Nitrogen-containing heterocyclic compounds and uses thereof

Abstract

Disclosed in the present invention are a series of nitrogen-containing heterocyclic compounds and uses thereof. Specifically disclosed are compounds represented by formulas (IIA-1) and (IIB), and stereoisomers thereof and pharmaceutically acceptable salts thereof.

Description

Nitrogen-containing heterocyclic compounds and their applications

[0001] Cross-reference to related applications

[0002] This application claims priority to two earlier patent applications filed with the China National Intellectual Property Administration on November 29, 2024 (application number CN2024117451721) and April 18, 2025 (application number CN2025104954873), the entire contents of which are incorporated herein by reference. Technical Field

[0003] This invention relates to a series of nitrogen-containing heterocyclic compounds and their applications, particularly to compounds of formulas (IIA-1) and (IIB), their stereoisomers, and pharmaceutically acceptable salts thereof. Background Technology

[0004] Protein arginine methyltransferase 5 (PRMT5) is a type II protein arginine methyltransferase (PRMT). PRMTs are classified into three types: I, II, and III. Type I catalyzes the formation of asymmetric dimethylated arginine and mainly includes PRMT1, PRMT2, PRMT3, PRMT4, PRMT6, and PRMT8. Type II catalyzes the formation of symmetric dimethylated arginine and includes PRMT5 and PRMT9. PRMT7 is type III, catalyzing the formation of monomethylated arginine from the substrate. Arginine methylation is a post-translational modification involved in regulating various biological processes, including transcription, cell signaling, mRNA translation, DNA damage, receptor transport, protein stability, and precursor mRNA splicing.

[0005] PRMT5 primarily uses S-adenosylmethionine (SAM) as a methyl donor, catalyzing a symmetrical dimethylation modification of S-adenosyl-1-homocysteine ​​(SAH) by transferring the methyl group from SAM to the guanidino nitrogen atom of the arginine residue. PRMT5 has been reported to be highly expressed in various tumors, such as glioblastoma, leukemia / lymphoma, prostate cancer, and colorectal cancer. In these tumors, both histone (e.g., histone H3, H4) and non-histone methylation are regulated by PRMT5. Furthermore, many proteins closely related to tumor growth and tumorigenesis are also regulated by PRMT5, such as RAF, epidermal growth factor receptor (EGFR), androgen receptor (AR), and p53. PRMT5 influences cell growth, proliferation, and differentiation by regulating substrate protein methylation, thereby altering substrate protein activity and protein-protein interactions. Numerous basic studies have shown that overexpression of PRMT5 leads to excessive cell proliferation in various tumor cell lines, while inhibiting PRMT5 can suppress tumor cell growth. Therefore, PRMT5 has attracted attention as a target for tumor therapy. Several companies have conducted research on PRMT5 inhibitors, with earlier products entering clinical trials including JNJ-64619178, GSK-3326595, and PF-06939999. However, these products have all experienced relatively high rates of adverse reactions, such as thrombocytopenia, anemia, and neutropenia, indicating unsuccessful development. Currently, these products are still in early clinical stages or have ceased development.

[0006] Subsequent studies showed that methylthioadenosine phosphorylase (MTAP) deficiency can enhance the sensitivity of tumor cells to PRMT5 inhibition. MTAP is a key enzyme catalyzing methionine (Met) compensatory metabolism, catalyzing the cleavage of methylthioadenosine (MTA) into 5-methylthioribose-1-phosphate (MTR-1-P), ultimately leading to methionine regeneration. The MTAP-encoding gene is widely expressed in normal tissues and is adjacent to CDKN2A; in cancer, MTAP is often deleted and mutated along with CDKN2A. Since MTAP is the only known enzyme catalyzing MTA degradation, MTAP deficiency in tumor cells leads to MTA accumulation, and MTA has been identified as a competitive inhibitor of PRMT5. Furthermore, the study found that MTAP deficiency and PRMT5 inhibition have a synthetic lethal effect, providing a theoretical basis for using PRMT5 inhibitors to treat MTAP-deficient tumors. MTAP deficiency occurs at a certain rate in various tumors, reaching 10-15% in all tumors. In malignant peripheral tenosynovitis, MTAP deficiency exceeds 50%, in glioma it exceeds 40%, and in mesothelioma it exceeds 30%. High rates of MTAP deficiency are also found in bladder cancer, pancreatic cancer, and esophageal cancer. Therefore, research on PRMT5 inhibitors has shifted towards PRMT5-MTA inhibitors. In MTAP-deficient cancer cells, MTA replaces SAM in binding to PRMT5, forming an inactive PRMT5-MTA complex. Second-generation PRMT5 inhibitors bind to the PRMT5-MTA complex, killing MTAP-deficient cancer cells. Normal cells lack the PRMT5-MTA complex, so their growth is not affected, theoretically reducing toxicity. Several products, such as MRTX-1719, AMG193, TNG-908, and TNG462, have entered early-stage clinical trials, all in phase I and II.

[0007] Based on the current state of research, developing novel PRMT5 inhibitors has significant clinical application value. Summary of the Invention

[0008] In a first aspect, the present invention provides compounds of formula (I), their stereoisomers, or pharmaceutically acceptable salts thereof.

[0009] in,

[0010] L1 is the key;

[0011] L2 is a bond or C 1-4 alkyl;

[0012] L3 is selected from the bond, CO, and optionally one or more R. L3 Replacement C 1-4 Alkyl, C2-4 alkenyl and C 2-4 alkynyl group;

[0013] R1 is selected from

[0014] R2 is selected from OH and NH2;

[0015] Ring A is selected from one or more R. a The following groups are substituted: phenyl, naphthyl, 5-10 heteroaryl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic alkyl;

[0016] Ring B is selected from one or more R. b Substituted 5-6 aryl groups;

[0017] Ring C is selected from Among them, ring C2 is connected to L3;

[0018] Ring C1 is selected from one or more Rs. c The following groups are substituted: phenyl, 5-6 membered heteroaryl and 5-8 membered heterocyclic alkyl;

[0019] Ring C2 is selected from one or more Rs. c The following groups are substituted: 5-6 membered heteroaryl and 5-8 membered heterocyclic alkyl;

[0020] R a1 R c1 They were selected independently from H and SF5, respectively;

[0021] R a2 Selected from H, -C 0-4 Alkyl-NR3-OR4, -C 0-4 Alkyl-NR3-N(R3)2, -C 0-4 Alkyl-ON(R3)2 and -C 0-4 Alkyl-ON=C(R3)2;

[0022] Each R a Each R b Each R c The following groups are independently selected from H, D, F, Cl, Br, I, OR3, SR3, N(R3)2, CN, =O, SF5, -COR3, -NR3COR4, and optionally substituted with one or more R groups: C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, phenyl and 5-6 membered heteroaryl;

[0023] R3 is selected from H, CN, -COR, and the following groups optionally substituted with one or more R groups: C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, -C 0- 4-alkyl-C 3-10 cycloalkyl, -C 0-4 Alkyl-3-10 membered heterocyclic alkyl, -C 0-4 Alkyl-phenyl and -C 0-4 Alkyl-5-6-membered heteroaryl;

[0024] R4 is selected from H, CN, and the following groups optionally substituted with one or more R groups: C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, phenyl and 5-6 membered heteroaryl;

[0025] Each R L3 The C atoms are independently selected from H, D, F, Cl, Br, I, OH, NH2, CN, =O, and C atoms optionally substituted with one or more R atoms. 1- 4-alkyl, C 2-4 alkenyl and C 2-4 alkynyl group;

[0026] Or 2 Rs a Connected together, or 2 Rs L3 Connected together, they independently form C, which can be arbitrarily replaced by one or more R's. 3- 6-membered cycloalkyl or 3-6-membered heterocyclic alkyl;

[0027] Or, R a With R c They are connected together to form a linker base L, where L is a C that can be arbitrarily replaced by one or more Rs. 2-12 Alkyl, the C 2-12 The 1, 2, 3, 4, 5, or 6 CH2, CH, or C groups of the alkyl group are independently and optionally replaced by the following groups: O, S, NH, N, CO, SO, SO2, CONH, vinyl, ethynyl, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl, wherein NH, CONH, vinyl, ethynyl, C 3-8 Cycloalkyl, 3-8-membered heterocycloalkyl, phenyl or 5-6-membered heteroaryl groups are each independently and optionally substituted with one or more R groups;

[0028] Each R is independently selected from H, D, F, Cl, Br, I, OH, NH2, CN, =O, SF5, and the following groups optionally substituted with one or more Fs: C 1-4 Alkyl, C2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, C 1-4 Alkylthio, C 1-4 Alkylamino, C 3-8 Cycloalkyl, 3-8 membered heterocyclic alkyl;

[0029] The condition is that one or more of the following are satisfied: (1) R a1 SF5; (2)R c1 For SF5; (3)R a2 Selected from -C 0-4 Alkyl-NR3-OR4, -C 0-4 Alkyl-NR3-N(R3)2, -C 0-4 Alkyl-ON(R3)2 and -C 0-4 Alkyl-ON=C(R3)2;(4)R a With R c (5) The ring C1 is selected from one or more Rs. c Substituted 5-6 heteroaryl groups.

[0030] The present invention also provides the compound of formula (I), its stereoisomers or pharmaceutically acceptable salts thereof,

[0031] in,

[0032] L1 is the key;

[0033] L2 is the bond;

[0034] L3 is selected from CO and is arbitrarily selected by one or more R. L3 Replacement C 1-4 Alkyl, C 2-4 alkenyl and C 2-4 alkynyl group;

[0035] R1 is selected from

[0036] R2 is selected from OH and NH2;

[0037] Ring A is selected from one or more R. a The following groups are substituted: phenyl, naphthyl, 5-10 heteroaryl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic alkyl;

[0038] Ring B is selected from one or more R. b Substituted 5-6 aryl groups;

[0039] Ring C is selected from Among them, ring C2 is connected to L3;

[0040] Ring C1 is selected from one or more Rs. c The following groups are substituted: phenyl, 5-6 membered heteroaryl and 5-8 membered heterocyclic alkyl;

[0041] Ring C2 is selected from one or more Rs. c The following groups are substituted: 5-6 membered heteroaryl and 5-8 membered heterocyclic alkyl;

[0042] R a1 R c1 They were selected independently from H and SF5, respectively;

[0043] R a2 Selected from H, -C 0-4 Alkyl-NR3-OR4, -C 0-4 Alkyl-NR3-N(R3)2, -C 0-4 Alkyl-ON(R3)2 and -C 0-4 Alkyl-ON=C(R3)2;

[0044] Each R a Each R b Each R c The following groups are independently selected from H, D, F, Cl, Br, I, OH, NH2, CN, =O, SF5, -COR3, -NR3COR4, and optionally substituted with one or more R groups: C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, C 1-4 Alkylthio, C 1-4 Alkylamino, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, phenyl and 5-6 membered heteroaryl;

[0045] R3 and R4 are independently selected from H, CN, and the following groups optionally substituted with one or more R groups: C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, phenyl and 5-6 membered heteroaryl;

[0046] Each R L3 The C atoms are independently selected from H, D, F, Cl, Br, I, OH, NH2, CN, =O, and C atoms optionally substituted with one or more R atoms. 1- 4-alkyl, C 2-4 alkenyl and C 2-4 alkynyl group;

[0047] Or 2 Rs a Connected together, or 2 RsL3 Connected together, they independently form C, which can be arbitrarily replaced by one or more R's. 3- 6-membered cycloalkyl or 3-6-membered heterocyclic alkyl;

[0048] Or, R a With R c They are connected together to form a linker base L, where L is a C that can be arbitrarily replaced by one or more Rs. 2-12 Alkyl, the C 2-12 The 1, 2, 3, 4, 5, or 6 CH2, CH, or C groups of the alkyl group are independently and optionally replaced by the following groups: O, S, NH, N, CO, SO, SO2, CONH, vinyl, ethynyl, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl, wherein NH, CONH, vinyl, ethynyl, C 3-8 Cycloalkyl, 3-8-membered heterocycloalkyl, phenyl or 5-6-membered heteroaryl groups are each independently and optionally substituted with one or more R groups;

[0049] Each R is independently selected from H, D, F, Cl, Br, I, OH, NH2, CN, =O, SF5, and the following groups optionally substituted with one or more Fs: C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, C 1-4 Alkylthio, C 1-4 Alkylamino, C 3-8 Cycloalkyl, 3-8 membered heterocyclic alkyl;

[0050] The condition is that one or more of the following are satisfied: (1) R a1 SF5; (2)R c1 For SF5; (3)R a2 Selected from -C 0-4 Alkyl-NR3-OR4, -C 0-4 Alkyl-NR3-N(R3)2, -C 0-4 Alkyl-ON(R3)2 and -C 0-4 Alkyl-ON=C(R3)2;(4)R a With R c They connect together to form a connecting base L.

[0051] The present invention also provides compounds of formula (IIA-1), their stereoisomers, or pharmaceutically acceptable salts thereof.

[0052] in,

[0053] Ring A is selected from one or more R. aThe following groups are substituted: phenyl, naphthyl, and 5-10 membered heteroaryl groups;

[0054] R a2 Selected from -C 0-4 Alkyl-NR3-OR4, -C 0-4 Alkyl-NR3-N(R3)2, -C 0-4 Alkyl-ON(R3)2 and -C 0-4 Alkyl-ON=C(R3)2;

[0055] R b Selected from CH3, CF3, CD3 and cyclopropyl;

[0056] R c Selected from H, D, F, Cl, Br, I, OCH3, SCH3, NHCH3, N(CH3)2, CN, and the following groups optionally substituted with one or more R: C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 Cycloalkyl, 3-6 membered heterocyclic alkyl;

[0057] R3 is selected from H, CN, -COR, and the following groups optionally substituted with one or more R groups: C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-10 Cycloalkyl, 3-10-membered heterocycloalkyl, phenyl, -CH2-phenyl, 5-6-membered heteroaryl and -CH2-5-6-membered heteroaryl;

[0058] R4 is selected from H, CN, and the following groups optionally substituted with one or more R groups: C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-10 Cycloalkyl and 3-10 membered heterocyclic alkyl groups;

[0059] Each R a The following groups are independently selected from H, D, F, Cl, Br, I, OR3, SR3, N(R3)2, CN, -COR3, -NR3COR4, and optionally substituted with one or more R groups: C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, phenyl and 5-6 membered heteroaryl;

[0060] Each R is independently selected from H, D, F, Cl, Br, I, OH, NH2, CN, =O, and the following groups optionally substituted by one or more F: C1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, C 1-4 Alkylthio, C 1-4 Alkylamino, C 3-8 Cycloalkyl and 3-8 membered heterocyclic alkyl; m is selected from 0, 1 and 2.

[0061] In some technical solutions of the present invention, in the above formula (I) or formula (IIA-1), each R is independently selected from H, D, F, Cl, Br, I, OH, NH2, CN, =O, CH3, CF3, CD3, CH2CH3, OCH3, OCF3, OCD3, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, and other variables are as defined in the present invention.

[0062] In some technical solutions of the present invention, in the above formula (I) or formula (IIA-1), each R is independently selected from H, D, F, Cl, Br, I, OH, NH2, CN, =O, CH3, CF3, CD3, CH2CH3, OCH3, OCF3, OCD3 and cyclopropyl, and other variables are as defined in the present invention.

[0063] In some technical solutions of the present invention, in the above formula (I) or formula (IIA-1), each R a Each R b Each R c The components are independently selected from H, D, F, Cl, Br, I, =O, OH, NH2, CN, CH3, CF3, CD3, CH2CH3, OCH3, OCF3, OCD3, cyclopropyl, and -COCH3, respectively, and other variables are as defined in this invention.

[0064] In some technical solutions of the present invention, in the above formula (I) or formula (IIA-1), each R b The components are independently selected from H, D, F, Cl, CN, CH3, CF3, CD3, and cyclopropyl, respectively, and other variables are as defined in this invention.

[0065] In some technical solutions of the present invention, in formula (I) or formula (IIA-1) above, R b Selected from methyl groups optionally substituted with one or more F or D, other variables as defined in this invention.

[0066] In some technical solutions of the present invention, in formula (I) or formula (IIA-1) above, R b Selected from CH3 and CD3, other variables are as defined in this invention.

[0067] In some technical solutions of the present invention, in the above formula (I) or formula (IIA-1), each R cThe methyl groups are independently selected from H, D, F and methyl groups optionally substituted with one or more R, and other variables are as defined in this invention.

[0068] In some technical solutions of the present invention, in the above formula (I) or formula (IIA-1), each R L3 The variables are independently selected from H, D, F and CH3, respectively, and other variables are as defined in this invention.

[0069] In some technical solutions of the present invention, in the above formula (I) or formula (IIA-1), the two R's L3 They connect together to form a cyclopropyl group, and other variables are as defined in this invention.

[0070] In some technical solutions of the present invention, in formula (I) or formula (IIA-1) above, R3 is selected from H, CN, COOCH3, COOCH2CH3, -COOC(CH3)3, COCH3, COCH2CH3, COCH=CH2 and the following groups optionally substituted by one or more R: methyl, ethyl, propyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, oxacyclobutyl, aziridine, pyrrolidinyl, piperidinyl, Oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazole, pyrrole, triazolyl, and -CH2-phenyl, with other variables as defined in this invention.

[0071] In some technical solutions of the present invention, in formula (I) or formula (IIA-1) above, R3 is selected from H, CN, COOCH3, COOCH2CH3, -COOC(CH3)3, COCH3, COCH2CH3, COCH=CH2 and the following groups optionally substituted by one or more R: methyl, ethyl, propyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, aziridine, pyrrolidinyl, piperidinyl, Oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazole, pyrrole, triazolyl, and -CH2-phenyl, with other variables as defined in this invention.

[0072] In some technical solutions of the present invention, in formula (I) or formula (IIA-1) above, R3 is selected from H, CN and the following groups optionally substituted with one or more R: methyl, cyclopropyl, cyclobutyl, cyclopentyl, aziridine, pyrrolidinyl, piperidinyl, Other variables are as defined in this invention.

[0073] In some technical solutions of the present invention, in formula (I) or formula (IIA-1) above, R3 is selected from H, -COR and the following groups optionally substituted by one or more R: C 1-4Alkyl, C 2-4 alkenyl and C 2-4 Alkyne group, other variables as defined in this invention.

[0074] In some technical solutions of the present invention, in the above formula (I) or formula (IIA-1), R3 is selected from H, CH3, CHF2, CF3, CD3, CH2CH3, CH2CHF2, CH2CF3, CD2CD3, and other variables are as defined in the present invention.

[0075] In some technical solutions of the present invention, in the above formula (I) or formula (IIA-1), R3 is selected from CN, and other variables are as defined in the present invention.

[0076] In some technical solutions of the present invention, in formula (I) or formula (IIA-1) above, R4 is selected from C that is optionally replaced by one or more R. 1-4 Alkyl groups, and other variables as defined in this invention.

[0077] In some technical solutions of the present invention, in the above formula (I) or formula (IIA-1), R4 is selected from H, CH3, CH2CH3, CHF2, CF3, CD3, CH2CHF2, CH2CF3 and CD2CD3, and other variables are as defined in the present invention.

[0078] In some technical solutions of the present invention, in the above formula (I) or formula (IIA-1), R4 is selected from H, CH3, CH2CH3, CF3 and CD3, and other variables are as defined in the present invention.

[0079] In some technical solutions of the present invention, in formula (I) or formula (IIA-1) above, R a2 Selected from -C 0-4 Alkyl-NR3-OR4, other variables as defined in this invention.

[0080] In some technical solutions of the present invention, in formula (I) or formula (IIA-1) above, R a2 Selected from H, OCH3, OCF3, and OCH2CH3, with other variables as defined in this invention.

[0081] In some technical solutions of the present invention, in formula (I) or formula (IIA-1) above, R a2 Selected from H, Other variables are as defined in this invention.

[0082] In some technical solutions of the present invention, in formula (I) or formula (IIA-1) above, R a2Selected from -C 0-4 Alkyl-NR3-OR4, other variables as defined in this invention.

[0083] In some technical solutions of the present invention, in formula (I) or formula (IIA-1) above, R a2 Selected from -NR3-OR4, other variables are as defined in this invention.

[0084] In some technical solutions of the present invention, in formula (I) or formula (IIA-1) above, R a2 Selected from Other variables are as defined in this invention.

[0085] In some technical solutions of the present invention, in the above formula (I), L3 is selected from bonds, CO, and optionally 1, 2, 3, 4, or 5 Rs. L3 The CH2 that is substituted, and other variables as defined in this invention.

[0086] In some technical solutions of the present invention, in formula (I) above, L3 is selected from bond, CH2, CH(CH3), C(CH3)2 and Other variables are as defined in this invention.

[0087] In some technical solutions of the present invention, in the above formula (I), L3 is selected from CO and optionally replaced by 1, 2, 3, 4 or 5 Rs. L3 The CH2 that is substituted, and other variables as defined in this invention.

[0088] In some technical solutions of the present invention, in formula (I) above, L3 is selected from CH2, CH(CH3), C(CH3)2 and Other variables are as defined in this invention.

[0089] In some technical solutions of the present invention, in the above formula (I) or formula (IIA-1), ring A is selected from 1, 2, 3, 4 or 5 R. a The following groups may be substituted: phenyl, naphthyl, quinolinyl, and benzothiazolyl, with other variables as defined in this invention.

[0090] In some technical solutions of the present invention, in the above formula (I) or formula (IIA-1), ring A is selected from 1, 2, 3, 4 or 5 R. a The following groups may be substituted: phenyl and naphthyl, and other variables as defined in this invention.

[0091] In some technical solutions of the present invention, in the above formula (I), the structural unit Selected from n is selected from 0, 1, 2, 3 and 4, and other variables are as defined in this invention.

[0092] In some technical solutions of the present invention, in the above formula (I), the structural unit Selected from Other variables are as defined in this invention.

[0093] In some technical solutions of the present invention, in the above formula (I), the structural unit Selected from Other variables are as defined in this invention.

[0094] In some technical solutions of the present invention, in the above formula (I), the structural unit Selected from Other variables are as defined in this invention.

[0095] In some technical solutions of the present invention, in the above formula (I), the structural unit Selected from Other variables are as defined in this invention.

[0096] In some technical solutions of the present invention, in the above formula (I), the structural unit Selected from Other variables are as defined in this invention.

[0097] In some technical solutions of the present invention, in the above formula (IIA-1), the structural unit Selected from n is selected from 0, 1, 2, 3 and 4, and other variables are as defined in this invention.

[0098] In some technical solutions of the present invention, in the above formula (IIA-1), the structural unit Selected from Other variables are as defined in this invention.

[0099] In some technical solutions of the present invention, in the above formula (IIA-1), the structural unit Selected from Other variables are as defined in this invention.

[0100] In some technical solutions of the present invention, in the above formula (IIA-1), the structural unit Selected from Other variables are as defined in this invention.

[0101] In some technical solutions of the present invention, in the above formula (I), R a With R c They are connected together to form a linker base L, where L is a C that can be arbitrarily replaced by one or more Rs. 5-12 Alkyl, the C 5-12 The 1, 2, 3, 4, 5, or 6 CH2, CH, or C groups of the alkyl group are each independently and optionally replaced by the following groups: O, S, NH, N, CO, SO, SO2, CONH, vinyl, ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, oxecyclobutyl, oxecyclopentyl, pyrrolidinyl, and furanyl, wherein the CONH, vinyl, ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, oxecyclobutyl, oxecyclopentyl, pyrrolidinyl, and furanyl groups are each independently and optionally replaced by one or more R groups, and other variables are as defined in this invention.

[0102] In some technical solutions of the present invention, in the above formula (I), L is selected from... Other variables are as defined in this invention.

[0103] In some technical solutions of the present invention, in the above formula (I), ring B is selected from 1, 2, 3, 4 or 5 R. b The substituted 5-membered heteroaryl group, and other variables as defined in this invention.

[0104] In some technical solutions of the present invention, in the above formula (I), ring B is selected from 1, 2, 3, 4 or 5 R. b The following groups may be substituted: pyrrole, pyrazol, imidazole, triazol, thiazolyl, and oxazolyl, with other variables as defined in this invention.

[0105] In some technical solutions of the present invention, in the above formula (I), ring B is selected from... Other variables are as defined in this invention.

[0106] In some technical solutions of the present invention, in the above formula (I), ring B is selected from... Other variables are as defined in this invention.

[0107] In some technical solutions of the present invention, in the above formula (I), the structural unit Selected from m is selected from 1, 2, and 3, and other variables are as defined in this invention.

[0108] In some technical solutions of the present invention, in the above formula (I), the structural unit Selected from Other variables are as defined in this invention.

[0109] In some technical solutions of the present invention, in the above formula (I), the structural unit Selected from Other variables are as defined in this invention.

[0110] In some technical solutions of the present invention, in the above formula (I), the structural unit Selected from m is selected from 1, 2, and 3, and other variables are as defined in this invention.

[0111] In some technical solutions of the present invention, in the above formula (I), the structural unit Selected from Other variables are as defined in this invention.

[0112] In some technical solutions of the present invention, in the above formula (I), the structural unit Selected from Other variables are as defined in this invention.

[0113] In some technical solutions of the present invention, in the above formula (IIA-1), the structural unit Selected from Other variables are as defined in this invention.

[0114] In some technical solutions of the present invention, in the above formula (IIA-1), the structural unit Selected from Other variables are as defined in this invention.

[0115] In some technical solutions of the present invention, m is 0 in the above formula (IIA-1), and other variables are as defined in the present invention.

[0116] In some technical solutions of the present invention, in the above formula (IIA-1), m is 0 or 1, and other variables are as defined in the present invention.

[0117] In some technical solutions of the present invention, the compound of formula (I), its stereoisomer, or its pharmaceutically acceptable salt is selected from:

[0118] Among them, ring A, ring B, and ring R a1 R a2 R c1 R c L3 and m are as defined in this invention.

[0119] In some technical solutions of the present invention, the compound of formula (I), its stereoisomer, or its pharmaceutically acceptable salt is selected from:

[0120] in,

[0121] R a2 Selected from -C 0-4 Alkyl-NR3-OR4, -C 0-4 Alkyl-NR3-N(R3)2, -C 0-4 Alkyl-ON(R3)2 and -C 0-4 Alkyl-ON=C(R3)2; preferably,

[0122] R a2 Selected from -C 0-4 Alkyl-NR3-OR4;

[0123] Among them, ring A, ring C, L2, L3, R3, R4, R b As defined in this invention.

[0124] In some technical solutions of the present invention, the compounds of formula (I) or (IIA), their stereoisomers, or pharmaceutically acceptable salts thereof are selected from:

[0125] Where m is selected from 0, 1, and 2, and rings A and R a2 R b R c As defined in this invention.

[0126] In some technical solutions of the present invention, compounds of formula (IIA-1), (IIA-2), or (IIA-3), their stereoisomers, or pharmaceutically acceptable salts thereof,

[0127] in,

[0128] Ring A is selected from one or more R. a The following groups are substituted: phenyl, naphthyl, and 5-10 membered heteroaryl groups;

[0129] R a2 Selected from -C 0-4 Alkyl-NR3-OR4, -C 0-4 Alkyl-NR3-N(R3)2, -C 0-4 Alkyl-ON(R3)2 and -C 0-4 Alkyl-ON=C(R3)2; preferably,

[0130] R a2 Selected from -C 0-4 Alkyl-NR3-OR4;

[0131] R b Selected from CH3, CF3, CD3 and cyclopropyl;

[0132] R c Selected from H, D, F, Cl, Br, I, OCH3, SCH3, NHCH3, N(CH3)2, CN, and the following groups optionally substituted with one or more R: C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 Cycloalkyl, 3-6 membered heterocyclic alkyl;

[0133] R3 is selected from H, CN, -COR, and the following groups optionally substituted with one or more R groups: C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-10 Cycloalkyl, 3-10-membered heterocycloalkyl, phenyl, -CH2-phenyl, 5-6-membered heteroaryl and -CH2-5-6-membered heteroaryl;

[0134] R4 is selected from H, CN, and the following groups optionally substituted with one or more R groups: C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-10 Cycloalkyl and 3-10 membered heterocyclic alkyl groups;

[0135] Each R a The following groups are independently selected from H, D, F, Cl, Br, I, OR3, SR3, N(R3)2, CN, -COR3, -NR3COR4, and optionally substituted with one or more R groups: C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, phenyl and 5-6 membered heteroaryl;

[0136] Each R is independently selected from H, D, F, Cl, Br, I, OH, NH2, CN, =O, and the following groups optionally substituted by one or more F: C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, C 1-4 Alkylthio, C 1-4 Alkylamino, C 3-8 Cycloalkyl and 3-8 membered heterocyclic alkyl; m is selected from 0, 1 and 2.

[0137] In some technical solutions of the present invention, the compounds of formula (IIA-1), (IIA-2) or (IIA-3), their stereoisomers or pharmaceutically acceptable salts thereof are selected from:

[0138] Among them, R a R a2 R b R c As defined in this invention.

[0139] The present invention also provides the compounds shown in Table A, their stereoisomers, or pharmaceutically acceptable salts thereof.

[0140] Table A Compounds

[0141] In some technical solutions of the present invention, the compounds shown in Table A above, their stereoisomers or pharmaceutically acceptable salts thereof are selected from the compounds in Table A1.

[0142] Table A1 Compounds

[0143] Secondly, the present invention also provides the compound of formula (I), its stereoisomers, or pharmaceutically acceptable salts thereof.

[0144] in,

[0145] L1 is L 21 L 21 Selected from bonds, CO, CS, SO, SO2 and optionally R L21 The following groups are substituted: C 1-4 Alkyl, C 2- 4-Alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, C 1-4 Alkylthio, C 1-4 Alkylamino, C 3-8 Cycloalkyl and 3-8 membered heterocyclic alkyl groups;

[0146] L2 is L 22 L 22 Selected from bonds, CO, CS, SO, SO2 and optionally R L22 The following groups are substituted: C 1-4 Alkyl, C 2- 4-Alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl and 3-8 membered heterocyclic alkyl groups;

[0147] L3 is L 23 L 23 Selected from bonds, CO, CS, SO, SO2 and optionally R L23 The following groups are substituted: C 1-4 Alkyl, C 2- 4-Alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl and 3-8 membered heterocyclic alkyl groups;

[0148] R1 is R 21 R 21 Selected from H and arbitrarily selected by one or more R 21aa The following groups are substituted: C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, phenyl, naphthyl and 5-10 membered heteroaryl;

[0149] R2 is R 22 R 22 Selected from OH and NH2;

[0150] Ring B is selected from

[0151] Selected from single and double bonds;

[0152] X and Y are selected separately from O and S, respectively;

[0153] Ring C is selected from Among them, ring C2 is connected to L3;

[0154] Ring C1 is selected from one or more Rs. c The following groups are substituted: phenyl, 5-6 membered heteroaryl and 5-8 membered heterocyclic alkyl;

[0155] Ring C2 is selected from one or more Rs. c The following groups are substituted: 5-6 membered heteroaryl and 5-8 membered heterocyclic alkyl;

[0156] Ring D is selected from one or more R. d The following groups are substituted: phenyl and 5-6 membered heteroaryl groups;

[0157] R 23 Selected from H and SF5;

[0158] Each R 24The molecules are independently selected from H, D, F, Cl, Br, I, OH, NH2, CN, =O, COCH3, and are arbitrarily selected by one or more R. 24a The following groups are substituted: C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, C 1-4 Alkylthio, C 1-4 Alkylamino, C 3-8 Cycloalkyl and 3-8 membered heterocyclic alkyl groups;

[0159] Each R L21 Each R L22 R 21a R 21b R 21c Each R c Each R d Each R 24a The following groups are selected independently from H, D, F, Cl, Br, I, =O, OH, NH2, CN, SF5, and optionally substituted with one or more of the following groups by R: C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, C 1-4 Alkylthio, C 1-4 Alkylamino, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, phenyl, naphthyl and 5-10 membered heteroaryl;

[0160] Each R 21aa Each of the following is independently selected from H, D, F, Cl, Br, I, =O, OH, NH2, CN, SF5, -C 0-4 Alkyl-ON = CR2, -C 0-4 Alkyl-O-CR=NR and optionally one or more of the following groups substituted with R: C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, C 1-4 Alkylthio, C 1-4 Alkylamino, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, phenyl, naphthyl and 5-10 membered heteroaryl;

[0161] Or 2 Rs d Connected together, or 2 Rs c Connected together, or 2 Rs 21aa Linked together, they independently form the following groups, optionally substituted with one or more R groups: C 3-8Cycloalkyl, 3-8 membered heterocycloalkyl, phenyl, naphthyl and 5-10 membered heteroaryl;

[0162] Each R is independently selected from H, D, F, Cl, Br, I, OH, NH2, CN, =O, COCH3, and the following groups optionally substituted by one or more F: C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, C 1-4 Alkylthio, C 1-4 Alkylamino, C 3-8 Cycloalkyl and 3-8 membered heterocyclic alkyl groups;

[0163] t is selected from 0, 1, 2, and 3;

[0164] s is selected from 0, 1, 2, 3, and 4;

[0165] The condition is that when L 21 Selected from C 1-4 Alkyl, L 22 Selected from CH2, ring D is selected from 1 or 2 R. d Substituted phenyl or pyridyl groups, structural units Selected from R c Selected from F, Cl, methyl and CN, R d When selected from F, Cl, methyl, and methoxy,

[0166] (1)R 23 Selected from SF5; or,

[0167] (2)R 23 For H, R 21 Selected from or,

[0168] (3)R 23 For H, R 21 Selected from one or more R 21aa The following groups are substituted: C 3-8 Cycloalkyl, 3-8 membered heterocyclic alkyl, phenyl, naphthyl and 5-10 membered heteroaryl, and at least one R 21aa Selected from SF5 -C 0-4 Alkyl-ON = CR2, -C 0-4 Alkyl-O-CR=NR; or,

[0169] (4) 2 R d Connected together, or 2 Rs c Connected together, or 2 Rs 21aaLinked together, they independently form the following groups, optionally substituted with one or more R groups: C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, phenyl, naphthyl and 5-10 membered heteroaryl.

