WO2022237825A1 - Azaaryl derivative with egfr inhibitory activity, preparation method therefor and use thereof - Google Patents
Azaaryl derivative with egfr inhibitory activity, preparation method therefor and use thereof Download PDFInfo
- Publication number
- WO2022237825A1 WO2022237825A1 PCT/CN2022/092150 CN2022092150W WO2022237825A1 WO 2022237825 A1 WO2022237825 A1 WO 2022237825A1 CN 2022092150 W CN2022092150 W CN 2022092150W WO 2022237825 A1 WO2022237825 A1 WO 2022237825A1
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- WO
- WIPO (PCT)
- Prior art keywords
- alkyl
- deuterium
- group
- halogen
- substituted
- Prior art date
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- 238000002360 preparation method Methods 0.000 title claims abstract description 18
- 230000002401 inhibitory effect Effects 0.000 title abstract description 6
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- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 5
- 102000052116 epidermal growth factor receptor activity proteins Human genes 0.000 claims abstract 5
- 108700015053 epidermal growth factor receptor activity proteins Proteins 0.000 claims abstract 5
- YOHYSYJDKVYCJI-UHFFFAOYSA-N n-[3-[[6-[3-(trifluoromethyl)anilino]pyrimidin-4-yl]amino]phenyl]cyclopropanecarboxamide Chemical compound FC(F)(F)C1=CC=CC(NC=2N=CN=C(NC=3C=C(NC(=O)C4CC4)C=CC=3)C=2)=C1 YOHYSYJDKVYCJI-UHFFFAOYSA-N 0.000 claims abstract 5
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- 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 claims description 67
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- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 28
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/04—Antineoplastic agents specific for metastasis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—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
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
Definitions
- the invention belongs to the field of drug synthesis, and specifically relates to an azaaryl derivative with EGFR inhibitory activity, a preparation method and application thereof.
- Lung cancer is the leading cause of cancer death worldwide, with non-small cell lung cancer (NSCLC) accounting for 85%.
- Targets epidermal growth factor receptor (EGFR) mutations, anaplastic lymphoma kinase (ALK) translocation, ROS1 proto-oncogene receptor tyrosine kinase (ROS1) rearrangement and B-raf proto-oncogene, serine/threonine Multi-targeted therapeutics against kinases (BRAF) have been developed and clinically validated.
- EGFR inhibition significantly improved progression-free survival in adenocarcinoma NSCLC whose acquired resistance mutations were subsequently targeted by third-generation inhibitors.
- Exon 20 mutations are heterogeneous and include in-frame insertions or duplications of 1–7 amino acids between amino acids 762–774 of the EGFR protein.
- NSCLC the mutation frequency of EGFR exon 20 accounts for 4-10% of all EGFR mutations.
- EGFR exon 20 insertion mutations are also found in a rare head and neck cancer, nasal squamous cell carcinoma (SNSCC).
- SNSCC nasal squamous cell carcinoma
- a structurally similar exon 20 insertion mutation was also found in HER2, another member of the receptor tyrosine kinase (RTK) EGFR family.
- the object of the present invention is to provide an azaaryl derivative with EGFR inhibitory activity, its preparation method and application.
- the series of compounds of the present invention have a strong inhibitory effect on the cytological activity of EGFR exon 20 insertions, deletions or other mutations, and can be widely used in the preparation of therapeutic and/or prevention of at least part of EGFR exon 20 insertions, deletions or other mutations
- the first aspect of the present invention provides a compound of formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof:
- X is CH or N
- Y 1 , Y 2 and Y 3 are each independently CR 10 or N, provided that at least one of Y 1 , Y 2 and Y 3 is N
- Z is CR 11 or N;
- R is selected from hydrogen, deuterium , hydroxyl, C 1-10 alkyl, halogen substituted C 1-10 alkyl, deuterium substituted C 1-10 alkyl, C 2-4 alkenyl, C 3-6 cycloalkyl and 3-6 membered heterocyclyl;
- R 7 and R 8 are each independently selected from hydrogen, deuterium, hydroxyl, C 1-10 alkyl, C 2-4 alkenyl, C 3-6 cycloalkyl and 3-6 membered heterocyclyl, or, R 7 and R 8 form a 3-12-membered heterocyclic group together with the nitrogen atom directly connected to it, and the above-mentioned group is optionally further replaced by one or more selected from deuterium, halogen, hydroxyl, C 1-10 alkyl, C 2-10 Alkenyl, C 2-10 alkynyl, halogen substituted C 1-10 alkyl, deuterium substituted C 1-10 alkyl, C 1-10 alkoxy, C 3-12 cycloalkyl, C 3-12 Cycloalkoxy, 3-12 membered heterocyclic group, 3-12 membered heterocyclic oxy group, C 6-10 aryl group, C 6-10 aryloxy group, 5-10 membered heteroaryl group, 5-10 membered heterocyclic group Substitu
- the other of R 6a or R 6b is as defined above, any of the above 4-6 membered heterocyclic groups
- One or more selected from deuterium, halogen, cyano, nitro, azido, C 1-10 alkyl, halogen substituted C 1-10 alkyl, deuterium substituted C 1-10 alkyl, C 2 -10 alkenyl, C 2-10 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, O, -SF 5.
- R 9a , R 9b and R 9c are each independently selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 3- 6 cycloalkyl, 3-6 membered heterocyclyl, -C(O)OR 13 , -C(O)R 14 , -C(O)NR 15 R 16 and -C 0-4 alkyl-NR 15 R 16 ;
- Each R 12 is independently selected from hydrogen, deuterium, hydroxyl, C 1-10 alkyl, C 2-10 alkenyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 Aryl, 5-10 membered heteroaryl and -NR 15 R 16 , the above groups are optionally further selected from one or more of deuterium, halogen, hydroxyl, oxo, C 1-10 alkyl, C 1-10 Alkoxyl group, C 3-12 cycloalkyl group, C 3-12 cycloalkoxy group, 3-12 membered heterocyclic group, 3-12 membered heterocyclic epoxy group, C 6-10 aryl group, C 6-10 aromatic group Oxygen, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy and -NR 15 R 16 are substituted by substituents;
- Each R 13 is independently selected from hydrogen, deuterium, C 1-10 alkyl, C 2-10 alkenyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, the above-mentioned groups are optionally further replaced by one or more selected from deuterium, halogen, hydroxyl, oxo, cyano, C 1-10 alkyl, C 1-10 alkoxy, C 3-12 cycloalkyl group, C 3-12 cycloalkoxy group, 3-12 membered heterocyclic group, 3-12 membered heterocyclic epoxy group, C 6-10 aryl group, C 6-10 aryloxy group, 5- Substituents of 10-membered heteroaryl, 5-10-membered heteroaryloxy and -NR 15 R 16 ;
- Each R 14 is independently selected from hydrogen, deuterium, hydroxyl, C 1-10 alkyl, C 1-10 alkoxy, C 2-10 alkenyl, C 2-10 alkynyl, C 3-12 Cycloalkyl, C 3-12 cycloalkoxy, 3-12 membered heterocyclic group, 3-12 membered heterocyclic epoxy group, C 6-10 aryl group, C 6-10 aryloxy group, 5-10 membered heterocyclic group Aryl, 5-10-membered heteroaryloxy and -NR 15 R 16 , the above-mentioned groups are optionally further replaced by one or more selected from deuterium, halogen, hydroxyl, cyano, C 1-10 alkyl, C 1- 10 alkoxy, C 3-12 cycloalkyl, C 3-12 cycloalkoxy, 3-12 heterocyclic, 3-12 heterocyclic, C 6-10 aryl, C 6-10 Substituted by aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroary
- Each R 15 and R 16 are each independently selected from hydrogen, deuterium, hydroxyl, C 1-10 alkoxy, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, sulfinyl, sulfonyl, methylsulfonyl, isopropylsulfonyl, cyclopropylsulfonyl Acyl, p-toluenesulfonyl, aminosulfonyl, dimethylaminosulfonyl, amino, single C 1-10 alkylamino, two C 1-10 alkylamino and C 1-10 alkanoyl, the above groups are optionally further By one or more selected from deuterium, halogen, hydroxyl, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl,
- R 15 and R 16 form a 4-10 membered heterocyclic group together with their directly connected nitrogen atoms, and the above-mentioned groups are optionally further replaced by one or more selected from deuterium, halogen, hydroxyl, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, halogen substituted C 1-10 alkyl, deuterium substituted C 1-10 alkyl, C 1-10 alkoxy, C 3-12 cycloalkyl, C 3-12 cycloalkoxy, 3-12 heterocyclic, 3-12 heterocyclic, C 6-10 aryl, C 6-10 aryloxy, 5-10 heteroaryl, 5- Substituents of 10-membered heteroaryloxy, amino, single C 1-10 alkylamino, di-C 1-10 alkylamino and C 1-10 alkanoyl;
- n 0, 1, 2 or 3;
- Each r is independently 0, 1 or 2.
- R is selected from hydrogen, deuterium , hydroxyl, C 1-4 alkyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 2-4 alkenyl, C 3-6 cycloalkyl and 3-6 membered heterocyclyl;
- R 7 and R 8 are each independently selected from hydrogen, deuterium, hydroxyl, C 1-4 alkyl, C 2-4 alkenyl, C 3-6 cycloalkyl and 3-6 membered heterocyclyl, or, R 7 and R 8 form a 3-6 membered heterocyclic group together with the nitrogen atom directly connected to it, and the above-mentioned groups are optionally further replaced by one or more selected from deuterium, halogen, hydroxyl, C 1-4 alkyl, C 2-4 Alkenyl, C 2-4 alkynyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, C 3-6 Cycloalkoxy, 3-6 membered heterocyclic group, 3-6 membered heterocyclic oxy group, C 6-8 aryl group, C 6-8 aryloxy group, 5-8 membered heteroaryl group, 5-8 membered heterocyclic group Substituent
- R 9a , R 9b and R 9c are each independently selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl and -C 0 -4 alkyl-NR 15 R 16 ;
- R 12 , R 13 , R 14 , R 15 , R 16 , m and r are as defined in the compound of formula (I)
- each R 12 is independently selected from hydrogen, deuterium, hydroxyl, C 1-4 alkyl, C 2-4 alkenyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic group, C 6-8 aryl, 5-8 membered heteroaryl and -NR 15 R 16 , the above groups are optional Further by one or more selected from deuterium, halogen, hydroxyl, oxo, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, 3 -6 membered heterocyclic group, 3-6 membered heterocyclic oxy group, C 6-8 aryl group, C 6-8 aryloxy group, 5-8 membered heteroaryl group, 5-8 membered heteroaryloxy group and -NR 15 R 16 is replaced by a substituent;
- Each R 13 is independently selected from hydrogen, deuterium, C 1-4 alkyl, C 2-4 alkenyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl and 5-8 membered heteroaryl, the above-mentioned groups are optionally further replaced by one or more selected from deuterium, halogen, hydroxyl, oxo, cyano, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl group, C 3-6 cycloalkoxy group, 3-6 membered heterocyclic group, 3-6 membered heterocyclic epoxy group, C 6-8 aryl group, C 6-8 aryloxy group, 5- Substituents of 8-membered heteroaryl, 5-8-membered heteroaryloxy and -NR 15 R 16 ;
- Each R 14 is independently selected from hydrogen, deuterium, hydroxyl, C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 Cycloalkyl, C 3-6 cycloalkoxy, 3-6 membered heterocyclic group, 3-6 membered heterocyclic epoxy group, C 6-8 aryl group, C 6-8 aryloxy group, 5-8 membered heterocyclic group Aryl, 5-8-membered heteroaryloxy and -NR 15 R 16 , the above-mentioned groups are optionally further replaced by one or more selected from deuterium, halogen, hydroxyl, cyano, C 1-4 alkyl, C 1- 4 alkoxyl, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, 3-6 heterocyclyl, 3-6 heterocyclyl, C 6-8 aryl, C 6-8 Substituents of aryloxy, 5-8 membered heteroaryl, 5-8 member
- Each R 15 and R 16 are each independently selected from hydrogen, deuterium, hydroxyl, C 1-4 alkoxy, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, sulfinyl, sulfonyl, methylsulfonyl, isopropylsulfonyl, cyclopropylsulfonyl Acyl, p-toluenesulfonyl, aminosulfonyl, dimethylaminosulfonyl, amino, single C 1-4 alkylamino, two C 1-4 alkylamino and C 1-4 alkanoyl, the above groups are optionally further By one or more selected from deuterium, halogen, hydroxyl, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl,
- R 15 and R 16 form a 4-8 membered heterocyclic group together with their directly connected nitrogen atoms, and the above-mentioned groups are optionally further replaced by one or more selected from deuterium, halogen, hydroxyl, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkoxy group, 3-6 membered heterocyclic group, 3-6 membered heterocyclic epoxy group, C 6-8 aryl group, C 6-8 aryloxy group, 5-8 membered heteroaryl group, 5- Substituents of 8-membered heteroaryloxy, amino, mono-C 1-4 alkylamino, di-C 1-4 alkylamino and C 1-4 alkanoyl.
- the compound of formula (I) is the compound of formula (II):
- each X is independently CH or N;
- Y1 is CH or N;
- Y2 and Y3 are each independently CR10 or N, provided that at least one of Y1 , Y2 and Y3 is N;
- Z is CH or N;
- R is selected from hydrogen, deuterium , hydroxyl, C 1-4 alkyl, halogen substituted C 1-4 alkyl and deuterium substituted C 1-4 alkyl;
- R 6a is selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-4 alkyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 2-4 chain Alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl and 5-8 membered heteroaryl;
- R 6b is selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-4 alkyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 2-4 chain Alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl and 5-8 membered heteroaryl;
- R 7 and R 8 are each independently selected from hydrogen, deuterium, hydroxyl, C 1-4 alkyl and C 2-4 alkenyl, or, R 7 and R 8 together form a 3-6 membered Heterocyclic group, the above group is optionally further substituted by one or more selected from deuterium, halogen, hydroxyl, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halogen substituted C 1 -4 alkyl, deuterium substituted C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, 3-6 membered heterocyclyl, 3-6 Substituents of membered heterooxyl group, C 6-8 aryl, C 6-8 aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy and -NR 15 R 16 ;
- R 9a is selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, halogen substituted C 1-4 alkyl and deuterium substituted C 1-4 alkyl;
- Each R 10 is independently selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3 -6 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, -OR 13 , -C(O)OR 13 , -C(O)R 14 and -OC(O)R 14 ,
- R 12 , R 13 , R 14 , R 15 , R 16 , m and r are as defined in the compound of formula (I).
- the compound of formula (I) is the compound of formula (III):
- X is CH or N;
- Y 1 is CH or N;
- Y 2 is CR 10a or N,
- Y 3 is CR 10b or N, provided that at least one of Y 1 , Y 2 and Y 3 is N;
- Z is CH or N;
- R 1a is selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl and 5-8 membered heteroaryl
- the above group is optionally further substituted by one or more selected from deuterium, halogen, cyano, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halogen substituted C 1- Substituents of 4 alkyl, deuterium substituted C 1-4 alkyl, C 3-6 cycloalkyl and 3-6 membered heterocyclyl;
- R 1b is selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl and 5-8 membered heteroaryl
- the above group is optionally further substituted by one or more selected from deuterium, halogen, cyano, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halogen substituted C 1- Substituents of 4 alkyl, deuterium substituted C 1-4 alkyl, C 3-6 cycloalkyl and 3-6 membered heterocyclyl;
- R 2 and R 3 are each independently selected from hydrogen, deuterium and C 1-4 alkyl, or, R 2 and R 3 form carbonyl, C 3-6 cycloalkyl or 3-6 membered carbon atoms together with their directly connected carbon atoms Heterocyclic group, the above group is optionally further substituted by one or more selected from deuterium, halogen, cyano, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halogen substituted C Substituents of 1-4 alkyl, deuterium-substituted C 1-4 alkyl, C 3-6 cycloalkyl and 3-6 membered heterocyclic groups;
- R is selected from hydrogen, deuterium , C 1-4 alkyl, halogen substituted C 1-4 alkyl and deuterium substituted C 1-4 alkyl;
- R 6a is selected from hydrogen, deuterium, C 1-4 alkyl, halogen substituted C 1-4 alkyl and deuterium substituted C 1-4 alkyl;
- R 6b is selected from hydrogen, deuterium, C 1-4 alkyl, halogen substituted C 1-4 alkyl and deuterium substituted C 1-4 alkyl;
- R 7 and R 8 are each independently selected from hydrogen, deuterium and C 1-4 alkyl, or, R 7 and R 8 form a 3-6 membered heterocyclic group together with the nitrogen atom directly connected to it, and the above-mentioned groups are optionally further By one or more selected from deuterium, halogen, hydroxyl, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1- Substituents of 4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl and C 3-6 cycloalkoxy;
- any of the above 4-6 membered heterocyclic groups is further selected from one or more groups selected from deuterium, halogen, cyano, nitro, azido, C 1-4 alkyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 2 Substituents of -4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl and 3-6 membered heterocyclyl;
- R 6b and R 7 form a 4-6-membered heterocyclic group together with the part directly connected to it, and the above-mentioned 4-6-membered heterocyclic group is optionally further replaced by one or more selected from deuterium, halogen, cyano, nitro, Azido, C 1-4 alkyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 ring Substituents of alkyl and 3-6 membered heterocyclic groups;
- R 9a is selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, halogen substituted methyl and deuterium substituted methyl;
- R 13 and R 14 are as defined in the compound of formula (I).
- Y 1 is N, Y 2 is CR 10a or N, Y 3 is N; or, Y 1 is N, Y 2 is CR 10a or N, Y 3 is CR 10b ; or, Y 1 is CH, Y 2 is CR 10a or N, Y 3 is N.
- R 10a is selected from hydrogen, deuterium, fluorine, chlorine, cyano, methyl, ethyl, Propyl, isopropyl, cyclopropyl, cyclobutyl, oxiranyl, aziridyl, oxetanyl, azetidinyl, imidazolyl, pyrazolyl, triazolyl, Tetrazolyl and -C(O)OR 13 , the above-mentioned groups are optionally further selected from deuterium, fluorine, chlorine, cyano, methyl, ethyl, propyl, isopropyl, a fluoromethyl radical, difluoromethyl, trifluoromethyl, one-deuteromethyl, dide-deuteromethyl, tri-deuteromethyl, cyclopropyl, cyclobutyl, oxirane, aziridyl
- R 10b is selected from hydrogen, deuterium, fluorine, chlorine, cyano, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, oxirane, aziridyl, oxa Cyclobutyl, azetidinyl, imidazolyl and pyrazolyl, the above-mentioned groups are optionally further selected from deuterium, fluorine, chlorine, cyano, methyl, ethyl, propyl, isopropyl fluoromethyl, difluoromethyl, trifluoromethyl, 1-deuteromethyl, dide-deuteromethyl, tri-deuteromethyl, cyclopropyl, cyclobutyl, oxirane, aziridine Substituents of group, oxetanyl and azetidinyl;
- R is selected from hydrogen, deuterium, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, oxirane, aziridyl , oxetanyl, azacycline Butyl, phenyl, imidazolyl and pyrazolyl, the above-mentioned groups are optionally further selected from deuterium, fluorine, chlorine, hydroxyl, oxo, cyano, methyl, ethyl, propyl, iso Propyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monodeuteromethyl, dideuteriomethyl, trideuteromethyl, cyclopropyl, cyclobutyl, oxirane, azacyclic Substituents of propyl, oxetanyl and azetidinyl.
- R is selected from hydrogen, deuterium, methyl, ethyl, isopropyl, cyclopropyl , cyclobutyl, oxirandyl, oxetyl, aziridyl and azetidinyl, the above-mentioned groups are optionally further selected from deuterium, fluorine, C 1-4 by one or more Substituents of alkyl and C 3-6 cycloalkyl are substituted.
- R 9a is selected from hydrogen, deuterium, fluorine, methyl, ethyl, propyl, isopropyl group, monofluoromethyl, difluoromethyl, trifluoromethyl, monodeuteromethyl, dideuteriomethyl and trideuteromethyl.
- R2 and R3 are each independently selected from hydrogen , deuterium, methyl, ethyl and iso Propyl, or, R 2 and R 3 form cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl together with the carbon atoms directly connected to them, and the above-mentioned groups are optionally further selected from one or more of deuterium, fluorine, Chlorine, bromine, cyano, methyl, ethyl, isopropyl, trifluoromethyl, difluoromethyl, trideuteromethyl, dideuteriomethyl, cyclopropyl, cyclobutyl, oxirane , Oxetanyl, aziridinyl and azetidinyl substituents.
- R is selected from hydrogen, deuterium, methyl, ethyl, isopropyl, trifluoromethane group, difluoromethyl, trideuteromethyl and dideuteriomethyl;
- R is selected from hydrogen, deuterium, methyl, ethyl, isopropyl, trifluoromethyl, difluoromethyl, trideuteromethyl and dideuteriomethyl;
- R is selected from hydrogen, deuterium, methyl, ethyl, isopropyl, trifluoromethyl, difluoromethyl, trideuteromethyl and dideuteriomethyl;
- R 7 and R 8 are each independently selected from hydrogen, deuterium, methyl, trifluoromethyl, difluoromethyl, trideuteromethyl, dideuteriomethyl, ethyl and isopropyl, or, R 7 and R 8 forms a 4-6 membered heterocyclic group together with the nitrogen atom directly connected to it;
- one of R 6a or R 6b and R 5 form a 4-6 membered heterocyclic group together with the part directly connected to it, and the 4-6 membered heterocyclic group forms the following structure with the part directly connected to it:
- each of R 6a , R 6b , R 7 and R 8 in the above structure is as defined above;
- R and R together form a 4-6 membered heterocyclic group with its directly connected part, and the 4-6 membered heterocyclic group forms the following structure with its directly connected part:
- R 5 , R 6a and R 8 in the above structure are as defined above;
- R 1a is selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl base, isopropyl, ethynyl, cyclopropyl, cyclobutyl, oxirandyl, oxetyl, aziridyl, azetidinyl, pyrazolyl, imidazolyl, oxazole Base, triazolyl, tetrazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, thiadiazolyl , thiazolyl, thienyl and triazinyl, the above groups are optionally further selected from one or more of
- R is selected from hydrogen, deuterium , fluorine, chlorine, bromine, cyano, methyl, ethyl, isopropyl, ethynyl, cyclopropyl, cyclobutyl, oxiranyl, oxetanyl, Aziridyl, azetidinyl, pyrazolyl, imidazolyl, oxazolyl and triazolyl, the above-mentioned groups are optionally further selected from deuterium, fluorine, chlorine, bromine, cyanogen methyl, ethyl, isopropyl, vinyl, ethynyl, trifluoromethyl, difluoromethyl, trideuteromethyl, dideuteriomethyl, cyclopropyl, cyclobutyl, oxirane Substituents of radical, oxetanyl, aziridinyl and azetidinyl.
- the compound of formula (I), its stereoisomer or its pharmaceutically acceptable salt includes but not limited to the following compounds:
- the second aspect of the present invention provides a method for preparing a compound of formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof, comprising the following steps:
- X 1 is halogen, selected from fluorine, chlorine and bromine;
- X, Y 1 , Y 2 , Y 3 , Z, R 1 , R 2 , R 3 , R 4 , R 5 , R 6a , R 6b , R 7 , R 8 , R 9a , R 9b , R 9c and m are as described for the compound of formula (I).
- the third aspect of the present invention provides a pharmaceutical composition, which comprises the compound of formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
- the present invention also relates to the preparation of the compound of formula (I), its stereoisomer or pharmaceutically acceptable salt thereof for the treatment and/or prevention of cancers and tumors at least partially related to EGFR exon 20 insertions, deletions or other mutations or use in medicines for metastatic disease.
- the present invention also relates to the preparation of the compound of formula (I), its stereoisomer or pharmaceutically acceptable salt thereof for the treatment and/or prevention of tumors, cancers and or metastatic diseases caused by excessive proliferation and induction of cell death disorders Uses in medicine.
- the present invention also relates to the preparation of the compound of formula (I), its stereoisomer or pharmaceutically acceptable salt thereof for the treatment and/or prevention of lung cancer, colon Cancer, pancreatic cancer, head and neck cancer, breast cancer, ovarian cancer, uterine cancer, gastric cancer, non-small cell lung cancer, leukemia, myelodysplastic syndrome, malignant lymphoma, head and neck cancer, thoracic tumor, gastrointestinal tumor, endocrine Tumors, breast and other gynecological tumors, urological tumors, skin tumors, sarcoma, sinonasal inverted papilloma or sinonasal squamous cell carcinoma associated with sinonasal inverted papilloma.
- the present invention also relates to said compound of formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof, for use as a medicament.
- the present invention also relates to the compound of formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof, which is used for treating and/or preventing at least some cancers related to EGFR exon 20 insertion, deletion or other mutations , tumor or metastatic disease.
- the present invention also relates to said compound of formula (I), its stereoisomer or pharmaceutically acceptable salt thereof, for the treatment and/or prevention of tumors, cancers and or metastatic disease use.
- the present invention also relates to the compound of formula (I), its stereoisomer or pharmaceutically acceptable salt thereof, which is used for treating and/or preventing lung cancer caused by at least part of EGFR exon 20 insertion, deletion or other mutations , colon cancer, pancreatic cancer, head and neck cancer, breast cancer, ovarian cancer, uterine cancer, gastric cancer, non-small cell lung cancer, leukemia, myelodysplastic syndrome, malignant lymphoma, head and neck cancer, chest cavity tumor, gastrointestinal tumor , endocrine tumors, breast and other gynecologic tumors, urologic tumors, skin tumors, sarcomas, sinonasal inverted papilloma, or sinonasal squamous cell carcinoma associated with sinonasal inverted papilloma.
- the present invention also relates to a method of treating and/or preventing cancer, tumor or metastatic disease at least partially related to EGFR exon 20 insertion, deletion or other mutations, which comprises administering a therapeutically effective amount of the A compound of formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof.
- the present invention also relates to a method of treating and/or preventing tumors, cancers and or metastatic diseases caused by hyperproliferative and induced cell death disorders, which comprises administering a therapeutically effective amount of the compound of formula (I) to a patient in need thereof , a stereoisomer thereof or a pharmaceutically acceptable salt thereof.
- the present invention also relates to a method for treating and/or preventing lung cancer, colon cancer, pancreatic cancer, head and neck cancer, breast cancer, ovarian cancer, uterine cancer, gastric cancer, non Small cell lung cancer, leukemia, myelodysplastic syndrome, malignant lymphoma, head and neck tumors, thoracic cavity tumors, gastrointestinal tumors, endocrine tumors, breast and other gynecological tumors, urological tumors, skin tumors, sarcoma, nasal cavity and sinuses
- a method for sinonasal squamous cell carcinoma associated with inverted papilloma or sinonasal inverted papilloma comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I), a stereoisomer thereof, or Its pharmaceutically acceptable salt.
- the series of compounds of the present invention can be widely used in the preparation of therapeutic and/or prophylaxis at least in part with Drugs for cancers, tumors or metastatic diseases related to EGFR exon 20 insertions, deletions or other mutations, especially drugs for the treatment of hyperproliferative diseases and diseases that induce cell death disorders, are expected to be developed into a new generation of EGFR inhibitors. On this basis, the present invention has been accomplished.
- Alkyl refers to a straight chain or branched saturated aliphatic hydrocarbon group, preferably including 1 to 10 (such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10) or 1 to 10 6 carbon atoms or 1 to 4 carbon atoms straight chain alkyl and branched chain alkyl, including but not limited to 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-dimethylmethyl
- C 1-10 alkyl refers to straight chain alkyl and branched chain alkyl including 1 to 10 carbon atoms
- C 1-4 alkyl refers to straight chain alkyl and branched chain including 1 to 4 carbon atoms Contains branched chain alkyl groups.
- Cycloalkyl or “carbocycle” refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, and the partially unsaturated cyclic hydrocarbon means that the cyclic hydrocarbon may contain one or more (preferably 1, 2 or 3) double bonds, but none of the rings has a fully conjugated ⁇ -electron system
- cycloalkyl is divided into monocyclic cycloalkyl, polycyclic cycloalkyl, preferably including 3 to 12 (such as 3, 4, 5 , 6, 7, 8, 9, 10, 11, 12) or a cycloalkyl group of 3 to 8 or 3 to 6 carbon atoms, for example, "C 3-12 cycloalkyl” refers to a cycloalkyl group comprising 3 to 12 A cycloalkyl group of carbon atoms, "C 3-6 cycloalkyl” refers to a cycloalkyl group comprising 3 to 6 carbon atoms, wherein:
- Monocyclic cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, Cyclooctyl et al.
- Multicyclic cycloalkyls include spiro, fused and bridged cycloalkyls.
- “Spirocycloalkyl” refers to polycyclic groups in which single rings share one carbon atom (called a spiro atom), these may contain one or more (preferably 1, 2 or 3) double bonds, but none of the rings has A fully conjugated ⁇ -electron system. According to the number of spiro atoms shared between rings, spirocycloalkyl groups are divided into single spirocycloalkyl, double spirocycloalkyl or polyspirocycloalkyl, spirocycloalkyl includes but not limited to:
- fused cycloalkyl means an all-carbon polycyclic group in which each ring of the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more rings may contain one or more (preferably 1, 2 or 3) double bonds, but none of the rings have a fully conjugated ⁇ -electron system. According to the number of rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl groups, fused cycloalkyl groups include but are not limited to:
- Bridged cycloalkyl means an all-carbon polycyclic group in which any two rings share two carbon atoms not directly attached, these may contain one or more (preferably 1, 2 or 3) double bonds, but none The ring has a fully conjugated ⁇ -electron system. According to the number of rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl groups. Bridged cycloalkyl groups include but are not limited to:
- the cycloalkyl ring can be fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring attached to the parent structure is a cycloalkyl group, including but not limited to indanyl, tetrahydronaphthyl , Benzocycloheptyl, etc.
- Heterocyclyl or “heterocycle” refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, and the partially unsaturated cyclic hydrocarbon means that the cyclic hydrocarbon can contain one or more (preferably 1, 2 or 3) double bonds, but none of the rings has a fully conjugated ⁇ -electron system, heterocyclyl in which one or more (preferably 1, 2, 3 or 4) ring atoms are selected from nitrogen, oxygen or S(O ) r (where r is an integer 0, 1, 2), but excluding the ring portion of -OO-, -OS- or -SS-, the remaining ring atoms being carbon.
- Heterocyclic groups comprising 3 to 12 (eg 3, 4, 5, 6, 7, 8, 9, 10, 11, 12) or 3 to 8 or 3 to 6 ring atoms are preferred, for example, "3 -6-membered heterocyclic group” refers to a ring group containing 3 to 6 ring atoms, “4-6 membered heterocyclic group” refers to a ring group containing 4 to 6 ring atoms, and “4-8 membered heterocyclic group” refers to A ring group containing 4 to 8 ring atoms, “4-10 membered heterocyclic group” refers to a ring group containing 4 to 10 ring atoms, “3-12 membered heterocyclic group” refers to a ring group containing 3 to 12 ring atoms Ring base.
- 3 -6-membered heterocyclic group refers to a ring group containing 3 to 6 ring atoms
- 4-6 membered heterocyclic group refers to a ring group containing 4 to 6 ring
- Monocyclic heterocyclyl groups include, but are not limited to, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, oxetanyl, tetrahydrofuranyl, and the like.
- Polycyclic heterocyclyls include spiro, fused and bridged heterocyclyls.
- “Spiroheterocyclyl” refers to a polycyclic heterocyclic group that shares one atom (called a spiro atom) between monocyclic rings, wherein one or more (preferably 1, 2, 3 or 4) ring atoms are selected from nitrogen, oxygen Or a heteroatom of S(O) r (wherein r is an integer 0, 1, 2), and the remaining ring atoms are carbon. These may contain one or more double bonds (preferably 1, 2 or 3), but none of the rings have a fully conjugated pi-electron system.
- spiroheterocyclyls are classified as single spiroheterocyclyls, double spiroheterocyclyls or polyspiroheterocyclyls.
- Spiroheterocyclyls include, but are not limited to:
- “Fused heterocyclyl” means a polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system, and one or more (preferably 1, 2, 3 or 4) rings can be Contains one or more (preferably 1, 2 or 3) double bonds, but none of the rings has a fully conjugated ⁇ -electron system, where one or more (preferably 1, 2, 3 or 4) ring atoms are selected from Heteroatoms of nitrogen, oxygen or S(O) r (where r is an integer 0, 1, 2) and the remaining ring atoms are carbon. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocycloalkyl groups.
- the fused heterocyclyl groups include but are not limited to:
- Bridged heterocyclyl means a polycyclic heterocyclic group in which any two rings share two atoms not directly connected, these may contain one or more (preferably 1, 2 or 3) double bonds, but none of the rings Having a fully conjugated ⁇ -electron system in which one or more (preferably 1, 2, 3 or 4) ring atoms are selected from nitrogen, oxygen or S(O) r (where r is an integer 0, 1, 2) heteroatoms, and the remaining ring atoms are carbon. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups. Bridged heterocyclic groups include but are not limited to:
- the heterocyclyl ring may be fused to an aryl, heteroaryl, or cycloalkyl ring where the ring attached to the parent structure is a heterocyclyl, including but not limited to:
- Aryl or "aromatic ring” means an all-carbon monocyclic or fused polycyclic (that is, rings that share adjacent pairs of ring) group of carbon atoms, preferably a full carbon aryl group containing 6-10 (eg 6, 7, 8, 9, 10) or 6-8 carbons, for example, "C 6-10 aryl” Refers to a full-carbon aryl group containing 6-10 carbons, including but not limited to phenyl and naphthyl, “C 6-10 aryl” refers to a full-carbon aryl group containing 6-10 carbons, “C 6-8 aryl "A group” refers to an all-carbon aryl group containing 6-8 carbons, the aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring attached to the parent structure is an aryl group rings, including but not limited to:
- Heteroaryl means a heteroaromatic system containing one or more (preferably 1, 2, 3 or 4) heteroatoms including nitrogen, oxygen and S(O) r (where r is the integer 0 , 1, 2), preferably heteroaromatic systems containing 5-10 (5, 6, 7, 8, 9, 10) or 5-8 or 5-6 ring atoms, for example, ""5-8 membered heteroaryl” refers to a heteroaromatic system containing 5-8 ring atoms, “5-10 membered heteroaryl” refers to a heteroaromatic system containing 5-10 ring atoms, including but not limited to furan base, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, etc.
- the heteroaryl ring may be fused to an aryl, heterocyclyl or cycloalkyl ring, where the ring bonded
- Alkenyl means an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, preferably containing 2-10 (eg 2, 3, 4, 5, 6, 7, 8 , 9, 10) or 2-4 carbon straight-chain or branched-chain alkenyl, for example, "C 2-10 alkenyl” refers to a straight-chain or branched-chain alkenyl containing 2-10 carbons, “C 2-4 alkenyl” refers to a straight chain or branched alkenyl group containing 2 to 4 carbons. Including but not limited to vinyl, 1-propenyl, 2-propenyl, 1-, 2- or 3-butenyl, etc.
- Alkynyl means an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon triple bond, preferably containing 2-10 (e.g. 2, 3, 4, 5, 6, 7, 8, 9, 10) or 2-4 carbon straight chain or branched chain alkynyl, for example, "C 2-10 alkynyl” refers to 2-10 carbon straight chain or branched chain alkynyl, " C 2-4 alkynyl”refers to a straight-chain or branched-chain alkynyl group containing 2-4 carbons. Including but not limited to ethynyl, 1-propynyl, 2-propynyl, 1-, 2- or 3-butynyl, etc.
- Alkoxy refers to -O-alkyl, wherein the definition of alkyl is as above, for example, “C 1-10 alkoxy” refers to an alkyloxy group containing 1-10 carbons, “C 1-4 "Alkoxy” refers to an alkyloxy group containing 1-4 carbons, including but not limited to methoxy, ethoxy, propoxy, butoxy and the like.
- Cycloalkoxy or “cycloalkyloxy” refers to -O-cycloalkyl, wherein the definition of cycloalkyl is as above, for example, “C 3-12 cycloalkoxy” refers to 3-12 Carbon cycloalkyloxy, “C 3-6 cycloalkoxy” refers to cycloalkyloxy containing 3-6 carbons, including but not limited to cyclopropoxy, cyclobutoxy, cyclopentyloxy , Cyclohexyl and so on.
