitting calculation equation is Y=Bottom+(Top-Bottom)/(1+10^((LogIC50-X)*HillSlope)) 5. Experimental results and conclusions:
表1Table 1
通过以上方案得出本发明所示的化合物在抑制试验中显示出较强的抑制活性。The above scheme shows that the compounds shown in the present invention show strong inhibitory activity in the inhibition test.
测试例2、本发明化合物对HT-29细胞分泌Groα的抑制作用的测定Test Example 2: Determination of the inhibitory effect of the compounds of the present invention on the secretion of Groα by HT-29 cells
实验目的：该测试例的目的是测量化合物对HT-29细胞分泌Groα的抑制能力，以评价化合物对IL-17A通路的抑制。Purpose of the experiment: The purpose of this test case is to measure the inhibitory ability of the compound on the secretion of Groα by HT-29 cells to evaluate the inhibition of the compound on the IL-17A pathway.
实验仪器和试剂：Experimental instruments and reagents:
仪器：instrument:
试剂：Reagents:
实验方法：Experimental methods:
配制50000个/ml的细胞悬液，在96孔板内，每孔加入200μl细胞悬液，即10000个/孔，过夜培养。在96孔V底板内，用DMSO对5mM化合物进行3倍梯度稀释；用完全培养基对每孔化合物稀释100倍。IL-17A蛋白(R&D，#BT7955-025/CF)储存浓度为100μg/ml，用完全培养基稀释333.33倍。按照体积比1比1，混匀化合物及IL-17A，37度孵育30分钟。在细胞孔中加入化合物及IL-17A混合物50μl，IL-17A蛋白终浓度为30ng/ml。在37℃、5％CO2细胞培养箱中孵育48小时。上清中的Groα浓度用ELISA方法Human GroαValukin Elisa kit(Biotechne，#VAL139)测定，用酶标仪(PE,EnVision2105)测定450nm的吸光强度。利用GraphPadPrism8.3.0分析数据。Prepare a cell suspension of 50,000 cells/ml, add 200 μl of cell suspension to each well of a 96-well plate, i.e., 10,000 cells/well, and culture overnight. In a 96-well V-bottom plate, dilute the 5 mM compound 3-fold with DMSO; dilute the compound 100-fold in each well with complete medium. The IL-17A protein (R&D, #BT7955-025/CF) has a storage concentration of 100 μg/ml and is diluted 333.33 times with complete medium. Mix the compound and IL-17A at a volume ratio of 1:1 and incubate at 37 degrees for 30 minutes. Add 50 μl of the compound and IL-17A mixture to the cell wells, and the final concentration of IL-17A protein is 30 ng/ml. Incubate in a cell culture incubator at 37°C and 5% CO 2 for 48 hours. The concentration of Groα in the supernatant was determined by ELISA method Human Groα Valukin Elisa kit (Biotechne, #VAL139), and the absorbance at 450 nm was measured by microplate reader (PE, EnVision 2105). The data were analyzed by GraphPad Prism 8.3.0.
实验数据处理方法：Experimental data processing method:
用GraphPad Prism 8.3.0对数据进行分析。Data were analyzed using GraphPad Prism 8.3.0.
抑制率％＝[(阳性对照孔平均值–样品孔值)/(阳性对照孔平均值–阴性对照孔平均值)]×100％，其中样品孔为细胞加不同浓度梯度化合物孔，阳性对照孔为细胞加IL-17A，阴性对照孔为培养基加IL-17A。Inhibition rate % = [(average value of positive control wells - value of sample wells) / (average value of positive control wells - average value of negative control wells)] × 100%, where the sample wells are cells plus different concentration gradient compound wells, the positive control wells are cells plus IL-17A, and the negative control wells are culture medium plus IL-17A.
曲线拟合：根据各浓度抑制率(％)，使用GraphPad Prism 6.0中的log(inhibitor)vs.response--Variable slope(four parameters)进行曲线拟合得到IC50值，计算方程为Y＝Bottom+(Top-Bottom)/(1+10^((LogIC50-X)*HillSlope))。Curve fitting: According to the inhibition rate (%) of each concentration, the IC50 value was obtained by curve fitting using log (inhibitor) vs. response--Variable slope (four parameters) in GraphPad Prism 6.0. The calculation equation was Y=Bottom+(Top-Bottom)/(1+10^((LogIC50-X)*HillSlope)).
实验结果和结论：Experimental results and conclusions:
表2Table 2
通过以上方案得出本发明所示的化合物在抑制试验中显示出较强的抑制活性。The above scheme shows that the compounds shown in the present invention show strong inhibitory activity in the inhibition test.
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