[0170] The present invention also provides the compound of formula (I), its stereoisomers or pharmaceutically acceptable salts thereof,

[0171] in,

[0172] L1 is L 21 L 21 Selected from bonds, CO, CS, SO, SO2 and optionally R L21 The following groups are substituted: C 1-4 Alkyl, C 2- 4-Alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, C 1-4 Alkylthio, C 1-4 Alkylamino, C 3-8 Cycloalkyl and 3-8 membered heterocyclic alkyl groups;

[0173] L2 is L 22 L 22 Selected from bonds, CO, CS, SO, SO2 and optionally R L22 The following groups are substituted: C 1-4 Alkyl, C 2- 4-Alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl and 3-8 membered heterocyclic alkyl groups;

[0174] L3 is the key;

[0175] R1 is R 21 R 21 Selected from H, and can be chosen by one or more R 21aa The following groups are substituted: C 1-6 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, C 1-4 Alkylthio, C 1-4 Alkylamino, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, phenyl, naphthyl and 5-10 membered heteroaryl;

[0176] R2 is R 22 R 22 Selected from OH, NH2, -CONH2, -CH2OH and -CH2NH2;

[0177] Ring B is selected from

[0178] Selected from single and double bonds;

[0179] X and Y are selected separately from O and S, respectively;

[0180] Ring C is selected from one or more R. c The following groups are substituted: benzo5-6 heteroaryl, 5-6 heteroaryl-benzo5-6 heteroaryl;

[0181] Ring D is selected from one or more R. d The following groups are substituted: phenyl and 5-6 membered heteroaryl groups;

[0182] R 23 Selected from H and SF5;

[0183] Each R 24 The molecules are independently selected from H, D, F, Cl, Br, I, OH, NH2, CN, =O, COCH3, and are arbitrarily selected by one or more R. 24a The following groups are substituted: C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, C 1-4 Alkylthio, C 1-4 Alkylamino, C 3-8 Cycloalkyl and 3-8 membered heterocyclic alkyl groups;

[0184] Each R L21 Each R L22 R 21a R 21b R 21c Each R c Each R d Each R 24a The following groups are selected independently from H, D, F, Cl, Br, I, =O, OH, NH2, CN, SF5, and optionally substituted with one or more of the following groups by R: C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, C 1-4 Alkylthio, C 1-4 Alkylamino, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, phenyl, naphthyl and 5-10 membered heteroaryl;

[0185] Each R 21aa Each of the following is independently selected from H, D, F, Cl, Br, I, =O, OH, NH2, CN, SF5, -C 0-4 Alkyl-ON = CR2, -C 0-4 Alkyl-O-CR=NR and optionally one or more of the following groups substituted with R: C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, C 1-4 Alkylthio, C 1-4 Alkylamino, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, phenyl, naphthyl and 5-10 membered heteroaryl;

[0186] Or 2 Rs d Connected together, or 2 Rs c Connected together, or 2 Rs 21aa Linked together, they independently form the following groups, optionally substituted with one or more R groups: C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, phenyl, naphthyl and 5-10 membered heteroaryl;

[0187] Each R is independently selected from H, D, F, Cl, Br, I, OH, NH2, CN, =O, COCH3, and the following groups optionally substituted by one or more F: C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, C 1-4 Alkylthio, C 1-4 Alkylamino, C 3-8 Cycloalkyl and 3-8 membered heterocyclic alkyl groups;

[0188] t is selected from 0, 1, 2, and 3;

[0189] s is selected from 0, 1, 2, 3, and 4;

[0190] The condition is that when L 21 Selected from C 1-4 Alkyl, L 22 Selected from CH2, ring D is selected from 1 or 2 R. d Substituted phenyl or pyridyl groups, structural units Selected from R c Selected from F, Cl, methyl and CN, R d When selected from F, Cl, methyl, and methoxy,

[0191] (1)R 23 Selected from SF5; or,

[0192] (2)R 23 For H, R 21 Selected from or,

[0193] (3)R 23 For H, R 21 Selected from one or more R 21aa The following groups are substituted: C 3-8 Cycloalkyl, 3-8 membered heterocyclic alkyl, phenyl, naphthyl and 5-10 membered heteroaryl, and at least one R 21aa Selected from SF5 -C 0-4 Alkyl-ON = CR2, -C 0-4 Alkyl-O-CR=NR; or,

[0194] (4) 2 R d Connected together, or 2 Rs c Connected together, or 2 Rs 21aa Linked together, they independently form the following groups, optionally substituted with one or more R groups: C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, phenyl, naphthyl and 5-10 membered heteroaryl.

[0195] In some technical solutions of the present invention, the compound of formula (I), its stereoisomer, or its pharmaceutically acceptable salt is selected from:

[0196] Among them, ring C, ring D, and L 21 L 22 R 21 R 23 t is as defined in this invention.

[0197] The present invention also provides compounds of formula (IIB), their stereoisomers, or pharmaceutically acceptable salts thereof.

[0198] in,

[0199] Selected from single and double bonds;

[0200] X and Y are selected separately from O and S, respectively;

[0201] L 21 Selected from bonds, CO, CS, SO, SO2 and optionally R L21 The following groups are substituted: C 1-4 Alkyl, C 2-4 alkenyl, C 2- 4-Alynyl group, C 1-4 Alkoxy, C 1-4 Alkylthio, C 1-4 Alkylamino, C 3-8Cycloalkyl and 3-8 membered heterocyclic alkyl groups;

[0202] L 22 Selected from bonds, CO, CS, SO, SO2 and optionally R L22 The following groups are substituted: C 1-4 Alkyl, C 2-4 alkenyl, C 2- 4-Alynyl group, C 3-8 Cycloalkyl and 3-8 membered heterocyclic alkyl groups;

[0203] L 23 Selected from bonds, CO, CS, SO, SO2 and optionally R L23 The following groups are substituted: C 1-4 Alkyl, C 2-4 alkenyl, C 2- 4-Alynyl group, C 3-8 Cycloalkyl and 3-8 membered heterocyclic alkyl groups;

[0204] R 21 Selected from H and arbitrarily selected by one or more R 21aa The following groups are substituted: C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, phenyl, naphthyl and 5-10 membered heteroaryl;

[0205] R 23 Selected from H and SF5;

[0206] Ring C is selected from Among them, ring C2 is connected to L3;

[0207] Ring C1 is selected from one or more Rs. c The following groups are substituted: phenyl, 5-6 membered heteroaryl and 5-8 membered heterocyclic alkyl;

[0208] Ring C2 is selected from one or more Rs. c The following groups are substituted: 5-6 membered heteroaryl and 5-8 membered heterocyclic alkyl;

[0209] Ring D is selected from one or more R. d The following groups are substituted: phenyl and 5-6 membered heteroaryl groups;

[0210] Each R L21 Each R L22 Each R L23 Each R c Each Rd The following groups are selected independently from H, D, F, Cl, Br, I, =O, OH, NH2, CN, SF5, and optionally substituted with one or more of the following groups by R: C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, C 1-4 Alkylthio, C 1-4 Alkylamino, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, phenyl, naphthyl and 5-10 membered heteroaryl;

[0211] Each R 21aa Each of the following is independently selected from H, D, F, Cl, Br, I, =O, OH, NH2, CN, SF5, -C 0-4 Alkyl-ON=C(R)2, -C 0-4 Alkyl-O-CR=NR and optionally one or more of the following groups substituted with R: C 1-4 Alkyl, vinyl, C 2-4 alkynyl group, C 1-4 Alkoxy, C 1-4 Alkylthio, C 1-4 Alkylamino, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, phenyl, naphthyl and 5-10 membered heteroaryl;

[0212] Or 2 Rs d Connected together, or 2 Rs c Connected together, or 2 Rs 21aa Linked together, they independently form the following groups, optionally substituted with one or more R groups: C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, phenyl, naphthyl and 5-10 membered heteroaryl;

[0213] Each R is independently selected from H, D, F, Cl, Br, I, OH, NH2, CN, =O, COCH3, and the following groups optionally substituted by one or more F: C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, C 1-4 Alkylthio, C 1-4 Alkylamino, C 3-8 Cycloalkyl and 3-8 membered heterocyclic alkyl groups;

[0214] t is selected from 0, 1, 2, and 3;

[0215] The condition is that when L 21 Selected from C 1-4 Alkyl, L22 Selected from CH2, ring D is selected from 1 or 2 R. d Substituted phenyl or pyridyl groups, structural units Selected from R c Selected from F, Cl, methyl and CN, R d When selected from F, Cl, methyl, and methoxy,

[0216] (1)R 23 Selected from SF5; or,

[0217] (2)R 23 For H, R 21 Selected from or,

[0218] (3)R 23 For H, R 21 Selected from one or more R 21aa The following groups are substituted: C 3-8 Cycloalkyl, 3-8 membered heterocyclic alkyl, phenyl, naphthyl and 5-10 membered heteroaryl, and at least one R 21aa Selected from SF5 -C 0-4 Alkyl-ON=C(R)2 and -C 0-4 Alkyl-O-CR=NR; or,

[0219] (4) 2 R d Connected together, or 2 Rs c Connected together, or 2 Rs 21aa Linked together, they independently form the following groups, optionally substituted with one or more R groups: C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, phenyl, naphthyl and 5-10 membered heteroaryl.

[0220] The present invention also provides compounds of formula (IIB), their stereoisomers, or pharmaceutically acceptable salts thereof.

[0221] in,

[0222] Selected from single and double bonds;

[0223] X and Y are selected separately from O and S, respectively;

[0224] L 21 Selected from bonds, CO, CS, SO, SO2 and optionally R L21 The following groups are substituted: C 1-4 Alkyl, C 2-4 alkenyl, C 2- 4-Alynyl group, C1-4 Alkoxy, C 1-4 Alkylthio, C 1-4 Alkylamino, C 3-8 Cycloalkyl and 3-8 membered heterocyclic alkyl groups;

[0225] L 22 Selected from bonds, CO, CS, SO, SO2 and optionally R L22 The following groups are substituted: C 1-4 Alkyl, C 2-4 alkenyl, C 2- 4-Alynyl group, C 3-8 Cycloalkyl and 3-8 membered heterocyclic alkyl groups;

[0226] L 23 Selected from bonds, CO, CS, SO, SO2 and optionally R L23 The following groups are substituted: C 1-4 Alkyl, C 2-4 alkenyl, C 2- 4-Alynyl group, C 3-8 Cycloalkyl and 3-8 membered heterocyclic alkyl groups;

[0227] R 21 Selected from

[0228] R 21a R 21b R 21c The following groups are independently selected from H, D, F, Cl, Br, I, OH, NH2, CN, SF5, and optionally substituted with one or more R groups: C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, C 1-4 Alkylthio, C 1-4 Alkylamino, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, phenyl, naphthyl and 5-10 membered heteroaryl;

[0229] Or, R 21a With R 21b Connected together, they form a C that can be arbitrarily replaced by one or more Rs. 3-8 cycloalkyl or 3-8 membered heterocyclic alkyl;

[0230] R 23 Selected from H and SF5;

[0231] Ring C is selected from Among them, ring C2 is connected to L3;

[0232] Ring C1 is selected from one or more Rs. cThe following groups are substituted: phenyl, 5-6 membered heteroaryl and 5-8 membered heterocyclic alkyl;

[0233] Ring C2 is selected from one or more Rs. c The following groups are substituted: 5-6 membered heteroaryl and 5-8 membered heterocyclic alkyl;

[0234] Ring D is selected from one or more R. d The following groups are substituted: phenyl and 5-6 membered heteroaryl groups;

[0235] Each R L21 Each R L22 Each R L23 Each R c Each R d The following groups are selected independently from H, D, F, Cl, Br, I, =O, OH, NH2, CN, SF5, and optionally substituted with one or more of the following groups by R: C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, C 1-4 Alkylthio, C 1-4 Alkylamino, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, phenyl, naphthyl and 5-10 membered heteroaryl;

[0236] Or 2 Rs d Connected together, or 2 Rs c Linked together, they independently form the following groups, optionally substituted with one or more R groups: C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, phenyl, naphthyl and 5-10 membered heteroaryl;

[0237] Each R is independently selected from H, D, F, Cl, Br, I, OH, NH2, CN, =O, COCH3, and the following groups optionally substituted by one or more F: C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, C 1-4 Alkylthio, C 1-4 Alkylamino, C 3-8 Cycloalkyl and 3-8 membered heterocyclic alkyl groups;

[0238] t is selected from 0, 1, 2, and 3.

[0239] In some technical solutions of the present invention, the compounds of formula (I-2) or (IIB), their stereoisomers or pharmaceutically acceptable salts thereof, wherein each R is independently selected from H, D, F, Cl, Br, I, OH, NH2, CN, =O, CH3, CF3, CD3, CH2CH3, OCH3, OCF3, OCD3, cyclopropyl and COCH3, and other variables are as defined in the present invention.

[0240] In some technical solutions of the present invention, the above-mentioned compound of formula (I-2), its stereoisomer or its pharmaceutically acceptable salt, wherein each R L21 Each R L22 Each R c Each R d Each R 24a The following groups are independently selected from H, D, F, Cl, Br, I, =O, OH, NH2, CN, SF5, and optionally substituted with 1, 2, 3, 4, or 5 R groups: CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, vinyl, ethynyl, OCH3, OCH2CH3, OC(CH3)2, SCH3, SCH2CH3, NHCH3, NHCH2CH3, N(CH3)2, CH2NHCH3, cyclopropyl, cyclobutyl, oxecyclobutyl, oxecyclopentyl, azircyclobutyl, pyrrolidinyl, and piperidinyl, with other variables as defined in this invention.

[0241] In some technical solutions of the present invention, the above-mentioned compound of formula (IIB), its stereoisomer, or its pharmaceutically acceptable salt, wherein each R L21 Each R L22 Each R L23 Each R c Each R d The following groups are independently selected from H, D, F, Cl, Br, I, =O, OH, NH2, CN, SF5, and optionally substituted with 1, 2, 3, 4, or 5 R groups: CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, vinyl, ethynyl, OCH3, OCH2CH3, OC(CH3)2, SCH3, SCH2CH3, NHCH3, NHCH2CH3, N(CH3)2, CH2NHCH3, cyclopropyl, cyclobutyl, oxecyclobutyl, oxecyclopentyl, azircyclobutyl, pyrrolidinyl, and piperidinyl, with other variables as defined in this invention.

[0242] In some technical solutions of the present invention, the compounds of formula (I-2) or (IIB), their stereoisomers, or pharmaceutically acceptable salts thereof, wherein R 21a R 21b R 21cThe following groups are independently selected from H, D, F, Cl, Br, I, OH, NH2, CN, and optionally substituted with one or more R groups: C 1-4 Alkyl, C 1-4 Alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, phenyl and 5-6 membered heteroaryl, other variables as defined in this invention.

[0243] In some technical solutions of the present invention, the compounds of formula (I-2) or (IIB), their stereoisomers, or pharmaceutically acceptable salts thereof, wherein R 21a R 21b R 21c Each of the following is independently selected from H, D, F, Cl, Br, I, OH, NH2, CN, CH3, CF3, CD3, CH2CH3, CH2CF3, CH2CH2CH3, CH(CH3)2, CH2CH(CH3)2, OCH3, OCF3, OCD3, -COCH3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, Other variables are as defined in this invention.

[0244] In some technical solutions of the present invention, the compounds of formula (I-2) or (IIB), their stereoisomers, or pharmaceutically acceptable salts thereof, wherein R 21a and R 21b They are linked together to form cyclohexyl groups, which may be substituted with one or more R groups, and other variables are as defined in this invention.

[0245] In some technical solutions of the present invention, the compounds of formula (I-2) or (IIB), their stereoisomers, or pharmaceutically acceptable salts thereof, wherein R 21a and R 21b They are linked together to form a cyclohexyl group, and other variables are as defined in this invention.

[0246] In some technical solutions of the present invention, the compound of formula (IIB), its stereoisomer, or a pharmaceutically acceptable salt thereof, wherein R 21a R 21b R 21c The components are independently selected from H, D, F, Cl, Br, I, OH, NH2, CN, CH3, CF3, CD3, CH2CH3, OCH3, OCF3, OCD3, cyclopropyl and -COCH3, and other variables are as defined in this invention.

[0247] In some technical solutions of the present invention, the compounds of formula (I-2) or (IIB), their stereoisomers, or pharmaceutically acceptable salts thereof, wherein each R 21aaThe following groups are independently selected from H, D, F, Cl, Br, I, =O, OH, NH2, CN, SF5, and optionally substituted with 1, 2, 3, 4, or 5 R groups: CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, vinyl, ethynyl, OCH3, OCH2CH3, OC(CH3)2, SCH3, SCH2CH3, NHCH3, NHCH2CH3, N(CH3)2, CH2NHCH3, cyclopropyl, cyclobutyl, oxacyclobutyl, oxacyclopentyl, aziridine, pyrrolyl, piperidinyl, phenyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrroloyl, imidazolyl, pyrazolyl, triazolyl, thiazolyl, and oxazolyl, with other variables as defined in this invention.

[0248] In some technical solutions of the present invention, the compounds of formula (I-2) or (IIB), their stereoisomers, or pharmaceutically acceptable salts thereof, wherein R L21 Selected from H, D, and F, with other variables as defined in this invention.

[0249] In some technical solutions of the present invention, the compounds of formula (I-2) or (IIB), their stereoisomers, or pharmaceutically acceptable salts thereof, wherein R L21 Selected from H and D, other variables are as defined in this invention.

[0250] In some technical solutions of the present invention, the compounds of formula (I-2) or (IIB), their stereoisomers, or pharmaceutically acceptable salts thereof, wherein L 21 Choose from 1, 2, 3, 4 or 5 Rs. L21 The following groups may be substituted: CH2, CH2CH2, ethynyl, propynyl, vinyl, propenyl, and butenyl, with other variables as defined in this invention.

[0251] In some technical solutions of the present invention, the compounds of formula (I-2) or (IIB), their stereoisomers, or pharmaceutically acceptable salts thereof, wherein L 21 Selected from the key and optionally by one or more R L21 The following groups are substituted: C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 Alkyne group, other variables as defined in this invention.

[0252] In some technical solutions of the present invention, the compounds of formula (I-2) or (IIB), their stereoisomers, or pharmaceutically acceptable salts thereof, wherein L 21 Selected from CH2 and CD2, other variables are as defined in this invention.

[0253] In some technical solutions of the present invention, the compounds of formula (I-2) or (IIB), their stereoisomers, or pharmaceutically acceptable salts thereof, wherein L 21 Selected from CH2 and Other variables are as defined in this invention.

[0254] In some technical solutions of the present invention, the compounds of formula (I-2) or (IIB), their stereoisomers, or pharmaceutically acceptable salts thereof, wherein L 22 Selected from the bond and CH2, other variables are as defined in this invention.

[0255] In some technical solutions of the present invention, the compounds of formula (I-2) or (IIB), their stereoisomers, or pharmaceutically acceptable salts thereof, wherein L 22 Selected from CH2, other variables are as defined in this invention.

[0256] In some technical solutions of the present invention, the compounds of formula (I-2) or (IIB), their stereoisomers, or pharmaceutically acceptable salts thereof, wherein R 21 Selected from H, And any 1, 2, 3, 4 or 5 R's can be selected. 21aa The following groups may be substituted: CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, vinyl, ethynyl, propynyl, OCH3, OCH2CH3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxecyclobutyl, oxecyclopentyl, oxecyclohexyl, aziroxybutyl, pyrrolidinyl, piperidinyl, piperidinyl, piperazine, morpholinyl, phenyl, pyridinyl, pyrimidinyl, pyrazine, pyridazine, indolyl, inzolyl, benzothiazolyl, and benzimidazolyl, with other variables as defined in this invention.

[0257] In some technical solutions of the present invention, the compounds of formula (I-2) or (IIB), their stereoisomers, or pharmaceutically acceptable salts thereof, wherein R 21 Selected from Other variables are as defined in this invention.

[0258] In some technical solutions of the present invention, the compounds of formula (I-2) or (IIB), their stereoisomers or pharmaceutically acceptable salts thereof, wherein the structural unit Selected from Other variables are as defined in this invention.

[0259] In some technical solutions of the present invention, the compounds of formula (I-2) or (IIB), their stereoisomers or pharmaceutically acceptable salts thereof, wherein the structural unit Selected from Other variables are as defined in this invention.

[0260] In some technical solutions of the present invention, the compounds of formula (I-2) or (IIB), their stereoisomers or pharmaceutically acceptable salts thereof, wherein the structural unit Selected from Other variables are as defined in this invention.

[0261] In some technical solutions of the present invention, the compounds of formula (I-2) or (IIB), their stereoisomers or pharmaceutically acceptable salts thereof, wherein the structural unit Selected from Other variables are as defined in this invention.

[0262] In some technical solutions of the present invention, the compounds of formula (I-2) or (IIB), their stereoisomers, or pharmaceutically acceptable salts thereof, wherein L 22 Selected from CH2, other variables are as defined in this invention.

[0263] In some technical solutions of the present invention, the compounds of formula (I-2) or (IIB), their stereoisomers, or pharmaceutically acceptable salts thereof, wherein L 23 Selected from the key, other variables are as defined in this invention.

[0264] In some technical solutions of the present invention, the compounds of formula (I-2) or (IIB), their stereoisomers, or pharmaceutically acceptable salts thereof, wherein ring D is selected from compounds optionally surrounded by one or more R d The following groups may be substituted: phenyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazoleyl, pyrazolyl, thiazolyl, and other variables as defined in this invention.

[0265] In some technical solutions of the present invention, the compounds of formula (I-2) or (IIB), their stereoisomers or pharmaceutically acceptable salts thereof, wherein ring D is selected from phenyl, and other variables are as defined in the present invention.

[0266] In some technical solutions of the present invention, the compounds of formula (I-2) or (IIB), their stereoisomers or pharmaceutically acceptable salts thereof, wherein the structural unit Selected from T1, T2, T3, and T4 are each independently selected from N and CR. d and CR 23 Other variables are as defined in this invention.

[0267] In some technical solutions of the present invention, the compounds of formula (I-2) or (IIB), their stereoisomers or pharmaceutically acceptable salts thereof, wherein the structural unit Selected from T1, T2, T3, and T4 are each independently selected from N and CR. d Other variables are as defined in this invention.

[0268] In some technical solutions of the present invention, the compounds of formula (I-2) or (IIB), their stereoisomers or pharmaceutically acceptable salts thereof, wherein the structural unit Selected from T1, T2, T3, and T4 are each independently selected from CR d Other variables are as defined in this invention.

[0269] In some technical solutions of the present invention, the compounds of formula (I-2) or (IIB), their stereoisomers or pharmaceutically acceptable salts thereof, wherein the structural unit Selected from Other variables are as defined in this invention.

[0270] In some technical solutions of the present invention, the compounds of formula (I-2) or (IIB), their stereoisomers or pharmaceutically acceptable salts thereof, wherein the structural unit Selected from Other variables are as defined in this invention.

[0271] In some technical solutions of the present invention, the compounds of formula (I-2) or (IIB), their stereoisomers, or pharmaceutically acceptable salts thereof, wherein the ring C is selected from those optionally surrounded by one or more R c The following groups may be substituted: quinolinyl, pyridopyridyl, benzimidazolyl, pyridopyrrolyl, and other variables as defined in this invention.

[0272] In some technical solutions of the present invention, the above-mentioned compound of formula (I-2), its stereoisomer or its pharmaceutically acceptable salt, wherein the structural unit Selected from Other variables are as defined in this invention.

[0273] In some technical solutions of the present invention, the above-mentioned compound of formula (I-2), its stereoisomer or its pharmaceutically acceptable salt, wherein the structural unit Selected from Other variables are as defined in this invention.

[0274] In some technical solutions of the present invention, the compound of formula (IIB), its stereoisomer, or a pharmaceutically acceptable salt thereof, wherein ring C1 is selected from one or more R... c The substituted phenyl, pyridyl, pyrroleyl, and imidazole groups, with ring C2 selected from one or more R groups. c The substituted pyridyl, pyridazinyl, pyridoneyl, and pyridazinoneyl groups, and other variables as defined in this invention.

[0275] In some technical solutions of the present invention, the compound of formula (IIB), its stereoisomer, or a pharmaceutically acceptable salt thereof, wherein the structural unit Selected from Other variables are as defined in this invention.

[0276] In some technical solutions of the present invention, the compound of formula (IIB), its stereoisomer, or a pharmaceutically acceptable salt thereof, wherein the structural unit Selected from Other variables are as defined in this invention.

[0277] In some technical solutions of the present invention, the compound of formula (IIB), its stereoisomer, or a pharmaceutically acceptable salt thereof, wherein the structural unit Selected from Other variables are as defined in this invention.

[0278] In some technical solutions of the present invention, the compound of formula (IIB), its stereoisomer, or a pharmaceutically acceptable salt thereof, wherein the structural unit Selected from Other variables are as defined in this invention.

[0279] In some technical solutions of this invention, the compounds of formula (I-2) or (IIB), their stereoisomers, or pharmaceutically acceptable salts thereof are selected from:

[0280] in, Rings D, X, Y, L 21 R 21 R 23 R c t is as defined in this invention.

[0281] In some technical solutions of the present invention, the compound of formula (IIB-1), its stereoisomer, or its pharmaceutically acceptable salt, wherein L 21 Selected from the key and optionally by one or more R L21 The following groups are substituted: C 1-4 Alkyl, C 2-4alkenyl, C 2-4 alkynyl group;

[0282] R 21 Selected from and by one or more R 21aa The following groups are substituted: C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, phenyl, naphthyl and 5-10 membered heteroaryl;

[0283] Each R 21aa Each of the following is independently selected from H, D, F, Cl, Br, I, =O, OH, NH2, CN, SF5, -C 0-4 Alkyl-ON=C(R)2, -C 0-4 Alkyl-O-CR=NR and optionally one or more of the following groups substituted with R: C 1-4 Alkyl, vinyl, C 2-4 alkynyl group, C 1-4 Alkoxy, C 1-4 Alkylthio, C 1-4 Alkylamino, C 3-8 Cycloalkyl, 3-8 membered heterocyclic alkyl, phenyl, naphthyl and 5-10 membered heteroaryl, and at least one R 21aa Selected from SF5 -C 0-4 Alkyl-ON=C(R)2 and -C 0-4 Alkyl-O-CR=NR;

[0284] R 21a R 21b R 21c The following groups are selected independently from H, D, F, Cl, Br, I, =O, OH, NH2, CN, SF5, and optionally substituted with one or more R groups: C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, C 1-4 Alkylthio, C 1-4 Alkylamino, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, phenyl, naphthyl and 5-10 membered heteroaryl;

[0285] Rings D, X, Y, R 23 R c R and t are as defined in this invention.

[0286] In some technical solutions of the present invention, the compound of formula (IIB-1), its stereoisomer, or a pharmaceutically acceptable salt thereof, wherein R 21 Selected from Other variables are as defined in this invention.

[0287] In some technical solutions of the present invention, the compound of formula (IIB-1), its stereoisomer, or a pharmaceutically acceptable salt thereof, wherein R 21a R 21b R 21c The following groups are independently selected from H, D, F, Cl, Br, I, OH, NH2, CN, and optionally substituted with one or more R groups: C 1-4 Alkyl, C 1-4 Alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, phenyl and 5-6 membered heteroaryl, other variables as defined in this invention.

[0288] In some technical solutions of the present invention, the compound of formula (IIB-1), its stereoisomer, or a pharmaceutically acceptable salt thereof, wherein R 21a R 21b R 21c Each of the following groups is independently selected from H, D, F, Cl, Br, I, OH, NH2, CN, CH3, CF3, CD3, CH2CH3, CH2CF3, CH2CH2CH3, CH(CH3)2, CH2CH(CH3)2, OCH3, OCF3, OCD3, cyclopropyl, -COCH3, cyclobutyl, cyclopentyl, cyclohexyl, phenyl. Other variables are as defined in this invention.

[0289] Some technical solutions of this invention are derived from arbitrary combinations of the above-mentioned variables.

[0290] The present invention also provides the compounds shown in Table B, their stereoisomers, or pharmaceutically acceptable salts thereof.

[0291] Table B Compounds

[0292] In some technical solutions of the present invention, the compounds shown in Table B above, their stereoisomers or pharmaceutically acceptable salts thereof are selected from the compounds shown in Table B1.

[0293] Table B1 Compounds

[0294] The present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of the compound of the present invention, its stereoisomer, or a pharmaceutically acceptable salt thereof. Further, it also includes a pharmaceutically acceptable carrier.

[0295] The present invention also provides the use of the above-mentioned compounds, their stereoisomers or pharmaceutically acceptable salts thereof in the preparation of medicaments for treating diseases related to PRMT5 inhibitors.

[0296] In some technical solutions of the present invention, the above-mentioned PRMT5 inhibitor-related diseases are MTAP-deficient solid tumors and / or brain metastases of MTAP-deficient solid tumors.

[0297] In some technical solutions of the present invention, the solid tumors lacking MTAP include, but are not limited to, lung cancer, pancreatic cancer, esophageal cancer, and malignant glioma.

[0298] The present invention also provides the following synthesis methods:

[0299] Method 1 (intermediate):

[0300] Method 2 (intermediate):

[0301] Method 3:

[0302] Among them, R b Selected from CH3 and CD3, R is selected from H and CH3.

[0303] Method 4:

[0304] Among them, R b Selected from CH3 and CD3.

[0305] Method 5:

[0306] Among them, R b Selected from CH3 and CD3.

[0307] Method 6:

[0308] Method 7:

[0309] Method 8:

[0310] The present invention also provides the following test methods:

[0311] Test Method 1: Anti-cell proliferation activity

[0312] Experimental methods:

[0313] HCT-116 (MTAP knockout) cells were seeded in white 96-well plates. The plates were incubated overnight in a CO2 incubator. A 3-fold diluted test compound was added to the culture medium, and after mixing, the medium containing the compound was added to the cell culture plates. The final compound concentration ranged from 3000 to 0.15 nM. Wells treated with DMSO served as a compound-free control. The cells were incubated in a CO2 incubator for 7–10 days.