- Heterocyclyloxy or “heterocyclyloxy” refers to -O-heterocyclyl, where the definition of heterocyclyl is as above, including but not limited to azetidinyloxy, oxetanyloxy radical, azacyclopentyloxy, nitrogen, oxepyloxy, etc.
- C 1-10 alkanoyl refers to the monovalent atomic group left after C 1-10 alkanoic acid removes the hydroxyl group, and is usually expressed as "C 0-9 alkyl-C(O)-", for example, “C 1 Alkyl-C(O)-” refers to acetyl; “C 2 alkyl-C(O)-” refers to propionyl; “C 3 alkyl-C(O)-” refers to butyryl or isobutyl Acyl.
- Halogen substituted C 1-10 alkyl refers to 1-10 carbon alkyl groups whose hydrogen on the alkyl is optionally substituted by fluorine, chlorine, bromine, iodine atoms, including but not limited to difluoromethyl, dichloro Methyl, dibromomethyl, trifluoromethyl, trichloromethyl, tribromomethyl, etc.
- Halogen substituted C 1-10 alkoxy refers to a 1-10 carbon alkoxy group in which the hydrogen on the alkyl group is optionally replaced by fluorine, chlorine, bromine, or iodine atoms. Including but not limited to difluoromethoxy, dichloromethoxy, dibromomethoxy, trifluoromethoxy, trichloromethoxy, tribromomethoxy and the like.
- Deuterium-substituted C 1-10 alkyl refers to a 1-10 carbon alkyl group in which the hydrogen on the alkyl is optionally replaced by a deuterium atom. Including but not limited to mono-deuteromethyl, dide-deuteromethyl, tri-deuteromethyl, etc.
- Halogen means fluorine, chlorine, bromine or iodine.
- Optional or “optionally” means that the subsequently described event or circumstance may but need not occur, and the description includes the occasion where the event or circumstance occurs or does not occur, that is, includes two situations of substitution or non-substitution .
- a heterocyclic group optionally substituted with an alkyl group means that an alkyl group may but need not be present, and the description includes cases where the heterocycle group is substituted with an alkyl group and cases where the heterocycle group is not substituted with an alkyl group .
- Substituted means that one or more "hydrogen atoms" in a group are independently substituted with the corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, consistent with the valence bond theory in chemistry, and a person skilled in the art can determine (by experiment or theory) that it is possible or impossible without undue effort of the replacement. For example, an amino or hydroxyl group with free hydrogen may be unstable when bonded to a carbon atom with an unsaturated bond such as an alkene.
- Stepoisomer its English name is stereoisomer, refers to the isomer produced by the different arrangement of atoms in the molecule in space, it can be divided into two kinds of cis-trans isomers and enantiomers, It can also be divided into two categories: enantiomers and diastereomers.
- Stereoisomers due to the rotation of a single bond are called conformational stereo-isomers, sometimes also called rotamers.
- Stereoisomers caused by bond length, bond angle, double bonds in the molecule, rings, etc. are called configuration isomers (configuration stereo-isomers), and configuration isomers are divided into two categories.
- geometric isomers also known as cis-trans isomers (cis-trans isomers), which are divided into Z, E two configurations.
- cis-2-butene and trans-2-butene are a pair of geometric isomers, and the stereoisomers with different optical rotation properties caused by the absence of anti-axis symmetry in the molecule are called optical isomers ( optical isomer), divided into R and S configurations.
- optical isomer optical isomer
- the "stereoisomer" mentioned in the present invention can be understood as including one or more of the above-mentioned enantiomers, configuration isomers and conformational isomers unless otherwise specified.
- “Pharmaceutically acceptable salt” in the present invention refers to pharmaceutically acceptable acid addition salts, including inorganic acid salts and organic acid salts, which salts can be prepared by methods known in the art.
- “Pharmaceutical composition” means a mixture containing one or more compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, and other chemical components, and other components such as a physiologically/pharmaceutically acceptable carrier and excipients.
- the purpose of the pharmaceutical composition is to promote the administration to the organism, facilitate the absorption of the active ingredient and thus exert biological activity.
- the structures of the compounds of the present invention are determined by nuclear magnetic resonance (NMR) or/and liquid chromatography-mass chromatography (LC-MS). NMR chemical shifts ( ⁇ ) are given in parts per million (ppm).
- the determination of NMR is to use Bruker AVANCE-400/500 nuclear magnetic apparatus, and the determination solvent is deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated methanol (CD 3 OD) and deuterated chloroform (CDCl 3 ), internal standard For tetramethylsilane (TMS).
- Agilent 6120 mass spectrometer was used for the determination of liquid chromatography-mass chromatography LC-MS.
- the determination of HPLC used Agilent 1200DAD high pressure liquid chromatography (Sunfire C18 150 ⁇ 4.6mm column) and Waters 2695-2996 high pressure liquid chromatography (Gimini C18 150 ⁇ 4.6mm column).
- Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates are used for thin-layer chromatography silica gel plates.
- the specifications used for TLC are 0.15mm-0.20mm, and the specifications used for thin-layer chromatography separation and purification products are 0.4mm-0.5mm.
- Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.
- the starting materials in the examples of the present invention are known and commercially available, or can be synthesized using or following methods known in the art.
- the second step the synthesis of 5-((tert-butyldimethylsilyl)oxy)-7,7-dimethyl-7H-cyclopentadieno[b]pyridine
- the third step Synthesis of 7,7-dimethyl-6,7-dihydro-5H-cyclopenta[b]pyridin-5-one
- N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(2,7,7-trimethyl-7H-cyclopentadien[b]pyridin-5-yl ) pyrimidin-2-amine (105mg, 0.25mmol) was dissolved in 1,4-dioxane (15mL), and (R)-N,N-dimethyl-1-(pyrrolidin-2-yl) was added The reaction of methylamine (43mg, 0.335mmol) and N,N-diisopropylethylamine (2mL) was stirred overnight at 120°C.
- the fifth step (R)-N-(2-(2-((dimethylamino)methyl)pyrrolidin-1-yl)-4-methoxy-5-((4-(2,7, Synthesis of 7-trimethyl-7H-cyclopentadieno[b]pyridin-5-yl)pyrimidin-2-yl)amino)phenyl)acrylamide
- Embodiment 2 ⁇ 63 can be prepared with reference to all or part of the synthetic method of embodiment 1 and select corresponding raw materials:
- the cells were placed in a 96-well plate filled with drugs at a temperature of 37° C., 5% CO 2 and 95% humidity, and continued to culture for 72 hours, and then CTG analysis was performed.
- Cell survival rate (%) (Lum test drug-Lum culture solution control)/(Lum cell control-Lum culture solution control) ⁇ 100%.
- the series of compounds of the present invention have a strong inhibitory effect on EGFR exon 20 insertion, deletion or other mutations at the cellular level, and the selectivity to EGFR WT is more than 10 times, Compared with the less than 5-fold selectivity of positive compounds, the series of compounds of the present invention have higher selectivity and better development prospects.
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Abstract
An azaaryl derivative with EGFR inhibitory activity, a preparation method therefor and the use thereof. In particular, the present invention relates to a azaaryl derivative having the structure of formula (I), a preparation method therefor, a pharmaceutical composition containing same, the use thereof as an EGFR inhibitor, and the use thereof in the treatment and/or prevention of cancers, tumors or metastatic diseases at least partially associated with EGFR exon 20 insertion or deletion mutation, and in particular, the use thereof in the treatment of hyperproliferative diseases and cell death-inducing disorders. In addition, the definition of each substituent in formula (I) is the same as the definition in the description.
Description
本发明属于药物合成领域，具体涉及具有EGFR抑制活性的氮杂芳基衍生物、其制备方法和应用。The invention belongs to the field of drug synthesis, and specifically relates to an azaaryl derivative with EGFR inhibitory activity, a preparation method and application thereof.
肺癌是全世界癌症死亡的主要原因，其中非小细胞肺癌(NSCLC)占85％。针对表皮生长因子受体(EGFR)突变、间变性淋巴瘤激酶(ALK)易位、ROS1原癌基因受体酪氨酸激酶(ROS1)重排和B-raf原癌基因、丝氨酸/苏氨酸激酶(BRAF)的多靶点治疗已经开发出来并在临床上得到验证。EGFR抑制能显著提高腺癌NSCLC的无进展生存期，其获得性耐药突变后继而被第三代抑制剂靶向。Lung cancer is the leading cause of cancer death worldwide, with non-small cell lung cancer (NSCLC) accounting for 85%. Targets epidermal growth factor receptor (EGFR) mutations, anaplastic lymphoma kinase (ALK) translocation, ROS1 proto-oncogene receptor tyrosine kinase (ROS1) rearrangement and B-raf proto-oncogene, serine/threonine Multi-targeted therapeutics against kinases (BRAF) have been developed and clinically validated. EGFR inhibition significantly improved progression-free survival in adenocarcinoma NSCLC whose acquired resistance mutations were subsequently targeted by third-generation inhibitors.
尽管成功地抑制了经典的EGFR激活突变(外显子19和21)和耐药突变(T790M)，外显子20的框内插入也导致了EGFR信号的结构性激活，并与对现有EGFR抑制剂的从头抵抗相关。外显子20突变是异质性的，包括1-7个氨基酸在EGFR蛋白的762-774个氨基酸之间的框内插入或重复。在NSCLC中，EGFR外显子20的突变频率占EGFR所有突变的4-10％。这些突变与其他已知的致癌基因驱动突变相互排斥，并且在女性、非吸烟者、亚洲人群和非小细胞肺癌患者的腺癌中富集。除NSCLC外，EGFR外显子20插入突变还见于一种罕见的头颈部癌，即鼻腔鳞状细胞癌(SNSCC)。此外，在受体酪氨酸激酶(RTK)EGFR家族的另一成员HER2中也发现了结构类似的外显子20插入突变。Despite successful suppression of canonical EGFR activating mutations (exons 19 and 21) and resistance mutations (T790M), an in-frame insertion of exon 20 also resulted in constitutive activation of EGFR signaling and was compatible with existing EGFR de novo resistance to inhibitors. Exon 20 mutations are heterogeneous and include in-frame insertions or duplications of 1–7 amino acids between amino acids 762–774 of the EGFR protein. In NSCLC, the mutation frequency of EGFR exon 20 accounts for 4-10% of all EGFR mutations. These mutations are mutually exclusive with other known oncogene driver mutations and are enriched in adenocarcinomas from women, non-smokers, Asian populations, and patients with non-small cell lung cancer. In addition to NSCLC, EGFR exon 20 insertion mutations are also found in a rare head and neck cancer, nasal squamous cell carcinoma (SNSCC). In addition, a structurally similar exon 20 insertion mutation was also found in HER2, another member of the receptor tyrosine kinase (RTK) EGFR family.
多重回顾性分析显示，目前可用的第1代、第2代和第3代EGFR抑制剂对外显子20插入突变的疗效有限，但A763-Y764insFQEA突变除外。不可逆抑制剂Poziotinib和EGFR/MET双特异性抗体amivantamab正在临床试验中。几种小分子抑制剂包括TAK-788和TAS-6417，在EGFR外显子20非小细胞肺癌患者中显示出临床上有意义的功效，但是，由于对EGFR WT的选择性有限，它们的不良反应是不可避免的，并可能导致剂量限制性毒性。因此，对于这些患者而言，迫切需要针对EGFR外显子20插入突变的高选择性小分子抑制剂。Multiple retrospective analyzes have shown that currently available 1st, 2nd, and 3rd generation EGFR inhibitors have limited efficacy for exon 20 insertion mutations, with the exception of the A763-Y764insFQEA mutation. The irreversible inhibitor Poziotinib and the EGFR/MET bispecific antibody amivantamab are in clinical trials. Several small molecule inhibitors, including TAK-788 and TAS-6417, have shown clinically meaningful efficacy in patients with EGFR exon 20 NSCLC, however, due to limited selectivity against EGFR WT, their poor Reactions are unavoidable and may result in dose-limiting toxicities. Therefore, highly selective small molecule inhibitors targeting EGFR exon 20 insertion mutations are urgently needed for these patients.
发明内容Contents of the invention
本发明的目的在于提供一种具有EGFR抑制活性的氮杂芳基衍生物、其制备方法和应用。本发明系列化合物对EGFR外显子20插入、缺失或其他突变细胞学活性具有很强的抑制作用，可广泛应用于制备治疗和/或预防至少部分与EGFR外显子20插入、缺失或其他突变相关的癌症、肿瘤或转移性疾病的药物，特别是治疗过度增殖性疾病和诱导细胞死亡障碍疾病的药物，从而有望开发出新一代EGFR抑制剂。The object of the present invention is to provide an azaaryl derivative with EGFR inhibitory activity, its preparation method and application. The series of compounds of the present invention have a strong inhibitory effect on the cytological activity of EGFR exon 20 insertions, deletions or other mutations, and can be widely used in the preparation of therapeutic and/or prevention of at least part of EGFR exon 20 insertions, deletions or other mutations Drugs for related cancers, tumors or metastatic diseases, especially drugs for the treatment of hyperproliferative diseases and diseases that induce cell death disorders, so it is expected to develop a new generation of EGFR inhibitors.
本发明第一方面提供式(I)化合物、其立体异构体或其药学上可接受盐：The first aspect of the present invention provides a compound of formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof:
其中，X为CH或N；Y
1、Y
2和Y
3各自独立地为CR
10或N，条件是Y
1、Y
2和Y
3中至少1个为N；Z为CR
11或N；
wherein, X is CH or N; Y 1 , Y 2 and Y 3 are each independently CR 10 or N, provided that at least one of Y 1 , Y 2 and Y 3 is N; Z is CR 11 or N;
每个R
1各自独立地选自氢、氘、卤素、氰基、硝基、叠氮基、C
1-10烷基、C
2-10链烯基、C
2-10链炔基、C
3-12环烷基、3-12元杂环基、C
6-10芳基、5-10元杂芳基、-SF
5、-S(O)
rR
12、-O-R
13、-C(O)OR
13、-C(O)R
14、-O-C(O)R
14、-NR
15R
16、-C(＝NR
15)R
14、-N(R
15)-C(＝NR
16)R
14、-C(O)NR
15R
16和-N(R
15)-C(O)R
14，或者，当m≥2时，任意两个R
1与其直接相连的部分一起形成C
3-12环烷基或3-12元杂环基，上述基团任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C
1-10烷基、C
2-10链烯基、C
2-10链炔基、卤取代C
1-10烷基、氘取代C
1-10烷基、C
3-12环烷基、3-12元杂环基、C
6-10芳基、5-10元杂芳基、＝O、-SF
5、-S(O)
rR
12、-O-R
13、-C(O)OR
13、-C(O)R
14、-O-C(O)R
14、-NR
15R
16、-C(＝NR
15)R
14、-N(R
15)-C(＝NR
16)R
14、-C(O)NR
15R
16和-N(R
15)-C(O)R
14的取代基所取代；
Each R 1 is independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3 -12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, -SF 5 , -S(O) r R 12 , -OR 13 , -C(O )OR 13 , -C(O)R 14 , -OC(O)R 14 , -NR 15 R 16 , -C(=NR 15 )R 14 , -N(R 15 )-C(=NR 16 )R 14. -C(O)NR 15 R 16 and -N(R 15 )-C(O)R 14 , or, when m≥2, any two R 1 and their directly connected parts together form C 3-12 Cycloalkyl or 3-12 membered heterocyclic group, the above group is optionally further replaced by one or more selected from deuterium, halogen, cyano, nitro, azido, C 1-10 alkyl, C 2-10 Alkenyl, C 2-10 alkynyl, halogen substituted C 1-10 alkyl, deuterium substituted C 1-10 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 Aryl, 5-10 membered heteroaryl, =O, -SF 5 , -S(O) r R 12 , -OR 13 , -C(O)OR 13 , -C(O)R 14 , -OC( O)R 14 , -NR 15 R 16 , -C(=NR 15 )R 14 , -N(R 15 )-C(=NR 16 )R 14 , -C(O)NR 15 R 16 and -N( R 15 )-C(O)R 14 is substituted by a substituent;
R
2和R
3各自独立地选自氢、氘、卤素、氰基、硝基、叠氮基、C
1-10烷基、C
2-10链烯基、C
2-10链炔基、C
3-12环烷基、3-12元杂环基、C
6-10芳基和5-10元杂芳基，或者，R
2和R
3与其直接相连的碳原子一起形成羰基、C
3-6环烷基或3-6元杂环基，上述基团任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C
1-10烷基、C
2-10链烯基、C
2-10链炔基、卤取代C
1-10烷基、氘取代C
1-10烷基、C
3-12环烷基、3-12元杂环基、C
6-10芳基、5-10元杂芳基、＝O、-SF
5、-S(O)
rR
12、-O-R
13、-C(O)OR
13、-C(O)R
14、-O-C(O)R
14、-NR
15R
16、-C(＝NR
15)R
14、-N(R
15)-C(＝NR
16)R
14、-C(O)NR
15R
16和-N(R
15)-C(O)R
14的取代基所取代；
R 2 and R 3 are each independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-10 aryl and 5-10 membered heteroaryl, or, R 2 and R 3 form carbonyl together with the carbon atom directly connected to it, C 3- 6 cycloalkyl groups or 3-6 membered heterocyclic groups, the above groups are optionally further replaced by one or more selected from deuterium, halogen, cyano, nitro, azido, C 1-10 alkyl, C 2- 10 alkenyl, C 2-10 alkynyl, halogen substituted C 1-10 alkyl, deuterium substituted C 1-10 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6- 10 aryl, 5-10 membered heteroaryl, =O, -SF 5 , -S(O) r R 12 , -OR 13 , -C(O)OR 13 , -C(O)R 14 , -OC (O)R 14 , -NR 15 R 16 , -C(=NR 15 )R 14 , -N(R 15 )-C(=NR 16 )R 14 , -C(O)NR 15 R 16 and -N (R 15 )-C(O)R 14 is substituted by a substituent;
R
4选自氢、氘、C
1-10烷基、C
2-10链烯基、C
3-12环烷基、3-12元杂环基、C
6-10芳基和5-10元杂芳基，上述基团任选进一步被一个或多个选自氘、卤素、羟基、＝O、氰基、C
1-10烷基、C
1-10烷氧基、C
3-12环烷基、C
3-12环烷氧基、3-12元杂环基、3-12元杂环氧基、C
6-10芳基、C
6-10芳氧基、5-10元杂芳基、5-10元杂芳氧基和-NR
15R
16的取代基所取代；
R 4 is selected from hydrogen, deuterium, C 1-10 alkyl, C 2-10 alkenyl, C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-10 aryl and 5-10 membered Heteroaryl, the above groups are optionally further replaced by one or more selected from deuterium, halogen, hydroxyl, =O, cyano, C 1-10 alkyl, C 1-10 alkoxy, C 3-12 cycloalkane Group, C 3-12 cycloalkoxy group, 3-12 membered heterocyclic group, 3-12 membered heterocyclic epoxy group, C 6-10 aryl group, C 6-10 aryloxy group, 5-10 membered heteroaryl group , 5-10 membered heteroaryloxy and -NR 15 R 16 substituents;
R
5选自氢、氘、羟基、C
1-10烷基、卤取代C
1-10烷基、氘取代C
1-10烷基、C
2-4 链烯基、C
3-6环烷基和3-6元杂环基；
R is selected from hydrogen, deuterium , hydroxyl, C 1-10 alkyl, halogen substituted C 1-10 alkyl, deuterium substituted C 1-10 alkyl, C 2-4 alkenyl, C 3-6 cycloalkyl and 3-6 membered heterocyclyl;
R
6a选自氢、氘、卤素、氰基、硝基、叠氮基、C
1-10烷基、卤取代C
1-10烷基、氘取代C
1-10烷基、C
2-10链烯基、C
2-10链炔基、C
3-12环烷基、3-12元杂环基、C
6-10芳基、5-10元杂芳基、-SF
5、-S(O)
rR
12、-O-R
13、-C(O)OR
13、-C(O)R
14、-O-C(O)R
14、-NR
15R
16、-C(＝NR
15)R
14、-N(R
15)-C(＝NR
16)R
14、-C(O)NR
15R
16和-N(R
15)-C(O)R
14；
R 6a is selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-10 alkyl, halogen substituted C 1-10 alkyl, deuterium substituted C 1-10 alkyl, C 2-10 chain Alkenyl, C 2-10 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, -SF 5 , -S(O ) r R 12 , -OR 13 , -C(O)OR 13 , -C(O)R 14 , -OC(O)R 14 , -NR 15 R 16 , -C(=NR 15 )R 14 , - N(R 15 )-C(=NR 16 )R 14 , -C(O)NR 15 R 16 and -N(R 15 )-C(O)R 14 ;
R
6b选自氢、氘、卤素、氰基、硝基、叠氮基、C
1-10烷基、卤取代C
1-10烷基、氘取代C
1-10烷基、C
2-10链烯基、C
2-10链炔基、C
3-12环烷基、3-12元杂环基、C
6-10芳基、5-10元杂芳基、-SF
5、-S(O)
rR
12、-O-R
13、-C(O)OR
13、-C(O)R
14、-O-C(O)R
14、-NR
15R
16、-C(＝NR
15)R
14、-N(R
15)-C(＝NR
16)R
14、-C(O)NR
15R
16和-N(R
15)-C(O)R
14；
R 6b is selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-10 alkyl, halogen substituted C 1-10 alkyl, deuterium substituted C 1-10 alkyl, C 2-10 chain Alkenyl, C 2-10 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, -SF 5 , -S(O ) r R 12 , -OR 13 , -C(O)OR 13 , -C(O)R 14 , -OC(O)R 14 , -NR 15 R 16 , -C(=NR 15 )R 14 , - N(R 15 )-C(=NR 16 )R 14 , -C(O)NR 15 R 16 and -N(R 15 )-C(O)R 14 ;
R
7和R
8各自独立地选自氢、氘、羟基、C
1-10烷基、C
2-4链烯基、C
3-6环烷基和3-6元杂环基，或者，R
7和R
8与其直接相连的氮原子一起形成3-12元杂环基，上述基团任选进一步被一个或多个选自氘、卤素、羟基、C
1-10烷基、C
2-10链烯基、C
2-10链炔基、卤取代C
1-10烷基、氘取代C
1-10烷基、C
1-10烷氧基、C
3-12环烷基、C
3-12环烷氧基、3-12元杂环基、3-12元杂环氧基、C
6-10芳基、C
6-10芳氧基、5-10元杂芳基、5-10元杂芳氧基和-NR
15R
16的取代基所取代；
R 7 and R 8 are each independently selected from hydrogen, deuterium, hydroxyl, C 1-10 alkyl, C 2-4 alkenyl, C 3-6 cycloalkyl and 3-6 membered heterocyclyl, or, R 7 and R 8 form a 3-12-membered heterocyclic group together with the nitrogen atom directly connected to it, and the above-mentioned group is optionally further replaced by one or more selected from deuterium, halogen, hydroxyl, C 1-10 alkyl, C 2-10 Alkenyl, C 2-10 alkynyl, halogen substituted C 1-10 alkyl, deuterium substituted C 1-10 alkyl, C 1-10 alkoxy, C 3-12 cycloalkyl, C 3-12 Cycloalkoxy, 3-12 membered heterocyclic group, 3-12 membered heterocyclic oxy group, C 6-10 aryl group, C 6-10 aryloxy group, 5-10 membered heteroaryl group, 5-10 membered heterocyclic group Substituents of aryloxy and -NR 15 R 16 ;
或者，R
6a或R
6b其中之一和R
5与其直接相连的部分一起形成4-6元杂环基，R
6a或R
6b其中另一个如前所定义，上述4-6元杂环基任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C
1-10烷基、卤取代C
1-10烷基、氘取代C
1-10烷基、C
2-10链烯基、C
2-10链炔基、C
3-12环烷基、3-12元杂环基、C
6-10芳基、5-10元杂芳基、＝O、-SF
5、-S(O)
rR
12、-O-R
13、-C(O)OR
13、-C(O)R
14、-O-C(O)R
14、-NR
15R
16、-C(＝NR
15)R
14、-N(R
15)-C(＝NR
16)R
14、-C(O)NR
15R
16和-N(R
15)-C(O)R
14的取代基所取代；
Alternatively, one of R 6a or R 6b and R 5 together with the part directly connected to it form a 4-6 membered heterocyclic group, the other of R 6a or R 6b is as defined above, any of the above 4-6 membered heterocyclic groups One or more selected from deuterium, halogen, cyano, nitro, azido, C 1-10 alkyl, halogen substituted C 1-10 alkyl, deuterium substituted C 1-10 alkyl, C 2 -10 alkenyl, C 2-10 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, =O, -SF 5. -S(O) r R 12 , -OR 13 , -C(O)OR 13 , -C(O)R 14 , -OC(O)R 14 , -NR 15 R 16 , -C(=NR 15 ) Substituents of R 14 , -N(R 15 )-C(=NR 16 )R 14 , -C(O)NR 15 R 16 and -N(R 15 )-C(O)R 14 ;
或者，R
6b和R
7与其直接相连的部分一起形成4-6元杂环基，上述4-6元杂环基任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C
1-10烷基、卤取代C
1-10烷基、氘取代C
1-10烷基、C
2-10链烯基、C
2-10链炔基、C
3-12环烷基、3-12元杂环基、C
6-10芳基、5-10元杂芳基、＝O、-SF
5、-S(O)
rR
12、-O-R
13、-C(O)OR
13、-C(O)R
14、-O-C(O)R
14、-NR
15R
16、-C(＝NR
15)R
14、-N(R
15)-C(＝NR
16)R
14、-C(O)NR
15R
16和-N(R
15)-C(O)R
14的取代基所取代；
Alternatively, R 6b and R 7 form a 4-6-membered heterocyclic group together with the part directly connected to it, and the above-mentioned 4-6-membered heterocyclic group is optionally further replaced by one or more selected from deuterium, halogen, cyano, nitro, Azido, C 1-10 alkyl, halogen substituted C 1-10 alkyl, deuterium substituted C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-12 ring Alkyl, 3-12 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, =O, -SF 5 , -S(O) r R 12 , -OR 13 , -C(O )OR 13 , -C(O)R 14 , -OC(O)R 14 , -NR 15 R 16 , -C(=NR 15 )R 14 , -N(R 15 )-C(=NR 16 )R 14. Substituents of -C(O)NR 15 R 16 and -N(R 15 )-C(O)R 14 ;
或者，
为如下结构：
其中R
5和R
8如前所定义；
or, For the following structure: Wherein R 5 and R 8 are as previously defined;
R
9a、R
9b和R
9c各自独立地选自氢、氘、卤素、氰基、C
1-4烷基、卤取代C
1-4烷基、氘取代C
1-4烷基、C
3-6环烷基、3-6元杂环基、-C(O)OR
13、-C(O)R
14、-C(O)NR
15R
16和-C
0-4烷基-NR
15R
16；
R 9a , R 9b and R 9c are each independently selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 3- 6 cycloalkyl, 3-6 membered heterocyclyl, -C(O)OR 13 , -C(O)R 14 , -C(O)NR 15 R 16 and -C 0-4 alkyl-NR 15 R 16 ;
每个R
10各自独立地选自氢、氘、卤素、氰基、硝基、叠氮基、C
1-10烷基、C
2-10链烯基、C
2-10链炔基、C
3-12环烷基、3-12元杂环基、C
6-10芳基、5-10元杂芳 基、-SF
5、-S(O)
rR
12、-O-R
13、-C(O)OR
13、-C(O)R
14、-O-C(O)R
14、-NR
15R
16、-C(＝NR
15)R
14、-N(R
15)-C(＝NR
16)R
14、-C(O)NR
15R
16和-N(R
15)-C(O)R
14，上述基团任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C
1-10烷基、C
2-10链烯基、C
2-10链炔基、卤取代C
1-10烷基、氘取代C
1-10烷基、C
3-12环烷基、3-12元杂环基、C
6-10芳基、5-10元杂芳基、＝O、-SF
5、-S(O)
rR
12、-O-R
13、-C(O)OR
13、-C(O)R
14、-O-C(O)R
14、-NR
15R
16、-C(＝NR
15)R
14、-N(R
15)-C(＝NR
16)R
14、-C(O)NR
15R
16和-N(R
15)-C(O)R
14的取代基所取代；
Each R 10 is independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3 -12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, -SF 5 , -S(O) r R 12 , -OR 13 , -C(O )OR 13 , -C(O)R 14 , -OC(O)R 14 , -NR 15 R 16 , -C(=NR 15 )R 14 , -N(R 15 )-C(=NR 16 )R 14. -C(O)NR 15 R 16 and -N(R 15 )-C(O)R 14 , the above groups are optionally further replaced by one or more selected from deuterium, halogen, cyano, nitro, azide Nitrogen, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, halogen substituted C 1-10 alkyl, deuterium substituted C 1-10 alkyl, C 3-12 cycloalkane radical, 3-12 membered heterocyclic group, C 6-10 aryl group, 5-10 membered heteroaryl group, =O, -SF 5 , -S(O) r R 12 , -OR 13 , -C(O) OR 13 , -C(O)R 14 , -OC(O)R 14 , -NR 15 R 16 , -C(=NR 15 )R 14 , -N(R 15 )-C(=NR 16 )R 14 , -C(O)NR 15 R 16 and -N(R 15 )-C(O)R 14 are substituted by substituents;
R
11选自氢、氘、卤素、氰基、硝基、叠氮基、C
1-10烷基、卤取代C
1-10烷基、氘取代C
1-10烷基、C
2-10链烯基、C
2-10链炔基、C
3-12环烷基、3-12元杂环基、C
6-10芳基、5-10元杂芳基、-SF
5、-S(O)
rR
12、-O-R
13、-C(O)OR
13、-C(O)R
14、-O-C(O)R
14、-NR
15R
16、-C(＝NR
15)R
14、-N(R
15)-C(＝NR
16)R
14、-C(O)NR
15R
16和-N(R
15)-C(O)R
14；
R 11 is selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-10 alkyl, halogen substituted C 1-10 alkyl, deuterium substituted C 1-10 alkyl, C 2-10 chain Alkenyl, C 2-10 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, -SF 5 , -S(O ) r R 12 , -OR 13 , -C(O)OR 13 , -C(O)R 14 , -OC(O)R 14 , -NR 15 R 16 , -C(=NR 15 )R 14 , - N(R 15 )-C(=NR 16 )R 14 , -C(O)NR 15 R 16 and -N(R 15 )-C(O)R 14 ;
每个R
12各自独立地选自氢、氘、羟基、C
1-10烷基、C
2-10链烯基、C
3-12环烷基、3-12元杂环基、C
6-10芳基、5-10元杂芳基和-NR
15R
16，上述基团任选进一步被一个或多个选自氘、卤素、羟基、氧代、C
1-10烷基、C
1-10烷氧基、C
3-12环烷基、C
3-12环烷氧基、3-12元杂环基、3-12元杂环氧基、C
6-10芳基、C
6-10芳氧基、5-10元杂芳基、5-10元杂芳氧基和-NR
15R
16的取代基所取代；
Each R 12 is independently selected from hydrogen, deuterium, hydroxyl, C 1-10 alkyl, C 2-10 alkenyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 Aryl, 5-10 membered heteroaryl and -NR 15 R 16 , the above groups are optionally further selected from one or more of deuterium, halogen, hydroxyl, oxo, C 1-10 alkyl, C 1-10 Alkoxyl group, C 3-12 cycloalkyl group, C 3-12 cycloalkoxy group, 3-12 membered heterocyclic group, 3-12 membered heterocyclic epoxy group, C 6-10 aryl group, C 6-10 aromatic group Oxygen, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy and -NR 15 R 16 are substituted by substituents;
每个R
13各自独立地选自氢、氘、C
1-10烷基、C
2-10链烯基、C
3-12环烷基、3-12元杂环基、C
6-10芳基和5-10元杂芳基，上述基团任选进一步被一个或多个选自氘、卤素、羟基、氧代、氰基、C
1-10烷基、C
1-10烷氧基、C
3-12环烷基、C
3-12环烷氧基、3-12元杂环基、3-12元杂环氧基、C
6-10芳基、C
6-10芳氧基、5-10元杂芳基、5-10元杂芳氧基和-NR
15R
16的取代基所取代；
Each R 13 is independently selected from hydrogen, deuterium, C 1-10 alkyl, C 2-10 alkenyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, the above-mentioned groups are optionally further replaced by one or more selected from deuterium, halogen, hydroxyl, oxo, cyano, C 1-10 alkyl, C 1-10 alkoxy, C 3-12 cycloalkyl group, C 3-12 cycloalkoxy group, 3-12 membered heterocyclic group, 3-12 membered heterocyclic epoxy group, C 6-10 aryl group, C 6-10 aryloxy group, 5- Substituents of 10-membered heteroaryl, 5-10-membered heteroaryloxy and -NR 15 R 16 ;
每个R
14各自独立地选自氢、氘、羟基、C
1-10烷基、C
1-10烷氧基、C
2-10链烯基、C
2-10链炔基、C
3-12环烷基、C
3-12环烷氧基、3-12元杂环基、3-12元杂环氧基、C
6-10芳基、C
6-10芳氧基、5-10元杂芳基、5-10元杂芳氧基和-NR
15R
16，上述基团任选进一步被一个或多个选自氘、卤素、羟基、氰基、C
1-10烷基、C
1-10烷氧基、C
3-12环烷基、C
3-12环烷氧基、3-12元杂环基、3-12元杂环氧基、C
6-10芳基、C
6-10芳氧基、5-10元杂芳基、5-10元杂芳氧基和-NR
15R
16的取代基所取代；
Each R 14 is independently selected from hydrogen, deuterium, hydroxyl, C 1-10 alkyl, C 1-10 alkoxy, C 2-10 alkenyl, C 2-10 alkynyl, C 3-12 Cycloalkyl, C 3-12 cycloalkoxy, 3-12 membered heterocyclic group, 3-12 membered heterocyclic epoxy group, C 6-10 aryl group, C 6-10 aryloxy group, 5-10 membered heterocyclic group Aryl, 5-10-membered heteroaryloxy and -NR 15 R 16 , the above-mentioned groups are optionally further replaced by one or more selected from deuterium, halogen, hydroxyl, cyano, C 1-10 alkyl, C 1- 10 alkoxy, C 3-12 cycloalkyl, C 3-12 cycloalkoxy, 3-12 heterocyclic, 3-12 heterocyclic, C 6-10 aryl, C 6-10 Substituted by aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy and -NR 15 R 16 ;
每个R
15和R
16各自独立地选自氢、氘、羟基、C
1-10烷氧基、C
1-10烷基、C
2-10链烯基、C
2-10链炔基、C
3-12环烷基、3-12元杂环基、C
6-10芳基、5-10元杂芳基、亚磺酰基、磺酰基、甲磺酰基、异丙磺酰基、环丙基磺酰基、对甲苯磺酰基、氨基磺酰基、二甲氨基磺酰基、氨基、单C
1-10烷基氨基、二C
1-10烷基氨基和C
1-10烷酰基，上述基团任选进一步被一个或多个选自氘、卤素、羟基、C
1-10烷基、C
2-10链烯基、C
2-10链炔基、卤取代C
1-10烷基、氘取代C
1-10烷基、C
1-10烷氧基、C
3-12环烷基、C
3-12环烷氧基、3-12元杂环基、3-12元杂环氧基、C
6-10芳基、C
6-10芳氧基、5-10元杂芳基、5-10元杂芳氧基、氨基、单C
1-10烷基氨基、二C
1-10烷基氨基和C
1-10烷酰基的取代基所取代，
Each R 15 and R 16 are each independently selected from hydrogen, deuterium, hydroxyl, C 1-10 alkoxy, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, sulfinyl, sulfonyl, methylsulfonyl, isopropylsulfonyl, cyclopropylsulfonyl Acyl, p-toluenesulfonyl, aminosulfonyl, dimethylaminosulfonyl, amino, single C 1-10 alkylamino, two C 1-10 alkylamino and C 1-10 alkanoyl, the above groups are optionally further By one or more selected from deuterium, halogen, hydroxyl, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, halogen substituted C 1-10 alkyl, deuterium substituted C 1- 10 alkyl, C 1-10 alkoxy, C 3-12 cycloalkyl, C 3-12 cycloalkoxy, 3-12 heterocyclic, 3-12 heterocyclic, C 6-10 Aryl, C 6-10 aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, amino, mono C 1-10 alkylamino, di C 1-10 alkylamino and C 1 Substituents of -10 alkanoyl,
或者，R
15和R
16与其直接相连的氮原子一起形成4-10元杂环基，上述基团任选进一步被一个或多个选自氘、卤素、羟基、C
1-10烷基、C
2-10链烯基、C
2-10链炔基、卤取代C
1-10烷基、氘取代C
1-10烷基、C
1-10烷氧基、C
3-12环烷基、C
3-12环烷氧基、3-12元杂环基、3-12元杂环氧基、C
6-10芳基、C
6-10芳氧基、5-10元杂芳基、5-10元杂芳氧基、氨基、单C
1-10烷基氨基、二C
1-10烷基氨基和C
1-10烷酰基的取代基所取代；
Alternatively, R 15 and R 16 form a 4-10 membered heterocyclic group together with their directly connected nitrogen atoms, and the above-mentioned groups are optionally further replaced by one or more selected from deuterium, halogen, hydroxyl, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, halogen substituted C 1-10 alkyl, deuterium substituted C 1-10 alkyl, C 1-10 alkoxy, C 3-12 cycloalkyl, C 3-12 cycloalkoxy, 3-12 heterocyclic, 3-12 heterocyclic, C 6-10 aryl, C 6-10 aryloxy, 5-10 heteroaryl, 5- Substituents of 10-membered heteroaryloxy, amino, single C 1-10 alkylamino, di-C 1-10 alkylamino and C 1-10 alkanoyl;
m为0、1、2或3；m is 0, 1, 2 or 3;
每个r各自独立地为0、1或2。Each r is independently 0, 1 or 2.
