CN115836064A - Triazine derivative with EGFR (epidermal growth factor receptor) inhibitory activity and preparation method and application thereof - Google Patents
Triazine derivative with EGFR (epidermal growth factor receptor) inhibitory activity and preparation method and application thereof Download PDFInfo
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- CN115836064A CN115836064A CN202180048451.0A CN202180048451A CN115836064A CN 115836064 A CN115836064 A CN 115836064A CN 202180048451 A CN202180048451 A CN 202180048451A CN 115836064 A CN115836064 A CN 115836064A
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- radical
- alkyl
- substituted
- deuterium
- membered
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- 238000002360 preparation method Methods 0.000 title claims abstract description 53
- 230000002401 inhibitory effect Effects 0.000 title abstract description 4
- 150000003918 triazines Chemical class 0.000 title abstract description 4
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- 125000001424 substituent group Chemical group 0.000 claims abstract description 103
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- 238000003780 insertion Methods 0.000 claims abstract description 17
- 230000037431 insertion Effects 0.000 claims abstract description 17
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 13
- 238000012217 deletion Methods 0.000 claims abstract description 12
- 230000037430 deletion Effects 0.000 claims abstract description 12
- 206010061289 metastatic neoplasm Diseases 0.000 claims abstract description 11
- 230000030833 cell death Effects 0.000 claims abstract description 7
- 230000003463 hyperproliferative effect Effects 0.000 claims abstract description 7
- 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
- -1 Alkyl radical Chemical class 0.000 claims description 527
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 claims description 246
- 229910052805 deuterium Inorganic materials 0.000 claims description 246
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- 125000000623 heterocyclic group Chemical group 0.000 claims description 156
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- 125000001072 heteroaryl group Chemical group 0.000 claims description 83
- 125000003118 aryl group Chemical group 0.000 claims description 79
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- 125000004093 cyano group Chemical group *C#N 0.000 claims description 66
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- 125000000000 cycloalkoxy group Chemical group 0.000 claims description 54
- 125000001313 C5-C10 heteroaryl group Chemical group 0.000 claims description 49
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- 150000005840 aryl radicals Chemical class 0.000 claims description 45
- 125000004104 aryloxy group Chemical group 0.000 claims description 44
- 125000005553 heteroaryloxy group Chemical group 0.000 claims description 42
- 150000003839 salts Chemical class 0.000 claims description 39
- 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 claims description 38
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- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 23
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- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 20
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- 125000002252 acyl group Chemical group 0.000 claims description 15
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- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 11
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- 125000006263 dimethyl aminosulfonyl group Chemical group [H]C([H])([H])N(C([H])([H])[H])S(*)(=O)=O 0.000 claims description 6
- 125000001153 fluoro group Chemical group F* 0.000 claims description 6
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- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 6
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 claims description 6
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 6
- 229910052717 sulfur Inorganic materials 0.000 claims description 6
- 125000006564 (C4-C8) cycloalkyl group Chemical group 0.000 claims description 5
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- 208000005718 Stomach Neoplasms Diseases 0.000 claims description 5
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- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims description 5
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- 208000008443 pancreatic carcinoma Diseases 0.000 claims description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 5
- 201000011549 stomach cancer Diseases 0.000 claims description 5
- 201000003957 thoracic cancer Diseases 0.000 claims description 5
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- 125000002861 (C1-C4) alkanoyl group Chemical group 0.000 claims description 4
- 201000011510 cancer Diseases 0.000 claims description 4
- 206010041823 squamous cell carcinoma Diseases 0.000 claims description 4
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 claims description 3
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 claims description 3
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 3
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 claims description 2
- 125000002393 azetidinyl group Chemical group 0.000 claims description 2
- 125000001246 bromo group Chemical group Br* 0.000 claims description 2
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 2
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- 201000009048 nasal cavity inverting papilloma Diseases 0.000 claims 2
- 238000004519 manufacturing process Methods 0.000 claims 1
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- 238000006243 chemical reaction Methods 0.000 description 140
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- 230000015572 biosynthetic process Effects 0.000 description 84
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- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical class OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 80
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- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 34
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- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 230000011664 signaling Effects 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- MSGMXYUAWZYTFC-UHFFFAOYSA-N sodium;2,2,2-trifluoroethanolate Chemical compound [Na+].[O-]CC(F)(F)F MSGMXYUAWZYTFC-UHFFFAOYSA-N 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 238000002626 targeted therapy Methods 0.000 description 1
- WAOQMSHPCRXODU-UHFFFAOYSA-N tert-butyl 5-ethynyl-3,3-dimethyl-2H-pyrrolo[3,2-b]pyridine-1-carboxylate Chemical compound CC(C)(C)OC(N1C2=CC=C(C#C)N=C2C(C)(C)C1)=O WAOQMSHPCRXODU-UHFFFAOYSA-N 0.000 description 1
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical group C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- IAQRGUVFOMOMEM-ONEGZZNKSA-N trans-but-2-ene Chemical compound C\C=C\C IAQRGUVFOMOMEM-ONEGZZNKSA-N 0.000 description 1
- 230000005945 translocation Effects 0.000 description 1
- 125000004784 trichloromethoxy group Chemical group ClC(O*)(Cl)Cl 0.000 description 1
- 125000003866 trichloromethyl group Chemical group ClC(Cl)(Cl)* 0.000 description 1
- WLPUWLXVBWGYMZ-UHFFFAOYSA-N tricyclohexylphosphine Chemical compound C1CCCCC1P(C1CCCCC1)C1CCCCC1 WLPUWLXVBWGYMZ-UHFFFAOYSA-N 0.000 description 1
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 238000004235 valence bond calculation Methods 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
- GTLDTDOJJJZVBW-UHFFFAOYSA-N zinc cyanide Chemical compound [Zn+2].N#[C-].N#[C-] GTLDTDOJJJZVBW-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/10—Spiro-condensed systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
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Abstract
Discloses triazine derivatives with EGFR inhibitory activity, and a preparation method and application thereof. In particular, an EGFR inhibitor with a structure shown in a formula (I), a preparation method thereof, a pharmaceutical composition containing the same, and application thereof in preparing an EGFR inhibitor and an application thereof in preparing a medicament for treating and/or preventing cancers, tumors or metastatic diseases at least partially related to insertion, deletion or other mutation of EGFR exon 20, especially in preparing a medicament for treating and/or preventing hyperproliferative diseases and diseases induced by cell death disorders are disclosed. Wherein each substituent group of the formula (I) is defined as the specification.
Description
The invention belongs to the field of drug synthesis, and particularly relates to a triazine derivative with EGFR (epidermal growth factor receptor) inhibitory activity, and 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%. Multi-target therapies against Epidermal Growth Factor Receptor (EGFR) mutations, anaplastic Lymphoma Kinase (ALK) translocations, ROS1 proto-oncogene receptor tyrosine kinase (ROS 1) rearrangements and B-raf proto-oncogenes, serine/threonine kinases (BRAF) have been successfully developed and clinically validated. Inhibitors against EGFR can significantly improve progression-free survival of adenocarcinomas in NSCLC, while their acquired resistance mutations can be targeted by third generation EGFR inhibitors.
Although classical EGFR activating mutations (exons 19 and 21) and drug resistance mutation (T790M) can be inhibited by existing drugs, insertional mutation of Exon 20 (Exon 20) also results in structural activation of EGFR signaling and is insensitive to existing EGFR inhibitors. Exon 20 mutations are heterogeneous, comprising insertions or repeats of 1-7 amino acids between amino acids 762-774 of the EGFR protein. In NSCLC, the mutation frequency of EGFR exon 20 is 4-10% of all mutations of EGFR. These mutations are mutually exclusive with other known oncogene-driven mutations and are enriched in adenocarcinomas in women, non-smokers, asian populations, and non-small cell lung cancer patients. In addition to NSCLC, EGFR exon 20 insertion mutation is 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 EGFR family.
Multiple retrospective analytical studies have shown that currently available EGFR inhibitors at passage 1,2 and 3 have limited efficacy against exon 20 insertion mutations, except for the a763-Y764insFQEA mutation. Irreversible inhibitors bosutinib (Poziotinib) and the EGFR/MET bispecific antibody Amivantamab are in clinical trials. Several small molecule inhibitors, including TAK-788 and TAS-6417, showed clinically significant efficacy in EGFR exon 20 non-small cell lung cancer patients. However, due to their limited selectivity for EGFR wild type, adverse effects in clinical use are inevitable and may lead to dose limiting toxicity. Meanwhile, the problem of insufficient exposure of the existing compound is clinically shown. Thus, there is an urgent need for small molecule inhibitors with higher exposure and/or high selectivity against EGFR exon 20 insertion mutations for these patients.
Disclosure of Invention
The series of compounds have strong inhibition effect on the cytological activity of insertion, deletion or other mutation of EGFR exon 20, have high selectivity on a wild type EGFR, and can be widely applied to preparation of medicaments for treating and/or preventing at least part of cancers, tumors or metastatic diseases related to insertion, deletion or other mutation of EGFR exon 20, particularly medicaments for treating hyperproliferative diseases and diseases for inducing cell death disorder, so that a new generation of EGFR inhibitors is expected to be developed.
In a first aspect, the present invention provides a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
wherein X is CH or N; y is a bond, O or S; z 1 And Z 2 Each independently is CR 10 Or N;
R 1 selected from hydrogen, deuterium, hydroxy, C 1-6 Alkyl, halo-substituted C 1-6 Alkyl, deuterium substituted C 1-6 Alkyl radical, C 2-4 Alkenyl radical, C 3-6 Cycloalkyl and 3-6 membered heterocyclyl;
R 2 and R 3 Each independently selected from hydrogen, deuterium, hydroxy, C 1-6 Alkyl radical, C 2-4 Alkenyl radical, C 3-6 Cycloalkyl and 3-6 membered heterocyclyl, independently optionally further substituted with one or more substituents selected from deuterium, halogen, hydroxy, C 1-10 Alkyl radical, C 2-10 Alkenyl radical, C 2-10 Alkynyl, halo-substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl radical, C 1-10 Alkoxy radical, C 3-12 Cycloalkyl radical, C 3-12 Cycloalkoxy, 3-12 membered heterocyclic group, 3-12 membered heterocyclic oxy, C 6-10 Aryl radical, C 6-10 Aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy and-C 0-8 alkyl-NR 14 R 15 Substituted with the substituent(s);
R 4 and R 5 Each independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, halo-substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl radical, C 2-10 Alkenyl radical, 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 11 、-OR 12 、-C(O)OR 12 、-C(O)R 13 、-O-C(O)R 13 、-NR 14 R 15 、-C(=NR 14 )R 13 、-N(R 14 )-C(=NR 15 )R 13 、-C(O)NR 14 R 15 and-N (R) 14 )-C(O)R 13 ;
Or, R 2 、R 4 Or R 5 One of them and R 1 Together with the moiety to which they are directly attached form a 4-8 membered heterocyclyl, R 2 、R 4 Or R 5 Wherein the other two are as defined above, or, R 4 Or R 5 One of them and R 2 Together with the moiety to which they are directly attached form a 4-8 membered heterocyclyl, R 4 Or R 5 Wherein another is as previously defined, said 4-8 membered heterocyclyl is optionally further substituted by one or more groups selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, halo-substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl radical, C 2-10 Alkenyl radical, 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 11 、-OR 12 、-C(O)OR 12 、-C(O)R 13 、-O-C(O)R 13 、-NR 14 R 15 、-C(=NR 14 )R 13 、-N(R 14 )-C(=NR 15 )R 13 、-C(O)NR 14 R 15 and-N (R) 14 )-C(O)R 13 Substituted with the substituent(s);
R 6 selected from hydrogen, deuterium, C 1-10 Alkyl radical, C 2-10 Alkenyl radical, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-10 Aryl and 5-10 membered heteroaryl, independently optionally further substituted with one or more substituents selected from deuterium, halogen, hydroxy, oxo, cyano, C 1-10 Alkyl radical, C 1-10 Alkoxy radical, C 3-12 Cycloalkyl radical, C 3-12 Cycloalkoxy, 3-12 membered heterocyclic group, 3-12 membered heterocyclic oxy, C 6-10 Aryl radical, C 6-10 Aryloxy, 5-to 10-membered heteroaryl, 5-to 10-membered heteroaryloxyand-NR 14 R 15 Substituted with the substituent(s);
R 7 selected from hydrogen, deuterium, halogen, cyano, C 1-4 Alkyl, halo-substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl radical, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, -C (O) OR 12 、-C(O)R 13 、-C(O)-NR 14 R 15 and-C 0-4 alkyl-NR 14 R 15 ;
R 8 And R 9 Each independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl radical, C 2-10 Alkenyl radical, C 2-10 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-10 Aryl and 5-10 membered heteroaryl, or, R 8 And R 9 Together with the carbon atom to which they are directly attached form C 3-6 Cycloalkyl or 3-6 membered heterocyclyl, independently optionally further substituted with one or more substituents selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl radical, C 2-10 Alkenyl radical, C 2-10 Alkynyl, halo-substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl radical, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-10 Aryl, 5-10 membered heteroaryl, = O, -SF 5 、-S(O) r R 11 、-O-R 12 、-C(O)OR 12 、-C(O)R 13 、-O-C(O)R 13 、-NR 14 R 15 、-C(=NR 14 )R 13 、-N(R 14 )-C(=NR 15 )R 13 、-C(O)NR 14 R 15 and-N (R) 14 )-C(O)R 13 Substituted with the substituent(s);
each R 10 Each independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl radical, C 2-10 Alkenyl radical, 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 11 、-O-R 12 、-C(O)OR 12 、-C(O)R 13 、-O-C(O)R 13 、-NR 14 R 15 、-C(=NR 14 )R 13 、-N(R 14 )-C(=NR 15 )R 13 、-C(O)NR 14 R 15 and-N (R) 14 )-C(O)R 13 Or, two adjacent R 10 Together with the directly attached part thereof form C 4-8 Cycloalkyl or 4-8 membered heterocyclyl, independently optionally further substituted with one or more substituents selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl radical, C 2-10 Alkenyl radical, C 2-10 Alkynyl, halo-substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl radical, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-10 Aryl, 5-10 membered heteroaryl, = O, -SF 5 、-S(O) r R 11 、-O-R 12 、-C(O)OR 12 、-C(O)R 13 、-O-C(O)R 13 、-NR 14 R 15 、-C(=NR 14 )R 13 、-N(R 14 )-C(=NR 15 )R 13 、-C(O)NR 14 R 15 and-N (R) 14 )-C(O)R 13 Substituted with the substituent(s);
each R 11 Each independently selected from hydrogen, deuterium, hydroxy, C 1-10 Alkyl radical, C 2-10 Alkenyl radical, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-10 Aryl, 5-10 membered heteroaryl and-NR 14 R 15 The above groups are independently optionally further substituted by one or more groups selected from deuterium, halogen, hydroxy, oxo, C 1-10 Alkyl radical, C 1-10 Alkoxy radical, C 3-12 Cycloalkyl radical, C 3-12 Cycloalkoxy, 3-12 membered heterocyclic group, 3-12 membered heterocyclic oxy, C 6-10 Aryl radical, C 6-10 Aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy and-NR 14 R 15 Substituted with the substituent(s);
each R 12 Each independently selected from hydrogen, deuterium, C 1-10 Alkyl radical, C 2-10 Alkenyl radical, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-10 Aryl and 5-10 membered heteroaryl, independently optionally further substituted with one or more substituents selected from deuterium, halogen, hydroxy, oxo, cyano, C 1-10 Alkyl radical, C 1-10 Alkoxy radical, C 3-12 Cycloalkyl radical, C 3-12 Cycloalkoxy, 3-12 membered heterocyclic group, 3-12 membered heterocyclic oxy, C 6-10 Aryl radical, C 6-10 Aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, and-NR 14 R 15 Substituted with the substituent(s);
each R 13 Each independently selected from hydrogen, deuterium, hydroxy, C 1-10 Alkyl radical, C 1-10 Alkoxy radical, C 2-10 Alkenyl radical, C 2-10 Alkynyl, C 3-12 Cycloalkyl radical, C 3-12 Cycloalkoxy, 3-12 membered heterocyclic group, 3-12 membered heterocyclic oxy, C 6-10 Aryl radical, C 6-10 Aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, and-NR 14 R 15 The above groups are independently optionally further substituted by one or more groups selected from deuterium, halogen, hydroxy, cyano, C 1-10 Alkyl radical, C 1-10 Alkoxy radical, C 3-12 Cycloalkyl radical, C 3-12 Cycloalkoxy, 3-12 membered heterocyclic group, 3-12 membered heterocyclic oxy, C 6-10 Aryl radical, C 6-10 Aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy and-NR 14 R 15 Substituted with the substituent(s);
each one of which isR 14 And R 15 Each independently selected from hydrogen, deuterium, hydroxy, C 1-10 Alkoxy radical, C 1-10 Alkyl radical, C 2-10 Alkenyl radical, C 2-10 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-10 Aryl, 5-to 10-membered heteroaryl, sulfinyl, sulfonyl, methanesulfonyl, isopropylsulfonyl, cyclopropylsulfonyl, p-toluenesulfonyl, aminosulfonyl, dimethylaminosulfonyl, amino, mono-C 1-10 Alkylamino, di-C 1-10 Alkylamino and C 1-10 Alkanoyl, said groups being independently optionally further substituted by one or more substituents selected from deuterium, halogen, hydroxy, C 1-10 Alkyl radical, C 2-10 Alkenyl radical, C 2-10 Alkynyl, halo-substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl radical, C 1-10 Alkoxy radical, C 3-12 Cycloalkyl, C 3-12 Cycloalkoxy, 3-12 membered heterocyclic group, 3-12 membered heterocyclic oxy, C 6-10 Aryl radical, 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 1-10 Substituted by the substituent of the alkanoyl group,
or, R 14 And R 15 Together with the nitrogen atom to which they are directly attached form a 4-10 membered heterocyclyl or 5-10 membered heteroaryl group, which groups are independently optionally further substituted by one or more groups selected from deuterium, halogen, hydroxy, C 1-10 Alkyl radical, C 2-10 Alkenyl radical, C 2-10 Alkynyl, halo-substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl radical, C 1-10 Alkoxy radical, C 3-12 Cycloalkyl radical, C 3-12 Cycloalkoxy, 3-12 membered heterocyclic group, 3-12 membered heterocyclic oxy, C 6-10 Aryl radical, C 6-10 Aryloxy, 5-to 10-membered heteroaryl, 5-to 10-membered heteroaryloxy, amino, mono C 1-10 Alkylamino, di-C 1-10 Alkylamino and C 1-10 Substituted by alkanoyl group;
m is 0, 1 or 2;
n is 0, 1 or 2; and is
Each r is independently 0, 1 or 2.
As a preferred embodiment, in said compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, R 6 Selected from hydrogen, deuterium, C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, C 6-8 Aryl and 5-8 membered heteroaryl, independently optionally further substituted with one or more substituents selected from deuterium, halogen, hydroxy, oxo, cyano, C 1-4 Alkyl radical, C 1-4 Alkoxy radical, C 3-8 Cycloalkyl, C 3-8 Cycloalkoxy, 3-to 8-membered heterocyclic group, 3-to 8-membered heterocyclic oxy group, C 6-8 Aryl radical, C 6-8 Aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy and-NR 14 R 15 Substituted with the substituent(s);
R 7 selected from hydrogen, deuterium, halogen, cyano, C 1-4 Alkyl, halo-substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl radical, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl and-C 0-4 alkyl-NR 14 R 15 ;
Wherein R is 14 And R 15 As defined for the compounds of formula (I).
As a preferred embodiment, in said compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, R 8 And R 9 Each independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, C 6-8 Aryl and 5-8 membered heteroaryl, or, R 8 And R 9 Together with the carbon atom to which it is directly attached form C 3-6 Cycloalkyl or 3-6 membered heterocyclyl, the above groupsIndependently optionally further substituted with one or more groups selected from deuterium, halogen, cyano, nitro, azido, C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, halo-substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl radical, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, C 6-8 Aryl, 5-8 membered heteroaryl, = O, -SF 5 、-S(O) r R 11 、-O-R 12 、-C(O)OR 12 、-C(O)R 13 、-O-C(O)R 13 、-NR 14 R 15 、-C(=NR 14 )R 13 、-N(R 14 )-C(=NR 15 )R 13 、-C(O)NR 14 R 15 and-N (R) 14 )-C(O)R 13 Substituted with the substituent(s);
wherein R is 11 、R 12 、R 13 、R 14 、R 15 And r is as defined for compounds of formula (I).
As a preferred embodiment, in said compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, each R is 10 Each independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-4 Alkyl radical, C 2-4 Alkenyl radical, 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 11 、-O-R 12 、-C(O)OR 12 、-C(O)R 13 、-O-C(O)R 13 、-NR 14 R 15 、-C(O)NR 14 R 15 and-N (R) 14 )-C(O)R 13 Or, two adjacent R 10 Together with the directly attached part thereof form C 4-8 Cycloalkyl or 4-8 membered heterocyclyl, independently optionally further substituted with one or more groups selected from deuterium, halogen, cyano, nitro, azido、C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, halo-substituted C 1-4 Alkyl radical, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, C 6-8 Aryl, 5-8 membered heteroaryl, = O, -SF 5 、-S(O) r R 11 、-O-R 12 、-C(O)OR 12 、-C(O)R 13 、-O-C(O)R 13 、-NR 14 R 15 、-C(=NR 14 )R 13 、-N(R 14 )-C(=NR 15 )R 13 、-C(O)NR 14 R 15 and-N (R) 14 )-C(O)R 13 Substituted with the substituent(s);
wherein R is 11 、R 12 、R 13 、R 14 、R 15 And r is as defined for compounds of formula (I).
As a preferred embodiment, in said compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, R 1 Selected from hydrogen, deuterium, hydroxy, C 1-4 Alkyl, halo-substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 3-6 Cycloalkyl and 3-6 membered heterocyclyl;
R 2 and R 3 Each independently selected from hydrogen, deuterium and C 1-4 Alkyl, said groups being independently optionally further substituted by one or more groups selected from deuterium, halogen, hydroxy, C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, halo-substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl radical, C 1-4 Alkoxy radical, C 3-8 Cycloalkyl radical, C 3-8 Cycloalkoxy, 3-to 8-membered heterocyclic group, 3-to 8-membered heterocyclic oxy group, C 6-8 Aryl radical, C 6-8 Aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy and-C 0-4 alkyl-NR 14 R 15 Substituted with a substituent of (a);
R 4 and R 5 Each independently selected from hydrogen, deuterium, halogen, cyano, C 1-4 Alkyl, halo-substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, C 6-8 Aryl, 5-8 membered heteroaryl, -OR 12 、-C(O)OR 12 、-C(O)R 13 、-O-C(O)R 13 、-NR 14 R 15 、-C(O)NR 14 R 15 and-N (R) 14 )-C(O)R 13 ;
Or, R 2 、R 4 Or R 5 One of them and R 1 Together with the directly attached parts, form the following structure:
R 2 、R 4 or R 5 Wherein the other two are as defined above, R 3 As previously defined;
or, R 4 Or R 5 One of them and R 2 Together with the directly connected parts, form the following structure:
R 4 or R 5 Wherein the other is as previously defined, R 1 Or R 3 As previously defined;
wherein R is 12 、R 13 、R 14 And R 15 As defined for the compounds of formula (I).