[0314] Cell viability was then assessed using CellTiter-Glo reagent (purchased from Promega). 25 μL of chemiluminescent cell viability assay reagent was added to each well of the cell plate, and the cells were incubated at room temperature for 10 minutes. The OD value of each well was then read using an EnVision multilabel analyzer (PerkinElmer).

[0315] Calculate the rate of cell proliferation inhibition by the compound based on the OD value of each well. Cell viability (%) = (Test compound well reading - Background value) / (DMSO well reading - Background value) * 100%. IC50 50 The value can be obtained by curve fitting using four parameters (obtained in the "log(inhibitor) vs. response--Variable slope" mode of GraphPad Prism).

[0316] Test Method 2: Enzyme Inhibition Activity Test

[0317] Experimental principle:

[0318] The MTase-Glo detection method utilizes the property of methyltransferases to transfer methyl groups from S-adenosylmethionine (SAM) to histone substrates, generating SAH, to screen for inhibitors with PRMT5 inhibitory activity. The detection principle involves adding the protein PRMT5, the substrate histone H4 (1-21) peptide, and SAM to the reaction system to initiate the reaction. SAM (S-adenosylmethionine) acts as a methyl donor, transferring the methyl group to the arginine residue of the substrate protein under the catalysis of PRMT5. Simultaneously, SAM itself is converted to SAH (S-adenosylhomocysteine). After the reaction, MTase-Glo Reagent is added to convert SAH to ADP, and then MTase-Glo Detection is added to convert ADP to ATP. The luminescence signal is then read using a microplate reader. Adding an inhibitor inhibits the methyltransferase activity of PRMT5, causing a decrease in the signal value. This change in signal value allows for the assessment of the inhibitor's effectiveness.

[0319] The MTase-Glo assay, by adding MTA, helps screen for inhibitors that selectively inhibit the PRMT5-MTA complex. The detection principle involves adding the protein PRMT5-MTA, the substrate histone H4(1-21) peptide, and SAM to the reaction system to initiate the reaction. SAM (S-adenosylmethionine) acts as a methyl donor, transferring the methyl group to the arginine residue of the substrate protein under the catalysis of PRMT5, while SAM itself is converted to SAH (S-adenosylhomocysteine). Upon addition of MTA (methionyladenosine), due to its high binding affinity to the SAM binding pocket, it competitively binds to PRMT5, forming the PRMT5-MTA complex, significantly inhibiting PRMT5 activity (simulating the situation in MTAP-deficient tumor cells, thus evaluating the efficacy of PRMT5 inhibitors under this specific condition). After the reaction, MTase-Glo Reagent is added to convert SAH to ADP, and then MTase-Glo Detection is added to convert ADP to ATP, which is then read using a microplate reader to detect the Luminescence signal. Adding an inhibitor will suppress the methyltransferase activity of PRMT5, causing the signal value to decrease. At this time, the effect of the inhibitor can be judged by the change in the signal.

[0320] Experimental methods:

[0321] Experimental materials: PRMT5, manufacturer Active Motife, catalog number 31921; MTA, manufacturer Sigma-Aidrich, catalog number D5011-25MG; Bio-H4(1-21), manufacturer GenScript; SAM, manufacturer Promega, catalog number V7602(A120C); MTase-Glo TM Methyltransferase, manufacturer Promega, catalog number V7602 (V760B, V761B).

[0322] After adding an inhibitor containing 0.5% DMSO using an Echo, first add 2 μL of PRMT5 enzyme solution (final reaction concentration 2 nM) or 2 μL of PRMT5 / MTA enzyme solution (final reaction concentration 2 nM / 1 μM), centrifuge at 1000 rpm for 1 minute, and react at 25°C for 10 minutes; next, add 2 μL of H4(1-21) & SAM mixed reagent, with final concentrations of 1 μM and 5 μM respectively, centrifuge at 1000 rpm for 1 minute, and react at 25°C for 240 minutes; after the reaction, first add 1 μL of MTase-Glo Reagent reagent, centrifuge at 1000 rpm for 1 minute, and react at 25°C for 40 minutes; then add 5 μL of MTase-Glo Detection reagent, centrifuge at 1000 rpm for 1 minute, and react at 25°C for 40 minutes; finally, use a BMG instrument to read the Luminescence signal value. The negative control (0.5% DMSO well) was set to 0% inhibition rate, and the positive control (MRTX-1719 highest concentration well) was set to 100% inhibition rate. The IC50 was determined by non-linearly fitting the data to an S-shaped dose-response curve using GraphPad Prism 8 software. 50 value.

[0323] Technical effect

[0324] The compounds of this invention exhibit significant inhibitory activity against the PRMT5-MTA complex, with weaker inhibition of PRMT5 and excellent selectivity; they also show significant inhibitory activity against LU99 cell proliferation; and significant inhibitory activity against human colon cancer HCT-116 (MTAP knockout) cell proliferation, with weaker inhibition of HCT-116 (WT) and excellent selectivity. The compounds of this invention demonstrate good stability in human and mouse hepatocytes; they exhibit good solubility under various conditions, with appropriate proportions of free drug concentrations in plasmas of different species, indicating good drug-like properties; they demonstrate high oral exposure and oral bioavailability in mouse pharmacokinetic studies, exhibiting favorable pharmacokinetic properties; and they also demonstrate significant antitumor effects in in vivo pharmacodynamic studies, with good tolerability and high safety in mice.

[0325] Definitions and Explanations

[0326] Unless otherwise stated, the following terms and phrases as used herein are intended to have the following meanings. A particular term or phrase should not be considered uncertain or unclear unless specifically defined, but should be understood in its ordinary sense. When a trade name appears herein, it is intended to refer to the corresponding product or its active ingredient.

[0327] The term “pharmaceutically acceptable” as used herein refers to compounds, materials, compositions, and / or dosage forms that, within the bounds of reliable medical judgment, are suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, in proportion to a reasonable benefit / risk ratio.

[0328] The term "pharmaceutically acceptable salt" refers to a salt of the compounds of the present invention, prepared by reacting a compound having specific substituents, as discovered in the present invention, with a relatively non-toxic acid or base. When the compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting such compounds with a sufficient amount of base in a pure solution or a suitable inert solvent. When the compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting such compounds with a sufficient amount of acid in a pure solution or a suitable inert solvent. The pharmaceutically acceptable salts of the present invention can be synthesized from parent compounds containing acid radicals or bases by conventional chemical methods. Generally, such salts are prepared by reacting these compounds in their free acid or base form with a stoichiometric amount of a suitable base or acid in water or an organic solvent or a mixture of both.

[0329] The compounds of this invention can exist in specific geometric or stereoisomeric forms. This invention envisions all such compounds, including cis and trans isomers, trans-isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic mixtures thereof, as well as other mixtures, such as mixtures enriched with enantiomers or diastereomers, all of which are within the scope of this invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and mixtures thereof are included within the scope of this invention. The optical purity of a single-configuration compound can be expressed by optical rotation, chiral purity, and / or ee, etc. Chiral purity refers to the content determined by testing methods (such as GC, HPLC, SFC, NMR, etc.); ee refers to the percentage excess of isomers or enantiomers, which is the difference in the percentage content of the two isomers or enantiomers. For example, if SFC testing shows that the content of one isomer a is 90% and the content of another isomer b is 10%, then the chiral purity of isomer a is 90% and the ee value is 80%.

[0330] The compounds of this invention can exist in specific tautomers. Unless otherwise stated, the term "tautomer" or "tautomer form" refers to a functional group isomer resulting from the rapid movement of one or more atoms in a molecule between two positions. A tautomer is a special type of functional group isomer. A pair of tautomers can interconvert, but usually the more stable isomer is the dominant form. Different functional group isomers are in dynamic equilibrium and can rapidly interconvert. If tautomers are possible (e.g., in solution), chemical equilibrium of the tautomers can be achieved. For example, proton tautomers (also called prototropic tautomers) include interconversions via proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers include interconversions via the rearrangement of some bonding electrons. For example, a specific instance of keto-enol tautomerization is the tautomerization between two tautomers: pentane-2,4-dione and 4-hydroxypent-3-en-2-one.

[0331] Unless otherwise stated, the terms "enantiomer" or "optical isomer" refer to stereoisomers that are mirror images of each other.

[0332] Unless otherwise stated, the terms "cis-trans isomers" or "geometric isomers" arise because the single bonds of double bonds or cyclic carbon atoms cannot rotate freely.

[0333] Unless otherwise stated, the term "diastereomer" refers to a stereoisomer of a molecule having two or more chiral centers and being in a non-mirror relationship with each other.

[0334] Unless otherwise stated, "(+)" indicates right-handed rotation, "(-)" indicates left-handed rotation, and "(±)" indicates racemic rotation.

[0335] Unless otherwise specified, use wedge-shaped solid line keys. and wedge-shaped dashed key The absolute configuration of the center of a solid is represented by a straight solid line key. and straight dashed key The relative configuration of the center of a solid is indicated by a wavy line. Indicates wedge-shaped solid line key and / or wedge-shaped dashed key Or use wavy lines Indicates a straight solid line key and / or straight dashed key

[0336] Unless otherwise stated, carbon atoms marked with an asterisk (*) are chiral carbon atoms, existing in a single enantiomer (R) or (S) or enriched with one enantiomer. For example, express or Or it may contain an enantiomer.

[0337] Unless otherwise stated, the terms "rich in one isomer," "isomer enrichment," "rich in one enantiomer," or "enantiomer enrichment" mean that the content of one isomer or enantiomer is less than 100%, and the content of the isomer or enantiomer is greater than or equal to 60%, or greater than or equal to 70%, or greater than or equal to 80%, or greater than or equal to 90%, or greater than or equal to 95%, or greater than or equal to 96%, or greater than or equal to 97%, or greater than or equal to 98%, or greater than or equal to 99%, or greater than or equal to 99.5%, or greater than or equal to 99.6%, or greater than or equal to 99.7%, or greater than or equal to 99.8%, or greater than or equal to 99.9%.

[0338] Optically active (R)- and (S)- isomers, as well as D- and L- isomers, can be prepared by chiral synthesis, chiral reagents, or other conventional techniques. To obtain an enantiomer of a compound of the present invention, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated, and the auxiliary group is cleaved to provide the desired enantiomer in pure form. Alternatively, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), a salt of the diastereomeric isomer is formed with a suitable optically active acid or base, followed by diastereomeric resolution using conventional methods known in the art, and then the pure enantiomer is recovered. Furthermore, the separation of enantiomers and diastereomeric isomers is typically accomplished by using chromatography employing a chiral stationary phase, optionally combined with chemical derivatization (e.g., from amines to carbamates).

[0339] Unless otherwise stated, when a compound contains a double bond structure, such as a carbon-carbon double bond, a carbon-nitrogen double bond, or a nitrogen-nitrogen double bond, and each atom in the double bond is bonded to two different substituents (in a double bond containing a nitrogen atom, the lone pair of electrons on the nitrogen atom is considered as one of the substituents it is bonded to), it has (Z)-type and / or (E)-type isomers. For example, in this compound, the atoms in the double bond and their substituents are connected by... If indicated, it means that the compound is a (Z) type isomer, a (E) type isomer, or a mixture of the two isomers.

[0340] Some compounds of this invention can exist as trans-block isomers, which are conformational isomers that occur when rotation around a single bond in the molecule is prevented or significantly slowed due to steric interactions with other parts of the molecule. The compounds disclosed in this invention include all trans-block isomers, which can be pure, single trans-block isomers, or mixtures enriched with one of the trans-block isomers, or nonspecific mixtures of each. Separation of isomers is permitted if the rotational potential around the single bond is sufficiently high and the interconversion between conformations is sufficiently slow. For example, (or )and (or ) are a pair of hindered transisomers, wherein the phenyl group has a... This indicates that the orientation of this three-dimensional object is outward. This indicates that the orientation of this three-dimensional object is inward.

[0341] The compounds of this invention may contain atomic isotopes in non-natural proportions on one or more atoms constituting the compound. For example, the compounds may be labeled with radioactive isotopes, such as tritium. 3 H), Iodine-125 125 I) or C-14 14 C). For example, deuterium can be used to replace hydrogen to form deuterated drugs. The bond between deuterium and carbon is stronger than that between ordinary hydrogen and carbon. Compared with undeuterated drugs, deuterated drugs have advantages such as reduced toxicity, increased drug stability, enhanced efficacy, and prolonged drug biological half-life. All isotopic variations of the compounds of this invention, regardless of radioactivity, are included within the scope of this invention.

[0342] The term "substituted" refers to the substitution of one or more hydrogen atoms on a particular atom by a substituent. Substituents can include deuterium and hydrogen variants, provided that the valence state of the particular atom is normal and the resulting compound is stable. When the substituent is oxygen (i.e., =O), it means that two hydrogen atoms are substituted.

[0343] The terms “optional” or “optionally” refer to events or conditions that may occur but are not required to occur as described below, and the description includes both cases where said events or conditions occur and cases where said events or conditions do not occur.

[0344] The term "optionally substituted" means that it may or may not be substituted, unless otherwise specified, and the type and number of substituents may be arbitrary on the basis of chemical feasibility.

[0345] In some technical solutions of the present invention, "optionally replaced by one or more R" means that it may not be replaced, or it may be replaced. The number of substituents R is 1 to 10, for example, it may be replaced by 1, 2, 3, 4, 5, 6, 7 or 8 R, or by 1, 2, 3, 4 or 5 R, or by 1, 2 or 3 R. When it is replaced by multiple R, each R may be the same or different.

[0346] When any variable (e.g., R) appears more than once in the composition or structure of a compound, its definition is independent in each case. Thus, for example, if a group is substituted by 0-2 Rs, the group can optionally be substituted by at most two Rs, and the Rs in each case have independent options. Furthermore, combinations of substituents and / or their variants are only permitted if such combinations produce a stable compound.

[0347] When the number of a linking group is 0, such as -(CRR)0-, it indicates that the linking group is a single bond.

[0348] When one of the variables is selected as a single bond or a bond, it means that the two groups it connects are directly connected. For example, when L in ALZ represents a single bond, it means that the structure is actually AZ.

[0349] When a substituent is vacant, it means that the substituent does not exist. For example, if X is vacant in AX, it means that the structure is actually A.

[0350] When the listed substituents do not specify which atom they are attached to the substituted group, they can be bonded to any of their atoms. For example, a pyridinium group, as a substituent, can be attached to the substituted group via any carbon atom on the pyridine ring. When the listed linking groups do not specify their attachment direction, the attachment direction is arbitrary. For example, The linker group L is -MW-. In this case, -MW- can connect ring A and ring B in the same direction as the reading order from left to right to form a ring. Alternatively, rings A and B can be connected in the opposite direction to the right-to-left reading order to form a ring. The combination of linking groups, substituents, and / or their variants is permitted only if such a combination produces a stable compound.

[0351] Unless otherwise specified, when a group has one or more connectable sites, any one or more sites of that group can be connected to other groups by chemical bonds. When the chemical bond connection is non-directional and the connectable site contains H atoms, the number of H atoms at that site will decrease accordingly with the number of chemical bonds connected, resulting in a group with a corresponding valence. The chemical bonds connecting the site to other groups can be straight solid line bonds. Straight dashed key or wavy line Indicated. Wherein, the key is represented by a straight dashed line. or wavy line When indicating a linking site, it can be a single bond, double bond, or triple bond, etc. For example, the straight solid line bond in -OCH3 indicates that the oxygen atom in this group is connected to other groups; The straight dashed bond in the diagram indicates that the group is connected to other groups through both ends of the nitrogen atom in the group; The wavy lines in the text indicate that the phenyl group is connected to other groups through the carbon atoms at positions 1 and 2 of the phenyl group. This indicates that any connectable site on the piperidinyl group can be linked to other groups via a single chemical bond, including at least... Even if H atoms are drawn on -N- in these four connection methods, Still includes In this type of linkage, when a chemical bond is attached, the number of hydrogen atoms at that site is reduced by one, resulting in a monovalent piperidinyl group.

[0352] Unless otherwise specified, C n-n+m Or C n -C n+m This includes any specific case with n to n+m carbons, and also any range from n to n+m. For example, C 1-12 Including C1, C2, C3, C4, C5, C6, C7, C8, C9, C 10 C 11 and C 12 etc., including C 1-3 C 1- 6. C 1-9 C 3-6 C 3-9 C 3-12 C 6-9 C 6-12 and C 9-12 etc.; C 0-4Alkyl groups consist of 0-4 carbon atoms. When there are 0 carbon atoms, it means that the group does not exist, i.e., the two groups it is attached to are directly connected. Similarly, n to n+m membered rings indicate that the number of atoms on the ring is n to n+m. For example, 3-12 membered rings include 3-membered, 4-membered, 5-membered, 6-membered, 7-membered, 8-membered, 9-membered, 10-membered, 11-membered, and 12-membered rings, as well as 3-6-membered, 3-9-membered, 5-6-membered, 5-7-membered, 6-7-membered, 6-8-membered, and 6-10-membered rings.

[0353] Unless otherwise specified, the term “halogen” or “halogen” itself or as part of another substituent means a fluorine, chlorine, bromine or iodine atom.

[0354] Unless otherwise specified, the term "alkyl" on its own or in combination with other terms refers to a straight-chain or branched saturated hydrocarbon group consisting of 1 to 20 carbon atoms. It can be monovalent (e.g., methyl), divalent (e.g., methylene), or polyvalent (e.g., methine). The alkyl group includes C... 1-10 Alkyl, C 1-6 Alkyl, C 1-5 Alkyl, C 1-4 Alkyl, C 1-3 Alkyl groups, examples of which include, but are not limited to, methyl (Me), methylene (CH2), methine (CH), ethyl (Et), propyl (including n-propyl and isopropyl), n-butyl, tert-butyl, n-pentyl, etc. For example, in some technical solutions of the present invention, the alkyl group is C24. 1-6 Alkyl groups, including C 1-2 C 1-3 C 1-4 C 2-3 C 2-4 C 2-5 C1, C2, C3, C4, C5, C6 alkyl groups, etc.; in other technical solutions of the present invention, the alkyl group is C1, C2, C3, C4, C5, C6 alkyl groups, etc. 1-4 Alkyl groups, including C 1-2 C 1-3 C 2-3 C 2-4 C1, C2, C3, C4 alkyl groups, etc.; in other technical solutions of the present invention, the alkyl group is C1, C2, C3, C4 alkyl group, etc. 1-3 Alkyl groups, including C 1-2 C 2-3 C1, C2, C3 alkyl groups, etc.

[0355] Unless otherwise specified, the term "alkenyl" itself, or in combination with other terms, refers to a straight-chain or branched hydrocarbon group consisting of 2 to 20 carbon atoms and containing at least one carbon-carbon double bond. It can be monovalent, divalent, or polyvalent. The alkenyl group can refer to a hydrocarbon group containing one carbon-carbon double bond; it can also refer to a hydrocarbon group containing two or more carbon-carbon double bonds. Alkenyl groups containing two or more carbon-carbon double bonds include, for example, cumulant dienyl (where two double bonds in the compound structure are connected to the same carbon atom, e.g., CH2=C=CH-CH2-), isolated dienyl (where two double bonds in the compound structure are separated by two or more single bonds, e.g., CH2=CH-CH2-CH=CH-), and conjugated dienyl (where two double bonds in the compound structure are separated by one single bond, e.g., CH2=CH-CH=CH-); the alkenyl group includes C 2-10 alkenyl, C 2-6 alkenyl, C 2-5 alkenyl, C 2-4 alkenyl, C 2-3 Alkenyl groups, etc., examples of which include, but are not limited to, vinyl, propenyl, 1-butenyl, cis-butadienyl, etc. For example, in some technical solutions of the present invention, the alkenyl group is C. 2-6 alkenyl groups, which include C 2-3 C 2-4 C 2-5 C2, C3, C4, C5, C6 alkenyl groups, etc.; in other technical solutions of the present invention, the alkenyl group is C 2-4 alkenyl groups, which contain C 2-3 C2, C3, C4 alkenyl groups, etc.; in other technical solutions of the present invention, the alkenyl group is C 2-3 Alkenyl groups, including C2 and C3 alkenyl groups, etc.

[0356] Unless otherwise specified, the term "alkynyl" on its own or in combination with other terms refers to a straight-chain or branched hydrocarbon group consisting of 2 to 20 carbon atoms and containing at least one carbon-carbon triple bond. It can be monovalent, divalent, or polyvalent. The alkynyl group includes C... 2-10 alkynyl group, C 2-6 alkynyl group, C 2-5 alkynyl group, C 2-4 alkynyl group, C 2-3 Alkyne groups, etc., examples of which include, but are not limited to, ethynyl, propynyl, 1-butynyl, etc. For example, in some technical solutions of the present invention, the alkynyl group is C. 2-6 Alkyne groups, which include C 2-3 C 2-4 C 2-5 C2, C3, C4, C5, C6 alkynyl groups, etc.; in other technical solutions of the present invention, the alkynyl group is C 2-4 Alkyne group, which includes C2-3 C2, C3, C4 alkynyl groups, etc.; in some other technical solutions of the present invention, the alkynyl group is C 2-3 Alkyne groups, including C2 and C3 alkynyl groups, etc.

[0357] Unless otherwise specified, the term "alkoxy" on its own, or in combination with other terms, refers to alkyl groups comprising 1 to 20 carbon atoms that are attached to the remainder of a molecule by an oxygen atom. It can be monovalent, divalent, or polyvalent. The alkoxy group includes C... 1-10 Alkoxy, C 1-6 Alkoxy, C 1-5 Alkoxy, C 1-4 Alkoxy, C 1-3 Alkoxy groups, etc., examples of which include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), etc. For example, in some technical solutions of the present invention, the alkoxy group is C. 1-6 Alkoxy groups, which include C 1-2 C 1-3 C 1-4 C 2-3 C 2-4 C 2-5 C1, C2, C3, C4, C5, C6 alkoxy groups, etc.; in other technical solutions of the present invention, the alkoxy group is C 1-4 Alkoxy groups, which include C 1-2 C 1-3 C 2-3 C 2-4 C1, C2, C3, C4 alkoxy groups, etc.; in some other technical solutions of the present invention, the alkoxy group is C 1-3 Alkoxy groups, which include C 1-2 C 2-3 C1, C2, C3 alkoxy groups, etc.

[0358] Unless otherwise specified, the term "alkathioyl" on its own or in combination with other terms refers to alkyl groups comprising 1 to 20 carbon atoms that are attached to the remainder of a molecule by a sulfur atom. It can be monovalent, divalent, or polyvalent. The alkathioyl group includes C... 1-10 Alkylthio, C 1-6 Alkylthio, C 1-5 Alkylthio, C 1-4 Alkylthio, C 1-3 Alkylthio groups, etc., examples of which include, but are not limited to, methylthio, ethylthio, propylthio (including n-propylthio and isopropylthio), etc. For example, in some technical solutions of the present invention, the alkylthio group is C10. 1-6 Alkylthio groups, which include C 1-2 C 1-3 C 1-4 C2-3 C 2-4 C 2-5 C1, C2, C3, C4, C5, C6 alkylthio groups, etc.; in some other technical solutions of the present invention, the alkylthio group is C1, C2, C3, C4, C5, C6 alkylthio groups, etc. 1-4 Alkylthio groups, which include C 1-2 C 1-3 C 2-3 C 2-4 C1, C2, C3, C4 alkylthio groups, etc.; in some other technical solutions of the present invention, the alkylthio group is C 1-3 Alkylthio groups, which include C 1-2 C 2-3 C1, C2, C3 alkylthio groups, etc.

[0359] Unless otherwise specified, the term "alkylamino" on its own or in combination with other terms refers to alkyl groups comprising 1 to 20 carbon atoms that are attached to the remainder of a molecule by a nitrogen atom. They can be monovalent, divalent, or polyvalent, including monoalkylamino and dialkylamino groups. The alkylamino group comprises C... 1-10 Alkylamino, C 1-6 Alkylamino, C 1-5 Alkylamino, C 1-4 Alkylamino, C 1-3 Alkylamino groups, etc., examples of which include, but are not limited to, -NHCH3, -N(CH3)2, -NHCH2CH3, -N(CH3)CH2CH3, -NHCH2CH2CH3, -NHCH(CH3)2, etc. For example, in some technical solutions of the present invention, the alkylamino group is C 1-6 Alkylamino, which includes C 1-2 C 1-3 C 1-4 C 2-3 C 2-4 C 2-5 C1, C2, C3, C4, C5, C6 alkylamino groups, etc.; in some other technical solutions of the present invention, the alkylamino group is C1, C2, C3, C4, C5, C6, etc. 1-4 Alkylamino, which includes C 1-2 C 1-3 C 2-3 C 2-4 C1, C2, C3, C4 alkylamino groups, etc.; in some other technical solutions of the present invention, the alkylamino group is C 1-3 Alkylamino, which includes C 1-2 C 2-3 C1, C2, C3 alkylamino, etc.

[0360] Unless otherwise specified, the term "cycloalkyl" on its own or in combination with other terms refers to a saturated or partially unsaturated cyclic hydrocarbon group consisting of 3 to 20 carbon atoms. It can be monovalent, divalent, or polyvalent. The cycloalkyl group may optionally contain one or more carbon-carbon double or triple bonds, but all rings must not be aromatic. The cycloalkyl group can be a saturated cycloalkyl group (meaning all rings are saturated), or a cycloalkenyl group (meaning a monocyclic or polycyclic system containing at least one double bond), etc. The cycloalkyl group can be monocyclic or polycyclic (e.g., spirocyclic, fused, bridged rings), etc. The cycloalkyl group includes C... 3-10 cycloalkyl, C 3-8 cycloalkyl, C 3-7 cycloalkyl, C 3-6 cycloalkyl, C 3-5 cycloalkyl, C 4-6 Cycloalkyl groups, etc., examples of which include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, etc. For example, in some technical solutions of the present invention, the cycloalkyl group is C10. 3-10 cycloalkyl groups, including C 3-5 C 3-6 C 3-8 C 4-5 C 4-6 C 5-6 C3, C4, C5, C6 cycloalkyl groups, etc. The cycloalkyl group is C6. 3-8 cycloalkyl groups, including C 3-5 C 3-6 C 4-5 C 4-6 C 5- 6. C3, C4, C5, C6 cycloalkyl groups, etc. In some technical solutions of the present invention, the cycloalkyl group is C6. 3-6 cycloalkyl groups, including C 3-5 C 4-5 C 4-6 C3, C4, C5, C6 cycloalkyl groups, etc.

[0361] Unless otherwise specified, the term "heterocyclic alkyl" on its own or in combination with other terms refers to a saturated or partially unsaturated cyclic group consisting of 3 to 20 ring atoms, wherein 1, 2, 3, 4, 5, 6, 7, or 8 of the ring atoms are heteroatoms independently selected from O, S, Se, and N, and the remainder are carbon atoms, wherein the carbon atoms are optionally oxidized (i.e., C(O)), the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S(O)2, p is 1 or 2), and the heteroatoms may occupy the connection positions between the heterocyclic alkyl group and the rest of the molecule. It can be monovalent, divalent, or polyvalent. The heterocyclic alkyl group may optionally contain one or more double or triple bonds, but all rings are not aromatic rings. The heterocyclic alkyl group may be a saturated heterocyclic alkyl group (meaning all rings are saturated), or a heterocyclic alkenyl group (meaning a monocyclic or polycyclic system containing at least one double bond), etc. The heterocyclic alkyl groups include 3-10-membered heterocyclic alkyl groups, 3-8-membered heterocyclic alkyl groups, 3-7-membered heterocyclic alkyl groups, 3-6-membered heterocyclic alkyl groups, 3-5-membered heterocyclic alkyl groups, 4-6-membered heterocyclic alkyl groups, etc. Examples of heterocyclic alkyl groups include, but are not limited to, azacyclic butyl, oxacyclic butyl, thiocyclic butyl, pyrrolidinyl, pyrazolyl, imidazolyl, tetrahydrothiophene (including tetrahydrothiophene-2-yl and tetrahydrothiophene-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxyl, dithiaalkyl, isoxazolyl, isothiazolyl, 1,2-oxazinyl, 1,2-thiaazinyl, hexahydropyridazinyl, etc. For example, in some technical solutions of the present invention, the cycloalkyl group is a 3-10 membered heterocyclic alkyl group, including 3-5, 3-6, 3-8, 4-5, 4-6, 5-6, 3, 4, 5, 6 membered heterocyclic alkyl groups, etc.; in some technical solutions of the present invention, the cycloalkyl group is a 3-8 membered heterocyclic alkyl group, including 3-5, 3-6, 4-5, 4-6, 5-6, 3, 4, 5, 6 membered heterocyclic alkyl groups, etc.; in some technical solutions of the present invention, the heterocyclic alkyl group is a 3-6 membered heterocyclic alkyl group, including 3-5, 4-5, 4-6, 3, 4, 5, 6 membered heterocyclic alkyl groups, etc.

[0362] Unless otherwise specified, the terms "heteroaryl ring" and "heteroaryl" are used interchangeably. The term "heteroaryl," either alone or in combination with other terms, refers to a monocyclic group or polycyclic ring system consisting of 5 to 20 ring atoms with a conjugated π-electron system, wherein 1, 2, 3, 4, 5, 6, 7, or 8 ring atoms are heteroatoms independently selected from O, S, Se, and N, and the remainder are carbon atoms. The nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms may optionally be oxidized (i.e., NO and S(O)₂, p is 1 or 2). The heteroaryl group can be attached to the rest of the molecule via a heteroatom or a carbon atom, and can be monovalent, divalent, or polyvalent. The heteroaryl groups include 5-6-membered, 5-8-membered, 5-9-membered, 5-10-membered, 6-8-membered, 6-9-membered, 6-10-membered, 5-membered, 6-membered, 7-membered, 8-membered, 9-membered, and 10-membered heteroaryl groups. Examples of the heteroaryl groups include, but are not limited to, pyrrole (including N-pyrrole, 2-pyrrole, and 3-pyrrole), pyrazolyl (including 2-pyrazolyl and 3-pyrazolyl), imidazole (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl, and 5-imidazolyl), oxazolyl (including 2-oxazolyl, 4-oxazolyl, and 5-oxazolyl), and triazolyl (1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl, and 4H-1,2,4-triazolyl). (e.g., tetrazolyl, isoxazolyl (3-isooxazolyl, 4-isooxazolyl and 5-isooxazolyl, etc.), thiazolyl (including 2-thiazolyl, 4-thiazolyl and 5-thiazolyl, etc.), furanyl (including 2-furanyl and 3-furanyl, etc.), thienyl (including 2-thienyl and 3-thienyl, etc.), pyridinyl (including 2-pyridinyl, 3-pyridinyl and 4-pyridinyl, etc.), pyrazinyl, pyrazinyl, pyrimidinyl (including 2-pyrimidinyl and 4-pyrimidinyl, etc.), indoleyl, indazoleyl, pyrimidinimidazoleyl, etc. For example, in some technical solutions of the present invention, the heteroaryl group is a 5-10 member heteroaryl group, including 5-6 member, 5-8 member, 5-9 member, 5 member, 6 member, 7 member, 8 member, 9 member, and 10 member heteroaryl groups; in other technical solutions of the present invention, the heteroaryl group is a 5-6 member heteroaryl group, including 5 member and 6 member heteroaryl groups; in some technical solutions of the present invention, the heteroaryl group is a 5-10 member Se-containing heteroaryl group, wherein one ring atom is a heteroatom independently selected from O, S, Se, and N, and the remainder are carbon atoms.

[0363] Unless otherwise specified, the term "aromatic ring" refers to a cyclic group with a conjugated π-electron system, whose atoms are covered by a delocalized π-electron cloud. In the structural formula, when conforming to the rules of atomic valence and covalent bonding, it can be written in the form of alternating single and double bonds, or it can be written using... This represents the delocalized π-electron cloud. For example, the structural formula... The structures represented are all the same; structural formula The structures represented are all the same; and The structures represented are identical. The aromatic ring can be a monocyclic or polycyclic system, wherein each ring in a polycyclic system is aromatic. Unless otherwise specified, the ring optionally contains 0, 1, or more heteroatoms or heterogroups independently selected from O, S, NH, and N.