作为优选的方案，在所述式(I)化合物、其立体异构体或其药学上可接受盐中，每个R
1各自独立地选自氢、氘、卤素、氰基、硝基、叠氮基、C
1-4烷基、C
2-4链烯基、C
2-4链炔基、C
3-6环烷基、3-6元杂环基、C
6-8芳基、5-8元杂芳基、-SF
5、-S(O)
rR
12、-O-R
13、-C(O)OR
13、-C(O)R
14、-O-C(O)R
14、-NR
15R
16、-C(＝NR
15)R
14、-N(R
15)-C(＝NR
16)R
14、-C(O)NR
15R
16和-N(R
15)-C(O)R
14，或者，当m≥2时，任意两个R
1与其直接相连的部分一起形成C
3-6环烷基或3-6元杂环基，上述基团任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C
1-4烷基、C
2-4链烯基、C
2-4链炔基、卤取代C
1-4烷基、氘取代C
1-4烷基、C
3-6环烷基、3-6元杂环基、C
6-8芳基、5-8元杂芳基、＝O、-SF
5、-S(O)
rR
12、-O-R
13、-C(O)OR
13、-C(O)R
14、-O-C(O)R
14、-NR
15R
16、-C(＝NR
15)R
14、-N(R
15)-C(＝NR
16)R
14、-C(O)NR
15R
16和-N(R
15)-C(O)R
14的取代基所取代；
As a preferred scheme, in the compound of formula ( I ), its stereoisomer or its pharmaceutically acceptable salt, each R is independently selected from hydrogen, deuterium, halogen, cyano, nitro, azide Nitrogen, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl, 5 -8-membered heteroaryl, -SF 5 , -S(O) r R 12 , -OR 13 , -C(O)OR 13 , -C(O)R 14 , -OC(O)R 14 , -NR 15 R 16 , -C(=NR 15 )R 14 , -N(R 15 )-C(=NR 16 )R 14 , -C(O)NR 15 R 16 and -N(R 15 )-C(O )R 14 , or, when m≥2, any two R 1 and their directly connected parts together form a C 3-6 cycloalkyl group or a 3-6 membered heterocyclic group, and the above groups are optionally further replaced by one or more One selected from deuterium, halogen, cyano, nitro, azido, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halogen substituted C 1-4 alkyl, deuterium Substituted C 1-4 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic group, C 6-8 aryl, 5-8 membered heteroaryl, =O, -SF 5 , -S(O ) r R 12 , -OR 13 , -C(O)OR 13 , -C(O)R 14 , -OC(O)R 14 , -NR 15 R 16 , -C(=NR 15 )R 14 , - Substituents of N(R 15 )-C(=NR 16 )R 14 , -C(O)NR 15 R 16 and -N(R 15 )-C(O)R 14 ;
R
2和R
3各自独立地选自氢、氘、卤素、氰基、硝基、叠氮基、C
1-4烷基、C
2-4链烯基、C
2-4链炔基、C
3-6环烷基、3-6元杂环基、C
6-8芳基和5-8元杂芳基，或者，R
2和R
3与其直接相连的碳原子一起形成羰基、C
3-6环烷基或3-6元杂环基，上述基团任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C
1-4烷基、C
2-4链烯基、C
2-4链炔基、卤取代C
1-4烷基、氘取代C
1-4烷基、C
3-6环烷基、3-6元杂环基、C
6-8芳基、5-8元杂芳基、＝O、-SF
5、-S(O)
rR
12、-O-R
13、-C(O)OR
13、-C(O)R
14、-O-C(O)R
14、-NR
15R
16、-C(＝NR
15)R
14、-N(R
15)-C(＝NR
16)R
14、-C(O)NR
15R
16和-N(R
15)-C(O)R
14的取代基所取代；
R 2 and R 3 are each independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl group, 3-6 membered heterocyclic group, C 6-8 aryl group and 5-8 membered heteroaryl group, or, R 2 and R 3 together form a carbonyl group, C 3- 6 cycloalkyl groups or 3-6 membered heterocyclic groups, the above groups are optionally further replaced by one or more selected from deuterium, halogen, cyano, nitro, azido, C 1-4 alkyl, C 2- 4 alkenyl, C 2-4 alkynyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6- 8 aryl, 5-8 membered heteroaryl, =O, -SF 5 , -S(O) r R 12 , -OR 13 , -C(O)OR 13 , -C(O)R 14 , -OC (O)R 14 , -NR 15 R 16 , -C(=NR 15 )R 14 , -N(R 15 )-C(=NR 16 )R 14 , -C(O)NR 15 R 16 and -N (R 15 )-C(O)R 14 is substituted by a substituent;
R
4选自氢、氘、C
1-4烷基、C
2-4链烯基、C
3-6环烷基、3-6元杂环基、C
6-8芳基和5-8元杂芳基，上述基团任选进一步被一个或多个选自氘、卤素、羟基、＝O、氰基、C
1-4烷基、C
1-4烷氧基、C
3-6环烷基、C
3-6环烷氧基、3-6元杂环基、3-6元杂环氧基、C
6-8芳基、C
6-8芳氧基、5-8元杂芳基、5-8元杂芳氧基和-NR
15R
16的取代基所取代；
R 4 is selected from hydrogen, deuterium, C 1-4 alkyl, C 2-4 alkenyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl and 5-8 membered Heteroaryl, the above group is optionally further replaced by one or more selected from deuterium, halogen, hydroxyl, =O, cyano, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkane Group, C 3-6 cycloalkoxy group, 3-6 membered heterocyclic group, 3-6 membered heterocyclic epoxy group, C 6-8 aryl group, C 6-8 aryloxy group, 5-8 membered heteroaryl group , 5-8 membered heteroaryloxy and -NR 15 R 16 substituents;
R
5选自氢、氘、羟基、C
1-4烷基、卤取代C
1-4烷基、氘取代C
1-4烷基、C
2-4链烯基、C
3-6环烷基和3-6元杂环基；
R is selected from hydrogen, deuterium , hydroxyl, C 1-4 alkyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 2-4 alkenyl, C 3-6 cycloalkyl and 3-6 membered heterocyclyl;
R
6a选自氢、氘、卤素、氰基、硝基、叠氮基、C
1-4烷基、卤取代C
1-4烷基、氘取代C
1-4烷基、C
2-4链烯基、C
2-4链炔基、C
3-6环烷基、3-6元杂环基、C
6-8芳基、 5-8元杂芳基、-SF
5、-S(O)
rR
12、-O-R
13、-C(O)OR
13、-C(O)R
14、-O-C(O)R
14、-NR
15R
16、-C(＝NR
15)R
14、-N(R
15)-C(＝NR
16)R
14、-C(O)NR
15R
16和-N(R
15)-C(O)R
14；
R 6a is selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-4 alkyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 2-4 chain Alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, -SF 5 , -S(O ) r R 12 , -OR 13 , -C(O)OR 13 , -C(O)R 14 , -OC(O)R 14 , -NR 15 R 16 , -C(=NR 15 )R 14 , - N(R 15 )-C(=NR 16 )R 14 , -C(O)NR 15 R 16 and -N(R 15 )-C(O)R 14 ;
R
6b选自氢、氘、卤素、氰基、硝基、叠氮基、C
1-4烷基、卤取代C
1-4烷基、氘取代C
1-4烷基、C
2-4链烯基、C
2-4链炔基、C
3-6环烷基、3-6元杂环基、C
6-8芳基、5-8元杂芳基、-SF
5、-S(O)
rR
12、-O-R
13、-C(O)OR
13、-C(O)R
14、-O-C(O)R
14、-NR
15R
16、-C(＝NR
15)R
14、-N(R
15)-C(＝NR
16)R
14、-C(O)NR
15R
16和-N(R
15)-C(O)R
14；
R 6b is selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-4 alkyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 2-4 chain Alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, -SF 5 , -S(O ) r R 12 , -OR 13 , -C(O)OR 13 , -C(O)R 14 , -OC(O)R 14 , -NR 15 R 16 , -C(=NR 15 )R 14 , - N(R 15 )-C(=NR 16 )R 14 , -C(O)NR 15 R 16 and -N(R 15 )-C(O)R 14 ;
R
7和R
8各自独立地选自氢、氘、羟基、C
1-4烷基、C
2-4链烯基、C
3-6环烷基和3-6元杂环基，或者，R
7和R
8与其直接相连的氮原子一起形成3-6元杂环基，上述基团任选进一步被一个或多个选自氘、卤素、羟基、C
1-4烷基、C
2-4链烯基、C
2-4链炔基、卤取代C
1-4烷基、氘取代C
1-4烷基、C
1-4烷氧基、C
3-6环烷基、C
3-6环烷氧基、3-6元杂环基、3-6元杂环氧基、C
6-8芳基、C
6-8芳氧基、5-8元杂芳基、5-8元杂芳氧基和-NR
15R
16的取代基所取代；
R 7 and R 8 are each independently selected from hydrogen, deuterium, hydroxyl, C 1-4 alkyl, C 2-4 alkenyl, C 3-6 cycloalkyl and 3-6 membered heterocyclyl, or, R 7 and R 8 form a 3-6 membered heterocyclic group together with the nitrogen atom directly connected to it, and the above-mentioned groups are optionally further replaced by one or more selected from deuterium, halogen, hydroxyl, C 1-4 alkyl, C 2-4 Alkenyl, C 2-4 alkynyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, C 3-6 Cycloalkoxy, 3-6 membered heterocyclic group, 3-6 membered heterocyclic oxy group, C 6-8 aryl group, C 6-8 aryloxy group, 5-8 membered heteroaryl group, 5-8 membered heterocyclic group Substituents of aryloxy and -NR 15 R 16 ;
或者，R
6a或R
6b其中之一和R
5与其直接相连的部分一起形成4-6元杂环基，R
6a或R
6b其中另一个如前所定义，上述4-6元杂环基任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C
1-4烷基、卤取代C
1-4烷基、氘取代C
1-4烷基、C
2-4链烯基、C
2-4链炔基、C
3-6环烷基、3-6元杂环基、C
6-8芳基、5-8元杂芳基、＝O、-SF
5、-S(O)
rR
12、-O-R
13、-C(O)OR
13、-C(O)R
14、-O-C(O)R
14、-NR
15R
16、-C(＝NR
15)R
14、-N(R
15)-C(＝NR
16)R
14、-C(O)NR
15R
16和-N(R
15)-C(O)R
14的取代基所取代；
Alternatively, one of R 6a or R 6b and R 5 together with the part directly connected to it form a 4-6 membered heterocyclic group, the other of R 6a or R 6b is as defined above, any of the above 4-6 membered heterocyclic groups is further selected from one or more groups selected from deuterium, halogen, cyano, nitro, azido, C 1-4 alkyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 2 -4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, =O, -SF 5. -S(O) r R 12 , -OR 13 , -C(O)OR 13 , -C(O)R 14 , -OC(O)R 14 , -NR 15 R 16 , -C(=NR 15 ) Substituents of R 14 , -N(R 15 )-C(=NR 16 )R 14 , -C(O)NR 15 R 16 and -N(R 15 )-C(O)R 14 ;
或者，R
6b和R
7与其直接相连的部分一起形成4-6元杂环基，上述4-6元杂环基任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C
1-4烷基、卤取代C
1-4烷基、氘取代C
1-4烷基、C
2-4链烯基、C
2-4链炔基、C
3-6环烷基、3-6元杂环基、C
6-8芳基、5-8元杂芳基、＝O、-SF
5、-S(O)
rR
12、-O-R
13、-C(O)OR
13、-C(O)R
14、-O-C(O)R
14、-NR
15R
16、-C(＝NR
15)R
14、-N(R
15)-C(＝NR
16)R
14、-C(O)NR
15R
16和-N(R
15)-C(O)R
14的取代基所取代；
Alternatively, R 6b and R 7 form a 4-6-membered heterocyclic group together with the part directly connected to it, and the above-mentioned 4-6-membered heterocyclic group is optionally further replaced by one or more selected from deuterium, halogen, cyano, nitro, Azido, C 1-4 alkyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 ring Alkyl, 3-6 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, =O, -SF 5 , -S(O) r R 12 , -OR 13 , -C(O )OR 13 , -C(O)R 14 , -OC(O)R 14 , -NR 15 R 16 , -C(=NR 15 )R 14 , -N(R 15 )-C(=NR 16 )R 14. Substituents of -C(O)NR 15 R 16 and -N(R 15 )-C(O)R 14 ;
或者，
为如下结构：
其中R
5和R
8如前所定义；
or, For the following structure: Wherein R 5 and R 8 are as previously defined;
R
9a、R
9b和R
9c各自独立地选自氢、氘、卤素、氰基、C
1-4烷基、卤取代C
1-4烷基、氘取代C
1-4烷基和-C
0-4烷基-NR
15R
16；
R 9a , R 9b and R 9c are each independently selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl and -C 0 -4 alkyl-NR 15 R 16 ;
每个R
10各自独立地选自氢、氘、卤素、氰基、硝基、叠氮基、C
1-4烷基、C
2-4链烯基、C
2-4链炔基、C
3-6环烷基、3-6元杂环基、C
6-8芳基、5-8元杂芳基、-SF
5、-S(O)
rR
12、-O-R
13、-C(O)OR
13、-C(O)R
14、-O-C(O)R
14、-NR
15R
16、-C(＝NR
15)R
14、-N(R
15)-C(＝NR
16)R
14、-C(O)NR
15R
16和-N(R
15)-C(O)R
14，上述基团任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C
1-4烷基、C
2-4链烯基、C
2-4链炔基、卤取代C
1-4烷基、氘取代C
1-4烷基、C
3-6环烷基、3-6元杂环基、C
6-8芳基、 5-8元杂芳基、＝O、-SF
5、-S(O)
rR
12、-O-R
13、-C(O)OR
13、-C(O)R
14、-O-C(O)R
14、-NR
15R
16、-C(＝NR
15)R
14、-N(R
15)-C(＝NR
16)R
14、-C(O)NR
15R
16和-N(R
15)-C(O)R
14的取代基所取代；
Each R 10 is independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3 -6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, -SF 5 , -S(O) r R 12 , -OR 13 , -C(O )OR 13 , -C(O)R 14 , -OC(O)R 14 , -NR 15 R 16 , -C(=NR 15 )R 14 , -N(R 15 )-C(=NR 16 )R 14. -C(O)NR 15 R 16 and -N(R 15 )-C(O)R 14 , the above groups are optionally further replaced by one or more selected from deuterium, halogen, cyano, nitro, azide Nitrogen, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 3-6 cycloalkane base, 3-6 membered heterocyclic group, C 6-8 aryl group, 5-8 membered heteroaryl group, =O, -SF 5 , -S(O) r R 12 , -OR 13 , -C(O) OR 13 , -C(O)R 14 , -OC(O)R 14 , -NR 15 R 16 , -C(=NR 15 )R 14 , -N(R 15 )-C(=NR 16 )R 14 , -C(O)NR 15 R 16 and -N(R 15 )-C(O)R 14 are substituted by substituents;
R
11选自氢、氘、卤素、氰基、硝基、叠氮基、C
1-4烷基、卤取代C
1-4烷基、氘取代C
1-4烷基、C
2-4链烯基、C
2-4链炔基、C
3-6环烷基、3-6元杂环基、C
6-8芳基、5-8元杂芳基、-SF
5、-S(O)
rR
12、-O-R
13、-C(O)OR
13、-C(O)R
14、-O-C(O)R
14、-NR
15R
16、-C(＝NR
15)R
14、-N(R
15)-C(＝NR
16)R
14、-C(O)NR
15R
16和-N(R
15)-C(O)R
14；
R 11 is selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-4 alkyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 2-4 chain Alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, -SF 5 , -S(O ) r R 12 , -OR 13 , -C(O)OR 13 , -C(O)R 14 , -OC(O)R 14 , -NR 15 R 16 , -C(=NR 15 )R 14 , - N(R 15 )-C(=NR 16 )R 14 , -C(O)NR 15 R 16 and -N(R 15 )-C(O)R 14 ;
其中，R
12、R
13、R
14、R
15、R
16、m和r如式(I)化合物中所定义
Wherein, R 12 , R 13 , R 14 , R 15 , R 16 , m and r are as defined in the compound of formula (I)
作为优选的方案，在所述式(I)化合物、其立体异构体或其药学上可接受盐中，每个R
12各自独立地选自氢、氘、羟基、C
1-4烷基、C
2-4链烯基、C
3-6环烷基、3-6元杂环基、C
6-8芳基、5-8元杂芳基和-NR
15R
16，上述基团任选进一步被一个或多个选自氘、卤素、羟基、氧代、C
1-4烷基、C
1-4烷氧基、C
3-6环烷基、C
3-6环烷氧基、3-6元杂环基、3-6元杂环氧基、C
6-8芳基、C
6-8芳氧基、5-8元杂芳基、5-8元杂芳氧基和-NR
15R
16的取代基所取代；
As a preferred scheme, in the compound of formula (I), its stereoisomer or its pharmaceutically acceptable salt, each R 12 is independently selected from hydrogen, deuterium, hydroxyl, C 1-4 alkyl, C 2-4 alkenyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic group, C 6-8 aryl, 5-8 membered heteroaryl and -NR 15 R 16 , the above groups are optional Further by one or more selected from deuterium, halogen, hydroxyl, oxo, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, 3 -6 membered heterocyclic group, 3-6 membered heterocyclic oxy group, C 6-8 aryl group, C 6-8 aryloxy group, 5-8 membered heteroaryl group, 5-8 membered heteroaryloxy group and -NR 15 R 16 is replaced by a substituent;
每个R
13各自独立地选自氢、氘、C
1-4烷基、C
2-4链烯基、C
3-6环烷基、3-6元杂环基、C
6-8芳基和5-8元杂芳基，上述基团任选进一步被一个或多个选自氘、卤素、羟基、氧代、氰基、C
1-4烷基、C
1-4烷氧基、C
3-6环烷基、C
3-6环烷氧基、3-6元杂环基、3-6元杂环氧基、C
6-8芳基、C
6-8芳氧基、5-8元杂芳基、5-8元杂芳氧基和-NR
15R
16的取代基所取代；
Each R 13 is independently selected from hydrogen, deuterium, C 1-4 alkyl, C 2-4 alkenyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl and 5-8 membered heteroaryl, the above-mentioned groups are optionally further replaced by one or more selected from deuterium, halogen, hydroxyl, oxo, cyano, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl group, C 3-6 cycloalkoxy group, 3-6 membered heterocyclic group, 3-6 membered heterocyclic epoxy group, C 6-8 aryl group, C 6-8 aryloxy group, 5- Substituents of 8-membered heteroaryl, 5-8-membered heteroaryloxy and -NR 15 R 16 ;
每个R
14各自独立地选自氢、氘、羟基、C
1-4烷基、C
1-4烷氧基、C
2-4链烯基、C
2-4链炔基、C
3-6环烷基、C
3-6环烷氧基、3-6元杂环基、3-6元杂环氧基、C
6-8芳基、C
6-8芳氧基、5-8元杂芳基、5-8元杂芳氧基和-NR
15R
16，上述基团任选进一步被一个或多个选自氘、卤素、羟基、氰基、C
1-4烷基、C
1-4烷氧基、C
3-6环烷基、C
3-6环烷氧基、3-6元杂环基、3-6元杂环氧基、C
6-8芳基、C
6-8芳氧基、5-8元杂芳基、5-8元杂芳氧基和-NR
15R
16的取代基所取代；
Each R 14 is independently selected from hydrogen, deuterium, hydroxyl, C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 Cycloalkyl, C 3-6 cycloalkoxy, 3-6 membered heterocyclic group, 3-6 membered heterocyclic epoxy group, C 6-8 aryl group, C 6-8 aryloxy group, 5-8 membered heterocyclic group Aryl, 5-8-membered heteroaryloxy and -NR 15 R 16 , the above-mentioned groups are optionally further replaced by one or more selected from deuterium, halogen, hydroxyl, cyano, C 1-4 alkyl, C 1- 4 alkoxyl, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, 3-6 heterocyclyl, 3-6 heterocyclyl, C 6-8 aryl, C 6-8 Substituents of aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy and -NR 15 R 16 ;
每个R
15和R
16各自独立地选自氢、氘、羟基、C
1-4烷氧基、C
1-4烷基、C
2-4链烯基、C
2-4链炔基、C
3-6环烷基、3-6元杂环基、C
6-8芳基、5-8元杂芳基、亚磺酰基、磺酰基、甲磺酰基、异丙磺酰基、环丙基磺酰基、对甲苯磺酰基、氨基磺酰基、二甲氨基磺酰基、氨基、单C
1-4烷基氨基、二C
1-4烷基氨基和C
1-4烷酰基，上述基团任选进一步被一个或多个选自氘、卤素、羟基、C
1-4烷基、C
2-4链烯基、C
2-4链炔基、卤取代C
1-4烷基、氘取代C
1-4烷基、C
1-4烷氧基、C
3-6环烷基、C
3-6环烷氧基、3-6元杂环基、3-6元杂环氧基、C
6-8芳基、C
6-8芳氧基、5-8元杂芳基、5-8元杂芳氧基、氨基、单C
1-4烷基氨基、二C
1-4烷基氨基和C
1-4烷酰基的取代基所取代，
Each R 15 and R 16 are each independently selected from hydrogen, deuterium, hydroxyl, C 1-4 alkoxy, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, sulfinyl, sulfonyl, methylsulfonyl, isopropylsulfonyl, cyclopropylsulfonyl Acyl, p-toluenesulfonyl, aminosulfonyl, dimethylaminosulfonyl, amino, single C 1-4 alkylamino, two C 1-4 alkylamino and C 1-4 alkanoyl, the above groups are optionally further By one or more selected from deuterium, halogen, hydroxyl, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1- 4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, C 3-6 Cycloalkoxy, 3-6 Heterocyclic, 3-6 Heterocyclic, C 6-8 Aryl, C 6-8 aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy, amino, mono C 1-4 alkylamino, di C 1-4 alkylamino and C 1 -4 alkanoyl substituents are substituted,
或者，R
15和R
16与其直接相连的氮原子一起形成4-8元杂环基，上述基团任选进一步被一个或多个选自氘、卤素、羟基、C
1-4烷基、C
2-4链烯基、C
2-4链炔基、 卤取代C
1-4烷基、氘取代C
1-4烷基、C
1-4烷氧基、C
3-6环烷基、C
3-6环烷氧基、3-6元杂环基、3-6元杂环氧基、C
6-8芳基、C
6-8芳氧基、5-8元杂芳基、5-8元杂芳氧基、氨基、单C
1-4烷基氨基、二C
1-4烷基氨基和C
1-4烷酰基的取代基所取代。
Alternatively, R 15 and R 16 form a 4-8 membered heterocyclic group together with their directly connected nitrogen atoms, and the above-mentioned groups are optionally further replaced by one or more selected from deuterium, halogen, hydroxyl, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkoxy group, 3-6 membered heterocyclic group, 3-6 membered heterocyclic epoxy group, C 6-8 aryl group, C 6-8 aryloxy group, 5-8 membered heteroaryl group, 5- Substituents of 8-membered heteroaryloxy, amino, mono-C 1-4 alkylamino, di-C 1-4 alkylamino and C 1-4 alkanoyl.
作为优选的方案，在所述式(I)化合物、其立体异构体或其药学上可接受盐中，式(I)化合物为如下式(Ⅱ)化合物：As a preferred scheme, in the compound of formula (I), its stereoisomer or pharmaceutically acceptable salt thereof, the compound of formula (I) is the compound of formula (II):
其中，X各自独立地为CH或N；Y
1为CH或N；Y
2和Y
3各自独立地为CR
10或N，条件是Y
1、Y
2和Y
3中至少1个为N；Z为CH或N；
wherein each X is independently CH or N; Y1 is CH or N; Y2 and Y3 are each independently CR10 or N, provided that at least one of Y1 , Y2 and Y3 is N; Z is CH or N;
每个R
1各自独立地选自氢、氘、卤素、氰基、C
1-4烷基、C
2-4链烯基、C
2-4链炔基、C
3-6环烷基、3-6元杂环基、C
6-8芳基、5-8元杂芳基和-SF
5，或者，当m≥2时，任意两个R
1与其直接相连的部分一起形成C
3-6环烷基或3-6元杂环基，上述基团任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C
1-4烷基、C
2-4链烯基、C
2-4链炔基、卤取代C
1-4烷基、氘取代C
1-4烷基、C
3-6环烷基、3-6元杂环基、C
6-8芳基、5-8元杂芳基、＝O、-SF
5、-S(O)
rR
12、-O-R
13、-C(O)OR
13、-C(O)R
14、-O-C(O)R
14、-NR
15R
16、-C(＝NR
15)R
14、-N(R
15)-C(＝NR
16)R
14、-C(O)NR
15R
16和-N(R
15)-C(O)R
14的取代基所取代；
Each R 1 is independently selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3 -6-membered heterocyclic group, C 6-8 aryl group, 5-8-membered heteroaryl group and -SF 5 , or, when m≥2, any two R 1 and their directly connected parts together form C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, the above group is optionally further replaced by one or more selected from deuterium, halogen, cyano, nitro, azido, C 1-4 alkyl, C 2-4 Alkenyl, C 2-4 alkynyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 Aryl, 5-8 membered heteroaryl, =O, -SF 5 , -S(O) r R 12 , -OR 13 , -C(O)OR 13 , -C(O)R 14 , -OC( O)R 14 , -NR 15 R 16 , -C(=NR 15 )R 14 , -N(R 15 )-C(=NR 16 )R 14 , -C(O)NR 15 R 16 and -N( R 15 )-C(O)R 14 is substituted by a substituent;
R
2和R
3各自独立地选自氢、氘、卤素、氰基、C
1-4烷基、C
2-4链烯基、C
2-4链炔基、C
3-6环烷基和3-6元杂环基，或者，R
2和R
3与其直接相连的碳原子一起形成羰基、C
3-6环烷基或3-6元杂环基，上述基团任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C
1-4烷基、C
2-4链烯基、C
2-4链炔基、卤取代C
1-4烷基、氘取代C
1-4烷基、C
3-6环烷基、3-6元杂环基、C
6-8芳基、5-8元杂芳基、＝O、-SF
5、-S(O)
rR
12、-O-R
13、-C(O)OR
13、-C(O)R
14、-O-C(O)R
14、-NR
15R
16、-C(＝NR
15)R
14、-N(R
15)-C(＝NR
16)R
14、-C(O)NR
15R
16和-N(R
15)-C(O)R
14的取代基所取代；
R 2 and R 3 are each independently selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl and 3-6 membered heterocyclic group, or, R 2 and R 3 form carbonyl, C 3-6 cycloalkyl or 3-6 membered heterocyclic group together with the carbon atom directly connected to it, and the above groups are optionally further replaced by one or Multiple selected from deuterium, halogen, cyano, nitro, azido, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halogen substituted C 1-4 alkyl, Deuterium-substituted C 1-4 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic group, C 6-8 aryl, 5-8 membered heteroaryl, =O, -SF 5 , -S( O) r R 12 , -OR 13 , -C(O)OR 13 , -C(O)R 14 , -OC(O)R 14 , -NR 15 R 16 , -C(=NR 15 )R 14 , Substituents of -N(R 15 )-C(=NR 16 )R 14 , -C(O)NR 15 R 16 and -N(R 15 )-C(O)R 14 ;
R
4选自氢、氘、C
1-4烷基、C
2-4链烯基、C
3-6环烷基和3-6元杂环基，上述基团任选进一步被一个或多个选自氘、卤素、羟基、＝O、氰基、C
1-4烷基、C
1-4烷氧基、C
3-6环烷基、C
3-6环烷氧基、3-6元杂环基、3-6元杂环氧基、C
6-8芳基、C
6-8芳氧基、5-8元杂芳基、5-8元杂芳氧基和-NR
15R
16的取代基所取代；
R 4 is selected from hydrogen, deuterium, C 1-4 alkyl, C 2-4 alkenyl, C 3-6 cycloalkyl and 3-6 membered heterocyclic group, the above groups are optionally further replaced by one or more Selected from deuterium, halogen, hydroxyl, =O, cyano, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, 3-6 members Heterocyclic group, 3-6 membered heterooxyl group, C 6-8 aryl group, C 6-8 aryloxy group, 5-8 membered heteroaryl group, 5-8 membered heteroaryloxy group and -NR 15 R 16 replaced by substituents;
R
5选自氢、氘、羟基、C
1-4烷基、卤取代C
1-4烷基和氘取代C
1-4烷基；
R is selected from hydrogen, deuterium , hydroxyl, C 1-4 alkyl, halogen substituted C 1-4 alkyl and deuterium substituted C 1-4 alkyl;
R
6a选自氢、氘、卤素、氰基、硝基、叠氮基、C
1-4烷基、卤取代C
1-4烷基、氘取代C
1-4烷基、C
2-4链烯基、C
2-4链炔基、C
3-6环烷基、3-6元杂环基、C
6-8芳基 和5-8元杂芳基；
R 6a is selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-4 alkyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 2-4 chain Alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl and 5-8 membered heteroaryl;
R
6b选自氢、氘、卤素、氰基、硝基、叠氮基、C
1-4烷基、卤取代C
1-4烷基、氘取代C
1-4烷基、C
2-4链烯基、C
2-4链炔基、C
3-6环烷基、3-6元杂环基、C
6-8芳基和5-8元杂芳基；
R 6b is selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-4 alkyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 2-4 chain Alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl and 5-8 membered heteroaryl;
R
7和R
8各自独立地选自氢、氘、羟基、C
1-4烷基和C
2-4链烯基，或者，R
7和R
8与其直接相连的氮原子一起形成3-6元杂环基，上述基团任选进一步被一个或多个选自氘、卤素、羟基、C
1-4烷基、C
2-4链烯基、C
2-4链炔基、卤取代C
1-4烷基、氘取代C
1-4烷基、C
1-4烷氧基、C
3-6环烷基、C
3-6环烷氧基、3-6元杂环基、3-6元杂环氧基、C
6-8芳基、C
6-8芳氧基、5-8元杂芳基、5-8元杂芳氧基和-NR
15R
16的取代基所取代；
R 7 and R 8 are each independently selected from hydrogen, deuterium, hydroxyl, C 1-4 alkyl and C 2-4 alkenyl, or, R 7 and R 8 together form a 3-6 membered Heterocyclic group, the above group is optionally further substituted by one or more selected from deuterium, halogen, hydroxyl, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halogen substituted C 1 -4 alkyl, deuterium substituted C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, 3-6 membered heterocyclyl, 3-6 Substituents of membered heterooxyl group, C 6-8 aryl, C 6-8 aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy and -NR 15 R 16 ;
或者，R
6a或R
6b其中之一和R
5与其直接相连的部分一起形成4-6元杂环基，R
6a或R
6b其中另一个如前所定义，上述4-6元杂环基任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C
1-4烷基、卤取代C
1-4烷基、氘取代C
1-4烷基、C
2-4链烯基、C
2-4链炔基、C
3-6环烷基、3-6元杂环基、C
6-8芳基、5-8元杂芳基、＝O、-SF
5、-S(O)
rR
12、-O-R
13、-C(O)OR
13、-C(O)R
14、-O-C(O)R
14、-NR
15R
16、-C(＝NR
15)R
14、-N(R
15)-C(＝NR
16)R
14、-C(O)NR
15R
16和-N(R
15)-C(O)R
14的取代基所取代；
Alternatively, one of R 6a or R 6b and R 5 together with the part directly connected to it form a 4-6 membered heterocyclic group, the other of R 6a or R 6b is as defined above, any of the above 4-6 membered heterocyclic groups is further selected from one or more groups selected from deuterium, halogen, cyano, nitro, azido, C 1-4 alkyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 2 -4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, =O, -SF 5. -S(O) r R 12 , -OR 13 , -C(O)OR 13 , -C(O)R 14 , -OC(O)R 14 , -NR 15 R 16 , -C(=NR 15 ) Substituents of R 14 , -N(R 15 )-C(=NR 16 )R 14 , -C(O)NR 15 R 16 and -N(R 15 )-C(O)R 14 ;
或者，R
6b和R
7与其直接相连的部分一起形成4-6元杂环基，上述4-6元杂环基任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C
1-4烷基、卤取代C
1-4烷基、氘取代C
1-4烷基、C
2-4链烯基、C
2-4链炔基、C
3-6环烷基、3-6元杂环基、C
6-8芳基、5-8元杂芳基、＝O、-SF
5、-S(O)
rR
12、-O-R
13、-C(O)OR
13、-C(O)R
14、-O-C(O)R
14、-NR
15R
16、-C(＝NR
15)R
14、-N(R
15)-C(＝NR
16)R
14、-C(O)NR
15R
16和-N(R
15)-C(O)R
14的取代基所取代；
Alternatively, R 6b and R 7 form a 4-6-membered heterocyclic group together with the part directly connected to it, and the above-mentioned 4-6-membered heterocyclic group is optionally further replaced by one or more selected from deuterium, halogen, cyano, nitro, Azido, C 1-4 alkyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 ring Alkyl, 3-6 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, =O, -SF 5 , -S(O) r R 12 , -OR 13 , -C(O )OR 13 , -C(O)R 14 , -OC(O)R 14 , -NR 15 R 16 , -C(=NR 15 )R 14 , -N(R 15 )-C(=NR 16 )R 14. Substituents of -C(O)NR 15 R 16 and -N(R 15 )-C(O)R 14 ;
或者，
为如下结构：
其中R
5和R
8如前所定义；
or, For the following structure: Wherein R 5 and R 8 are as previously defined;
R
9a选自氢、氘、卤素、氰基、C
1-4烷基、卤取代C
1-4烷基和氘取代C
1-4烷基；
R 9a is selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, halogen substituted C 1-4 alkyl and deuterium substituted C 1-4 alkyl;
每个R
10各自独立地选自氢、氘、卤素、氰基、C
1-4烷基、C
2-4链烯基、C
2-4链炔基、C
3-6环烷基、3-6元杂环基、C
6-8芳基、5-8元杂芳基、-O-R
13、-C(O)OR
13、-C(O)R
14和-O-C(O)R
14，上述基团任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C
1-4烷基、C
2-4链烯基、C
2-4链炔基、卤取代C
1-4烷基、氘取代C
1-4烷基、C
3-6环烷基、3-6元杂环基、C
6-8芳基、5-8元杂芳基、＝O、-SF
5、-S(O)
rR
12、-O-R
13、-C(O)OR
13、-C(O)R
14、-O-C(O)R
14、-NR
15R
16、-C(＝NR
15)R
14、-N(R
15)-C(＝NR
16)R
14、-C(O)NR
15R
16和-N(R
15)-C(O)R
14的取代基所取代；
Each R 10 is independently selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3 -6 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, -OR 13 , -C(O)OR 13 , -C(O)R 14 and -OC(O)R 14 , The above-mentioned groups are optionally further replaced by one or more selected from deuterium, halogen, cyano, nitro, azido, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, Halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic group, C 6-8 aryl, 5-8 membered heteroaryl, = O, -SF 5 , -S(O)rR 12 , -OR 13 , -C(O)OR 13 , -C(O) R 14 , -OC(O)R 14 , -NR 15 R 16 , - Substitution of C(=NR 15 )R 14 , -N(R 15 )-C(=NR 16 )R 14 , -C(O)NR 15 R 16 and -N(R 15 )-C(O)R 14 base replaced;
其中，R
12、R
13、R
14、R
15、R
16、m和r如式(I)化合物中所定义。
Wherein, R 12 , R 13 , R 14 , R 15 , R 16 , m and r are as defined in the compound of formula (I).