As a further preferred embodiment, the compound of formula (I) is a compound of formula (iia) as follows:
wherein, X is CH or N; z 2 Is CH or N;
R 2 、R 4 or R 5 One of them and R 1 Together with the directly connected parts, form the following structure:
each R 2 And R 3 Each independently selected from hydrogen, deuterium and C 1-4 Alkyl, said groups being independently optionally further substituted by one or more groups selected from deuterium, halogen, hydroxy, C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, halo-substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl and-C 0-4 alkyl-NR 14 R 15 Substituted with the substituent(s);
or, R 4 Or R 5 One of them and R 2 Together with the directly attached parts, form the following structure:
each R 1 Each independently selected from hydrogen, deuterium, C 1-4 Alkyl, halo-substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl and C 2-4 An alkenyl group;
each R 3 Each independently selected from hydrogen, deuterium and C 1-4 Alkyl, said groups being independently optionally further substituted by one or more groups selected from deuterium, halogen, hydroxy, C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, halo-substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl and-C 0-4 alkyl-NR 14 R 15 Substituted with a substituent of (a);
R 6 selected from hydrogen, deuterium, C 1-4 Alkyl, halo-substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 3-8 Cycloalkyl and 3-8 membered heterocyclyl;
R 8 and R 9 Each independently selected from hydrogen, deuterium, halogen, cyano, C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, C 6-8 Aryl and 5-8 membered heteroaryl, or, R 8 And R 9 Together with the carbon atom to which they are directly attached form C 3-6 Cycloalkyl or 3-6 membered heterocyclyl, independently optionally further substituted with one or more substituents selected from deuterium, halogen, cyano, hydroxy, C 1-4 Alkyl radical, C 1-4 Alkoxy radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, halo-substituted C 1-4 Alkyl, halo-substituted C 1-4 Alkoxy, deuterium substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkoxy radical, C 3-8 Cycloalkyl radical, C 3-8 Cycloalkoxy, 3-to 8-membered heterocyclic group, 3-to 8-membered heterocyclic oxy group, C 6-8 Aryl and 5-8 membered heteroaryl;
each R 10 Each independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-4 Alkyl radical, C 2-4 Alkenyl radical, 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 11 、-O-R 12 、-C(O)OR 12 、-C(O)R 13 、-O-C(O)R 13 、-NR 14 R 15 、-C(O)NR 14 R 15 and-N (R) 14 )-C(O)R 13 Or, two adjacent R 10 Together with the directly attached part thereof form C 4-6 Cycloalkyl or 4-6 membered heterocyclyl, independently optionally further substituted by one or more substituents selected from deuterium, halogen, cyano, nitro, azido, C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, halo-substituted C 1-4 Alkyl radical, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, C 6-8 Aryl, 5-8 membered heteroaryl, = O, -SF 5 、-S(O) r R 11 、-O-R 12 、-C(O)OR 12 、-C(O)R 13 、-O-C(O)R 13 、-NR 14 R 15 、-C(=NR 14 )R 13 、-N(R 14 )-C(=NR 15 )R 13 、-C(O)NR 14 R 15 and-N (R) 14 )-C(O)R 13 Substituted with the substituent(s);
each R 11 Each independently selected from hydrogen, deuterium, hydroxy, C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, C 6-8 Aryl, 5-8 membered heteroaryl and-NR 14 R 15 The above groups are independently optionally further substituted by one or more groups selected from deuterium, halogen, hydroxy, oxo, C 1-4 Alkyl radical, C 1-4 Alkoxy radical, C 3-8 Cycloalkyl radical, C 3-8 Cycloalkoxy, 3-to 8-membered heterocyclic group, 3-to 8-membered heterocyclic oxy group, C 6-8 Aryl radical, C 6-8 Aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy and-NR 14 R 15 Substituted with the substituent(s);
each R 12 Each independently selected from hydrogen, deuterium, C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, C 6-8 Aryl and 5-8 membered heteroaryl, independently optionally further substituted with one or more substituents selected from deuterium, halogen, hydroxy, oxo, cyano, C 1-4 Alkyl radical, C 1-4 Alkoxy radical, C 3-8 Cycloalkyl radical, C 3-8 Cycloalkoxy, 3-to 8-membered heterocyclic group, 3-to 8-membered heterocyclic oxy group, C 6-8 Aryl radical, C 6-8 Aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy and-NR 14 R 15 Substituted with the substituent(s);
each R 13 Each independently selected from hydrogen, deuterium, hydroxy, C 1-4 Alkyl radical, C 1-4 Alkoxy radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, C 3-8 Cycloalkyl, C 3-8 Cycloalkoxy, 3-to 8-membered heterocyclic group, 3-to 8-membered heterocyclic oxy group, C 6-8 Aryl radical, C 6-8 Aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy and-NR 14 R 15 The above groups are independently optionally further substituted by one or more groups selected from deuterium, halogen, hydroxy, cyano, C 1-4 Alkyl radical, C 1-4 Alkoxy radical, C 3-8 Cycloalkyl radical, C 3-8 Cycloalkoxy, 3-to 8-membered heterocyclic group, 3-to 8-membered heterocyclic oxy group, C 6-8 Aryl radical, C 6-8 Aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy and-NR 14 R 15 Substituted with the substituent(s);
each R 14 And R 15 Each independently selected from hydrogen, deuterium, hydroxy, C 1-4 Alkoxy radical, C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, C 6-8 Aryl, 5-8 membered heteroaryl, sulfinyl, sulfonyl, methanesulfonyl, isopropylsulfonyl, cyclopropylsulfonyl, p-toluenesulfonyl, aminosulfonylAlkyl, dimethylaminosulfonyl, amino, mono C 1-4 Alkylamino, di-C 1-4 Alkylamino and C 1-4 Alkanoyl, said groups being independently optionally further substituted by one or more substituents selected from deuterium, halogen, hydroxy, C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, halo-substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl radical, C 1-4 Alkoxy radical, C 3-8 Cycloalkyl radical, C 3-8 Cycloalkoxy, 3-8 membered heterocyclic group, 3-8 membered heterocyclic oxy, C 6-8 Aryl radical, 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 Substituted by the substituent of the alkanoyl group,
or, R 14 And R 15 Together with the nitrogen atom to which they are directly attached form a 4-8 membered heterocyclyl or 5-8 membered heteroaryl group, which groups are independently optionally further substituted by one or more groups selected from deuterium, halogen, hydroxy, C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, halo-substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl radical, C 1-4 Alkoxy radical, C 3-8 Cycloalkyl, C 3-8 Cycloalkoxy, 3-to 8-membered heterocyclic group, 3-to 8-membered heterocyclic oxy group, C 6-8 Aryl radical, 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 Substituted by a substituent of alkanoyl;
m is 0, 1 or 2;
n is 0, 1 or 2; and is
Each r is independently 0, 1 or 2.
As a still further preferred embodiment, the compound of formula (I) is a compound of formula (iiia) as follows:
wherein X is CH or N; z 2 Is CH or N;
R 2 、R 4 or R 5 One of them and R 1 Together with the directly connected parts, form the following structure:
R 6 selected from hydrogen, deuterium, C 1-2 Alkyl, halo-substituted C 1-2 Alkyl and deuterium substituted C 1-2 An alkyl group;
R 8 and R 9 Each independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, cyclopropyl, -CHF 2 、-CF 3 、-CHD 2 and-CD 3 ;
R 10a And R 10b Each independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, propyl, isopropyl, cyclopropyl, -CHF 2 、-CF 3 、-CHD 2 、-CD 3 Methoxy, azetidinyl, ethenyl, ethynyl and phenyl, or, R 10a And R 10b Together with the directly attached part thereof form C 4-6 Cycloalkyl or 4-6 membered heterocyclyl.
As a further preferred embodiment, the compound of formula (I) is a compound of formula (iib) as follows:
wherein X is CH or N; y is a bond, O or S; z is a linear or branched member 1 Is CR 10 Or N; z 2 Is CH or N;
R 1 selected from hydrogen, deuterium, C 1-4 Alkyl, halo-substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl and C 2-4 An alkenyl group;
R 2 and R 3 Each independently selected from hydrogen, deuterium and C 1-4 Alkyl, said groups being independently optionally further substituted by one or more groups selected from deuterium, halogen, hydroxy, C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, halo-substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl and-C 0-4 alkyl-NR 14 R 15 Substituted with a substituent of (a);
R 4 selected from hydrogen, deuterium, halogen, C 1-4 Alkyl, halo-substituted C 1-4 Alkyl and deuterium substituted C 1-4 An alkyl group;
R 5 selected from hydrogen, deuterium, halogen, C 1-4 Alkyl, halo-substituted C 1-4 Alkyl and deuterium substituted C 1-4 An alkyl group;
R 6 selected from hydrogen, deuterium, C 1-4 Alkyl, halo-substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 3-8 Cycloalkyl and 3-8 membered heterocyclyl;
R 8 and R 9 Each independently selected from hydrogen, deuterium, halogen, cyano, C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, C 6-8 Aryl and 5-8 membered heteroaryl, or, R 8 And R 9 Together with the carbon atom to which it is directly attached form C 3-6 Cycloalkyl or 3-6 membered heterocyclyl, independently optionally further substituted with one or more substituents selected from deuterium, halogen, cyano, hydroxy, C 1-4 Alkyl radical, C 1-4 Alkoxy radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, halo-substituted C 1-4 Alkyl, halo-substituted C 1-4 Alkoxy, deuterium substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkoxy radical, C 3-8 Cycloalkyl radical, C 3-8 Cycloalkoxy, 3-8 membered heterocyclic group, 3-8 membered heterocyclic oxy, C 6-8 Aryl and 5-8 membered heteroaryl;
each R 10 Each independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-4 Alkyl radical, C 2-4 Alkenyl radical, 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 11 、-O-R 12 、-C(O)OR 12 、-C(O)R 13 、-O-C(O)R 13 、-NR 14 R 15 、-C(O)NR 14 R 15 and-N (R) 14 )-C(O)R 13 Or, two adjacent R 10 Together with the directly attached part thereof form C 4-6 Cycloalkyl or 4-6 membered heterocyclyl, independently optionally further substituted by one or more groups selected from deuterium, halogen, cyano, nitro, azido, C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, halo-substituted C 1-4 Alkyl radical, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, C 6-8 Aryl, 5-8 membered heteroaryl, = O, -SF 5 、-S(O) r R 11 、-O-R 12 、-C(O)OR 12 、-C(O)R 13 、-O-C(O)R 13 、-NR 14 R 15 、-C(=NR 14 )R 13 、-N(R 14 )-C(=NR 15 )R 13 、-C(O)NR 14 R 15 and-N (R) 14 )-C(O)R 13 Provided that when X is CH, Y is a bond, and n is 1, R is 10 And R 10a One of them is hydrogen, halogen or C 1-4 When alkyl, the other is not hydrogen, halogen or C 1-4 An alkyl group;
each R 11 Each independently selected from hydrogen, deuterium, hydroxy, C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, C 6-8 Aryl, 5-8 membered heteroaryl and-NR 14 R 15 The above groups are independently optionally further substituted by one or more groups selected from deuterium, halogen, hydroxy, oxo, C 1-4 Alkyl radical, C 1-4 Alkoxy radical, C 3-8 Cycloalkyl radical, C 3-8 Cycloalkoxy, 3-to 8-membered heterocyclic group, 3-to 8-membered heterocyclic oxy group, C 6-8 Aryl radical, C 6-8 Aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy and-NR 14 R 15 Substituted with a substituent of (a);
each R 12 Each independently selected from hydrogen, deuterium, C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, C 6-8 Aryl and 5-8 membered heteroaryl, independently optionally further substituted with one or more substituents selected from deuterium, halogen, hydroxy, oxo, cyano, C 1-4 Alkyl radical, C 1-4 Alkoxy radical, C 3-8 Cycloalkyl radical, C 3-8 Cycloalkoxy, 3-to 8-membered heterocyclic group, 3-to 8-membered heterocyclic oxy group, C 6-8 Aryl radical, C 6-8 Aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy and-NR 14 R 15 Substituted with the substituent(s);
each R 13 Each independently selected from hydrogen, deuterium, hydroxy, C 1-4 Alkyl radical, C 1-4 Alkoxy radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, C 3-8 Cycloalkyl radical, C 3-8 Cycloalkoxy, 3-to 8-membered heterocyclic group, 3-to 8-membered heterocyclic oxy group, C 6-8 Aryl radical, C 6-8 Aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy and-NR 14 R 15 The above groups are independently optionally further substituted by one or more groups selected from deuterium, halogen, hydroxy, cyano, C 1-4 Alkyl radical, C 1-4 Alkoxy radical, C 3-8 Cycloalkyl radical, C 3-8 Cycloalkoxy, 3-to 8-membered heterocyclic group, 3-to 8-membered heterocyclic oxy group, C 6-8 Aryl radical, C 6-8 Aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy and-NR 14 R 15 Substituted with the substituent(s);
each R 14 And R 15 Each independently selected from hydrogen, deuterium, hydroxy, C 1-4 Alkoxy radical, C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, C 6-8 Aryl, 5-8 membered heteroaryl, sulfinyl, sulfonyl, methanesulfonyl, isopropylsulfonyl, cyclopropylsulfonyl, p-toluenesulfonyl, aminosulfonyl, dimethylaminosulfonyl, amino, mono-C 1-4 Alkylamino, di-C 1-4 Alkylamino and C 1-4 Alkanoyl, said groups being independently optionally further substituted by one or more substituents selected from deuterium, halogen, hydroxy, C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, halo-substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl radical, C 1-4 Alkoxy radical, C 3-8 Cycloalkyl radical, C 3-8 Cycloalkoxy, 3-8 membered heterocyclic group, 3-8 membered heterocyclic oxy, C 6-8 Aryl radical, 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 Substitution of alkanoyl groupsThe substituent(s) of the group(s),
or, R 14 And R 15 Together with the nitrogen atom to which they are directly attached form a 4-8 membered heterocyclyl or 5-8 membered heteroaryl group, which groups are independently optionally further substituted by one or more groups selected from deuterium, halogen, hydroxy, C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, halo-substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl radical, C 1-4 Alkoxy radical, C 3-8 Cycloalkyl radical, C 3-8 Cycloalkoxy, 3-to 8-membered heterocyclic group, 3-to 8-membered heterocyclic oxy group, C 6-8 Aryl radical, 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 Substituted by alkanoyl group;
m is 0, 1 or 2;
n is 0, 1 or 2; and is
Each r is independently 0, 1 or 2.
As a still further preferred embodiment, the compound of formula (I) is a compound of formula (iiib) as follows:
wherein X is CH or N; y is a bond, O or S; z 1 Is CR 10 Or N; z is a linear or branched member 2 Is CH or N;
R 6 selected from hydrogen, deuterium, C 1-4 Alkyl, halo-substituted C 1-2 Alkyl and deuterium substituted C 1-2 An alkyl group;
R 8 and R 9 Each independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, cyclopropyl, -CHF 2 、-CF 3 、-CHD 2 and-CD 3 ;
R 10 And R 10a Each independently selected from hydrogen, deuterium, fluoro, chloro, bromo, cyano, methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, ethynyl, azetidinyl, pyrazole, and phenyl, or R 10 And R 10a The directly linked parts of which together form a cyclopentyl or 5-membered heterocyclyl group, which groups are independently optionally further substituted by one or more groups selected from deuterium, fluoro, chloro, bromo, cyano, C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, halo-substituted C 1-4 Alkyl and cyclopropyl, provided that when X is CH, Y is a bond, and n is 1, R is 10 And R 10a One of which is hydrogen, deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, propyl or isopropyl, and the other is not hydrogen, deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, propyl or isopropyl;
n is 0, 1 or 2.
As a most preferred embodiment, the compound of formula (I), its stereoisomers or pharmaceutically acceptable salts thereof include, but are not limited to, the following compounds:
in a second aspect, the present invention provides a process for the preparation of a compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, comprising the steps of:
or,
wherein R is 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 、R 10 、X、Y、Z 1 、Z 2 M and n are as defined for compounds of formula (I).
In a third aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
The invention also relates to the use of said compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the treatment and/or prevention of cancer, tumors or metastatic diseases associated at least in part with EGFR exon 20 insertions, deletions or other mutations.
The invention also relates to the use of a compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the prevention and/or treatment of tumors, cancers and/or metastatic diseases caused by hyperproliferative and induced cell death disorders. The invention also relates to application of the compound shown in the formula (I), a stereoisomer or a pharmaceutically acceptable salt thereof in preparing a medicament for preventing and/or treating 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 tumors, gastrointestinal tumors, endocrine tumors, breast and other gynecological tumors, urological tumors, skin tumors, sarcomas, nasal sinus inversion papilloma or sinus squamous cell carcinoma of nasal cavity related to the nasal sinus inversion papilloma.
The invention also relates to said compounds of formula (I), their stereoisomers or pharmaceutically acceptable salts thereof, for use as a medicament.
The invention also relates to said compounds of formula (I), stereoisomers thereof or pharmaceutically acceptable salts thereof, for use in the treatment and/or prevention of cancer, tumors or metastatic diseases associated at least in part with EGFR exon 20 insertions, deletions or other mutations.
The present invention also relates to said compounds of formula (I), their stereoisomers or pharmaceutically acceptable salts thereof, and their use for the prevention and/or treatment of tumors, cancers and/or metastatic diseases caused by hyperproliferative and cell death-inducing disorders.
The invention also relates to the use of said compound of formula (I), a stereoisomer thereof or a 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 syndromes, malignant lymphomas, head and neck tumors, thoracic tumors, gastrointestinal tumors, endocrine tumors, breast and other gynecological tumors, urological tumors, skin tumors, sarcomas, sinus papillomas or sinus squamous cell carcinoma of the nasal cavity associated with sinus papillomas inverted from the sinus of the nasal cavity.
The present invention also relates to a method of treating and/or preventing cancer, tumor or metastatic disease associated at least in part with an EGFR exon 20 insertion, deletion or other mutation, comprising administering to a patient in need thereof a therapeutically effective amount of said compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof.
The present invention also relates to a method for preventing and/or treating tumors, cancers and/or metastatic diseases caused by hyperproliferative and cell death-inducing disorders, which comprises administering a therapeutically effective amount of the compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof to a patient in need thereof.
The present invention also relates to a method of 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 tumors, gastrointestinal tumors, endocrine tumors, breast and other gynecological tumors, urological tumors, skin tumors, sarcomas, sinus-inversion papillomas of the nasal cavity or sinus-squamous carcinoma of the nasal cavity associated with sinus-inversion papillomas of the nasal cavity, associated at least in part with EGFR exon 20 insertion, deletion or other mutation, comprising administering to a patient in need thereof a therapeutically effective amount of said compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.
The inventor of the present invention has studied extensively and deeply, and developed an EGFR inhibitor having the structure of the following formula (i) for the first time, and the series of compounds of the present invention can be widely used for preparing drugs for treating and/or preventing cancers, tumors or metastatic diseases associated at least in part with insertion, deletion or other mutation of EGFR exon 20, particularly drugs for treating hyperproliferative diseases and inducing cell death disorder diseases, and are expected to be developed into a new generation of EGFR inhibitors. On the basis of this, the present invention has been completed.
Detailed description: unless stated to the contrary or otherwise indicated, the following terms used in the specification and claims have the following meanings.
"alkyl" refers to a straight or branched chain saturated aliphatic hydrocarbon group, preferably including straight and branched chain alkyl groups of 1 to 10 or 1 to 6 carbon atoms or 1 to 4 carbon atoms, including but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl1, 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-dimethylpentyl, 2, 4-dimethylpentyl, 2-dimethylpentyl, 3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2, 3-dimethylhexyl, 2, 4-dimethylhexyl, 2, 5-dimethylhexyl, 2-dimethylhexyl, 3-dimethylhexyl, 4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, or various branched isomers thereof, and the like. "C 1-10 Alkyl "refers to straight and branched alkyl groups comprising 1 to 10 carbon atoms," C 1-6 Alkyl "refers to straight and branched alkyl groups comprising 1 to 6 carbon atoms," C 1-4 Alkyl "refers to straight and branched alkyl groups comprising 1 to 4 carbon atoms," C 1-2 Alkyl "refers to a straight chain alkyl group comprising 1 to 2 carbon atoms," C 0-8 Alkyl "refers to straight and branched alkyl groups comprising from 0 to 8 carbon atoms," C 0-4 Alkyl "refers to straight and branched alkyl groups comprising 0 to 4 carbon atoms," C 0-2 Alkyl "refers to straight chain alkyl and branched chain containing alkyl groups comprising from 0 to 2 carbon atoms.
Alkyl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more (preferably 1,2,3 or 4) groups independently selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl radical, C 2-10 Alkenyl radical, C 2-10 Alkynyl, halo-substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl radical, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-10 Aryl, 5-to 10-membered heteroaryl, = O, -SF 5 、-S(O) r R 11 、-O-R 12 、-C(O)OR 12 、-C(O)R 13 、-O-C(O)R 13 、-NR 14 R 15 、-C(=NR 14 )R 13 、-N(R 14 )-C(=NR 15 )R 13 、-C(O)NR 14 R 15 or-N (R) 14 )-C(O)R 13 Substituted with the substituent(s).
"cycloalkyl" or "carbocycle" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, by which is meant a cyclic hydrocarbon which may contain one or more (preferably 1,2 or 3) double bonds, but none of the rings have a fully conjugated pi-electron system, and is classified as monocyclic cycloalkyl, polycyclic cycloalkyl, preferably cycloalkyl containing from 3 to 12 or from 3 to 8 or from 3 to 6 carbon atoms, e.g., "C 3-12 Cycloalkyl "refers to a cycloalkyl group comprising 3 to 12 carbon atoms," C 3-8 Cycloalkyl "refers to a cycloalkyl group comprising 3 to 8 carbon atoms," C 3-6 Cycloalkyl "refers to a cycloalkyl group comprising 3 to 6 carbon atoms," C 4-8 Cycloalkyl "refers to a cycloalkyl group comprising 4 to 8 carbon atoms," C 4-6 Cycloalkyl "refers to a cycloalkyl group comprising 4 to 6 carbon atoms, wherein:
monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like.
Polycyclic cycloalkyl groups include spiro, fused and bridged cycloalkyl groups. "spirocycloalkyl" refers to polycyclic groups which share a carbon atom (referred to as a spiro atom) between single rings, and these may contain one or more (preferably 1,2 or 3) double bonds, but none of the rings have a completely conjugated pi-electron system. Spirocycloalkyl groups are classified as mono-, di-or multi-spirocycloalkyl depending on the number of spiro atoms shared between rings, including but not limited to:
"fused cyclic alkyl" refers to an all-carbon polycyclic group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more of the rings may contain one or more (preferably 1,2 or 3) double bonds, but none of the rings has a completely conjugated pi-electron system. And may be classified as bicyclic, tricyclic, tetracyclic, or polycyclic fused ring alkyl groups depending on the number of constituent rings, including, but not limited to:
"bridged cycloalkyl" refers to an all-carbon polycyclic group in which any two rings share two carbon atoms not directly connected, and these may contain one or more (preferably 1,2 or 3) double bonds, but none of the rings have a completely conjugated pi-electron system. Depending on the number of constituent rings, bicyclic, tricyclic, tetracyclic, or polycyclic bridged cycloalkyl groups may be included, including but not limited to:
the cycloalkyl ring may be fused to an aryl, heteroaryl or heterocycloalkyl ring, where the ring to which the parent structure is attached is a cycloalkyl group, including but not limited to indanyl, tetrahydronaphthyl, benzocycloheptanyl, and the like.
Cycloalkyl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more (preferably 1,2,3 or 4) groups independently selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl radical, C 2-10 Alkenyl radical, C 2-10 Alkynyl, halo-substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl radical, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-10 Aryl, 5-10 membered heteroaryl, = O, -SF 5 、-S(O) r R 11 、-O-R 12 、-C(O)OR 12 、-C(O)R 13 、-O-C(O)R 13 、-NR 14 R 15 、-C(=NR 14 )R 13 、-N(R 14 )-C(=NR 15 )R 13 、-C(O)NR 14 R 15 or-N (R) 14 )-C(O)R 13 Substituted with the substituent(s).
"Heterocyclyl" or "heterocycle" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, by which is meant a cyclic hydrocarbon which may contain one or more (preferably 1,2 or 3) double bonds, but none of the rings have a fully conjugated pi-electron system, and heterocyclyl, wherein one or more (preferably 1,2,3 or 4) ring atoms are selected from nitrogen, oxygen or S (O) r (wherein r is an integer of 0, 1, 2), but excludes the ring moiety of-O-O-, -O-S-, or-S-S-, the remaining ring atoms being carbon, preferably a heterocyclic group comprising 3 to 12 or 3 to 8 or 3 to 6 ring atoms, e.g., "3-6 membered heterocyclic group" means a cyclic group containing 3 to 6 ring atoms, "3-8 membered heterocyclic group" means a cyclic group containing 3 to 8 ring atoms, "3-12 membered heterocyclic group" means a cyclic group containing 3 to 12 ring atoms, "4-6 membered heterocyclic group" means a cyclic group containing 4 to 6 ring atoms, "4-8 membered heterocyclic group" means a cyclic group containing 4 to 8 ring atoms, "4-10 membered heterocyclic group" means a cyclic group containing 4 to 10 ring atoms, and "5 membered heterocyclic group" means a cyclic group containing 5 ring atoms.
Monocyclic heterocyclyl groups include, but are not limited to, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and the like.