[0364] Unless otherwise specified, the term "spiroring" refers to a structure in which two rings share a single atom, which can be a bicyclic or polycyclic system, for example... The term "fused ring" (also known as a fused ring) refers to a structure formed by two rings sharing two adjacent atoms; it can be a bicyclic or polycyclic system, for example... The term "bridging ring" refers to a structure formed by two rings sharing two non-adjacent atoms; it can be a bicyclic or polycyclic system, for example... In some technical solutions of the present invention, the "ring system containing bridge rings" refers to a ring system containing bridge rings, which may contain only bridge rings, or may contain parallel rings and / or spiral rings in addition to bridge rings.

[0365] The compounds of the present invention can be prepared by a variety of synthetic methods known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthetic methods, and equivalent substitutions known to those skilled in the art. Preferred embodiments include, but are not limited to, the embodiments of the present invention.

[0366] The structures of the compounds of this invention can be confirmed by conventional methods well known to those skilled in the art. If this invention relates to the absolute configuration of a compound, that absolute configuration can be confirmed by conventional techniques in the art. For example, single-crystal X-ray diffraction (SXRD) is used, where the cultured single crystal is used to collect diffraction intensity data using a Bruker D8 venture diffractometer with CuKα radiation as the light source. The scanning method is as follows: After scanning and collecting relevant data, the crystal structure can be further analyzed using the direct method (Shelxs97) to confirm the absolute configuration.

[0367] Abbreviations used in this invention: Pd(dtbpf)Cl2 represents 1,1'-bis(di-tert-butylphosphino)ferrocene palladium dichloride; CataCXium A Pd G3 (or A Pd G3) represents [(di(1-adamantyl)butylphosphino)-2-(2′-amino-1,1′-biphenyl)]palladium(II), CAS: 1651823-59-4; Ad2nBuP Pd G3 represents (tri-tert-butylphosphino)(2'-amino-1,1'-biphenyl-2-yl)palladium(II), CAS: 14430886-17-8; PE represents petroleum ether; EA (or EtOAc) represents ethyl acetate; DCM represents dichloromethane; DMA represents dimethylacetamide; PEG400 represents polyethylene glycol 400; Captisol represents sodium sulfobutyl-β-cyclodextrin.

[0368] The solvents used in this invention are commercially available. Compounds are named according to conventional naming principles in the art or using… Software naming conventions are used; commercially available compounds use supplier catalog names. Detailed Implementation

[0369] The present invention will be described in detail below with reference to embodiments, but this does not imply any adverse limitation on the invention. The present invention has been described in detail, and specific embodiments thereof have been disclosed. It will be apparent to those skilled in the art that various changes and modifications can be made to the specific embodiments of the present invention without departing from the spirit and scope thereof.

[0370] Intermediates M1 and M2

[0371] Step 1: Under nitrogen protection, palladium acetate (1.03 g, 4.61 mmol), N-iodosuccinimide (20.74 g, 92.19 mmol), and p-toluenesulfonic acid (3.97 g, 23.05 mmol) were added to a solution of compound M1-1 (8 g, 46.10 mmol) in 100 mL of 1,2-dichloroethane. The reaction system was reacted at 75 °C for 16 hours. The reaction solution was cooled to room temperature, diluted with 100 mL of dichloromethane, washed with 100 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (PE:EA = 95:5) to obtain compound M1-2. 1 H NMR (400MHz, CDCl3) δ = 7.37 (dd, J = 5.7, 7.6Hz, 1H).

[0372] Step 2: Under nitrogen protection, compound M1-3 (3.82 g, 18.37 mmol), sodium carbonate (2.34 g, 22.04 mmol), and Pd(dtbpf)Cl2 (478.83 mg, 734.70 μmol) were added to a mixed solution of compound M1-2 (2.2 g, 7.35 mmol) in 1,4-dioxane (30 mL) and water (6 mL). The reaction system was reacted at 75 °C for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE:EA = 78:22) to give compound M1-4. LCMS (m / z): 254.1 [M+H] + .

[0373] Step 3: At room temperature, N-iodosuccinimide (1.24 g, 5.52 mmol) was added to a 7 mL acetic acid solution of compound M1-4 (700 mg, 2.76 mmol). The reaction solution was heated to 80 °C and reacted for 3 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE:EA = 85:15) to obtain compound M1-5. LCMS (m / z): 379.9 [M+H] + ; 1 H NMR (400MHz, CDCl3) δ = 7.69 (s, 1H), 7.53 (dd, J = 5.6, 7.6Hz, 1H), 3.86 (s, 3H).

[0374] Step 4: Compound M1-6 (387.77 mg, 2.63 mmol) and potassium carbonate (1.09 g, 7.90 mmol) were added to a DMF (10.0 mL) solution of compound M1-5 (1.0 g, 2.63 mmol). The reaction mixture was incubated at 60 °C for 1 hour. Water (5 mL) was added to the reaction mixture, and the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA = 3:1) to obtain compound M1. LCMS (m / z): 501.7 [M+H] + ; 1 H NMR (400MHz, CDCl3) δ = 7.79 (d, J = 6.4Hz, 1H), 7.68 (s, 1H), 3.88 (s, 3H), 3.84 (s, 3H), 1.54 (s, 9H).

[0375] Step 5: Under a nitrogen atmosphere, add 1.97 mL of 2 M hydrochloric acid methanol solution to 1 mL of methanol containing 200 mg (394.71 μmol). Stir the reaction solution at 25 °C for 1 hour. Concentrate the reaction solution under reduced pressure to obtain compound M2. LCMS (m / z): 406.9 [M+1] + .

[0376] intermediate M3

[0377] Step 1: Under a nitrogen atmosphere at 25°C, Boc₂O (24.1 g, 110 mmol) was added in portions to a solution of compound M3-1 (9 g, 92.3 mmol, HCl salt) and sodium carbonate (39.1 g, 369 mmol) in dichloroethane (90 mL) and water (90 mL). The reaction mixture was stirred at 25°C for 3 hours. The mixture was diluted with 800 mL of water and extracted with ethyl acetate (500 mL × 3). The combined organic phases were washed with 500 mL of saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product, which was then purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:0-1:1) to obtain compound M3-2. 1 H NMR (400MHz, DMSO-d6) δ = 9.88 (br s, 1H), 3.72 (q, J = 7.2Hz, 2H), 1.40 (s, 9H), 1.09 (t, J = 7.2Hz, 3H).

[0378] Step 2: Under a nitrogen atmosphere at 25°C, potassium carbonate (655 mg, 4.74 mmol) was added to a solution of compound M3-2 (255 mg, 1.58 mmol) and compound M1-5 (600 mg, 1.58 mmol) in N,N-dimethylformamide (6 mL). The reaction mixture was stirred at 60°C for 2 hours. 50 mL of water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with 50 mL of saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product, which was then preparatively separated by reversed-phase column chromatography (column: Phenomenex luna C18 150 × 25 mm × 10 μm; mobile phase: water (0.1% formic acid)-acetonitrile; gradient (acetonitrile %): 50%-70%) to obtain compound M3-3. LCMS (m / z): 521.1 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ = 8.27-8.17 (m, 1H), 7.80 (s, 1H), 4.02 (dd, J = 3.6, 7.2Hz, 2H), 3.80 (s, 3H), 1.44 (s, 9H), 1.21-1.16 (m, 3H).

[0379] Step 3: Under a nitrogen atmosphere at 0°C, dioxane hydrochloride (2M, 4mL) was slowly added to compound M3-3 (500mg, 960.20μmol). The reaction solution was reacted at 25°C for 1 hour. The reaction solution was concentrated under reduced pressure to obtain crude compound M3-4. LCMS (m / z): 421.0 [M+H] + .

[0380] Step 4: Under a nitrogen atmosphere at 0°C, sodium hydroxide (76.1 mg, 1.90 mmol, 60% purity) was slowly added in portions to a solution of compound M3-4 (400 mg, 951 μmol) in N,N-dimethylformamide (5 mL). The reaction mixture was stirred at 0°C for 5 minutes, followed by the addition of iodoethane (297 mg, 1.90 mmol), and stirring was continued at 0°C for 25 minutes. 50 mL of ammonium chloride aqueous solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with 50 mL of saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product, which was then preparatively separated by reversed-phase column chromatography (column: Phenomenex luna C18 150 × 25 mm × 10 μm; mobile phase: [water (0.1% formic acid) - acetonitrile]; gradient (acetonitrile %): 50%-60%) to obtain compound M3. LCMS(m / z): 449.1 [M+H] + .

[0381] intermediate M4

[0382] Step 1: Under a nitrogen atmosphere at 25°C, iodomethane (3.21 mL, 51.54 mmol) was added to a mixed solution of compound M4-1 (10 g, 51.54 mmol) and cesium carbonate (16.7 g, 51.5 mmol) in acetonitrile (100 mL), and the mixture was stirred at 25°C for 4 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product, which was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain compound M4-2. 1 H NMR (400MHz, CDCl3) δ = 7.51 (d, J = 1.6 Hz, 1H), 6.74 (d, J = 1.6 Hz, 1H), 1.37 (s, 12H).

[0383] Step 2: Under a nitrogen atmosphere at 25°C, compound M1-2 (5.46 g, 18.24 mmol) was added to a mixed solution of compound M4-2 (3.5 g, 16.58 mmol), 1,1-bis(tert-butylphosphine)ferrocene palladium chloride (1.08 g, 1.66 mmol), and sodium carbonate (5.27 g, 49.74 mmol) in dioxane (30 mL) and water (3 mL). The reaction was carried out at 80°C for 2 hours. Water (10 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 mL × 2). The combined organic phases were concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain compound M4-3. LCMS (m / z): 257.1 [M+1] + ; 1H NMR (400MHz, CDCl3) δ = 7.66 (d, J = 2.0 Hz, 1H), 7.50-7.40 (m, 1H), 6.56 (d, J = 2.0 Hz, 1H).

[0384] Step 3: Under a nitrogen atmosphere at 25°C, N-iodosuccinimide (1.58 g, 7.01 mmol) was added in portions to a 10 mL acetic acid solution of compound M4-3 (900 mg, 3.51 mmol). After the addition was complete, the temperature was raised to 80°C and stirred for 2 hours. The reaction solution was cooled to room temperature, and water (20 mL) was added. The mixture was extracted with ethyl acetate (50 mL × 2). The combined organic phases were washed with an aqueous sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1) to give compound M4-4. LCMS (m / z): 383.0 [M+1] + ; 1 ¹H NMR (400MHz, CDCl₃) δ=7.70(s,1H), 7.55-7.50(m,1H); 2D carbon NMR further confirmed the structure of compound M4-4.

[0385] Step 4: Under a nitrogen atmosphere at 25°C, compound M1-6 (384.71 mg, 2.61 mmol) was slowly added to a solution of compound M4-4 (1 g, 2.61 mmol) and potassium carbonate (1.08 g, 7.84 mmol) in N,N-dimethylformamide (10 mL). The mixture was stirred at 60°C for 2 hours. Water (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL × 2). The combined organic phases were washed with an aqueous sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 4:1) to give compound M4-5. 1 H NMR (400MHz, CDCl3) δ = 7.80 (d, J = 6.4Hz, 1H), 7.70 (s, 1H), 3.89 (s, 3H), 1.57 (s, 9H).

[0386] Step 5: Under a nitrogen atmosphere at 25°C, compound M4-5 (1.1 g, 2.16 mmol) was added to an HCl / methanol solution (4 M, 10 mL), and the mixture was stirred at 25°C for 2 hours. After the reaction was complete, the solution was concentrated under reduced pressure to obtain crude hydrochloride of compound M4-6. LCMS (m / z): 410.0 [M+1] + .

[0387] Step 6: Under a nitrogen atmosphere at 0°C, sodium hydroxide (156.24 mg, 3.91 mmol, 60% purity) was added to a tetrahydrofuran (10 mL) solution of compound M4-6 (0.8 g, crude hydrochloride). After stirring at 0°C for 0.5 hours, iodoethane (312.43 μL, 3.91 mmol) was added, and stirring continued at 25°C for 1 hour. Deuterium water (10 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (25 mL × 2). The combined organic phases were washed with saturated sodium chloride aqueous solution (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain compound M4. LCMS (m / z): 438.1 [M+1] + .

[0388] intermediate M5

[0389] Under a nitrogen atmosphere at 0°C, sodium hydride (156.25 mg, 3.91 mmol, 60% purity) was added to a solution of compound M4-5 (400 mg, 976.56 μmol) in N,N-dimethylformamide (3 mL). After stirring at 0°C for 30 minutes, 2,2-difluoroethyl trifluoromethanesulfonate (627.28 mg, 2.93 mmol) was added to the reaction mixture, and stirring was continued at 0°C for 1 hour. A saturated ammonium chloride solution (5 mL) and water (10 mL) were added dropwise to the reaction mixture, and the mixture was extracted with ethyl acetate (10 mL × 3). The combined organic phases were washed with a saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1–3 / 1) to give compound M5. LCMS (m / z): 474.0 [M+H] + .

[0390] intermediate M6

[0391] Compound M6 was prepared according to the synthetic method of compound 1'-2 in EP2208728A1. LCMS (m / z): 432.0 [M+H] + .

[0392] Examples A1 and A2

[0393] Step 1: Under a nitrogen atmosphere, cataCXium A Pd G3 (28.75 mg, 39.47 μmol), cesium carbonate (385.82 mg, 1.18 mmol), and compound A1-1 (158.38 mg, 394.71 μmol) were added sequentially to a mixed solution of compound M1 (200 mg, 394.71 μmol) in toluene (2 mL) and water (0.2 mL). The reaction solution was heated to 80 °C and stirred for 1 hour. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. Compound A1-2 was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:0-1:1). LCMS (m / z): 654.1 [M+1] + .

[0394] Step 2: Under a nitrogen atmosphere, add HCl / methanol solution (1M, 1.22mL) to a MeOH (1mL) solution of compound A1-2 (80mg, 122.31μmol), and stir the reaction solution at 25°C for 1 hour. Filter the reaction solution.

[0395] The filtrate was purified by reversed-phase column chromatography (column: Phenomenex luna C18 150*25mm*10μm; mobile phase: water (0.05% HCl)-acetonitrile; gradient (acetonitrile%): 5%-35%) to give the hydrochloride salt of compound A1. LCMS (m / z): 554.2 [M+1] + ,1H NMR (400MHz, DMSO-d6)δ=12.88(s,1H),8.39(s,1H),8.28(s,1H),8.32-8.20(m,1H),8.14(d,J=8.3Hz,1H),7.88(s,1H),7.47(br d,J=8.1Hz,1H),4.50-4.28(m,2H),3.81(s,3H),3.75(s,3H),1.33(s,9H); 19 F NMR (376MHz, DMSO-d6) δ = -111.833.

[0396] The filter cake was collected and dried under vacuum to obtain the hydrochloride salt of compound A2. LCMS (m / z): 454.1 [M+1] + ; 1H NMR (400MHz, DMSO-d6) δ = 12.89 (s, 1H), 10.24 (br s, 1H), 8.59 (br s,3H),8.40(s,1H),8.16(d,J=8.4Hz,1H),7.86(d,J=1.2Hz,1H),7.58-7.42(m,2H),4.52-4.23(m,2H),3.78(s,3H),3.68(s,3H); 19 F NMR (376MHz, DMSO-d6) δ = -124.301.

[0397] Example A3

[0398] Step 1: Under a nitrogen atmosphere, sodium hydride (88.53 mg, 2.21 mmol, 60% purity) was added to a solution of compound M2 (150 mg, 368.93 μmol) in N,N-dimethylformamide (1 mL). The mixture was stirred at 0 °C for 30 minutes, followed by the addition of isopropane iodoformide (188.14 mg, 1.11 mmol). Stirring continued at 0 °C for 1 hour. At 0 °C, saturated ammonium chloride solution (5 mL) was added dropwise to the reaction mixture, followed by water (10 mL). The mixture was extracted with ethyl acetate (10 mL × 3). The combined organic phases were washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1-3 / 1) to give compound A3-1. LCMS (m / z): 449.1 [M+H] + ; 1 H NMR (400MHz, CDCl3) δ = 7.70 (d, J = 6.8Hz, 1H), 7.67 (s, 1H), 3.86 (s, 3H), 3.81-3.68 (m, 1H), 3.62 (s, 3H), 1.33-1.27 (m, 3H), 1.19-1.13 (m, 3H).

[0399] Step 2: Under a nitrogen atmosphere, CataCXium A Pd G3 (24.35 mg, 33.43 μmol), cesium carbonate (326.79 mg, 1.00 mmol), and compound A1-1 (134.15 mg, 334.33 μmol) were added to a mixed solution of compound A3-1 (150 mg, 334.33 μmol) in toluene (1.5 mL) and water (0.2 mL). The reaction solution was heated to 80 °C and stirred for 1 hour. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:0-1:1) to obtain compound A3-2. LCMS (m / z): 596.3 [M+1]+ .

[0400] Step 3: Under a nitrogen atmosphere, a 2M, 150.99 μmol / mL methanol solution of compound A3-2 (180 mg, 301.99 μmol) was added. The reaction mixture was stirred at 25 °C for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain a crude product, which was then purified by reversed-phase column chromatography (column: Phenomenex luna C18 150*25 mm*10 μm; mobile phase: [water (0.05% HCl)-acetonitrile]; gradient (acetonitrile %): 18%-48% B over 13.0 min) to obtain the hydrochloride salt of compound A3. LCMS (m / z): 496.3 [M+1] + ; 1 H NMR (400MHz, DMSO-d6) δ = 12.91 (s, 1H), 8.48 (br d,J=1.6Hz,3H),8.40(s,1H),8.12(d,J=8.4Hz,1H),7.95(s,1H),7.90(d,J=6.4Hz,1H),7.39(dd,J=1.2, 8.4Hz,1H),4.53-4.35(m,2H),3.83(s,3H),3.58-3.54(m,1H),3.53(s,3H),1.09(dd,J=6.8,8.0Hz,6H); F NMR (376MHz, DMSO-d6) δ = -117.721.

[0401] Step 4: Compound A3-2 was separated by SFC (column: DAICEL CHIRALCEL OX (250mm*30mm, 10μm); mobile phase: phase A was supercritical carbon dioxide, phase B was MeOH (0.1% ammonia); gradient (B%): 40%) to obtain compounds A3-2a and A3-2b. LCMS (m / z): 596.3 [M+1] + SFC analysis (column: Lux 3um Cellulose-4 50*4.6mm ID, 3μm; mobile phase: phase A is supercritical carbon dioxide, phase B is MeOH (0.05% diethylamine); gradient (B%): 30%-60%) showed that the retention time of compound A3-2a was 1.174 min, with a chiral purity of 100%; and the retention time of compound A3-2b was 1.541 min, with a chiral purity of 100%.

[0402] Step 5: Using compound A3-2a as the starting material, crude compound A3a was prepared according to Step 3. The crude product was then purified by reversed-phase column chromatography (column: Phenomenex luna C18 150*25mm*10μm; mobile phase: [water (0.05% HCl)-acetonitrile]; gradient (acetonitrile%): 15%-45%) to obtain the hydrochloride salt of compound A3a. LCMS (m / z): 496.1 [M+1] + ; 1 H NMR (400MHz, DMSO-d6) δ = 12.89 (s, 1H), 8.50 (br s,3H),8.39(s,1H),8.11(d,J=8.4Hz,1H),7.95(d,J=1.1Hz,1H),7.89(d,J=6.4Hz,1H),7.38(dd,J=1.2, 8.4Hz,1H),4.52-4.33(m,2H),3.82(s,3H),3.59-3.53(m,1H),3.52(s,3H),1.08(dd,J=6.8,7.9Hz,6H); F NMR (376MHz, DMSO-d6) δ = -117.715. SFC detection (column: Lux 3um Cellulose-4 50*4.6mm ID, 3μm; mobile phase: phase A is supercritical carbon dioxide, phase B is MeOH (0.05% diethylamine); gradient (B%): 30%-60%), the retention time of compound A3a was 1.397 min, and the chiral purity was 100%.

[0403] Crude compound A3b was prepared from compound A3-2b and purified by reversed-phase column chromatography (column: Phenomenex luna C18 150*25mm*10μm; mobile phase: water (0.05% HCl)-acetonitrile; gradient (acetonitrile%): 15%-45%) to obtain the hydrochloride salt of compound A3b. LCMS (m / z): 496.1 [M+1] + ; 1H NMR (400MHz, DMSO-d6) δ = 12.90 (s, 1H), 8.37 (br s,3H),8.35(s,1H),8.11(d,J=8.4Hz,1H),7.95(d,J=1.1Hz,1H),7.89(d,J=6.4Hz,1H),7.39(dd,J =1.2,8.4Hz,1H),4.52-4.33(m,2H),3.82(s,3H),3.59-3.52(m,4H),1.08(dd,J=6.8,7.9Hz,6H); F NMR (376MHz, DMSO-d6) δ = -117.727. SFC detection (column: Lux 3um Cellulose-4 50*4.6mm ID, 3μm; mobile phase: phase A is supercritical carbon dioxide, phase B is MeOH (0.05% diethylamine); gradient (B%): 30%-60%), the retention time of compound A3b was 1.721 min, and the chiral purity was 99.36%.

[0404] Example A4

[0405] Step 1: At 0°C under a nitrogen atmosphere, sodium hydride (295.14 mg, 7.38 mmol, 60% purity) was added to a solution of compound M2 (600 mg, 1.48 mmol) in N,N-dimethylformamide (6 mL). The mixture was stirred at 0°C for 30 minutes, then iodocyclopropane (743.66 mg, 4.43 mmol) was added, and the mixture was stirred at 50°C for 16 hours. A saturated ammonium chloride solution (5 mL) was added dropwise to the reaction mixture at 0°C, followed by water (20 mL). The mixture was extracted with ethyl acetate (10 × 3 mL). The combined organic phases were washed with a saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1-3 / 1) to give compound A4-1. LCMS (m / z): 447.0 [M+H] + .

[0406] Step 2: Under a nitrogen atmosphere, CataCXium A Pd G3 (9.13 mg, 12.54 μmol), cesium carbonate (122.55 mg, 376.14 μmol), and compound A1-1 (50.31 mg, 125.38 μmol) were added sequentially to a mixed solution of compound A4-1 (56 mg, 125.38 μmol) in toluene (1 mL) and water (0.1 mL). The reaction solution was heated to 80 °C and stirred for 2 hours. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. This crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:0-0:1) to obtain compound A4-2. LCMS (m / z): 594.2 [M+1] + .

[0407] Step 3: Under a nitrogen atmosphere, HCl / MeOH (2M, 0.75mL) was added to a MeOH (1mL) solution of compound A4-2 (9mg, 15.15μmol), and the reaction solution was stirred at 25℃ for 1 hour. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was then purified by reversed-phase column chromatography (column: Phenomenex luna C18 150*25mm*10μm; mobile phase: water (0.05% HCl)-acetonitrile; gradient (acetonitrile%): 5%-35%) to obtain the hydrochloride salt of compound A4. LCMS (m / z): 494.2 [M+1] + ; 1 ¹H NMR (400MHz, DMSO-d⁶) δ = 12.87 (s, 1H), 9.64 (s, 1H), 8.51 (br s, 3H), 8.37 (s, 1H), 8.15 (d, J = 8.4Hz, 1H), 7.86 (s, 1H), 7.48 (br d, J = 8.4Hz, 1H), 4.36 (br d, J = 5.6Hz, 2H), 3.74 (s, 3H), 3.69 (s, 3H), 1.77 (br s, 1H), 1.22 (br d, J = 7.2Hz, 2H), 0.70 (br d, J = 5.6Hz, 2H); F NMR (376MHz, DMSO-d⁶) δ = -120.218. Two-dimensional NMR confirmed the structure of compound A4.

[0408] Example A5

[0409] Step 1: Under a nitrogen atmosphere at 0°C, sodium hydride (88.54 mg, 2.21 mmol, 60% purity) was added to a solution of compound M2 (150 mg, 368.93 μmol) in N,N-dimethylformamide (2 mL), and the mixture was stirred for 0.5 hours. Then, iodoethane (88.52 μL, 1.11 mmol) was added, and the mixture was stirred for another 1 hour at 0°C. A saturated ammonium chloride solution (5 mL) and water (10 mL) were added dropwise to the reaction mixture. The mixture was extracted with ethyl acetate (10 × 3 mL), and the combined organic phases were washed with a saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1-3 / 1) to give compound A5-1. LCMS (m / z): 434.9 [M+H] + .

[0410] Step 2: Under a nitrogen atmosphere, Ad2nBuP Pd G3 (18.43 mg, 25.31 μmol), cesium carbonate (247.38 mg, 759.26 μmol), and tert-butyl carbamate (101.55 mg, 253.09 μmol) were added sequentially to a mixed solution of compound A5-1 (110 mg, 253.09 μmol) in toluene (2 mL) and water (0.2 mL). The reaction solution was heated to 80 °C and stirred for 2 hours. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:0-1:1) to obtain compound A5-2. LCMS (m / z): 582.1 [M+1] + .

[0411] Step 3: Under a nitrogen atmosphere, HCl / MeOH (2M, 60.13μL) was added to a MeOH (1mL) solution of compound A5-2 (70mg, 120.27μmol), and the reaction solution was stirred at 25℃ for 1 hour. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was then purified by reversed-phase column chromatography (column: Phenomenex luna C18 150*25mm*10μm; mobile phase: water (0.05% HCl)-acetonitrile; gradient (acetonitrile%): 18%-48%) to obtain the hydrochloride salt of compound A5. LCMS (m / z): 482.2 [M+1] + ; 1H NMR (400MHz, DMSO-d6) δ = 12.89 (s, 1H), 8.52 (s, 3H), 8.40 (s, 1H), 8.13 (d, J = 8.4Hz, 1H), 7.89 (d, J = 6.4Hz, 2H) ,7.44(dd,J=1.6,8.3Hz,1H),4.38(s,2H),3.81(s,3H),3.57(s,3H),3.34-3.23(m,2H),1.13(t,J=6.8Hz,3H); 19 F NMR (376MHz, DMSO-d6) δ = -118.484.

[0412] Step 4: Compound A5 was separated by SFC (column: DAICEL CHIRALCEL OX (250mm*30mm, 10μm; mobile phase: A phase is supercritical carbon dioxide, B phase is EtOH (0.1% ammonia); gradient (B%): 50%) to obtain two crude products, which were then further separated by high performance liquid chromatography (column: Phenomenex luna C18 150*25mm*10μm; mobile phase: water (0.05% HCl)-acetonitrile; gradient (acetonitrile%): 12%-42%) to obtain the hydrochloride salts of compound A5a and compound A5b.

[0413] Characterization of compound A5a hydrochloride: LCMS (m / z): 482.3 [M+1] + ; 1 ¹H NMR (400MHz, DMSO-d6) δ = 12.89 (s, 1H), 8.38 (br s, 3H), 8.13 (d, J = 8.4Hz, 1H), 7.89 (d, J = 6.4Hz, 2H), 7.44 (dd, J = 1.6, 8.3Hz, 1H), 4.38 (br s, 2H), 3.81 (s, 3H), 3.57 (s, 3H), 3.34–3.23 (m, 2H), 1.13 (t, J = 6.8Hz, 3H); F NMR (376MHz, DMSO-d6) δ = -118.484; SFC detection (column: Chiralcel OX-3 50*4.6mm) ID, 3 μm; Mobile phase: Phase A is supercritical carbon dioxide, Phase B is EtOH (0.05% diethylamine); Gradient (B%): 10%-60%), the retention time of compound A5a is 1.948 min, and the chiral purity is 100%.

[0414] Characterization of compound A5b hydrochloride: LCMS (m / z): 482.2 [M+1] + ; 1¹H NMR (400MHz, DMSO-d6) δ = 12.89 (s, 1H), 8.35 (br s, 3H), 8.13 (d, J = 8.4Hz, 1H), 7.89 (d, J = 6.4Hz, 2H), 7.44 (dd, J = 1.6, 8.3Hz, 1H), 4.38 (br s, 2H), 3.81 (s, 3H), 3.57 (s, 3H), 3.34–3.23 (m, 2H), 1.13 (t, J = 6.8Hz, 3H); F NMR (376MHz, DMSO-d6) δ = -118.478; SFC detection (column: Chiralcel OX-3 50*4.6mm) ID, 3 μm; Mobile phase: Phase A is supercritical carbon dioxide, Phase B is EtOH (0.05% diethylamine); Gradient (B%): 10%-60%), the retention time of compound A5b is 2.155 min, and the chiral purity is 95.85%.

[0415] Example A6

[0416] Step 1: Under a nitrogen atmosphere, sodium hydride (177.09 mg, 4.43 mmol, 60% purity) was added to a solution of compound M2 (300 mg, 737.86 μmol) in N,N-dimethylformamide (3 mL). The mixture was stirred at 0 °C for 30 minutes, then deuterated iodomethane (137.77 μL, 2.21 mmol) was added, and stirring continued at 0 °C for 1 hour. The reaction mixture was quenched dropwise with saturated ammonium chloride solution (5 mL), followed by the addition of water (10 mL). Extraction was performed with ethyl acetate (10 mL × 3). The combined organic phases were washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1-3 / 1) to give compound A6-1. LCMS (m / z): 424.0 [M+H] + .

[0417] Step 2: Under a nitrogen atmosphere, CataCXium A Pd G3 (34.38 mg, 47.21 μmol), cesium carbonate (461.47 mg, 1.42 mmol), and compound A1-1 (189.44 mg, 472.11 μmol) were added sequentially to a mixed solution of compound A6-1 (200.00 mg, 472.11 μmol) in toluene (2 mL) and water (0.2 mL). The reaction solution was heated to 80 °C and stirred for 1 hour. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. Compound A6-2 was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:0-0:1). LCMS (m / z): 571.1 [M+1] + .

[0418] Step 3: Under a nitrogen atmosphere, HCl / MeOH (2M, 2mL) was added to a MeOH (1mL) solution of compound A6-2 (120.00mg, 210.15μmol), and the reaction solution was stirred at 25℃ for 1 hour. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was then purified by reversed-phase column chromatography (column: Phenomenex luna C18 150*25mm*10μm; mobile phase: water (0.05% HCl)-acetonitrile; gradient (acetonitrile%): 18%-48%) to obtain the hydrochloride salt of compound A6. LCMS (m / z): 471.0 [M+1] + ; 1 H NMR (400MHz, DMSO-d6) δ = 12.88 (s, 1H), 8.52 (br s,3H),8.40(s,1H),8.15(d,J=8.4Hz,1H),7.84(s,1H),7.81(d,J=6.5Hz,1H),7.48(dd,J=1.3,8.4Hz,1H),4.35(br dd, J=5.7, 8.7Hz, 2H), 3.79 (s, 3H), 3.63 (s, 3H); F NMR (376MHz, DMSO-d6) δ = -119.522.

[0419] Example A7

[0420] Step 1: Under a nitrogen atmosphere, compound A7-1 (288.66 mg, 2.63 mmol, HCl) and potassium carbonate (910.40 mg, 6.59 mmol) were added to a DMF (5.0 mL) solution of compound M1-5 (500 mg, 1.32 mmol), and the mixture was heated to 60 °C for 3 hours. The reaction solution was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 3:1) to obtain compound A7-2. LCMS (m / z): 432.9 [M+1] + .

[0421] Step 2: Under a nitrogen atmosphere, CataCXium A Pd G3 (CAS: 1651823-59-4, 21.88 mg, 30.05 μmol), cesium carbonate (293.72 mg, 901.49 μmol), and compound A1-1 (132.64 mg, 330.55 μmol) were added to a mixed solution of compound A7-2 (130 mg, 300.50 μmol) in toluene (2 mL) and water (0.2 mL). The reaction solution was heated to 80 °C and stirred for 1 hour. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:0-0:1) to obtain compound A7-3. LCMS (m / z): 580.3 [M+1] + .