作为优选的方案，在所述式(I)化合物、其立体异构体或其药学上可接受盐中， 式(I)化合物为如下式(Ⅲ)化合物：As a preferred scheme, in the compound of formula (I), its stereoisomer or pharmaceutically acceptable salt thereof, the compound of formula (I) is the compound of formula (III):
其中，X为CH或N；Y
1为CH或N；Y
2为CR
10a或N，Y
3为CR
10b或N，条件是Y
1、Y
2和Y
3中至少1个为N；Z为CH或N；
wherein X is CH or N; Y 1 is CH or N; Y 2 is CR 10a or N, Y 3 is CR 10b or N, provided that at least one of Y 1 , Y 2 and Y 3 is N; Z is CH or N;
R
1a选自氢、氘、卤素、氰基、C
1-4烷基、C
2-4链炔基、C
3-6环烷基、3-6元杂环基和5-8元杂芳基，上述基团任选进一步被一个或多个选自氘、卤素、氰基、C
1-4烷基、C
2-4链烯基、C
2-4链炔基、卤取代C
1-4烷基、氘取代C
1-4烷基、C
3-6环烷基和3-6元杂环基的取代基所取代；
R 1a is selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl and 5-8 membered heteroaryl The above group is optionally further substituted by one or more selected from deuterium, halogen, cyano, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halogen substituted C 1- Substituents of 4 alkyl, deuterium substituted C 1-4 alkyl, C 3-6 cycloalkyl and 3-6 membered heterocyclyl;
R
1b选自氢、氘、卤素、氰基、C
1-4烷基、C
2-4链炔基、C
3-6环烷基、3-6元杂环基和5-8元杂芳基，上述基团任选进一步被一个或多个选自氘、卤素、氰基、C
1-4烷基、C
2-4链烯基、C
2-4链炔基、卤取代C
1-4烷基、氘取代C
1-4烷基、C
3-6环烷基和3-6元杂环基的取代基所取代；
R 1b is selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl and 5-8 membered heteroaryl The above group is optionally further substituted by one or more selected from deuterium, halogen, cyano, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halogen substituted C 1- Substituents of 4 alkyl, deuterium substituted C 1-4 alkyl, C 3-6 cycloalkyl and 3-6 membered heterocyclyl;
R
2和R
3各自独立地选自氢、氘和C
1-4烷基，或者，R
2和R
3与其直接相连的碳原子一起形成羰基、C
3-6环烷基或3-6元杂环基，上述基团任选进一步被一个或多个选自氘、卤素、氰基、C
1-4烷基、C
2-4链烯基、C
2-4链炔基、卤取代C
1-4烷基、氘取代C
1-4烷基、C
3-6环烷基和3-6元杂环基的取代基所取代；
R 2 and R 3 are each independently selected from hydrogen, deuterium and C 1-4 alkyl, or, R 2 and R 3 form carbonyl, C 3-6 cycloalkyl or 3-6 membered carbon atoms together with their directly connected carbon atoms Heterocyclic group, the above group is optionally further substituted by one or more selected from deuterium, halogen, cyano, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halogen substituted C Substituents of 1-4 alkyl, deuterium-substituted C 1-4 alkyl, C 3-6 cycloalkyl and 3-6 membered heterocyclic groups;
R
4选自氢、氘、C
1-4烷基、C
3-6环烷基和3-6元杂环基，上述基团任选进一步被一个或多个选自氘、卤素、＝O、氰基、C
1-4烷基、C
3-6环烷基和3-6元杂环基的取代基所取代；
R 4 is selected from hydrogen, deuterium, C 1-4 alkyl, C 3-6 cycloalkyl and 3-6 membered heterocyclyl, and the above-mentioned groups are optionally further selected from one or more of deuterium, halogen, =O , cyano, C 1-4 alkyl, C 3-6 cycloalkyl and 3-6 membered heterocyclic substituents;
R
5选自氢、氘、C
1-4烷基、卤取代C
1-4烷基和氘取代C
1-4烷基；
R is selected from hydrogen, deuterium , C 1-4 alkyl, halogen substituted C 1-4 alkyl and deuterium substituted C 1-4 alkyl;
R
6a选自氢、氘、C
1-4烷基、卤取代C
1-4烷基和氘取代C
1-4烷基；
R 6a is selected from hydrogen, deuterium, C 1-4 alkyl, halogen substituted C 1-4 alkyl and deuterium substituted C 1-4 alkyl;
R
6b选自氢、氘、C
1-4烷基、卤取代C
1-4烷基和氘取代C
1-4烷基；
R 6b is selected from hydrogen, deuterium, C 1-4 alkyl, halogen substituted C 1-4 alkyl and deuterium substituted C 1-4 alkyl;
R
7和R
8各自独立地选自氢、氘和C
1-4烷基，或者，R
7和R
8与其直接相连的氮原子一起形成3-6元杂环基，上述基团任选进一步被一个或多个选自氘、卤素、羟基、C
1-4烷基、C
2-4链烯基、C
2-4链炔基、卤取代C
1-4烷基、氘取代C
1-4烷基、C
1-4烷氧基、C
3-6环烷基和C
3-6环烷氧基的取代基所取代；
R 7 and R 8 are each independently selected from hydrogen, deuterium and C 1-4 alkyl, or, R 7 and R 8 form a 3-6 membered heterocyclic group together with the nitrogen atom directly connected to it, and the above-mentioned groups are optionally further By one or more selected from deuterium, halogen, hydroxyl, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1- Substituents of 4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl and C 3-6 cycloalkoxy;
或者，R
6a或R
6b其中之一和R
5与其直接相连的部分一起形成4-6元杂环基，R
6a或R
6b其中另一个如前所定义，上述4-6元杂环基任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C
1-4烷基、卤取代C
1-4烷基、氘取代C
1-4烷基、C
2-4链烯基、C
2-4链炔基、C
3-6环烷基和3-6元杂环基的取代基所取代；
Alternatively, one of R 6a or R 6b and R 5 together with the part directly connected to it form a 4-6 membered heterocyclic group, the other of R 6a or R 6b is as defined above, any of the above 4-6 membered heterocyclic groups is further selected from one or more groups selected from deuterium, halogen, cyano, nitro, azido, C 1-4 alkyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 2 Substituents of -4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl and 3-6 membered heterocyclyl;
或者，R
6b和R
7与其直接相连的部分一起形成4-6元杂环基，上述4-6元杂环基任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C
1-4烷基、卤取代C
1-4烷基、氘取代C
1-4烷基、C
2-4链烯基、C
2-4链炔基、C
3-6环烷基和3-6元杂环基的取代基所取代；
Alternatively, R 6b and R 7 form a 4-6-membered heterocyclic group together with the part directly connected to it, and the above-mentioned 4-6-membered heterocyclic group is optionally further replaced by one or more selected from deuterium, halogen, cyano, nitro, Azido, C 1-4 alkyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 ring Substituents of alkyl and 3-6 membered heterocyclic groups;
或者，
为如下结构：
其中R
5和R
8如前所定义；
or, For the following structure: Wherein R 5 and R 8 are as previously defined;
R
9a选自氢、氘、卤素、氰基、C
1-4烷基、卤取代甲基和氘取代甲基；
R 9a is selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, halogen substituted methyl and deuterium substituted methyl;
R
10a选自氢、氘、卤素、氰基、C
1-4烷基、C
3-6环烷基、3-6元杂环基、5-6元杂芳基、-O-R
13和-C(O)OR
13，上述基团任选进一步被一个或多个选自氘、卤素、氰基、C
1-4烷基、卤取代C
1-4烷基、氘取代C
1-4烷基、C
3-6环烷基、3-6元杂环基、5-6元杂芳基、＝O、-O-R
13、-C(O)OR
13和-C(O)R
14的取代基所取代；
R 10a is selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, 5-6 membered heteroaryl, -OR 13 and -C (O) OR 13 , the above group is optionally further selected from one or more groups selected from deuterium, halogen, cyano, C 1-4 alkyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl , C 3-6 cycloalkyl, 3-6 membered heterocyclyl, 5-6 membered heteroaryl, =O, -OR 13 , -C(O)OR 13 and -C(O)R 14 substituents replaced by
R
10b选自氢、氘、卤素、氰基、C
1-4烷基、C
3-6环烷基、3-6元杂环基、5-6元杂芳基、-O-R
13和-C(O)OR
13，上述基团任选进一步被一个或多个选自氘、卤素、氰基、C
1-4烷基、卤取代C
1-4烷基、氘取代C
1-4烷基、C
3-6环烷基、3-6元杂环基、5-6元杂芳基、＝O、-O-R
13、-C(O)OR
13和-C(O)R
14的取代基所取代；
R 10b is selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, 5-6 membered heteroaryl, -OR 13 and -C (O) OR 13 , the above group is optionally further selected from one or more groups selected from deuterium, halogen, cyano, C 1-4 alkyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl , C 3-6 cycloalkyl, 3-6 membered heterocyclyl, 5-6 membered heteroaryl, =O, -OR 13 , -C(O)OR 13 and -C(O)R 14 substituents replaced by
其中，R
13和R
14如式(I)化合物中所定义。
Wherein, R 13 and R 14 are as defined in the compound of formula (I).
作为进一步优选的方案，在所述式(I)化合物、其立体异构体或其药学上可接受盐中，Y
1为N，Y
2为CR
10a或N，Y
3为N；或者，Y
1为N，Y
2为CR
10a或N，Y
3为CR
10b；或者，Y
1为CH，Y
2为CR
10a或N，Y
3为N。
As a further preferred scheme, in the compound of formula (I), its stereoisomer or its pharmaceutically acceptable salt, Y 1 is N, Y 2 is CR 10a or N, Y 3 is N; or, Y 1 is N, Y 2 is CR 10a or N, Y 3 is CR 10b ; or, Y 1 is CH, Y 2 is CR 10a or N, Y 3 is N.
作为进一步优选的方案，在所述式(I)化合物、其立体异构体或其药学上可接受盐中，R
10a选自氢、氘、氟、氯、氰基、甲基、乙基、丙基、异丙基、环丙基、环丁基、氧杂环丙基、氮杂环丙基、氧杂环丁基、氮杂环丁基、咪唑基、吡唑基、三唑基、四唑基和-C(O)OR
13，上述基团任选进一步被一个或多个选自氘、氟、氯、氰基、甲基、乙基、丙基、异丙基、一氟甲基、二氟甲基、三氟甲基、一氘甲基、二氘甲基、三氘甲基、环丙基、环丁基、氧杂环丙基、氮杂环丙基、氧杂环丁基和氮杂环丁基的取代基所取代；
As a further preferred scheme, in the compound of formula (I), its stereoisomer or its pharmaceutically acceptable salt, R 10a is selected from hydrogen, deuterium, fluorine, chlorine, cyano, methyl, ethyl, Propyl, isopropyl, cyclopropyl, cyclobutyl, oxiranyl, aziridyl, oxetanyl, azetidinyl, imidazolyl, pyrazolyl, triazolyl, Tetrazolyl and -C(O)OR 13 , the above-mentioned groups are optionally further selected from deuterium, fluorine, chlorine, cyano, methyl, ethyl, propyl, isopropyl, a fluoromethyl radical, difluoromethyl, trifluoromethyl, one-deuteromethyl, dide-deuteromethyl, tri-deuteromethyl, cyclopropyl, cyclobutyl, oxirane, aziridyl, oxetane Substituents of butyl and azetidinyl;
R
10b选自氢、氘、氟、氯、氰基、甲基、乙基、丙基、异丙基、环丙基、环丁基、氧杂环丙基、氮杂环丙基、氧杂环丁基、氮杂环丁基、咪唑基和吡唑基，上述基团任选进一步被一个或多个选自氘、氟、氯、氰基、甲基、乙基、丙基、异丙基、一氟甲基、二氟甲基、三氟甲基、一氘甲基、二氘甲基、三氘甲基、环丙基、环丁基、氧杂环丙基、氮杂环丙基、氧杂环丁基和氮杂环丁基的取代基所取代；
R 10b is selected from hydrogen, deuterium, fluorine, chlorine, cyano, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, oxirane, aziridyl, oxa Cyclobutyl, azetidinyl, imidazolyl and pyrazolyl, the above-mentioned groups are optionally further selected from deuterium, fluorine, chlorine, cyano, methyl, ethyl, propyl, isopropyl fluoromethyl, difluoromethyl, trifluoromethyl, 1-deuteromethyl, dide-deuteromethyl, tri-deuteromethyl, cyclopropyl, cyclobutyl, oxirane, aziridine Substituents of group, oxetanyl and azetidinyl;
R
13选自氢、氘、甲基、乙基、丙基、异丙基、环丙基、环丁基、氧杂环丙基、氮杂环丙基、氧杂环丁基、氮杂环丁基、苯基、咪唑基和吡唑基，上述基团任选进一步被一个或多个选自氘、氟、氯、羟基、氧代、氰基、甲基、乙基、丙基、 异丙基、一氟甲基、二氟甲基、三氟甲基、一氘甲基、二氘甲基、三氘甲基、环丙基、环丁基、氧杂环丙基、氮杂环丙基、氧杂环丁基和氮杂环丁基的取代基所取代。
R is selected from hydrogen, deuterium, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, oxirane, aziridyl , oxetanyl, azacycline Butyl, phenyl, imidazolyl and pyrazolyl, the above-mentioned groups are optionally further selected from deuterium, fluorine, chlorine, hydroxyl, oxo, cyano, methyl, ethyl, propyl, iso Propyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monodeuteromethyl, dideuteriomethyl, trideuteromethyl, cyclopropyl, cyclobutyl, oxirane, azacyclic Substituents of propyl, oxetanyl and azetidinyl.
作为进一步优选的方案，在所述式(I)化合物、其立体异构体或其药学上可接受盐中，R
4选自氢、氘、甲基、乙基、异丙基、环丙基、环丁基、氧杂环丙基、氧杂环丁基、氮杂环丙基和氮杂环丁基，上述基团任选进一步被一个或多个选自氘、氟、C
1-4烷基和C
3-6环烷基的取代基所取代。
As a further preferred scheme, in the compound of formula (I), its stereoisomer or its pharmaceutically acceptable salt, R is selected from hydrogen, deuterium, methyl, ethyl, isopropyl, cyclopropyl , cyclobutyl, oxirandyl, oxetyl, aziridyl and azetidinyl, the above-mentioned groups are optionally further selected from deuterium, fluorine, C 1-4 by one or more Substituents of alkyl and C 3-6 cycloalkyl are substituted.
作为进一步优选的方案，在所述式(I)化合物、其立体异构体或其药学上可接受盐中，R
9a选自氢、氘、氟、甲基、乙基、丙基、异丙基、一氟甲基、二氟甲基、三氟甲基、一氘甲基、二氘甲基和三氘甲基。
As a further preferred scheme, in the compound of formula (I), its stereoisomer or its pharmaceutically acceptable salt, R 9a is selected from hydrogen, deuterium, fluorine, methyl, ethyl, propyl, isopropyl group, monofluoromethyl, difluoromethyl, trifluoromethyl, monodeuteromethyl, dideuteriomethyl and trideuteromethyl.
作为进一步优选的方案，在所述式(I)化合物、其立体异构体或其药学上可接受盐中，R
2和R
3各自独立地选自氢、氘、甲基、乙基和异丙基，或者，R
2和R
3与其直接相连的碳原子一起形成环丙基、环丁基、环戊基或环己基，上述基团任选进一步被一个或多个选自氘、氟、氯、溴、氰基、甲基、乙基、异丙基、三氟甲基、二氟甲基、三氘甲基、二氘甲基、环丙基、环丁基、氧杂环丙基、氧杂环丁基、氮杂环丙基和氮杂环丁基的取代基所取代。
As a further preferred scheme, in the compound of formula (I), its stereoisomer or its pharmaceutically acceptable salt, R2 and R3 are each independently selected from hydrogen , deuterium, methyl, ethyl and iso Propyl, or, R 2 and R 3 form cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl together with the carbon atoms directly connected to them, and the above-mentioned groups are optionally further selected from one or more of deuterium, fluorine, Chlorine, bromine, cyano, methyl, ethyl, isopropyl, trifluoromethyl, difluoromethyl, trideuteromethyl, dideuteriomethyl, cyclopropyl, cyclobutyl, oxirane , Oxetanyl, aziridinyl and azetidinyl substituents.
作为进一步优选的方案，在所述式(I)化合物、其立体异构体或其药学上可接受盐中，R
5选自氢、氘、甲基、乙基、异丙基、三氟甲基、二氟甲基、三氘甲基和二氘甲基；
As a further preferred scheme, in the compound of formula (I), its stereoisomer or its pharmaceutically acceptable salt, R is selected from hydrogen, deuterium, methyl, ethyl, isopropyl, trifluoromethane group, difluoromethyl, trideuteromethyl and dideuteriomethyl;
R
6a选自氢、氘、甲基、乙基、异丙基、三氟甲基、二氟甲基、三氘甲基和二氘甲基；
R is selected from hydrogen, deuterium, methyl, ethyl, isopropyl, trifluoromethyl, difluoromethyl, trideuteromethyl and dideuteriomethyl;
R
6b选自氢、氘、甲基、乙基、异丙基、三氟甲基、二氟甲基、三氘甲基和二氘甲基；
R is selected from hydrogen, deuterium, methyl, ethyl, isopropyl, trifluoromethyl, difluoromethyl, trideuteromethyl and dideuteriomethyl;
R
7和R
8各自独立地选自氢、氘、甲基、三氟甲基、二氟甲基、三氘甲基、二氘甲基、乙基和异丙基，或者，R
7和R
8与其直接相连的氮原子一起形成4-6元杂环基；
R 7 and R 8 are each independently selected from hydrogen, deuterium, methyl, trifluoromethyl, difluoromethyl, trideuteromethyl, dideuteriomethyl, ethyl and isopropyl, or, R 7 and R 8 forms a 4-6 membered heterocyclic group together with the nitrogen atom directly connected to it;
或者，R
6a或R
6b其中之一和R
5与其直接相连的部分一起形成4-6元杂环基，所述4-6元杂环基与其直接相连的部分形成如下结构：
Alternatively, one of R 6a or R 6b and R 5 form a 4-6 membered heterocyclic group together with the part directly connected to it, and the 4-6 membered heterocyclic group forms the following structure with the part directly connected to it:
其中，上述结构中每个R
6a、R
6b、R
7和R
8如前所定义；
Wherein, each of R 6a , R 6b , R 7 and R 8 in the above structure is as defined above;
或者，R
6b和R
7与其直接相连的部分一起形成4-6元杂环基，所述4-6元杂环 基与其直接相连的部分形成如下结构：
其中，上述结构中R
5、R
6a和R
8如前所定义；
Alternatively, R and R together form a 4-6 membered heterocyclic group with its directly connected part, and the 4-6 membered heterocyclic group forms the following structure with its directly connected part: Wherein, R 5 , R 6a and R 8 in the above structure are as defined above;
或者，
为如下结构：
其中R
5和R
8如前所定义。
or, For the following structure: Wherein R 5 and R 8 are as previously defined.
作为进一步优选的方案，在所述式(I)化合物、其立体异构体或其药学上可接受盐中，R
1a选自氢、氘、氟、氯、溴、氰基、甲基、乙基、异丙基、乙炔基、环丙基、环丁基、氧杂环丙基、氧杂环丁基、氮杂环丙基、氮杂环丁基、吡唑基、咪唑基、噁唑基、三氮唑基、四唑基、异噻唑基、异噁唑基、噁二唑基、噁唑基、吡嗪基、哒嗪基、吡啶基、嘧啶基、吡咯基、噻二唑基、噻唑基、噻吩基和三嗪基，上述基团任选进一步被一个或多个选自氘、氟、氯、溴、氰基、甲基、乙基、异丙基、乙烯基、乙炔基、三氟甲基、二氟甲基、三氘甲基、二氘甲基、环丙基、环丁基、氧杂环丙基、氧杂环丁基、氮杂环丙基和氮杂环丁基的取代基所取代；
As a further preferred scheme, in the compound of formula (I), its stereoisomer or its pharmaceutically acceptable salt, R 1a is selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl base, isopropyl, ethynyl, cyclopropyl, cyclobutyl, oxirandyl, oxetyl, aziridyl, azetidinyl, pyrazolyl, imidazolyl, oxazole Base, triazolyl, tetrazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, thiadiazolyl , thiazolyl, thienyl and triazinyl, the above groups are optionally further selected from one or more of deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, isopropyl, vinyl, ethynyl , trifluoromethyl, difluoromethyl, trideuteromethyl, dideuteriomethyl, cyclopropyl, cyclobutyl, oxiranyl, oxetanyl, aziridyl and azacycline Butyl substituents are substituted;
R
1b选自氢、氘、氟、氯、溴、氰基、甲基、乙基、异丙基、乙炔基、环丙基、环丁基、氧杂环丙基、氧杂环丁基、氮杂环丙基、氮杂环丁基、吡唑基、咪唑基、噁唑基和三氮唑基，上述基团任选进一步被一个或多个选自氘、氟、氯、溴、氰基、甲基、乙基、异丙基、乙烯基、乙炔基、三氟甲基、二氟甲基、三氘甲基、二氘甲基、环丙基、环丁基、氧杂环丙基、氧杂环丁基、氮杂环丙基和氮杂环丁基的取代基所取代。
R is selected from hydrogen, deuterium , fluorine, chlorine, bromine, cyano, methyl, ethyl, isopropyl, ethynyl, cyclopropyl, cyclobutyl, oxiranyl, oxetanyl, Aziridyl, azetidinyl, pyrazolyl, imidazolyl, oxazolyl and triazolyl, the above-mentioned groups are optionally further selected from deuterium, fluorine, chlorine, bromine, cyanogen methyl, ethyl, isopropyl, vinyl, ethynyl, trifluoromethyl, difluoromethyl, trideuteromethyl, dideuteriomethyl, cyclopropyl, cyclobutyl, oxirane Substituents of radical, oxetanyl, aziridinyl and azetidinyl.
作为最优选的方案，所述式(I)化合物、其立体异构体或其药学上可接受盐包括但不限于如下化合物：As the most preferred solution, the compound of formula (I), its stereoisomer or its pharmaceutically acceptable salt includes but not limited to the following compounds:
本发明第二方面提供式(I)化合物、其立体异构体或其药学上可接受盐的制备方法，包括如下步骤：The second aspect of the present invention provides a method for preparing a compound of formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof, comprising the following steps:
其中，X
1为卤素，选自氟、氯和溴；X、Y
1、Y
2、Y
3、Z、R
1、R
2、R
3、R
4、R
5、R
6a、R
6b、R
7、R
8、R
9a、R
9b、R
9c和m如式(I)化合物所述。
Wherein, X 1 is halogen, selected from fluorine, chlorine and bromine; X, Y 1 , Y 2 , Y 3 , Z, R 1 , R 2 , R 3 , R 4 , R 5 , R 6a , R 6b , R 7 , R 8 , R 9a , R 9b , R 9c and m are as described for the compound of formula (I).
本发明第三方面提供一种药物组合物，其包括式(I)化合物、其立体异构体或其药学上可接受盐及可药用的载体。The third aspect of the present invention provides a pharmaceutical composition, which comprises the compound of formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
本发明还涉及所述式(I)化合物、其立体异构体或其药学上可接受盐在制备治疗和/或预防至少部分与EGFR外显子20插入、缺失或其他突变相关的癌症、肿 瘤或转移性疾病的药物中的用途。The present invention also relates to the preparation of the compound of formula (I), its stereoisomer or pharmaceutically acceptable salt thereof for the treatment and/or prevention of cancers and tumors at least partially related to EGFR exon 20 insertions, deletions or other mutations or use in medicines for metastatic disease.
本发明还涉及所述式(I)化合物、其立体异构体或其药学上可接受盐在制备治疗和/或预防由过度增殖和诱导细胞死亡障碍引起的肿瘤、癌症和或转移性疾病的药物中的用途。The present invention also relates to the preparation of the compound of formula (I), its stereoisomer or pharmaceutically acceptable salt thereof for the treatment and/or prevention of tumors, cancers and or metastatic diseases caused by excessive proliferation and induction of cell death disorders Uses in medicine.
本发明还涉及所述式(I)化合物、其立体异构体或其药学上可接受盐在制备治疗和/或预防至少部分与EGFR外显子20插入、缺失或其他突变引起的肺癌、结肠癌、胰腺癌、头颈癌、乳腺癌，卵巢癌，子宫癌、胃癌、非小细胞肺癌、白血病、骨髓增生异常综合症、恶性淋巴瘤、头颈部肿瘤、胸腔肿瘤、胃肠道肿瘤、内分泌肿瘤、乳腺和其他妇科肿瘤、泌尿科肿瘤、皮肤肿瘤、肉瘤、鼻腔鼻窦内翻性乳头状瘤或鼻腔鼻窦内翻性乳头状瘤相关的鼻腔鼻窦鳞状细胞癌药物中的用途。The present invention also relates to the preparation of the compound of formula (I), its stereoisomer or pharmaceutically acceptable salt thereof for the treatment and/or prevention of lung cancer, colon Cancer, pancreatic cancer, head and neck cancer, breast cancer, ovarian cancer, uterine cancer, gastric cancer, non-small cell lung cancer, leukemia, myelodysplastic syndrome, malignant lymphoma, head and neck cancer, thoracic tumor, gastrointestinal tumor, endocrine Tumors, breast and other gynecological tumors, urological tumors, skin tumors, sarcoma, sinonasal inverted papilloma or sinonasal squamous cell carcinoma associated with sinonasal inverted papilloma.
本发明还涉及所述式(I)化合物、其立体异构体或其药学上可接受盐，其用作药物。The present invention also relates to said compound of formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof, for use as a medicament.
本发明还涉及所述式(I)化合物、其立体异构体或其药学上可接受盐，其用于治疗和/或预防至少部分与EGFR外显子20插入、缺失或其他突变相关的癌症、肿瘤或转移性疾病的用途。The present invention also relates to the compound of formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof, which is used for treating and/or preventing at least some cancers related to EGFR exon 20 insertion, deletion or other mutations , tumor or metastatic disease.
本发明还涉及所述式(I)化合物、其立体异构体或其药学上可接受盐，其用于治疗和/或预防由过度增殖和诱导细胞死亡障碍引起的肿瘤、癌症和或转移性疾病的用途。The present invention also relates to said compound of formula (I), its stereoisomer or pharmaceutically acceptable salt thereof, for the treatment and/or prevention of tumors, cancers and or metastatic disease use.
本发明还涉及所述式(I)化合物、其立体异构体或其药学上可接受盐，其用于治疗和/或预防至少部分与EGFR外显子20插入、缺失或其他突变引起的肺癌、结肠癌、胰腺癌、头颈癌、乳腺癌，卵巢癌，子宫癌、胃癌、非小细胞肺癌、白血病、骨髓增生异常综合症、恶性淋巴瘤、头颈部肿瘤、胸腔肿瘤、胃肠道肿瘤、内分泌肿瘤、乳腺和其他妇科肿瘤、泌尿科肿瘤、皮肤肿瘤、肉瘤、鼻腔鼻窦内翻性乳头状瘤或鼻腔鼻窦内翻性乳头状瘤相关的鼻腔鼻窦鳞状细胞癌的用途。The present invention also relates to the compound of formula (I), its stereoisomer or pharmaceutically acceptable salt thereof, which is used for treating and/or preventing lung cancer caused by at least part of EGFR exon 20 insertion, deletion or other mutations , colon cancer, pancreatic cancer, head and neck cancer, breast cancer, ovarian cancer, uterine cancer, gastric cancer, non-small cell lung cancer, leukemia, myelodysplastic syndrome, malignant lymphoma, head and neck cancer, chest cavity tumor, gastrointestinal tumor , endocrine tumors, breast and other gynecologic tumors, urologic tumors, skin tumors, sarcomas, sinonasal inverted papilloma, or sinonasal squamous cell carcinoma associated with sinonasal inverted papilloma.
本发明还涉及一种治疗和/或预防至少部分与EGFR外显子20插入、缺失或其他突变相关的癌症、肿瘤或转移性疾病的方法，其包括向所需患者施用治疗有效量的所述式(I)化合物、其立体异构体或其药学上可接受盐。The present invention also relates to a method of treating and/or preventing cancer, tumor or metastatic disease at least partially related to EGFR exon 20 insertion, deletion or other mutations, which comprises administering a therapeutically effective amount of the A compound of formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof.
本发明还涉及一种治疗和/或预防由过度增殖和诱导细胞死亡障碍引起的肿瘤、癌症和或转移性疾病的方法，其包括向所需患者施用治疗有效量的所述式(I)化合物、其立体异构体或其药学上可接受盐。The present invention also relates to a method of treating and/or preventing tumors, cancers and or metastatic diseases caused by hyperproliferative and induced cell death disorders, which comprises administering a therapeutically effective amount of the compound of formula (I) to a patient in need thereof , a stereoisomer thereof or a pharmaceutically acceptable salt thereof.
本发明还涉及一种治疗和/或预防至少部分与EGFR外显子20插入、缺失或其他突变引起的肺癌、结肠癌、胰腺癌、头颈癌、乳腺癌，卵巢癌，子宫癌、胃癌、非小细胞肺癌、白血病、骨髓增生异常综合症、恶性淋巴瘤、头颈部肿瘤、胸腔肿瘤、胃肠道肿瘤、内分泌肿瘤、乳腺和其他妇科肿瘤、泌尿科肿瘤、皮肤肿瘤、肉瘤、鼻腔鼻窦内翻性乳头状瘤或鼻腔鼻窦内翻性乳头状瘤相关的鼻腔鼻 窦鳞状细胞癌的方法，其包括向所需患者施用治疗有效量的所述式(I)化合物、其立体异构体或其药学上可接受盐。The present invention also relates to a method for treating and/or preventing lung cancer, colon cancer, pancreatic cancer, head and neck cancer, breast cancer, ovarian cancer, uterine cancer, gastric cancer, non Small cell lung cancer, leukemia, myelodysplastic syndrome, malignant lymphoma, head and neck tumors, thoracic cavity tumors, gastrointestinal tumors, endocrine tumors, breast and other gynecological tumors, urological tumors, skin tumors, sarcoma, nasal cavity and sinuses A method for sinonasal squamous cell carcinoma associated with inverted papilloma or sinonasal inverted papilloma, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I), a stereoisomer thereof, or Its pharmaceutically acceptable salt.
本申请的发明人经过广泛而深入地研究，首次研发出一种具有式(I)结构的氮杂芳基衍生物衍生物，本发明系列化合物可广泛应用于制备治疗和/或预防至少部分与EGFR外显子20插入、缺失或其他突变相关的癌症、肿瘤或转移性疾病的药物，特别是治疗过度增殖性疾病和诱导细胞死亡障碍疾病的药物，有望开发成新一代EGFR抑制剂。在此基础上，完成了本发明。After extensive and in-depth research, the inventors of the present application have developed for the first time an azaaryl derivative derivative with a structure of formula (I). The series of compounds of the present invention can be widely used in the preparation of therapeutic and/or prophylaxis at least in part with Drugs for cancers, tumors or metastatic diseases related to EGFR exon 20 insertions, deletions or other mutations, especially drugs for the treatment of hyperproliferative diseases and diseases that induce cell death disorders, are expected to be developed into a new generation of EGFR inhibitors. On this basis, the present invention has been accomplished.
详细说明：除非有相反陈述或特别说明，下列用在说明书和权利要求书中的术语具有下述含义。Detailed Description: Unless stated to the contrary or otherwise specified, the following terms used in the specification and claims have the following meanings.
“烷基”指直链或含支链的饱和脂族烃基团，优选包括1至10个(例如1、2、3、4、5、6、7、8、9、10个)或1至6个碳原子或1至4个碳原子的直链烷基和含支链烷基，包括但不限于甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基、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-乙基戊基或其各种支链异构体等。“C
1-10烷基”指包括1至10个碳原子的直链烷基和含支链烷基，“C
1-4烷基”指包括1至4个碳原子的直链烷基和含支链烷基。
"Alkyl" refers to a straight chain or branched saturated aliphatic hydrocarbon group, preferably including 1 to 10 (such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10) or 1 to 10 6 carbon atoms or 1 to 4 carbon atoms straight chain alkyl and branched chain alkyl, including but not limited to 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-di Methylpentyl, 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 or Various branched chain isomers, etc. "C 1-10 alkyl" refers to straight chain alkyl and branched chain alkyl including 1 to 10 carbon atoms, "C 1-4 alkyl" refers to straight chain alkyl and branched chain including 1 to 4 carbon atoms Contains branched chain alkyl groups.
烷基可以是任选取代的或未取代的，当被取代时，取代基优选为一个或多个(优选1、2、3或4个)以下基团，独立地选自氘、卤素、氰基、硝基、叠氮基、C
1-10烷基、C
2-10链烯基、C
2-10链炔基、卤取代C
1-10烷基、氘取代C
1-10烷基、C
3-12环烷基、3-12元杂环基、C
6-10芳基、5-10元杂芳基、＝O、-SF
5、-S(O)
rR
12、-O-R
13、-C(O)OR
13、-C(O)R
14、-O-C(O)R
14、-NR
15R
16、-C(＝NR
15)R
14、-N(R
15)-C(＝NR
16)R
14、-C(O)NR
15R
16和-N(R
15)-C(O)R
14的取代基所取代。
Alkyl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) of the following groups independently selected from deuterium, halogen, cyano Base, nitro, azido, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, halogen substituted C 1-10 alkyl, deuterium substituted C 1-10 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, =O, -SF 5 , -S(O) r R 12 , -OR 13 , -C(O)OR 13 , -C(O)R 14 , -OC(O)R 14 , -NR 15 R 16 , -C(=NR 15 )R 14 , -N(R 15 )-C( =NR 16 )R 14 , -C(O)NR 15 R 16 and -N(R 15 )-C(O)R 14 are substituted.
“环烷基”或“碳环”指饱和或部分不饱和单环或多环环状烃取代基，所述部分不饱和环状烃是指环状烃可以含有一个或多个(优选1、2或3个)双键，但没有一个环具有完全共轭的π电子系统，环烷基分为单环环烷基、多环环烷基，优选包括3至12个(例如3、4、5、6、7、8、9、10、11、12个)或3至8个或3至6个碳原子的环烷基，例如，“C
3-12环烷基”指包括3至12个碳原子的环烷基，“C
3-6环烷基”指包括3至6个碳原子的环烷基，其中：
"Cycloalkyl" or "carbocycle" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, and the partially unsaturated cyclic hydrocarbon means that the cyclic hydrocarbon may contain one or more (preferably 1, 2 or 3) double bonds, but none of the rings has a fully conjugated π-electron system, cycloalkyl is divided into monocyclic cycloalkyl, polycyclic cycloalkyl, preferably including 3 to 12 (such as 3, 4, 5 , 6, 7, 8, 9, 10, 11, 12) or a cycloalkyl group of 3 to 8 or 3 to 6 carbon atoms, for example, "C 3-12 cycloalkyl" refers to a cycloalkyl group comprising 3 to 12 A cycloalkyl group of carbon atoms, "C 3-6 cycloalkyl" refers to a cycloalkyl group comprising 3 to 6 carbon atoms, wherein:
单环环烷基包括但不限于环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基、环庚三烯基、环辛基等。Monocyclic cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, Cyclooctyl et al.