Polycyclic heterocyclic groups include spiro, fused and bridged heterocyclic groups. "Spiroheterocyclyl" refers to polycyclic heterocyclic groups having a single ring atom in common (called the spiro atom) wherein one or more (preferably 1,2,3 or 4) ring atoms are selected from nitrogen, oxygen or S (O) r (wherein r is an integer of 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 has a completely conjugated pi-electron system. Spiro heterocyclic groups are classified into a mono-spiro heterocyclic group, a di-spiro heterocyclic group, or a multi-spiro heterocyclic group according to the number of spiro atoms shared between rings. Screw threadHeterocyclic groups 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 may contain one or more (preferably 1,2 or 3) double bonds, but none of the rings has a fully conjugated pi-electron system, wherein one or more (preferably 1,2,3 or 4) ring atoms is selected from nitrogen, oxygen or S (O) r (wherein r is an integer of 0, 1, 2) and the remaining ring atoms are carbon. They may be classified as bicyclic, tricyclic, tetracyclic, or polycyclic fused heterocycloalkyl depending on the number of rings comprising, but not limited to:
"bridged heterocyclyl" means polycyclic heterocyclic groups in which any two rings share two atoms which are not directly attached, and these may contain one or more (preferably 1,2 or 3) double bonds, but none of the rings has a completely conjugated pi-electron system, where one or more (preferably 1,2,3 or 4) ring atoms are selected from nitrogen, oxygen or S (O) r (wherein r is an integer of 0, 1, 2) and the remaining ring atoms are carbon. They may be classified as bicyclic, tricyclic, tetracyclic, or polycyclic bridged heterocyclic groups, depending on the number of constituent rings, including but not limited to:
the heterocyclyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring to which the parent structure is attached is heterocyclyl, including but not limited to:
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) groups independently selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl radical, C 2-10 Alkenyl radical, C 2-10 Alkynyl, halo-substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl radical, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-10 Aryl, 5-10 membered heteroaryl, = O, -SF 5 、-S(O) r R 11 、-O-R 12 、-C(O)OR 12 、-C(O)R 13 、-O-C(O)R 13 、-NR 14 R 15 、-C(=NR 14 )R 13 、-N(R 14 )-C(=NR 15 )R 13 、-C(O)NR 14 R 15 or-N (R) 14 )-C(O)R 13 Substituted with the substituent(s).
"aryl" or "aromatic ring" refers to an all-carbon monocyclic or fused polycyclic (i.e., rings which share adjacent pairs of carbon atoms) group, a polycyclic (i.e., rings which carry adjacent pairs of carbon atoms) group having a conjugated pi-electron system, preferably an all-carbon aryl group containing 6 to 10 or 6 to 8 carbons, e.g., "C 6-10 Aryl "refers to a fully carbon aryl group containing 6-10 carbons," C 6-8 Aryl "refers to all-carbon aryl groups containing 6 to 8 carbons, including but not limited to phenyl and naphthyl. The aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring attached to the parent structure is an aryl ring, including but not limited to:
"aryl" may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more (preferably 1,2,3 or 4) groups independently selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl radical, C 2-10 Alkenyl radical, C 2-10 Alkynyl, halo-substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl radical, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-10 Aryl, 5-10 membered heteroaryl, = O, -SF 5 、-S(O) r R 11 、-O-R 12 、-C(O)OR 12 、-C(O)R 13 、-O-C(O)R 13 、-NR 14 R 15 、-C(=NR 14 )R 13 、-N(R 14 )-C(=NR 15 )R 13 、-C(O)NR 14 R 15 or-N (R) 14 )-C(O)R 13 Substituted with a substituent (b).
"heteroaryl" refers to a heteroaromatic system containing one or more (preferably 1,2,3, or 4) heteroatoms including nitrogen, oxygen, and S (O) r (where r is an integer 0, 1, 2), preferably a heteroaromatic system containing 5 to 10 or 5 to 8 or 5 to 6 ring atoms, e.g., "5-8 membered heteroaryl" refers to a heteroaromatic system containing 5 to 8 ring atoms, "5-10 membered heteroaryl" refers to a heteroaromatic system containing 5 to 10 ring atoms, including but not limited to furyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, and the like. The heteroaryl ring may be fused to an aryl, heterocyclyl, or cycloalkyl ring, wherein the ring joined together with the parent structure is a heteroaryl ring, including, but not limited to:
"heteroaryl" may be optionally substituted or unsubstituted, when substitutedThe substituents are preferably one or more (preferably 1,2,3 or 4) groups independently selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl radical, C 2-10 Alkenyl radical, C 2-10 Alkynyl, halo-substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl radical, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-10 Aryl, 5-10 membered heteroaryl, = O, -SF 5 、-S(O) r R 11 、-O-R 12 、-C(O)OR 12 、-C(O)R 13 、-O-C(O)R 13 、-NR 14 R 15 、-C(=NR 14 )R 13 、-N(R 14 )-C(=NR 15 )R 13 、-C(O)NR 14 R 15 or-N (R) 14 )-C(O)R 13 Substituted with the substituent(s).
"alkenyl" means an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, preferably a straight or branched chain alkenyl group containing 2 to 10 or 2 to 4 carbons, e.g., "C 2-10 Alkenyl "means a straight or branched chain alkenyl group having 2 to 10 carbons," C 2-4 Alkenyl "means a straight or branched chain alkenyl group containing 2 to 4 carbons. Including but not limited to ethenyl, 1-propenyl, 2-propenyl, 1-, 2-or 3-butenyl, and the like.
"alkenyl" may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more (preferably 1,2,3 or 4) groups independently selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl radical, C 2-10 Alkenyl radical, C 2-10 Alkynyl, halo-substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl radical, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-10 Aryl, 5-10 membered heteroaryl, = O, -SF 5 、-S(O) r R 11 、-O-R 12 、-C(O)OR 12 、-C(O)R 13 、-O-C(O)R 13 、-NR 14 R 15 、-C(=NR 14 )R 13 、-N(R 14 )-C(=NR 15 )R 13 、-C(O)NR 14 R 15 or-N (R) 14 )-C(O)R 13 Substituted with the substituent(s).
"alkynyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon triple bond, preferably a straight or branched chain alkynyl group containing 2-10 or 2-4 carbons, e.g., "C 2-10 Alkynyl "refers to a straight or branched chain alkynyl group containing 2-10 carbons," C 2-4 Alkynyl "refers to straight or branched chain alkynyl groups containing 2-4 carbons. Including but not limited to ethynyl, 1-propynyl, 2-propynyl, 1-, 2-or 3-butynyl, and the like.
"alkynyl" groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more (preferably 1,2,3 or 4) groups independently selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl radical, C 2-10 Alkenyl radical, C 2-10 Alkynyl, halo-substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl radical, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-10 Aryl, 5-to 10-membered heteroaryl, = O, -SF 5 、-S(O) r R 11 、-O-R 12 、-C(O)OR 12 、-C(O)R 13 、-O-C(O)R 13 、-NR 14 R 15 、-C(=NR 14 )R 13 、-N(R 14 )-C(=NR 15 )R 13 、-C(O)NR 14 R 15 or-N (R) 14 )-C(O)R 13 Substituted with the substituent(s).
"alkoxy" refers to-O-alkyl, wherein alkyl is as defined above, e.g., "C 1-10 Alkoxy "means an alkyloxy group having 1 to 10 carbons," C 1-4 Alkoxy "refers to an alkyl group having 1-4 carbonsOxy includes, but is not limited to, methoxy, ethoxy, propoxy, butoxy, and the like.
"alkoxy" may be optionally substituted or unsubstituted, and when substituted, the substituents, preferably one or more (preferably 1,2,3 or 4) groups independently selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl radical, C 2-10 Alkenyl radical, C 2-10 Alkynyl, halo-substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl radical, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-10 Aryl, 5-10 membered heteroaryl, = O, -SF 5 、-S(O) r R 11 、-O-R 12 、-C(O)OR 12 、-C(O)R 13 、-O-C(O)R 13 、-NR 14 R 15 、-C(=NR 14 )R 13 、-N(R 14 )-C(=NR 15 )R 13 、-C(O)NR 14 R 15 or-N (R) 14 )-C(O)R 13 Substituted with the substituent(s).
"Cycloalkoxy" refers to-O-cycloalkyl wherein cycloalkyl is as defined above, e.g., "C 3-12 Cycloalkoxy "means a cycloalkyloxy group having 3 to 12 carbons," C 3-8 Cycloalkoxy "refers to cycloalkyloxy groups of 3-8 carbons, including but not limited to cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like.
"cycloalkoxy" may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more (preferably 1,2,3 or 4) groups independently selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl radical, C 2-10 Alkenyl radical, C 2-10 Alkynyl, halo-substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl radical, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-10 Aryl, 5-to 10-membered heteroaryl, = O, -SF 5 、-S(O) r R 11 、-O-R 12 、-C(O)OR 12 、-C(O)R 13 、-O-C(O)R 13 、-NR 14 R 15 、-C(=NR 14 )R 13 、-N(R 14 )-C(=NR 15 )R 13 、-C(O)NR 14 R 15 or-N (R) 14 )-C(O)R 13 Substituted with the substituent(s).
"heterocyclyloxy" refers to-O-heterocyclyl, wherein heterocyclyl is defined above, heterocyclyloxy including, but not limited to, azetidinyloxy, oxetanyloxy, cyclopentyloxy, nitrogen, oxacyclohexyloxy, and the like.
"heterocyclyloxy" may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more (preferably 1,2,3 or 4) groups independently selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl radical, C 2-10 Alkenyl radical, C 2-10 Alkynyl, halo-substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl radical, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-10 Aryl, 5-10 membered heteroaryl, = O, -SF 5 、-S(O) r R 11 、-O-R 12 、-C(O)OR 12 、-C(O)R 13 、-O-C(O)R 13 、-NR 14 R 15 、-C(=NR 14 )R 13 、-N(R 14 )-C(=NR 15 )R 13 、-C(O)NR 14 R 15 or-N (R) 14 )-C(O)R 13 Substituted with the substituent(s).
“C 1-10 Alkanoyl "means C 1-10 The monovalent radical remaining after removal of the hydroxyl group from the alkyl acid, also commonly referred to as "C 0-9 alkyl-C (O) - ", e.g.," 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 isobutyryl.
“-C 0-8 -NR 14 R 15 "means-NR 14 R 15 In which the nitrogen atom is bound to C 0-8 On the alkyl radical, wherein C 0-8 The alkyl group is as defined above.
"halogen substituted C 1-6 Alkyl refers to a 1-6C alkyl group optionally substituted with fluorine, chlorine, bromine, iodine atoms for the hydrogen on the alkyl group, including but not limited to difluoromethyl (-CHF) 2 ) Dichloromethyl (-CHCl) 2 ) Dibromomethyl (-CHBr) 2 ) Trifluoromethyl (-CF) 3 ) Trichloromethyl (-CCl) 3 ) Tribromomethyl (-CBr) 3 ) And the like.
"halogen substituted C 1-10 Alkoxy "refers to a 1-10 carbon alkoxy group wherein the hydrogen on the alkyl group is optionally substituted with fluorine, chlorine, bromine, or iodine atoms. Including but not limited to difluoromethoxy, dichloromethoxy, dibromomethoxy, trifluoromethoxy, trichloromethoxy, tribromomethoxy, and the like.
"deuterium substituted C 1-6 Alkyl "refers to a 1-6 carbon alkyl group optionally substituted with deuterium atoms for the hydrogen on the alkyl group. Including but not limited to, deuteromethyl (-CH) 2 D) Dideuteromethyl (-CHD) 2 ) Trideuteromethyl (-CD) 3 ) And so on.
"deuterium substituted C 1-10 Alkoxy "refers to a 1-10 carbon alkyl group optionally substituted with deuterium atoms for the hydrogen on the alkyl group. Including but not limited to mono-deuteromethoxy, di-deuteromethoxy, tri-deuteromethoxy, and the like.
"halogen" means fluorine, chlorine, bromine or iodine.
"optional" or "optionally" means that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where the event or circumstance occurs or does not occur, i.e., both substituted and unsubstituted. For example, "a heterocyclic group optionally substituted with an alkyl" means that an alkyl may, but need not, be present, and the description includes the case where the heterocyclic group is substituted with an alkyl and the heterocyclic group is not substituted with an alkyl.
"substituted" means that one or more "hydrogen atoms" in a group are substituted, independently of each other, with a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, in accordance with the chemical valence bond theory, and that the person skilled in the art is able to determine (experimentally or theoretically) possible or impossible substitutions without undue effort. For example, amino or hydroxyl groups having free hydrogen may be unstable in combination with carbon atoms having unsaturated bonds (e.g., olefins).
"stereoisomers", whose english name is stereooisomer, refer to isomers produced by different arrangement of atoms in a molecule in space, and can be divided into cis-trans isomers, enantiomers, and also into enantiomers and diastereomers. Stereoisomers resulting from rotation of single bonds are called conformational isomers (conformational stereo-isomers) and sometimes rotamers (rotamers). Stereoisomers caused by bond length, bond angle, double bond in a molecule, ring and the like are called configurational isomers (configurational isomers), and the configurational isomers are divided into two types. Wherein the isomers caused by the single bond of the double bond or the ring-forming carbon atom can not rotate freely become geometrical isomers (cis-trans isomers), which are divided into two configurations of Z and E. For example: cis-2-butene and trans-2-butene are a pair of geometric isomers, and the compounds of the present invention, if containing a double bond, are understood to contain the E and/or Z forms, if not specifically indicated. Stereoisomers with different optical rotation properties due to lack of trans-axial symmetry in the molecule are called optical isomers (optical isomers) and are divided into R, S configurations. In the present invention, the term "stereoisomer" is understood to include one or more of the above enantiomers, configurational isomers and conformational isomers, preferably the S configuration, unless otherwise specified.
"pharmaceutically acceptable salts" as used herein refers to pharmaceutically acceptable acid addition salts or base addition salts, including inorganic acid salts and organic acid salts, which salts may 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, as well as other components such as physiological/pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to facilitate administration to an organism, facilitate absorption of the active ingredient and exert biological activity.
The present invention will be described more fully hereinafter with reference to the following examples, but the present invention is not limited thereto, and is not limited thereto.
The structure of the compounds of the invention is determined by Nuclear Magnetic Resonance (NMR) or/and liquid mass chromatography (LC-MS). NMR chemical shifts (δ) are given in parts per million (ppm). NMR was measured using a Bruker AVANCE-400/500 NMR spectrometer using deuterated dimethyl sulfoxide (DMSO-d) 6 ) Deuterium substituted Carbinol (CD) 3 OD) and deuterated chloroform (CDCl) 3 ) Internal standard is Tetramethylsilane (TMS).
The LC-MS was measured using an Agilent 6120 mass spectrometer. HPLC was carried out using an Agilent 1200DAD high pressure liquid chromatograph (Sunfire C18X 4.6mm column) and a Waters 2695-2996 high pressure liquid chromatograph (Gimini C18X 4.6mm column).
The thin layer chromatography silica gel plate adopts a tobacco yellow sea HSGF254 or Qingdao GF254 silica gel plate, the specification adopted by TLC is 0.15 mm-0.20 mm, and the specification adopted by the thin layer chromatography separation and purification product is 0.4 mm-0.5 mm. The column chromatography generally uses 200-300 mesh silica gel of the Tibet Huanghai silica gel as a carrier.
The starting materials in the examples of the present invention are known and commercially available, or may be synthesized using or according to methods known in the art.
All reactions of the present invention are carried out under continuous magnetic stirring in a dry nitrogen or argon atmosphere, without specific indication, in dry solvents and at reaction temperatures in degrees Celsius (. Degree. C.).
1. Preparation of intermediates
Intermediate A1: preparation of (R) -1- (4-amino-5-methoxy-2-nitrophenyl) -N, N-dimethylpyrrolidin-3-amine
4-fluoro-2-methoxy-5-nitroaniline (500mg, 2.69mmol) was dissolved in N, N-dimethylformamide (10 mL). (R) -N, N-dimethylpyrrolidin-3-amine (367mg, 3.22mmol) and potassium carbonate (742mg, 5.38mmol) were added to the solution at room temperature. The reaction was stirred at room temperature for 16 hours. Water was added to the solution, and extracted three times with ethyl acetate. The organic phases were combined, washed with saturated brine and dried over anhydrous sodium sulfate. After removal of the solvent, silica gel column chromatography separation [ dichloromethane: methanol =10]To give (R) -1- (4-amino-5-methoxy-2-nitrophenyl) -N, N-dimethylpyrrolidin-3-amine (480 mg, yield: 60%). ESI-MS:281.0[ M ] +1] + 。
Intermediate A2: n is a radical of 1 - (2- (dimethylamino) ethyl) -5-methoxy-N 1 Preparation of (E) -methyl-2-nitrophenyl-1, 4-diamine
Preparation of intermediate A2 (R) -N, N-dimethylpyrrolidin-3-amine was exchanged for N with reference to the synthesis of intermediate A1 1 ,N 1 ,N 2 -trimethylethane-1, 2-diamine.
Intermediate A3: preparation of (R) -6- (3- (dimethylamino) pyrrolidin-1-yl) -2-methoxy-5-nitropyridin-3-amine
The first step is as follows: synthesis of 6-bromo-2-methoxy-3-nitropyridine
Sodium methoxide (5.3 g,78.0mmol, 1.1eq.) was added to a solution of 2, 6-dibromo-3-nitropyridine (20g, 70.9mmol, 1eq.) in tetrahydrofuran (300 mL) under ice-cooling. The reaction was stirred at room temperature for 3 hours. The reaction solution was poured into ice water, and extracted with ethyl acetate. The organic phases are combined, washed with saturated brine, concentrated and separated by column chromatography [ petroleum ether: ethyl acetate =5]6-bromo-2-methoxy-3-nitropyridine (13.9 g, yield: 85%) was obtained. ESI-MS:217.1[ 2 ] M-15] + 。
The second step is that: synthesis of 6-bromo-2-methoxypyridin-3-amine
In a mixture of 6-bromo-2-methoxy-3-nitropyridine (13.9g, 60.1mmol, 1eq.) in [ ethanol/water =2]To the solution were added iron powder (26.9g, 480.8mmol, 8eq.) and ammonium chloride (25.9g, 480.8mmol, 8eq.). The reaction was stirred at about 90 ℃ for 3 hours. The mixture was separated with dichloromethane and water. The organic phase was concentrated and separated by column chromatography [ petroleum ether: ethyl acetate =3]6-bromo-2-methoxypyridin-3-amine (9.1 g, yield: 75%) was obtained. ESI-MS 203.1[ deg. ] M +1] + 。
1 H NMR(400MHz,DMSO-d 6 )δ6.89(d,J=7.9Hz,1H),6.83(d,J=7.9Hz,1H),5.10(s,2H),3.84(s,3H)。
The third step: synthesis of N- (6-bromo-2-methoxypyridin-3-yl) acetamide
Triethylamine (6.7g, 67.2mmol, 1.5eq.) and acetyl chloride (3.8g, 49.2mmol, 1.1eq.) were added to a solution of 6-bromo-2-methoxypyridin-3-amine (9.1g, 44.8mmol, 1eq.) in dichloromethane (200 mL) under ice-cooling. The reaction was stirred for 1 hour under ice bath. The mixture is separated with dichloromethane and water, the organic phase is concentrated and separated by column chromatography [ petroleum ether: ethyl acetate =5 ] gave N- (6-bromo-2-methoxypyridin-3-yl) acetamide (9.5 g, yield: 86%). Used directly in the next step.
The fourth step: synthesis of N- (6-bromo-2-methoxy-5-nitropyridin-3-yl) acetamide
Concentrated nitric acid (65%, 46.6mmol, 1.2eq.) was added to a solution of N- (6-bromo-2-methoxypyridin-3-yl) acetamide (9.5g, 38.9mmol, 1eq.) in trifluoroacetic anhydride (80 mL) under ice-bath. The reaction was stirred for 1 hour under ice bath. The reaction mixture was slowly poured into ice water, stirred for 1 hour, and a solid was precipitated, filtered, and the filter cake was dried to give N- (6-bromo-2-methoxy-5-nitropyridin-3-yl) acetamide (11.5 g, yield: 100%). ESI-MS:290.1[ deg. ] M +1]] + 。
1 H NMR(400MHz,DMSO-d 6 )δ9.90(s,1H),9.12(s,1H),4.06(s,3H),2.16(s,3H)。
The fifth step: synthesis of (R) -N- (6- (3- (dimethylamino) pyrrolidin-1-yl) -2-methoxy-5-nitropyridin-3-yl) acetamide
To a solution of N- (6-bromo-2-methoxy-5-nitropyridin-3-yl) acetamide (1.0g, 3.4mmol, 1eq.) in acetonitrile (20 mL) was added (R) -N, N-dimethylpyrrolidin-3-amine (581mg, 5.1mmol, 1.5eq.). The reaction solution was stirred at 80 ℃ for 1 hour. After removal of the solvent, silica gel column chromatography separation [ dichloromethane: methanol =10]To give (R) -N- (6- (3- (dimethylamino) pyrrolidin-1-yl) -2-methoxy-5-nitropyridin-3-yl) acetamide (864 mg, yield: 86%). ESI-MS:324.3 2[ M ] +1] + 。
And a sixth step: synthesis of (R) -6- (3- (dimethylamino) pyrrolidin-1-yl) -2-methoxy-5-nitropyridin-3-amine
Concentrated hydrochloric acid (37%, 1.5ml,18mmol, 6.2eq.) was added to a solution of (R) -N- (6- (3- (dimethylamino) pyrrolidin-1-yl) -2-methoxy-5-nitropyridin-3-yl) acetamide (864mg, 2.9mmol, 1eq.) in methanol (10 mL). The reaction was stirred at 60 ℃ for 5 hours. With saturated NaHCO 3 The solution and dichloromethane were partitioned. The organic phase was concentrated to give (R) -6- (3- (dimethylamino) pyrrolidin-1-yl) -2-methoxy-5-nitropyridin-3-amine (845 mg, yield: 100%). ESI-MS:282.3[ deg. ] M +1] + 。
Intermediate A4: n is a radical of 2 - (2- (dimethylamino) ethyl) -6-methoxy-N 2 Preparation of (E) -methyl-3-nitropyridine-2, 5-diamine
The first step is as follows: synthesis of N- (6- ((2- (dimethylamino) ethyl) (methyl) amino) -2-methoxy-5-nitropyridin-3-yl) acetamide
To a solution of N- (6-bromo-2-methoxy-5-nitropyridin-3-yl) acetamide (1.0g, 3.4mmol, 1eq.) in acetonitrile (20 mL) was added N 1 ,N 1 ,N 2 Trimethylethane-1, 2-diamine (520mg, 5.1mmol, 1.5eq.). The reaction solution was stirred at 80 ℃ for 1 hour. After removal of the solvent, silica gel column chromatography separation [ dichloromethane: methanol =10]To give N- (6- ((2- (dimethylamino) ethyl) (methyl) amino) -2-methoxy-5-nitropyridin-3-yl) acetamide (756 mg)The yield is as follows: 71%). ESI-MS:312.3[ deg. ] M +1] + 。
The second step is that: n is a radical of 2 - (2- (dimethylamino) ethyl) -6-methoxy-N 2 Synthesis of (methyl) -3-nitropyridine-2, 5-diamine
To a solution of N- (6- ((2- (dimethylamino) ethyl) (methyl) amino) -2-methoxy-5-nitropyridin-3-yl) acetamide (756 mg,2.4mmol, 1eq.) in methanol (10 mL) was added concentrated hydrochloric acid (37%, 1.5mL,18mmol, 7.5eq.). The reaction was stirred at 60 ℃ for 5 hours. With saturated NaHCO 3 The solution and dichloromethane were partitioned. Concentrating the organic phase to obtain N 2 - (2- (dimethylamino) ethyl) -6-methoxy-N 2 -methyl-3-nitropyridine-2, 5-diamine (645 mg, yield: 100%). ESI-MS:270.3 2[ M ] +1] + 。
Intermediate A5: preparation of (R) -6- (3- (dimethylamino) pyrrolidin-1-yl) -5-nitro-2- (2, 2-trifluoroethoxy) pyridin-3-amine
The first step is as follows: synthesis of 6-bromo-3-nitro-2- (2, 2-trifluoroethoxy) pyridine
Sodium hydrogen (60%, 0.88g, 0.22mmol) was slowly added to a solution of trifluoroethanol (2.0 g, 0.2mmol) in tetrahydrofuran (10 mL) under ice-cooling. Stir for 1 hour in ice bath. 2, 6-dibromo-3-nitropyridine (5g, 17.7 mmol) and THF (150 mL) were sequentially added to a three-necked flask at room temperature, and a tetrahydrofuran solution of sodium trifluoroethoxide was added under ice bath. After completion of the reaction, the reaction mixture was poured into ice water (100 mL), MTBE (methyl tert-butyl ether) (100mL. Multidot.3) was added and extracted, the organic phases were combined, washed with saturated brine, the organic phase was concentrated, and the crude product was isolated to give 6-bromo-3-nitro-2- (2, 2-trifluoroethoxy) pyridine (3.2 g, yield: 60%).