[0422] Step 3: Under a nitrogen atmosphere, HCl / MeOH (2M, 862.06μL) was added to a MeOH (1mL) solution of compound A7-3 (100mg, 172.41μmol). The reaction solution was stirred at 25℃ for 1 hour. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was then preparatively separated by reversed-phase column chromatography (column: Phenomenex luna C18 150*25mm*10μm; mobile phase: water (0.05% HCl)-acetonitrile; gradient (acetonitrile%): 5%-35%) to obtain the hydrochloride salt of compound A7. LCMS (m / z): 480.1 [M+1] + ; 1 H NMR (400MHz, DMSO-d6) δ = 12.92-12.83 (m, 1H), 8.59 (br s,3H),8.44-8.36(m,1H),8.15(d,J=8.3Hz,1H),7.95-7.88(m,1H),7.77(d,J=6.4Hz,1H),7.45(dd,J=1.2,8.4Hz,1H),4.38(br d,J=5.6Hz,2H),4.13-4.01(m,2H),3.81-3.76(m,3H),3.69(br dd,J=3.2,7.0Hz,1H),3.56-3.50(m,1H),2.36-2.23(m,2H); 19 F NMR (376MHz, DMSO-d6) δ = -121.169 (s, 1F).

[0423] Example A8

[0424] Step 1: Following the synthesis method described in the above embodiments, crude compound A8 was prepared and purified by reversed-phase column chromatography (column: Phenomenex luna C18 150*25mm*10μm; mobile phase: [water (0.05% HCl)-acetonitrile]; gradient (acetonitrile%): 18%-48%) to obtain the hydrochloride salt of compound A8. LCMS (m / z): 518.1 [M+1] + ; 1 H NMR (400MHz, DMSO-d6) δ = 12.89 (s, 1H), 8.52-8.41 (m, 3H), 8.40 (s, 1H), 8.14 (d, J = 8.4Hz, 1H), 8.0 6(d,J=6.8Hz,1H),7.88(d,J=1.4Hz,1H),7.47(dd,J=1.6,8.4Hz,1H),6.49-6.15(m,1H),4.37(br s, 2H), 3.81 (s, 5H), 3.58 (s, 3H); F NMR (376MHz, DMSO-d6) δ = -116.786, -120.945.

[0425] Step 2: Compound A8-3 was separated by SFC (column: DAICEL CHIRALCEL OX (250mm*30mm, 10μm); mobile phase: phase A was supercritical carbon dioxide, phase B was EtOH (0.1% ammonia); gradient (B%): 30%) to obtain compounds A8-3a and A8-3b. LCMS (m / z): 618.0 [M+1] + SFC detection (column: (S,S)Whelk-O1 50*4.6mm ID, 3.5μm; mobile phase: phase A is supercritical carbon dioxide, phase B is EtOH (0.05% diethylamine); gradient (B%): 20%-60%), the retention time of compound A8-3a was 1.580 min, and the chiral purity was 99.35%; the retention time of compound A8-3b was 1.468 min, and the chiral purity was 98.33%.

[0426] Step 2: Under a nitrogen atmosphere, HCl / MeOH (2M, 20.99mL) was added to a MeOH (2mL) solution of compound A8-3a (519.00mg, 839.80μmol), and the reaction solution was stirred at 25℃ for 1 hour. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was then purified by reversed-phase column chromatography (column: Phenomenex luna C18 (250*70mm, 10µm); mobile phase: [water (0.05% HCl)-acetonitrile]; gradient (acetonitrile%): 5%-45%) to obtain the hydrochloride salt of compound A8a. LCMS (m / z): 518.0 [M+1] + ; 1 ¹H NMR (400MHz, DMSO-d6) δ=12.89(s, 1H), 8.51(br s, 3H), 8.41(s, 1H), 8.13(d, J=8.4Hz, 1H), 8.06(d, J=6.4Hz, 1H), 7.88(s, 1H), 7.47(d, J=8.4Hz, 1H), 6.48-6.17(m, 1H), 4.37(br d, J=5.6Hz, 2H), 3.86-3.72(m, 5H), 3.58(s, 3H); F NMR (376MHz, DMSO-d6) δ=-116.792(s, 1F), -120.916(s, 1F); SFC detection (column: Lux 3um Cellulose-4 50*4.6mm) ID, 3 μm; Mobile phase: Phase A is supercritical carbon dioxide, Phase B is EtOH (0.05% diethylamine); Gradient (B%): 30%), the retention time of compound A8a is 2.048 min, and the chiral purity is 97.68%.

[0427] Crude compound A8b was prepared from compound A8-3b as a starting material. The crude product was then purified by reversed-phase column chromatography (column: Phenomenex luna C18 150*25mm*10μm; mobile phase: [water (0.05% HCl)-acetonitrile]; gradient (acetonitrile%): 15%-45%) to obtain the hydrochloride salt of compound A8b. LCMS (m / z): 518.0 [M+1] +,1H NMR(400MHz,DMSO-d6)δ=12.90(s,1H),8.44(br s,3H),8.39(s,1H),8.14(d,J=8.4Hz,1H),8.06(d,J=6.4Hz,1H),7.87(d,J=1.0Hz,1H),7.47(dd,J=1.3,8.4Hz,1H),6.57-6.04(m,1H),4.38(br d, J = 5.6Hz, 2H), 3.86-3.72 (m, 5H), 3.58 (s, 3H); F NMR (376MHz, DMSO-d6) δ = -116.792 (s, 1F), -120.916 (s, 1F). SFC detection (column: Lux 3um Cellulose-4 50*4.6mm ID, 3μm; mobile phase: phase A is supercritical carbon dioxide, phase B is EtOH (0.05% diethylamine); gradient (B%): 30%), the retention time of compound A8b was 3.190 min, and the chiral purity was 98.44%.

[0428] Example A9

[0429] Step 1: Under a nitrogen atmosphere at -65°C, a tetrahydrofuran solution (2M, 395.22μL) of lithium diisopropylamine in tetrahydrofuran was added dropwise to a tetrahydrofuran solution (2mL) of compound M1-5 (200mg, 526.97μmol). The mixture was stirred at -65°C for 30 minutes, then iodoethane (164.38mg, 1.05mmol) was added, and the temperature was raised to 0°C with stirring for 2 hours. The reaction mixture was quenched by adding saturated ammonium chloride solution (10mL), diluted with water (10mL), extracted with ethyl acetate (10mL×2), washed with saturated sodium chloride solution (20mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was preparatively separated by reversed-column chromatography (column: Phenomenex luna C18 (100 g); mobile phase: [water (0.1% formic acid)-acetonitrile]; gradient (acetonitrile %): 35%-60%) to obtain compound A9-1. LCMS (m / z): 408.1 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ = 7.80 (s, 1H), 3.81 (s, 3H), 2.97-2.84 (m, 2H), 1.22 (t, J = 7.6Hz, 3H).

[0430] Step 2: Under a nitrogen atmosphere, compound A9-2 (113.74 mg, 772.85 μmol) was added to a solution of compound A9-1 (350 mg, 858.72 μmol) and potassium carbonate (356.05 mg, 2.58 mmol) in N,N-dimethylformamide (5 mL). The reaction mixture was heated to 80 °C and stirred for 2 hours. The solution was diluted with water (10 mL), extracted with ethyl acetate (10 mL × 2), washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by column chromatography (petroleum ether:ethyl acetate = 10:1–3:1) to give compound A9-3. LCMS (m / z): 535.2 [M+1] + ; 1 H NMR (400MHz, DMSO-d6) δ=7.82-7.78(m,1H),3.86-3.74(m,6H),3.01-2.91(m,1H),2.84-2.74(m,1H),1.42(br s,9H),1.23-1.18(m,3H).

[0431] Step 3: Under a nitrogen atmosphere, Ad2nBuP Pd G3 (27.24 mg, 37.40 μmol), cesium carbonate (365.58 mg, 1.12 mmol), and compound A1-1 (300.15 mg, 748.01 μmol) were added sequentially to a mixed solution of compound A9-3 (200 mg, 374.01 μmol) in toluene (2 mL) and water (0.4 mL). The reaction solution was heated to 80 °C and stirred for 2 hours. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. This crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1-1:1) to obtain compound A9-4. LCMS (m / z): 682.3 [M+1] + .

[0432] Step 4: Compound A9-4 (120 mg, 175.92 μmol) was separated by SFC (column: DAICEL CHIRALPAK IM (250 mm * 30 mm, 10 μm); mobile phase: phase A was supercritical carbon dioxide, phase B was EtOH (0.1% ammonia); gradient (B%): 30%) to obtain two compounds, A9-4a and A9-4b. SFC detection (column: Chiralpak IM-3 50 × 4.6 mm ID, 3 μm; mobile phase: phase A was supercritical carbon dioxide, phase B was EtOH (0.05% diethylamine); gradient (B%): 5%-40%) showed that compound A9-4a had a retention time of 1.973 min and a chiral purity of 100%; compound A9-4b had a retention time of 2.076 min and a chiral purity of 99.49%.

[0433] Step 5: Under a nitrogen atmosphere, compound A9-4a (35.00 mg, 51.31 μmol) was added to a 2 M, 2 mL solution of methanol hydrochloric acid, and stirred at 25 °C for 12 hours. The reaction solution was then directly separated by reversed-phase column chromatography (column: Phenomenex luna C18 150*25 mm*10 μm; mobile phase: [water (0.05% HCl)-acetonitrile]; gradient (acetonitrile%): 11%-41%) to obtain the hydrochloride salt of compound A9a. LCMS (m / z): 482.1 [M+1] + ; 1 H NMR (400MHz, DMSO-d6) δ = 12.87 (s, 1H), 9.74 (s, 1H), 8.42 (br s,3H),8.35(s,1H),8.15(d,J=8.4Hz,1H),7.88(s,1H),7.46-7.40(m,1H),4.44-4. 35(m,2H),3.76(s,3H),3.66(s,3H),2.88(q,J=7.4Hz,2H),1.13(t,J=7.4Hz,3H); F NMR (376MHz, DMSO-d6) δ = -118.657. SFC detection (column: Chiralpak IC-3 50*4.6mm ID, 3μm; mobile phase: phase A is supercritical carbon dioxide, phase B is EtOH (0.05% diethylamine); gradient (B%): 30%-50%), the retention time of compound A9a was 2.484 min, and the chiral purity was 99.22%.

[0434] Crude compound A9b was prepared from compound A9-4b as a starting material. The crude product was then separated by reversed-phase column chromatography (column: Phenomenex luna C18 150*25mm*10μm; mobile phase: [water (0.05% HCl)-acetonitrile]; gradient (acetonitrile%): 11%-41%) to obtain the hydrochloride salt of compound A9b. LCMS (m / z): 482.1 [M+1] + ; 1H NMR (400MHz, DMSO-d6) δ = 12.87 (s, 1H), 9.75 (s, 1H), 8.43 (br s,3H),8.35(s,1H),8.15(d,J=8.4Hz,1H),7.88(s,1H),7.44(dd,J=1.2,8.4Hz,1H),4.4 8-4.33(m,2H),3.76(s,3H),3.66(s,3H),2.88(q,J=7.4Hz,2H),1.13(t,J=7.4Hz,3H); F NMR (376MHz, DMSO-d6) δ = -118.657. SFC detection (column: Chiralpak IC-3 50*4.6mm ID, 3μm; mobile phase: phase A is supercritical carbon dioxide, phase B is EtOH (0.05% diethylamine); gradient (B%): 30%-50%), the retention time of compound A9b was 2.078 min, and the chiral purity was 98.00%.

[0435] Example A10

[0436] Step 1: Under a nitrogen atmosphere at 25°C, cesium carbonate (327 mg, 1.00 mmol) and CataCXium A Pd G3 (24.3 mg, 33.4 μmol) were added to a toluene (2 mL) and water (0.4 mL) solution of compound M3 (150 mg, 334 μmol) and compound A1-1 (268 mg, 669 μmol). The reaction solution was stirred at 80°C for 8 hours. 50 mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with 50 mL of saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product. Compound A10-1 was preparatively separated by reversed-phase column chromatography {column: Phenomenex luna C18 150 × 25 mm × 10 μm; mobile phase: [water (0.1% formic acid) - acetonitrile]; gradient (acetonitrile %): 55%-65%}. LCMS(m / z): 596.3 [M+H] + .

[0437] Step 2: Compound A10-1 (65 mg) was separated by SFC (column: REGIS(s,s)WHELK-O1 (250 mm * 30 mm, 10 μm); mobile phase: phase A is supercritical carbon dioxide, phase B is EtOH (0.1% ammonia); gradient (B%): 45%) to obtain compounds A10-1a and A10-1b. SFC detection (column: (S,S)Whelk-O1 50 * 4.6 mm ID, 3.5 μm; mobile phase: phase A is supercritical carbon dioxide, phase B is EtOH (0.05% diethylamine); gradient (B%): 20%-60%) showed that compound A10-1a had a retention time of 1.471 min and a chiral purity of 99.84%; compound A10-1b had a retention time of 1.584 min and a chiral purity of 99.63%.

[0438] Step 3: Under a nitrogen atmosphere at 0°C, dioxane hydrochloride (2M, 0.5mL) was slowly added to compound A10-1a (25mg, 41.9μmol), and the reaction solution was reacted at 25°C for 1 hour. The reaction solution was concentrated under reduced pressure to obtain the crude product, which was then preparatively separated by reversed-phase column chromatography (column: Phenomenex luna C18 150*25mm*10μm; mobile phase: [water (0.05% HCl)-acetonitrile]; gradient (acetonitrile%): 21%-51%) to obtain the hydrochloride salt of compound A10a. LCMS (m / z): 496.2 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ = 12.89 (s, 1H), 8.52 (br s,3H),8.40(s,1H),8.12(d,J=8.4Hz,1H),7.95-7.86(m,2H),7.41(dd,J=1.2,8.4Hz, 1H),4.49-4.31(m,2H),3.87-3.73(m,5H),3.35-3.22(m,2H),1.13(q,J=7.2Hz,6H); F NMR (376MHz, DMSO-d6) δ = -118.436. SFC detection (column: Lux 3um Cellulose-4 50*4.6mm ID, 3μm; mobile phase: phase A is supercritical carbon dioxide, phase B is EtOH (0.05% diethylamine); gradient (B%): 20%-60%), the retention time of compound A10a was 2.084 min, and the chiral purity was 97.34%.

[0439] Crude compound A10b was prepared from compound A10-1b (25 mg, 41.9 μmol). The crude product was then separated by reversed-phase column chromatography (column: Phenomenex luna C18 150*25 mm*10 μm; mobile phase: [water (0.05% HCl)-acetonitrile]; gradient (acetonitrile%): 21%-51%) to obtain the hydrochloride salt of compound A10b. LCMS (m / z): 496.3 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ = 12.89 (s, 1H), 8.50 (br s,3H),8.39(s,1H),8.12(d,J=8.3Hz,1H),7.90(dd,J=2.4,4.0Hz,2H),7.42(dd,J=1.6,8.3Hz,1 H),4.44-4.28(m,2H),3.81(s,3H),3.79-3.73(m,2H),3.32-3.21(m,2H),1.13(q,J=7.2Hz,6H); F NMR (376MHz, DMSO-d6) δ = -118.436. SFC detection (column: Lux 3um Cellulose-4 50*4.6mm ID, 3μm; mobile phase: phase A is supercritical carbon dioxide, phase B is EtOH (0.05% diethylamine); gradient (B%): 20%-60%), the retention time of compound A10b was 1.800 min, and the chiral purity was 98.54%.

[0440] Example A11

[0441] Compounds A11a and A11b were prepared using the synthesis methods described in the above embodiments. LCMS (m / z): 518.2 [M+H] + .

[0442] Example A12

[0443] Following the synthesis method described in the above embodiments, hydrochloride salts of compound A12a and compound A12b were prepared.

[0444] Characterization of the hydrochloride salt of compound A12a: LCMS (m / z): 485.2 [M+1] + ; 1H NMR (400MHz, DMSO-d6) δ = 12.90 (s, 1H), 8.49 (br s,3H),8.40(s,1H),8.14(d,J=8.4Hz,1H),7.89(dd,J=2.8,4.0Hz,2H),7.45(dd,J=1.6,8.4Hz,1H),4.38(br d,J=6.0Hz,2H),3.58(s,3H),3.34-3.22(m,2H),1.13(t,J=6.8Hz,3H); 19 F NMR (376MHz, DMSO-d6) δ=-118.50; SFC detection (column: Chiralcel OX-3 50*4.6mm ID, 3um; mobile phase: phase A is supercritical carbon dioxide, phase B is EtOH (0.05% diethylamine); gradient (B%): 10%-60%), the retention time of compound A12a was 1.948 min, and the chiral purity was 98.40%. Hydrochloride characterization of compound A12b: LCMS (m / z): 485.3 [M+1] + ; 1 H NMR (400MHz, DMSO-d6) δ=12.90(s,1H),8.48(br s,3H),8.39(s,1H),8.14(d,J=8.4Hz,1H),7.93-7.85(m,2H),7.45(dd,J=1.6,8.4Hz,1H),4.39(br t,J=6.0Hz,2H),3.58(s,3H),3.34-3.24(m,2H),1.13(t,J=6.8Hz,3H); 19 F NMR (376MHz, DMSO-d6) δ=-118.50; SFC detection (column: Chiralcel OX-3 50*4.6mm ID, 3um; mobile phase: A phase is supercritical carbon dioxide, B phase is EtOH (0.05% diethylamine); gradient (B%): 10%-60%), the retention time of compound A12b is 2.161 min, and the chiral purity is 92.23%.

[0445] Example A13

[0446] Step 1: Under a nitrogen atmosphere at 0°C, sodium hydroxide (88.5 mg, 2.21 mmol, 60% purity) was added to a tetrahydrofuran (30 mL) solution of compound M2 (300 mg, 737.86 μmol). After stirring for 0.5 hours, compound A13-1 (267.79 mg, 2.21 mmol) was added, and stirring was continued for another 0.5 hours. At 0°C, saturated ammonium chloride aqueous solution (20 mL) was added to the reaction mixture, and extraction was performed with ethyl acetate (60 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure to obtain the crude product. Purification was achieved by silica gel column chromatography (petroleum ether:ethyl acetate = 3 / 1) to obtain compound A13-2. LCMS (m / z): 447.0 [M+1] + ; 1 H NMR (400MHz, CDCl3) δ = 7.73 (d, J = 6.4Hz, 1H), 7.67 (s, 1H), 6.04 (tdd, J = 6.4, 10.3 ,17.0Hz,1H),5.38-5.15(m,2H),4.01(t,J=6.0Hz,2H),3.85(s,3H),3.67(s,3H).

[0447] Step 2: Following the synthesis method described in the above embodiments, compound A13 was prepared. LCMS (m / z): 494.1 [M+1] + .

[0448] Step 3: Following the synthesis method described in the above embodiments, crude hydrochloride products of compound A13a and compound A13b were prepared. The crude hydrochloride product of compound A13a was further separated by reversed-phase column chromatography (column: Phenomenex Luna C18 150*25mm*10um; mobile phase: water (0.225% formic acid)-acetonitrile; gradient (acetonitrile%): 12%-42%) to obtain compound A13a; the crude hydrochloride product of compound A13b was further separated by reversed-phase column chromatography (column: Phenomenex Luna C18 150*25mm*10um; mobile phase: water (0.225% formic acid)-acetonitrile; gradient (acetonitrile%): 10%-40%) to obtain compound A13b.

[0449] Characterization of compound A13a: LCMS (m / z): 494.1 [M+1] + ; 1H NMR (400MHz, DMSO-d6) δ=12.67-12.36(m,1H),8.30(s,1H),8.15(d,J=8.3Hz,1H),7.88(d,J= 6.6Hz,1H),7.75(s,1H),7.65(d,J=8.7Hz,1H),5.99-5.80(m,1H),5.26-5.16(m,2H),3.97(br t,J=7.3Hz,2H),3.87(s,2H),3.80(s,3H),3.57(s,3H); 19 F NMR (376MHz, DMSO-d6) δ=-118.539. SFC detection (column: Lux 3um Cellulose-4 50*4.6mm ID, 3μm; mobile phase: phase A is supercritical carbon dioxide, phase B is EtOH (0.05% diethylamine); gradient (B%): 20%-60%), the retention time of compound A13a was 1.861 min, and the chiral purity was 95.60%.

[0450] Characterization of compound A13b: LCMS (m / z): 494.1 [M+1] + ; 1 H NMR (400MHz, DMSO-d6) δ=12.56-12.53(m,1H),8.30(s,1H),8.15(d,J=8.3Hz,1H),7.88(d,J= 6.6Hz,1H),7.75(s,1H),7.65(d,J=8.7Hz,1H),5.99-5.80(m,1H),5.26-5.16(m,2H),3.97(br t, J = 7.3Hz, 2H), 3.87 (s, 2H), 3.80 (s, 3H), 3.57 (s, 3H); F NMR (376MHz, DMSO-d6) δ = -118.532. SFC detection (column: Lux 3um Cellulose-4 50*4.6mm ID, 3μm; mobile phase: phase A is supercritical carbon dioxide, phase B is EtOH (0.05% diethylamine); gradient (B%): 20%-60%), the retention time of compound A13b was 2.122 min, and the chiral purity was 99.01%.

[0451] Example A14

[0452] Step 1: Following the synthesis method described in the above examples, compound A14-1 was prepared. LCMS (m / z): 516.9 [M+1] + .

[0453] Step 2: Compound A14-1 was separated by SFC (column: DAICEL CHIRALPAK IG 250mm*30mm*5um; mobile phase: phase A was supercritical carbon dioxide, phase B was EtOH (0.1% ammonia); gradient (B%): 25%) to obtain compounds A14-1a and A14-1b. SFC detection (column: Chiralpak IG-3 50*4.6mm ID, 3μm; mobile phase: phase A was supercritical carbon dioxide, phase B was isopropanol (0.05% diethylamine); gradient (B%): 5%-40%) showed that compound A14-1a had a retention time of 1.717 min and a chiral purity of 100%; compound A14-1b had a retention time of 1.790 min and a chiral purity of 96.68%.

[0454] Step 3: Under a nitrogen atmosphere, HCl / MeOH (2M, 3.00 mL) was added to compound A14-1a (60 mg, 90.33 μmol), and the reaction solution was stirred at 25 °C for 1 hour. The reaction solution was concentrated under reduced pressure, and DMF (3 mL) and CsF (36.35 mg, 239.33 μmol) were added to the residue. The mixture was stirred at 35 °C for 3 hours. The reaction solution was directly separated by reversed-phase column chromatography (column: Phenomenex Luna C18 150*25 mm*10 μm; mobile phase: [water (0.225% formic acid)-acetonitrile]; gradient (acetonitrile%): 15%-45%) to obtain compound A14a. LCMS (m / z): 492.0 [M+1] + ; 1 H NMR (400MHz, DMSO-d6) δ=13.09-12.14(m,1H),8.32(s,1H),8.28(s,1H),8.15(d,J=8.3Hz,1H),7.93(d,J=6.6Hz,1H),7. 76(s,1H),7.64(dd,J=1.5,8.3Hz,1H),4.37-4.25(m,2H),3.92(s,2H),3.80(s,3H),3.64(s,3H),3.32(t,J=2.2Hz,1H); 19 F NMR (376MHz, DMSO-d6) δ=-117.392. SFC detection (column: Lux 3um Cellulose-2 50*4.6mm ID, 3μm; mobile phase: phase A is supercritical carbon dioxide, phase B is ethanol / acetonitrile (0.05% diethylamine); gradient (B%): 20%-60%), the retention time of compound A14a was 1.809 min, and the chiral purity was 100%.

[0455] Crude compound A14b was prepared from compound A14-1b and then separated by reversed-phase column chromatography (column: Phenomenex Luna C18 150*25mm*10μm; mobile phase: [water (0.225% formic acid)-acetonitrile]; gradient (acetonitrile%): 15%-45%) to obtain compound A14b. LCMS (m / z): 492.0 [M+1] + ; 1 H NMR (400MHz, DMSO-d6) δ = 12.54 (s, 1H), 8.31 (s, 1H), 8.26 (s, 1H), 8.15 (d, J = 8.3Hz, 1H), 7.93 (d, J = 6.6Hz, 1H), 7.76 ( s,1H),7.64(dd,J=1.5,8.3Hz,1H),4.37-4.25(m,2H),3.90(s,2H),3.80(s,3H),3.64(s,3H),3.32(t,J=2.2Hz,1H); 19 F NMR (376MHz, DMSO-d6) δ=-117.407. SFC detection (column: Lux 3um Cellulose-2 50*4.6mm ID, 3μm; mobile phase: phase A is supercritical carbon dioxide, phase B is ethanol / acetonitrile (0.05% diethylamine); gradient (B%): 20%-60%), the retention time of compound A14b was 1.921 min, and the chiral purity was 95.99%.

[0456] Example A15

[0457] Step 1: Under a nitrogen atmosphere, at 0°C, triethylamine (223.99 mg, 2.21 mmol) was added to a solution of compound M2 (300 mg, 737.86 μmol) in N,N-dimethylformamide (3 mL). The mixture was stirred at 0°C for 30 minutes, then compound A15-1 (methyl chloroformate, 310.28 mg, 3.28 mmol) was added, and the mixture was stirred at 0°C for 1 hour. The reaction mixture was quenched dropwise with saturated ammonium chloride solution (5 mL), water (10 mL) was added, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phase was washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 5 / 1-3 / 1) to give compound A15-2. LC-MS m / z: 465.1 [M+H] + .

[0458] Step 2: Under a nitrogen atmosphere, Ad2nBuP Pd G3 (27.43 mg, 37.67 μmol), cesium carbonate (368.16 mg, 1.13 mmol), and compound A1-1 (151.14 mg, 376.65 μmol) were added sequentially to a mixed solution of compound A15-2 (175 mg, 376.65 μmol) in toluene (2 mL) and water (0.2 mL). The reaction solution was heated to 80 °C and stirred for 3 hours. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. This crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:0-0:1) to obtain compound A15-3. LCMS (m / z): 612.0 [M+1] + .

[0459] Step 3: Compound A15-3 was separated by SFC (column: DAICEL CHIRALCEL OX (250mm*30mm, 10μm); mobile phase: phase A was supercritical carbon dioxide, phase B was EtOH (0.1% ammonia); gradient (B%): 50%) to obtain two compounds, A15-3a and A15-3b. LCMS (m / z): 612.1 [M+1] + SFC detection (column: Chiralcel OX-3 50*4.6mm ID, 3μm; mobile phase: phase A is supercritical carbon dioxide, phase B is ethanol (0.05% diethylamine); gradient (B%): 25%-35%), the retention time of compound A15-3a was 1.703 min, and the chiral purity was 100%; the retention time of compound A15-3b was 2.023 min, and the chiral purity was 98.98%.

[0460] Step 4: Under a nitrogen atmosphere, HCl / MeOH (2M, 1.80mL) was added to a MeOH (2mL) solution of compound A15-3a (519.00mg, 839.80μmol), and the reaction solution was stirred at 25℃ for 1 hour. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was then preparatively separated by reversed-phase column chromatography (column: Phenomenex luna C18 150*25mm*10μm; mobile phase: [water (0.05% HCl)-acetonitrile]; gradient (acetonitrile%): 5%-35%) to obtain the hydrochloride salt of compound A15a. LCMS (m / z): 512.1 [M+1] + ; 1H NMR (400MHz, DMSO-d6) δ = 12.89 (s, 1H), 8.49 (br s,3H),8.41(s,1H),8.29(d,J=6.4Hz,1H),8.15(d,J=8.4Hz,1H),7.80(s,1H),7.55 (dd,J=1.2,8.3Hz,1H),4.42-4.26(m,2H),3.84(s,3H),3.76(s,3H),3.67(s,3H); F NMR (376MHz, DMSO-d6) δ = -111.130. SFC detection (column: Chiralpak IK-3 50×4.6mm ID, 3μm; mobile phase: phase A is supercritical carbon dioxide, phase B is isopropanol / acetonitrile (0.05% diethylamine); gradient (B%): 5%-40%), the retention time of compound A15a was 3.547 min, and the chiral purity was 96.67%.

[0461] Crude compound A15b was prepared from compound A15-3b and purified by reversed-phase column chromatography (column: Phenomenex luna C18 150*25mm*10μm; mobile phase: [water (0.05% HCl)-acetonitrile]; gradient (acetonitrile%): 5%-35%) to obtain the hydrochloride salt of compound A15b. LCMS (m / z): 512.1 [M+1] + ; 1 H NMR (400MHz, DMSO-d6) δ = 12.90 (s, 1H), 8.50 (br s,3H),8.42(s,1H),8.30(d,J=6.4Hz,1H),8.16(d,J=8.2Hz,1H),7.81(s,1H),7.56 (dd,J=1.2,8.3Hz,1H),4.43-4.26(m,2H),3.85(s,3H),3.77(s,3H),3.68(s,3H); F NMR (376MHz, DMSO-d6) δ = -111.130. SFC detection (column: Chiralpak IK-3 50×4.6mm ID, 3μm; mobile phase: phase A is supercritical carbon dioxide, phase B is isopropanol / acetonitrile (0.05% diethylamine); gradient (B%): 5%-40%), the retention time of compound A15b was 3.837 min, and the chiral purity was 95.73%.

[0462] Example A16

[0463] Following the synthesis method described in the above embodiments, hydrochloride salts of compound A16a and compound A16b were prepared.

[0464] Characterization of the hydrochloride salt of compound A16a: LCMS (m / z): 526.0 [M+1] + ; 1 ¹H NMR (400MHz, DMSO-d6) δ = 12.89 (s, 1H), 8.53 (br s, 3H), 8.42 (s, 1H), 8.29 (d, J = 6.6Hz, 1H), 8.14 (d, J = 8.4Hz, 1H), 7.84 (d, J = 1.2Hz, 1H), 7.52 (dd, J = 1.6, 8.4Hz, 1H), 4.35 (br dd, J = 5.6, 13.6Hz, 2H), 4.22–4.02 (m, 2H), 3.83 (s, 3H), 3.77 (s, 3H), 1.07 (t, J = 7.2Hz, 3H); F NMR (376MHz, DMSO-d6) δ = -111.317; SFC detection (column: Chiralpak IK-3) 50×4.6mm ID, 3μm; mobile phase: phase A is supercritical carbon dioxide, phase B is isopropanol / acetonitrile (0.05% diethylamine); gradient (B%): 30%), the retention time of compound A16a is 2.323 min, and the chiral purity is 97.90%.

[0465] Characterization of the hydrochloride salt of compound A16b: LCMS (m / z): 526.1 [M+1] + ; 1 ¹H NMR (400MHz, DMSO-d6) δ=12.90(s, 1H), 8.54(br s, 3H), 8.42(s, 1H), 8.29(d, J=6.6Hz, 1H), 8.14(d, J=8.4Hz, 1H), 7.84(s, 1H), 7.60-7.43(m, 1H), 4.46-4.25(m, 2H), 4.22-4.03(m, 2H), 3.83(s, 3H), 3.77(s, 3H), 1.07(t, J=7.0Hz, 3H); F NMR (376MHz, DMSO-d6) δ=-111.317; SFC detection (column: Chiralpak IK-3 50×4.6mm) ID, 3 μm; Mobile phase: Phase A is supercritical carbon dioxide, Phase B is isopropanol / acetonitrile (0.05% diethylamine); Gradient (B%): 30%), the retention time of compound A16b is 3.483 min, and the chiral purity is 96.71%.

[0466] Example A17

[0467] Following the synthesis method described in the above embodiments, hydrochloride salts of compound A17a and compound A17b were prepared.

[0468] Characterization of the hydrochloride salt of compound A17a: LCMS (m / z): 532.1 [M+1] + ; 1 H NMR (400MHz, DMSO-d6) δ = 12.89 (s, 1H), 8.49 (br s,3H),8.40(s,1H),8.11(d,J=8.2Hz,1H),8.00(d,J=6.4Hz,1H),7.91(d,J=1.4Hz,1H),7.42(dd,J=1.6,8.4Hz,1H),6.45-5.94(m,1H),4.39(br d,J=5.6Hz,2H),4.06(dt,J=3.6,14.9Hz,2H),3.81(s,3H),3.33-3.23(m,2H),1.14(t,J=6.8Hz,3H); F NMR (376MHz, DMSO-d6) δ = -116.643 (s, 1F), -125.720 (s, 2F). SFC detection (column: Lux 3um Cellulose-4 50*4.6mm ID, 3μm; mobile phase: A phase is supercritical carbon dioxide, B phase is methanol (0.05% diethylamine); gradient (B%): 30%-60%), the retention time of compound A17a was 1.196 min, and the chiral purity was 98.49%.