多环环烷基包括螺环、稠环和桥环的环烷基。“螺环烷基”指单环之间共用一个碳原子(称螺原子)的多环基团，这些可以含有一个或多个(优选1、2或3个)双键，但没有一个环具有完全共轭的π电子系统。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，螺环烷基包括但不限于：Multicyclic cycloalkyls include spiro, fused and bridged cycloalkyls. "Spirocycloalkyl" refers to polycyclic groups in which single rings share one carbon atom (called a spiro atom), these may contain one or more (preferably 1, 2 or 3) double bonds, but none of the rings has A fully conjugated π-electron system. According to the number of spiro atoms shared between rings, spirocycloalkyl groups are divided into single spirocycloalkyl, double spirocycloalkyl or polyspirocycloalkyl, spirocycloalkyl includes but not limited to:
“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(优选1、2或3个)双键，但没有一个环具有完全共轭的π电子系统。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，稠环烷基包括但不限于："fused cycloalkyl" means an all-carbon polycyclic group in which each ring of the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more rings may contain one or more (preferably 1, 2 or 3) double bonds, but none of the rings have a fully conjugated π-electron system. According to the number of rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl groups, fused cycloalkyl groups include but are not limited to:
“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，这些可以含有一个或多个(优选1、2或3个)双键，但没有一个环具有完全共轭的π电子系统。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，桥环烷基包括但不限于："Bridged cycloalkyl" means an all-carbon polycyclic group in which any two rings share two carbon atoms not directly attached, these may contain one or more (preferably 1, 2 or 3) double bonds, but none The ring has a fully conjugated π-electron system. According to the number of rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl groups. Bridged cycloalkyl groups include but are not limited to:
所述环烷基环可以稠合于芳基、杂芳基或杂环烷基环上，其中与母体结构连接在一起的环为环烷基，包括但不限于茚满基、四氢萘基、苯并环庚烷基等。The cycloalkyl ring can be fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring attached to the parent structure is a cycloalkyl group, including but not limited to indanyl, tetrahydronaphthyl , Benzocycloheptyl, etc.
环烷基可以是任选取代的或未取代的，当被取代时，取代基优选为一个或多个(优选1、2、3或4个)以下基团，独立地选自氘、卤素、氰基、硝基、叠氮基、C
1-10烷基、C
2-10链烯基、C
2-10链炔基、卤取代C
1-10烷基、氘取代C
1-10烷基、C
3-12环烷基、3-12元杂环基、C
6-10芳基、5-10元杂芳基、＝O、-SF
5、-S(O)
rR
12、-O-R
13、-C(O)OR
13、-C(O)R
14、-O-C(O)R
14、-NR
15R
16、-C(＝NR
15)R
14、-N(R
15)-C(＝NR
16)R
14、-C(O)NR
15R
16和-N(R
15)-C(O)R
14的取代基所取代。
Cycloalkyl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) of the following groups independently selected from deuterium, halogen, Cyano, nitro, azido, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, halogen substituted C 1-10 alkyl, deuterium substituted C 1-10 alkyl , C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, =O, -SF 5 , -S(O) r R 12 , -OR 13 , -C(O)OR 13 , -C(O)R 14 , -OC(O)R 14 , -NR 15 R 16 , -C(=NR 15 )R 14 , -N(R 15 )-C (=NR 16 )R 14 , -C(O)NR 15 R 16 and -N(R 15 )-C(O)R 14 are substituted.
“杂环基”或“杂环”指饱和或部分不饱和单环或多环环状烃取代基，所述部分不饱和环状烃是指环状烃可以含有一个或多个(优选1、2或3个)双键，但没有一个环具有完全共轭的π电子系统，杂环基其中一个或多个(优选1、2、3或4个)环原子选自氮、氧或S(O)
r(其中r是整数0、1、2)的杂原子，但不包括-O-O-、-O-S-或-S-S-的环部分，其余环原子为碳。优选包括3至12个(例如3、4、5、6、7、8、9、10、11、12个)或3至8个或3至6个环原子的杂环基，例如，“3-6元杂环基”指包含3至6个环原子的环基，“4-6元杂环基”指包含4至6个环原子的环基，“4-8元杂环基”指包含4至8个环原子的环基，“4-10元杂环基”指包含4至10个环原子的环基，“3-12元杂环基”指包含3至12个环原子的环基。
"Heterocyclyl" or "heterocycle" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, and the partially unsaturated cyclic hydrocarbon means that the cyclic hydrocarbon can contain one or more (preferably 1, 2 or 3) double bonds, but none of the rings has a fully conjugated π-electron system, heterocyclyl in which one or more (preferably 1, 2, 3 or 4) ring atoms are selected from nitrogen, oxygen or S(O ) r (where r is an integer 0, 1, 2), but excluding the ring portion of -OO-, -OS- or -SS-, the remaining ring atoms being carbon. Heterocyclic groups comprising 3 to 12 (eg 3, 4, 5, 6, 7, 8, 9, 10, 11, 12) or 3 to 8 or 3 to 6 ring atoms are preferred, for example, "3 -6-membered heterocyclic group" refers to a ring group containing 3 to 6 ring atoms, "4-6 membered heterocyclic group" refers to a ring group containing 4 to 6 ring atoms, and "4-8 membered heterocyclic group" refers to A ring group containing 4 to 8 ring atoms, "4-10 membered heterocyclic group" refers to a ring group containing 4 to 10 ring atoms, "3-12 membered heterocyclic group" refers to a ring group containing 3 to 12 ring atoms Ring base.
单环杂环基包括但不限于吡咯烷基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、高哌嗪基、氧杂环丁烷基、四氢呋喃基等。Monocyclic heterocyclyl groups include, but are not limited to, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, oxetanyl, tetrahydrofuranyl, and the like.
多环杂环基包括螺环、稠环和桥环的杂环基。“螺杂环基”指单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(优选1、2、3或4个)环原子选自氮、氧或S(O)
r(其中r是整数0、1、2)的杂原子，其余环原子为碳。这些可以含有一个或多个双键(优选1、2或3个)，但没有一个环具有完全共轭的π电子系统。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。螺杂环基包括但不限于：
Polycyclic heterocyclyls include spiro, fused and bridged heterocyclyls. "Spiroheterocyclyl" refers to a polycyclic heterocyclic group that shares one atom (called a spiro atom) between monocyclic rings, wherein one or more (preferably 1, 2, 3 or 4) ring atoms are selected from nitrogen, oxygen Or a heteroatom of S(O) r (wherein r is an integer 0, 1, 2), and the remaining ring atoms are carbon. These may contain one or more double bonds (preferably 1, 2 or 3), but none of the rings have a fully conjugated pi-electron system. According to the number of spiro atoms shared between the rings, spiroheterocyclyls are classified as single spiroheterocyclyls, double spiroheterocyclyls or polyspiroheterocyclyls. Spiroheterocyclyls include, but are not limited to:
“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(优选1、2、3或4个)环可以含有一个或多个(优选1、2或3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(优选1、2、3或4个)环原子选自氮、氧或S(O)
r(其中r是整数0、1、2)的杂原子，其余环原子为碳。根据组成环的数目可以分为双环、三环、四环或多环稠杂环烷基，稠杂环基包括但不限于：
"Fused heterocyclyl" means a polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system, and one or more (preferably 1, 2, 3 or 4) rings can be Contains one or more (preferably 1, 2 or 3) double bonds, but none of the rings has a fully conjugated π-electron system, where one or more (preferably 1, 2, 3 or 4) ring atoms are selected from Heteroatoms of nitrogen, oxygen or S(O) r (where r is an integer 0, 1, 2) and the remaining ring atoms are carbon. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocycloalkyl groups. The fused heterocyclyl groups include but are not limited to:
“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，这些可以含有一个或多个(优选1、2或3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(优选1、2、3或4个)环原子选自氮、氧或S(O)
r(其中r是整数0、1、2)的杂原子，其余环原子为碳。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，桥杂环基包括但不限于：
"Bridged heterocyclyl" means a polycyclic heterocyclic group in which any two rings share two atoms not directly connected, these may contain one or more (preferably 1, 2 or 3) double bonds, but none of the rings Having a fully conjugated π-electron system in which one or more (preferably 1, 2, 3 or 4) ring atoms are selected from nitrogen, oxygen or S(O) r (where r is an integer 0, 1, 2) heteroatoms, and the remaining ring atoms are carbon. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups. Bridged heterocyclic groups include but are not limited to:
所述杂环基环可以稠合于芳基、杂芳基或环烷基环上，其中与母体结构连接在一起的环为杂环基，包括但不限于：The heterocyclyl ring may be fused to an aryl, heteroaryl, or cycloalkyl ring where the ring attached to the parent structure is a heterocyclyl, including but not limited to:
杂环基可以是任选取代的或未取代的，当被取代时，取代基优选为一个或多个(优选1、2、3或4个)以下基团，独立地选自氘、卤素、氰基、硝基、叠氮基、C
1-10烷基、C
2-10链烯基、C
2-10链炔基、卤取代C
1-10烷基、氘取代C
1-10烷基、C
3-12环烷基、3-12元杂环基、C
6-10芳基、5-10元杂芳基、＝O、-SF
5、-S(O)
rR
12、-O-R
13、-C(O)OR
13、-C(O)R
14、-O-C(O)R
14、-NR
15R
16、-C(＝NR
15)R
14、-N(R
15)-C(＝NR
16)R
14、-C(O)NR
15R
16和-N(R
15)-C(O)R
14所取代。
The heterocyclyl group may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) of the following groups independently selected from deuterium, halogen, Cyano, nitro, azido, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, halogen substituted C 1-10 alkyl, deuterium substituted C 1-10 alkyl , C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, =O, -SF 5 , -S(O) r R 12 , -OR 13 , -C(O)OR 13 , -C(O)R 14 , -OC(O)R 14 , -NR 15 R 16 , -C(=NR 15 )R 14 , -N(R 15 )-C (=NR 16 )R 14 , -C(O)NR 15 R 16 and -N(R 15 )-C(O)R 14 substituted.
“芳基”或“芳环”指全碳单环或稠合多环(也就是共享毗邻碳原子对的环)基团，具有共轭的π电子体系的多环(即其带有相邻对碳原子的环)基团，优选含有6-10个(例如6、7、8、9、10个)或6-8个碳的全碳芳基，例如，“C
6-10芳基”指含有6-10个碳的全碳芳基，包括但不限于苯基和萘基，“C
6-10芳基”指含有6-10个碳的全碳芳基，“C
6-8芳基”指含有6-8个碳的全碳芳基，所述芳基环可以稠合于杂芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为芳基环，包括但不限于：
"Aryl" or "aromatic ring" means an all-carbon monocyclic or fused polycyclic (that is, rings that share adjacent pairs of ring) group of carbon atoms, preferably a full carbon aryl group containing 6-10 (eg 6, 7, 8, 9, 10) or 6-8 carbons, for example, "C 6-10 aryl" Refers to a full-carbon aryl group containing 6-10 carbons, including but not limited to phenyl and naphthyl, "C 6-10 aryl" refers to a full-carbon aryl group containing 6-10 carbons, "C 6-8 aryl "A group" refers to an all-carbon aryl group containing 6-8 carbons, the aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring attached to the parent structure is an aryl group rings, including but not limited to:
“芳基”可以是取代的或未取代的，当被取代时，取代基优选为一个或多个(优选1、2、3或4个)以下基团，独立地选自氘、卤素、氰基、硝基、叠氮基、C
1-10烷基、C
2-10链烯基、C
2-10链炔基、卤取代C
1-10烷基、氘取代C
1-10烷基、C
3-12环烷基、3-12元杂环基、C
6-10芳基、5-10元杂芳基、＝O、-SF
5、-S(O)
rR
12、-O-R
13、-C(O)OR
13、-C(O)R
14、-O-C(O)R
14、-NR
15R
16、-C(＝NR
15)R
14、-N(R
15)-C(＝NR
16)R
14、-C(O)NR
15R
16和-N(R
15)-C(O)R
14的取代基所取代。
"Aryl" may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) of the following groups independently selected from deuterium, halogen, cyano Base, nitro, azido, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, halogen substituted C 1-10 alkyl, deuterium substituted C 1-10 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, =O, -SF 5 , -S(O) r R 12 , -OR 13 , -C(O)OR 13 , -C(O)R 14 , -OC(O)R 14 , -NR 15 R 16 , -C(=NR 15 )R 14 , -N(R 15 )-C( =NR 16 )R 14 , -C(O)NR 15 R 16 and -N(R 15 )-C(O)R 14 are substituted.
“杂芳基”指包含一个或多个(优选1、2、3或4个)杂原子的杂芳族体系，所述杂原子包括氮、氧和S(O)
r(其中r是整数0、1、2)的杂原子，优选含有5-10个(5、6、7、8、9、10个)或5-8个或5-6个环原子的杂芳族体系，例如，“5-8元杂芳基”指含有5-8个环原子的杂芳族体系，“5-10元杂芳基”指含有5-10个环原子的杂芳族体系，包括但不限于呋喃基、噻吩基、吡啶基、吡咯基、N-烷基吡咯基、嘧啶基、吡嗪基、咪唑基、四唑基等。所述杂芳基环可以稠合于芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为杂芳基环，包括但不限于：
"Heteroaryl" means a heteroaromatic system containing one or more (preferably 1, 2, 3 or 4) heteroatoms including nitrogen, oxygen and S(O) r (where r is the integer 0 , 1, 2), preferably heteroaromatic systems containing 5-10 (5, 6, 7, 8, 9, 10) or 5-8 or 5-6 ring atoms, for example, ""5-8 membered heteroaryl" refers to a heteroaromatic system containing 5-8 ring atoms, "5-10 membered heteroaryl" refers to a heteroaromatic system containing 5-10 ring atoms, including but not limited to furan base, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, etc. The heteroaryl ring may be fused to an aryl, heterocyclyl or cycloalkyl ring, where the ring bonded to the parent structure is a heteroaryl ring, including but not limited to:
“杂芳基”可以是任选取代的或未取代的，当被取代时，取代基优选为一个或多个(优选1、2、3或4个)以下基团，独立地选自氘、卤素、氰基、硝基、叠氮基、C
1-10烷基、C
2-10链烯基、C
2-10链炔基、卤取代C
1-10烷基、氘取代C
1-10烷基、C
3-12环烷基、3-12元杂环基、C
6-10芳基、5-10元杂芳基、＝O、-SF
5、-S(O)
rR
12、-O-R
13、-C(O)OR
13、-C(O)R
14、-O-C(O)R
14、-NR
15R
16、-C(＝NR
15)R
14、-N(R
15)-C(＝NR
16)R
14、-C(O)NR
15R
16和-N(R
15)-C(O)R
14的取代基所取代。
"Heteroaryl" may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) of the following groups independently selected from deuterium, Halogen, cyano, nitro, azido, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, halogen substituted C 1-10 alkyl, deuterium substituted C 1-10 Alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-10 aryl, 5-10 membered heteroaryl, =O, -SF 5 , -S(O) r R 12 , -OR 13 , -C(O)OR 13 , -C(O)R 14 , -OC(O)R 14 , -NR 15 R 16 , -C(=NR 15 )R 14 , -N(R 15 ) -C(=NR 16 )R 14 , -C(O)NR 15 R 16 and -N(R 15 )-C(O)R 14 are substituted.
“链烯基”指由至少两个碳原子和至少一个碳-碳双键组成的如上述定义的烷基，优选含有2-10个(例如2、3、4、5、6、7、8、9、10个)或2-4个碳的直链或含支链烯基，例如，“C
2-10链烯基”指含有2-10个碳的直链或含支链烯基，“C
2-4链烯基”指含有2-4个碳的直链或含支链烯基。包括但不限于乙烯基、1-丙烯基、2-丙 烯基、1-，2-或3-丁烯基等。
"Alkenyl" means an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, preferably containing 2-10 (eg 2, 3, 4, 5, 6, 7, 8 , 9, 10) or 2-4 carbon straight-chain or branched-chain alkenyl, for example, "C 2-10 alkenyl" refers to a straight-chain or branched-chain alkenyl containing 2-10 carbons, "C 2-4 alkenyl" refers to a straight chain or branched alkenyl group containing 2 to 4 carbons. Including but not limited to vinyl, 1-propenyl, 2-propenyl, 1-, 2- or 3-butenyl, etc.
“链烯基”可以是取代的或未取代的，当被取代时，取代基优选为一个或多个(优选1、2、3或4个)以下基团，独立地选自氘、卤素、氰基、硝基、叠氮基、C
1-10烷基、C
2-10链烯基、C
2-10链炔基、卤取代C
1-10烷基、氘取代C
1-10烷基、C
3-12环烷基、3-12元杂环基、C
6-10芳基、5-10元杂芳基、＝O、-SF
5、-S(O)
rR
12、-O-R
13、-C(O)OR
13、-C(O)R
14、-O-C(O)R
14、-NR
15R
16、-C(＝NR
15)R
14、-N(R
15)-C(＝NR
16)R
14、-C(O)NR
15R
16和-N(R
15)-C(O)R
14的取代基所取代。
"Alkenyl" may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) of the following groups independently selected from deuterium, halogen, Cyano, nitro, azido, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, halogen substituted C 1-10 alkyl, deuterium substituted C 1-10 alkyl , C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, =O, -SF 5 , -S(O) r R 12 , -OR 13 , -C(O)OR 13 , -C(O)R 14 , -OC(O)R 14 , -NR 15 R 16 , -C(=NR 15 )R 14 , -N(R 15 )-C (=NR 16 )R 14 , -C(O)NR 15 R 16 and -N(R 15 )-C(O)R 14 are substituted.
“链炔基”指至少两个碳原子和至少一个碳-碳三键组成的如上所定义的烷基，优选含有2-10个(例如2、3、4、5、6、7、8、9、10个)或2-4个碳的直链或含支链炔基，例如，“C
2-10链炔基”指含有2-10个碳的直链或含支链炔基，“C
2-4链炔基”指含有2-4个碳的直链或含支链炔基。包括但不限于乙炔基、1-丙炔基、2-丙炔基、1-，2-或3-丁炔基等。
"Alkynyl" means an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon triple bond, preferably containing 2-10 (e.g. 2, 3, 4, 5, 6, 7, 8, 9, 10) or 2-4 carbon straight chain or branched chain alkynyl, for example, "C 2-10 alkynyl" refers to 2-10 carbon straight chain or branched chain alkynyl, " C 2-4 alkynyl"refers to a straight-chain or branched-chain alkynyl group containing 2-4 carbons. Including but not limited to ethynyl, 1-propynyl, 2-propynyl, 1-, 2- or 3-butynyl, etc.
“链炔基”可以是取代的或未取代的，当被取代时，取代基优选为一个或多个(优选1、2、3或4个)以下基团，独立地选自氘、卤素、氰基、硝基、叠氮基、C
1-10烷基、C
2-10链烯基、C
2-10链炔基、卤取代C
1-10烷基、氘取代C
1-10烷基、C
3-12环烷基、3-12元杂环基、C
6-10芳基、5-10元杂芳基、＝O、-SF
5、-S(O)
rR
12、-O-R
13、-C(O)OR
13、-C(O)R
14、-O-C(O)R
14、-NR
15R
16、-C(＝NR
15)R
14、-N(R
15)-C(＝NR
16)R
14、-C(O)NR
15R
16和-N(R
15)-C(O)R
14的取代基所取代。
"Alkynyl" may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) of the following groups independently selected from deuterium, halogen, Cyano, nitro, azido, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, halogen substituted C 1-10 alkyl, deuterium substituted C 1-10 alkyl , C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, =O, -SF 5 , -S(O) r R 12 , -OR 13 , -C(O)OR 13 , -C(O)R 14 , -OC(O)R 14 , -NR 15 R 16 , -C(=NR 15 )R 14 , -N(R 15 )-C (=NR 16 )R 14 , -C(O)NR 15 R 16 and -N(R 15 )-C(O)R 14 are substituted.
“烷氧基”指-O-烷基，其中烷基的定义如上所述，例如，“C
1-10烷氧基”指含1-10个碳的烷基氧基，“C
1-4烷氧基”指含1-4个碳的烷基氧基包括但不限于甲氧基、乙氧基、丙氧基、丁氧基等。
"Alkoxy" refers to -O-alkyl, wherein the definition of alkyl is as above, for example, "C 1-10 alkoxy" refers to an alkyloxy group containing 1-10 carbons, "C 1-4 "Alkoxy" refers to an alkyloxy group containing 1-4 carbons, including but not limited to methoxy, ethoxy, propoxy, butoxy and the like.
“烷氧基”可以是任选取代的或未取代的，当被取代时，取代基，优选为一个或多个(优选1、2、3或4个)以下基团，独立地选自氘、卤素、氰基、硝基、叠氮基、C
1-10烷基、C
2-10链烯基、C
2-10链炔基、卤取代C
1-10烷基、氘取代C
1-10烷基、C
3-12环烷基、3-12元杂环基、C
6-10芳基、5-10元杂芳基、＝O、-SF
5、-S(O)
rR
12、-O-R
13、-C(O)OR
13、-C(O)R
14、-O-C(O)R
14、-NR
15R
16、-C(＝NR
15)R
14、-N(R
15)-C(＝NR
16)R
14、-C(O)NR
15R
16和-N(R
15)-C(O)R
14的取代基所取代。
"Alkoxy" may be optionally substituted or unsubstituted, and when substituted, the substituents, preferably one or more (preferably 1, 2, 3 or 4) of the following groups, are independently selected from deuterium , halogen, cyano, nitro, azido, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, halogen substituted C 1-10 alkyl, deuterium substituted C 1- 10 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, =O, -SF 5 , -S(O) r R 12 , -OR 13 , -C(O)OR 13 , -C(O)R 14 , -OC(O)R 14 , -NR 15 R 16 , -C(=NR 15 )R 14 , -N(R 15 )-C(=NR 16 )R 14 , -C(O)NR 15 R 16 and -N(R 15 )-C(O)R 14 are substituted.
“环烷氧基”或“环烷基氧基”指-O-环烷基，其中环烷基的定义如上所述，例如，“C
3-12环烷氧基”指含3-12个碳的环烷基氧基，“C
3-6环烷氧基”指含3-6个碳的环烷基氧基，包括但不限于环丙氧基、环丁氧基、环戊氧基、环己氧基等。
"Cycloalkoxy" or "cycloalkyloxy" refers to -O-cycloalkyl, wherein the definition of cycloalkyl is as above, for example, "C 3-12 cycloalkoxy" refers to 3-12 Carbon cycloalkyloxy, "C 3-6 cycloalkoxy" refers to cycloalkyloxy containing 3-6 carbons, including but not limited to cyclopropoxy, cyclobutoxy, cyclopentyloxy , Cyclohexyl and so on.
“环烷氧基”或“环烷基氧基”可以是任选取代的或未取代的，当被取代时，取代基优选为一个或多个(优选1、2、3或4个)以下基团，独立地选自氘、卤素、氰基、硝基、叠氮基、C
1-10烷基、C
2-10链烯基、C
2-10链炔基、卤取代C
1-10烷基、氘取代C
1-10烷基、C
3-12环烷基、3-12元杂环基、C
6-10芳基、5-10元杂芳基、＝O、-SF
5、-S(O)
rR
12、-O-R
13、-C(O)OR
13、-C(O)R
14、-O-C(O)R
14、-NR
15R
16、-C(＝NR
15)R
14、-N(R
15)-C(＝NR
16)R
14、-C(O)NR
15R
16和-N(R
15)-C(O)R
14的取代基所取代。
"Cycloalkoxy" or "cycloalkyloxy" may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) or less Groups independently selected from deuterium, halogen, cyano, nitro, azido, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, halogen substituted C 1-10 Alkyl, deuterium substituted C 1-10 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, =O, -SF 5 , -S(O) r R 12 , -OR 13 , -C(O)OR 13 , -C(O)R 14 , -OC(O)R 14 , -NR 15 R 16 , -C(=NR 15 ) Substituents of R 14 , -N(R 15 )-C(=NR 16 )R 14 , -C(O)NR 15 R 16 and -N(R 15 )-C(O)R 14 are substituted.
“杂环氧基”或“杂环基氧基”指-O-杂环基，其中杂环基的定义如上所述，包括但不限于氮杂环丁基氧基、氧杂环丁基氧基、氮杂环戊基氧基、氮、氧杂环己基氧基等。"Heterocyclyloxy" or "heterocyclyloxy" refers to -O-heterocyclyl, where the definition of heterocyclyl is as above, including but not limited to azetidinyloxy, oxetanyloxy radical, azacyclopentyloxy, nitrogen, oxepyloxy, etc.
“杂环氧基”或“杂环基氧基”可以是任选取代的或未取代的，当被取代时，取代基优选为一个或多个(优选1、2、3或4个)以下基团，独立地选自氘、卤素、氰基、硝基、叠氮基、C
1-10烷基、C
2-10链烯基、C
2-10链炔基、卤取代C
1-10烷基、氘取代C
1-10烷基、C
3-12环烷基、3-12元杂环基、C
6-10芳基、5-10元杂芳基、＝O、-SF
5、-S(O)
rR
12、-O-R
13、-C(O)OR
13、-C(O)R
14、-O-C(O)R
14、-NR
15R
16、-C(＝NR
15)R
14、-N(R
15)-C(＝NR
16)R
14、-C(O)NR
15R
16和-N(R
15)-C(O)R
14的取代基所取代。
"Heterocyclyloxy" or "heterocyclyloxy" may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) or less Groups independently selected from deuterium, halogen, cyano, nitro, azido, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, halogen substituted C 1-10 Alkyl, deuterium substituted C 1-10 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, =O, -SF 5 , -S(O) r R 12 , -OR 13 , -C(O)OR 13 , -C(O)R 14 , -OC(O)R 14 , -NR 15 R 16 , -C(=NR 15 ) Substituents of R 14 , -N(R 15 )-C(=NR 16 )R 14 , -C(O)NR 15 R 16 and -N(R 15 )-C(O)R 14 are substituted.
“C
1-10烷酰基”指C
1-10烷基酸去掉羟基后剩下的一价原子团，通常也表示为“C
0-9烷基-C(O)-”，例如，“C
1烷基-C(O)-”是指乙酰基；“C
2烷基-C(O)-”是指丙酰基；“C
3烷基-C(O)-”是指丁酰基或异丁酰基。
"C 1-10 alkanoyl" refers to the monovalent atomic group left after C 1-10 alkanoic acid removes the hydroxyl group, and is usually expressed as "C 0-9 alkyl-C(O)-", for example, "C 1 Alkyl-C(O)-" refers to acetyl; "C 2 alkyl-C(O)-" refers to propionyl; "C 3 alkyl-C(O)-" refers to butyryl or isobutyl Acyl.
“卤取代C
1-10烷基”指烷基上的氢任选的被氟、氯、溴、碘原子取代的1-10个碳烷基团，包括但不限于二氟甲基、二氯甲基、二溴甲基、三氟甲基、三氯甲基、三溴甲基等。
"Halogen substituted C 1-10 alkyl" refers to 1-10 carbon alkyl groups whose hydrogen on the alkyl is optionally substituted by fluorine, chlorine, bromine, iodine atoms, including but not limited to difluoromethyl, dichloro Methyl, dibromomethyl, trifluoromethyl, trichloromethyl, tribromomethyl, etc.
“卤取代C
1-10烷氧基”指烷基上的氢任选的被氟、氯、溴、碘原子取代的1-10个碳烷氧基团。包括但不限于二氟甲氧基、二氯甲氧基、二溴甲氧基、三氟甲氧基、三氯甲氧基、三溴甲氧基等。
"Halogen substituted C 1-10 alkoxy" refers to a 1-10 carbon alkoxy group in which the hydrogen on the alkyl group is optionally replaced by fluorine, chlorine, bromine, or iodine atoms. Including but not limited to difluoromethoxy, dichloromethoxy, dibromomethoxy, trifluoromethoxy, trichloromethoxy, tribromomethoxy and the like.
“氘取代C
1-10烷基”指烷基上的氢任选的被氘原子取代的1-10个碳烷基团。包括但不限于一氘甲基、二氘甲基、三氘甲基等。
"Deuterium-substituted C 1-10 alkyl" refers to a 1-10 carbon alkyl group in which the hydrogen on the alkyl is optionally replaced by a deuterium atom. Including but not limited to mono-deuteromethyl, dide-deuteromethyl, tri-deuteromethyl, etc.
“卤素”指氟、氯、溴或碘。"Halogen" means fluorine, chlorine, bromine or iodine.
“任选”或“任选地”意味着随后所描述地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地场合，也即包括取代的或未取代的两种情形。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 the occasion where the event or circumstance occurs or does not occur, that is, includes two situations of substitution or non-substitution . 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 cases where the heterocycle group is substituted with an alkyl group and cases where the heterocycle group is not substituted with an alkyl group .
“取代的”指基团中的一个或多个“氢原子”彼此独立地被相应数目的取代基取代。不言而喻，取代基仅处在它们的可能的化学位置，符合化学上的价键理论，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键的碳原子(如烯烃)结合时可能是不稳定的。"Substituted" means that one or more "hydrogen atoms" in a group are independently substituted with the corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, consistent with the valence bond theory in chemistry, and a person skilled in the art can determine (by experiment or theory) that it is possible or impossible without undue effort of the replacement. For example, an amino or hydroxyl group with free hydrogen may be unstable when bonded to a carbon atom with an unsaturated bond such as an alkene.
“立体异构体”，其英文名称为stereoisomer，是指由分子中原子在空间上排列方式不同所产生的异构体，它可分为顺反异构体、对映异构体两种，也可分为对映异构体和非对映异构体两大类。由于单键的旋转而引起的立体异构体称为构象异构体(conformational stereo-isomer)，有时也称为旋转异构体(rotamer)。因键长、键角、分子内有双键、有环等原因引起的立体异构体称为构型异构体(configuration stereo-isomer)，构型异构体又分为两类。其中因双键或成环碳原子的单键不能自由 旋转而引起的异构体成为几何异构体(geometric isomer)，也称为顺反异构体(cis-trans isomer)，分为Z、E两种构型。例如：顺-2-丁烯和反-2-丁烯是一对几何异构体，因分子中没有反轴对称性而引起的具有不同旋光性能的立体异构体称为旋光异构体(optical isomer)，分为R、S构型。在本发明中所述“立体异构体”如未特别指明，可理解为包含上述对映异构体、构型异构体和构象异构体中的一种或几种。"Stereoisomer", its English name is stereoisomer, refers to the isomer produced by the different arrangement of atoms in the molecule in space, it can be divided into two kinds of cis-trans isomers and enantiomers, It can also be divided into two categories: enantiomers and diastereomers. Stereoisomers due to the rotation of a single bond are called conformational stereo-isomers, sometimes also called rotamers. Stereoisomers caused by bond length, bond angle, double bonds in the molecule, rings, etc. are called configuration isomers (configuration stereo-isomers), and configuration isomers are divided into two categories. Among them, the isomers caused by double bonds or single bonds of ring-forming carbon atoms cannot freely rotate become geometric isomers (geometric isomers), also known as cis-trans isomers (cis-trans isomers), which are divided into Z, E two configurations. For example: cis-2-butene and trans-2-butene are a pair of geometric isomers, and the stereoisomers with different optical rotation properties caused by the absence of anti-axis symmetry in the molecule are called optical isomers ( optical isomer), divided into R and S configurations. The "stereoisomer" mentioned in the present invention can be understood as including one or more of the above-mentioned enantiomers, configuration isomers and conformational isomers unless otherwise specified.
“药学上可接受盐”在本发明中是指药学上可接受的酸加成盐，包括无机酸盐和有机酸盐，这些盐可通过本专业已知的方法制备。"Pharmaceutically acceptable salt" in the present invention refers to pharmaceutically acceptable acid addition salts, including inorganic acid salts and organic acid salts, which salts can be prepared by methods known in the art.
“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 a physiologically/pharmaceutically acceptable salt or prodrug thereof, and other chemical components, and other components such as a physiologically/pharmaceutically acceptable carrier and excipients. The purpose of the pharmaceutical composition is to promote the administration to the organism, facilitate the absorption of the active ingredient and thus exert biological activity.
下面结合实施例对本发明做进一步详细、完整地说明，但决非限制本发明，本发明也并非仅局限于实施例的内容。The present invention will be described in further detail and completely below in conjunction with the examples, but it is by no means limiting the present invention, and the present invention is not limited only to the content of the examples.
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-400/500核磁仪，测定溶剂为氘代二甲基亚砜(DMSO-d
6)，氘代甲醇(CD
3OD)和氘代氯仿(CDCl
3)，内标为四甲基硅烷(TMS)。
The structures of the compounds of the present invention are determined by nuclear magnetic resonance (NMR) or/and liquid chromatography-mass chromatography (LC-MS). NMR chemical shifts (δ) are given in parts per million (ppm). The determination of NMR is to use Bruker AVANCE-400/500 nuclear magnetic apparatus, and the determination solvent is deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated methanol (CD 3 OD) and deuterated chloroform (CDCl 3 ), internal standard For tetramethylsilane (TMS).
液质联用色谱LC-MS的测定用Agilent 6120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)。Agilent 6120 mass spectrometer was used for the determination of liquid chromatography-mass chromatography LC-MS. The determination of HPLC used Agilent 1200DAD high pressure liquid chromatography (Sunfire C18 150×4.6mm column) and Waters 2695-2996 high pressure liquid chromatography (Gimini C18 150×4.6mm 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。Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates are used for thin-layer chromatography silica gel plates. The specifications used for TLC are 0.15mm-0.20mm, and the specifications used for thin-layer chromatography separation and purification products are 0.4mm-0.5mm. Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.
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 commercially available, or can be synthesized using or following 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 in the present invention are carried out under continuous magnetic stirring, under dry nitrogen or argon atmosphere, the solvent is a dry solvent, and the unit of reaction temperature is Celsius (° C.).
一、中间体的制备1. Preparation of intermediates
中间体A1:7,7-二甲基-5-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)-7H-环戊二烯并[b]吡啶的制备Intermediate A1: 7,7-Dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-7H-cyclopentadiene Preparation of [b]pyridine
第一步：5-((叔-丁基二甲基甲硅烷基)氧基)-7H-环戊二烯并[b]吡啶的合成Step 1: Synthesis of 5-((tert-butyldimethylsilyl)oxy)-7H-cyclopenta[b]pyridine
将6,7-二氢-5H-环戊二烯并[b]吡啶-5-酮(7.5g，56.4mmol)溶于甲苯(100mL)中，然后加入1,8-二氮杂二环[5.4.0]十一碳-7-烯(25.7g，169.2mmol)和叔丁基二甲基氯硅烷(17.1g，112.8mmol)。反应在室温下搅拌2小时。浓缩后柱层析[洗脱剂:石油醚～石油醚/乙酸乙酯(2:1)]得到5-((叔-丁基二甲基甲硅烷基)氧基)-7H-环戊二烯并[b]吡啶(13.9g，产率99.7％)。ESI-MS:248.0[M+H]
+。
6,7-Dihydro-5H-cyclopenta[b]pyridin-5-one (7.5 g, 56.4 mmol) was dissolved in toluene (100 mL), then 1,8-diazabicyclo[ 5.4.0] Undec-7-ene (25.7 g, 169.2 mmol) and tert-butyldimethylsilyl chloride (17.1 g, 112.8 mmol). The reaction was stirred at room temperature for 2 hours. After concentration, column chromatography [eluent: petroleum ether ~ petroleum ether/ethyl acetate (2:1)] gave 5-((tert-butyldimethylsilyl)oxy)-7H-cyclopentadiene Alkeno[b]pyridine (13.9 g, 99.7% yield). ESI-MS: 248.0 [M+H] + .
第二步：5-((叔-丁基二甲基甲硅烷基)氧基)-7,7-二甲基-7H-环戊二烯并[b]吡啶的合成The second step: the synthesis of 5-((tert-butyldimethylsilyl)oxy)-7,7-dimethyl-7H-cyclopentadieno[b]pyridine
将5-((叔-丁基二甲基甲硅烷基)氧基)-7H-环戊二烯并[b]吡啶(13.9g，56.23mmol)溶于四氢呋喃(300mL)中，加入二异丙基氨基锂溶液(84mL，2M的四氢呋喃溶液)，0℃搅拌30分钟后滴加碘甲烷(19.96g，140.5mmol)。反应在0℃搅拌1小时，倒入饱和氯化铵溶液中，用乙酸乙酯萃取(200mL*2)，有机相用水和饱和氯化钠溶液各洗一遍，浓缩后得到5-((叔-丁基二甲基甲硅烷基)氧基)-7,7-二甲基-7H-环戊二烯并[b]吡啶粗品，直接用于下一步。ESI-MS:276.3[M+H]
+。
5-((tert-butyldimethylsilyl)oxy)-7H-cyclopenta[b]pyridine (13.9 g, 56.23 mmol) was dissolved in tetrahydrofuran (300 mL) and diisopropyl Lithium amide solution (84mL, 2M solution in tetrahydrofuran), stirred at 0°C for 30 minutes, and then methyl iodide (19.96g, 140.5mmol) was added dropwise. The reaction was stirred at 0°C for 1 hour, poured into saturated ammonium chloride solution, extracted with ethyl acetate (200mL*2), the organic phase was washed once with water and saturated sodium chloride solution, and concentrated to obtain 5-((tert- The crude butyldimethylsilyl)oxy)-7,7-dimethyl-7H-cyclopenta[b]pyridine was used directly in the next step. ESI-MS: 276.3 [M+H] + .