1 H NMR(400MHz,CDCl 3 )δ8.22(d,J=8.4Hz,1H),7.36(d,J=4.0Hz,1H),4.94-4.87(m,2H)。
The second step is that: synthesis of 6-bromo-2- (2, 2-trifluoroethoxy) pyridin-3-amine
6-bromo-3-nitro-2- (2, 2-trifluoroethoxy) pyridine (3.2g, 10.6 mmol) was dissolved in 90mL of a mixed solution [ ethanol/water =2]To the solution were added iron powder (2.97g, 53mmol) and ammonium chloride (2.86g, 53mmol) at room temperature. The reaction solution was heated to 90 ℃ and the reaction was completed after 1 hour. The reaction solution was filtered through celite, concentrated, and water was added thereto, followed by extraction with ethyl acetate three times. The organic phases were combined, washed with saturated brine and dried over anhydrous sodium sulfate. After the solvent was removed, 6-bromo-2- (2, 2-trifluoroethoxy) pyridin-3-amine (2.8 g, yield: 100%) was obtained. ESI-MS:271.1[ deg. ] M +1]] + 。
The third step: synthesis of N- (6-bromo-2- (2, 2-trifluoroethoxy) pyridin-3-yl) acetamide
6-bromo-2- (2, 2-trifluoroethoxy) pyridin-3-amine (2.8g, 10.6mmol) was dissolved in acetic anhydride (8.6g, 84.8mmol), and the reaction was terminated after stirring at room temperature for 1 hour. The reaction mixture was stirred with water for 1 hour to precipitate a solid, which was then filtered and the filter cake was dried to give N- (6-bromo-2- (2, 2-trifluoroethoxy) pyridin-3-yl) acetamide (2.2 g, yield: 68%). ESI-MS 312.8.[ M +1]] + 。
The fourth step: synthesis of N- (6-bromo-5-nitro-2- (2, 2-trifluoroethoxy) pyridin-3-yl) acetamide
N- (6-bromo-2- (2, 2-trifluoroethoxy) pyridin-3-yl) acetamide (2.2g, 7.0 mmol) was dissolved in trifluoroacetic anhydride (20 mL), cooled to 0 ℃ and concentrated nitric acid (65%, 1.13g, 10.5mmol) was added under ice bath. After stirring in ice bath for 1 hour, the reaction was complete. The reaction mixture was slowly poured into ice water, stirred for 1 hour, and a solid was precipitated, which was filtered under suction, and the filter cake was dried to give N- (6-bromo-5-nitro-2- (2, 2-trifluoroethoxy) pyridin-3-yl) acetamide (2.14 g, yield: 86%). Directly used for the next reaction.
The fifth step: synthesis of (R) -N- (6- (3- (dimethylamino) pyrrolidin-1-yl) -5-nitro-2- (2, 2-trifluoroethoxy) pyridin-3-yl) acetamide
N- (6-bromo-5-nitro-2- (2, 2-trifluoroethoxy) pyridin-3-yl) acetamide (1.0 g, 2.79mmol) was dissolved in acetonitrile (20 mL), and (R) -N, N-dimethylpyrrolidin-3-amine (382mg, 3.35mmol) was added to the solution at room temperature. The reaction solution was heated to 80 ℃ and the reaction was completed after 1 hour. After removal of the solvent, silica gel column chromatography separation [ dichloromethane: methanol =10]To give (R) -N- (6- (3- (dimethylamino) pyrrolidin-1-yl) -5-nitro-2- (2, 2-trifluoroethoxy) pyridin-3-yl) acetamide (684 mg, yield: 63%). ESI-MS:392.0.[ M +1]] + 。
And a sixth step: synthesis of (R) -6- (3- (dimethylamino) pyrrolidin-1-yl) -5-nitro-2- (2, 2-trifluoroethoxy) pyridin-3-amine
(R) -N- (6- (3- (dimethylamino) pyrrolidin-1-yl) -5-nitro-2- (2, 2-trifluoroethoxy) pyridin-3-yl) acetamide (658mg, 1.68mmol) was dissolved in methanol (5 mL) and concentrated hydrochloric acid (37%, 331mg, 3.36mmol) was added at room temperature. The reaction was heated to 60 ℃ and stirred for 10 hours, after which the reaction was complete. Adding saturated NaHCO into the reaction liquid 3 The solution was neutralized to pH = 8-9. After removal of the solvent, water was added and extraction with dichloromethane was carried out. The organic phases were combined, washed with saturated brine and dried over anhydrous sodium sulfate. After removal of the solvent, silica gel column chromatography separation [ dichloromethane: methanol =10]To give (R) -6- (3- (dimethylamino) pyrrolidin-1-yl) -5-nitro-2- (2, 2-trifluoroethoxy) pyridin-3-amine (530 mg, yield: 90%). ESI-MS:350.0[ deg. ] M +1] + 。
The preparation of the intermediates A6 to A8 can be obtained by referring to the preparation method of the intermediate A1:
intermediate A9: n is a radical of 2 - (2- (dimethylamino) ethyl) -N 2 Preparation of (E) -methyl-3-nitro-6- (2, 2-trifluoroethoxy) pyridine-2, 5-diamine
The first step is as follows: synthesis of N- (6- ((2- (dimethylamino) ethyl) (methyl) amino) -5-nitro-2- (2, 2-trifluoroethoxy) pyridin-3-yl) acetamide
N- (6-bromo-5-nitro-2- (2, 2-trifluoroethoxy) pyridin-3-yl) acetamide (1.0 g, 2.79mmol) was dissolved in acetonitrile (20 mL), and N was added to the solution at room temperature 1 ,N 1 ,N 2 Trimethylethane-1, 2-diamine (426mg, 4.17mmol). The reaction solution was heated to 80 ℃ and the reaction was completed after 1 hour. After removal of the solvent, silica gel column chromatography separation [ dichloromethane: methanol =10]N- (6- ((2- (dimethylamino) ethyl) (methyl) amino) -5-nitro-2- (2, 2-trifluoroethoxy) pyridin-3-yl) acetamide (795 mg, yield: 75%) was obtained. ESI-MS:380.0[ deg. ] M +1] + 。
The second step is that: n is a radical of 2 - (2- (dimethylamino) ethyl) -N 2 Synthesis of (methyl) -3-nitro-6- (2, 2-trifluoroethoxy) pyridine-2, 5-diamine
N- (6- ((2- (dimethylamino) ethyl) (methyl) amino) -5-nitro-2- (2, 2-trifluoroethoxy) pyridin-3-yl) acetamide (795mg, 2.09mmol) was dissolved in methanol (5 mL), and concentrated hydrochloric acid (37%, 412mg, 4.18mmol) was added at room temperature. The reaction was heated to 60 ℃ and stirred for 10 hours, after which the reaction was complete. Adding saturated NaHCO into the reaction liquid 3 The solution was neutralized to pH = 8-9. After removal of the solvent, water was added and extraction with dichloromethane was carried out. The organic phases were combined, washed with saturated brine and dried over anhydrous sodium sulfate. After removal of the solvent, silica gel column chromatography separation [ dichloromethane: methanol =10]To obtain N 2 - (2- (dimethylamino) ethyl) -N 2 -methyl-3-nitro-6- (2, 2-trifluoroethoxy) pyridine-2, 5-diamine (633 mg, yield: 90%). ESI-MS:338.0[ 2 ] M +1] + 。
Preparation of intermediates a10 to a11 reference was made to the preparation of intermediate A9 to give:
intermediate B1: preparation of 6-chloro-5-fluoro-3, 3-dimethylindoline
The first step is as follows: synthesis of 6-chloro-5-fluoro-3, 3-dimethylindolin-2-one
To a suspension of 6-chloro-5-fluoroindolin-2-one (4.0g, 21.6mmol, 1eq.) and lithium chloride (4.5g, 108mmol, 5eq.) in tetrahydrofuran (100 mL) was slowly dropped a 2.5M n-butyllithium solution (43.2mL, 108mmol, 5eq.) at-78 ℃. The reaction was stirred at-78 ℃ for 30 minutes, then iodomethane (15.3g, 108mmol, 5eq.) was added. The reaction was stirred at-78 ℃ for an additional 30 minutes and then at room temperature for 2 hours. Separate from ethyl acetate and water. The organic phase is washed successively with water and saturated sodium chloride, then dried over anhydrous sodium sulfate, filtered, concentrated and separated by column chromatography [ petroleum ether/ethyl acetate =5]6-chloro-5-fluoro-3, 3-dimethylindolidin-2-one (2.8 g, yield: 60%) was obtained. ESI-MS:214.0[ deg. ] M +1] + 。
1 H NMR(400MHz,DMSO-d 6 )δ10.44(s,1H),7.48(d,J=8.9Hz,1H),6.94(d,J=6.2Hz,1H),1.26(d,J=2.1Hz,6H)。
The second step is that: synthesis of 6-chloro-5-fluoro-3, 3-dimethylindoline
To a solution of 6-chloro-5-fluoro-3, 3-dimethylindolin-2-one (2.2g, 10.2mmol, 1eq.) in tetrahydrofuran (80 mL) was added a solution of 2.5M lithium aluminum tetrahydride in tetrahydrofuran (12.2mL, 30.6mmol, 3eq.). The mixture was stirred at 50 ℃ for 3 hours. Quench with sodium sulfate decahydrate and filter. The organic phase was concentrated and separated by column chromatography [ petroleum ether/ethyl acetate =3]To obtain 6-chloro-5-fluoro-3, 3-dimethylindolineIndole (1.7 g, yield: 83%). ESI-MS:200.2[ deg. ] M +1] + 。
Intermediate B2: preparation of 5, 6-difluoro-3, 3-dimethylindoline
The first step is as follows: synthesis of 5, 6-difluoro-3, 3-dimethylindolin-2-one
To a suspension of 5, 6-difluoroindolin-2-one (5.0g, 29.5mmol, 1eq.) and lithium chloride (6.2g, 148mmol, 5eq.) in tetrahydrofuran (100 mL) was slowly dropped a 2.5M n-butyllithium solution (59.2mL, 148mmol, 5eq.) at-78 ℃. The reaction was stirred at-78 ℃ for 30 minutes, then iodomethane (21.0 g,148mmol, 5eq.) was added. The reaction was stirred at-78 ℃ for an additional 30 minutes and then at room temperature for 2 hours. Separate from ethyl acetate and water. The organic phase was washed successively with water and saturated sodium chloride, then dried over anhydrous sodium sulfate, filtered, concentrated and separated by column chromatography [ petroleum ether/ethyl acetate =5]To give 5, 6-difluoro-3, 3-dimethylindolin-2-one (3.6 g, yield: 61%). ESI-MS:198.0[ deg. ] M +1] + 。
The second step is that: synthesis of 5, 6-difluoro-3, 3-dimethylindoline
To a solution of 5,6-difluoro-3, 3-dimethylindolin-2-one (3.6g, 18mmol, 1eq.) in tetrahydrofuran (80 mL) was added a 2.5M solution of lithium aluminum hydride in tetrahydrofuran (28.8mL, 72mmol, 4eq.). Stirring was carried out at 50 ℃ for 3 hours. Quench with sodium sulfate decahydrate and filter. Concentrating organic phase, and separating by column chromatographyEster =3]5, 6-difluoro-3, 3-dimethylindoline (1.8 g, yield: 54%) was obtained. ESI-MS:184.0[ mu ] M +1] + 。
1 H NMR(400MHz,DMSO-d 6 )δ7.03(dd,J=10.4,8.3Hz,1H),6.40(dd,J=11.8,6.7Hz,1H),5.58(s,1H),3.19(s,2H),1.20(s,6H)。
Intermediate B3: preparation of 3, 3-dimethyl-2, 3-dihydro-1H-pyrrolo [3,2-b ] pyridine
The first step is as follows: synthesis of diethyl 2- (3-nitropyridin-2-yl) malonate
Diethyl malonate (21.1mL, 139.3 mmol) was slowly dropped into a suspension of sodium hydride (3.33g, 139.3 mmol) in dimethyl sulfoxide (140 mL) at 0 ℃. The mixture was stirred at room temperature for 0.5 hour, and 2-chloro-3-nitropyridine (9.58g, 60.6 mmol) was added to the mixture. The reaction solution was stirred at 100 ℃ for 1.5 hours, after the reaction was completed, it was cooled to 0 ℃ and saturated sodium bicarbonate was slowly added to quench the reaction. The mixture was washed with water, extracted with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate, distilled under reduced pressure, and the crude product was separated by flash silica gel column [ eluent: ethyl acetate/petroleum ether: 0 to 50 percent]Diethyl 2- (3-nitropyridin-2-yl) malonate was obtained (15.2 g, yield: 88.9%). ESI-MS:283.0[ m ] +1] + 。
The second step is that: synthesis of Ethyl 2- (3-nitropyridin-2-yl) acetate
To diethyl 2- (3-nitropyridin-2-yl) propaneWater (0.37ml, 20mmol) and lithium chloride (2.1g, 50mmol) were added to a solution of a dibasic ester (5.6g, 20mmol) in dimethyl sulfoxide (65 mL). The mixture was stirred at 100 ℃ for 4 days. The reaction solution was cooled to room temperature, washed with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, distilled under reduced pressure, and the crude product was separated by flash silica gel column [ eluent: ethyl acetate/petroleum ether: 0 to 50 percent]Ethyl 2- (3-nitropyridin-2-yl) acetate (3.1 g, yield: 73.8%) was obtained. ESI-MS:211.0[ deg. ] M +1] + 。
The third step: synthesis of ethyl 2-methyl-2- (3-nitropyridin-2-yl) propionate
To a solution of ethyl 2- (3-nitropyridin-2-yl) acetate (3.1g, 14.7 mmol) in N, N dimethylformamide (30 mL) at 0 deg.C was added methyl iodide (6.25g, 44mmol), 18-crown-6 (0.39g, 1.47mmol), sodium hydride (1.2g, 29.4mmol) was slowly added, the mixture was stirred at 0 deg.C for 1 hour, the reaction was completed, quenched with ice water, washed with water, extracted with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate, distilled under reduced pressure, and the crude product was separated by a flash silica gel column [ eluent: ethyl acetate/petroleum ether: 0 to 25% ] Ethyl 2-methyl-2- (3-nitropyridin-2-yl) propionate was obtained (3.2 g, yield: 91%). ESI-MS:239.0[ m ] +1] +.
The fourth step: synthesis of 3, 3-dimethyl-1, 3-dihydro-2H-pyrrolo [3,2-b ] pyridin-2-one
To a solution of 2-methyl-2- (3-nitropyridin-2-yl) propionate (3.2g, 13.4 mmol) in ethanol (20 mL) were added ammonium formate (3.4 g,53.7 mmol) and 10% palladium on carbon (300 mg), and the mixture was stirred at 90 ℃ for 2 hours. After the reaction, the reaction solution was filtered, the filtrate was concentrated, the residue was washed with water, extracted with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate, and distilled under reduced pressureTo obtain crude 3, 3-dimethyl-1, 3-dihydro-2H-pyrrolo [3,2-b ] product]Pyridin-2-one (1.72 g, yield: 79%) was used directly in the next reaction. ESI-MS:163.0[ mu ] M +1] + 。
The fifth step: synthesis of 3, 3-dimethyl-2, 3-dihydro-1H-pyrrolo [3,2-b ] pyridine
Reacting 3, 3-dimethyl-1, 3-dihydro-2H-pyrrolo [3,2-b ]]Pyridin-2-one (1.22g, 7.53mmol) was dissolved in tetrahydrofuran (20 mL), cooled to 0 deg.C, and a solution of lithium aluminum tetrahydride in tetrahydrofuran (4 mL, 2.5M) was added dropwise to the solution. The mixture was stirred at 50 ℃ for 3 hours. After the reaction, the reaction solution was quenched with sodium sulfate decahydrate until no bubbles were generated. Filtering the mixture, and distilling the filtrate under reduced pressure to obtain 3, 3-dimethyl-2, 3-dihydro-1H-pyrrolo [3,2-b ]]Pyridine (1.2 g, yield: 100%). ESI-MS:149.0[ 2 ], [ M ] +1] + 。
Intermediate B4: preparation of 3, 3-dimethyl-5- (trifluoromethyl) -2, 3-dihydro-1H-pyrrolo [3,2-b ] pyridine
The first step is as follows: synthesis of 2-iodo-N- (2-methallyl) -6- (trifluoromethyl) pyridin-3-amine
To a solution of 2-iodo-6- (trifluoromethyl) pyridin-3-amine (2g, 6.94mmol) in tetrahydrofuran (30 mL) was added potassium tert-butoxide (933mg, 8.33mmol) at room temperature. The mixture was stirred at room temperature for 15 minutes. 3-bromo-2-methylpropan-1-ene (1.17g, 8.33mmol) was then slowly added dropwise to the mixture. Stirring the reaction solution at room temperature for 2 hours, after the reaction is finished, concentrating under reduced pressure to remove the solvent, and obtaining residuesSeparation by flash silica gel column [ eluent: ethyl acetate/petroleum ether: 0 to 20 percent]To give 2-iodo-N- (2-methallyl) -6- (trifluoromethyl) pyridin-3-amine (888 mg, yield: 37%). ESI-MS:342.9[ deg. ] M +1]] + 。
The second step is that: synthesis of 3, 3-dimethyl-5- (trifluoromethyl) -2, 3-dihydro-1H-pyrrolo [3,2-b ] pyridine
To a reaction flask were added 2-iodo-N- (2-methallyl) -6- (trifluoromethyl) pyridin-3-amine (888mg, 2.6 mmol), sodium formate (212mg, 3.1mmol), tetrabutylammonium chloride (862mg, 3.1mmol), triethylamine (788mg, 7.8mmol), palladium acetate (116mg, 0.52mmol), dimethyl sulfoxide (10 mL) and water (1 mL). The mixture was purged with nitrogen three times, heated to 100 ℃ under nitrogen protection, and stirred for 1 hour. The reaction solution was filtered, the filtrate was washed with water, extracted with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate, distilled under reduced pressure, and the crude product was separated by flash silica gel column [ eluent: ethyl acetate/petroleum ether: 0 to 30 percent]To obtain 3, 3-dimethyl-5- (trifluoromethyl) -2, 3-dihydro-1H-pyrrolo [3,2-b]Pyridine (430 mg, yield: 76%). ESI-MS:217.0[ mu ] M +1] + 。
Intermediate B5: preparation of 3, 5-trimethyl-2, 3-dihydro-1H-pyrrolo [3,2-b ] pyridine
The first step is as follows: synthesis of 2-iodo-6-methyl-N- (2-methallyl) pyridin-3-amine
To a solution of 2-iodo-6-methylpyridin-3-amine (2g, 8.5 mmol) in tetrahydrofuran (40 mL) at room temperature was addedPotassium tert-butoxide (1.14g, 10.2mmol). The mixture was stirred at room temperature for 15 minutes. 3-bromo-2-methylpropan-1-ene (1.27g, 9.4 mmol) was slowly added dropwise to the mixture. The reaction solution was stirred at room temperature for 2 hours, after completion of the reaction, the solvent was removed by concentration under reduced pressure, and the residue was separated by flash silica gel column [ eluent: ethyl acetate/petroleum ether: 0 to 20 percent]To give 2-iodo-6-methyl-N- (2-methallyl) pyridin-3-amine (1.46 g, yield: 59%). ESI-MS:288.9[ deg. ] M +1] + 。
The second step is that: synthesis of 3, 5-trimethyl-2, 3-dihydro-1H-pyrrolo [3,2-b ] pyridine
To a reaction flask were added 2-iodo-6-methyl-N- (2-methallyl) pyridin-3-amine (1.46g, 5 mmol), sodium formate (413mg, 6 mmol), tetrabutylammonium chloride (1.67g, 6 mmol), triethylamine (1.5g, 15mmol), palladium acetate (224mg, 1mmol), dimethyl sulfoxide (40 mL) and water (1.5 mL). The mixture was purged with nitrogen three times, heated to 120 ℃ under nitrogen protection, and stirred for 1 hour. The reaction solution was filtered, the filtrate was washed with water, extracted with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate, distilled under reduced pressure, and the crude product was separated by flash silica gel column [ eluent: ethyl acetate/petroleum ether: 0 to 30 percent]To give 3, 5-trimethyl-2, 3-dihydro-1H-pyrrolo [3,2-b ]]Pyridine (660 mg, yield: 81%). ESI-MS:163.0[ mu ] M +1] + 。
Intermediate B6: preparation of 5- (azetidin-1-yl) -3, 3-dimethyl-2, 3-dihydro-1H-pyrrolo [3,2-b ] pyridine
The first step is as follows: synthesis of 6-chloro-2-iodopyridin-3-amine
To a solution of 6-chloropyridin-3-amine (10g, 77.8mmol) in N, N-dimethylformamide (150 mL) was added N-iodosuccinimide (19.3g, 85.6 mmol) at room temperature. The mixture was stirred at room temperature overnight. After the reaction, the reaction solution was washed with water, extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the solvent, and the residue was separated by flash silica gel column [ eluent: ethyl acetate/petroleum ether: 0 to 20 percent]6-chloro-2-iodopyridin-3-amine (15.5 g, yield: 78.3%) was obtained. ESI-MS:254.8[ deg. ] M +1] + 。
The second step: synthesis of 6-chloro-2-iodo-N- (2-methallyl) pyridin-3-amine
To a solution of 6-chloro-2-iodopyridin-3-amine (15.5, 60.9 mmol) in tetrahydrofuran (200 mL) was added potassium tert-butoxide (8.2g, 73.1 mmol) at room temperature. The mixture was stirred at room temperature for 15 minutes. 3-bromo-2-methylpropan-1-ene (9.9 g,73.1 mmol) was then slowly added dropwise to the mixture. The reaction solution was stirred at room temperature for 2 hours, after completion of the reaction, the solvent was removed by concentration under reduced pressure, and the residue was separated by flash silica gel column [ eluent: ethyl acetate/petroleum ether: 0 to 20 percent]6-chloro-2-iodo-N- (2-methallyl) pyridin-3-amine (15.5 g, yield: 82.5%) was obtained. ESI-MS:308.8[ deg. ] M +1]] + 。
The third step: synthesis of 5-chloro-3, 3-dimethyl-2, 3-dihydro-1H-pyrrolo [3,2-b ] pyridine
To a reaction flask were added 6-chloro-2-iodo-N- (2-methylallyl) pyridin-3-amine (15.5g, 50.2mmol), sodium formate (4.2g, 60.3mmol), tetrabutylammonium chloride (16.8g, 60.3mmol), triethylamine (15.3g, 150.7mmol), palladium acetate (1.69g, 7.5mmol), dimethyl sulfoxide (200 mL) and water (R: (R) (15.3g, 150.7mmol))6.7 mL). The mixture was purged with nitrogen three times, heated to 120 ℃ under nitrogen protection, and stirred for 1 hour. The reaction solution was filtered, the filtrate was washed with water, extracted with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate, distilled under reduced pressure, and the crude product was separated by flash silica gel column [ eluent: ethyl acetate/petroleum ether: 0 to 30 percent]To obtain 5-chloro-3, 3-dimethyl-2, 3-dihydro-1H-pyrrolo [3,2-b ]]Pyridine (6.6 g, yield: 70.8%). ESI-MS:183.1[ deg. ] M +1]] + 。
The fourth step: synthesis of tert-butyl 5-chloro-3, 3-dimethyl-2, 3-dihydro-1H-pyrrolo [3,2-b ] pyridine-1-carboxylate
To 5-chloro-3, 3-dimethyl-2, 3-dihydro-1H-pyrrolo [3,2-b ] at room temperature]To a solution of pyridine (1g, 5.5 mmol) in 1, 4-dioxane (15 mL) were added di-tert-butyl dicarbonate (5 mL) and triethylamine (1 mL). The mixture was stirred at 120 ℃ overnight. After the reaction, the reaction solution was washed with water, extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the solvent, and the residue was separated by flash silica gel column [ eluent: ethyl acetate/petroleum ether: 0 to 20 percent]To give tert-butyl 5-chloro-3, 3-dimethyl-2, 3-dihydro-1H-pyrrolo [3,2-b ]]Pyridine-1-carboxylic acid ester (1.32 g, yield: 84.6%). ESI-MS:283.1[ deg. ] M +1]] + 。
The fifth step: synthesis of tert-butyl 5- (azetidin-1-yl) -3, 3-dimethyl-2, 3-dihydro-1H-pyrrolo [3,2-b ] pyridine-1-carboxylate