[0469] Characterization of the hydrochloride salt of compound A17b: LCMS (m / z): 532.1 [M+1] + ; 1H NMR (400MHz, DMSO-d6) δ = 12.90 (s, 1H), 8.45 (br s,3H),8.40-8.37(m,1H),8.12(d,J=8.2Hz,1H),8.00(d,J=6.8Hz,1H),7.91(s,1H),7.42(dd,J=1.6,8.2Hz,1H),6.37-6.06(m,1H),4.40(br s,2H),4.06(dt,J=3.6,14.8Hz,2H),3.82(s,3H),3.31-3.15(m,2H),1.14(t,J=6.8Hz,3H); F NMR (376MHz, DMSO-d6) δ = -116.643 (s, 1F), -125.715 (s, 2F). SFC detection (column: Lux 3um Cellulose-4 50*4.6mm ID, 3μm; mobile phase: A phase is supercritical carbon dioxide, B phase is methanol (0.05% diethylamine); gradient (B%): 30%-60%), the retention time of compound A17b was 1.420 min, and the chiral purity was 99.45%.

[0470] Example A18

[0471] Step 1: Under a nitrogen atmosphere at room temperature, 1,1-bis(tert-butylphosphine)ferrocene palladium chloride (67.19 mg, 103.09 μmol), potassium carbonate (213.71 mg, 1.55 mmol), and methylboronic acid (154.27 mg, 2.58 mmol) were added sequentially to a mixed solution of compound A5-2 (300 mg, 515.44 μmol) containing 1,4-dioxane (3 mL) and water (0.6 mL). The reaction solution was heated to 120 °C and stirred for 2 hours. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was then purified by reverse-phase column chromatography (column: Waters Xbridge C18 150*25 mm*5 μm; mobile phase: water (10 mM NH4HCO3)-acetonitrile; gradient (acetonitrile %): 30%-60% B over 15.0 min) to obtain compound A18-1. LCMS(m / z): 562.2 [M+1] + .

[0472] Step 2: Compound A18-1 (130 mg) was separated by SFC (column: ChiralPak IH, 250*30 mm, 10 μm; mobile phase: phase A was supercritical carbon dioxide, phase B was isopropanol (0.1% ammonia); gradient (B%): 25%) to obtain compounds A18-1a and A18-1b. SFC detection (column: (S,S)Whelk-O1 50*4.6 mm ID, 3.5 μm; mobile phase: phase A was supercritical carbon dioxide, phase B was methanol (0.05% diethylamine); gradient (B%): 5%-40%) showed that compound A18-1a had a retention time of 2.927 min and a chiral purity of 99.36%; compound A18-1b had a retention time of 3.031 min and a chiral purity of 97.98%.

[0473] Step 3: Under a nitrogen atmosphere, an HCl / methanol solution (2M, 1.09mL) was added to an anhydrous methanol (5mL) solution of compound A18-1a (61mg, 108.62μmol). The reaction solution was stirred at 25℃ for 2 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was then purified by reversed-phase column chromatography (column: Phenomenex luna C18 150*25mm*10um; mobile phase: water (0.05% HCl)-acetonitrile; gradient (acetonitrile%): 10%-40%) to obtain the hydrochloride salt of compound A18a. LCMS (m / z): 462.1 [M+1] + ; 1 H NMR (400MHz, DMSO-d6) δppm 1.11 (t, J = 7.2Hz, 3H), 2.40-2.48 (m, 3H), 3.16-3.30 (m, 2H), 3.54 (s, 3H), 3.76 (s, 3H), 4.32 (br d,J=17.6Hz,2H),7.44(br d,J=6.4Hz,1H),7.69(br F NMR (376MHz, DMSO-d6) δ=-119.777; SFC detection (column: Chiralcel OX-3 50*4.6mm ID, 3μm; mobile phase: phase A is supercritical carbon dioxide, phase B is ethanol (0.05% diethylamine); gradient (B%): 30%-40%), the retention time of compound A18a was 2.288 min, and the chiral purity was 99.96%.

[0474] The hydrochloride salt of compound A18b was prepared from compound A18-1b. LCMS (m / z): 462.1 [M+1] + ; 1 H NMR (400MHz, DMSO-d6) δppm 1.11 (t, J = 7.2Hz, 3H), 2.39-2.48 (m, 3H), 3.17-3.30 (m, 2H), 3.54 (s, 3H), 3.76 (s, 3H), 4.32 (br d,J=14Hz,2H),7.40-7.48(m,1H),7.69(br d,J=6.4Hz,1H),7.81(s,1H),8.12(d,J=8.0Hz,1H),8.36-8.41(m,1H),8.61(br s,3H),12.88(s,1H); 19 FNMR (376MHz, DMSO-d6) δ=-119.777; SFC detection (column: Chiralcel OX-3 50*4.6mm ID, 3μm; mobile phase: phase A is supercritical carbon dioxide, phase B is ethanol (0.05% diethylamine); gradient (B%): 30%-40%), the retention time of compound A18b was 1.897 min, and the chiral purity was 96.42%.

[0475] Example A19

[0476] Step 1: Under a nitrogen atmosphere, to a mixed solution of compound M5 (400 mg, 844.53 μmol) in toluene (7 mL) and heavy water (1.5 mL), add methanesulfonic acid (docosyl-n-butylphosphino) (2-amino-1,1-biphenyl-2-yl)palladium(II) (CAS: 1651823-59-4, 123.01 mg, 168.91 μmol), cesium carbonate (825.50 mg, 2.53 mmol), and compound A1-1 (406.66 mg, 1.01 mmol). The reaction solution was heated to 80 °C and stirred for 6 hours. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. This crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:0-0:1) to obtain compound A19-1. LCMS (m / z): 621.1 [M+1] + ; 1H NMR (400MHz, CDCl3-d) δppm=1.45(s,9H),1.70(s,2H),3.49-3.70(m,5H),4.48(br d,J=5.6Hz,2H),6.11(tt,J=55.6,4.4Hz,1H),7.43(d,J=8.4Hz,1H),7.74-7.89(m,2H),8.01(s,1H),8.32(d,J=8.0Hz,1H),10.71(br s,1H).

[0477] Step 2: Compound A19-1 was separated by SFC (column: DAICL CHIRALCEL OX (250mm*30mm, 10µm); mobile phase: phase A was supercritical carbon dioxide, phase B was EtOH (0.1% ammonia); gradient (B%): 40%) to obtain compounds A19-1a and A19-1b. LCMS (m / z): 621.1 [M+1] + SFC analysis (column: Chiralcel OX-3 50×4.6mm ID, 3μm; mobile phase: A phase: supercritical carbon dioxide, B phase: ethanol (0.05% diethylamine); gradient (B%): 20%-60%) showed that compound A19-1a had a retention time of 1.157 min and a chiral purity of 100%, while compound A19-1b had a retention time of 1.406 min and a chiral purity of 100%.

[0478] Step 3: Under a nitrogen atmosphere, HCl / methanol solution (2M, 1.45mL) was added to an anhydrous methanol (5mL) solution of compound A19-1a (90mg, 144.92μmol), and the mixture was stirred at 25°C for 2 hours. The filtrate was concentrated under reduced pressure to obtain the crude product, which was then preparatively separated by reversed-phase column chromatography (column: Phenomenex luna C18 150*25mm*10um; mobile phase: H2O (0.05% HCl)-acetonitrile; gradient (acetonitrile%): 10%-40%) to obtain the hydrochloride salt of compound A19a. LCMS (m / z): 520.9 [M+1] + ; 1H NMR (400MHz, DMSO-d6) δppm=3.58(s,3H),3.74-3.89(m,2H),4.37(br s,2H),6.33(tt,J=54.8,4.0Hz,1H),7.48(dd,J=8.4,1.6Hz,1H),7.88(s,1 H),8.06(d,J=6.8Hz,1H),8.14(d,J=8.0Hz,1H),8.35-8.42(m,1H),8.43(br s,2H),12.89(s,1H); 19 F NMR (376MHz, DMSO-d6) δ=-116.804(s,1F),-120.917(s,1F); Chirality detection (column: Chiralpak IM-3 50*4.6mm ID, 3μm; mobile phase: phase A is n-hexane, phase B is ethanol (0.05% diethylamine); gradient (B%): 35%), the retention time of compound A19a was 8.604 min, and the chiral purity was 98.56%.

[0479] The hydrochloride salt of compound A19b was prepared from compound A19-1b. LCMS (m / z): 521.0 [M+1] + ; 1 H NMR (400MHz, DMSO-d6) δppm=3.53-3.63(m,3H),3.74-3.88(m,2H),4.38(br s,2H),6.33(tt,J=55.2,4.0Hz,1H),7.48(dd,J=8.0,1.2Hz,1H),7.88(s,1H),8.05(d,J=6.4Hz,1H),8.14(d,J=8.4Hz,1H),8.40(br s,1H),8.47(br dd,J=5.2,2.8Hz,2H),12.89(s,1H); 19 F NMR (376MHz, DMSO-d6) δ=-116.804(s,1F),-120.917(s,1F); Chirality detection (column: Chiralpak IM-3 50*4.6mm ID, 3μm; mobile phase: phase A is n-hexane, phase B is ethanol (0.05% diethylamine); gradient (B%): 35%), the retention time of compound A19b was 12.298 min, and the chiral purity was 99.33%.

[0480] Example A20

[0481] Compounds A20, A20a, and A20b were prepared according to the synthesis methods described in the above embodiments. LCMS (m / z): 479.1 [M+1] + .

[0482] Intermediate N1

[0483] Step 1: Under a nitrogen atmosphere at -70°C, a solution of n-butyllithium (2.5M tetrahydrofuran, 104.6mL) was slowly added dropwise to a tetrahydrofuran (600mL) solution of compound N1-1 (40g, 237.77mmol). After the addition was complete, the reaction mixture was stirred at -70°C for 1 hour. Then, paraformaldehyde (21.42g, 713.30mmol) was added, and the mixture was stirred at -70°C for another hour, followed by stirring at 20°C for 12 hours. At 0°C, water (600mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (500mL × 2). The combined organic phases were washed with saturated brine (300mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 50:1-10:1) to obtain compound N1-2. 1 H NMR (400MHz, CDCl3) δ = 5.09 (s, 1H), 4.30 (s, 2H), 4.04-3.91 (m, 1H), 3.62-3.47 (m,1H),2.69(s,1H),1.92-1.80(m,1H),1.77-1.67(m,1H),1.59-1.48(m,10H).

[0484] Step 2: An anhydrous tetrahydrofuran (400 mL) solution of compound N1-2 (39 g) was pumped into flow reactor 1 by pump 1 (flow rate 14 mL / min). A tetrahydrofuran solution of lithium aluminum hydride (2.5 M, 159 mL) was pumped into flow reactor 1 by pump 2 (flow rate 6 mL / min). Pumps 1 and 2 were started simultaneously, and the reaction mixture was collected after running for 5 min. The reaction solution was cooled to 0 °C and quenched dropwise in a tetrahydrofuran (100 mL) suspension of sodium sulfate decahydrate (50 g) under nitrogen protection. The mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 20:1-10:1) to obtain compound N1-3. 1 H NMR (400MHz, CDCl3) δ = 5.19 (tt, J = 2.8, 5.7Hz, 1H), 4.07 (d, J = 5.6Hz, 2H), 1.72 (d, J = 2.9Hz, 6H), 1.62 (s, 1H).

[0485] Step 3: Under a nitrogen atmosphere at 0°C, methanesulfonyl chloride (620.00 mg, 5.41 mmol) was slowly added dropwise to a solution of compound N1-3 (350 mg, 3.57 mmol), 4-dimethylaminopyridine (43.00 mg, 351.98 μmol), and triethylamine (541.30 mg, 5.35 mmol) in dichloromethane (4 mL). The mixture was stirred at 0°C for 1.5 hours. The reaction mixture was then quenched with water (10 mL) at 0°C, stirred for 10 minutes, and extracted with dichloromethane (15 mL × 3). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound N1. 1 H NMR (400MHz, CDCl3) δ5.22-5.17 (m, 1H), 4.70 (d, J = 7.2Hz, 2H), 3.05 (s, 3H), 1.75 (s, 6H).

[0486] Compound N2

[0487] Step 1: Under a nitrogen atmosphere at 0°C, sodium hydride (1.39 g, 34.8 mmol, 60% purity) was added to a tetrahydrofuran (280 mL) solution of compound N2-1 (18.65 g, 29.0 mmol), and the mixture was stirred at 0°C for 30 minutes. Then, trimethylsilyl)ethoxymethyl chloride (6.29 g, 37.7 mmol) was added, and the reaction was allowed to proceed at room temperature for 1 hour. The reaction mixture was quenched dropwise with saturated ammonium chloride (300 mL) solution, extracted with ethyl acetate (500 mL × 3), and the combined organic phases were washed with saturated sodium chloride solution (200 mL), dried over anhydrous sodium sulfate, filtered, and the crude product obtained by concentration under reduced pressure was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 50:1-7:3) to obtain pure compound N2-2. LCMS (m / z): 773.5 [M+H] + .

[0488] Step 2: At 0°C, potassium osmium tetroxide dihydrate (405 mg, 1.10 mmol) and sodium periodate (18.8 mg, 88.0 mmol) were added sequentially to anhydrous dioxane (720 mL) and water (240 mL) solutions of compound N2-2 (17 g, 22.0 mmol), 2,6-dimethylpyridine (4.71 g, 44.0 mmol), and the reaction solution was reacted at 25°C for 15 hours. 100 mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate (200 mL × 3). The combined organic phases were washed sequentially with dilute hydrochloric acid (200 mL, 1 mol / L), saturated sodium bicarbonate (200 mL), and saturated brine (200 mL). The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 100:1-2:3) to obtain compound N2-3. LCMS(m / z): 775.2 [M+H] + ; 1 H NMR (400MHz, CDCl3) δ = 9.20 (s, 1H), 7.60 (dd, J = 2.0, 7.2Hz, 1H), 7.55-7.43 (m, 2H), 7.37-7.29 (m, 1H), 6.47 (s, 1H), 5.53 (d, J = 11.2Hz, 1 H),5.40(d,J=11.2Hz,1H),5.36-5.10(m,3H),4.97(d,J=16.8Hz,1H),3.83-3.63(m,2H),3.62-3.47(m,5H),3.47-3.23(m,2H),1.41(br s, 9H), 1.00-0.71 (m, 4H), -0.02 (d, J = 5.2Hz, 18H).

[0489] Step 3: Under a nitrogen atmosphere at 25°C, sodium acetate (4.27 g, 52.0 mmol) was added to a methanol (443 mL) solution of compound N2-3 (13.44 g, 17.3 mmol) and hydroxylamine hydrochloride (2.41 g, 34.7 mmol), and the mixture was stirred at 25°C for 1 hour. The reaction solution was concentrated to obtain a crude product, which was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 100:1-1:1) to obtain compound N2-4. LCMS (m / z): 790.5 [M+H] + .

[0490] Step 4: Fluid Chemistry Method: A solution of compound N2-4 (13.2 g) in anhydrous methanol (200 mL) and ammonia-methanol (200 mL) was pumped into a flow reactor 1 (5 mL, 115 °C) using pump 1 (1.2 mL / min). A fixed bed was filled with 14% Ni / Al2O3 catalyst (2.79 g). The hydrogen atmosphere was pressurized to 2.5 MPa at a flow rate of 5 mL / min. After the reaction was complete, the reaction solution was collected, concentrated under reduced pressure to obtain a crude product, and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1-1:4) to obtain compound N2. LCMS (m / z): 744.5 [M+H] + ; 1 H NMR (400MHz, CDCl3)δ=7.67-7.45(m,2H),7.41-7.27(m,2H),6.69(br s,1H),6.62(s,1H),5.77-5.41(m,2H),5.40-5.05(m,3H),5.01-4.49(m,1H),3.9 3-3.64(m,2H),3.62-3.29(m,4H),2.78-2.39(m,1H),2.38-2.19(m,1H),1.43(br s,9H),1.06-0.85(m,2H),0.84-0.51(m,2H),-0.01(s,9H),-0.10(s,9H); 19 F NMR (376MHz, CDCl3) δ = -111.02 (s, 1F), -130.57 (s, 1F).

[0491] Intermediate N3

[0492] Step 1: Under a nitrogen atmosphere at -20°C, a tetrahydrofuran solution (50 mL) of compound N3-1 (15.5 g, 91.03 mmol) was slowly added dropwise to a tetrahydrofuran solution (200 mL) of lithium aluminum hydride (3.45 g, 91 mmol). The mixture was then slowly heated to 20°C and stirred for 2 hours. Excess sodium sulfate decahydrate was added to the reaction mixture in an ice-water bath, and the mixture was stirred for 30 minutes. The mixture was filtered, and the filtrate was concentrated to obtain compound N3-2. 1 H NMR (400MHz, CDCl3) δ = 0.067 (s, 9H).

[0493] Step 2: Under a nitrogen atmosphere at 0°C, 3,4-dihydropyran (43g, 512mmol) was slowly added dropwise to a solution of p-toluenesulfonic acid (4.06g, 21.3mmol) and compound N3-2 (56g, 426mmol) in dichloromethane (500mL). After the addition was complete, the reaction mixture was reacted at 25°C for 2 hours. 200mL of saturated sodium bicarbonate solution was added to the reaction mixture, and the mixture was extracted with dichloromethane (200mL x 3). The combined organic phases were washed with saturated sodium chloride aqueous solution (200mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 3:1) to give compound N3-3.

[0494] Step 3: Under a nitrogen atmosphere at room temperature, a tetrahydrofuran (100 mL) solution of compound N3-3 (60 g, 280 mmol) was slowly added dropwise to tetrabutylammonium fluoride (1 M tetrahydrofuran solution, 420 mL). After the addition was complete, the reaction mixture was reacted at 20 °C for 2 hours. The reaction solution was concentrated, diluted with 300 mL of water, and extracted with ethyl acetate (250 mL × 3). The combined organic phases were washed with saturated sodium chloride aqueous solution (200 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 3:1) to give compound N3-4. 1 H NMR (400MHz, CDCl3) δ = 4.82 (t, J = 3.6Hz, 1H), 3.89-3.78 (m, 1H), 3.58-3.50 (m, 1H), 2.40 (s, 1H), 1.89-1.71 (m, 2H), 1.67-1.48 (m, 4H).

[0495] Step 4: Under a nitrogen atmosphere at -70°C, n-butyllithium (2.5M tetrahydrofuran solution, 49.5mL) was slowly added dropwise to a tetrahydrofuran (600mL) solution of compound N3-4 (16g, 113mmol). The mixture was stirred at -70°C for 30min, followed by slow addition of paraformaldehyde (10g, 337mmol). The reaction mixture was slowly heated to 25°C and stirred for 16h. At 0°C, a saturated ammonium chloride solution (200mL) was added to the reaction system, and the mixture was extracted with methyl tert-butyl ether (250mL × 2). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10 / 1-5 / 1) to give compound N3-5. 1 H NMR (400MHz, CDCl3) δ = 4.81 (t, J = 3.6Hz, 1H), 4.29 (s, 2H), 3.87-3.78 (m, 1H), 3.58-3.49 (m, 1H), 1.89-1.68 (m, 2H), 1.67-1.41 (m, 4H).

[0496] Step 5: Under a nitrogen atmosphere at 0°C, slowly add a solution of compound N3-5 (14 g, 81.3 mmol) in tetrahydrofuran (250 mL) to a solution of lithium aluminum hydride (2.5 M tetrahydrofuran solution, 35.8 mL) in 100 mL of tetrahydrofuran. Then heat to 70°C and stir for 1.5 hours. Cool the reaction solution to 0°C, and slowly add sodium sulfate decahydrate solid (15 g) in portions. Stir at room temperature for 30 minutes, filter, and collect the filtrate. Add tetrahydrofuran (200 mL) to the filter residue, stir for 0.5 hours, and filter again. Combine all filtrates and concentrate under reduced pressure to obtain the crude product. Purify the crude product by silica gel column chromatography (petroleum ether: methyl tert-butyl ether = 1:0-1:9) to obtain compound N3-6. 1 H NMR (400MHz, CDCl3) δ = 5.35 (t, J = 6.4Hz, 1H), 4.14 (d, J = 4.0Hz, 2H).

[0497] Step 6: Under a nitrogen atmosphere at 0°C, tributyl cyanimide (15 g, 62.15 mmol) was added to a solution of compound N3-6 (2.69 g, 37.3 mmol) and bis(tert-butyloxycarbonyl)amine (2.7 g, 12.4 mmol) in dioxane (15 mL), followed by heating to 60°C and stirring for 1 hour. Water (50 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (50 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:0-8:1) to obtain compound N3-7. 1 H NMR (400MHz, CDCl3) δ = 5.22 (t, J = 6.0Hz, 1H), 4.18 (d, J = 6.0Hz, 2H), 1.51 (s, 18H).

[0498] Step 7: Under a nitrogen atmosphere at 0°C, compound N3-7 (5.4 g, 19.9 mmol) was slowly added to an HCl / ethyl acetate solution (2 M, 100 mL), and stirred at room temperature for 1 hour. The reaction solution was concentrated, and methyl tert-butyl ether (50 mL) was added to the residue. The mixture was stirred at room temperature for 0.5 hours, filtered, and the filter cake was collected to obtain the crude hydrochloride of compound N3.

[0499] Example B1

[0500] Step 1: Under a nitrogen atmosphere at 0°C, N-bromosuccinimide (1.79 g, 10.0 mmol) was added in portions to a solution of compound B1-1 (2 g, 9.13 mmol) in N,N-dimethylacetamide (20 mL). The reaction mixture was reacted at 20°C for 1 hour. Ethyl acetate (50 mL) was added to the reaction mixture, and the mixture was washed with water (50 mL × 3). The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product, which was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1 to 5 / 1) to obtain compound B1-2. 1 H NMR (400MHz, CDCl3) δ=7.82 (d, J=2.4Hz, 1H), 7.50 (dd, J=2.4, 8.8Hz, 1H), 6.72 (d, J=8.8Hz, 1H), 4.48 (br s, 2H).

[0501] Step 2: Under a nitrogen atmosphere at 25°C, compound B1-2 (2.1 g, 7.05 mmol), 1,1-bis(diphenylphosphine)ferrocene palladium chloride (516 mg, 705 μmol), and N,N-diisopropylethylamine (1.82 g, 14.1 mmol) were dissolved in methanol (60 mL), and CO gas was purged. The reaction mixture was then reacted at 80°C for 16 hours under a CO atmosphere. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was then subjected to silica gel column chromatography (petroleum ether / ethyl acetate = 4 / 1 to 1 / 1) to obtain compound B1-3. 1 H NMR (400MHz, CDCl3) δ=8.27 (d, J=2.8Hz, 1H), 7.60 (dd, J=2.8, 9.2Hz, 1H), 6.64 (d, J=9.2Hz, 1H), 3.91 (s, 3H).

[0502] Step 3: Under a nitrogen atmosphere at 0°C, compound B1-3 (6.1 g, 22.0 mmol) was added to acetonitrile (60 mL), followed by cuprous bromide (9.47 g, 66.0 mmol) and tert-butyl nitrite (3.40 g, 33.0 mmol). The reaction mixture was stirred at 60°C for 2 hours. After cooling to room temperature, the mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. This crude product was then subjected to silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 20 / 1) to obtain compound B1-4. 1 HNMR (400MHz, CDCl3) δ = 8.12 (d, J = 2.8Hz, 1H), 7.74-7.68 (m, 1H), 7.66-7.59 (m, 1H), 3.91 (s, 3H).

[0503] Step 4: Under a nitrogen atmosphere at 25°C, add ethyl bromoacetate (3.19 g, 19.1 mmol), (4,4-di-tert-butyl-2,2-bipyridine)bis[3,5-difluoro-2-[5-trifluoromethyl-2-pyridyl-κN]phenyl-κC]iridium(III) hexafluorophosphate (CAS: 870987-63-6, 224 mg, 0.15 mmol), 4,4-di-tert-butyl-2,2-bipyridine nickel(II) chloride (CAS: 1034901-50-2, 30 mg, 0.07 mmol), tris(trimethylsilyl)silane (3.64 g, 14.66 mmol), and sodium carbonate (42.4 mg, 29.3 mmol) to a solution of compound B1-4 (5.0 g, 14.7 mmol) in ethylene glycol dimethyl ether (50 mL). Nitrogen gas was purged, and the reaction mixture was stirred at 25°C for 16 hours under illumination (455nm blue LED). The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was then subjected to silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 20 / 1) to give compound B1-5. 1 HNMR (400MHz, CDCl3) δ = 8.41 (d, J = 2.4Hz, 1H), 7.86 (dd, J = 2.8, 8.4Hz, 1H), 7.39 (d, J =8.4Hz, 1H), 4.18 (q, J = 7.2Hz, 2H), 4.08 (s, 2H), 3.93 (s, 3H), 1.27 (t, J = 7.2Hz, 3H).

[0504] Step 5: Under a nitrogen atmosphere at 0°C, N-bromosuccinimide (590 mg, 3.32 mmol) and azobisisobutyronitrile (77.8 mg, 474 μmol) were added to a carbon tetrachloride (20 mL) solution of compound B1-5 (1.1 g, 3.16 mmol). The reaction solution was stirred at 85°C for 2 hours. Ethyl acetate (50 mL) was added to the reaction solution, and the mixture was washed with water (50 mL × 3). The organic phase was then washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product, which was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 20 / 1) to obtain compound B1-6. 1 HNMR (400MHz, CDCl3) δ = 8.37 (d, J = 2.4Hz, 1H), 8.09-8.02 (m, 1H), 7.95 (dd, J = 2.4 ,8.8Hz,1H),6.54(s,1H),4.32-4.24(m,2H),3.98(s,3H),1.31(t,J=7.2Hz,3H).

[0505] Step 6: Under a nitrogen atmosphere at 0°C, sodium bicarbonate (393 mg, 4.68 mmol) and p-methoxybenzylamine (385 mg, 2.81 mmol) were added to a 20 mL solution of compound B1-6 (1 g, 2.34 mmol) in acetonitrile. The reaction mixture was stirred at 80°C for 3 hours. Ethyl acetate (50 mL) was added to the reaction mixture, and the mixture was washed with water (50 mL × 3). The organic phase was then washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product, which was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 20 / 1) to obtain compound B1-7. 1 HNMR (400MHz, CDCl3) δ=8.29(d,J=1.6Hz,1H),7.94(dd,J=2.0,8.4Hz,1H),7.65(d,J=8.4Hz,1H),7.19(d,J=8.8Hz,2 H), 6.87 (d, J = 8.4Hz, 2H), 5.44 (d, J = 14.8Hz, 1H), 4.92 (s, 1H), 4.34-4.21 (m, 3H), 3.80 (s, 3H), 1.32 (t, J = 7.2Hz, 3H).

[0506] Step 7: Under a nitrogen atmosphere at 0°C, cesium carbonate (1.73 g, 5.32 mmol) and 3-bromopropene (643 mg, 5.32 mmol) were added to a solution of compound B1-7 (800 mg, 1.77 mmol) in N,N-dimethylacetamide (10 mL). The reaction mixture was stirred at 80°C for 1.5 hours. Ethyl acetate (50 mL) was added to the reaction mixture, and the solution was washed with water (50 mL × 3). The organic phase was then washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product, which was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 10 / 1) to obtain compound B1-8. LCMS (m / z): 492.1 [M+1] + .

[0507] Step 8: Under a nitrogen atmosphere at 0°C, cerium ammonium nitrate (1.67 g, 3.05 mmol) was added to a solution of compound B1-8 (600 mg, 1.22 mmol) in acetonitrile (4 mL) and water (2 mL), and the mixture was stirred at 20°C for 1.5 hours. Ethyl acetate (50 mL) was added to the reaction solution, and the mixture was washed with water (50 mL × 3). The organic phase was then washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product, which was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 1 / 1) to give compound B1-9. LCMS (m / z): 372.1 [M+1] + .

[0508] Step 9: Under a nitrogen atmosphere at 0°C, cesium carbonate (724 mg, 2.22 mmol) and compound B1-16 (326 mg, 933 μmol) were added to a solution of compound B1-9 (330 mg, 889 μmol) in N,N-dimethylacetamide (10 mL). The reaction mixture was stirred at 60°C for 2 hours. After the reaction was complete, the solution was diluted with ethyl acetate (50 mL), washed with water (50 mL × 3), and the organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 1 / 1) to obtain compound B1-10. LCMS (m / z): 684.1 [M+1] + .

[0509] Step 10: Under a nitrogen atmosphere at 25°C, add tert-butyl carbamate (68.5 mg, 585 μmol) and methanesulfonic acid (2-dicyclohexylphosphine-3,6-dimethoxy-2,4,6-triisopropyl-1,1-biphenyl)(2-amino-1,1-biphenyl-2-yl)palladium (II) to a 200 mL solution of compound B1-10 (200 mg, 292 μmol) in 2-methyltetrahydrofuran (200 mL). (CAS: 1470372-59-8, 26.5 mg, 29.2 μmol), 2-(dicyclohexylphosphino)-3,6-dimethoxy-2-4-6-triisopropyl-1,1-biphenyl (CAS: 1070663-78-3, 15.7 mg, 29.2 μmol) and cesium carbonate (238 mg, 731 μmol), purged with nitrogen, reacted at 80 °C for 3 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product, which was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4 / 1 to 1 / 1) to give compound B1-11. LCMS (m / z): 765.3 [M+1] + .

[0510] Step 11: Under a nitrogen atmosphere at 0°C, potassium osmium tetroxide (1.35 mg, 3.66 μmol), sodium periodate (157 mg, 732 μmol), and 2,6-dimethylpyridine (39.2 mg, 366 μmol) were added to a solution of compound B1-11 (140 mg, 183 μmol) in dioxane (2 mL) and water (0.6 mL). The reaction mixture was stirred at 20°C for 2 hours. Ethyl acetate (50 mL) was added to the reaction mixture, and the solution was washed with sodium sulfite aqueous solution (50 mL × 3). The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20 / 1 to 1 / 1) to obtain compound B1-12.

[0511] Step 12: Under a nitrogen atmosphere at 0°C, triethylamine (19.1 μL, 137 μmol) was added to a dichloromethane (2 mL) solution of compound B1-12 (70 mg, 91.3 μmol) and compound B1-13 (14.4 mg, 137 μmol). After stirring for 30 minutes, sodium cyanoborohydride acetate (38.7 mg, 183 μmol) was added to the reaction solution, and the reaction solution was stirred at 20°C for 12 hours. Ethyl acetate (50 mL) was added to the reaction solution, and the mixture was washed with sodium bicarbonate aqueous solution (50 mL × 3). The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20 / 1 to 0 / 1) to obtain compound B1-14. LCMS (m / z): 774.3 [M+1] + .

[0512] Step 13: Under a nitrogen atmosphere at 0°C, trifluoroacetic acid (240 μL) was added to a dichloromethane (2 mL) solution of compound B1-14 (60 mg, 77.5 μmol). The reaction mixture was stirred at 20°C for 2 hours. The reaction mixture was concentrated under reduced pressure to obtain crude compound B1-15, which was used directly in the next step. LCMS (m / z): 574.2 [M+1] + .

[0513] Step 14: Under a nitrogen atmosphere at 0°C, ammonia (106 μL, 767 μmol, 28% purity) was added to a 1 mL solution of acetonitrile containing 44 mg of crude compound B1-15. The reaction mixture was stirred at 40°C for 3 hours. The reaction mixture was then concentrated under reduced pressure to obtain compound B1. LCMS (m / z): 544.2 [M+1] + .

[0514] Step 15: Compound B1 (40 mg) was prepared and separated by SFC (column: DAICEL CHIRALPAK AS-H (250 mm * 30 mm, 5 μm); mobile phase: phase A is supercritical carbon dioxide, phase B is ethanol (0.1% ammonia); gradient (B%): 25%), and then prepared and separated by HPLC (column: water Xbridge C18 150 * 25 mm * 5 μm; mobile phase: water (0.05% ammonia) - acetonitrile; gradient (acetonitrile%): 32%-62%) to obtain compounds B1a and B1b.