第三步：7,7-二甲基-6,7-二氢-5H-环戊二烯并[b]吡啶-5-酮的合成The third step: Synthesis of 7,7-dimethyl-6,7-dihydro-5H-cyclopenta[b]pyridin-5-one
将5-((叔-丁基二甲基甲硅烷基)氧基)-7,7-二甲基-7H-环戊二烯并[b]吡啶(上一步粗品)溶于四氢呋喃(100mL)中，加入四丁基氟化铵(56.23mL，1M的四氢呋喃溶液)，反应在室温下搅拌30分钟。浓缩后柱层析[洗脱剂:石油醚～石油醚/乙酸乙酯(2:1)]得到7,7-二甲基-6,7-二氢-5H-环戊二烯并[b]吡啶-5-酮(4.9g,两步产率54％)。ESI-MS:162.3[M+H]
+。
Dissolve 5-((tert-butyldimethylsilyl)oxy)-7,7-dimethyl-7H-cyclopenta[b]pyridine (crude from previous step) in THF (100 mL) In, tetrabutylammonium fluoride (56.23 mL, 1M solution in tetrahydrofuran) was added, and the reaction was stirred at room temperature for 30 minutes. After concentration, column chromatography [eluent: petroleum ether ~ petroleum ether/ethyl acetate (2:1)] gave 7,7-dimethyl-6,7-dihydro-5H-cyclopentadiene[b ] Pyridin-5-one (4.9 g, 54% yield over two steps). ESI-MS: 162.3 [M+H] + .
第四步：7,7-二甲基-7H-环戊二烯并[b]吡啶-5-基三氟甲磺酸的合成Step 4: Synthesis of 7,7-dimethyl-7H-cyclopentadieno[b]pyridin-5-yltrifluoromethanesulfonic acid
将7,7-二甲基-6,7-二氢-5H-环戊二烯并[b]吡啶-5-酮(3.0g，18.6mmol)溶于四氢呋喃(100mL)中，在-78℃加入双三甲基硅基胺基锂(18.5mL，2M的四氢呋喃溶液)，然后滴加N-苯基双(三氟甲烷磺酰)亚胺(10.8g，27.9mmol)的四氢呋喃溶液。倒入饱和氯化铵溶液中，用乙酸乙酯萃取(200mL*2)，有机相用水和饱和氯化钠溶液各洗一遍，浓缩后柱层析[洗脱剂:石油醚～石油醚/乙酸乙酯(4:1)]得到7,7-二甲基-7H-环戊二烯并[b]吡啶-5-基三氟甲磺酸(5.2g，产率95％)。ESI-MS:294.1[M+H]
+。
Dissolve 7,7-dimethyl-6,7-dihydro-5H-cyclopenta[b]pyridin-5-one (3.0g, 18.6mmol) in tetrahydrofuran (100mL) at -78°C Lithium bistrimethylsilylamide (18.5 mL, 2M in tetrahydrofuran) was added, followed by a solution of N-phenylbis(trifluoromethanesulfonyl)imide (10.8 g, 27.9 mmol) in tetrahydrofuran dropwise. Pour into saturated ammonium chloride solution, extract with ethyl acetate (200mL*2), wash the organic phase with water and saturated sodium chloride solution once, concentrate and column chromatography [eluent: petroleum ether ~ petroleum ether/acetic acid Ethyl ester (4:1 )] afforded 7,7-dimethyl-7H-cyclopenta[b]pyridin-5-yltrifluoromethanesulfonic acid (5.2 g, 95% yield). ESI-MS: 294.1 [M+H] + .
第五步：7,7-二甲基-5-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)-7H-环戊二烯并[b]吡啶的合成The fifth step: 7,7-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-7H-cyclopentadiene Synthesis of [b]pyridine
将7,7-二甲基-7H-环戊二烯并[b]吡啶-5-基三氟甲磺酸(1.6g，5.46mmol)溶于二氧六环(20mL)中，加入联硼酸频那醇酯(1.66g，6.55mmol)，醋酸钾(1.6g，16.38mmol)和[1,1'-双(二苯基膦基)二茂铁]二氯化钯(400mg，0.546mmol)。反应在100℃搅拌2小时。浓缩后柱层析[洗脱剂:石油醚～石油醚/乙酸乙酯(3:1)]得到7,7-二甲基-5-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)-7H-环戊二烯并[b]吡啶(1.3g，产率87.8％)。ESI-MS:272.4[M+H]
+。
7,7-Dimethyl-7H-cyclopenta[b]pyridin-5-yltrifluoromethanesulfonic acid (1.6 g, 5.46 mmol) was dissolved in dioxane (20 mL) and diboronic acid was added Pinacol ester (1.66g, 6.55mmol), potassium acetate (1.6g, 16.38mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (400mg, 0.546mmol) . The reaction was stirred at 100°C for 2 hours. After concentration, column chromatography [eluent: petroleum ether ~ petroleum ether/ethyl acetate (3:1)] gave 7,7-dimethyl-5-(4,4,5,5-tetramethyl-1 , 3,2-Dioxaborolan-2-yl)-7H-cyclopenta[b]pyridine (1.3 g, 87.8% yield). ESI-MS: 272.4 [M+H] + .
中间体A2～A27的制备参照中间体A1的合成方法制备得到：Intermediates A2-A27 were prepared according to the synthesis method of intermediate A1:
二、具体实施例化合物的制备Two, the preparation of specific embodiment compound
实施例1：(R)-N-(2-(2-((二甲氨基)甲基)吡咯烷-1-基)-4-甲氧基-5-((4-(2,7,7-三甲基-7H-环戊二烯并[b]吡啶-5-基)嘧啶-2-基)氨基)苯基)丙烯酰胺的制备Example 1: (R)-N-(2-(2-((dimethylamino)methyl)pyrrolidin-1-yl)-4-methoxy-5-((4-(2,7, Preparation of 7-trimethyl-7H-cyclopentadieno[b]pyridin-5-yl)pyrimidin-2-yl)amino)phenyl)acrylamide
第一步：5-(2-氯嘧啶-4-基)-2,7,7-三甲基-7H-环戊二烯并[b]吡啶的合成Step 1: Synthesis of 5-(2-chloropyrimidin-4-yl)-2,7,7-trimethyl-7H-cyclopenta[b]pyridine
将2,7,7-三甲基-5-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)-7H-环戊二烯并[b]吡啶(1.0g，3.5mmol)和2,4-二氯嘧啶(784mg，5.26mmol)溶于1,4-二氧六环/水(15mL/1.5mL)中，加入四(三苯基膦)钯(202mg，0.175mmol)和碳酸铯(2.28g，7.0mmol)。反应在110℃微波反应1小时。浓缩后柱层析[洗脱剂:石油醚～石油醚/乙酸乙酯(4:1)]得到5-(2-氯嘧啶-4-基)-2,7,7-三甲基-7H-环戊二烯并[b]吡啶(0.7g，产率73％)。ESI-MS:272.0[M+H]
+。
2,7,7-trimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-7H-cyclopentadiene [b] Pyridine (1.0g, 3.5mmol) and 2,4-dichloropyrimidine (784mg, 5.26mmol) were dissolved in 1,4-dioxane/water (15mL/1.5mL), tetrakis(triphenyl phosphine)palladium (202mg, 0.175mmol) and cesium carbonate (2.28g, 7.0mmol). The reaction was microwaved at 110°C for 1 hour. After concentration, column chromatography [eluent: petroleum ether ~ petroleum ether/ethyl acetate (4:1)] gave 5-(2-chloropyrimidin-4-yl)-2,7,7-trimethyl-7H - Cyclopenta[b]pyridine (0.7 g, 73% yield). ESI-MS: 272.0 [M+H] + .
第二步：N-(4-氟-2-甲氧基-5-硝基苯基)-4-(2,7,7-三甲基-7H-环戊二烯并[b]吡啶-5-基)嘧啶-2-胺的合成The second step: N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(2,7,7-trimethyl-7H-cyclopentadieno[b]pyridine- Synthesis of 5-yl)pyrimidin-2-amine
将4-氟-2-甲氧基-5-硝基苯胺(575mg，3.09mmol)和5-(2-氯嘧啶-4-基)-2,7,7-三甲基-7H-环戊二烯并[b]吡啶(0.7g，2.57mmol)溶于1,4-二氧六环(30mL)，加入碳酸铯(1.67g，5.14mmol)，1,1'-联萘-2,2'-双二苯膦(240mg，0.385mmol)和醋酸钯(58mg，0.257mmol)。反应在氮气保护下，120℃反应3小时。浓缩后 柱层析[洗脱剂:石油醚～石油醚/乙酸乙酯(2:1)]得到N-(4-氟-2-甲氧基-5-硝基苯基)-4-(2,7,7-三甲基-7H-环戊二烯并[b]吡啶-5-基)嘧啶-2-胺(0.93g，产率88％)。ESI-MS:422.2[M+H]
+。
4-Fluoro-2-methoxy-5-nitroaniline (575 mg, 3.09 mmol) and 5-(2-chloropyrimidin-4-yl)-2,7,7-trimethyl-7H-cyclopentyl Dieno[b]pyridine (0.7 g, 2.57 mmol) was dissolved in 1,4-dioxane (30 mL), cesium carbonate (1.67 g, 5.14 mmol), 1,1'-binaphthyl-2,2 '-Bisdiphenylphosphine (240 mg, 0.385 mmol) and palladium acetate (58 mg, 0.257 mmol). The reaction was carried out at 120° C. for 3 hours under the protection of nitrogen. Column chromatography after concentration [eluent: petroleum ether ~ petroleum ether/ethyl acetate (2:1)] obtains N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-( 2,7,7-Trimethyl-7H-cyclopenta[b]pyridin-5-yl)pyrimidin-2-amine (0.93 g, 88% yield). ESI-MS: 422.2 [M+H] + .
第三步：(R)-N-(4-(2-((二甲氨基)甲基)吡咯烷-1-基)-2-甲氧基-5-硝基苯基)-4-(2,7,7-三甲基-7H-环戊二烯并[b]吡啶-5-基)嘧啶-2-胺的合成The third step: (R)-N-(4-(2-((dimethylamino)methyl)pyrrolidin-1-yl)-2-methoxy-5-nitrophenyl)-4-( Synthesis of 2,7,7-trimethyl-7H-cyclopenta[b]pyridin-5-yl)pyrimidin-2-amine
将N-(4-氟-2-甲氧基-5-硝基苯基)-4-(2,7,7-三甲基-7H-环戊二烯并[b]吡啶-5-基)嘧啶-2-胺(105mg，0.25mmol)溶于1,4-二氧六环(15mL)中，加入(R)-N,N-二甲基-1-(吡咯烷-2-基)甲胺(43mg，0.335mmol)和N,N-二异丙基乙胺(2mL)反应在120℃搅拌过夜。浓缩后柱层析[洗脱剂:乙酸乙酯～乙酸乙酯/甲醇(4:1)]得到(R)-N-(4-(2-((二甲氨基)甲基)吡咯烷-1-基)-2-甲氧基-5-硝基苯基)-4-(2,7,7-三甲基-7H-环戊二烯并[b]吡啶-5-基)嘧啶-2-胺(105mg，产率76.4％)。ESI-MS:530.2[M+H]
+。
N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(2,7,7-trimethyl-7H-cyclopentadien[b]pyridin-5-yl ) pyrimidin-2-amine (105mg, 0.25mmol) was dissolved in 1,4-dioxane (15mL), and (R)-N,N-dimethyl-1-(pyrrolidin-2-yl) was added The reaction of methylamine (43mg, 0.335mmol) and N,N-diisopropylethylamine (2mL) was stirred overnight at 120°C. After concentration, column chromatography [eluent: ethyl acetate to ethyl acetate/methanol (4:1)] gave (R)-N-(4-(2-((dimethylamino)methyl)pyrrolidine- 1-yl)-2-methoxy-5-nitrophenyl)-4-(2,7,7-trimethyl-7H-cyclopentadien[b]pyridin-5-yl)pyrimidine- 2-Amine (105 mg, 76.4% yield). ESI-MS: 530.2 [M+H] + .
第四步：(R)-4-(2-((二甲氨基)甲基)吡咯烷-1-基)-6-甲氧基-N
1-(4-(2,7,7-三甲基-7H-环戊二烯并[b]吡啶-5-基)嘧啶-2-基)苯-1,3-二胺的合成
The fourth step: (R)-4-(2-((dimethylamino)methyl)pyrrolidin-1-yl)-6-methoxy-N 1 -(4-(2,7,7-tri Synthesis of Methyl-7H-cyclopentadieno[b]pyridin-5-yl)pyrimidin-2-yl)benzene-1,3-diamine
将(R)-N-(4-(2-((二甲氨基)甲基)吡咯烷-1-基)-2-甲氧基-5-硝基苯基)-4-(2,7,7-三甲基-7H-环戊二烯并[b]吡啶-5-基)嘧啶-2-胺(105mg，0.198mmol)溶于乙腈/水(5mL/5mL)中，加入铁粉(110mg，1.98mmol)和氯化铵(106mg，1.98mmol)，反应在75℃搅拌2小时，倒入水中，用二氯甲烷萃取(20mL*2)，有机相用水和饱和氯化钠溶液各洗一遍，浓缩后得到(R)-4-(2-((二甲氨基)甲基)吡咯烷-1-基)-6-甲氧基-N
1-(4-(2,7,7-三甲基-7H-环戊二烯并[b]吡啶-5-基)嘧啶-2-基)苯-1,3-二胺粗品，直接用于下一步。ESI-MS:500.2[M+H]
+。
(R)-N-(4-(2-((Dimethylamino)methyl)pyrrolidin-1-yl)-2-methoxy-5-nitrophenyl)-4-(2,7 , 7-trimethyl-7H-cyclopenta[b]pyridin-5-yl)pyrimidin-2-amine (105mg, 0.198mmol) was dissolved in acetonitrile/water (5mL/5mL) and iron powder ( 110mg, 1.98mmol) and ammonium chloride (106mg, 1.98mmol), the reaction was stirred at 75°C for 2 hours, poured into water, extracted with dichloromethane (20mL*2), and the organic phase was washed with water and saturated sodium chloride solution Once, after concentration, (R)-4-(2-((dimethylamino)methyl)pyrrolidin-1-yl)-6-methoxy-N 1 -(4-(2,7,7- The crude trimethyl-7H-cyclopenta[b]pyridin-5-yl)pyrimidin-2-yl)benzene-1,3-diamine was used directly in the next step. ESI-MS: 500.2 [M+H] + .
第五步：(R)-N-(2-(2-((二甲氨基)甲基)吡咯烷-1-基)-4-甲氧基-5-((4-(2,7,7-三甲基-7H-环戊二烯并[b]吡啶-5-基)嘧啶-2-基)氨基)苯基)丙烯酰胺的合成The fifth step: (R)-N-(2-(2-((dimethylamino)methyl)pyrrolidin-1-yl)-4-methoxy-5-((4-(2,7, Synthesis of 7-trimethyl-7H-cyclopentadieno[b]pyridin-5-yl)pyrimidin-2-yl)amino)phenyl)acrylamide
将(R)-4-(2-((二甲氨基)甲基)吡咯烷-1-基)-6-甲氧基-N
1-(4-(2,7,7-三甲基-7H-环戊二烯并[b]吡啶-5-基)嘧啶-2-基)苯-1,3-二胺(上一步粗品)溶于甲醇/水(5mL/5mL)中，加入N,N-二异丙基乙胺(0.5mL)和丙烯酰氯(40mg，0.438mmol)，反应在0℃搅拌10分钟，倒入水中，用二氯甲烷萃取(20mL*2)，有机相用水和饱和氯化钠溶液各洗一遍，浓缩后反相碱性制备得到(R)-N-(2-(2-((二甲氨基)甲基)吡咯烷-1-基)-4-甲氧基-5-((4-(2,7,7-三甲基-7H-环戊二烯并[b]吡啶-5-基)嘧啶-2-基)氨基)苯基)丙烯酰胺(15.2mg，产率18.04％)。ESI-MS:554.2[M+H]
+。
(R)-4-(2-((Dimethylamino)methyl)pyrrolidin-1-yl)-6-methoxy-N 1 -(4-(2,7,7-trimethyl- 7H-cyclopentadien[b]pyridin-5-yl)pyrimidin-2-yl)benzene-1,3-diamine (crude product from previous step) was dissolved in methanol/water (5mL/5mL), added N, N-Diisopropylethylamine (0.5mL) and acryloyl chloride (40mg, 0.438mmol), the reaction was stirred at 0°C for 10 minutes, poured into water, extracted with dichloromethane (20mL*2), the organic phase was saturated with water and The sodium chloride solution was washed once, concentrated and reversed-phase alkaline preparation to obtain (R)-N-(2-(2-((dimethylamino)methyl)pyrrolidin-1-yl)-4-methoxy -5-((4-(2,7,7-trimethyl-7H-cyclopentadien[b]pyridin-5-yl)pyrimidin-2-yl)amino)phenyl)acrylamide (15.2mg , yield 18.04%). ESI-MS: 554.2 [M+H] + .
1H NMR(400MHz,DMSO-d
6)δ9.48(s,1H),8.41(d,J＝5.2Hz,1H),8.29(d,J＝12.2Hz,2H),8.23(s,1H),7.49(s,1H),7.24(d,J＝5.1Hz,1H),7.02(d,J＝7.9Hz,1H),6.80(s,1H),6.56(dd,J＝17.0,10.2Hz,1H),6.23–6.13(m,1H),5.70(dd,J＝10.1,2.1Hz,1H),3.79(s,3H),3.68(t,J＝6.6Hz,1H),3.42(q,J＝7.4Hz,1H),2.95(q,J＝7.7Hz,1H),2.49(s,3H),2.28(dd,J＝12.1,4.7Hz,1H),2.22–2.15(m,1H),2.13(s,6H),2.10–2.05(m,1H),1.90(q,J＝8.9,7.5Hz,2H),1.69(dd,J＝13.0,6.4Hz,1H),1.32(s,6H)。
1 H NMR (400MHz,DMSO-d 6 )δ9.48(s,1H),8.41(d,J=5.2Hz,1H),8.29(d,J=12.2Hz,2H),8.23(s,1H) ,7.49(s,1H),7.24(d,J=5.1Hz,1H),7.02(d,J=7.9Hz,1H),6.80(s,1H),6.56(dd,J=17.0,10.2Hz, 1H),6.23–6.13(m,1H),5.70(dd,J＝10.1,2.1Hz,1H),3.79(s,3H),3.68(t,J＝6.6Hz,1H),3.42(q,J =7.4Hz,1H),2.95(q,J=7.7Hz,1H),2.49(s,3H),2.28(dd,J=12.1,4.7Hz,1H),2.22–2.15(m,1H),2.13 (s, 6H), 2.10–2.05 (m, 1H), 1.90 (q, J=8.9, 7.5Hz, 2H), 1.69 (dd, J=13.0, 6.4Hz, 1H), 1.32 (s, 6H).
实施例2～63可参照实施例1全部或部分合成方法选择相应的原料进行制备:Embodiment 2～63 can be prepared with reference to all or part of the synthetic method of embodiment 1 and select corresponding raw materials:
上述实施例制备得到的化合物核磁数据如下：The NMR data of the compound prepared in the foregoing examples are as follows:
生物学测试评价Biology Test Evaluation
(细胞增殖实验)(cell proliferation assay)
(一)试剂和耗材(1) Reagents and consumables
胎牛血清FBS(GBICO,Cat#10099-141)；Fetal bovine serum FBS (GBICO, Cat#10099-141);
黑色透明平底96孔板，(
Cat#3603)。
Black transparent flat-bottom 96-well plate, ( Cat #3603).
(二)仪器(2) Instruments
SpectraMax多标记微孔板检测仪MD,2104-0010A；SpectraMax multi-label microplate detector MD, 2104-0010A;
二氧化碳培养箱，Thermo Scientific 3100系列；Carbon dioxide incubator, Thermo Scientific 3100 series;
生物安全柜，Thermo Scientific，1300系列A2型；Biological safety cabinet, Thermo Scientific, 1300 series A2 type;
倒置显微镜，Olympus,CKX41SF；Inverted microscope, Olympus, CKX41SF;
西门子冰箱KK25E76TI。Siemens refrigerator KK25E76TI.
(三)细胞系和培养条件(3) Cell lines and culture conditions
(四)实验步骤(4) Experimental steps
1、细胞培养和接种：1. Cell culture and inoculation:
(1)收获处于对数生长期的细胞，并使用血小板计数器对细胞进行计数。通过锥虫蓝排除法检测细胞活力，以确保细胞活力在90％以上。(1) Harvest the cells in the logarithmic growth phase, and count the cells using a platelet counter. Cell viability was tested by trypan blue exclusion to ensure that the cell viability was above 90%.
(2)调整细胞浓度以达到最终密度；将90μL细胞悬液添加到96孔板中。(2) Adjust the cell concentration to achieve the final density; add 90 μL of the cell suspension to the 96-well plate.
(3)将细胞在96孔板中于37℃，5％CO
2和95％湿度下孵育过夜。
(3) Incubate the cells overnight in a 96-well plate at 37°C, 5% CO 2 and 95% humidity.
2、T0基准数据：2. T0 benchmark data:
(1)在装有细胞的T0平板的每个孔中加入10μL PBS。(1) Add 10 μL of PBS to each well of the T0 plate containing cells.
(2)解冻CTG试剂，并将细胞板平衡至室温30分钟。(2) Thaw the CTG reagent and equilibrate the cell plate to room temperature for 30 minutes.
(3)向每个孔中添加等体积的CTG溶液。(3) Add an equal volume of CTG solution to each well.
(4)在定轨振荡器上振动5分钟以裂解细胞。(4) Shake on an orbital shaker for 5 minutes to lyse the cells.
(5)将细胞板在室温下放置20分钟以稳定发光信号。(5) Place the cell plate at room temperature for 20 minutes to stabilize the luminescent signal.
(6)读取T0发光信号值。(6) Read the T0 luminous signal value.
3、化合物稀释和添加3. Compound dilution and addition
(1)根据化合物信息表，将相应体积的DMSO加入相应的化合物粉末中，以制备10mM储备液。(1) Add the corresponding volume of DMSO to the corresponding compound powder according to the compound information sheet to prepare a 10 mM stock solution.
(2)准备1000倍，3.16倍稀释的化合物溶液。(2) Prepare compound solutions diluted 1000 times and 3.16 times.
(3)用PBS将1000×稀释的化合物溶液稀释100倍，以制备10倍的化合物溶液，最高浓度为10μM，9种浓度，稀释3.16倍，在接种有96孔板的每个孔中加入10μL药物溶液，接种细胞。每个化合物的浓度设置三个重复孔，DMSO的最终浓度为0.1％。(3) Dilute the 1000× diluted compound solution 100 times with PBS to prepare a 10-fold compound solution, the highest concentration is 10 μM, 9 concentrations, diluted 3.16 times, and 10 μL was added to each well of a 96-well plate Drug solution, inoculated cells. Three replicate wells were set for each compound concentration, and the final concentration of DMSO was 0.1%.
(4)将细胞置于装有药物的96孔板中，温度为37℃，5％CO
2和95％湿度，继续培养72小时，然后进行CTG分析。
(4) The cells were placed in a 96-well plate filled with drugs at a temperature of 37° C., 5% CO 2 and 95% humidity, and continued to culture for 72 hours, and then CTG analysis was performed.
4、发光信号读取4. Read the luminescent signal
(1)解冻CTG试剂，并将细胞板平衡至室温30分钟。(1) Thaw the CTG reagent and equilibrate the cell plate to room temperature for 30 minutes.
(2)向每个孔中添加等体积的CTG溶液。(2) Add an equal volume of CTG solution to each well.
(3)在定轨振荡器上振动5分钟以裂解细胞。(3) Shake on an orbital shaker for 5 minutes to lyse the cells.
(4)将细胞板在室温放置20分钟以稳定发光信号。(4) Place the cell plate at room temperature for 20 minutes to stabilize the luminescent signal.
(5)读取发光值。(5) Read the luminescence value.
5、数据处理5. Data processing
使用GraphPad Prism 7.0软件分析数据，并使用非线性S曲线回归拟合数据以获得剂量效应曲线，并据此计算IC
50值(单位：nM)，具体实验结果见表1：
The data was analyzed using GraphPad Prism 7.0 software, and the data was fitted using nonlinear S-curve regression to obtain a dose-effect curve, and the IC50 value (unit: nM) was calculated accordingly. The specific experimental results are shown in Table 1:
细胞存活率(％)＝(Lum试验药物-Lum培养液对照)/(Lum细胞对照-Lum培养液对照)×100％。Cell survival rate (%)=(Lum test drug-Lum culture solution control)/(Lum cell control-Lum culture solution control)×100%.
表1：生物学测试结果Table 1: Biological Test Results
从具体实施例化合物生物活性数据来看，本发明系列化合物在细胞水平上对EGFR外显子20插入、缺失或其它突变具有很强的抑制作用，且对EGFR WT的选择性达到10倍以上，相对于阳性化合物不足5倍的选择性，本发明系列化合物获得的选择性更高，具有更好的开发前景。From the biological activity data of the compounds in the specific examples, the series of compounds of the present invention have a strong inhibitory effect on EGFR exon 20 insertion, deletion or other mutations at the cellular level, and the selectivity to EGFR WT is more than 10 times, Compared with the less than 5-fold selectivity of positive compounds, the series of compounds of the present invention have higher selectivity and better development prospects.
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述公开内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。All documents mentioned in this application are incorporated by reference in this application as if each were individually incorporated by reference. In addition, it should be understood that after reading the above disclosure of the present invention, those skilled in the art may make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the appended claims of the present application.