Adding tert-butyl 5-chloro-3, 3-dimethyl-2, 3-dihydro-1H-pyrrolo [3,2-b ] to the sealed tube]Pyridine-1-carboxylic acid ester (706mg, 2.5mmol), cesium carbonate (1.22g, 3.75mmol), 1 '-binaphthyl-2, 2' -bisdiphenylphosphine (0.3mg, 0.5mmol), cyclobutylamine (428mg, 7.5mmol), palladium acetate (112mg, 0.5mmol), 1, 4-dioxane (8 mL). Mixture ofThe mixture was purged with nitrogen three times, sealed, heated to 120 ℃ and stirred for 16 hours. The reaction solution was filtered, the filtrate was washed with water, extracted with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate, distilled under reduced pressure, and the crude product was separated by flash silica gel column [ eluent: ethyl acetate/petroleum ether: 0 to 30 percent]To give tert-butyl 5- (azetidin-1-yl) -3, 3-dimethyl-2, 3-dihydro-1H-pyrrolo [3, 2-b)]Pyridine-1-carboxylate (534 mg, yield: 70.8%). ESI-MS:304.1[ deg. ] M +1]] + 。
And a sixth step: synthesis of 5- (azetidin-1-yl) -3, 3-dimethyl-2, 3-dihydro-1H-pyrrolo [3,2-b ] pyridine
To tert-butyl 5- (azetidin-1-yl) -3, 3-dimethyl-2, 3-dihydro-1H-pyrrolo [3, 2-b)]Trifluoroacetic acid (2 mL) was added to a solution of pyridine-1-carboxylic acid ester (534mg, 1.8mmol) in dichloromethane (6 mL). Stirring the reaction solution at room temperature for 2 hours, after the reaction is completed, adding a saturated aqueous sodium bicarbonate solution, extracting with dichloromethane, drying the organic layer with anhydrous sodium sulfate, and concentrating under reduced pressure to remove the solvent to obtain 5- (azetidin-1-yl) -3, 3-dimethyl-2, 3-dihydro-1H-pyrrolo [3,2-b ]]Pyridine (350 mg, yield: 98.9%). ESI-MS:204.1[ deg. ] M +1]] + 。
Intermediate B7: preparation of 5-cyclopropyl-3, 3-dimethyl-2, 3-dihydro-1H-pyrrolo [3,2-b ] pyridine
Adding 5-chloro-3, 3-dimethyl-2, 3-dihydro-1H-pyrrolo [3,2-b ] into a reaction bottle]Pyridine (450mg, 2.5mmol), cyclopropylboronic acid (1.1g, 12.4mmol), potassium phosphate (1.94g, 9.1mmol), tricyclohexylphosphine (138mg, 0.5mmol), palladium acetate (55mg, 0.3mmol), toluene (30 mL). The mixture was purged with nitrogen three times, heated to 110 ℃ under nitrogen blanket, and stirred for 6 hours. Filtering the reaction solution, washing the filtrate with water, extracting with ethyl acetate, and extracting with anhydrous sulfuric acidThe organic layer was dried with sodium, distilled under reduced pressure, and the crude product was separated by flash silica gel column [ eluent: ethyl acetate/petroleum ether: 0 to 30 percent]To obtain 5-cyclopropyl-3, 3-dimethyl-2, 3-dihydro-1H-pyrrolo [3,2-b ]]Pyridine (152 mg, yield: 33.0%). ESI-MS:189.0 2[ M ] +1] + 。
Intermediate B8: preparation of 5-methoxy-3, 3-dimethyl-1H, 2H, 3H-pyrrolo [3,2-b ] pyridine
Reacting 5-chloro-3, 3-dimethyl-1H, 2H, 3H-pyrrolo [3,2-b ]]Pyridine (210mg, 1.15mmol) was dissolved in N, N-dimethylformamide (20 mL), and a methanol solution of sodium methoxide (2.1 mL) and cuprous iodide (110mg, 0.575mmol) were added. The reaction solution was heated to 140 ℃ and the reaction was completed after 2 hours. Water was added and extracted three times with dichloromethane. The organic phases were combined, washed with saturated brine and dried over anhydrous sodium sulfate. After removal of the solvent, silica gel column chromatography separation [ petroleum ether: ethyl acetate =1]To obtain 5-methoxy-3, 3-dimethyl-1H, 2H, 3H-pyrrolo [3,2-b ]]Pyridine (110 mg, yield: 54%). ESI-MS:179.0[ deg. ] M +1] + 。
Intermediate B9: preparation of 5-bromo-3, 3-dimethyl-1H, 2H, 3H-pyrrolo [3,2-b ] pyridine
The first step is as follows: synthesis of 1-tert-butyl 3-ethyl 2- (6-methoxy-3-nitropyridin-2-yl) malonate
Ethyl malonate tert-butyl ester (8.4g, 44.5 mmol) was dissolved in anhydrous tetrahydrofuran (100 mL), sodium hydride (1.8g, 44.5 mmol) was added in portions, and the reaction was stirred at room temperatureAfter stirring for 20 minutes, 2-chloro-6-methoxy-3-nitropyridine (7.0 g, 37.1mmol) was added and the reaction was stirred at 80 ℃ for 2 hours. After completion of the reaction, the reaction mixture was partitioned between ethyl acetate (100 mL) and saturated brine (100 mL), and the organic phase was washed with saturated brine (50 mL). The resulting organic phase was concentrated to give 1-tert-butyl 3-ethyl 2- (6-methoxy-3-nitropyridin-2-yl) malonate (10.2 g, yield: 80%). ESI-MS of 225.0[ m-56 ]] + 。
The second step is that: synthesis of ethyl 2- (6-methoxy-3-nitropyridin-2-yl) acetate
1-tert-butyl 3-ethyl 2- (6-methoxy-3-nitropyridin-2-yl) malonate (10.2g, 30mmol) was dissolved in dichloromethane (30 mL), trifluoroacetic acid (25 mL) was added to the solution, the reaction was refluxed for 2 hours, the reaction was terminated, the reaction solution was concentrated, the residue was partitioned between ethyl acetate (100 mL) and saturated brine (100 mL), and the organic phase was washed with saturated brine (50 mL). The resulting organic phase was concentrated to give ethyl 2- (6-methoxy-3-nitropyridin-2-yl) acetate (6.9 g, yield: 95%). ESI-MS:241.0[ 2 ] M +1] + 。
The third step: synthesis of ethyl 2- (6-methoxy-3-nitropyridin-2-yl) -2-methylpropionate
Ethyl 2- (6-methoxy-3-nitropyridin-2-yl) acetate (4.0g, 16.6 mmol) was dissolved in tetrahydrofuran (100 mL), and methyl iodide (2.6mL, 41.6 mmol) and sodium hydride (2.0g, 50.0 mmol) were added to the reaction mixture. The reaction was stirred at 0 ℃ for 3 hours under nitrogen, LCMS showed completion of the reaction, the reaction was partitioned between ethyl acetate (100 mL) and saturated brine (100 mL), and the organic phase was washed with saturated brine (50 mL). The resulting organic phase was concentrated and the residue was separated by flash column chromatography on silica gel [ petroleum ether/ethyl acetate =3/1 ]]To obtain ethyl 2- (6-methoxy)3-Nitropyridin-2-yl) -2-methylpropionate (4.2 g, yield: 94%). ESI-MS:269.0[ m ] +1] + 。
The fourth step: synthesis of 5-methoxy-3, 3-dimethyl-1H, 2H, 3H-pyrrolo [3,2-b ] pyridin-2-one
Ethyl 2- (6-methoxy-3-nitropyridin-2-yl) -2-methylpropionate (4.2g, 15.7 mmol), palladium on carbon (200mg, 10%) was dissolved in methanol (50 mL). The reaction was stirred at room temperature under hydrogen for 2 hours. The reaction mixture was filtered through celite, and the filtrate was stirred at 90 ℃ for 16 hours, after which the reaction was completed and the reaction mixture was concentrated. The obtained residue was partitioned between ethyl acetate (100 mL) and saturated brine (100 mL). The organic phase was concentrated and the residue was separated by flash column chromatography on silica gel [ petroleum ether/ethyl acetate =2/1 ]]To obtain 5-methoxy-3, 3-dimethyl-1H, 2H, 3H-pyrrolo [3,2-b ]]Pyridin-2-one (2.3 g, yield: 66%). ESI-MS:193.0[ m ] +1] + 。
The fifth step: synthesis of 5-methoxy-3, 3-dimethyl-1H, 2H, 3H-pyrrolo [3,2-b ] pyridine
Reacting 5-methoxy-3, 3-dimethyl-1H, 2H, 3H-pyrrolo [3,2-b ]]Pyridine-2-one (2.3g, 12.0 mmol) was dissolved in tetrahydrofuran (50 mL), borane-tetrahydrofuran solution (36mL, 36.0 mmol) was added to the reaction solution, and the reaction solution was stirred at room temperature for 16 hours under nitrogen protection, whereupon the reaction was terminated. The reaction mixture was partitioned between ethyl acetate (50 mL) and saturated brine (50 mL), and the organic phase was washed with saturated brine (50 mL). The resulting organic phase was concentrated and the residue was separated by flash column chromatography on silica gel [ petroleum ether/ethyl acetate =2/1 ]]To obtain 5-methoxy-3, 3-dimethyl-1H, 2H, 3H-pyrrolo [3,2-b ]]Pyridine (1.98 g, yield: 93%). ESI-MS:179.1[ deg. ] M +1]] + 。
And a sixth step: synthesis of 3, 3-dimethyl-1H, 2H,3H,4H, 5H-pyrrolo [3,2-b ] pyridin-5-one
Reacting 5-methoxy-3, 3-dimethyl-1H, 2H, 3H-pyrrolo [3,2-b ]]Pyridine (1.98g, 11.1mmol) is dissolved in hydrogen bromide solution (20ml, 40%), the reaction solution is stirred for 3 hours at 90 ℃, the reaction is finished, the reaction solution is directly concentrated to be dry, and crude products of 3, 3-dimethyl-1H, 2H,3H,4H, 5H-pyrrolo [3,2-b ] are obtained]Pyridin-5-one (1.6 g, yield: 88%). ESI-MS:165.1[ deg. ] M +1]] + 。
The seventh step: synthesis of 5-bromo-3, 3-dimethyl-1H, 2H, 3H-pyrrolo [3,2-b ] pyridine
Reacting 3, 3-dimethyl-1H, 2H,3H,4H, 5H-pyrrolo [3,2-b ]]Pyridin-5-one (1.6 g,9.7 mmol) was dissolved in phosphorus oxybromide (10mL, 98mmol), the reaction was stirred at 100 ℃ for 18 hours, the reaction solution was quenched into dichloromethane (200 mL) and saturated sodium carbonate (200 mL), and the organic phase was washed with saturated brine (50 mL). The resulting organic phase was concentrated and the residue was separated by flash column chromatography on silica gel [ dichloromethane/methanol = 10/1%]To obtain 5-bromo-3, 3-dimethyl-1H, 2H, 3H-pyrrolo [3,2-b ]]Pyridine (280 mg, yield: 12%). ESI-MS:226.9,228.9, [2 ] M +1] + 。
Intermediate B10: preparation of 3, 3-dimethyl-1, 2,3,5,6, 7-hexahydrocyclopenta [ b ] pyrrolo [2,3-e ] pyridine
The first step is as follows: synthesis of 3-nitro-1, 5,6, 7-tetrahydro-2H-cyclopenta [ b ] pyridin-2-one
To 1,5,6, 7-tetrahydro-2H-cyclopenta [ b ] at 0 deg.C]Slowly adding dropwise nitric acid (65% mass fraction, 5.4g,55.6 mmol) into concentrated sulfuric acid (98% mass fraction, 30 mL) of pyridin-2-one (450mg, 2.5 mmol), stirring the mixture at 0 deg.C for 1 hour, slowly pouring into ice water, stirring for 1 hour, filtering, and drying the filter cake to obtain 3-nitro-1, 5,6, 7-tetrahydro-2H-cyclopenta [ b ] s]Pyridin-2-one (3.5 g, yield: 52.5%). ESI-MS:181.0[ mu ] M +1] + 。
The second step is that: synthesis of 2-chloro-3-nitro-6, 7-dihydro-5H-cyclopenta [ b ] pyridine
To 3-nitro-1, 5,6, 7-tetrahydro-2H-cyclopenta [ b ]]To a solution of pyridin-2-one (2.5g, 13.9mmol) in acetonitrile (50 mL) was added phosphorus oxychloride (6.4g, 41.6 mmol) and triethylbenzylammonium chloride (1.9g, 7.0mmol), and the mixture was stirred at 80 ℃ for 1 hour, concentrated under reduced pressure to remove the solvent, and the residue was slowly poured into ice water and stirred for 30 minutes. Extraction with dichloromethane, drying of the organic layer over anhydrous sodium sulfate, distillation under reduced pressure, and separation of the crude product through flash silica gel column [ eluent: ethyl acetate/petroleum ether: 0 to 50 percent]To obtain 2-chloro-3-nitro-6, 7-dihydro-5H-cyclopenta [ b ]]Pyridine (985 mg, yield: 36.0%). ESI-MS:198.9[ deg. ] M +1]] + 。
The third step: synthesis of diethyl 2- (3-nitro-6, 7-dihydro-5H-cyclopenta [ b ] pyridin-2-yl) malonate
To 2-chloro-3-nitro-6, 7-dihydro-5H-cyclopenta [ b ] at 0 deg.C]Hydrogen was added to a solution of pyridine (814mg, 5.1mmol) in dimethyl sulfoxide (10 mL)Sodium chloride (220mg, 5.5 mmol), the mixture was stirred at 0 ℃ for 0.5 hour, diethyl malonate (840mg, 4.2mmol) was added to the mixture, the reaction was stirred at 100 ℃ for 1 hour, cooled to room temperature, the reaction was quenched with saturated ammonium chloride solution, the reaction solution was washed with water, extracted with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate, distilled under reduced pressure, and the crude product was separated by flash silica gel column [ eluent: ethyl acetate/petroleum ether: 0 to 30 percent]To obtain diethyl 2- (3-nitro-6, 7-dihydro-5H-cyclopenta [ b ]]Pyridin-2-yl) malonate (409 mg, yield: 30.0%). ESI-MS:323.0[ mu ] M +1] + 。
The fourth step: synthesis of ethyl 2- (3-nitro-6, 7-dihydro-5H-cyclopenta [ b ] pyridin-2-yl) acetate
To diethyl 2- (3-nitro-6, 7-dihydro-5H-cyclopenta [ b ]]To a solution of pyridin-2-yl) malonate (409mg, 1.3 mmol) in dimethyl sulfoxide (5 mL) was added water (0.91ml, 5.1mmol) and lithium chloride (267mg, 6.4 mmol). The mixture was stirred at 100 ℃ for 24 hours. The reaction solution was cooled to room temperature, washed with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, distilled under reduced pressure, and the crude product was separated by flash silica gel column [ eluent: ethyl acetate/petroleum ether: 0 to 50 percent]To obtain ethyl 2- (3-nitro-6, 7-dihydro-5H-cyclopenta [ b ]]Pyridin-2-yl) acetate (240 mg, yield: 76.0%). ESI-MS:251.0[ deg. ] M +1] + 。
The fifth step: synthesis of ethyl 2-methyl-2- (3-nitro-6, 7-dihydro-5H-cyclopenta [ b ] pyridin-2-yl) propionate
To ethyl 2- (3-nitro-6, 7-dihydro-5H-cyclopenta [ b ] at 0 deg.C]Pyridin-2-yl) acetate (240mg, 0.96mmol) in N, N dimethylformamide (5 mL) was added methyl iodide (300mg, 2)1 mmol), 18-crown-6 (26mg, 0.1mmol), sodium hydride (88mg, 2.2mmol) was slowly added, the mixture was stirred at 0 ℃ for 1 hour, the reaction was completed, quenched with ice water, washed with water, extracted with ethyl acetate, dried organic layer over anhydrous sodium sulfate, distilled under reduced pressure, and the crude product was separated by flash silica gel column [ eluent: ethyl acetate/petroleum ether: 0 to 25 percent]To obtain ethyl 2-methyl-2- (3-nitro-6, 7-dihydro-5H-cyclopenta [ b ]]Pyridin-2-yl) propionate (150 mg, yield: 56.0%). ESI-MS:279.0[ m ] +1] + 。
And a sixth step: synthesis of 3, 3-dimethyl-3, 5,6, 7-tetrahydrocyclopenta [ b ] pyrrolo [2,3-e ] pyridin-2 (1H) -one
To 2-methyl-2- (3-nitro-6, 7-dihydro-5H-cyclopenta [ b)]To a solution of pyridin-2-yl) propionate (150mg, 0.54mmol) in ethanol (5 mL) was added ammonium formate (272mg, 4.3mmol) and 10% palladium on carbon (50 mg), and the mixture was stirred at 90 ℃ for reaction for 16 hours. After the reaction, the reaction solution is filtered, the filtrate is concentrated, the residue is washed by water, extracted by ethyl acetate, an organic layer is dried by anhydrous sodium sulfate, and then the organic layer is distilled under reduced pressure to obtain a crude product of 3, 3-dimethyl-3, 5,6, 7-tetrahydrocyclopenta [ b ] product]Pyrrolo [2,3-e]Pyridin-2 (1H) -one was used directly in the next reaction. ESI-MS:203.0[ 2 ] M +1] + 。
The seventh step: synthesis of 3, 3-dimethyl-1, 2,3,5,6, 7-hexahydrocyclopenta [ b ] pyrrolo [2,3-e ] pyridine
3, 3-dimethyl-3, 5,6, 7-tetrahydrocyclopenta [ b ] is reacted with a catalyst]Pyrrolo [2,3-e]The crude pyridin-2 (1H) -one was dissolved in tetrahydrofuran (5 mL), cooled to 0 deg.C, and a solution of lithium aluminum hydride in tetrahydrofuran (2mL, 2.5M) was added dropwise to the solution. The mixture was stirred at room temperature for 4 hours. After the reaction is finished, sodium sulfate decahydrate is used for reaction liquidQuenching until no bubbles are produced. Filtering the mixture, and distilling the filtrate under reduced pressure to obtain 3, 3-dimethyl-1, 2,3,5,6, 7-hexahydrocyclopenta [ b ]]Pyrrolo [2,3-e]And (4) crude pyridine. ESI-MS:189.0[ deg. ] M +1] + 。
Intermediate B11: preparation of 3, 3-dimethyl-6-phenyl-1H, 2H, 3H-pyrrolo [3,2-b ] pyridine
The first step is as follows: synthesis of ethyl 2- (5-bromo-3-nitropyridin-2-yl) acetate
5-bromo-2-chloro-3-nitropyridine (2.5g, 10.53mmol) was dissolved in acetonitrile (50 mL). Potassium 3-ethoxy-3-oxopropionate (2.15g, 12.64mmol), magnesium chloride (1.5g, 15.79mmol) and triethylamine (2.93mL, 21.06mmol) were added. The reaction was stirred at 70 ℃ for 16 hours. The reaction solution was adjusted to pH =7 with 1N HCl, extracted with dichloromethane (100 mL), and the organic phase was washed with water (50 mL) and saturated brine (50 mL) in this order. The organic phase is concentrated and the residue is separated with a flash silica gel column [ petroleum ether: ethyl acetate =3]Ethyl 2- (5-bromo-3-nitropyridin-2-yl) acetate (890mg, 29%) was obtained. ESI-MS:289.0, 290.9[ deg. ] M +1]] + 。
The second step is that: synthesis of ethyl 2- (5-bromo-3-nitropyridin-2-yl) -2-methylpropionate
Ethyl 2- (5-bromo-3-nitropyridin-2-yl) acetate (710mg, 2.46mmol) was dissolved in tetrahydrofuran (50 mL), and 18-crown-6 (64.9mg, 0.25mmol), methyl iodide (0.46mL, 7.37mmol) and sodium hydride (177mg, 7.37mmol) were added to the reaction mixture. The reaction solution is at 0 ℃ under the protection of nitrogenAfter stirring for 3 hours, the reaction mixture was quenched, and the reaction mixture was partitioned with ethyl acetate (100 mL) and brine (100 mL) and the organic phase was washed with brine (50 mL). The organic phase was concentrated and the residue was passed through a flash column of silica gel [ petroleum ether/ethyl acetate =3/1 ]]Ethyl 2- (5-bromo-3-nitropyridin-2-yl) -2-methylpropionate (532mg, 68%) was obtained. ESI-MS:317.0, 319.0[ 2 ], [ M ] +1] + 。
The third step: synthesis of 6-bromo-3, 3-dimethyl-1H, 2H, 3H-pyrrolo [3,2-b ] pyridin-2-one
Ethyl 2- (5-bromo-3-nitropyridin-2-yl) -2-methylpropionate (532mg, 1.68mmol), iron powder (940mg, 16.77mmol) was dissolved in glacial acetic acid (10 mL). The reaction solution was stirred at 80 ℃ for 16 hours. The reaction solution was filtered through celite, and the filtrate was concentrated. The obtained residue was partitioned with ethyl acetate (50 mL) and saturated brine (50 mL). The organic phase is concentrated and the residue is separated by flash column chromatography on silica gel [ petroleum ether/ethyl acetate = 2/1%]To obtain 6-bromo-3, 3-dimethyl-1H, 2H, 3H-pyrrolo [3,2-b ]]Pyridin-2-one (270mg, 66%). ESI-MS 241.0, 243.0[ m ] +1] + 。
The fourth step: synthesis of 3, 3-dimethyl-6-phenyl-1H, 2H, 3H-pyrrolo [3,2-b ] pyridin-2-one
Reacting 6-bromo-3, 3-dimethyl-1H, 2H, 3H-pyrrolo [3,2-b ]]Pyridin-2-one (140mg, 0.58mmol), phenylboronic acid (106mg, 0.87mmol), [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride (42mg, 0.058 mmol) and potassium carbonate (161mg, 1.16mmol) were dissolved in dimethoxyethylene glycol (5 mL), and the reaction mixture was stirred at 90 ℃ for 1 hour under nitrogen protection, whereupon the reaction was terminated. The reaction mixture was partitioned with ethyl acetate (50 mL) and saturated brine (50 mL), and the organic phase was washed with saturated brine (50 mL). The organic phase is concentrated and the residue is rapidly purifiedSilica gel column separation [ petroleum ether/ethyl acetate =2/1]To obtain 3, 3-dimethyl-6-phenyl-1H, 2H, 3H-pyrrolo [3,2-b ]]Pyridin-2-one (110mg, 78%). ESI-MS:239.0[ mu ] M +1] + 。
The fifth step: synthesis of 3, 3-dimethyl-6-phenyl-1H, 2H, 3H-pyrrolo [3,2-b ] pyridine
Reacting 3, 3-dimethyl-6-phenyl-1H, 2H, 3H-pyrrolo [3,2-b ]]Pyridine-2-ketone (110mg, 0.46mmol) is dissolved in tetrahydrofuran (20 mL), borane tetrahydrofuran solution (1.4 mL,1.4 mmol) is added into the reaction solution, and the reaction solution is stirred for 16 hours at 70 ℃ under the protection of nitrogen, thus finishing the reaction. The reaction mixture was partitioned with ethyl acetate (50 mL) and saturated brine (50 mL), and the organic phase was washed with saturated brine (50 mL). The resulting organic phase was concentrated and the residue was separated by flash column chromatography on silica gel [ petroleum ether/ethyl acetate = 2/1%]To obtain 3, 3-dimethyl-6-phenyl-1H, 2H, 3H-pyrrolo [3,2-b ]]Pyridine (91mg, 88%). ESI-MS:225.0[ mu ] M +1] + 。
Preparation of intermediates B12 to B14 reference to the preparation of intermediate B11 was prepared by:
intermediate B15: preparation of 5-ethynyl-3, 3-dimethyl-1H, 2H, 3H-pyrrolo [3,2-b ] pyridine
The first step is as follows: synthesis of methyl 5-amino-6-iodopyridine-2-carboxylate
Methyl 5-aminopyridine-2-carboxylate (10g, 65.7mmol) was dissolved in N, N-dimethylformamide (60 mL), and iodine (18.35g, 72.3mmol) and sodium periodate (33.7g, 157.7mmol) were added. The reaction was stirred at 60 ℃ for 6 hours. Poured into water, extracted three times with ethyl acetate, and the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. After removal of the solvent, silica gel column chromatography separation [ petroleum ether: ethyl acetate =1]Methyl 5-amino-6-iodopyridine-2-carboxylate (12 g, yield: 65.6%) was obtained. ESI-MS:278.8 2[ 2 ] M +1] + 。
The second step: synthesis of methyl 6-iodo-5- ((2-methallyl) amino) picolinate
Methyl 5-amino-6-iodopyridine-2-carboxylate (11g, 39.56mmol) dissolved in tetrahydrofuran (150 mL) was added a solution of potassium tert-butoxide in tetrahydrofuran (47.5mL, 47.5 mmol) and 3-bromo-2-methylpropan-1-ene (4.78mL, 47.5 mmol). The reaction was stirred at room temperature for 1 hour, then quenched with 10mL of methanol and stirred for an additional 10 minutes. After removal of the solvent, silica gel column chromatography separation [ petroleum ether: ethyl acetate =1]Methyl 6-iodo-5- ((2-methallyl) amino) picolinate (5.2 g, yield: 39.57%) was obtained. ESI-MS:333.1[ deg. ] M +1] + 。