[0515] Characterization of compound B1a: LCMS (m / z): 544.2 [M+1] + ; 1H NMR (400MHz, DMSO-d6) δ = 10.69 (d, J = 1.2Hz, 1H), 8.26 (dd, J = 2.2, 8.4Hz, 1H), 8.17 (d, J = 2 .0Hz,1H),7.80(d,J=8.4Hz,1H),7.35(d,J=11.6Hz,1H),6.13(d,J=1.2Hz,1H),5.51(s,2 H),5.04(d,J=16.4Hz,1H),4.31(d,J=16.4Hz,1H),4.17-3.97(m,2H),3.84-3.72(m,1H), 3.57(dt,J=3.2,9.6Hz,1H),2.55-2.52(m,1H),2.45-2.34(m,1H),1.87(t,J=2.4Hz,3H); 19 F NMR (376MHz, DMSO-d6) δ=86.20-85.39(m,1F), 64.69(d,J=150.8Hz,4F), -144.69(s,1F); SFC detection (column: Chiralpak AS-3 50×4.6mm ID, 3μm; mobile phase: A phase is supercritical carbon dioxide, B phase is EtOH (0.05% diethylamine); gradient (B%): 5%-40%), the retention time of compound B1a was 1.329 min, and the chiral purity was 100%.

[0516] Characterization of compound B1b: LCMS (m / z): 544.2 [M+1] + ; 1 HNMR(400MHz, DMSO-d6)δ=10.69(d,J=1.6Hz,1H),8.26(dd,J=2.2,8.4Hz,1H),8.17(d,J=2.0Hz,1H),7.80(d,J=8.4Hz,1H),7.35(d,J=11.6Hz,1H), 6.13(s,1H),5.51(s,2H),5.04(d,J=16.4Hz,1H),4.31(d,J=16.4Hz,1H), 4.18-3.97(m,2H),3.84-3.73(m,1H),3.56(dt,J=3.2,9.6Hz,1H),2.54(br d,J=2.8Hz,1H),2.45-2.34(m,1H),1.87(t,J=2.3Hz,3H); 19F NMR (376MHz, DMSO-d6) δ=86.19-85.39(m,1F), 64.69(d,J=150.8Hz,4F), -144.70(s,1F); SFC detection (column: Chiralpak AS-3 50×4.6mm ID, 3μm; mobile phase: A phase is supercritical carbon dioxide, B phase is EtOH (0.05% diethylamine); gradient (B%): 5%-40%), the retention time of compound B1b was 1.481 min, and the chiral purity was 96.20%.

[0517] Example B2

[0518] Step 1: At room temperature, ammonium acetate (3.00 g, 38.9 mmol) and acetic acid (650 mg, 10.8 mmol) were added to a mixed solution of compound B2-1 (500 mg, 776 μmol), methanol (5 mL), and tetrahydrofuran (5 mL). The reaction solution was reacted at 25 °C for 1 hour. Then, sodium cyanoborohydride (82.9 mg, 1.32 mmol) was added to the reaction solution, and the reaction was continued at 25 °C for 4 hours. The reaction solution was cooled to room temperature, and water (50 mL) was added. Extraction was performed with dichloromethane (50 mL × 2). The combined organic phases were washed successively with saturated sodium bicarbonate aqueous solution and saturated brine (20 mL × 2). The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. Purification was achieved by reversed-phase column chromatography (column: Phenomenex Luna C18 150 × 25 mm × 10 μm; mobile phase: [water (0.1% trifluoroacetic acid) - acetonitrile]; gradient (acetonitrile %): 18%-48%) to give compound B2-2. LCMS (m / z): 646.2 [M + H] + .

[0519] Step 2: Under a nitrogen atmosphere at 25°C, sodium bicarbonate (130 mg, 1.55 mmol) was added to a methanol (3 mL) solution of compound B2-2 (100 mg, 154.85 μmol), and the mixture was stirred at 25°C for 4 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by reversed-phase column chromatography (column: Phenomenex luna C18 150 × 25 mm × 10 μm; mobile phase: [water (0.225% formic acid) - acetonitrile]; gradient (acetonitrile %): 53%-83%) to obtain compound B2-3. LCMS (m / z): 614.2 [M+H] + .

[0520] Step 3: Under a nitrogen atmosphere at 0°C, sodium hydride (8.08 mg, 202.04 μmol, 60% purity) was added to a tetrahydrofuran (2 mL) solution of compound B2-3 (62 mg, 101.02 μmol). The mixture was stirred at 0°C for 30 minutes, followed by the addition of compound N1 (17.80 mg, 101.02 μmol) and sodium iodide (7.57 mg, 50.51 μmol). The reaction mixture was stirred at 25°C for 2 hours. A saturated ammonium chloride solution (5 mL) was added dropwise to the reaction mixture, followed by dilution with water (10 mL). The mixture was extracted with ethyl acetate (10 mL × 3). The combined organic phases were washed with a saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was preparatively separated by reversed-phase column chromatography (column: FLASH C18, 60 g; mobile phase: water-acetonitrile; gradient (acetonitrile%): 0–95%) to obtain compound B2-4. LCMS (m / z): 694.3 [M+H] + .

[0521] Step 4: Under ice-water bath conditions, trifluoroacetic acid (25.69 μL, 345.89 μmol) was added to a solution of compound B2-4 (12 mg, 17.29 μmol) in dichloromethane (0.5 mL). The mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure. Tetrahydrofuran (1 mL) and ammonia (7 M, 23.16 μL) were added to the residue, and the mixture was stirred at 40 °C for 1 hour. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was preparatively purified by reverse-phase column chromatography (column: Phenomenex Luna C18150*25 mm*10 μm; mobile phase: [water (0.225% acetic acid)-acetonitrile]; gradient (acetonitrile%): 15%-35%) to obtain compound B2. LCMS (m / z): 464.2 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ = 10.76 (br d, J = 5.6Hz, 1H), 7.63-7.48 (m, 3H), 7.40 (br d,J=11.6Hz,1H),6.11(s,1H),5.74-5.51(m,2H),5.10-5.00(m,2H),4.35-4.17(m,1H),3.96(br t, J=6.8Hz, 1H), 3.78-3.66 (m, 1H), 3.53-3.39 (m, 1H), 2.02-1.45 (m, 6H); F NMR (376MHz, DMSO-d6) δ = -112.269, -144.793.

[0522] Examples B2a and B2b

[0523] Step 1: Under a nitrogen atmosphere at 0°C, sodium hydride (8.06 mg, 202 μmol, 60% purity) was added to a tetrahydrofuran (3 mL) solution of compound N2 (100 mg, 134 μmol), and the mixture was stirred at 0°C for 30 minutes. Then, compound N1 (35.5 mg, 202 μmol) and sodium iodide (30.2 mg, 202 μmol) were added, and the mixture was stirred at 25°C for 0.5 hours. Compound N1 (35.5 mg, 202 μmol) and sodium hydride (8.06 mg, 202 μmol, 60% purity) were added again at 0°C. The mixture was stirred at 25°C for 0.5 hours. The reaction mixture was quenched by adding 20 mL of saturated ammonium chloride solution dropwise at 0°C. The mixture was extracted with ethyl acetate (20 mL × 3), washed with 20 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1-1:1) to give compound B2-5. LCMS (m / z): 824.5 [M+H] + .

[0524] Step 2: Compound B2-5 was prepared and separated by SFC (column: DAICEL CHIRALCEL OX (250mm*30mm, 10μm); mobile phase: phase A is supercritical carbon dioxide, phase B is MeOH (0.1% ammonia); gradient (B%): 40%) to obtain compounds B2-5a and B2-5b.

[0525] Characterization of compound B2-5a: 1 H NMR (400MHz, CDCl3) δ = 7.67-7.45 (m, 2H), 7.27-7.10 (m, 2H), 6.55 (s, 1H) ,5.64-5.40(m,2H),5.39-5.02(m,3H),5.02-4.63(m,2H),3.98-3.59(m, 4H),3.57-3.22(m,4H),2.77-2.39(m,1H),2.32-2.17(m,1H),1.71(dd,J =2.4,17.6Hz,6H),1.42(s,9H),0.95-0.69(m,4H),0.08--0.17(m,18H). SFC detection (column: Chiralcel OX-3 50*4.6mm ID, 3um; mobile phase: phase A is supercritical carbon dioxide, phase B is MeOH (0.05% diethylamine); gradient (B%): 10%-60%), the retention time of compound B2-5a was 1.749 min, and the chiral purity was 99.19%.

[0526] Characterization of compound B2-5b: 1H NMR(400MHz, CDCl3)δ=7.70-7.51(m,2H),7.38-7.26(m,2H),6.60(s,1H) ,5.68-5.46(m,2H),5.45-5.08(m,3H),5.08-4.62(m,2H),4.10-3.63(m, 4H),3.63-3.22(m,4H),2.80-2.41(m,1H),2.40-2.20(m,1H),1.77(dd,J =2.4,18.0Hz,6H),1.47(s,9H),1.14-0.72(m,4H),0.19--0.12(m,18H). SFC detection (column: Chiralcel OX-3 50*4.6mm ID, 3um; mobile phase: phase A is supercritical carbon dioxide, phase B is MeOH (0.05% diethylamine); gradient (B%): 10%-60%), the retention time of compound B2-5b was 1.485 min, and the chiral purity was 100%.

[0527] Step 3: Under a nitrogen atmosphere at room temperature, add 0.6 mL of trifluoroacetic acid to a 3 mL solution of compound B2-5a (15 mg, 18.2 μmol) in dichloromethane. Stir at room temperature for 3 hours, then concentrate under reduced pressure. Add 1 mL of tetrahydrofuran and 1 mL of ammonia to the residue, and stir at 25 °C for 14 hours. Concentrate the reaction solution under reduced pressure, and preparatively separate the residue by high performance liquid chromatography (HPLC) (column: Phenomenex Luna C18 150*25 mm*10 μm; mobile phase: water (0.225% formic acid)-acetonitrile; gradient (acetonitrile%): 9%-39%) to obtain compound B2a. LCMS (m / z): 464.3 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ=10.79(s,1H),7.84-7.50(m,3H),7.43(d,J=11.6Hz,1H),6.11(s,1H),5.96-5.36(m,2H),5.17-4.87(m,2H),4.25( d,J=16.4Hz,1H),3.98-3.82(m,1H),3.82-3.65(m,2H),3.51-3.44(m,1H),2.46-2.36(m,2H),1.71(d,J=2.8Hz,3H),1.65(d,J=2.8Hz,3H); 19F NMR (376MHz, DMSO-d6) δ=-112.23(s,1F), -144.78(s,1F). SFC detection (column: Chiralpak IK-3 50*4.6mm ID, 3μm; mobile phase: phase A is supercritical carbon dioxide, phase B is isopropanol / acetonitrile (0.05% diethylamine); gradient (B%): 20%-60%), the retention time of compound B2a was 1.668 min, and the chiral purity was 97.19%.

[0528] Using the same method as above, crude compound B2b was obtained from compound B2-5b. The crude product was then preparatively separated by high-performance liquid chromatography (HPLC) (column: Phenomenex Luna C18 150*25mm*10μm; mobile phase: water (0.225% formic acid)-acetonitrile; gradient (acetonitrile%): 8%-38%) to obtain compound B2b. LCMS (m / z): 464.3 [M+1] + ; 1 H NMR (400MHz, DMSO-d6) δ=10.78(s,1H),7.64-7.47(m,3H),7.42(d,J=11.6Hz,1H),6.11(s,1H),5.93-5.40(m,2H),5.20-4.79(m,2H),4.25( d,J=16.4Hz,1H),3.96-3.82(m,1H),3.81-3.62(m,2H),3.51-3.44(m,1H),2.45-2.34(m,2H),1.71(d,J=2.8Hz,3H),1.65(d,J=2.8Hz,3H); 19 F NMR (376MHz, DMSO-d6) δ=-112.24(s,1F), -144.78(s,1F). SFC detection (column: Chiralpak IK-350*4.6mm ID, 3μm; mobile phase: phase A is supercritical carbon dioxide, phase B is isopropanol / acetonitrile (0.05% diethylamine); gradient (B%): 20%-60%), the retention time of compound B2b was 1.870 min, and the chiral purity was 98.22%.

[0529] Example B3

[0530] Step 1: Under a nitrogen atmosphere at room temperature, compound B3-3 (1.35 g, 7.98 mmol) was added to a solution of dioxane (2 M, 28 mL) of hydrogen chloride, and the reaction was carried out at 25 °C for 1 hour. The reaction solution was concentrated under reduced pressure to obtain crude hydrochloride of compound B3-1.

[0531] Step 2: Under a nitrogen atmosphere at room temperature, triethylamine (1.18 mg, 11.6 mmol) and compound B3-1 (817 mg, crude hydrochloride) were added sequentially to a solution of compound N2-3 (3 g, 3.87 mmol) in 1,2-dichloroethane (75 mL). The reaction was carried out at 25 °C for 0.5 h. Sodium borohydride acetate (2.46 g, 11.6 mmol) was then added to the reaction solution, and the reaction was continued at 25 °C for 15 h. Water (25 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (25 mL × 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1-1:1) to obtain compound B3-2. LCMS (m / z): 796.5 [M+H] + .

[0532] Step 3: Under a nitrogen atmosphere at room temperature, trifluoroacetic acid (5.4 mL) was added to a solution of compound B3-2 (2.7 g, 3.39 mmol) in dichloromethane (27 mL). The reaction mixture was reacted at room temperature for 2 hours. The reaction mixture was then purged with a nitrogen stream to remove trifluoroacetic acid and dichloromethane. Acetonitrile (20.25 mL) and ammonia (13.5 mL) were then added, and the reaction was continued at 40 °C for 14 hours. The reaction mixture was concentrated under reduced pressure to obtain the residue, which was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1-0:1) to obtain compound B3. LCMS (m / z): 436.2 [M+H] + .

[0533] Step 4: Compound B3 (800 mg) was prepared and separated by SFC (column: DAICEL CHIRALCEL OD (250 mm * 30 mm, 10 μm); mobile phase: phase A is supercritical carbon dioxide, phase B is isopropanol (0.1% ammonia); gradient (B%): 50%) to obtain compounds B3a and B3b.

[0534] Characterization of compound B3a: LCMS (m / z): 436.3 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ = 10.79 (s, 1H), 7.68-7.55 (m, 2H), 7.55-7.48 (m, 1H), 7.44 (d, J = 11.2Hz, 1H), 6.12 (s, 1H), 5.95-5.53 (m, 2H), 5. 35-5.21(m,1H),5.09-4.91(m,3H),4.29(d,J=16.0Hz,1H),4.01-3.80(m,2H),3.80-3.70(m,1H),3.51-3.46(m,1H),2.45-2.33(m,2H); 19F NMR (376MHz, DMSO-d6) δ=-112.25(s,1F),-144.76(s,1F); SFC detection (column: Chiralcel OD-3 50*4.6mm ID, 3μm; mobile phase: phase A is supercritical carbon dioxide, phase B is isopropanol (0.05% diethylamine); gradient (B%): 20%-60%): the retention time of compound B3a was 1.188 min, and the chiral purity was 99.60%.

[0535] Characterization of compound B3b: LCMS (m / z): 436.2 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ = 10.73 (s, 1H), 7.71-7.55 (m, 2H), 7.55-7.47 (m, 1H), 7.40 (d, J = 11.6Hz, 1H), 6.11 (s, 1H), 5.87-5.40 (m, 2H), 5. 35-5.21(m,1H),5.10-4.92(m,3H),4.28(d,J=16.8Hz,1H),4.02-3.80(m,2H),3.80-3.68(m,1H),3.52-3.45(m,1H),2.48-2.30(m,2H); 19 F NMR (376MHz, DMSO-d6) δ=-112.27(s,1F),-144.80(s,1F); SFC detection (column: Chiralcel OD-3 50*4.6mm ID, 3μm; mobile phase: phase A is supercritical carbon dioxide, phase B is isopropanol (0.05% diethylamine); gradient (B%): 20%-60%): the retention time of compound B3b was 1.456 min, and the chiral purity was 99.87%.

[0536] Example B4

[0537] Steps 1-3: Following the synthesis method of Example B3, compound B4 was prepared. LCMS (m / z): 518.4 [M+H] + .

[0538] Step 4: Compound B4 was separated by SFC (column: DAICEL CHIRALCEL OD (250mm*30mm, 10um); mobile phase: phase A was supercritical carbon dioxide, phase B was isopropanol (0.1% ammonia); gradient (B%): 30%-60%) to obtain two crude products, which were then further separated by reversed-phase column chromatography (column: Waters Xbridge C18 150*25mm*5um; mobile phase: water (0.05% ammonia)-acetonitrile; gradient (acetonitrile%): 32%-62%) to obtain compounds B4a and B4b.

[0539] Characterization of compound B4a: LCMS (m / z): 518.3 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ = 10.70 (s, 1H), 7.72-7.55 (m, 2H), 7.52 (s, 1H), 7.36 (d, J = 11 .2Hz,1H),6.07(s,1H),5.50(s,2H),5.44-5.34(m,1H),5.32-5.17(m,1H),5.01(d,J= 16.8Hz,1H),4.23(d,J=16.4Hz,1H),4.03-3.86(m,1H),3.85-3.69(m,2H),3.51-3.4 1(m,1H),2.48-2.29(m,2H),2.02-1.85(m,1H),1.78-1.46(m,5H),1.29-0.90(m,5H); 19 F NMR (376MHz, DMSO-d6) δ=-112.28(s,1F), -144.90(s,1F). SFC detection (column: Lux 3um Cellulose-4 50*4.6mm ID, 3μm; mobile phase: phase A is supercritical carbon dioxide, phase B is isopropanol / acetonitrile (0.05% diethylamine); gradient (B%): 20%-60%), the retention time of compound B4a was 1.889 min, and the chiral purity was 100%.

[0540] Characterization of compound B4b: LCMS (m / z): 518.4 [M+H] + ; 1H NMR (400MHz, DMSO-d6) δ = 10.94 (s, 1H), 7.75-7.40 (m, 4H), 6.35-5.65 (m, 3H), 5.48-5.32 (m, 1H), 5.29-5.16 (m, 1H), 4.96 (d, J = 16.4Hz, 1H) ,4.31(d,J=16.4Hz,1H),4.04-3.66(m,3H),3.55-3.46(m,1H),2.47- 2.34(m,2H),2.04-1.88(m,1H),1.74-1.53(m,5H),1.26-0.98(m,5H); 19 F NMR (376MHz, DMSO-d6) δ=-112.27(s,1F), -144.73(s,1F). SFC detection (column: Lux 3um Cellulose-450*4.6mm ID, 3μm; mobile phase: phase A is supercritical carbon dioxide, phase B is isopropanol / acetonitrile (0.05% diethylamine); gradient (B%): 20%-60%), the retention time of compound B4b was 2.182 min, and the chiral purity was 90.69%.

[0541] Step 5: Using compound B4-4 as raw material, and referring to steps 1-4 above, crude products of compound B4c and compound B4d are prepared. These are then separated by reversed-phase column chromatography (column: Phenomenex Luna C18 150*25mm*10um; mobile phase: water (0.025% formic acid)-acetonitrile; gradient (acetonitrile%): 20%-50%) to obtain formate salts of compound B4c and compound B4d.

[0542] Characterization of the formate salt of compound B4c: LCMS (m / z): 518.3 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ = 10.78 (s, 1H), 8.44 (s, 1H), 7.67-7.55 (m, 2H), 7.55-7. 45(m,1H),7.36(d,J=11.2Hz,1H),6.06(s,1H),5.49(s,2H),5.44-5.34(m,1H),5 .29-5.18(m,1H),5.00(d,J=16.4Hz,1H),4.23(d,J=16.4Hz,1H),4.01-3.60(m, 4H),2.46-2.33(m,2H),2.03-1.83(m,1H),1.73-1.50(m,5H),1.25-0.93(m,5H); 19F NMR (376MHz, DMSO-d6) δ=-112.29(s,1F), -144.93(s,1F). SFC detection (column: Chiralpak IK-3 50*4.6mm ID, 3μm; mobile phase: phase A is supercritical carbon dioxide, phase B is isopropanol / acetonitrile (0.05% diethylamine); gradient (B%): 20%-60%): retention time of compound B4c is 1.806 min, chiral purity is 92.91%.

[0543] Characterization of the formate salt of compound B4d: LCMS (m / z): 518.4 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ = 10.68 (s, 1H), 7.69-7.55 (m, 2H), 7.55-7.45 (m, 1H), 7.36 (d, J = 12.0Hz, 1H), 6.10 (s, 1H), 5.50 (br s,2H),5.42-5.33(m,1H),5.31-5.19(m,1H),4.99(d,J=16.4Hz,1H),4.26(d,J=16.4Hz,1H),3.99-3.80(m,2H),3 .79-3.66(m,1H),3.61-3.45(m,1H),2.47-2.30(m,2H),2.05-1.91(m,1H),1.81-1.50(m,5H),1.31-0.97(m,5H); 19 F NMR (376MHz, DMSO-d6) δ=-112.31(s,1F), -144.82(s,1F). SFC detection (column: Chiralpak IK-3 50*4.6mm ID, 3μm; mobile phase: phase A is supercritical carbon dioxide, phase B is isopropanol / acetonitrile (0.05% diethylamine); gradient (B%): 20%-60%), the retention time of compound B4d was 2.195 min, and the chiral purity was 100%.

[0544] Example B5

[0545] Steps 1-2: Following the synthesis method of Example B3, compound B5-3 was prepared. LCMS (m / z): 872.3 [M+1] + ; 1H NMR (400MHz, CDCl3) δ = 7.56-7.47 (m, 2H), 7.37-7.30 (m, 2H), 7.26-7.18 (m, 3H), 7.11-7.05 (m, 1H), 6.97-6.66 (m, 1H), 6.55 (d, J = 3.9Hz, 1H), 6.42-6.18(m,1H),5.47-5.40(m,3H),5.14-4.89(m,2H),4.04-3.84(m ,1H),3.81-3.42(m,8H),2.61-2.41(m,1H),2.36-2.12(m,1H),1.43(br s,9H),0.97-0.71(m,5H),0.00(s,9H),-0.07(d,J=2.1Hz,9H); 19 F NMR (376MHz, CDCl3) δ = -112.273 (s, 1F), -111.577 (s, 1F).

[0546] Step 3: Under a nitrogen atmosphere, trifluoroacetic acid (888.87 μL, 11.97 mmol) was added to a solution of compound B5-3 (80 mg, 91.73 μmol) in dichloromethane (5 mL), and the mixture was stirred at 25 °C for 2 hours. The reaction solution was concentrated under reduced pressure to obtain compound B5-4. LCMS (m / z): 542.3 [M+1] + .

[0547] Step 4: Under a nitrogen atmosphere, 25% ammonia (3.20 mL, 20.77 mmol) was added to a tetrahydrofuran (5 mL) solution of compound B5-4 (55 mg, 101.56 μmol), and the mixture was stirred at 20 °C for 12 hours. The reaction solution was concentrated under reduced pressure, and the residue was preparatively separated by reversed-phase column chromatography (column: Waters Xbridge C18 150*25 mm*5 μm; mobile phase: water (0.05% ammonia)-acetonitrile; gradient (acetonitrile%): 25%-55%) to obtain compound B5. LCMS (m / z): 512.3 [M+1] + .

[0548] Step 5: Compound B5 was separated by SFC (column: REGIS(s,s)WHELK-O1 (250mm*30mm, 10um); mobile phase: phase A was supercritical carbon dioxide, phase B was isopropanol / acetonitrile + 0.2% ammonia; gradient (B%): 55%) to obtain compounds B5a and B5b. Characterization of compound B5a: LCMS (m / z): 512.3 [M+1] + ; 1H NMR(400MHz, DMSO-d6)δ=10.71-10.54(m,1H),7.60-7.51(m,1H),7.49-7.42(m,1H) ),7.40-7.31(m,2H),7.27-7.23(m,3H),7.20-7.15(m,1H),6.61-6.48(m,1H),6.04 -5.93(m,1H),5.80-5.72(m,1H),5.49(s,2H),5.03-4.81(m,1H),4.24(d,J=16.5H z,1H),4.17-4.05(m,1H),4.03-3.77(m,2H),3.52-3.40(m,2H),2.37-2.28(m,2H); 19 F NMR (376MHz, DMSO-d6) δ=-112.453(s,1F), -114.885(s,1F); SFC detection (column: (S,S)Whelk-O1 50*4.6mm ID, 3.5um; mobile phase: phase A is supercritical carbon dioxide, phase B is isopropanol / acetonitrile + 0.05% diethylamine; gradient (B%): 20%~60%), the retention time of compound B5a was 1.743 min, and the chiral purity was 99.50%.

[0549] Characterization of compound B5b: LCMS (m / z): 512.2 [M+1] + ; 1 H NMR (400MHz, DMSO-d6)δ=10.70-10.49(m,1H),7.59-7.52(m,1H),7.49-7.40(m,2H ),7.36-7.31(m,4H),7.26-7.23(m,1H),6.63-6.44(m,1H),6.08-5.89(m,1H),5.7 8(q,J=5.6Hz,1H),5.50(s,2H),5.08-4.64(m,1H),4.31-4.09(m,1H),4.04-3.99( m,1H),3.78-3.67(m,1H),3.61-3.52(m,1H),3.43-3.36(m,2H),2.41-2.28(m,2H); 19F NMR (376MHz, DMSO-d6) δ=-112.232(s,1F), -144.824(s,1F); SFC detection (column: (S,S)Whelk-O1 50*4.6mm ID, 3.5um; mobile phase: phase A is supercritical carbon dioxide, phase B is isopropanol / acetonitrile + 0.05% diethylamine; gradient (B%): 20%~60%), the retention time of compound B5b was 1.895min, and the chiral purity was 99.40%.

[0550] Step 6: Using compound B5-5 as a raw material, and referring to the above steps, compounds B5c and B5d are prepared.

[0551] Characterization of compound B5c: LCMS (m / z): 512.2 [M+1] + ; 1 H NMR (400MHz, DMSO-d6)δ=10.71-10.57(m,1H),7.60-7.39(m,3H),7.36-7.32(m,2H),7.29-7.22(m,2H),7.22-7.12(m,1H),6.68-6.45(m,1H),6. 08-5.95(m,1H),5.84-5.73(m,1H),5.50(s,2H),5.08-4.80(m,1H),4.3 4-3.88(m,3H),3.86-3.70(m,1H),3.61-3.39(m,2H),2.42-2.22(m,2H); 19 F NMR (376MHz, DMSO-d6) δ=-112.250(d,1F), -144.832(s,1F); SFC detection (column: Chiralpak IK-3 50*4.6mm ID,3um; mobile phase: phase A is supercritical carbon dioxide, phase B is ethanol (0.05% diethylamine); gradient (B%): 20%~60%), the retention time of compound B5c is 2.097min, and the chiral purity is 93.94%.

[0552] Characterization of compound B5d: LCMS (m / z): 512.2 [M+1] + ; 1H NMR(400MHz, DMSO-d6)δ=10.76-10.55(m,1H),7.60-7.38(m,3H),7.36-7.31(m,2H),7.29-7.24(m,2H),7.22-7.12(m,1H),6.62-6.50 (m,1H),6.06-5.96(m,1H),5.84-5.73(m,1H),5.50(s,2H),5.0-4.82(m,1H),4.30-3.68(m,4H),3.63-3.41(m,2H),2.40-2.26(m,2H); 19 F NMR (376MHz, DMSO-d6) δ=-112.250(d,1F), -144.900(s,1F); SFC detection (column: Chiralpak IK-3 50*4.6mm ID,3um; mobile phase: phase A is supercritical carbon dioxide, phase B is ethanol (0.05% diethylamine); gradient (B%): 20%~60%), the retention time of compound B5d was 2.441min, and the chiral purity was 99.88%.

[0553] Example B6

[0554] Step 1: Under a nitrogen atmosphere at -78°C, add n-butyllithium (2.5M tetrahydrofuran solution, 31.39mL) dropwise to a tetrahydrofuran (10g, 71.34mmol) solution of compound B6-1 (10g, 71.34mmol), stir at -78°C for 30 minutes, then slowly add compound B6-2 (5.00g, 71.34mmol), stir for 30 minutes, and then add iodomethane (17.76mL, 285.35mmol). Slowly heat the reaction solution to -20°C and add 1,3-dimethyl-3,4,5,6-tetrahydro-2-pyrimidinone (DMPU, 22.86g, 178.34mmol). Continue stirring the reaction solution at room temperature for 2 hours. Saturated ammonium chloride solution (200 mL) and water (200 mL) were added to the reaction solution, and the mixture was extracted with ethyl acetate (400 mL * 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 20:1) to give compound B6-3.

[0555] Step 2: Under a nitrogen atmosphere at room temperature, pyridine p-toluenesulfonate (1.46 g, 5.80 mmol) was added to a methanol (50 mL) solution of compound B6-3 (13 g, 57.96 mmol), and the reaction was carried out at 25 °C for 2 hours. The reaction solution was concentrated under reduced pressure, and the pH of the residue was adjusted to approximately 8 by adding saturated sodium bicarbonate solution. Water (100 mL) was added, and the mixture was extracted with ethyl acetate (100 mL * 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1) to give compound B6-4. 1 H NMR (400MHz, CDCl3) δ = 4.34 (d, J = 1.2Hz, 2H), 3.81 (d, J = 6.8Hz, 1H), 3.44 (s, 3H), 1.24-1.20 (m, 1H), 0.61-0.55 (m, 2H), 0.48-0.44 (m, 2H).

[0556] Step 3: Under a nitrogen atmosphere at room temperature, slowly add lithium aluminum tetrahydrofuran (2.5M tetrahydrofuran solution, 45.66 mL) to a tetrahydrofuran (4 g, 28.53 mmol) solution of compound B6-4, and stir for 30 minutes. Cool the reaction solution to -78°C, then add solid iodine (21.73 g, 85.60 mmol), and stir at -78°C for 2 hours. Add excess sodium sulfate decahydrate solid in portions under an ice-water bath until no gas is produced, then heat to 25°C and stir for 30 minutes. Filter, wash the filtrate with ethyl acetate (50 mL * 2), extract, wash the organic phase with saturated sodium chloride aqueous solution (10 mL), dry with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. Purify the residue by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain compound B6-5. 1 H NMR (400MHz, CDCl3) δ = 5.42-5.26 (m, 1H), 5.08 (ddd, J = 3.2, 4.8, 6.0Hz, 1H), 4.03 (t, J = 2.4Hz, 2H), 1.39 (br s,1H),1.28-1.14(m,1H),0.71-0.59(m,2H),0.41-0.20(m,2H).

[0557] Step 4: Under a nitrogen atmosphere at 0°C, potassium hydroxide (916.81 mg, 16.34 mmol) and p-toluenesulfonyl chloride (1.04 g, 5.45 mmol) were added sequentially to a tetrahydrofuran (5 mL) and water (1 mL) solution of compound B6-5 (600 mg, 5.45 mmol), and the mixture was stirred at 0°C for 2 hours. Water (100 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (100 mL * 2). The combined organic phases were washed with saturated sodium chloride aqueous solution (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1) to give compound B6-6. 1 H NMR (400MHz, CDCl3) δ = 7.73 (d, J = 8.4Hz, 2H), 7.27 (d, J = 8.0Hz, 2H), 5.20-5.15 (m, 1H), 5.06-5.02 ( m,1H),4.45(t,J=7.2Hz,2H),2.38(s,3H),1.15-1.12(m,1H),0.66-0.62(m,2H),0.31-0.23(m,2H).