Claims (19)
- 式(I)化合物、其立体异构体或其药学上可接受盐：Compound of formula (I), its stereoisomer or pharmaceutically acceptable salt thereof:
其中，X为CH或N；Y 1、Y 2和Y 3各自独立地为CR 10或N，条件是Y 1、Y 2和Y 3中至少1个为N；Z为CR 11或N； wherein, X is CH or N; Y 1 , Y 2 and Y 3 are each independently CR 10 or N, provided that at least one of Y 1 , Y 2 and Y 3 is N; Z is CR 11 or N;每个R 1各自独立地选自氢、氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、C 3-12环烷基、3-12元杂环基、C 6-10芳基、5-10元杂芳基、-SF 5、-S(O) rR 12、-O-R 13、-C(O)OR 13、-C(O)R 14、-O-C(O)R 14、-NR 15R 16、-C(＝NR 15)R 14、-N(R 15)-C(＝NR 16)R 14、-C(O)NR 15R 16和-N(R 15)-C(O)R 14，或者，当m≥2时，任意两个R 1与其直接相连的部分一起形成C 3-12环烷基或3-12元杂环基，上述基团任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、卤取代C 1-10烷基、氘取代C 1-10烷基、C 3-12环烷基、3-12元杂环基、C 6-10芳基、5-10元杂芳基、＝O、-SF 5、-S(O) rR 12、-O-R 13、-C(O)OR 13、-C(O)R 14、-O-C(O)R 14、-NR 15R 16、-C(＝NR 15)R 14、-N(R 15)-C(＝NR 16)R 14、-C(O)NR 15R 16和-N(R 15)-C(O)R 14的取代基所取代； Each R 1 is independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3 -12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, -SF 5 , -S(O) r R 12 , -OR 13 , -C(O )OR 13 , -C(O)R 14 , -OC(O)R 14 , -NR 15 R 16 , -C(=NR 15 )R 14 , -N(R 15 )-C(=NR 16 )R 14. -C(O)NR 15 R 16 and -N(R 15 )-C(O)R 14 , or, when m≥2, any two R 1 and their directly connected parts together form C 3-12 Cycloalkyl or 3-12 membered heterocyclic group, the above group is optionally further replaced by one or more selected from deuterium, halogen, cyano, nitro, azido, C 1-10 alkyl, C 2-10 Alkenyl, C 2-10 alkynyl, halogen substituted C 1-10 alkyl, deuterium substituted C 1-10 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 Aryl, 5-10 membered heteroaryl, =O, -SF 5 , -S(O) r R 12 , -OR 13 , -C(O)OR 13 , -C(O)R 14 , -OC( O)R 14 , -NR 15 R 16 , -C(=NR 15 )R 14 , -N(R 15 )-C(=NR 16 )R 14 , -C(O)NR 15 R 16 and -N( R 15 )-C(O)R 14 is substituted by a substituent;R 2和R 3各自独立地选自氢、氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、C 3-12环烷基、3-12元杂环基、C 6-10芳基和5-10元杂芳基，或者，R 2和R 3与其直接相连的碳原子一起形成羰基、C 3-6环烷基或3-6元杂环基，上述基团任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、卤取代C 1-10烷基、氘取代C 1-10烷基、C 3-12环烷基、3-12元杂环基、C 6-10芳基、5-10元杂芳基、＝O、-SF 5、-S(O) rR 12、-O-R 13、-C(O)OR 13、-C(O)R 14、-O-C(O)R 14、-NR 15R 16、-C(＝NR 15)R 14、-N(R 15)-C(＝NR 16)R 14、-C(O)NR 15R 16和-N(R 15)-C(O)R 14的取代基所取代； R 2 and R 3 are each independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-10 aryl and 5-10 membered heteroaryl, or, R 2 and R 3 form carbonyl together with the carbon atom directly connected to it, C 3- 6 cycloalkyl groups or 3-6 membered heterocyclic groups, the above groups are optionally further replaced by one or more selected from deuterium, halogen, cyano, nitro, azido, C 1-10 alkyl, C 2- 10 alkenyl, C 2-10 alkynyl, halogen substituted C 1-10 alkyl, deuterium substituted C 1-10 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6- 10 aryl, 5-10 membered heteroaryl, =O, -SF 5 , -S(O) r R 12 , -OR 13 , -C(O)OR 13 , -C(O)R 14 , -OC (O)R 14 , -NR 15 R 16 , -C(=NR 15 )R 14 , -N(R 15 )-C(=NR 16 )R 14 , -C(O)NR 15 R 16 and -N (R 15 )-C(O)R 14 is substituted by a substituent;R 4选自氢、氘、C 1-10烷基、C 2-10链烯基、C 3-12环烷基、3-12元杂环基、C 6-10芳基和5-10元杂芳基，上述基团任选进一步被一个或多个选自氘、卤素、羟基、＝O、氰基、C 1-10烷基、C 1-10烷氧基、C 3-12环烷基、C 3-12环烷氧基、3-12元杂环基、3-12元杂环氧基、C 6-10芳基、C 6-10芳氧基、5-10元杂芳基、5-10元杂芳氧基和-NR 15R 16的取代基所取代； R 4 is selected from hydrogen, deuterium, C 1-10 alkyl, C 2-10 alkenyl, C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-10 aryl and 5-10 membered Heteroaryl, the above groups are optionally further replaced by one or more selected from deuterium, halogen, hydroxyl, =O, cyano, C 1-10 alkyl, C 1-10 alkoxy, C 3-12 cycloalkane Group, C 3-12 cycloalkoxy group, 3-12 membered heterocyclic group, 3-12 membered heterocyclic epoxy group, C 6-10 aryl group, C 6-10 aryloxy group, 5-10 membered heteroaryl group , 5-10 membered heteroaryloxy and -NR 15 R 16 substituents;R 5选自氢、氘、羟基、C 1-10烷基、卤取代C 1-10烷基、氘取代C 1-10烷基、C 2-4链烯基、C 3-6环烷基和3-6元杂环基； R is selected from hydrogen, deuterium , hydroxyl, C 1-10 alkyl, halogen substituted C 1-10 alkyl, deuterium substituted C 1-10 alkyl, C 2-4 alkenyl, C 3-6 cycloalkyl and 3-6 membered heterocyclyl;R 6a选自氢、氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、卤取代C 1-10烷基、氘取代C 1-10烷基、C 2-10链烯基、C 2-10链炔基、C 3-12环烷基、3-12元杂环基、C 6-10芳基、5-10元杂芳基、-SF 5、-S(O) rR 12、-O-R 13、-C(O)OR 13、-C(O)R 14、-O-C(O)R 14、-NR 15R 16、-C(＝NR 15)R 14、-N(R 15)-C(＝NR 16)R 14、-C(O)NR 15R 16和-N(R 15)-C(O)R 14； R 6a is selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-10 alkyl, halogen substituted C 1-10 alkyl, deuterium substituted C 1-10 alkyl, C 2-10 chain Alkenyl, C 2-10 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, -SF 5 , -S(O ) r R 12 , -OR 13 , -C(O)OR 13 , -C(O)R 14 , -OC(O)R 14 , -NR 15 R 16 , -C(=NR 15 )R 14 , - N(R 15 )-C(=NR 16 )R 14 , -C(O)NR 15 R 16 and -N(R 15 )-C(O)R 14 ;R 6b选自氢、氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、卤取代C 1-10烷基、氘取代C 1-10烷基、C 2-10链烯基、C 2-10链炔基、C 3-12环烷基、3-12元杂环基、C 6-10芳基、5-10元杂芳基、-SF 5、-S(O) rR 12、-O-R 13、-C(O)OR 13、-C(O)R 14、-O-C(O)R 14、-NR 15R 16、-C(＝NR 15)R 14、-N(R 15)-C(＝NR 16)R 14、-C(O)NR 15R 16和-N(R 15)-C(O)R 14； R 6b is selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-10 alkyl, halogen substituted C 1-10 alkyl, deuterium substituted C 1-10 alkyl, C 2-10 chain Alkenyl, C 2-10 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, -SF 5 , -S(O ) r R 12 , -OR 13 , -C(O)OR 13 , -C(O)R 14 , -OC(O)R 14 , -NR 15 R 16 , -C(=NR 15 )R 14 , - N(R 15 )-C(=NR 16 )R 14 , -C(O)NR 15 R 16 and -N(R 15 )-C(O)R 14 ;R 7和R 8各自独立地选自氢、氘、羟基、C 1-10烷基、C 2-4链烯基、C 3-6环烷基和3-6元杂环基，或者，R 7和R 8与其直接相连的氮原子一起形成3-12元杂环基，上述基团任选进一步被一个或多个选自氘、卤素、羟基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、卤取代C 1-10烷基、氘取代C 1-10烷基、C 1-10烷氧基、C 3-12环烷基、C 3-12环烷氧基、3-12元杂环基、3-12元杂环氧基、C 6-10芳基、C 6-10芳氧基、5-10元杂芳基、5-10元杂芳氧基和-NR 15R 16的取代基所取代； R 7 and R 8 are each independently selected from hydrogen, deuterium, hydroxyl, C 1-10 alkyl, C 2-4 alkenyl, C 3-6 cycloalkyl and 3-6 membered heterocyclyl, or, R 7 and R 8 form a 3-12-membered heterocyclic group together with the nitrogen atom directly connected to it, and the above-mentioned group is optionally further replaced by one or more selected from deuterium, halogen, hydroxyl, C 1-10 alkyl, C 2-10 Alkenyl, C 2-10 alkynyl, halogen substituted C 1-10 alkyl, deuterium substituted C 1-10 alkyl, C 1-10 alkoxy, C 3-12 cycloalkyl, C 3-12 Cycloalkoxy, 3-12 membered heterocyclic group, 3-12 membered heterocyclic oxy group, C 6-10 aryl group, C 6-10 aryloxy group, 5-10 membered heteroaryl group, 5-10 membered heterocyclic group Substituents of aryloxy and -NR 15 R 16 ;或者，R 6a或R 6b其中之一和R 5与其直接相连的部分一起形成4-6元杂环基，R 6a或R 6b其中另一个如前所定义，上述4-6元杂环基任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、卤取代C 1-10烷基、氘取代C 1-10烷基、C 2-10链烯基、C 2-10链炔基、C 3-12环烷基、3-12元杂环基、C 6-10芳基、5-10元杂芳基、＝O、-SF 5、-S(O) rR 12、-O-R 13、-C(O)OR 13、-C(O)R 14、-O-C(O)R 14、-NR 15R 16、-C(＝NR 15)R 14、-N(R 15)-C(＝NR 16)R 14、-C(O)NR 15R 16和-N(R 15)-C(O)R 14的取代基所取代； Alternatively, one of R 6a or R 6b and R 5 together with the part directly connected to it form a 4-6 membered heterocyclic group, the other of R 6a or R 6b is as defined above, any of the above 4-6 membered heterocyclic groups One or more selected from deuterium, halogen, cyano, nitro, azido, C 1-10 alkyl, halogen substituted C 1-10 alkyl, deuterium substituted C 1-10 alkyl, C 2 -10 alkenyl, C 2-10 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, =O, -SF 5. -S(O) r R 12 , -OR 13 , -C(O)OR 13 , -C(O)R 14 , -OC(O)R 14 , -NR 15 R 16 , -C(=NR 15 ) Substituents of R 14 , -N(R 15 )-C(=NR 16 )R 14 , -C(O)NR 15 R 16 and -N(R 15 )-C(O)R 14 ;或者，R 6b和R 7与其直接相连的部分一起形成4-6元杂环基，上述4-6元杂环基任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、卤取代C 1-10烷基、氘取代C 1-10烷基、C 2-10链烯基、C 2-10链炔基、C 3-12环烷基、3-12元杂环基、C 6-10芳基、5-10元杂芳基、＝O、-SF 5、-S(O) rR 12、-O-R 13、-C(O)OR 13、-C(O)R 14、-O-C(O)R 14、-NR 15R 16、-C(＝NR 15)R 14、-N(R 15)-C(＝NR 16)R 14、-C(O)NR 15R 16和-N(R 15)-C(O)R 14的取代基所取代； Alternatively, R 6b and R 7 form a 4-6-membered heterocyclic group together with the part directly connected to it, and the above-mentioned 4-6-membered heterocyclic group is optionally further replaced by one or more selected from deuterium, halogen, cyano, nitro, Azido, C 1-10 alkyl, halogen substituted C 1-10 alkyl, deuterium substituted C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-12 ring Alkyl, 3-12 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, =O, -SF 5 , -S(O) r R 12 , -OR 13 , -C(O )OR 13 , -C(O)R 14 , -OC(O)R 14 , -NR 15 R 16 , -C(=NR 15 )R 14 , -N(R 15 )-C(=NR 16 )R 14. Substituents of -C(O)NR 15 R 16 and -N(R 15 )-C(O)R 14 ;或者，为如下结构：
其中R 5和R 8如前所定义； or,
For the following structure:Wherein R 5 and R 8 are as previously defined;R 9a、R 9b和R 9c各自独立地选自氢、氘、卤素、氰基、C 1-4烷基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 3-6环烷基、3-6元杂环基、-C(O)OR 13、-C(O)R 14、-C(O)NR 15R 16和-C 0-4烷基-NR 15R 16； R 9a , R 9b and R 9c are each independently selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 3- 6 cycloalkyl, 3-6 membered heterocyclyl, -C(O)OR 13 , -C(O)R 14 , -C(O)NR 15 R 16 and -C 0-4 alkyl-NR 15 R 16 ;每个R 10各自独立地选自氢、氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、 C 2-10链烯基、C 2-10链炔基、C 3-12环烷基、3-12元杂环基、C 6-10芳基、5-10元杂芳基、-SF 5、-S(O) rR 12、-O-R 13、-C(O)OR 13、-C(O)R 14、-O-C(O)R 14、-NR 15R 16、-C(＝NR 15)R 14、-N(R 15)-C(＝NR 16)R 14、-C(O)NR 15R 16和-N(R 15)-C(O)R 14，上述基团任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、卤取代C 1-10烷基、氘取代C 1-10烷基、C 3-12环烷基、3-12元杂环基、C 6-10芳基、5-10元杂芳基、＝O、-SF 5、-S(O) rR 12、-O-R 13、-C(O)OR 13、-C(O)R 14、-O-C(O)R 14、-NR 15R 16、-C(＝NR 15)R 14、-N(R 15)-C(＝NR 16)R 14、-C(O)NR 15R 16和-N(R 15)-C(O)R 14的取代基所取代； Each R 10 is independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3 -12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, -SF 5 , -S(O) r R 12 , -OR 13 , -C(O )OR 13 , -C(O)R 14 , -OC(O)R 14 , -NR 15 R 16 , -C(=NR 15 )R 14 , -N(R 15 )-C(=NR 16 )R 14. -C(O)NR 15 R 16 and -N(R 15 )-C(O)R 14 , the above groups are optionally further replaced by one or more selected from deuterium, halogen, cyano, nitro, azide Nitrogen, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, halogen substituted C 1-10 alkyl, deuterium substituted C 1-10 alkyl, C 3-12 cycloalkane radical, 3-12 membered heterocyclic group, C 6-10 aryl group, 5-10 membered heteroaryl group, =O, -SF 5 , -S(O) r R 12 , -OR 13 , -C(O) OR 13 , -C(O)R 14 , -OC(O)R 14 , -NR 15 R 16 , -C(=NR 15 )R 14 , -N(R 15 )-C(=NR 16 )R 14 , -C(O)NR 15 R 16 and -N(R 15 )-C(O)R 14 are substituted by substituents;R 11选自氢、氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、卤取代C 1-10烷基、氘取代C 1-10烷基、C 2-10链烯基、C 2-10链炔基、C 3-12环烷基、3-12元杂环基、C 6-10芳基、5-10元杂芳基、-SF 5、-S(O) rR 12、-O-R 13、-C(O)OR 13、-C(O)R 14、-O-C(O)R 14、-NR 15R 16、-C(＝NR 15)R 14、-N(R 15)-C(＝NR 16)R 14、-C(O)NR 15R 16和-N(R 15)-C(O)R 14； R 11 is selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-10 alkyl, halogen substituted C 1-10 alkyl, deuterium substituted C 1-10 alkyl, C 2-10 chain Alkenyl, C 2-10 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, -SF 5 , -S(O ) r R 12 , -OR 13 , -C(O)OR 13 , -C(O)R 14 , -OC(O)R 14 , -NR 15 R 16 , -C(=NR 15 )R 14 , - N(R 15 )-C(=NR 16 )R 14 , -C(O)NR 15 R 16 and -N(R 15 )-C(O)R 14 ;每个R 12各自独立地选自氢、氘、羟基、C 1-10烷基、C 2-10链烯基、C 3-12环烷基、3-12元杂环基、C 6-10芳基、5-10元杂芳基和-NR 15R 16，上述基团任选进一步被一个或多个选自氘、卤素、羟基、氧代、C 1-10烷基、C 1-10烷氧基、C 3-12环烷基、C 3-12环烷氧基、3-12元杂环基、3-12元杂环氧基、C 6-10芳基、C 6-10芳氧基、5-10元杂芳基、5-10元杂芳氧基和-NR 15R 16的取代基所取代； Each R 12 is independently selected from hydrogen, deuterium, hydroxyl, C 1-10 alkyl, C 2-10 alkenyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 Aryl, 5-10 membered heteroaryl and -NR 15 R 16 , the above groups are optionally further selected from one or more of deuterium, halogen, hydroxyl, oxo, C 1-10 alkyl, C 1-10 Alkoxyl group, C 3-12 cycloalkyl group, C 3-12 cycloalkoxy group, 3-12 membered heterocyclic group, 3-12 membered heterocyclic epoxy group, C 6-10 aryl group, C 6-10 aromatic group Oxygen, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy and -NR 15 R 16 are substituted by substituents;每个R 13各自独立地选自氢、氘、C 1-10烷基、C 2-10链烯基、C 3-12环烷基、3-12元杂环基、C 6-10芳基和5-10元杂芳基，上述基团任选进一步被一个或多个选自氘、卤素、羟基、氧代、氰基、C 1-10烷基、C 1-10烷氧基、C 3-12环烷基、C 3-12环烷氧基、3-12元杂环基、3-12元杂环氧基、C 6-10芳基、C 6-10芳氧基、5-10元杂芳基、5-10元杂芳氧基和-NR 15R 16的取代基所取代； Each R 13 is independently selected from hydrogen, deuterium, C 1-10 alkyl, C 2-10 alkenyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, the above-mentioned groups are optionally further replaced by one or more selected from deuterium, halogen, hydroxyl, oxo, cyano, C 1-10 alkyl, C 1-10 alkoxy, C 3-12 cycloalkyl group, C 3-12 cycloalkoxy group, 3-12 membered heterocyclic group, 3-12 membered heterocyclic epoxy group, C 6-10 aryl group, C 6-10 aryloxy group, 5- Substituents of 10-membered heteroaryl, 5-10-membered heteroaryloxy and -NR 15 R 16 ;每个R 14各自独立地选自氢、氘、羟基、C 1-10烷基、C 1-10烷氧基、C 2-10链烯基、C 2-10链炔基、C 3-12环烷基、C 3-12环烷氧基、3-12元杂环基、3-12元杂环氧基、C 6-10芳基、C 6-10芳氧基、5-10元杂芳基、5-10元杂芳氧基和-NR 15R 16，上述基团任选进一步被一个或多个选自氘、卤素、羟基、氰基、C 1-10烷基、C 1-10烷氧基、C 3-12环烷基、C 3-12环烷氧基、3-12元杂环基、3-12元杂环氧基、C 6-10芳基、C 6-10芳氧基、5-10元杂芳基、5-10元杂芳氧基和-NR 15R 16的取代基所取代； Each R 14 is independently selected from hydrogen, deuterium, hydroxyl, C 1-10 alkyl, C 1-10 alkoxy, C 2-10 alkenyl, C 2-10 alkynyl, C 3-12 Cycloalkyl, C 3-12 cycloalkoxy, 3-12 membered heterocyclic group, 3-12 membered heterocyclic epoxy group, C 6-10 aryl group, C 6-10 aryloxy group, 5-10 membered heterocyclic group Aryl, 5-10-membered heteroaryloxy and -NR 15 R 16 , the above-mentioned groups are optionally further replaced by one or more selected from deuterium, halogen, hydroxyl, cyano, C 1-10 alkyl, C 1- 10 alkoxy, C 3-12 cycloalkyl, C 3-12 cycloalkoxy, 3-12 heterocyclic, 3-12 heterocyclic, C 6-10 aryl, C 6-10 Substituted by aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy and -NR 15 R 16 ;每个R 15和R 16各自独立地选自氢、氘、羟基、C 1-10烷氧基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、C 3-12环烷基、3-12元杂环基、C 6-10芳基、5-10元杂芳基、亚磺酰基、磺酰基、甲磺酰基、异丙磺酰基、环丙基磺酰基、对甲苯磺酰基、氨基磺酰基、二甲氨基磺酰基、氨基、单C 1-10烷基氨基、二C 1-10烷基氨基和C 1-10烷酰基，上述基团任选进一步被一个或多个选自氘、卤素、羟基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、卤取代C 1-10烷基、氘取代C 1-10烷基、C 1-10烷氧基、C 3-12环烷基、C 3-12环烷氧基、3-12元杂环基、3-12元杂环氧基、C 6-10芳基、C 6-10芳氧基、5-10元杂芳基、5-10元杂芳氧基、氨基、单C 1-10烷基氨基、二C 1-10烷基氨基 和C 1-10烷酰基的取代基所取代， Each R 15 and R 16 are each independently selected from hydrogen, deuterium, hydroxyl, C 1-10 alkoxy, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, sulfinyl, sulfonyl, methylsulfonyl, isopropylsulfonyl, cyclopropylsulfonyl Acyl, p-toluenesulfonyl, aminosulfonyl, dimethylaminosulfonyl, amino, single C 1-10 alkylamino, two C 1-10 alkylamino and C 1-10 alkanoyl, the above groups are optionally further By one or more selected from deuterium, halogen, hydroxyl, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, halogen substituted C 1-10 alkyl, deuterium substituted C 1- 10 alkyl, C 1-10 alkoxy, C 3-12 cycloalkyl, C 3-12 cycloalkoxy, 3-12 heterocyclic, 3-12 heterocyclic, C 6-10 Aryl, C 6-10 aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, amino, mono C 1-10 alkylamino, di C 1-10 alkylamino and C 1 Substituents of -10 alkanoyl,或者，R 15和R 16与其直接相连的氮原子一起形成4-10元杂环基，上述基团任选进一步被一个或多个选自氘、卤素、羟基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、卤取代C 1-10烷基、氘取代C 1-10烷基、C 1-10烷氧基、C 3-12环烷基、C 3-12环烷氧基、3-12元杂环基、3-12元杂环氧基、C 6-10芳基、C 6-10芳氧基、5-10元杂芳基、5-10元杂芳氧基、氨基、单C 1-10烷基氨基、二C 1-10烷基氨基和C 1-10烷酰基的取代基所取代； Alternatively, R 15 and R 16 form a 4-10 membered heterocyclic group together with their directly connected nitrogen atoms, and the above-mentioned groups are optionally further replaced by one or more selected from deuterium, halogen, hydroxyl, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, halogen substituted C 1-10 alkyl, deuterium substituted C 1-10 alkyl, C 1-10 alkoxy, C 3-12 cycloalkyl, C 3-12 cycloalkoxy, 3-12 heterocyclic, 3-12 heterocyclic, C 6-10 aryl, C 6-10 aryloxy, 5-10 heteroaryl, 5- Substituents of 10-membered heteroaryloxy, amino, single C 1-10 alkylamino, di-C 1-10 alkylamino and C 1-10 alkanoyl;m为0、1、2或3；m is 0, 1, 2 or 3;每个r各自独立地为0、1或2。Each r is independently 0, 1 or 2. - 根据权利要求1所述的式(I)化合物、其立体异构体或其药学上可接受盐，其特征在于，每个R 1各自独立地选自氢、氘、卤素、氰基、硝基、叠氮基、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基、3-6元杂环基、C 6-8芳基、5-8元杂芳基、-SF 5、-S(O) rR 12、-O-R 13、-C(O)OR 13、-C(O)R 14、-O-C(O)R 14、-NR 15R 16、-C(＝NR 15)R 14、-N(R 15)-C(＝NR 16)R 14、-C(O)NR 15R 16和-N(R 15)-C(O)R 14，或者，当m≥2时，任意两个R 1与其直接相连的部分一起形成C 3-6环烷基或3-6元杂环基，上述基团任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 3-6环烷基、3-6元杂环基、C 6-8芳基、5-8元杂芳基、＝O、-SF 5、-S(O) rR 12、-O-R 13、-C(O)OR 13、-C(O)R 14、-O-C(O)R 14、-NR 15R 16、-C(＝NR 15)R 14、-N(R 15)-C(＝NR 16)R 14、-C(O)NR 15R 16和-N(R 15)-C(O)R 14的取代基所取代； The compound of formula (I) according to claim 1 , its stereoisomer or its pharmaceutically acceptable salt, is characterized in that, each R is independently selected from hydrogen, deuterium, halogen, cyano, nitro , azido, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl , 5-8 membered heteroaryl, -SF 5 , -S(O) r R 12 , -OR 13 , -C(O)OR 13 , -C(O)R 14 , -OC(O)R 14 , -NR 15 R 16 , -C(=NR 15 )R 14 , -N(R 15 )-C(=NR 16 )R 14 , -C(O)NR 15 R 16 and -N(R 15 )-C (O)R 14 , or, when m≥2, any two R 1 and the part directly connected together form a C 3-6 cycloalkyl group or a 3-6 membered heterocyclic group, and the above groups are optionally further replaced by one Or more selected from deuterium, halogen, cyano, nitro, azido, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halogen substituted C 1-4 alkyl , deuterium substituted C 1-4 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, =O, -SF 5 , -S (O) r R 12 , -OR 13 , -C(O)OR 13 , -C(O)R 14 , -OC(O)R 14 , -NR 15 R 16 , -C(=NR 15 )R 14 , -N(R 15 )-C(=NR 16 )R 14 , -C(O)NR 15 R 16 and -N(R 15 )-C(O)R 14 are substituted by substituents;R 2和R 3各自独立地选自氢、氘、卤素、氰基、硝基、叠氮基、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基、3-6元杂环基、C 6-8芳基和5-8元杂芳基，或者，R 2和R 3与其直接相连的碳原子一起形成羰基、C 3-6环烷基或3-6元杂环基，上述基团任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 3-6环烷基、3-6元杂环基、C 6-8芳基、5-8元杂芳基、＝O、-SF 5、-S(O) rR 12、-O-R 13、-C(O)OR 13、-C(O)R 14、-O-C(O)R 14、-NR 15R 16、-C(＝NR 15)R 14、-N(R 15)-C(＝NR 16)R 14、-C(O)NR 15R 16和-N(R 15)-C(O)R 14的取代基所取代； R 2 and R 3 are each independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl group, 3-6 membered heterocyclic group, C 6-8 aryl group and 5-8 membered heteroaryl group, or, R 2 and R 3 together form a carbonyl group, C 3- 6 cycloalkyl groups or 3-6 membered heterocyclic groups, the above groups are optionally further replaced by one or more selected from deuterium, halogen, cyano, nitro, azido, C 1-4 alkyl, C 2- 4 alkenyl, C 2-4 alkynyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6- 8 aryl, 5-8 membered heteroaryl, =O, -SF 5 , -S(O) r R 12 , -OR 13 , -C(O)OR 13 , -C(O)R 14 , -OC (O)R 14 , -NR 15 R 16 , -C(=NR 15 )R 14 , -N(R 15 )-C(=NR 16 )R 14 , -C(O)NR 15 R 16 and -N (R 15 )-C(O)R 14 is substituted by a substituent;R 4选自氢、氘、C 1-4烷基、C 2-4链烯基、C 3-6环烷基、3-6元杂环基、C 6-8芳基和5-8元杂芳基，上述基团任选进一步被一个或多个选自氘、卤素、羟基、＝O、氰基、C 1-4烷基、C 1-4烷氧基、C 3-6环烷基、C 3-6环烷氧基、3-6元杂环基、3-6元杂环氧基、C 6-8芳基、C 6-8芳氧基、5-8元杂芳基、5-8元杂芳氧基和-NR 15R 16的取代基所取代； R 4 is selected from hydrogen, deuterium, C 1-4 alkyl, C 2-4 alkenyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl and 5-8 membered Heteroaryl, the above group is optionally further replaced by one or more selected from deuterium, halogen, hydroxyl, =O, cyano, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkane Group, C 3-6 cycloalkoxy group, 3-6 membered heterocyclic group, 3-6 membered heterocyclic epoxy group, C 6-8 aryl group, C 6-8 aryloxy group, 5-8 membered heteroaryl group , 5-8 membered heteroaryloxy and -NR 15 R 16 substituents;R 5选自氢、氘、羟基、C 1-4烷基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 2-4链烯基、C 3-6环烷基和3-6元杂环基； R is selected from hydrogen, deuterium , hydroxyl, C 1-4 alkyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 2-4 alkenyl, C 3-6 cycloalkyl and 3-6 membered heterocyclyl;R 6a选自氢、氘、卤素、氰基、硝基、叠氮基、C 1-4烷基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基、3-6元杂环基、C 6-8芳基、5-8元杂芳基、-SF 5、-S(O) rR 12、-O-R 13、-C(O)OR 13、-C(O)R 14、-O-C(O)R 14、-NR 15R 16、-C(＝NR 15)R 14、-N(R 15)-C(＝NR 16)R 14、-C(O)NR 15R 16和-N(R 15)-C(O)R 14； R 6a is selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-4 alkyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 2-4 chain Alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, -SF 5 , -S(O ) r R 12 , -OR 13 , -C(O)OR 13 , -C(O)R 14 , -OC(O)R 14 , -NR 15 R 16 , -C(=NR 15 )R 14 , - N(R 15 )-C(=NR 16 )R 14 , -C(O)NR 15 R 16 and -N(R 15 )-C(O)R 14 ;R 6b选自氢、氘、卤素、氰基、硝基、叠氮基、C 1-4烷基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基、3-6元杂环基、C 6-8芳基、5-8元杂芳基、-SF 5、-S(O) rR 12、-O-R 13、-C(O)OR 13、-C(O)R 14、-O-C(O)R 14、-NR 15R 16、-C(＝NR 15)R 14、-N(R 15)-C(＝NR 16)R 14、-C(O)NR 15R 16和-N(R 15)-C(O)R 14； R 6b is selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-4 alkyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 2-4 chain Alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, -SF 5 , -S(O ) r R 12 , -OR 13 , -C(O)OR 13 , -C(O)R 14 , -OC(O)R 14 , -NR 15 R 16 , -C(=NR 15 )R 14 , - N(R 15 )-C(=NR 16 )R 14 , -C(O)NR 15 R 16 and -N(R 15 )-C(O)R 14 ;R 7和R 8各自独立地选自氢、氘、羟基、C 1-4烷基、C 2-4链烯基、C 3-6环烷基和3-6元杂环基，或者，R 7和R 8与其直接相连的氮原子一起形成3-6元杂环基，上述基团任选进一步被一个或多个选自氘、卤素、羟基、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 1-4烷氧基、C 3-6环烷基、C 3-6环烷氧基、3-6元杂环基、3-6元杂环氧基、C 6-8芳基、C 6-8芳氧基、5-8元杂芳基、5-8元杂芳氧基和-NR 15R 16的取代基所取代； R 7 and R 8 are each independently selected from hydrogen, deuterium, hydroxyl, C 1-4 alkyl, C 2-4 alkenyl, C 3-6 cycloalkyl and 3-6 membered heterocyclyl, or, R 7 and R 8 form a 3-6 membered heterocyclic group together with the nitrogen atom directly connected to it, and the above-mentioned groups are optionally further replaced by one or more selected from deuterium, halogen, hydroxyl, C 1-4 alkyl, C 2-4 Alkenyl, C 2-4 alkynyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, C 3-6 Cycloalkoxy, 3-6 membered heterocyclic group, 3-6 membered heterocyclic oxy group, C 6-8 aryl group, C 6-8 aryloxy group, 5-8 membered heteroaryl group, 5-8 membered heterocyclic group Substituents of aryloxy and -NR 15 R 16 ;或者，R 6a或R 6b其中之一和R 5与其直接相连的部分一起形成4-6元杂环基，R 6a或R 6b其中另一个如前所定义，上述4-6元杂环基任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-4烷基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基、3-6元杂环基、C 6-8芳基、5-8元杂芳基、＝O、-SF 5、-S(O) rR 12、-O-R 13、-C(O)OR 13、-C(O)R 14、-O-C(O)R 14、-NR 15R 16、-C(＝NR 15)R 14、-N(R 15)-C(＝NR 16)R 14、-C(O)NR 15R 16和-N(R 15)-C(O)R 14的取代基所取代； Alternatively, one of R 6a or R 6b and R 5 together with the part directly connected to it form a 4-6 membered heterocyclic group, the other of R 6a or R 6b is as defined above, any of the above 4-6 membered heterocyclic groups is further selected from one or more groups selected from deuterium, halogen, cyano, nitro, azido, C 1-4 alkyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 2 -4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, =O, -SF 5. -S(O) r R 12 , -OR 13 , -C(O)OR 13 , -C(O)R 14 , -OC(O)R 14 , -NR 15 R 16 , -C(=NR 15 ) Substituents of R 14 , -N(R 15 )-C(=NR 16 )R 14 , -C(O)NR 15 R 16 and -N(R 15 )-C(O)R 14 ;或者，R 6b和R 7与其直接相连的部分一起形成4-6元杂环基，上述4-6元杂环基任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-4烷基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基、3-6元杂环基、C 6-8芳基、5-8元杂芳基、＝O、-SF 5、-S(O) rR 12、-O-R 13、-C(O)OR 13、-C(O)R 14、-O-C(O)R 14、-NR 15R 16、-C(＝NR 15)R 14、-N(R 15)-C(＝NR 16)R 14、-C(O)NR 15R 16和-N(R 15)-C(O)R 14的取代基所取代； Alternatively, R 6b and R 7 form a 4-6-membered heterocyclic group together with the part directly connected to it, and the above-mentioned 4-6-membered heterocyclic group is optionally further replaced by one or more selected from deuterium, halogen, cyano, nitro, Azido, C 1-4 alkyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 ring Alkyl, 3-6 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, =O, -SF 5 , -S(O) r R 12 , -OR 13 , -C(O )OR 13 , -C(O)R 14 , -OC(O)R 14 , -NR 15 R 16 , -C(=NR 15 )R 14 , -N(R 15 )-C(=NR 16 )R 14. Substituents of -C(O)NR 15 R 16 and -N(R 15 )-C(O)R 14 ;或者，为如下结构：
其中R 5和R 8如前所定义； or,
For the following structure:Wherein R 5 and R 8 are as previously defined;R 9a、R 9b和R 9c各自独立地选自氢、氘、卤素、氰基、C 1-4烷基、卤取代C 1-4烷基、氘取代C 1-4烷基和-C 0-4烷基-NR 15R 16； R 9a , R 9b and R 9c are each independently selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl and -C 0 -4 alkyl-NR 15 R 16 ;每个R 10各自独立地选自氢、氘、卤素、氰基、硝基、叠氮基、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基、3-6元杂环基、C 6-8芳基、5-8元杂芳基、-SF 5、-S(O) rR 12、-O-R 13、-C(O)OR 13、-C(O)R 14、-O-C(O)R 14、-NR 15R 16、-C(＝NR 15)R 14、-N(R 15)-C(＝NR 16)R 14、-C(O)NR 15R 16和-N(R 15)-C(O)R 14，上述基团任选进一步被一 个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 3-6环烷基、3-6元杂环基、C 6-8芳基、5-8元杂芳基、＝O、-SF 5、-S(O) rR 12、-O-R 13、-C(O)OR 13、-C(O)R 14、-O-C(O)R 14、-NR 15R 16、-C(＝NR 15)R 14、-N(R 15)-C(＝NR 16)R 14、-C(O)NR 15R 16和-N(R 15)-C(O)R 14的取代基所取代； Each R 10 is independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3 -6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, -SF 5 , -S(O) r R 12 , -OR 13 , -C(O )OR 13 , -C(O)R 14 , -OC(O)R 14 , -NR 15 R 16 , -C(=NR 15 )R 14 , -N(R 15 )-C(=NR 16 )R 14. -C(O)NR 15 R 16 and -N(R 15 )-C(O)R 14 , the above groups are optionally further replaced by one or more selected from deuterium, halogen, cyano, nitro, azide Nitrogen, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 3-6 cycloalkane radical, 3-6 membered heterocyclic group, C 6-8 aryl group, 5-8 membered heteroaryl group, =O, -SF 5 , -S(O) r R 12 , -OR 13 , -C(O) OR 13 , -C(O)R 14 , -OC(O)R 14 , -NR 15 R 16 , -C(=NR 15 )R 14 , -N(R 15 )-C(=NR 16 )R 14 , -C(O)NR 15 R 16 and -N(R 15 )-C(O)R 14 are substituted by substituents;R 11选自氢、氘、卤素、氰基、硝基、叠氮基、C 1-4烷基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基、3-6元杂环基、C 6-8芳基、5-8元杂芳基、-SF 5、-S(O) rR 12、-O-R 13、-C(O)OR 13、-C(O)R 14、-O-C(O)R 14、-NR 15R 16、-C(＝NR 15)R 14、-N(R 15)-C(＝NR 16)R 14、-C(O)NR 15R 16和-N(R 15)-C(O)R 14； R 11 is selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-4 alkyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 2-4 chain Alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, -SF 5 , -S(O ) r R 12 , -OR 13 , -C(O)OR 13 , -C(O)R 14 , -OC(O)R 14 , -NR 15 R 16 , -C(=NR 15 )R 14 , - N(R 15 )-C(=NR 16 )R 14 , -C(O)NR 15 R 16 and -N(R 15 )-C(O)R 14 ;其中，R 12、R 13、R 14、R 15、R 16、m和r如权利要求1中所定义。 Wherein, R 12 , R 13 , R 14 , R 15 , R 16 , m and r are as defined in claim 1. - 根据权利要求1所述的式(I)化合物、其立体异构体或其药学上可接受盐，其特征在于，每个R 12各自独立地选自氢、氘、羟基、C 1-4烷基、C 2-4链烯基、C 3-6环烷基、3-6元杂环基、C 6-8芳基、5-8元杂芳基和-NR 15R 16，上述基团任选进一步被一个或多个选自氘、卤素、羟基、氧代、C 1-4烷基、C 1-4烷氧基、C 3-6环烷基、C 3-6环烷氧基、3-6元杂环基、3-6元杂环氧基、C 6-8芳基、C 6-8芳氧基、5-8元杂芳基、5-8元杂芳氧基和-NR 15R 16的取代基所取代； The compound of formula (I) according to claim 1, its stereoisomer or its pharmaceutically acceptable salt, is characterized in that, each R 12 is independently selected from hydrogen, deuterium, hydroxyl, C 1-4 alkane Group, C 2-4 alkenyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic group, C 6-8 aryl, 5-8 membered heteroaryl and -NR 15 R 16 , the above groups Optionally, one or more selected from deuterium, halogen, hydroxyl, oxo, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkoxy , 3-6 membered heterocyclic group, 3-6 membered heterocyclic oxy group, C 6-8 aryl group, C 6-8 aryloxy group, 5-8 membered heteroaryl group, 5-8 membered heteroaryloxy group and - NR 15 R 16 is substituted by a substituent;每个R 13各自独立地选自氢、氘、C 1-4烷基、C 2-4链烯基、C 3-6环烷基、3-6元杂环基、C 6-8芳基和5-8元杂芳基，上述基团任选进一步被一个或多个选自氘、卤素、羟基、氧代、氰基、C 1-4烷基、C 1-4烷氧基、C 3-6环烷基、C 3-6环烷氧基、3-6元杂环基、3-6元杂环氧基、C 6-8芳基、C 6-8芳氧基、5-8元杂芳基、5-8元杂芳氧基和-NR 15R 16的取代基所取代； Each R 13 is independently selected from hydrogen, deuterium, C 1-4 alkyl, C 2-4 alkenyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl and 5-8 membered heteroaryl, the above-mentioned groups are optionally further replaced by one or more selected from deuterium, halogen, hydroxyl, oxo, cyano, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl group, C 3-6 cycloalkoxy group, 3-6 membered heterocyclic group, 3-6 membered heterocyclic epoxy group, C 6-8 aryl group, C 6-8 aryloxy group, 5- Substituents of 8-membered heteroaryl, 5-8-membered heteroaryloxy and -NR 15 R 16 ;每个R 14各自独立地选自氢、氘、羟基、C 1-4烷基、C 1-4烷氧基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基、C 3-6环烷氧基、3-6元杂环基、3-6元杂环氧基、C 6-8芳基、C 6-8芳氧基、5-8元杂芳基、5-8元杂芳氧基和-NR 15R 16，上述基团任选进一步被一个或多个选自氘、卤素、羟基、氰基、C 1-4烷基、C 1-4烷氧基、C 3-6环烷基、C 3-6环烷氧基、3-6元杂环基、3-6元杂环氧基、C 6-8芳基、C 6-8芳氧基、5-8元杂芳基、5-8元杂芳氧基和-NR 15R 16的取代基所取代； Each R 14 is independently selected from hydrogen, deuterium, hydroxyl, C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 Cycloalkyl, C 3-6 cycloalkoxy, 3-6 membered heterocyclic group, 3-6 membered heterocyclic epoxy group, C 6-8 aryl group, C 6-8 aryloxy group, 5-8 membered heterocyclic group Aryl, 5-8-membered heteroaryloxy and -NR 15 R 16 , the above-mentioned groups are optionally further replaced by one or more selected from deuterium, halogen, hydroxyl, cyano, C 1-4 alkyl, C 1- 4 alkoxyl, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, 3-6 heterocyclyl, 3-6 heterocyclyl, C 6-8 aryl, C 6-8 Substituents of aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy and -NR 15 R 16 ;每个R 15和R 16各自独立地选自氢、氘、羟基、C 1-4烷氧基、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基、3-6元杂环基、C 6-8芳基、5-8元杂芳基、亚磺酰基、磺酰基、甲磺酰基、异丙磺酰基、环丙基磺酰基、对甲苯磺酰基、氨基磺酰基、二甲氨基磺酰基、氨基、单C 1-4烷基氨基、二C 1-4烷基氨基和C 1-4烷酰基，上述基团任选进一步被一个或多个选自氘、卤素、羟基、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 1-4烷氧基、C 3-6环烷基、C 3-6环烷氧基、3-6元杂环基、3-6元杂环氧基、C 6-8芳基、C 6-8芳氧基、5-8元杂芳基、5-8元杂芳氧基、氨基、单C 1-4烷基氨基、二C 1-4烷基氨基和C 1-4烷酰基的取代基所取 代， Each R 15 and R 16 are each independently selected from hydrogen, deuterium, hydroxyl, C 1-4 alkoxy, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, sulfinyl, sulfonyl, methylsulfonyl, isopropylsulfonyl, cyclopropylsulfonyl Acyl, p-toluenesulfonyl, aminosulfonyl, dimethylaminosulfonyl, amino, single C 1-4 alkylamino, two C 1-4 alkylamino and C 1-4 alkanoyl, the above groups are optionally further By one or more selected from deuterium, halogen, hydroxyl, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1- 4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, C 3-6 Cycloalkoxy, 3-6 Heterocyclic, 3-6 Heterocyclic, C 6-8 Aryl, C 6-8 aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy, amino, mono C 1-4 alkylamino, di C 1-4 alkylamino and C 1 -4 alkanoyl substituents are substituted,或者，R 15和R 16与其直接相连的氮原子一起形成4-8元杂环基，上述基团任选进一步被一个或多个选自氘、卤素、羟基、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 1-4烷氧基、C 3-6环烷基、C 3-6环烷氧基、3-6元杂环基、3-6元杂环氧基、C 6-8芳基、C 6-8芳氧基、5-8元杂芳基、5-8元杂芳氧基、氨基、单C 1-4烷基氨基、二C 1-4烷基氨基和C 1-4烷酰基的取代基所取代。 Alternatively, R 15 and R 16 form a 4-8 membered heterocyclic group together with their directly connected nitrogen atoms, and the above-mentioned groups are optionally further replaced by one or more selected from deuterium, halogen, hydroxyl, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkoxy group, 3-6 membered heterocyclic group, 3-6 membered heterocyclic epoxy group, C 6-8 aryl group, C 6-8 aryloxy group, 5-8 membered heteroaryl group, 5- Substituents of 8-membered heteroaryloxy, amino, mono-C 1-4 alkylamino, di-C 1-4 alkylamino and C 1-4 alkanoyl.