The third step: synthesis of methyl 3, 3-dimethyl-1H, 2H, 3H-pyrrolo [3,2-b ] pyridine-5-carboxylate
Methyl 6-iodo-5- ((2-methallyl) amino) picolinate (5.0g, 15.05mmol) was dissolved in dimethyl sulfoxide (90 mL) and water (36 mL), and sodium formate (1.23g, 18.06mmol), triethylamine (6.3mL, 45.16mmol), tetrabutylammonium chloride (1.6g, 5.7mmol) and palladium acetate (0) were added.51g, 2.26mmol). The reaction was stirred at 120 ℃ for 1 hour under nitrogen. Poured into water and extracted three times with ethyl acetate. The organic phases were combined, washed with saturated brine and dried over anhydrous sodium sulfate. After removal of the solvent, silica gel column chromatography separation [ petroleum ether: ethyl acetate =1]To obtain methyl 3, 3-dimethyl-1H, 2H, 3H-pyrrolo [3,2-b ]]Pyridine-5-carboxylic acid ester (2.2g, 71%). ESI-MS:207.2[ deg. ] M +1] + 。
The fourth step: synthesis of 1-tert-butyl 5-methyl 3, 3-dimethyl-1H, 2H, 3H-pyrrolo [3,2-b ] pyridine-1, 5-dicarboxylate
Methyl 3, 3-dimethyl-1H, 2H, 3H-pyrrolo [3,2-b ]]Pyridine-5-carboxylate (2.2g, 10.67mmol) was dissolved in 1, 4-dioxane (50 mL), and di-tert-butyl dicarbonate (7.65g, 35mmol) was added. The reaction was stirred at 120 ℃ for 2 hours. After concentration, silica gel column chromatography separation [ petroleum ether: ethyl acetate =1]To obtain 1-tert-butyl-5-methyl-3, 3-dimethyl-1H, 2H, 3H-pyrrolo [3,2-b ]]Pyridine-1, 5-dicarboxylic acid ester (3.25 g, yield: 96.47%). ESI-MS:307.2[ deg. ] M +1]] + 。
The fifth step: synthesis of tert-butyl 5- (hydroxymethyl) -3, 3-dimethyl-1H, 2H, 3H-pyrrolo [3,2-b ] pyridine-1-carboxylic acid ester
1-tert-butyl-5-methyl-3, 3-dimethyl-1H, 2H, 3H-pyrrolo [3,2-b ]]Pyridine-1, 5-dicarboxylate (3.2g, 10.45mmol) was dissolved in tetrahydrofuran (60 mL), and lithium aluminum hydride (2.0 g, 92mmol) was added. Stirred at room temperature for 1 hour. Adding sodium sulfate decahydrate, quenching, filtering, separating with ethyl acetate and water, mixing organic phases, drying, and concentrating to obtain tert-butyl 5- (hydroxymethyl) -3, 3-dimethyl-1H, 2H, 3H-pyrrolo [3,2-b ]]Pyridine-1-carboxylic acid ester (2.2 g, yield: 76%). ESI-MS:279.3[ 2 ] M +1] + 。
And a sixth step: synthesis of tert-butyl 5-formyl-3, 3-dimethyl-1H, 2H, 3H-pyrrolo [3,2-b ] pyridine-1-carboxylate
Tert-butyl 5- (hydroxymethyl) -3, 3-dimethyl-1H, 2H, 3H-pyrrolo [3,2-b ]]Pyridine-1-carboxylate (2.2 g,7.9 mmol) was dissolved in dichloromethane (80 mL), and manganese dioxide (6.87g, 79mmol) was added. The reaction was stirred at room temperature for 2 hours, filtered and concentrated to give tert-butyl 5-formyl-3, 3-dimethyl-1H, 2H, 3H-pyrrolo [3,2-b ]]Pyridine-1-carboxylic acid ester (1.8 g, yield: 82.4%). ESI-MS:277.0[ 2 ] M +1] + 。
The seventh step: synthesis of tert-butyl 5-ethynyl-3, 3-dimethyl-1H, 2H, 3H-pyrrolo [3,2-b ] pyridine-1-carboxylate
Tert-butyl 5-formyl-3, 3-dimethyl-1H, 2H, 3H-pyrrolo [3,2-b ]]Pyridine-1-carboxylate (811mg, 2.94mmol) was dissolved in methanol (3.0 mL), potassium carbonate (811mg, 5.87mmol) was added, and then a solution of (1Z) -1- (diazoyn-1-ium-1-yl) -1- (dimethoxyphosphanyl) prop-1-ene-2-oic acid (620mg, 2.23mmol) in methanol (3.0 mL) was added dropwise. The reaction was stirred at room temperature for 1.5 hours, and the reaction solution was poured into a sodium carbonate solution (1 mol/L) and extracted three times with ethyl acetate. The organic phases were combined, washed with saturated brine and dried over anhydrous sodium sulfate. After removal of the solvent, the column was chromatographed on silica gel [ ether =100%]To give tert-butyl 5-ethynyl-3, 3-dimethyl-1H, 2H, 3H-pyrrolo [3,2-b ]]Pyridine-1-carboxylate (740 mg, yield: 93%). ESI-MS:273.3[ deg. ] M +1]] + 。
Eighth step: synthesis of 5-ethynyl-3, 3-dimethyl-1H, 2H, 3H-pyrrolo [3,2-b ] pyridine
Tert-butyl-5-ethynyl-3, 3-dimethyl-1H, 2H, 3H-pyrrolo [3,2-b ]]Pyridine-1-carboxylate (650 mg, 2.38mmol) was dissolved in dichloromethane (4.0 mL), and trifluoroacetic acid (2.0 mL) was added. Stirring at room temperature for 5 hr, concentrating, adding saturated sodium bicarbonate solution, extracting with dichloromethane for three times, mixing organic phases, and concentrating to obtain 5-ethynyl-3, 3-dimethyl-1H, 2H, 3H-pyrrolo [3,2-b ] compound]Pyridine (350 mg, yield: 96.10%). ESI-MS:173.3[ deg. ] M +1] + 。
Intermediate B16: preparation of 3, 3-dimethyl-2, 3-dihydro-1H-pyrido [2,3-b ] [1,4] oxazines
The first step is as follows: synthesis of 2-bromo-2-methyl-N- (2-carbonyl-1, 2-dihydropyridin-3-yl) propanamide
Triethylamine (7.5g, 74.4 mmol) and 2-bromo-2-methylpropionylbromide (9.4g, 40.9mmol) were added to a solution of 3-aminopyridin-2 (1H) -one (4.1g, 37.2 mmol) in tetrahydrofuran (150 mL) while cooling on ice. The reaction solution was stirred for 1.5 hours while being cooled on ice. After the reaction, the mixture was extracted with ethyl acetate and water. The organic phase was concentrated and separated by flash silica gel column [ eluent: ethyl acetate/petroleum ether =0-50%]To give 2-bromo-2-methyl-N- (2-carbonyl-1, 2-dihydropyridin-3-yl) propanamide (5.7 g, yield: 59%). ESI-MS:261.1[ 2 ] M +1] + 。
The second step is that: synthesis of 3, 3-dimethyl-1H, 2H, 3H-pyrido [2,3-b ] [1,4] oxazin-2-one
To a solution of 2-bromo-2-methyl-N- (2-carbonyl-1, 2-dihydropyridin-3-yl) propionamide (5.7g, 21.9mmol) in N, N-dimethylformamide (50 mL) was added potassium carbonate (7.6 g, 54.9mmol) at room temperature. The reaction mixture was stirred at 70 ℃ for 3 hours. After the reaction, the mixture was extracted with ethyl acetate and water. The organic phase was concentrated and separated by flash silica gel column [ eluent: ethyl acetate/petroleum ether =0-50%]To obtain 3, 3-dimethyl-1H, 2H, 3H-pyrido [2,3-b ]][1,4]Oxazin-2-one (1.0 g, yield: 25%). ESI-MS:179.2[ M ] +1] + 。
The third step: synthesis of 3, 3-dimethyl-2, 3-dihydro-1H-pyrido [2,3-b ] [1,4] oxazines
3, 3-dimethyl-1H, 2H, 3H-pyrido [2,3-b ] under ice bath][1,4]2.5M LiAlH was added to a solution of oxazin-2-one (500mg, 2.8 mmol) in tetrahydrofuran (20 mL) 4 In tetrahydrofuran (1.1 mL, 2.8 mmol). The reaction solution was stirred at room temperature for 2 hours. After the reaction was completed, sodium sulfate decahydrate was added to quench, and after concentration, separation was performed by flash silica gel column [ eluent: ethyl acetate/petroleum ether =0-50%]To obtain 3, 3-dimethyl-2, 3-dihydro-1H-pyrido [2,3-b ]][1,4]Oxazine (460 mg, yield: 91%). ESI-MS:165.3[ m ] +1] + 。
Intermediate B17 preparation of 2, 2-dimethyl-3, 4-dihydro-2H-benzo [ B ] [1,4] oxazine
Preparation of intermediate B17 was prepared according to the procedure for intermediate B16. ESI-MS:164.2[ mu ] M +1] + 。
Intermediate B18: preparation of 6-fluoro-4, 4-dimethyl-1, 2,3, 4-tetrahydroquinoline
The first step is as follows: synthesis of N- (4-fluorophenyl) -3-methylbut-2-enamide
4-fluoroaniline (5.55g, 50mmol) was dissolved in dichloromethane (100 mL), potassium carbonate (10.35g, 75mmol) was added, and 3-methylcrotonyl chloride (7.1g, 60mmol) was slowly added dropwise. The reaction solution was stirred at room temperature for 2 hours. The reaction solution was poured into water, extracted three times with ethyl acetate, and the organic phases were combined, concentrated and dried to give N- (4-fluorophenyl) -3-methylbut-2-enamide (8.69 g, yield: 90.1%). ESI-MS:194.1 2[ 2 ] M +1] + 。
The second step is that: synthesis of 6-fluoro-4, 4-dimethyl-3, 4-dihydroquinolin-2 (1H) -one
N- (4-fluorophenyl) -3-methylbut-2-enamide (8.69g, 45mmol) was dissolved in methylene chloride (100 mL), anhydrous aluminum trichloride (9 g,67.5 mmol) was added under ice bath, and the reaction solution was stirred at room temperature for 2 hours. Slowly dropwise adding 1M hydrochloric acid under ice bath to quench the reaction, demixing the reaction liquid, extracting the aqueous phase by dichloromethane, combining organic phases, concentrating to obtain a crude product 6-fluoro-4, 4-dimethyl-3, 4-dihydroquinolin-2 (1H) -one (7.7 g, yield: 89.1%), ESI-MS:194.1[ M ] +1 +] + 。
The third step: synthesis of 6-fluoro-4, 4-dimethyl-1, 2,3, 4-tetrahydroquinoline
6-fluoro-4, 4-dimethyl-3, 4-dihydroquinolin-2 (1H) -one (7.7 g, 40mmol) was dissolved in tetrahydrofuran (100 mL) and a 1M borane in tetrahydrofuran solution (80mL, 80mmol) was added. The reaction mixture was warmed to 90 ℃ and reacted overnight. Slowly dropwise adding ice water (50 mL) to quench the reaction, extracting twice with ethyl acetate, combining the organic phases, concentrating and drying, and separating by silica gel column chromatography to obtain 6-fluoro-4, 4-dimethyl-1, 2,3, 4-tetrahydroquinoline (5.1 g, yield: 72%). ESI-MS:180.3[ deg. ] M +1] + 。
Preparation of intermediates B19 to B21 reference was made to the preparation of intermediate B18 to give:
intermediate C1: (R) -N 1 - (4- (3, 3-dimethyl-2, 3-dihydro-1H-pyrrolo [3, 2-b)]Preparation of pyridin-1-yl) -1,3, 5-triazin-2-yl-4- (3- (dimethylamino) pyrrolidin-1-yl) -6-methoxybenzene-1, 3-diamine
The first step is as follows: synthesis of 1- (4-chloro-1, 3, 5-triazin-2-yl) -3, 3-dimethyl-2, 3-dihydro-1H-pyrrolo [3,2-b ] pyridine
2, 4-dichloro-1, 3, 5-triazine (747mg, 4.98mmol) was dissolved in dichloromethane (20 mL) at room temperature and 3, 3-dimethyl-2, 3-dihydro-1H-pyrrolo [3,2-b ] was added sequentially]Pyridine (614mg, 4.15mmol) and N, N-diisopropylethylamine (1.2g, 9.30mmol). The reaction solution was stirred at room temperature for 1 hour. After the reaction was completed, the solvent was removed, and the reaction mixture was separated by silica gel column chromatography [ petroleum ether: ethyl acetate =4]To obtain 1- (4-chloro)-1,3, 5-triazin-2-yl) -3, 3-dimethyl-2, 3-dihydro-1H-pyrrolo [3,2-b]Pyridine (684 mg, yield: 63%). ESI-MS:262.1[ deg. ] M +1]] + 。
The second step is that: synthesis of (R) -4- (3, 3-dimethyl-2, 3-dihydro-1H-pyrrolo [3,2-b ] pyridin-1-yl) -N- (4- (3- (dimethylamino) pyrrolidin-1-yl) -2-methoxy-5-nitrophenyl) -1,3, 5-triazin-2-amine
(R) -1- (4-amino-5-methoxy-2-nitrophenyl) -N, N-dimethylpyrrolidin-3-amine (156mg, 0.56mmol) was dissolved in 5mL of N-butanol. Adding 1- (4-chloro-1, 3, 5-triazin-2-yl) -3, 3-dimethyl-2, 3-dihydro-1H-pyrrolo [3,2-b ] to the solution]Pyridine (121mg, 0.46mmol) and trifluoroacetic acid (0.5 mL). The reaction solution was reacted at 50 ℃ for 16 hours. After completion of the reaction, the reaction mixture was concentrated, and after removal of the solvent, the reaction mixture was separated by silica gel column chromatography [ dichloromethane: methanol =5]To obtain (R) -4- (3, 3-dimethyl-2, 3-dihydro-1H-pyrrolo [3, 2-b)]Pyridin-1-yl) -N- (4- (3- (dimethylamino) pyrrolidin-1-yl) -2-methoxy-5-nitrophenyl) -1,3, 5-triazin-2-amine (242 mg, yield: 89%). ESI-MS:506.2[ 2 ] M +1] + 。
The third step: (R) -N 1 - (4- (3, 3-dimethyl-2, 3-dihydro-1H-pyrrolo [3, 2-b)]Synthesis of pyridin-1-yl) -1,3, 5-triazin-2-yl-4- (3- (dimethylamino) pyrrolidin-1-yl) -6-methoxybenzene-1, 3-diamine
Reacting (R) -4- (3, 3-dimethyl-2, 3-dihydro-1H-pyrrolo [3, 2-b)]Pyridin-1-yl) -N- (4- (3- (dimethylamino) pyrrolidin-1-yl) -2-methoxy-5-nitrophenyl) -1,3, 5-triazin-2-amine (242mg, 0.48mmol) was dissolved in 20mL of methanol. Platinum dioxide (15 mg) was added to the solution. The reaction solution was stirred at room temperature for 16 hours. After the reaction was completed, the mixture was filtered through celite. Removing the solventAnd then separated by column chromatography over silica gel [ eluent: dichloromethane/methanol (5]To obtain (R) -N 1 - (4- (3, 3-dimethyl-2, 3-dihydro-1H-pyrrolo [3, 2-b)]Pyridin-1-yl) -1,3, 5-triazin-2-yl) -4- (3- (dimethylamino) pyrrolidin-1-yl) -6-methoxybenzene-1, 3-diamine (133 mg, yield: 58%). ESI-MS 476.2.[ M +1]] + 。
Intermediate C2-1: preparation of (R) -4- (6-chloro-5-fluoro-3, 3-dimethylindolin-1-yl) -N- (4- (3- (dimethylamino) pyrrolidin-1-yl) -2-methoxy-5-nitrophenyl) -1,3, 5-triazin-2-amine
The first step is as follows: synthesis of 4-chloro-N- (4-fluoro-2-methoxy-5-nitrophenyl) -1,3, 5-triazin-2-amine
2, 4-dichloro-1, 3, 5-triazine (9.67g, 64.46mmol) was dissolved in dichloromethane (150 mL) at room temperature, and 4-fluoro-2-methoxy-5-nitroaniline (10 g, 53.72mmol) and N, N-diisopropylethylamine (13.86g, 107.44mmol) were added in this order. The reaction solution was stirred at room temperature for 1 hour. After completion of the reaction, the solvent was removed to obtain a crude product, and methylene chloride (80 mL) was added, stirred for 30 minutes and then filtered. The obtained filter cake was washed twice with dichloromethane and dried to obtain 4-chloro-N- (4-fluoro-2-methoxy-5-nitrophenyl) -1,3, 5-triazin-2-amine (10.15 g, yield: 63%). ESI-MS:300.1[ deg. ] M +1]] + 。
The second step is that: synthesis of 4- (6-chloro-5-fluoro-3, 3-dimethylindolin-1-yl) -N- (4-fluoro-2-methoxy-5-nitrophenyl) -1,3, 5-triazin-2-amine
To a solution of 6-chloro-5-fluoro-3, 3-dimethylindoline (270mg, 1.35mmol, 1eq.) in 1, 4-dioxane (20 mL) was added 4-chloro-N- (4-fluoro-2-methoxy-5-nitrophenyl) -1,3, 5-triazin-2-amine (444mg, 1.48mmol, 1.1eq.) and p-toluenesulfonic acid monohydrate (256mg, 1.35mmol, 1eq.). The reaction was stirred at 100 ℃ for 1 hour. Separate from ethyl acetate and water. The organic phase was washed successively with water and saturated sodium chloride, then dried over anhydrous sodium sulfate, filtered, and concentrated to give 4- (6-chloro-5-fluoro-3, 3-dimethylindolin-1-yl) -N- (4-fluoro-2-methoxy-5-nitrophenyl) -1,3, 5-triazin-2-amine (660 mg, yield: 100%). ESI-MS:463.1[ 2 ], [ M ] +1] + 。
The third step: synthesis of (R) -4- (6-chloro-5-fluoro-3, 3-dimethylindolin-1-yl) -N- (4- (3- (dimethylamino) pyrrolidin-1-yl) -2-methoxy-5-nitrophenyl) -1,3, 5-triazin-2-amine
To a solution of 4- (6-chloro-5-fluoro-3, 3-dimethylindolin-1-yl) -N- (4-fluoro-2-methoxy-5-nitrophenyl) -1,3, 5-triazin-2-amine (660mg, 1.42mmol, 1eq.) in N, N-dimethylformamide (20 mL) were added (R) -N, N-dimethylpyrrolidin-3-amine (161mg, 1.42mmol, 1eq.) and potassium carbonate (587mg, 4.26 mmol, 3eq.). The reaction was stirred at 90 ℃ for 2 hours. The mixture was separated with dichloromethane and water. The organic phase was washed successively with water and saturated sodium chloride, then dried over anhydrous sodium sulfate, filtered, concentrated and separated by column chromatography [ dichloromethane: methanol =10]To give (R) -4- (6-chloro-5-fluoro-3, 3-dimethylindolin-1-yl) -N- (4- (3- (dimethylamino) pyrrolidin-1-yl) -2-methoxy-5-nitrophenyl) -1,3, 5-triazin-2-amine (690 mg, yield: 87%). ESI-MS:557.3[ M ] +1] + 。
Intermediate C2: (R) -N 1 Preparation of (4- (6-chloro-5-fluoro-3, 3-dimethylindolin-1-yl) -1,3, 5-triazin-2-yl) -4- (3- (dimethylamino) pyrrolidin-1-yl) -6-methoxybenzene-1, 3-diamine
Iron powder (688mg, 12.3mmol, 10eq.) and ammonium chloride (66mg, 12.3mmol, 10eq.) were added to a suspension of (R) -4- (6-chloro-5-fluoro-3, 3-dimethylindolin-1-yl) -N- (4- (3- (dimethylamino) pyrrolidin-1-yl) -2-methoxy-5-nitrophenyl) -1,3, 5-triazin-2-amine (690mg, 1.23mmol, 1eq.) in methanol/water (200 mL/50 mL). The reaction was stirred at 95 ℃ for 2 hours. Separating with dichloromethane and water, washing organic phase with water and saturated sodium chloride, drying with anhydrous sodium sulfate, filtering, and concentrating to obtain (R) -N 1 - (4- (6-chloro-5-fluoro-3, 3-dimethylindolin-1-yl) -1,3, 5-triazin-2-yl) -4- (3- (dimethylamino) pyrrolidin-1-yl) -6-methoxybenzene-1, 3-diamine (600 mg, yield: 92%). ESI-MS:527.3[ deg. ] M +1] + 。
Preparation of intermediates C3 to C54 reference the synthesis of intermediates C1, C2-1 or C2:
2. preparation of specific examples
Example 1: preparation of (R) -N- (5- ((4- (3, 3-dimethyl-2, 3-dihydro-1H-pyrrolo [3,2-b ] pyridin-1-yl) -1,3, 5-triazin-2-yl) amino) -2- (3- (dimethylamino) pyrrolidin-1-yl) -4-methoxyphenyl) acrylamide
Reacting (R) -N 1 - (4- (3, 3-dimethyl-2, 3-dihydro-1H-pyrrolo [3, 2-b)]Pyridin-1-yl) -1,3, 5-triazin-2-yl-4- (3- (dimethylamino) pyrrolidin-1-yl) -6-methoxybenzene-1, 3-diamine (133mg, 0.28mmol) was dissolved in anhydrous DMF (1.5 mL). To the solution was added triethylamine (85mg, 0.84mmol). Acryloyl chloride (27mg, 0.33mmol) was added to the reaction mixture at 0 ℃. Quenching the reaction solution with 0.1mL of water, and separating by reversed phase column chromatography [40-50% acetonitrile/water ]]To obtain (R) -N- (5- ((4- (3, 3-dimethyl-2, 3-dihydro-1H-pyrrolo [3, 2-b))]Pyridin-1-yl) -1,3, 5-triazin-2-yl) amino) -2- (3- (dimethylamino) pyrroleAlk-1-yl) -4-methoxyphenyl) acrylamide (19.5 mg, yield: 13%). ESI-MS:530.2[ mu ] M +1] + 。
1 H NMR(400MHz,DMSO-d 6 )δ9.36(s,1H),8.90-8.67(m,2H)8.34(s,1H),8.09(s,1H),7.36-7.02(m,2H),6.51(s,2H),6.19-6.13(m,1H),5.74–5.62(m,1H),3.95(s,2H),3.79(s,3H),3.39-3.22(m,4H)2.70(d,J=8.0Hz,1H),2.17(s,6H),2.08(s,1H),1.74(t,J=9.8Hz,1H),1.31(s,6H)。
Example 48: preparation of N- (5- ((4- (5-cyano-3, 3-dimethyl-1H, 2H, 3H-pyrrolo [3,2-b ] pyridin-1-yl) -1,3, 5-triazin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) prop-2-enamide
The first step is as follows: synthesis of N- (5- ((4- (5-bromo-3, 3-dimethyl-1H, 2H, 3H-pyrrolo [3,2-b ] pyridin-1-yl) -1,3, 5-triazin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) prop-2-enamide
Will N 4 - (4- (5-bromo-3, 3-dimethyl-1H, 2H, 3H-pyrrolo [3, 2-b)]Pyridin-1-yl) -1,3, 5-triazin-2-yl-N 1 - (2- (dimethylamino) ethyl) -5-methoxy-N 1 -methylbenzene-1, 2, 4-triamine (120mg, 0.22mmol) was dissolved in acetonitrile (10 mL), water (10 mL). Diisopropylethylamine (143mg, 1.11mmol) was added to the solution. The reaction mixture was stirred at 0 ℃ for 30 minutes with addition of acryloyl chloride (60mg, 0.66mmol). Reaction solution reversed phase column chromatography separation (40-50% acetonitrile/water)]To obtain N- (5- ((4- (5-bromo-3, 3-dimethyl-1H, 2H, 3H-pyrrolo [3,2-b ]]Pyridin-1-yl) -1,3, 5-triazin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) prop-2-enamide (37.0 mg, yield: 28%). ESI-MS:597.1[ deg. ] M +1]] + 。
1 H NMR(400MHz,CDCl 3 )δ10.01(s,1H),9.68(s,1H),8.54–8.30(m,2H),7.76(s,1H),7.26(s,1H),6.77(s,1H),6.44(br,2H),5.71(br,1H),,4.38(s,2H),3.88(s,3H),2.92(s,2H),2.72(s,3H),2.33(s,8H),1.47(s,6H)。
The second step is that: synthesis of N- (5- ((4- (5-cyano-3, 3-dimethyl-1H, 2H, 3H-pyrrolo [3,2-b ] pyridin-1-yl) -1,3, 5-triazin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) prop-2-enamide
Reacting N- (5- ((4- (5-bromo-3, 3-dimethyl-1H, 2H, 3H-pyrrolo [3,2-b ]]Pyridin-1-yl) -1,3, 5-triazin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) propan-2-enamide (15mg, 0.025mmol), zinc cyanide (9mg, 0.075mmol), tetratriphenylphosphine palladium (3mg, 0.003mmol) were dissolved in N, N-dimethylformamide (2 mL), and the reaction mixture was stirred at 80 ℃ for 1 hour under nitrogen protection, whereupon the reaction was terminated. The reaction mixture was partitioned with ethyl acetate (50 mL) and saturated brine (50 mL), and the organic phase was washed with saturated brine (50 mL). The resulting organic phase was concentrated, and the residue was separated by preparative chromatography to give N- (5- ((4- (5-cyano-3, 3-dimethyl-1H, 2H, 3H-pyrrolo [3,2-b ]]Pyridin-1-yl) -1,3, 5-triazin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) prop-2-enamide. ESI-MS:543.2[ deg. ] M +1] + 。
1 H NMR(400MHz,CDCl 3 )δ10.07(s,1H),9.66(s,1H),8.63(d,J=8.4Hz,1H),8.46(s,1H),7.83(s,1H),7.52(s,1H),6.78(s,1H),6.44(br,2H),5.73(br,1H),4.43(s,2H),3.89(s,3H),2.90(s,4H),2.73(s,3H),2.44–2.20(m,6H),1.48(s,6H)。
Example 49: preparation of N- (5- ((4- (3, 3-dimethyl-5- (1-methyl-1H-pyrazol-4-yl) -1H,2H, 3H-pyrrolo [3,2-b ] pyridin-1-yl) -1,3, 5-triazin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) prop-2-enamide
The first step is as follows: n is a radical of 4 - (4- (3, 3-dimethyl-5- (1-methyl-1H-pyrazol-4-yl) -1H,2H, 3H-pyrrolo [3, 2-b)]Pyridin-1-yl) -1,3, 5-triazin-2-yl-N 1 - (2- (dimethylamino) ethyl) -5-methoxy-N 1 Synthesis of (methyl) -2-nitrobenzene-1, 4-diamine
Will N 4 - (4- (5-bromo-3, 3-dimethyl-1H, 2H, 3H-pyrrolo [3, 2-b)]Pyridin-1-yl) -1,3, 5-triazin-2-yl-N 1 - (2- (dimethylamino) ethyl) -5-methoxy-N 1 -methyl-2-nitrophenyl-1, 4-diamine (see intermediate C2-1 synthetic route) (50mg, 0.087mmol), 1-methyl-4- (tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (28mg, 0.131mmol), pd (dppf) Cl 2 (7mg, 0.009mmol) and potassium carbonate (24mg, 0.175mmol) were dissolved in dioxane-water (4) (10 mL), and the reaction was stirred at 90 ℃ for 1 hour under nitrogen protection, and the reaction was completed. The reaction mixture was partitioned with ethyl acetate (50 mL) and saturated brine (50 mL), and the organic phase was washed with saturated brine (50 mL). The resulting organic phase was concentrated and the residue was separated by flash silica gel column [ dichloromethane: methanol =10]To obtain N 4 - (4- (3, 3-dimethyl-5- (1-methyl-1H-pyrazol-4-yl) -1H,2H, 3H-pyrrolo [3, 2-b)]Pyridin-1-yl) -1,3, 5-triazin-2-yl-N 1 - (2- (dimethylamino) ethyl) -5-methoxy-N 1 Methyl-2-nitrophenyl-1, 4-diamine (40 mg, yield: 80%). ESI-MS:574.3[ 2 ] M +1] + 。
The second step is that: n is a radical of 4 - (4- (3, 3-dimethyl-5- (1-methyl-1H-pyrazol-4-yl) -1H,2H, 3H-pyrrolo [3, 2-b)]Pyridin-1-yl-1, 3, 5-triazin-2-yl) -N 1 - (2- (dimethylamino) ethyl) -5-methoxy-N 1 -methylbenzeneSynthesis of (E) -1,2, 4-triamines
In N 4 - (4- (3, 3-dimethyl-5- (1-methyl-1H-pyrazol-4-yl) -1H,2H, 3H-pyrrolo [3, 2-b)]Pyridin-1-yl) -1,3, 5-triazin-2-yl-N 1 - (2- (dimethylamino) ethyl) -5-methoxy-N 1 To a suspension of methyl-2-nitrobenzene-1, 4-diamine (40mg, 0.070mmol, 1eq.) in methanol/water (20 mL/5 mL) were added iron powder (39mg, 0.70mmol, 10eq.) and ammonium chloride (37mg, 0.70mmol, 10eq.). The reaction was stirred at 95 ℃ for 2 hours. Separating with dichloromethane and water, washing the organic phase with water and saturated sodium chloride, drying with anhydrous sodium sulfate, filtering, and concentrating to obtain N 4 - (4- (3, 3-dimethyl-5- (1-methyl-1H-pyrazol-4-yl) -1H,2H, 3H-pyrrolo [3, 2-b)]Pyridin-1-yl) -1,3, 5-triazin-2-yl-N 1 - (2- (dimethylamino) ethyl) -5-methoxy-N 1 -methylbenzene-1, 2, 4-triamine (35 mg, yield: 92%). ESI-MS:544.3[ deg. ] M +1] + 。
The third step: synthesis of N- (5- ((4- (3, 3-dimethyl-5- (1-methyl-1H-pyrazol-4-yl) -1H,2H, 3H-pyrrolo [3,2-b ] pyridin-1-yl) -1,3, 5-triazin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) prop-2-enamide
Will N 4 - (4- (3, 3-dimethyl-5- (1-methyl-1H-pyrazol-4-yl) -1H,2H, 3H-pyrrolo [3, 2-b)]Pyridin-1-yl) -1,3, 5-triazin-2-yl-N 1 - (2- (dimethylamino) ethyl) -5-methoxy-N 1 -methylbenzene-1, 2, 4-triamine (35mg, 0.064mmol) was dissolved in acetonitrile (10 mL), water (10 mL). To the solution was added diisopropylethylamine (83 mg, 0.64 mmol). The reaction mixture was stirred at 0 ℃ for 30 minutes with addition of acryloyl chloride (17mg, 0.20mmol). Reaction ofLiquid reversed phase column chromatography separation [40-50% acetonitrile/water]To obtain N- (5- ((4- (3, 3-dimethyl-5- (1-methyl-1H-pyrazol-4-yl) -1H,2H, 3H-pyrrolo [3, 2-b)]Pyridin-1-yl) -1,3, 5-triazin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) prop-2-enamide (7.9 mg, yield: 20%). ESI-MS:598.4[ M ] +1] + 。
1 H NMR(400MHz,CDCl 3 )δ10.00(s,1H),9.71(s,1H),8.53(d,J=8.5Hz,1H),8.42(s,1H),7.91(d,J=3.4Hz,2H),7.72(s,1H),6.79(s,1H),6.43(br,2H),5.85–5.56(m,1H),4.38(s,2H),3.95(s,3H),3.88(s,3H),2.91(s,2H),2.83–2.61(m,3H),2.31(s,8H),1.49(s,6H)。
Example 51: preparation of N- (5- ((4- (5- (2-cyclopropylethynyl) -3, 3-dimethyl-1H, 2H, 3H-pyrrolo [3,2-b ] pyridin-1-yl) -1,3, 5-triazin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) prop-2-enamide
The first step is as follows: n is a radical of 4 - (4- (5- (2-cyclopropylethynyl) -3, 3-dimethyl-1H, 2H, 3H-pyrrolo [3,2-b ]]Pyridin-1-yl) -1,3, 5-triazin-2-yl-N 1 - (2- (dimethylamino) ethyl) -5-methoxy-N 1 Synthesis of (methyl) -2-nitrobenzene-1, 4-diamine
Will N 4 - (4- (5-bromo-3, 3-dimethyl-1H, 2H, 3H-pyrrolo [3, 2-b)]Pyridin-1-yl) -1,3, 5-triazin-2-yl-N 1 - (2- (dimethylamino) ethyl) -5-methoxy-N 1 Methyl-2-nitrophenyl-1, 4-diamine (cf. Intermediate C2-1 synthetic route) (70mg, 0.122mmol), ethynylcyclopropane (0.1mL, 1.22mmol), bis Triphenylphosphinpalladium dichloride (9mg, 0.012mmol) and cuprous iodide (3mg, 0.012mmol) were dissolved in tetrahydrofuran (THF: (TM))5 mL) and triethylamine (5 mL), and the reaction mixture was stirred at 50 ℃ for 16 hours under nitrogen protection to complete the reaction. The reaction mixture was partitioned with ethyl acetate (50 mL) and saturated brine (50 mL), and the organic phase was washed with saturated brine (50 mL). The resulting organic phase was concentrated and the residue was separated by flash silica gel column [ dichloromethane: methanol =10]To obtain N 4 - (4- (5- (2-cyclopropylethynyl) -3, 3-dimethyl-1H, 2H, 3H-pyrrolo [3,2-b ]]Pyridin-1-yl) -1,3, 5-triazin-2-yl-N 1 - (2- (dimethylamino) ethyl) -5-methoxy-N 1 Methyl-2-nitrophenyl-1, 4-diamine (40 mg, yield: 58%). ESI-MS:558.3[ deg. ] M +1] + 。
The second step is that: n is a radical of 4 - (4- (5- (2-cyclopropylethynyl) -3, 3-dimethyl-1H, 2H, 3H-pyrrolo [3,2-b ]]Pyridin-1-yl) -1,3, 5-triazin-2-yl-N 1 - (2- (dimethylamino) ethyl) -5-methoxy-N 1 Synthesis of (E) -methylbenzene-1, 2, 4-triamine
In N 4 - (4- (5- (2-cyclopropylethynyl) -3, 3-dimethyl-1H, 2H, 3H-pyrrolo [3,2-b ]]Pyridin-1-yl) -1,3, 5-triazin-2-yl-N 1 - (2- (dimethylamino) ethyl) -5-methoxy-N 1 To a suspension of (E) -methyl-2-nitrobenzene-1, 4-diamine (40mg, 0.072mmol, 1eq.) in methanol/water (20 mL/5 mL) were added iron powder (40mg, 0.72mmol, 10eq.) and ammonium chloride (40mg, 0.72mmol, 10eq.). The reaction was stirred at 95 ℃ for 2 hours. Separating with dichloromethane and water, washing the organic phase with water and saturated sodium chloride, drying with anhydrous sodium sulfate, filtering, and concentrating to obtain N 4 - (4- (5- (2-cyclopropylethynyl) -3, 3-dimethyl-1H, 2H, 3H-pyrrolo [3,2-b ]]Pyridin-1-yl) -1,3, 5-triazin-2-yl-N 1 - (2- (dimethylamino) ethyl) -5-methoxy-N 1 -methylbenzene-1, 2, 4-triamine (35 mg, yield: 91%). ESI-MS:529.3[ 2 ], [ M ] +1] + 。
The third step: synthesis of N- (5- ((4- (5- (2-cyclopropylethynyl) -3, 3-dimethyl-1H, 2H, 3H-pyrrolo [3,2-b ] pyridin-1-yl) -1,3, 5-triazin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) prop-2-enamide
Will N 4 - (4- (5-bromo-3, 3-dimethyl-1H, 2H, 3H-pyrrolo [3, 2-b)]Pyridin-1-yl) -1,3, 5-triazin-2-yl-N 1 - (2- (dimethylamino) ethyl) -5-methoxy-N 1 -methylbenzene-1, 2, 4-triamine (35mg, 0.066 mmol) was dissolved in acetonitrile (10 mL), water (10 mL). Diisopropylethylamine (86mg, 0.66mmol) was added to the solution. Acryloyl chloride (18mg, 0.22mmol) was added to the reaction mixture at 0 ℃ and the mixture was stirred for 30 minutes. Reaction liquid reversed phase column chromatography separation [40-50% acetonitrile/water]To obtain N- (5- ((4- (5-bromo-3, 3-dimethyl-1H, 2H, 3H-pyrrolo [3,2-b ]]Pyridin-1-yl) -1,3, 5-triazin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) prop-2-enamide (3.2 mg, yield: 8%). ESI-MS:582.3[ deg. ] M +1] + 。
1 H NMR(400MHz,CDCl 3 )δ9.95(s,1H),9.68(s,1H),8.55–8.26(m,2H),7.75(s,1H),7.26(s,1H),6.78(s,1H),6.44(br,2H),5.91–5.63(m,1H),4.36(s,2H),3.88(s,3H),2.93(s,2H),2.71(s,3H),2.34(s,6H),1.85(s,2H),1.48(s,6H),1.34–1.14(m,1H),0.87(br,4H)。
Examples 2-47, example 50, examples 52-56 were prepared according to the synthesis method of example 1 or example 49 to give:
the nuclear magnetic data of the compounds prepared in the above examples are as follows:
biological test evaluation
1. Cell proliferation assay
Reagent and consumable
Fetal bovine serum FBS (GBICO, cat # 10099-141)
(II) Instrument
SpectraMax multi-label micropore plate detector MD,2104-0010A;
carbon dioxide incubator, thermo Scientific 3100 series;
biological safety cabinet, thermo Scientific,1300 series type A2;
inverted microscope, olympus, CKX41SF;
siemens refrigerator KK25E76TI.
(III) cell lines and culture conditions
No. | Cell lines | Cell culture medium | Cell density |
1 | A431 | DMEM+15%FBS | 5000 |
2 | Ba/F3 EGFR-WT | RPMI1640+10%FBS | 3000 |
3 | Ba/F3 EGFR-D770-N771ins_SVD | RPMI1640+10%FBS | 3000 |
4 | Ba/F3 EGFR-V769_D770insASV | RPMI1640+10%FBS | 3000 |
(IV) Experimental procedures
1. Cell culture and inoculation:
(1) Cells in the logarithmic growth phase were harvested and counted using a platelet counter. Cell viability was checked by trypan blue exclusion to ensure cell viability above 90%.
(2) Adjusting the cell concentration to achieve a desired final density; 90 μ L of cell suspension was added to 96-well plates.
(3) Cells were assayed in 96-well plates at 37 ℃ 5% 2 And incubated overnight at 95% humidity.
2. T0 reference data:
(1) Add 10. Mu.L PBS to each well of the T0 plate containing the cells.
(2) The CTG reagents were thawed and the cell plates were equilibrated to room temperature for 30 minutes.
(3) An equal volume of CTG solution was added to each well.
(4) Cells were lysed by shaking on an orbital shaker for 5 minutes.
(5) The cell plate was left at room temperature for 20 minutes to stabilize the luminescence signal.
(6) The value of the T0 fluorescence signal is read.
3. Compound dilution and addition
(1) According to the compound information table, a corresponding volume of DMSO was added to the corresponding compound powder to prepare a10 mM stock solution.
(2) A 1000-fold, 3.16-fold dilution of the compound solution was prepared.
(3) The 1000 × diluted compound solution was diluted 100-fold with PBS to prepare a 10-fold compound solution with a maximum concentration of 10 μ M,9 concentrations, diluted 3.16-fold, and 10 μ L of the drug solution was added to each well seeded with a 96-well plate to seed the cells. Triplicate wells were set for each compound concentration, with a final concentration of DMSO of 0.1%.
(4) Placing the cells in a 96-well plate filled with the drug at 37 ℃ 5% 2 And 95% humidity, and the culture was continued for 72 hours, followed by CTG analysis.
4. Fluorescent signal reading
(1) The CTG reagents were thawed and the cell plates were equilibrated to room temperature for 30 minutes.
(2) An equal volume of CTG solution was added to each well.
(3) The cells were lysed by shaking on an orbital shaker for 5 minutes.
(4) The cell plate was left at room temperature for 20 minutes to stabilize the fluorescence signal.
(5) The fluorescence values are read.
5. Data processing
Data were analyzed using GraphPad Prism 7.0 software and fitted using nonlinear S-curve regression to obtain dose-effect curves from which IC was calculated 50 Values (units: nM), specific experimental results are shown in Table 1:
cell survival (%) = (Lum test drug-Lum culture control)/(Lum cell control-Lum culture control) × 100%.
Table 1: biological test results
From the biological activity data of the compounds of the specific examples, the compounds of the series of the invention have strong inhibition effect on insertion, deletion or other mutation of EGFR exon 20 at cellular level. In addition, some compounds have high selectivity for EGFR WT.
All documents referred to herein are incorporated by reference into this application as if each were individually incorporated by reference. Further, it should be understood that various changes or modifications of the present invention may be made by those skilled in the art after reading the above disclosure of the present invention, and such equivalents may fall within the scope of the present invention as defined by the appended claims.
Claims (16)
- A compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:wherein,x is CH or N;y is a bond, O or S;Z 1 and Z 2 Each independently is CR 10 Or N;R 1 selected from hydrogen, deuterium, hydroxy, C 1-6 Alkyl, halo-substituted C 1-6 Alkyl, deuterium substituted C 1-6 Alkyl radical, C 2-4 Alkenyl radical, C 3-6 Cycloalkyl and 3-6 membered heterocyclyl;R 2 and R 3 Each independently selected from hydrogen, deuterium, hydroxy, C 1-6 Alkyl radical, C 2-4 Alkenyl radical, C 3-6 Cycloalkyl and 3-6 membered heterocyclyl, independently optionally further substituted with one or more substituents selected from deuterium, halogen, hydroxy, C 1-10 Alkyl radical, C 2-10 Alkenyl radical, C 2-10 Alkynyl, halo-substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl radical, C 1-10 Alkoxy radical, C 3-12 Cycloalkyl radical, C 3-12 Cycloalkoxy, 3-12 membered heterocyclic group, 3-12 membered heterocyclic oxy, C 6-10 Aryl radical, C 6-10 Aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy and-C 0-8 alkyl-NR 14 R 15 Substituted with the substituent(s);R 4 and R 5 Each independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, halo-substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl radical, C 2-10 Alkenyl radical, 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 11 、-OR 12 、-C(O)OR 12 、-C(O)R 13 、-O-C(O)R 13 、-NR 14 R 15 、-C(=NR 14 )R 13 、-N(R 14 )-C(=NR 15 )R 13 、-C(O)NR 14 R 15 and-N (R) 14 )-C(O)R 13 ;Or, R 2 、R 4 Or R 5 One of them and R 1 Together with the moiety to which they are directly attached form a 4-8 membered heterocyclyl, R 2 、R 4 Or R 5 Wherein the other two are as defined above, or, R 4 Or R 5 One of them and R 2 Together with the moiety to which they are directly attached form a 4-8 membered heterocyclyl, R 4 Or R 5 Wherein another is as previously defined, said 4-8 membered heterocyclyl is optionally further substituted by one or more groups selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, halo-substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl radical, C 2-10 Alkenyl radical, 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 11 、-OR 12 、-C(O)OR 12 、-C(O)R 13 、-O-C(O)R 13 、-NR 14 R 15 、-C(=NR 14 )R 13 、-N(R 14 )-C(=NR 15 )R 13 、-C(O)NR 14 R 15 and-N (R) 14 )-C(O)R 13 Substituted with the substituent(s);R 6 selected from hydrogen, deuterium, C 1-10 Alkyl radical, C 2-10 Alkenyl radical, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-10 Aryl and 5-10 membered heteroaryl, independently optionally further substituted with one or more substituents selected from deuterium, halogen, hydroxy, oxo, cyano, C 1-10 Alkyl radical, C 1-10 Alkoxy radical, C 3-12 Cycloalkyl, C 3-12 Cycloalkoxy, 3-12 membered heterocyclic group, 3-12 membered heterocyclic oxy, C 6-10 Aryl radical, C 6-10 Aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy and-NR 14 R 15 Substituted with the substituent(s);R 7 selected from hydrogen, deuterium, halogen, cyano, C 1-4 Alkyl, halo-substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl radical, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, -C (O) OR 12 、-C(O)R 13 、-C(O)-NR 14 R 15 and-C 0-4 alkyl-NR 14 R 15 ;R 8 And R 9 Each independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl radical, C 2-10 Alkenyl radical, C 2-10 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-10 Aryl and 5-10 membered heteroaryl, or, R 8 And R 9 Together with the carbon atom to which they are directly attached form C 3-6 Cycloalkyl or 3-6 membered heterocyclyl, independently optionally further substituted with one or more substituents selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl radical, C 2-10 Alkenyl radical, C 2-10 Alkynyl, halo-substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl radical, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-10 Aryl, 5-10 membered heteroaryl, = O, -SF 5 、-S(O) r R 11 、-O-R 12 、-C(O)OR 12 、-C(O)R 13 、-O-C(O)R 13 、-NR 14 R 15 、-C(=NR 14 )R 13 、-N(R 14 )-C(=NR 15 )R 13 、-C(O)NR 14 R 15 and-N (R) 14 )-C(O)R 13 Substituted with a substituent of (a);each R 10 Each independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl radical, C 2-10 Alkenyl radical, 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 11 、-O-R 12 、-C(O)OR 12 、-C(O)R 13 、-O-C(O)R 13 、-NR 14 R 15 、-C(=NR 14 )R 13 、-N(R 14 )-C(=NR 15 )R 13 、-C(O)NR 14 R 15 and-N (R) 14 )-C(O)R 13 Or, two adjacent R 10 Together with the directly attached part thereof form C 4-8 Cycloalkyl or 4-8 membered heterocyclyl, each of which is independently optionally further substituted by one or moreA plurality of the groups are selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl radical, C 2-10 Alkenyl radical, C 2-10 Alkynyl, halo-substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl radical, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-10 Aryl, 5-10 membered heteroaryl, = O, -SF 5 、-S(O) r R 11 、-O-R 12 、-C(O)OR 12 、-C(O)R 13 、-O-C(O)R 13 、-NR 14 R 15 、-C(=NR 14 )R 13 、-N(R 14 )-C(=NR 15 )R 13 、-C(O)NR 14 R 15 and-N (R) 14 )-C(O)R 13 Substituted with the substituent(s);each R 11 Each independently selected from hydrogen, deuterium, hydroxy, C 1-10 Alkyl radical, C 2-10 Alkenyl radical, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-10 Aryl, 5-10 membered heteroaryl and-NR 14 R 15 The above groups are independently optionally further substituted by one or more groups selected from deuterium, halogen, hydroxy, oxo, C 1-10 Alkyl radical, C 1-10 Alkoxy radical, C 3-12 Cycloalkyl radical, C 3-12 Cycloalkoxy, 3-12 membered heterocyclic group, 3-12 membered heterocyclic oxy, C 6-10 Aryl radical, C 6-10 Aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy and-NR 14 R 15 Substituted with the substituent(s);each R 12 Each independently selected from hydrogen, deuterium, C 1-10 Alkyl radical, C 2-10 Alkenyl radical, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-10 Aryl and 5-10 membered heteroaryl, independently optionally further substituted with one or more substituents selected from deuterium, halogen, hydroxy, oxo, cyano, C 1-10 Alkyl radical, C 1-10 Alkoxy radical, C 3-12 Cycloalkyl radical, C 3-12 Cycloalkoxy, 3-12 membered heterocyclic group, 3-12 membered heterocyclic oxy, C 6-10 Aryl radical, C 6-10 Aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy and-NR 14 R 15 Substituted with the substituent(s);each R 13 Each independently selected from hydrogen, deuterium, hydroxy, C 1-10 Alkyl radical, C 1-10 Alkoxy radical, C 2-10 Alkenyl radical, C 2-10 Alkynyl, C 3-12 Cycloalkyl, C 3-12 Cycloalkoxy, 3-12 membered heterocyclic group, 3-12 membered heterocyclic oxy, C 6-10 Aryl radical, C 6-10 Aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy and-NR 14 R 15 The above groups are independently optionally further substituted by one or more groups selected from deuterium, halogen, hydroxy, cyano, C 1-10 Alkyl radical, C 1-10 Alkoxy radical, C 3-12 Cycloalkyl radical, C 3-12 Cycloalkoxy, 3-12 membered heterocyclic group, 3-12 membered heterocyclic oxy, C 6-10 Aryl radical, C 6-10 Aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy and-NR 14 R 15 Substituted with the substituent(s);each R 14 And R 15 Each independently selected from hydrogen, deuterium, hydroxy, C 1-10 Alkoxy radical, C 1-10 Alkyl radical, C 2-10 Alkenyl radical, C 2-10 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-10 Aryl, 5-to 10-membered heteroaryl, sulfinyl, sulfonyl, methanesulfonyl, isopropylsulfonyl, cyclopropylsulfonyl, p-toluenesulfonyl, aminosulfonyl, dimethylaminosulfonyl, amino, mono-C 1-10 Alkylamino, di-C 1-10 Alkylamino and C 1-10 Alkanoyl, which is independently optionally further substituted by oneOr more are selected from deuterium, halogen, hydroxy, C 1-10 Alkyl radical, C 2-10 Alkenyl radical, C 2-10 Alkynyl, halo-substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl radical, C 1-10 Alkoxy radical, C 3-12 Cycloalkyl radical, C 3-12 Cycloalkoxy, 3-12 membered heterocyclic group, 3-12 membered heterocyclic oxy, C 6-10 Aryl radical, C 6-10 Aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, amino, mono C 1-10 Alkylamino radical, di-C 1-10 Alkylamino and C 1-10 Substituted by the substituent of the alkanoyl group,or, R 14 And R 15 Together with the nitrogen atom to which they are directly attached form a 4-10 membered heterocyclyl or 5-10 membered heteroaryl group, independently optionally further substituted with one or more substituents selected from deuterium, halogen, hydroxy, C 1-10 Alkyl radical, C 2-10 Alkenyl radical, C 2-10 Alkynyl, halo-substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl radical, C 1-10 Alkoxy radical, C 3-12 Cycloalkyl radical, C 3-12 Cycloalkoxy, 3-12 membered heterocyclic group, 3-12 membered heterocyclic oxy, C 6-10 Aryl radical, 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 1-10 Substituted by alkanoyl group;m is 0, 1 or 2;n is 0, 1 or 2; and isEach r is independently 0, 1 or 2.