- 根据权利要求1所述的式(I)化合物、其立体异构体或其药学上可接受盐，其特征在于，式(I)化合物为如下式(Ⅱ)化合物：The compound of formula (I), its stereoisomer or pharmaceutically acceptable salt thereof according to claim 1, wherein the compound of formula (I) is the compound of formula (II):
其中，X各自独立地为CH或N；Y 1为CH或N；Y 2和Y 3各自独立地为CR 10或N，条件是Y 1、Y 2和Y 3中至少1个为N；Z为CH或N； wherein each X is independently CH or N; Y1 is CH or N; Y2 and Y3 are each independently CR10 or N, provided that at least one of Y1 , Y2 and Y3 is N; Z is CH or N;每个R 1各自独立地选自氢、氘、卤素、氰基、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基、3-6元杂环基、C 6-8芳基、5-8元杂芳基和-SF 5，或者，当m≥2时，任意两个R 1与其直接相连的部分一起形成C 3-6环烷基或3-6元杂环基，上述基团任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 3-6环烷基、3-6元杂环基、C 6-8芳基、5-8元杂芳基、＝O、-SF 5、-S(O) rR 12、-O-R 13、-C(O)OR 13、-C(O)R 14、-O-C(O)R 14、-NR 15R 16、-C(＝NR 15)R 14、-N(R 15)-C(＝NR 16)R 14、-C(O)NR 15R 16和-N(R 15)-C(O)R 14的取代基所取代； Each R 1 is independently selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3 -6-membered heterocyclic group, C 6-8 aryl group, 5-8-membered heteroaryl group and -SF 5 , or, when m≥2, any two R 1 and their directly connected parts together form C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, the above group is optionally further replaced by one or more selected from deuterium, halogen, cyano, nitro, azido, C 1-4 alkyl, C 2-4 Alkenyl, C 2-4 alkynyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 Aryl, 5-8 membered heteroaryl, =O, -SF 5 , -S(O) r R 12 , -OR 13 , -C(O)OR 13 , -C(O)R 14 , -OC( O)R 14 , -NR 15 R 16 , -C(=NR 15 )R 14 , -N(R 15 )-C(=NR 16 )R 14 , -C(O)NR 15 R 16 and -N( R 15 )-C(O)R 14 is substituted by a substituent;R 2和R 3各自独立地选自氢、氘、卤素、氰基、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基和3-6元杂环基，或者，R 2和R 3与其直接相连的碳原子一起形成羰基、C 3-6环烷基或3-6元杂环基，上述基团任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 3-6环烷基、3-6元杂环基、C 6-8芳基、5-8元杂芳基、＝O、-SF 5、-S(O) rR 12、-O-R 13、-C(O)OR 13、-C(O)R 14、-O-C(O)R 14、-NR 15R 16、-C(＝NR 15)R 14、-N(R 15)-C(＝NR 16)R 14、-C(O)NR 15R 16和-N(R 15)-C(O)R 14的取代基所取代； R 2 and R 3 are each independently selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl and 3-6 membered heterocyclic group, or, R 2 and R 3 form carbonyl, C 3-6 cycloalkyl or 3-6 membered heterocyclic group together with the carbon atom directly connected to it, and the above groups are optionally further replaced by one or Multiple selected from deuterium, halogen, cyano, nitro, azido, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halogen substituted C 1-4 alkyl, Deuterium-substituted C 1-4 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic group, C 6-8 aryl, 5-8 membered heteroaryl, =O, -SF 5 , -S( O) r R 12 , -OR 13 , -C(O)OR 13 , -C(O)R 14 , -OC(O)R 14 , -NR 15 R 16 , -C(=NR 15 )R 14 , Substituents of -N(R 15 )-C(=NR 16 )R 14 , -C(O)NR 15 R 16 and -N(R 15 )-C(O)R 14 ;R 4选自氢、氘、C 1-4烷基、C 2-4链烯基、C 3-6环烷基和3-6元杂环基，上述基团任选进一步被一个或多个选自氘、卤素、羟基、＝O、氰基、C 1-4烷基、C 1-4烷氧基、C 3-6环烷基、C 3-6环烷氧基、3-6元杂环基、3-6元杂环氧基、C 6-8芳基、C 6-8 芳氧基、5-8元杂芳基、5-8元杂芳氧基和-NR 15R 16的取代基所取代； R 4 is selected from hydrogen, deuterium, C 1-4 alkyl, C 2-4 alkenyl, C 3-6 cycloalkyl and 3-6 membered heterocyclic group, the above groups are optionally further replaced by one or more Selected from deuterium, halogen, hydroxyl, =O, cyano, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, 3-6 members Heterocyclic group, 3-6 membered heterooxyl group, C 6-8 aryl group, C 6-8 aryloxy group, 5-8 membered heteroaryl group, 5-8 membered heteroaryloxy group and -NR 15 R 16 replaced by substituents;R 5选自氢、氘、羟基、C 1-4烷基、卤取代C 1-4烷基和氘取代C 1-4烷基； R is selected from hydrogen, deuterium , hydroxyl, C 1-4 alkyl, halogen substituted C 1-4 alkyl and deuterium substituted C 1-4 alkyl;R 6a选自氢、氘、卤素、氰基、硝基、叠氮基、C 1-4烷基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基、3-6元杂环基、C 6-8芳基和5-8元杂芳基； R 6a is selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-4 alkyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 2-4 chain Alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl and 5-8 membered heteroaryl;R 6b选自氢、氘、卤素、氰基、硝基、叠氮基、C 1-4烷基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基、3-6元杂环基、C 6-8芳基和5-8元杂芳基； R 6b is selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-4 alkyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 2-4 chain Alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl and 5-8 membered heteroaryl;R 7和R 8各自独立地选自氢、氘、羟基、C 1-4烷基和C 2-4链烯基，或者，R 7和 R 7 and R 8 are each independently selected from hydrogen, deuterium, hydroxyl, C 1-4 alkyl and C 2-4 alkenyl, or, R 7 andR 8与其直接相连的氮原子一起形成3-6元杂环基，上述基团任选进一步被一个或多个选自氘、卤素、羟基、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 1-4烷氧基、C 3-6环烷基、C 3-6环烷氧基、3-6元杂环基、3-6元杂环氧基、C 6-8芳基、C 6-8芳氧基、5-8元杂芳基、5-8元杂芳氧基和-NR 15R 16的取代基所取代； R 8 forms a 3-6 membered heterocyclic group together with its directly connected nitrogen atom, and the above-mentioned group is optionally further replaced by one or more selected from deuterium, halogen, hydroxyl, C 1-4 alkyl, C 2-4 alkene Base, C 2-4 alkynyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkane Oxygen, 3-6 membered heterocyclic group, 3-6 membered heterocyclic oxy group, C 6-8 aryl group, C 6-8 aryloxy group, 5-8 membered heteroaryl group, 5-8 membered heteroaryloxy group and -NR 15 R 16 substituents;或者，R 6a或R 6b其中之一和R 5与其直接相连的部分一起形成4-6元杂环基，R 6a或R 6b其中另一个如前所定义，上述4-6元杂环基任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-4烷基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基、3-6元杂环基、C 6-8芳基、5-8元杂芳基、＝O、-SF 5、-S(O) rR 12、-O-R 13、-C(O)OR 13、-C(O)R 14、-O-C(O)R 14、-NR 15R 16、-C(＝NR 15)R 14、-N(R 15)-C(＝NR 16)R 14、-C(O)NR 15R 16和-N(R 15)-C(O)R 14的取代基所取代； Alternatively, one of R 6a or R 6b and R 5 together with the part directly connected to it form a 4-6 membered heterocyclic group, the other of R 6a or R 6b is as defined above, any of the above 4-6 membered heterocyclic groups is further selected from one or more groups selected from deuterium, halogen, cyano, nitro, azido, C 1-4 alkyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 2 -4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, =O, -SF 5. -S(O) r R 12 , -OR 13 , -C(O)OR 13 , -C(O)R 14 , -OC(O)R 14 , -NR 15 R 16 , -C(=NR 15 ) Substituents of R 14 , -N(R 15 )-C(=NR 16 )R 14 , -C(O)NR 15 R 16 and -N(R 15 )-C(O)R 14 ;或者，R 6b和R 7与其直接相连的部分一起形成4-6元杂环基，上述4-6元杂环基任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-4烷基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基、3-6元杂环基、C 6-8芳基、5-8元杂芳基、＝O、-SF 5、-S(O) rR 12、-O-R 13、-C(O)OR 13、-C(O)R 14、-O-C(O)R 14、-NR 15R 16、-C(＝NR 15)R 14、-N(R 15)-C(＝NR 16)R 14、-C(O)NR 15R 16和-N(R 15)-C(O)R 14的取代基所取代； Alternatively, R 6b and R 7 form a 4-6-membered heterocyclic group together with the part directly connected to it, and the above-mentioned 4-6-membered heterocyclic group is optionally further replaced by one or more selected from deuterium, halogen, cyano, nitro, Azido, C 1-4 alkyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 ring Alkyl, 3-6 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, =O, -SF 5 , -S(O) r R 12 , -OR 13 , -C(O )OR 13 , -C(O)R 14 , -OC(O)R 14 , -NR 15 R 16 , -C(=NR 15 )R 14 , -N(R 15 )-C(=NR 16 )R 14. Substituents of -C(O)NR 15 R 16 and -N(R 15 )-C(O)R 14 ;或者，为如下结构：
其中R 5和R 8如前所定义； or,
as the following structure:Wherein R 5 and R 8 are as previously defined;R 9a选自氢、氘、卤素、氰基、C 1-4烷基、卤取代C 1-4烷基和氘取代C 1-4烷基； R 9a is selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, halogen substituted C 1-4 alkyl and deuterium substituted C 1-4 alkyl;每个R 10各自独立地选自氢、氘、卤素、氰基、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基、3-6元杂环基、C 6-8芳基、5-8元杂芳基、-O-R 13、-C(O)OR 13、-C(O)R 14和-O-C(O)R 14，上述基团任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 3-6环烷基、3-6元杂环基、C 6-8芳基、5-8元杂芳基、＝O、-SF 5、-S(O) rR 12、 -O-R 13、-C(O)OR 13、-C(O)R 14、-O-C(O)R 14、-NR 15R 16、-C(＝NR 15)R 14、-N(R 15)-C(＝NR 16)R 14、-C(O)NR 15R 16和-N(R 15)-C(O)R 14的取代基所取代； Each R 10 is independently selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3 -6 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, -OR 13 , -C(O)OR 13 , -C(O)R 14 and -OC(O)R 14 , The above-mentioned groups are optionally further replaced by one or more selected from deuterium, halogen, cyano, nitro, azido, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, Halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic group, C 6-8 aryl, 5-8 membered heteroaryl, = O, -SF 5 , -S(O)rR 12 , -OR 13 , -C(O)OR 13 , -C(O) R 14 , -OC(O)R 14 , -NR 15 R 16 , - Substitution of C(=NR 15 )R 14 , -N(R 15 )-C(=NR 16 )R 14 , -C(O)NR 15 R 16 and -N(R 15 )-C(O)R 14 base replaced;其中，R 12、R 13、R 14、R 15、R 16、m和r如权利要求1中所定义。 Wherein, R 12 , R 13 , R 14 , R 15 , R 16 , m and r are as defined in claim 1. - 根据权利要求1所述的式(I)化合物、其立体异构体或其药学上可接受盐，其特征在于，式(I)化合物为如下式(Ⅲ)化合物：The compound of formula (I), its stereoisomer or pharmaceutically acceptable salt thereof according to claim 1, wherein the compound of formula (I) is the compound of formula (III):
其中，X为CH或N；Y 1为CH或N；Y 2为CR 10a或N，Y 3为CR 10b或N，条件是Y 1、Y 2和Y 3中至少1个为N；Z为CH或N； wherein X is CH or N; Y 1 is CH or N; Y 2 is CR 10a or N, Y 3 is CR 10b or N, provided that at least one of Y 1 , Y 2 and Y 3 is N; Z is CH or N;R 1a选自氢、氘、卤素、氰基、C 1-4烷基、C 2-4链炔基、C 3-6环烷基、3-6元杂环基和5-8元杂芳基，上述基团任选进一步被一个或多个选自氘、卤素、氰基、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 3-6环烷基和3-6元杂环基的取代基所取代； R 1a is selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl and 5-8 membered heteroaryl The above group is optionally further substituted by one or more selected from deuterium, halogen, cyano, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halogen substituted C 1- Substituents of 4 alkyl, deuterium substituted C 1-4 alkyl, C 3-6 cycloalkyl and 3-6 membered heterocyclyl;R 1b选自氢、氘、卤素、氰基、C 1-4烷基、C 2-4链炔基、C 3-6环烷基、3-6元杂环基和5-8元杂芳基，上述基团任选进一步被一个或多个选自氘、卤素、氰基、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 3-6环烷基和3-6元杂环基的取代基所取代； R 1b is selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl and 5-8 membered heteroaryl The above group is optionally further substituted by one or more selected from deuterium, halogen, cyano, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halogen substituted C 1- Substituents of 4 alkyl, deuterium substituted C 1-4 alkyl, C 3-6 cycloalkyl and 3-6 membered heterocyclyl;R 2和R 3各自独立地选自氢、氘和C 1-4烷基，或者，R 2和R 3与其直接相连的碳原子一起形成羰基、C 3-6环烷基或3-6元杂环基，上述基团任选进一步被一个或多个选自氘、卤素、氰基、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 3-6环烷基和3-6元杂环基的取代基所取代； R 2 and R 3 are each independently selected from hydrogen, deuterium and C 1-4 alkyl, or, R 2 and R 3 form carbonyl, C 3-6 cycloalkyl or 3-6 membered carbon atoms together with their directly connected carbon atoms Heterocyclic group, the above group is optionally further substituted by one or more selected from deuterium, halogen, cyano, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halogen substituted C Substituents of 1-4 alkyl, deuterium-substituted C 1-4 alkyl, C 3-6 cycloalkyl and 3-6 membered heterocyclic groups;R 4选自氢、氘、C 1-4烷基、C 3-6环烷基和3-6元杂环基，上述基团任选进一步被一个或多个选自氘、卤素、＝O、氰基、C 1-4烷基、C 3-6环烷基和3-6元杂环基的取代基所取代； R 4 is selected from hydrogen, deuterium, C 1-4 alkyl, C 3-6 cycloalkyl and 3-6 membered heterocyclyl, and the above-mentioned groups are optionally further selected from one or more of deuterium, halogen, =O , cyano, C 1-4 alkyl, C 3-6 cycloalkyl and 3-6 membered heterocyclic substituents;R 5选自氢、氘、C 1-4烷基、卤取代C 1-4烷基和氘取代C 1-4烷基； R is selected from hydrogen, deuterium , C 1-4 alkyl, halogen substituted C 1-4 alkyl and deuterium substituted C 1-4 alkyl;R 6a选自氢、氘、C 1-4烷基、卤取代C 1-4烷基和氘取代C 1-4烷基； R 6a is selected from hydrogen, deuterium, C 1-4 alkyl, halogen substituted C 1-4 alkyl and deuterium substituted C 1-4 alkyl;R 6b选自氢、氘、C 1-4烷基、卤取代C 1-4烷基和氘取代C 1-4烷基； R 6b is selected from hydrogen, deuterium, C 1-4 alkyl, halogen substituted C 1-4 alkyl and deuterium substituted C 1-4 alkyl;R 7和R 8各自独立地选自氢、氘和C 1-4烷基，或者，R 7和R 8与其直接相连的氮原子一起形成3-6元杂环基，上述基团任选进一步被一个或多个选自氘、卤素、羟基、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、卤取代C 1-4烷基、氘取代C 1-4烷基、 C 1-4烷氧基、C 3-6环烷基和C 3-6环烷氧基的取代基所取代； R 7 and R 8 are each independently selected from hydrogen, deuterium and C 1-4 alkyl, or, R 7 and R 8 form a 3-6 membered heterocyclic group together with the nitrogen atom directly connected to it, and the above-mentioned groups are optionally further By one or more selected from deuterium, halogen, hydroxyl, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1- Substituents of 4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl and C 3-6 cycloalkoxy;或者，R 6a或R 6b其中之一和R 5与其直接相连的部分一起形成4-6元杂环基，R 6a或R 6b其中另一个如前所定义，上述4-6元杂环基任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-4烷基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基和3-6元杂环基的取代基所取代； Alternatively, one of R 6a or R 6b and R 5 together with the part directly connected to it form a 4-6 membered heterocyclic group, the other of R 6a or R 6b is as defined above, any of the above 4-6 membered heterocyclic groups is further selected from one or more groups selected from deuterium, halogen, cyano, nitro, azido, C 1-4 alkyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 2 Substituents of -4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl and 3-6 membered heterocyclyl;或者，R 6b和R 7与其直接相连的部分一起形成4-6元杂环基，上述4-6元杂环基任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-4烷基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基和3-6元杂环基的取代基所取代； Alternatively, R 6b and R 7 form a 4-6-membered heterocyclic group together with the part directly connected to it, and the above-mentioned 4-6-membered heterocyclic group is optionally further replaced by one or more selected from deuterium, halogen, cyano, nitro, Azido, C 1-4 alkyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 ring Substituents of alkyl and 3-6 membered heterocyclic groups;或者，为如下结构：
其中R 5和R 8如前所定义； or,
For the following structure:Wherein R 5 and R 8 are as previously defined;R 9a选自氢、氘、卤素、氰基、C 1-4烷基、卤取代甲基和氘取代甲基； R 9a is selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, halogen substituted methyl and deuterium substituted methyl;R 10a选自氢、氘、卤素、氰基、C 1-4烷基、C 3-6环烷基、3-6元杂环基、5-6元杂芳基、-O-R 13和-C(O)OR 13，上述基团任选进一步被一个或多个选自氘、卤素、氰基、C 1-4烷基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 3-6环烷基、3-6元杂环基、5-6元杂芳基、＝O、-O-R 13、-C(O)OR 13和-C(O)R 14的取代基所取代； R 10a is selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, 5-6 membered heteroaryl, -OR 13 and -C (O) OR 13 , the above group is optionally further selected from one or more groups selected from deuterium, halogen, cyano, C 1-4 alkyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl , C 3-6 cycloalkyl, 3-6 membered heterocyclyl, 5-6 membered heteroaryl, =O, -OR 13 , -C(O)OR 13 and -C(O)R 14 substituents replaced byR 10b选自氢、氘、卤素、氰基、C 1-4烷基、C 3-6环烷基、3-6元杂环基、5-6元杂芳基、-O-R 13和-C(O)OR 13，上述基团任选进一步被一个或多个选自氘、卤素、氰基、C 1-4烷基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 3-6环烷基、3-6元杂环基、5-6元杂芳基、＝O、-O-R 13、-C(O)OR 13和-C(O)R 14的取代基所取代； R 10b is selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, 5-6 membered heteroaryl, -OR 13 and -C (O) OR 13 , the above group is optionally further selected from one or more groups selected from deuterium, halogen, cyano, C 1-4 alkyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl , C 3-6 cycloalkyl, 3-6 membered heterocyclyl, 5-6 membered heteroaryl, =O, -OR 13 , -C(O)OR 13 and -C(O)R 14 substituents replaced by其中，R 13和R 14如权利要求1中所定义。 Wherein, R 13 and R 14 are as defined in claim 1. - 根据权利要求5所述的式(I)化合物、其立体异构体或其药学上可接受盐，其特征在于，Y 1为N，Y 2为CR 10a或N，Y 3为N；或者，Y 1为N，Y 2为CR 10a或N，Y 3为CR 10b；或者，Y 1为CH，Y 2为CR 10a或N，Y 3为N。 The compound of formula (I), its stereoisomer or pharmaceutically acceptable salt thereof according to claim 5, wherein Y1 is N, Y2 is CR10a or N, Y3 is N; or, Y 1 is N, Y 2 is CR 10a or N, Y 3 is CR 10b ; or, Y 1 is CH, Y 2 is CR 10a or N, Y 3 is N.
- 根据权利要求5所述的式(I)化合物、其立体异构体或其药学上可接受盐，其特征在于，R 10a选自氢、氘、氟、氯、氰基、甲基、乙基、丙基、异丙基、环丙基、环丁基、氧杂环丙基、氮杂环丙基、氧杂环丁基、氮杂环丁基、咪唑基、吡唑基、三唑基、四唑基和-C(O)OR 13，上述基团任选进一步被一个或多个选自氘、氟、氯、氰基、甲基、乙基、丙基、异丙基、一氟甲基、二氟甲基、三氟甲基、一氘甲基、二氘甲基、三氘甲基、环丙基、环丁基、氧杂环丙基、氮杂环丙基、氧杂环丁基和氮杂环丁基的取代基所取代； The compound of formula (I) according to claim 5, its stereoisomer or its pharmaceutically acceptable salt, is characterized in that, R 10a is selected from hydrogen, deuterium, fluorine, chlorine, cyano, methyl, ethyl , Propyl, Isopropyl, Cyclopropyl, Cyclobutyl, Oxycyclopropyl, Aziridyl, Oxetanyl, Azetidinyl, Imidazolyl, Pyrazolyl, Triazolyl , tetrazolyl and -C(O)OR 13 , the above groups are optionally further selected from one or more of deuterium, fluorine, chlorine, cyano, methyl, ethyl, propyl, isopropyl, monofluoro Methyl, difluoromethyl, trifluoromethyl, monodeuteromethyl, dideuteriomethyl, trideuteromethyl, cyclopropyl, cyclobutyl, oxiranyl, aziridyl, oxa Substituents of cyclobutyl and azetidinyl;R 10b选自氢、氘、氟、氯、氰基、甲基、乙基、丙基、异丙基、环丙基、环丁基、氧杂环丙基、氮杂环丙基、氧杂环丁基、氮杂环丁基、咪唑基和吡唑基，上 述基团任选进一步被一个或多个选自氘、氟、氯、氰基、甲基、乙基、丙基、异丙基、一氟甲基、二氟甲基、三氟甲基、一氘甲基、二氘甲基、三氘甲基、环丙基、环丁基、氧杂环丙基、氮杂环丙基、氧杂环丁基和氮杂环丁基的取代基所取代； R 10b is selected from hydrogen, deuterium, fluorine, chlorine, cyano, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, oxirane, aziridyl, oxa Cyclobutyl, azetidinyl, imidazolyl and pyrazolyl, the above-mentioned groups are optionally further selected from deuterium, fluorine, chlorine, cyano, methyl, ethyl, propyl, isopropyl fluoromethyl, difluoromethyl, trifluoromethyl, 1-deuteromethyl, dide-deuteromethyl, tri-deuteromethyl, cyclopropyl, cyclobutyl, oxirane, aziridine Substituents of group, oxetanyl and azetidinyl;R 13选自氢、氘、甲基、乙基、丙基、异丙基、环丙基、环丁基、氧杂环丙基、氮杂环丙基、氧杂环丁基、氮杂环丁基、苯基、咪唑基和吡唑基，上述基团任选进一步被一个或多个选自氘、氟、氯、羟基、氧代、氰基、甲基、乙基、丙基、异丙基、一氟甲基、二氟甲基、三氟甲基、一氘甲基、二氘甲基、三氘甲基、环丙基、环丁基、氧杂环丙基、氮杂环丙基、氧杂环丁基和氮杂环丁基的取代基所取代。 R is selected from hydrogen, deuterium, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, oxirane, aziridyl , oxetanyl, azacycline Butyl, phenyl, imidazolyl and pyrazolyl, the above-mentioned groups are optionally further selected from deuterium, fluorine, chlorine, hydroxyl, oxo, cyano, methyl, ethyl, propyl, iso Propyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monodeuteromethyl, dideuteriomethyl, trideuteromethyl, cyclopropyl, cyclobutyl, oxirane, azacyclic Substituents of propyl, oxetanyl and azetidinyl.
- 根据权利要求5所述的式(I)化合物、其立体异构体或其药学上可接受盐，其特征在于，R 4选自氢、氘、甲基、乙基、异丙基、环丙基、环丁基、氧杂环丙基、氧杂环丁基、氮杂环丙基和氮杂环丁基，上述基团任选进一步被一个或多个选自氘、氟、C 1-4烷基和C 3-6环烷基的取代基所取代。 The compound of formula (I) according to claim 5 , its stereoisomer or its pharmaceutically acceptable salt, is characterized in that, R is selected from hydrogen, deuterium, methyl, ethyl, isopropyl, cyclopropyl group, cyclobutyl group, oxirandyl group, oxetanyl group, aziridyl group and azetidinyl group, the above-mentioned groups are optionally further selected from deuterium, fluorine, C 1- 4 alkyl and C 3-6 cycloalkyl substituents are substituted.
- 根据权利要求5所述的式(I)化合物、其立体异构体或其药学上可接受盐，其特征在于，R 9a选自氢、氘、氟、甲基、乙基、丙基、异丙基、一氟甲基、二氟甲基、三氟甲基、一氘甲基、二氘甲基和三氘甲基。 The compound of formula (I) according to claim 5, its stereoisomer or its pharmaceutically acceptable salt, is characterized in that R 9a is selected from hydrogen, deuterium, fluorine, methyl, ethyl, propyl, iso Propyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monodeuteromethyl, dideuteriomethyl and trideuteromethyl.
- 根据权利要求5所述的式(I)化合物、其立体异构体或其药学上可接受盐，其特征在于，R 2和R 3各自独立地选自氢、氘、甲基、乙基和异丙基，或者，R 2和R 3与其直接相连的碳原子一起形成环丙基、环丁基、环戊基或环己基，上述基团任选进一步被一个或多个选自氘、氟、氯、溴、氰基、甲基、乙基、异丙基、三氟甲基、二氟甲基、三氘甲基、二氘甲基、环丙基、环丁基、氧杂环丙基、氧杂环丁基、氮杂环丙基和氮杂环丁基的取代基所取代。 The compound of formula (I) according to claim 5, its stereoisomer or its pharmaceutically acceptable salt, is characterized in that, R 2 and R 3 are each independently selected from hydrogen, deuterium, methyl, ethyl and Isopropyl, or, R 2 and R 3 form cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl together with the carbon atoms directly connected to them, and the above-mentioned groups are optionally further selected from one or more groups selected from deuterium, fluorine , chlorine, bromine, cyano, methyl, ethyl, isopropyl, trifluoromethyl, difluoromethyl, trideuteromethyl, dideuteriomethyl, cyclopropyl, cyclobutyl, oxirane Substituents of radical, oxetanyl, aziridinyl and azetidinyl.
- 根据权利要求5所述的式(I)化合物、其立体异构体或其药学上可接受盐，其特征在于，R 5选自氢、氘、甲基、乙基、异丙基、三氟甲基、二氟甲基、三氘甲基和二氘甲基； The compound of formula (I) according to claim 5 , its stereoisomer or its pharmaceutically acceptable salt, is characterized in that, R is selected from hydrogen, deuterium, methyl, ethyl, isopropyl, trifluoro Methyl, difluoromethyl, trideuteromethyl and dideuteriomethyl;R 6a选自氢、氘、甲基、乙基、异丙基、三氟甲基、二氟甲基、三氘甲基和二氘甲基； R is selected from hydrogen, deuterium, methyl, ethyl, isopropyl, trifluoromethyl, difluoromethyl, trideuteromethyl and dideuteriomethyl;R 6b选自氢、氘、甲基、乙基、异丙基、三氟甲基、二氟甲基、三氘甲基和二氘甲基； R is selected from hydrogen, deuterium, methyl, ethyl, isopropyl, trifluoromethyl, difluoromethyl, trideuteromethyl and dideuteriomethyl;R 7和R 8各自独立地选自氢、氘、甲基、三氟甲基、二氟甲基、三氘甲基、二氘甲基、乙基和异丙基，或者，R 7和R 8与其直接相连的氮原子一起形成4-6元杂环基； R 7 and R 8 are each independently selected from hydrogen, deuterium, methyl, trifluoromethyl, difluoromethyl, trideuteromethyl, dideuteriomethyl, ethyl and isopropyl, or, R 7 and R 8 forms a 4-6 membered heterocyclic group together with the nitrogen atom directly connected to it;或者，R 6a或R 6b其中之一和R 5与其直接相连的部分一起形成4-6元杂环基，所述4-6元杂环基与其直接相连的部分形成如下结构： Alternatively, one of R 6a or R 6b and R 5 form a 4-6 membered heterocyclic group together with the part directly connected to it, and the 4-6 membered heterocyclic group forms the following structure with the part directly connected to it:
其中，上述结构中每个R 6a、R 6b、R 7和R 8如前所定义； Wherein, each of R 6a , R 6b , R 7 and R 8 in the above structure is as defined above;或者，R 6b和R 7与其直接相连的部分一起形成4-6元杂环基，所述4-6元杂环基与其直接相连的部分形成如下结构：其中，上述结构中R 5、R 6a和R 8如前所定义； Alternatively, R and R together form a 4-6 membered heterocyclic group with its directly connected part, and the 4-6 membered heterocyclic group forms the following structure with its directly connected part:
Wherein, R 5 , R 6a and R 8 in the above structure are as defined above;或者，为如下结构：
其中R 5和R 8如前所定义。 or,
For the following structure:Wherein R 5 and R 8 are as previously defined. - 根据权利要求5所述的式(I)化合物、其立体异构体或其药学上可接受盐，其特征在于，R 1a选自氢、氘、氟、氯、溴、氰基、甲基、乙基、异丙基、乙炔基、环丙基、环丁基、氧杂环丙基、氧杂环丁基、氮杂环丙基、氮杂环丁基、吡唑基、咪唑基、噁唑基、三氮唑基、四唑基、异噻唑基、异噁唑基、噁二唑基、噁唑基、吡嗪基、哒嗪基、吡啶基、嘧啶基、吡咯基、噻二唑基、噻唑基、噻吩基和三嗪基，上述基团任选进一步被一个或多个选自氘、氟、氯、溴、氰基、甲基、乙基、异丙基、乙烯基、乙炔基、三氟甲基、二氟甲基、三氘甲基、二氘甲基、环丙基、环丁基、氧杂环丙基、氧杂环丁基、氮杂环丙基和氮杂环丁基的取代基所取代； The compound of formula (I) according to claim 5, its stereoisomer or its pharmaceutically acceptable salt, is characterized in that, R 1a is selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, methyl, Ethyl, isopropyl, ethynyl, cyclopropyl, cyclobutyl, oxirane, oxetanyl, aziridyl, azetidinyl, pyrazolyl, imidazolyl, oxa Azolyl, triazolyl, tetrazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, thiadiazole group, thiazolyl group, thienyl group and triazinyl group, the above-mentioned groups are optionally further selected from one or more groups selected from deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, isopropyl, vinyl, acetylene , trifluoromethyl, difluoromethyl, trideuteromethyl, dideuteriomethyl, cyclopropyl, cyclobutyl, oxiranyl, oxetanyl, aziridyl and azepine Cyclobutyl substituents are substituted;R 1b选自氢、氘、氟、氯、溴、氰基、甲基、乙基、异丙基、乙炔基、环丙基、环丁基、氧杂环丙基、氧杂环丁基、氮杂环丙基、氮杂环丁基、吡唑基、咪唑基、噁唑基和三氮唑基，上述基团任选进一步被一个或多个选自氘、氟、氯、溴、氰基、甲基、乙基、异丙基、乙烯基、乙炔基、三氟甲基、二氟甲基、三氘甲基、二氘甲基、环丙基、环丁基、氧杂环丙基、氧杂环丁基、氮杂环丙基和氮杂环丁基的取代基所取代。 R is selected from hydrogen, deuterium , fluorine, chlorine, bromine, cyano, methyl, ethyl, isopropyl, ethynyl, cyclopropyl, cyclobutyl, oxiranyl, oxetanyl, Aziridyl, azetidinyl, pyrazolyl, imidazolyl, oxazolyl and triazolyl, the above-mentioned groups are optionally further selected from deuterium, fluorine, chlorine, bromine, cyanogen methyl, ethyl, isopropyl, vinyl, ethynyl, trifluoromethyl, difluoromethyl, trideuteromethyl, dideuteriomethyl, cyclopropyl, cyclobutyl, oxirane Substituents of radical, oxetanyl, aziridinyl and azetidinyl.
- 根据权利要求1-12中任一项所述的式(I)化合物、其立体异构体或其药学上可接受盐，其特征在于，选自如下化合物：According to the compound of formula (I) described in any one of claims 1-12, its stereoisomer or pharmaceutically acceptable salt thereof, it is characterized in that, be selected from the following compounds:
- 一种根据权利要求1所述的式(I)化合物、其立体异构体或其药学上可接受盐的制备方法，其特征在于，包括如下步骤：A method for preparing a compound of formula (I) according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that it comprises the steps of:
其中，X 1为卤素，选自氟、氯和溴；X、Y 1、Y 2、Y 3、Z、R 1、R 2、R 3、R 4、 R 5、R 6a、R 6b、R 7、R 8、R 9a、R 9b、R 9c和m如权利要求1中所定义。 Wherein, X 1 is halogen, selected from fluorine, chlorine and bromine; X, Y 1 , Y 2 , Y 3 , Z, R 1 , R 2 , R 3 , R 4 , R 5 , R 6a , R 6b , R 7 , R 8 , R 9a , R 9b , R 9c and m are as defined in claim 1 . - 一种药物组合物，其包含根据权利要求1-13中任一项所述的式(I)化合物、其立体异构体或其药学上可接受盐及可药用的载体。A pharmaceutical composition comprising the compound of formula (I) according to any one of claims 1-13, its stereoisomer or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
- 根据权利要求1-13中任一项所述的式(I)化合物、其立体异构体或其药学上可接受盐在制备治疗和/或预防至少部分与EGFR外显子20插入、缺失或其他突变相关的癌症、肿瘤或转移性疾病的药物中的用途。According to any one of claims 1-13, the compound of formula (I), its stereoisomer or pharmaceutically acceptable salt thereof is used in the preparation of treatment and/or prevention of at least part of EGFR exon 20 insertion, deletion or Use in medicine for other mutation-associated cancers, tumors or metastatic disease.
- 根据权利要求1-13中任一项所述的式(I)化合物、其立体异构体或其药学上可接受盐在制备治疗和/或预防由过度增殖和诱导细胞死亡障碍引起的肿瘤、癌症和或转移性疾病的药物中的用途。According to any one of claims 1-13, the compound of formula (I), its stereoisomer or pharmaceutically acceptable salt thereof is used in the preparation of treatment and/or prevention of tumors caused by excessive proliferation and induction of cell death disorders, Use in medicine for cancer and or metastatic disease.
- 根据权利要求1-13中任一项所述的式(I)化合物、其立体异构体或其药学上可接受盐在制备治疗和/或预防至少部分与EGFR外显子20插入、缺失或其他突变引起的肺癌、结肠癌、胰腺癌、头颈癌、乳腺癌、卵巢癌、子宫癌、胃癌、非小细胞肺癌、白血病、骨髓增生异常综合症、恶性淋巴瘤、头颈部肿瘤、胸腔肿瘤、胃肠道肿瘤、内分泌肿瘤、乳腺和其他妇科肿瘤、泌尿科肿瘤、皮肤肿瘤、肉瘤、鼻腔鼻窦内翻性乳头状瘤或鼻腔鼻窦内翻性乳头状瘤相关的鼻腔鼻窦鳞状细胞癌的药物中的用途。According to any one of claims 1-13, the compound of formula (I), its stereoisomer or pharmaceutically acceptable salt thereof is used in the preparation of treatment and/or prevention of at least part of EGFR exon 20 insertion, deletion or Lung cancer, colon cancer, pancreatic cancer, head and neck cancer, breast cancer, ovarian cancer, uterine cancer, gastric cancer, non-small cell lung cancer, leukemia, myelodysplastic syndrome, malignant lymphoma, head and neck cancer, thoracic tumor caused by other mutations , gastrointestinal tumors, endocrine tumors, breast and other gynecologic tumors, urologic tumors, skin tumors, sarcomas, sinonasal inverted papillomas, or sinonasal squamous cell carcinomas associated with sinonasal inverted papillomas Uses in medicine.
- 根据权利要求1-13中任一项所述的式(I)化合物、其立体异构体或其药学上可接受盐，其用于治疗和/或预防至少部分与EGFR外显子20插入、缺失或其他突变引起的肺癌、结肠癌、胰腺癌、头颈癌、乳腺癌、卵巢癌、子宫癌、胃癌、非小细胞肺癌、白血病、骨髓增生异常综合症、恶性淋巴瘤、头颈部肿瘤、胸腔肿瘤、胃肠道肿瘤、内分泌肿瘤、乳腺和其他妇科肿瘤、泌尿科肿瘤、皮肤肿瘤、肉瘤、鼻腔鼻窦内翻性乳头状瘤或鼻腔鼻窦内翻性乳头状瘤相关的鼻腔鼻窦鳞状细胞癌的用途。According to the compound of formula (I) according to any one of claims 1-13, its stereoisomer or pharmaceutically acceptable salt thereof, it is used for the treatment and/or prevention of at least part of EGFR exon 20 insertion, Lung cancer, colon cancer, pancreatic cancer, head and neck cancer, breast cancer, ovarian cancer, uterine cancer, gastric cancer, non-small cell lung cancer, leukemia, myelodysplastic syndrome, malignant lymphoma, head and neck tumors caused by deletion or other mutations Thoracic tumors, gastrointestinal tumors, endocrine tumors, breast and other gynecologic tumors, urologic tumors, skin tumors, sarcomas, sinonasal inverted papillomas, or sinonasal squamous cells associated with sinonasal inverted papillomas cancer use.
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| CN106928200A (en) * | 2015-12-30 | 2017-07-07 | 湖南福沃药业有限公司 | For the pyrrolotriazine derivatives for the treatment of cancer |
| CN107406442A (en) * | 2014-12-23 | 2017-11-28 | 达纳－法伯癌症研究所公司 | New pyrimidine and sanatory method as EGFR inhibitor |
| CN108864079A (en) * | 2017-05-15 | 2018-11-23 | 深圳福沃药业有限公司 | A kind of triaizine compounds and its pharmaceutically acceptable salt |
| CN111747931A (en) * | 2019-03-29 | 2020-10-09 | 深圳福沃药业有限公司 | Azaaromatic cyclic amide derivatives for the treatment of cancer |
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| CN107406442A (en) * | 2014-12-23 | 2017-11-28 | 达纳－法伯癌症研究所公司 | New pyrimidine and sanatory method as EGFR inhibitor |
| CN106928200A (en) * | 2015-12-30 | 2017-07-07 | 湖南福沃药业有限公司 | For the pyrrolotriazine derivatives for the treatment of cancer |
| CN108864079A (en) * | 2017-05-15 | 2018-11-23 | 深圳福沃药业有限公司 | A kind of triaizine compounds and its pharmaceutically acceptable salt |
| CN111747931A (en) * | 2019-03-29 | 2020-10-09 | 深圳福沃药业有限公司 | Azaaromatic cyclic amide derivatives for the treatment of cancer |
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