- The compound of formula (I), its stereoisomers, or a pharmaceutically acceptable salt thereof, according to claim 1, wherein R is 6 Selected from hydrogen, deuterium, C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, C 6-8 Aryl and 5-8 membered heteroaryl, independently optionally further substituted with one or more substituents selected from deuterium, halogen, hydroxy, oxo, cyano, C 1-4 Alkyl radical, C 1-4 Alkoxy radical, C 3-8 Cycloalkyl radical, C 3-8 Cycloalkoxy, 3-to 8-membered heterocyclic group, 3-to 8-membered heterocyclic oxy group, C 6-8 Aryl radical, C 6-8 Aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy and-NR 14 R 15 Substituted with the substituent(s);R 7 selected from hydrogen, deuterium, halogen, cyano, C 1-4 Alkyl, halo-substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl radical, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl and-C 0-4 alkyl-NR 14 R 15 ;Wherein R is 14 And R 15 As defined in claim 1.
- The compound of formula (I), its stereoisomers, or a pharmaceutically acceptable salt thereof, according to claim 1, wherein R is 8 And R 9 Each independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, C 6-8 Aryl and 5-8 membered heteroaryl, or, R 8 And R 9 Together with the carbon atom to which they are directly attached form C 3-6 Cycloalkyl or 3-6 membered heterocyclyl, independently optionally further substituted with one or more substituents selected from deuterium, halogen, cyano, nitro, azido, C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, halo-substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl radical, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, C 6-8 Aryl, 5-8 membered heteroaryl, = O, -SF 5 、-S(O) r R 11 、-O-R 12 、-C(O)OR 12 、-C(O)R 13 、-O-C(O)R 13 、-NR 14 R 15 、-C(=NR 14 )R 13 、-N(R 14 )-C(=NR 15 )R 13 、-C(O)NR 14 R 15 and-N (R) 14 )-C(O)R 13 Substituted with a substituent of (a);wherein R is 11 、R 12 、R 13 、R 14 、R 15 And r is as defined in claim 1.
- The compound of formula (I), its stereoisomers, or pharmaceutically acceptable salts thereof, according to claim 1, wherein each R is 10 Each independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-4 Alkyl radical, C 2-4 Alkenyl radical, 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 11 、-O-R 12 、-C(O)OR 12 、-C(O)R 13 、-O-C(O)R 13 、-NR 14 R 15 、-C(O)NR 14 R 15 and-N (R) 14 )-C(O)R 13 Or, two adjacent R 10 Together with the directly attached part thereof form C 4-8 Cycloalkyl or 4-8 membered heterocyclyl, independently optionally further substituted with one or more substituents selected from deuterium, halogen, cyano, nitro, azido, C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, halo-substituted C 1-4 Alkyl radical, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, C 6-8 Aryl radicals a,5-8 membered heteroaryl, = O, -SF 5 、-S(O) r R 11 、-O-R 12 、-C(O)OR 12 、-C(O)R 13 、-O-C(O)R 13 、-NR 14 R 15 、-C(=NR 14 )R 13 、-N(R 14 )-C(=NR 15 )R 13 、-C(O)NR 14 R 15 and-N (R) 14 )-C(O)R 13 Substituted with a substituent of (a);wherein R is 11 、R 12 、R 13 、R 14 、R 15 And r is as defined in claim 1.
- The compound of formula (I), its stereoisomers, or a pharmaceutically acceptable salt thereof, according to claim 1,R 1 selected from hydrogen, deuterium, hydroxy, C 1-4 Alkyl, halo-substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 3-6 Cycloalkyl and 3-6 membered heterocyclyl;R 2 and R 3 Each independently selected from hydrogen, deuterium and C 1-4 Alkyl, said groups being independently optionally further substituted by one or more groups selected from deuterium, halogen, hydroxy, C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, halo-substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl radical, C 1-4 Alkoxy radical, C 3-8 Cycloalkyl, C 3-8 Cycloalkoxy, 3-to 8-membered heterocyclic group, 3-to 8-membered heterocyclic oxy group, C 6-8 Aryl radical, C 6-8 Aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy and-C 0-4 alkyl-NR 14 R 15 Substituted with the substituent(s);R 4 and R 5 Each independently selected from hydrogen, deuterium, halogen, cyano, C 1-4 Alkyl, halo-substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, C 6-8 Aryl, 5-8 membered heteroaryl, -OR 12 、-C(O)OR 12 、-C(O)R 13 、-O-C(O)R 13 、-NR 14 R 15 、-C(O)NR 14 R 15 and-N (R) 14 )-C(O)R 13 ;Or, R 2 、R 4 Or R 5 One of them and R 1 Together with the directly connected parts, form the following structure:R 2 、R 4 or R 5 Wherein the other two are as defined above, R 3 As previously defined;or, R 4 Or R 5 One of them and R 2 Together with the directly connected parts, form the following structure:R 4 or R 5 Wherein the other is as previously defined, R 1 Or R 3 As previously defined;wherein R is 12 、R 13 、R 14 And R 15 As defined in claim 1.
- The compound of formula (I), its stereoisomers, or a pharmaceutically acceptable salt thereof, as claimed in claim 1, wherein the compound of formula (I) is a compound of formula (iia):wherein,x is CH or N;Z 2 is CH or N;R 2 、R 4 or R 5 One of them and R 1 Together with the directly connected parts, form the following structure:each R 2 And R 3 Each independently selected from hydrogen, deuterium and C 1-4 Alkyl, the above groups are independently optionally further substituted by one or more groups selected from deuterium, halogen, hydroxy, C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, halo-substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl and-C 0-4 alkyl-NR 14 R 15 Substituted with the substituent(s);or, R 4 Or R 5 One of them and R 2 Together with the directly connected parts, form the following structure:each R 1 Each independently selected from hydrogen, deuterium, C 1-4 Alkyl, halo-substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl and C 2-4 An alkenyl group;each R 3 Each independently selected from hydrogen, deuterium and C 1-4 Alkyl, said groups being independently optionally further substituted by one or more groups selected from deuterium, halogen, hydroxy, C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, halo-substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl and-C 0-4 alkyl-NR 14 R 15 Substituted with the substituent(s);R 6 selected from hydrogen, deuterium, C 1-4 Alkyl, halo-substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 3-8 Cycloalkyl and 3-8 membered heterocyclyl;R 8 and R 9 Each independently selected from hydrogen, deuterium, halogen, cyano, C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, C 6-8 Aryl and 5-8 membered heteroaryl, or, R 8 And R 9 Together with the carbon atom to which they are directly attached form C 3-6 Cycloalkyl or 3-6 membered heterocyclyl, independently optionally further substituted with one or more substituents selected from deuterium, halogen, cyano, hydroxy, C 1-4 Alkyl radical, C 1-4 Alkoxy radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, halo-substituted C 1-4 Alkyl, halo-substituted C 1-4 Alkoxy, deuterium substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkoxy radical, C 3-8 Cycloalkyl radical, C 3-8 Cycloalkoxy, 3-to 8-membered heterocyclic group, 3-to 8-membered heterocyclic oxy group, C 6-8 Aryl and 5-8 membered heteroaryl;each R 10 Each independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-4 Alkyl radical, C 2-4 Alkenyl radical, 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 11 、-O-R 12 、-C(O)OR 12 、-C(O)R 13 、-O-C(O)R 13 、-NR 14 R 15 、-C(O)NR 14 R 15 and-N (R) 14 )-C(O)R 13 Or, two adjacent R 10 Together with the directly attached part thereof form C 4-6 Cycloalkyl or 4-6 membered heterocyclyl, independently optionally further substituted by one or more groups selected from deuterium, halogen, cyano, nitro, azido, C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, halo-substituted C 1-4 Alkyl radical, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, C 6-8 Aryl, 5-8 membered heteroaryl, = O, -SF 5 、-S(O) r R 11 、-O-R 12 、-C(O)OR 12 、-C(O)R 13 、-O-C(O)R 13 、-NR 14 R 15 、-C(=NR 14 )R 13 、-N(R 14 )-C(=NR 15 )R 13 、-C(O)NR 14 R 15 and-N (R) 14 )-C(O)R 13 Substituted with the substituent(s);each R 11 Each independently selected from hydrogen, deuterium, hydroxy, C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, C 6-8 Aryl, 5-8 membered heteroaryl and-NR 14 R 15 The above groupsIndependently optionally further substituted with one or more groups selected from deuterium, halogen, hydroxy, oxo, C 1-4 Alkyl radical, C 1-4 Alkoxy radical, C 3-8 Cycloalkyl radical, C 3-8 Cycloalkoxy, 3-to 8-membered heterocyclic group, 3-to 8-membered heterocyclic oxy group, C 6-8 Aryl radical, C 6-8 Aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy and-NR 14 R 15 Substituted with the substituent(s);each R 12 Each independently selected from hydrogen, deuterium, C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, C 6-8 Aryl and 5-8 membered heteroaryl, independently optionally further substituted with one or more substituents selected from deuterium, halogen, hydroxy, oxo, cyano, C 1-4 Alkyl radical, C 1-4 Alkoxy radical, C 3-8 Cycloalkyl radical, C 3-8 Cycloalkoxy, 3-8 membered heterocyclic group, 3-8 membered heterocyclic oxy, C 6-8 Aryl radical, C 6-8 Aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy and-NR 14 R 15 Substituted with a substituent of (a);each R 13 Each independently selected from hydrogen, deuterium, hydroxy, C 1-4 Alkyl radical, C 1-4 Alkoxy radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, C 3-8 Cycloalkyl, C 3-8 Cycloalkoxy, 3-to 8-membered heterocyclic group, 3-to 8-membered heterocyclic oxy group, C 6-8 Aryl radical, C 6-8 Aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy and-NR 14 R 15 The above groups are independently optionally further substituted by one or more groups selected from deuterium, halogen, hydroxy, cyano, C 1-4 Alkyl radical, C 1-4 Alkoxy radical, C 3-8 Cycloalkyl radical, C 3-8 Cycloalkoxy, 3-to 8-membered heterocyclic group, 3-to 8-membered heterocyclic oxy group, C 6-8 Aryl radical, C 6-8 Aryloxy, 5-8 membered heteroarylOxy and-NR 14 R 15 Substituted with the substituent(s);each R 14 And R 15 Each independently selected from hydrogen, deuterium, hydroxy, C 1-4 Alkoxy radical, C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, C 6-8 Aryl, 5-8 membered heteroaryl, sulfinyl, sulfonyl, methanesulfonyl, isopropylsulfonyl, cyclopropylsulfonyl, p-toluenesulfonyl, aminosulfonyl, dimethylaminosulfonyl, amino, mono-C 1-4 Alkylamino radical, di-C 1-4 Alkylamino and C 1-4 Alkanoyl, said groups being independently optionally further substituted by one or more substituents selected from deuterium, halogen, hydroxy, C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, halo-substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl radical, C 1-4 Alkoxy radical, C 3-8 Cycloalkyl radical, C 3-8 Cycloalkoxy, 3-to 8-membered heterocyclic group, 3-to 8-membered heterocyclic oxy group, C 6-8 Aryl radical, 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 Substituted by the substituent of the alkanoyl group,or, R 14 And R 15 Together with the nitrogen atom to which they are directly attached form a 4-8 membered heterocyclyl or 5-8 membered heteroaryl group, which groups are independently optionally further substituted by one or more groups selected from deuterium, halogen, hydroxy, C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, halo-substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl radical, C 1-4 Alkoxy radical, C 3-8 Cycloalkyl radical, C 3-8 Cycloalkoxy, 3-to 8-membered heterocyclic group, 3-to 8-membered heterocyclic oxy group, C 6-8 Aryl radical, C 6-8 An aryloxy group,5-8 membered heteroaryl, 5-8 membered heteroaryloxy, amino, mono C 1-4 Alkylamino radical, di-C 1-4 Alkylamino and C 1-4 Substituted by alkanoyl group;m is 0, 1 or 2;n is 0, 1 or 2; and isEach r is independently 0, 1 or 2.
- The compound of formula (I), its stereoisomers, or a pharmaceutically acceptable salt thereof, according to claim 6, wherein the compound of formula (I) is a compound of formula (iiia) as follows:wherein,x is CH or N;Z 2 is CH or N;R 2 、R 4 or R 5 One of them and R 1 Together with the directly connected parts, form the following structure:R 6 selected from hydrogen, deuterium, C 1-2 Alkyl, halo-substituted C 1-2 Alkyl and deuterium substituted C 1-2 An alkyl group;R 8 and R 9 Each independently selected from hydrogenDeuterium, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, cyclopropyl, -CHF 2 、-CF 3 、-CHD 2 and-CD 3 ;R 10a And R 10b Each independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, propyl, isopropyl, cyclopropyl, -CHF 2 、-CF 3 、-CHD 2 、-CD 3 Methoxy, azetidinyl, ethenyl, ethynyl and phenyl, or, R 10a And R 10b Together with the directly attached part thereof form C 4-6 Cycloalkyl or 4-6 membered heterocyclyl.
- The compound of formula (I), its stereoisomers, or a pharmaceutically acceptable salt thereof, as claimed in claim 1, wherein the compound of formula (I) is a compound of formula (lib) as follows:wherein,x is CH or N;y is a bond, O or S;Z 1 is CR 10 Or N;Z 2 is CH or N;R 1 selected from hydrogen, deuterium, C 1-4 Alkyl, halo-substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl and C 2-4 An alkenyl group;R 2 and R 3 Each independently selected from hydrogen, deuterium and C 1-4 Alkyl, said groups being independently optionally further substituted by one or more groups selected from deuterium, halogen, hydroxy, C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, haloSubstituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl and-C 0-4 alkyl-NR 14 R 15 Substituted with the substituent(s);R 4 selected from hydrogen, deuterium, halogen, C 1-4 Alkyl, halo-substituted C 1-4 Alkyl and deuterium substituted C 1-4 An alkyl group;R 5 selected from hydrogen, deuterium, halogen, C 1-4 Alkyl, halo-substituted C 1-4 Alkyl and deuterium substituted C 1-4 An alkyl group;R 6 selected from hydrogen, deuterium, C 1-4 Alkyl, halo-substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 3-8 Cycloalkyl and 3-8 membered heterocyclyl;R 8 and R 9 Each independently selected from hydrogen, deuterium, halogen, cyano, C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, C 6-8 Aryl and 5-8 membered heteroaryl, or, R 8 And R 9 Together with the carbon atom to which they are directly attached form C 3-6 Cycloalkyl or 3-6 membered heterocyclyl, independently optionally further substituted with one or more substituents selected from deuterium, halogen, cyano, hydroxy, C 1-4 Alkyl radical, C 1-4 Alkoxy radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, halo-substituted C 1-4 Alkyl, halo-substituted C 1-4 Alkoxy, deuterium substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkoxy radical, C 3-8 Cycloalkyl radical, C 3-8 Cycloalkoxy, 3-to 8-membered heterocyclic group, 3-to 8-membered heterocyclic oxy group, C 6-8 Aryl and 5-8 membered heteroaryl;each R 10 And R 10a Each independentlySelected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-4 Alkyl radical, C 2-4 Alkenyl radical, 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 11 、-O-R 12 、-C(O)OR 12 、-C(O)R 13 、-O-C(O)R 13 、-NR 14 R 15 、-C(O)NR 14 R 15 and-N (R) 14 )-C(O)R 13 Or, or R 10 And R 10a Together with the directly attached part thereof form C 4-6 Cycloalkyl or 4-6 membered heterocyclyl, independently optionally further substituted by one or more groups selected from deuterium, halogen, cyano, nitro, azido, C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, halo-substituted C 1-4 Alkyl radical, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, C 6-8 Aryl, 5-8 membered heteroaryl, = O, -SF 5 、-S(O) r R 11 、-O-R 12 、-C(O)OR 12 、-C(O)R 13 、-O-C(O)R 13 、-NR 14 R 15 、-C(=NR 14 )R 13 、-N(R 14 )-C(=NR 15 )R 13 、-C(O)NR 14 R 15 and-N (R) 14 )-C(O)R 13 Provided that when X is CH, Y is a bond, and n is 1, R is 10 And R 10a One of them is hydrogen, halogen or C 1-4 When alkyl, the other is not hydrogen, halogen or C 1-4 An alkyl group;each R 11 Each independently selected from hydrogen, deuterium, hydroxy, C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, C 6-8 Aryl, 5-8 membered heteroaryl and-NR 14 R 15 The above groups are independently optionally further substituted by one or more groups selected from deuterium, halogen, hydroxy, oxo, C 1-4 Alkyl radical, C 1-4 Alkoxy radical, C 3-8 Cycloalkyl radical, C 3-8 Cycloalkoxy, 3-to 8-membered heterocyclic group, 3-to 8-membered heterocyclic oxy group, C 6-8 Aryl radical, C 6-8 Aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy and-NR 14 R 15 Substituted with the substituent(s);each R 12 Each independently selected from hydrogen, deuterium, C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, C 6-8 Aryl and 5-8 membered heteroaryl, independently optionally further substituted with one or more substituents selected from deuterium, halogen, hydroxy, oxo, cyano, C 1-4 Alkyl radical, C 1-4 Alkoxy radical, C 3-8 Cycloalkyl radical, C 3-8 Cycloalkoxy, 3-to 8-membered heterocyclic group, 3-to 8-membered heterocyclic oxy group, C 6-8 Aryl radical, C 6-8 Aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy and-NR 14 R 15 Substituted with the substituent(s);each R 13 Each independently selected from hydrogen, deuterium, hydroxy, C 1-4 Alkyl radical, C 1-4 Alkoxy radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, C 3-8 Cycloalkyl, C 3-8 Cycloalkoxy, 3-to 8-membered heterocyclic group, 3-to 8-membered heterocyclic oxy group, C 6-8 Aryl radical, C 6-8 Aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy and-NR 14 R 15 The above groups are independently optionally further substituted by one or more groups selected from deuterium, halogen, hydroxy, cyano, C 1-4 Alkyl radical, C 1-4 Alkoxy radical, C 3-8 Cycloalkyl, C 3-8 Cycloalkoxy, 3-to 8-membered heterocyclic group, 3-to 8-membered heterocyclic oxy group, C 6-8 Aryl radical, C 6-8 Aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy and-NR 14 R 15 Substituted with the substituent(s);each R 14 And R 15 Each independently selected from hydrogen, deuterium, hydroxy, C 1-4 Alkoxy radical, C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, C 6-8 Aryl, 5-8 membered heteroaryl, sulfinyl, sulfonyl, methanesulfonyl, isopropylsulfonyl, cyclopropylsulfonyl, p-toluenesulfonyl, aminosulfonyl, dimethylaminosulfonyl, amino, mono-C 1-4 Alkylamino, di-C 1-4 Alkylamino and C 1-4 Alkanoyl, said groups independently optionally further substituted with one or more substituents selected from deuterium, halogen, hydroxy, C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, halo-substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl radical, C 1-4 Alkoxy radical, C 3-8 Cycloalkyl, C 3-8 Cycloalkoxy, 3-to 8-membered heterocyclic group, 3-to 8-membered heterocyclic oxy group, C 6-8 Aryl radical, 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 Substituted by the substituent of the alkanoyl group,or, R 14 And R 15 Together with the nitrogen atom to which they are directly attached form a 4-8 membered heterocyclyl or 5-8 membered heteroaryl group, which groups are independently optionally further substituted by one or more groups selected from deuterium, halogen, hydroxy, C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, halo-substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl radical, C 1-4 Alkoxy radical, C 3-8 CycloalkanesBase, C 3-8 Cycloalkoxy, 3-to 8-membered heterocyclic group, 3-to 8-membered heterocyclic oxy group, C 6-8 Aryl radical, 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 Substituted by alkanoyl group;n is 0, 1 or 2; and isEach r is independently 0, 1 or 2.
- The compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, as claimed in claim 8, wherein the compound of formula (I) is a compound of formula (iiib) as follows:wherein,x is CH or N;y is a bond, O or S;Z 1 is CR 10 Or N;Z 2 is CH or N;R 6 selected from hydrogen, deuterium, C 1-4 Alkyl, halo-substituted C 1-2 Alkyl and deuterium substituted C 1-2 An alkyl group;R 8 and R 9 Each independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, cyclopropyl, -CHF 2 、-CF 3 、-CHD 2 and-CD 3 ;R 10 And R 10a Each independently selected from hydrogen, deuterium, fluoro, chloro, bromo, cyano, methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, ethynyl, azetidinyl, pyrazole, and phenyl, or R 10 And R 10a And itThe directly linked moieties together form a cyclopentyl or 5-membered heterocyclyl group, which groups are independently optionally further substituted with one or more substituents selected from deuterium, fluoro, chloro, bromo, cyano, C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, halo-substituted C 1-4 Alkyl and cyclopropyl substituents,provided that when X is CH, Y is a bond, and n is 1, R 10 And R 10a One of which is hydrogen, deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, propyl or isopropyl, and the other is not hydrogen, deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, propyl or isopropyl;n is 0, 1 or 2.
- A pharmaceutical composition comprising a compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 10, and a pharmaceutically acceptable carrier.
- Use of a compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 10, for the manufacture of a medicament for the treatment and/or prevention of a cancer, a tumor or a metastatic disease associated at least in part with an EGFR exon 20 insertion, deletion or other mutation.
- Use of a compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 10, for the preparation of a medicament for the prevention and/or treatment of tumors, cancers and/or metastatic diseases caused by hyperproliferative and cell death-inducing disorders.
- Use of a compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 10, for the preparation of a medicament for the prevention and/or treatment 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 syndromes, malignant lymphomas, head and neck tumors, thoracic tumors, gastrointestinal tumors, endocrine tumors, breast and other gynecological tumors, urological tumors, skin tumors, sarcomas, sinus rhinopolyporum papillomas or sinus nasale squamous carcinoma associated with sinus rhinopolyporum papillomas, associated at least in part with EGFR exon 20 insertion, deletion or other mutation.
- A compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 10 for use in 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 syndromes, malignant lymphomas, head and neck tumors, thoracic tumors, gastrointestinal tumors, endocrine tumors, breast and other gynecological tumors, urological tumors, skin tumors, sarcomas, sinus of nasal cavity inverted papillomas or sinus of nasal cavity squamous cell carcinoma associated with sinus of nasal cavity inverted papillomas associated with EGFR exon 20 insertion, deletion or other mutation.
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PCT/CN2021/111694 WO2022033455A1 (en) | 2020-08-13 | 2021-08-10 | Triazine derivative having egfr inhibitory activity, preparation method therefor and use thereof |
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Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN104860941A (en) * | 2014-02-25 | 2015-08-26 | 上海海雁医药科技有限公司 | 2,4-disubstituted phenyl-1,5-diamine derivatives and use thereof, and pharmaceutical composition and medicinal composition prepared from 2,4-disubstituted phenyl-1,5-diamine derivative |
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 |
CN106928150A (en) * | 2015-12-31 | 2017-07-07 | 恩瑞生物医药科技(上海)有限公司 | Acrylamide anil and its application pharmaceutically |
WO2018210246A1 (en) * | 2017-05-15 | 2018-11-22 | 朱程刚 | Triazine compound and pharmaceutically acceptable salt thereof |
CN111747950A (en) * | 2019-03-29 | 2020-10-09 | 深圳福沃药业有限公司 | Pyrimidine derivatives for the treatment of cancer |
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CN105461695B (en) * | 2014-09-29 | 2018-03-27 | 齐鲁制药有限公司 | Pyrimidine or pyrrolotriazine derivatives and its production and use |
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Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN104860941A (en) * | 2014-02-25 | 2015-08-26 | 上海海雁医药科技有限公司 | 2,4-disubstituted phenyl-1,5-diamine derivatives and use thereof, and pharmaceutical composition and medicinal composition prepared from 2,4-disubstituted phenyl-1,5-diamine derivative |
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 |
CN106928150A (en) * | 2015-12-31 | 2017-07-07 | 恩瑞生物医药科技(上海)有限公司 | Acrylamide anil and its application pharmaceutically |
WO2018210246A1 (en) * | 2017-05-15 | 2018-11-22 | 朱程刚 | Triazine compound and pharmaceutically acceptable salt thereof |
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 |
CN111747950A (en) * | 2019-03-29 | 2020-10-09 | 深圳福沃药业有限公司 | Pyrimidine derivatives for the treatment of cancer |
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