[0558] Step 5: Under a nitrogen atmosphere at 0°C, sodium hydroxide (60.52 mg, 1.51 mmol, 60% purity) was added to a tetrahydrofuran (1 mL) solution of compound N2 (337.74 mg, 453.96 μmol), and the mixture was stirred for 0.5 hours. Then, compound B6-6 (200 mg, 756.60 μmol) was added, and the mixture was stirred for another 1.5 hours at room temperature. A saturated ammonium chloride aqueous solution (2 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (10 mL x 2). The combined organic phases were washed with a saturated sodium chloride aqueous solution (5 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:1) to give compound B6-7. LCMS (m / z): 836.6 [M+1] + .

[0559] Step 6: Under a nitrogen atmosphere at room temperature, hexafluoroisopropanol (4 mL) and tetrabutylammonium fluoride (4 mL) were added to a tetrahydrofuran (10 mL) solution of compound B6-7 (80 mg, 95.68 μmol), and the reaction was carried out under fluid chemistry conditions (220 °C, 3 MPa) for 10 minutes. The reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 0:1) to obtain compound B6-8. LCMS (m / z): 606.3 [M+1] + .

[0560] Step 7: Under a nitrogen atmosphere at room temperature, add 0.2 mL of trifluoroacetic acid to a 1 mL solution of compound B6-8 (50.00 mg, 82.56 μmol) in dichloromethane, and stir at 25 °C for 1 hour. After purging with nitrogen to remove the organic solvent, add 0.5 mL of ammonia and 0.5 mL of acetonitrile, and stir at 20 °C for 1 hour. Concentrate the reaction solution under reduced pressure to obtain compound B6. LCMS (m / z): 476.4 [M+1] + .

[0561] Step 8: B6 (12 mg) was separated by SFC (column: DAICEL CHIRALPAK IK (250 mm * 25 mm, 10 μm); mobile phase: phase A is supercritical carbon dioxide, phase B is isopropanol / acetonitrile (0.1% ammonia); gradient (B%): 60%) to obtain crude products of two compounds, which were then further separated by reversed column chromatography (column: Phenomenex Luna C18 150 * 25 mm * 10 μm; mobile phase: water (0.225% formic acid) - acetonitrile; gradient (acetonitrile%): 15%-45%) to obtain compounds B6a and B6b.

[0562] Characterization of compound B6a: LCMS (m / z): 476.2 [M+1] + ; 1 H NMR (400MHz, DMSO-d6) δ = 10.67 (br d, J = 4.1Hz, 1H), 7.70-7.47 (m, 3H), 7.36 (d, J = 11.6Hz, 1H), 6.09 (br d,J=8.0Hz,1H),5.48(s,2H),5.35-5.20(m,2H),4.99(dd,J=4.0,16.6Hz,1H),4.26(t,J=16.4Hz,1H),3.97- 3.65(m,3H),3.58-3.42(m,1H),2.45-2.25(m,2H),1.35-1.15(m,1H),0.80-0.59(m,2H),0.43-0.18(m,2H); 19 F NMR (376MHz, DMSO-d6) δ=-112.280(s,1F), -144.808(s,1F); SFC detection (column: Chiralpak IK-3 50*4.6mm ID, 3um; mobile phase: A phase is supercritical carbon dioxide, B phase is isopropanol / acetonitrile (0.05% diethylamine); gradient (B%): 20%~60%), the retention time of compound B6a was 1.747 min, and the chiral purity was 99.16%. Characterization of compound B6b: LCMS (m / z): 476.2; 1H NMR (400MHz, DMSO-d6) δ=10.67(br d,J=5.2Hz,1H),7.73-7.45(m,3H),7.36(d,J=11.6Hz,1H),6.09(br d,J=8.8Hz,1H),5.49(s,2H),5.27(br t,J=5.6Hz,2H),4.99(br dd,J=4.0,16.0Hz,1H),4.38-4.15(m,1H),4.00-3.71(m,3H),3.59-3.42(m,1H) ),2.45-2.26(m,2H),1.37-1.16(m,1H),0.77-0.58(m,2H),0.42-0.20(m,2H); 19 F NMR (376MHz, DMSO-d6) δ=-112.2698(s,1F), -144.814(s,1F); SFC detection (column: Chiralpak IK-3 50*4.6mm ID,3um; mobile phase: phase A is supercritical carbon dioxide, phase B is isopropanol / acetonitrile (0.05% diethylamine); gradient (B%): 20%~60%), the retention time of compound B6b was 1.993min, and the chiral purity was 100%.

[0563] Example B7

[0564] Step 1: Under a nitrogen atmosphere at -78°C, add n-butyllithium (2.5M tetrahydrofuran solution, 18.83mL) dropwise to a tetrahydrofuran solution of compound B6-1 (6g, 42.80mmol), and stir at -78°C for 30 minutes. Then, slowly add compound B7-1 (5M acetaldehyde tetrahydrofuran solution, 8.56mL), and stir for 30 minutes. Next, add iodomethane (10.66mL, 171.21mmol) dropwise at -78°C. Slowly raise the temperature of the reaction solution to -20°C, add DMPU (10.97g, 85.60mmol), and stir at room temperature for 2 hours. Add saturated ammonium chloride solution (100mL) to the reaction solution, separate the layers, collect the organic phase, extract the aqueous phase with methyl tert-butyl ether (100mL × 2), combine all organic phases, dry with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 20:1) to give compound B7-2.

[0565] Step 2: Under a nitrogen atmosphere at room temperature, pyridine p-toluenesulfonate (621.10 mg, 2.47 mmol) was added to a methanol (40 mL) solution of compound B7-2 (4.9 g, 24.72 mmol), and the reaction was carried out at 25 °C for 16 hours. The reaction solution was concentrated under reduced pressure, and saturated sodium bicarbonate solution (50 mL) was added. The mixture was extracted with ethyl acetate (60 mL × 3). The combined organic phases were washed with saturated sodium chloride aqueous solution (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 3:1) to give compound B7-3.

[0566] Step 3: Under a nitrogen atmosphere at -20°C, slowly add lithium aluminum tetrahydrofuran (2.5M tetrahydrofuran solution, 35.04 mL) to a tetrahydrofuran (50 mL) solution of compound B7-3 (2.5 g, 21.90 mmol). Cool the reaction solution to -78°C, add solid iodine (16.68 g, 65.71 mmol), and then heat to -20°C and stir for 2 hours. Under an ice-water bath, add excess sodium sulfate decahydrate in portions until no gas is produced, then stir at 25°C for 30 min. Filter, and wash the residue with methyl tert-butyl ether (50 mL × 2). Concentrate the filtrate. Add methyl tert-butyl ether (50 mL) to the residue, and wash successively with saturated sodium sulfite solution (30 mL) and saturated sodium chloride aqueous solution (30 mL). Collect the organic phase, dry with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain compound B7-4. 1 H NMR (400MHz, CDCl3) δ = 5.35-5.17 (m, 2H), 4.09 (dd, J = 2.8, 5.6Hz, 2H), 1.87-1.82 (m, 1H), 1.68 (dd, J = 3.6, 6.8Hz, 3H).

[0567] Step 4: Under a nitrogen atmosphere, tributyl cyanimide (1.13 g, 4.70 mmol) was added to a 2 mL solution of dioxane (2 mL) containing compound N2 (350 mg, 469.80 μmol) and compound B7-4 (118.55 mg, 1.41 mmol), and the mixture was stirred at 60 °C for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate = 10 / 1 to 1 / 1) to give compound B7-5. LCMS (m / z): 810.4 [M+1] + .

[0568] Step 5: Under a nitrogen atmosphere at room temperature, trifluoroacetic acid (256.74 μL, 3.46 mmol) was added to a solution of compound B7-5 (200 mg, 246.89 μmol) in dichloromethane (2 mL), and the mixture was stirred at 25 °C for 2 hours. The reaction solution was concentrated under reduced pressure, and then tetrahydrofuran (1 mL) and ammonia (0.3 mL) were added. The mixture was stirred at 25 °C for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was preparatively separated by reversed-phase column chromatography (column: Phenomenex Luna C18150*25 mm*10 μm; mobile phase: water (0.225% formic acid)-acetonitrile; gradient (acetonitrile %): 14%-34%) to obtain compound B7. LCMS (m / z): 450.3 [M+1] + .

[0569] Step 6: Compound B7 (51 mg) was prepared and separated by SFC (column: DAICEL CHIRALPAK IK (250 mm * 25 mm, 10 μm); mobile phase: phase A is supercritical carbon dioxide, phase B is isopropanol / acetonitrile (0.1% ammonia); gradient (B%): 60%) to obtain compounds B7-P1 and B7-P2.

[0570] (1) Compound B7-P1 was detected by SFC (column: Chiralpak IK-3 50*4.6mm ID, 3um; mobile phase: phase A is supercritical carbon dioxide, phase B is isopropanol / acetonitrile (0.05% diethylamine); gradient (B%): 20%-60%) and showed that it contained one main peak (retention time of 1.654 min). It was detected by SFC (column: Chiralpak IH-3 50*4.6mm ID, 3um; mobile phase: phase A is supercritical carbon dioxide, phase B is ethanol (0.05% diethylamine); gradient (B%): 5%-40%) and showed that it contained two main peaks (retention times of 1.592 min and 1.733 min, with a ratio of approximately 1:1). Compound B7-P1 was further separated by SFC (column: ChiralPak IH, 250*30mm, 10um; mobile phase: A phase was supercritical carbon dioxide, B phase was ethanol (0.1% ammonia); gradient (B%): 30%) to obtain compounds B7a and B7b.

[0571] (2) Compound B7-P2 was detected by SFC (column: Chiralpak IK-3 50*4.6mm ID, 3um; mobile phase: phase A is supercritical carbon dioxide, phase B is isopropanol / acetonitrile (0.05% diethylamine); gradient (B%): 20%-60%) and showed one main peak (retention time 1.911 min). It was detected by SFC (column: Chiralpak IA-3 150*6mm ID, 3um; mobile phase: phase A is n-hexane, phase B is isopropanol (0.05% diethylamine); gradient (B%): 80%) and showed two main peaks (retention times 6.113 min and 6.987 min, with a ratio of approximately 1:1). Compound B7-P2 was further separated by SFC (column: DAICEL CHIRALCEL OD (250mm*30mm, 10µm); mobile phase: phase A was supercritical carbon dioxide, phase B was isopropanol (0.1% ammonia); gradient (B%): 30%) to obtain compounds B7c and B7d. Compound B7a was characterized: LCMS (m / z): 450.1 [M+1] + ; 1 H NMR (400MHz, DMSO-d6) δ = 10.68 (br s, 1H), 7.65-7.47 (m, 3H), 7.36 (d, J = 11.6Hz, 1H), 6.10 (s, 1H), 5.51 (s, 2H), 5.42-5.29 (m, 1H), 5.18 (br dd,J=3.2,6.0Hz,1H),5.00(d,J=16.4Hz,1H),4.26(d,J=16.4Hz,1H),3.94-3.80(m,2H),3.78-3.68(m,1H),3.50(br d,J=2.4Hz,1H),2.46-2.34(m,2H),1.68(dd,J=3.2,7.0Hz,3H); 19 F NMR (376MHz, DMSO-d6) δppm=-112.280(s,1F), -144.808(s,1F); SFC detection (column: Chiralpak IH-3 50*4.6mm ID, 3um; mobile phase: phase A is supercritical carbon dioxide, phase B is ethanol (0.05% diethylamine); gradient (B%): 5%-40%), the retention time of compound B7a was 1.583 min, and the chiral purity was 99.47%. Characterization of compound B7b: LCMS (m / z): 450.1 [M+1] + ; 1H NMR (400MHz, DMSO-d6) δ = 10.68 (br s, 1H), 7.65-7.47 (m, 3H), 7.36 (d, J = 11.6Hz, 1H), 6.10 (s, 1H), 5.51 (s, 2H), 5.42-5.29 (m, 1H), 5.18 (br dd,J=3.2,6.0Hz,1H),5.00(d,J=16.4Hz,1H),4.26(d,J=16.4Hz,1H),3.94-3.80(m,2H),3.78-3.68(m,1H),3.50(br d,J=2.4Hz,1H),2.46-2.34(m,2H),1.68(dd,J=3.2,7.0Hz,3H); 19 F NMR (376MHz, DMSO-d6) δppm=-112.280(s,1F), -144.808(s,1F); SFC detection (column: Chiralpak IH-3 50*4.6mm ID, 3um; mobile phase: phase A is supercritical carbon dioxide, phase B is ethanol (0.05% diethylamine); gradient (B%): 5%-40%), the retention time of compound B7b was 1.724 min, and the chiral purity was 96.22%. Characterization of compound B7c: LCMS (m / z): 450.1 [M+1] + ; 1 H NMR (400MHz, DMSO-d6) δ = 10.68 (br s, 1H), 7.65-7.47 (m, 3H), 7.36 (d, J = 11.6Hz, 1H), 6.10 (s, 1H), 5.51 (s, 2H), 5.42-5.29 (m, 1H), 5.18 (br dd,J=3.2,6.0Hz,1H),5.00(d,J=16.4Hz,1H),4.26(d,J=16.4Hz,1H),3.94-3.80(m,2H),3.78-3.68(m,1H),3.50(br d,J=2.4Hz,1H),2.46-2.34(m,2H),1.68(dd,J=3.2,7.0Hz,3H); 19 F NMR (376MHz, DMSO-d6) δppm=-112.280(s,1F),-144.808(s,1F); SFC detection (column: Chiralpak IA-3 150*6mm ID,3um; mobile phase: phase A is n-hexane, phase B is isopropanol (0.05% diethylamine); gradient (B%): 80%), the retention time of compound B7c was 6.096 min, and the chiral purity was 99.06%.

[0572] Characterization of compound B7d: LCMS (m / z): 450.1 [M+1] + ; 1 H NMR (400MHz, DMSO-d6) δ = 10.68 (br s, 1H), 7.65-7.47 (m, 3H), 7.36 (d, J = 11.6Hz, 1H), 6.10 (s, 1H), 5.51 (s, 2H), 5.42-5.29 (m, 1H), 5.18 (br dd,J=3.2,6.0Hz,1H),5.00(d,J=16.4Hz,1H),4.26(d,J=16.4Hz,1H),3.94-3.80(m,2H),3.78-3.68(m,1H),3.50(br d,J=2.4Hz,1H),2.46-2.34(m,2H),1.68(dd,J=3.2,7.0Hz,3H); 19 F NMR (376MHz, DMSO-d6) δppm=-112.280(s,1F),-144.808(s,1F); SFC detection (column: Chiralpak IA-3 150*6mm ID,3um; mobile phase: phase A is n-hexane, phase B is isopropanol (0.05% diethylamine); gradient (B%): 80%), the retention time of compound B7d was 7.002 min, and the chiral purity was 98.49%.

[0573] Example B8

[0574] Steps 1-4: Compound B8 was prepared according to the synthesis method of Example B5. LCMS (m / z): 492.4 [M+1] + .

[0575] Step 5: Compound B8 (147 mg) was prepared and separated by SFC (column: DAICEL CHIRALCEL OD (250 mm * 30 mm, 10 μm); mobile phase: phase A is supercritical carbon dioxide, phase B is isopropanol (0.1% ammonia); gradient (B%): 45%) to obtain compounds B8-P1 and B8-P2.

[0576] (1) Compound B8-P1 was detected by SFC (column: Chiralcel OD-3 50*4.6mm ID, 3um; mobile phase: phase A is supercritical carbon dioxide, phase B is isopropanol (0.05% diethylamine); gradient (B%): 20%-60%) and showed that it contained one main peak (retention time 1.110 min). It was detected by SFC (column: Chiralpak AS-3 50*4.6mm ID, 3um; mobile phase: phase A is supercritical carbon dioxide, phase B is ethanol (0.05% diethylamine); gradient (B%): 5%-40%) and showed that it contained two main peaks (retention times 1.313 min and 1.456 min, with a ratio of approximately 1:1). Compound B8-P1 was further separated by SFC (column: DAICL CHIRALPAK AS (250 mm * 30 mm, 10 μm); mobile phase: phase A is supercritical carbon dioxide, phase B is EtOH (0.1% ammonia); gradient (B%): 25%) to obtain compounds B8a and B8b.

[0577] (2) Compound B8-P2 was detected by SFC (column: Chiralcel OD-3 50*4.6mm ID, 3um; mobile phase: phase A: supercritical carbon dioxide, phase B: isopropanol (0.05% diethylamine); gradient (B%): 5%-40%), showing two main peaks (retention times of 3.057 min and 3.159 min, with a ratio of approximately 1:1). Compound B8-P2 was further separated by SFC (column: DAICL CHIRALCEL OD-H (250mm*30mm, 5um); mobile phase: phase A: supercritical carbon dioxide, phase B: isopropanol (0.1% ammonia); gradient (B%): 30%) to obtain compounds B8c and B8d.

[0578] Characterization of compound B8a: LCMS (m / z): 492.2 [M+1] + ; 1H NMR (400MHz, DMSO-d6) δppm=0.88(d,J=6.40Hz,6H),1.64(dt,J=13.2,6.40Hz,1H),1.89(td,J=6.8,2.40Hz,2H),2.35-2.44(m,2H),3.49(br d,J=3.2Hz,1H),3.72(br d,J=10.0Hz,1H),3.85(br dd,J=5.6,2.00Hz,2H),4.26(d,J=16.4Hz,1H),4.98(br d,J=16.0Hz,1H),5.08-5.26(m,1H),5.33(br d,J=6.0Hz,1H),5.49(s,2H),6.09(s,1H),7.35(d,J=11.6Hz,1H),7.52(br dd,J=9.2,2.4Hz,1H),7.55-7.65(m,2H),10.67(s,1H); 19 F NMR (376MHz, DMSO-d6) δppm=-112.298(s,1F),-144.820(s,1F); SFC (column: Chiralpak AS-3 50*4.6mm ID,3um; mobile phase: A phase is supercritical carbon dioxide, B phase is ethanol (0.05% diethylamine); gradient (B%): 5%-40%) showed that the retention time of compound B8a was 1.425 min and the chiral purity was 100%.

[0579] Characterization of compound B8b: LCMS (m / z): 492.2 [M+1] + ; 1 H NMR (400MHz, DMSO-d6) δppm=0.84(dd,J=6.4,2.75Hz,6H),1.59(dt,J=13.2,6.8Hz,1H),1.80(td,J=6.8,2.8Hz,2H),2.34-2 .46(m,2H),3.42-3.48(m,1H),3.72-3.80(m,1H),3.80-3.92(m,2H),4.24(d,J=16.4Hz,1H),5.01(d,J=16.4Hz,1H),5.18(br dd,J=5.2,2.8Hz,1H),5.31-5.40(m,1H),5.54(br s,2H),6.07(s,1H),7.37(d,J=11.2Hz,1H),7.48-7.55(m,1H),7.56-7.65(m,2H),10.72(br s,1H); 19F NMR (376MHz, DMSO-d6) δppm=-112.274(s,1F),-144.892(s,1F); SFC (column: Chiralpak AS-3 50*4.6mm ID,3um; mobile phase: A phase is supercritical carbon dioxide, B phase is ethanol (0.05% diethylamine); gradient (B%): 5%-40%) showed that the retention time of compound B8b was 1.563 min and the chiral purity was 99.56%.

[0580] Characterization of compound B8c: LCMS (m / z): 492.2 [M+1] + ; 1 H NMR (400MHz, DMSO-d6) δppm=0.89(d,J=6.4Hz,6H),1.64(dt,J=13.2,6.4Hz,1H),1.89(td,J=7.0 ,2.75Hz,2H),2.32-2.49(m,2H),3.46-3.52(m,1H),3.68-3.76(m,1H),3.85(dd,J=6.0,2.40Hz, 2H),4.26(d,J=16.4Hz,1H),4.98(d,J=16.0Hz,1H),5.15-5.21(m,1H),5.29-5.36(m,1H),5.50( s,2H),6.09(s,1H),7.35(d,J=11.6Hz,1H),7.48-7.55(m,1H),7.56-7.62(m,2H),10.68(s,1H); 19 F NMR (376MHz, DMSO-d6) δppm=-112.298(s,1F),-144.820(s,1F); SFC (column: Chiralcel OD-350×4.6mm ID,3um; mobile phase: A phase is supercritical carbon dioxide, B phase is isopropanol (0.05% diethylamine); gradient (B%): 5%-40%) showed that the retention time of compound B8c was 3.081 min and the chiral purity was 100%.

[0581] Characterization of compound B8d: LCMS (m / z): 492.3 [M+1] + ; 1H NMR (400MHz, DMSO-d6) δppm=0.83(dd,J=6.40,2.40Hz,6H),1.59(dt,J=13.2,6.8H z,1H),1.73-1.85(m,2H),2.34-2.45(m,2H),3.41-3.47(m,1H),3.71-3.79(m,1H), 3.79-3.94(m,2H),4.29(d,J=16.8Hz,1H),4.99(d,J=16.8Hz,1H),5.14-5.19(m,1 H),5.30-5.38(m,1H),5.70-6.11(m,1H),6.13(s,1H),7.47-7.65(m,4H),10.96(br s,1H); 19 F NMR (376MHz, DMSO-d6) δppm=-112.226(s,1F),-144.772(s,1F); SFC (column: Chiralcel OD-3 50×4.6mm ID,3um; mobile phase: A phase is supercritical carbon dioxide, B phase is isopropanol (0.05% diethylamine); gradient (B%): 5%-40%) showed that the retention time of compound B8d was 3.179 min and the chiral purity was 98.04%.

[0582] Example B9

[0583] Step 1: Under a nitrogen atmosphere at 0°C, triethylamine (1.07 g, 10.6 mmol) was slowly added dropwise to a solution of compound N3 (851 mg, crude hydrochloride) and compound B2-1 (3.4 g, 5.27 mmol) in 1,2-dichloroethane (100 mL). After the addition was complete, the mixture was stirred at room temperature for 0.5 hours. Then, sodium borohydride acetate (3.35 g, 15.8 mmol) was added in portions, and the reaction mixture was allowed to continue reacting at room temperature for 16 hours. Water (50 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (100 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was preparatively separated by reversed-phase column chromatography (column: Phenomenex luna C18 20-45 μm). Mobile phase: water (0.1% formic acid) - acetonitrile; gradient (acetonitrile %): 45%-55% to give compound B9-1. LCMS (m / z): 668.2 [M+H] + .

[0584] Step 2: Under a nitrogen atmosphere at 0°C, trifluoroacetic acid (20 mL) was added to a solution of compound B9-1 (6.3 g, 9.43 mmol) in anhydrous dichloromethane (20 mL), and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated to obtain crude trifluoroacetate of compound B9-2. LCMS (m / z): 468.3 [M+H] + .

[0585] Step 3: Under a nitrogen atmosphere at 0°C, ammonia (20 mL) was slowly added dropwise to a tetrahydrofuran (10 mL) solution of compound B9-2 (5.49 g, crude trifluoroacetate). After the addition was complete, the mixture was stirred at room temperature for 16 hours. Then, sodium borohydride acetate (3.35 g, 15.8 mmol) was added in portions, and the reaction was continued at room temperature for another 16 hours. The reaction solution was concentrated to obtain the crude product, which was then preparatively separated by high-performance liquid chromatography (HPLC) (column: Waters Xbridge Prep OBD; C18, 150 × 40 mm × 10 μm; mobile phase: water (0.1% ammonium bicarbonate) - acetonitrile; gradient (acetonitrile %): 15%-45%) to obtain compound B9. LCMS (m / z): 438.3 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ=10.67(s,1H),7.66-7.55(m,2H),7.55-7.48(m,1H),7.36(d,J=11.6Hz,1H),6.10(s,1H),5.51(s,2H),5.28(t,J=5.6 Hz,1H),5.00(d,J=16.4Hz,1H),4.27(d,J=16.4Hz,1H),3.95-3.81(m,2H),3.80-3.70(m,1H),3.48(dt,J=2.8,9.6Hz,1H),2.48-2.30(m,2H); 19 F NMR (376MHz, DMSO-d6) δ (ppm) = -112.274, -144.820.

[0586] Step 4: Compound B9 was prepared by SFC (column: DAICEL CHIRALCEL OD (250mm×30mm, 10um); mobile phase: phase A is supercritical carbon dioxide, phase B is isopropanol (0.1% ammonia); gradient (B%): 50%) to obtain compounds B9a and B9b.

[0587] Characterization of compound B9a: LCMS: 438.1 [M+H] + ; 1H NMR (400MHz, DMSO-d6) δ=10.67(s,1H),7.66-7.55(m,2H),7.55-7.48(m,1H),7.36(d,J=11.6Hz,1H),6.10(s,1H),5.51(s,2H),5.28(t,J=5.6 Hz,1H),5.00(d,J=16.4Hz,1H),4.27(d,J=16.4Hz,1H),3.95-3.81(m,2H),3.80-3.70(m,1H),3.48(dt,J=2.8,9.6Hz,1H),2.48-2.30(m,2H); 19 F NMR (376MHz, DMSO-d6) δ (ppm) = -112.280, -144.826; SFC detection (column: Chiralpak OD-3 50×4.6mm ID, 3μm; mobile phase: A phase is supercritical carbon dioxide, B phase is isopropanol (0.05% diethylamine); gradient (B%): 20%-60%), the retention time of compound B9a was 1.215 min, and the chiral purity was 99.56%.

[0588] Characterization of compound B9b: LCMS: 438.0 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ=10.67(s,1H),7.66-7.55(m,2H),7.55-7.48(m,1H),7.36(d,J=11.6Hz,1H),6.10(s,1H),5.51(s,2H),5.28(t,J=5.6 Hz,1H),5.00(d,J=16.4Hz,1H),4.27(d,J=16.4Hz,1H),3.95-3.81(m,2H),3.80-3.70(m,1H),3.48(dt,J=2.8,9.6Hz,1H),2.48-2.30(m,2H); 19 F NMR (376MHz, DMSO-d6) δ (ppm) = -112.274, -144.820; SFC detection (column: Chiralpak OD-3 50×4.6mm ID, 3μm; mobile phase: A phase is supercritical carbon dioxide, B phase is isopropanol (0.05% diethylamine); gradient (B%): 20%-60%), the retention time of compound B9b was 1.498 min, and the chiral purity was 99.50%.

[0589] Example B10

[0590] Steps 1-3: Compound B10-4 was prepared by referring to the synthesis method of Example B7. 1 H NMR (400MHz, CDCl3) δ = 5.45-5.28 (m, 2H), 4.12 (br t, J = 4.0Hz, 2H), 3.68-3.61 (m, 1H), 2.05 (tq, J = 4.8, 7.2Hz, 2H), 1.02 (t, J = 7.2Hz, 3H).

[0591] Steps 4-5: Following the synthesis method of Example B7, compound B10 was prepared. LCMS (m / z): 464.1 [M+H] + .

[0592] Step 6: Compound B10 was separated by SFC (column: DAICEL CHIRALPAK IK (250mm*25mm, 10um); mobile phase: phase A is supercritical carbon dioxide, phase B is EtOH (0.1% ammonia); gradient (B%): 72%) to obtain compounds B10a and B10b.

[0593] Characterization of compound B10a: LCMS (m / z): 464.2 [M+1] + ; 1 H NMR (400MHz, DMSO-d6) δppm=0.85-1.00(m,3H),1.89-2.08(m,2H),2.31-2.46(m,2H),3.47(br d,J=6.4Hz,1H),3.70-3.78(m,1H),3.79-3.99(m,2H),4.24(dd,J=16.4,4.80Hz,1H),5.00(dd,J=16.4,7.6Hz,1H),5.20-5.29(m,1H),5.46(br dd,J=6.0,2.8Hz,1H),5.49(s,2H),6.08(br d,J=6.0Hz,1H),7.36(d,J=11.6Hz,1H),7.46-7.66(m,3H),10.67(br s,1H); 19 F NMR (376MHz, DMSO-d6) δppm=-112.274(s,1F),-144.862(s,1F); SFC detection (column: Chiralpak IK-3 50*4.6mm ID,3um; mobile phase: phase A is supercritical carbon dioxide, phase B is ethanol (0.05% diethylamine); gradient (B%): 20%-60%), the retention time of compound B10a was 1.750 min, and the chiral purity was 100%.

[0594] Characterization of compound B10b: LCMS (m / z): 464.2 [M+1] + ; 1 H NMR (400MHz, DMSO-d6) δppm=0.86-0.99(m,3H),1.86-2.10(m,2H),2.33-2.47(m,2H),3.43-3.54(m,1H), 3.72-3.79(m,1H),3.84-3.91(m,1H),4.24(dd,J=16.4,4.4Hz,1H),5.00(dd,J=16.4,8.4Hz,1H),5.24(br s,1H),5.48(br s,1H),5.49(s,2H),6.08(br d,J=4.4Hz,1H),7.36(d,J=12.0Hz,1H),7.48-7.65(m,3H),10.68(br s,1H); 19 F NMR (376MHz, DMSO-d6) δppm=-112.274(s,1F),-144.862(s,1F); SFC detection (column: Chiralpak IK-3 50*4.6mm ID,3um; mobile phase: phase A is supercritical carbon dioxide, phase B is ethanol (0.05% diethylamine); gradient (B%): 20%-60%), the retention time of compound B10b was 2.267min, and the chiral purity was 99.78%.

[0595] Biological test data

[0596] Test Example 1: Enzyme Activity Detection

[0597] Experimental principle:

[0598] (1) Principle of PRMT5 Methyltransferase Activity Assay: The MTase-Glo detection method utilizes the property of methyltransferases to transfer methyl groups donated by S-adenosylmethionine (SAM) to histone substrates, generating SAH, to screen for inhibitors with PRMT5 inhibitory activity. The detection principle involves adding the protein PRMT5, the substrate histone H4 (1-21) peptide, and SAM to the reaction system to initiate the reaction. SAM (S-adenosylmethionine) acts as a methyl donor, transferring the methyl group to the arginine residue of the substrate protein under the catalysis of PRMT5. Simultaneously, SAM itself is converted to SAH (S-adenosylhomocysteine). After the reaction, MTase-Glo Reagent is added to convert SAH to ADP, and then MTase-Glo Detection is added to convert ADP to ATP. The Luminescence signal is then read using a microplate reader. The addition of inhibitors inhibits the PRMT5 methyltransferase activity, causing a decrease in the signal value. The effect of the inhibitor can be determined by observing the change in the signal.

[0599] (2) Principle of PRMT5-MTA Methyltransferase Activity Assay: The MTase-Glo assay method utilizes MTA to screen for inhibitors that selectively inhibit the PRMT5-MTA complex. The assay involves adding the protein PRMT5-MTA, the substrate histone H4(1-21) peptide, and SAM to the reaction system to initiate the reaction. SAM (S-adenosylmethionine) acts as a methyl donor, transferring the methyl group to the arginine residue of the substrate protein under the catalysis of PRMT5. Simultaneously, SAM itself is converted to SAH (S-adenosylhomocysteine). Upon addition of MTA (methionine), due to its high binding affinity to the SAM binding pocket, it competitively binds to PRMT5, forming the PRMT5-MTA complex, significantly inhibiting PRMT5 activity (simulating the situation in MTAP-deficient tumor cells, thus evaluating the effectiveness of PRMT5 inhibitors under this specific condition). After the reaction was complete, SAH was converted to ADP by adding MTase-Glo Reagent, and then ADP was converted to ATP by adding MTase-Glo Detection. The Luminescence signal was then read using a microplate reader. Adding an inhibitor inhibits the methyltransferase activity of PRMT5, causing a decrease in the signal value. At this point, the effect of the inhibitor can be judged by observing the change in the signal.

[0600] Experimental materials:

[0601] PRMT5, produced by Active motife, catalog number 31921; MTA, produced by Sigma-Aidrich, catalog number D5011-25MG; Bio-H4(1-21), produced by GenScript; SAM, produced by Promega, catalog number V7602(A120C); MTase-Glo TM Methyltransferase, produced by Promega, catalog number V7602(V760B, V761B).

[0602] Experimental method:

[0603] After adding inhibitors containing 0.5% DMSO using Echo, first add 2 μL of PRMT5 enzyme solution (final reaction concentration is 2 nM) or add 2 μL of PRMT5 / MTA enzyme solution (final reaction concentration is 2 nM / 1 μM). After centrifuging at 1000 rpm for 1 minute, react at 25°C for 10 minutes; then add 2 μL of H4(1-21)&SAM mixed reagent, with final concentrations of 1 μM and 5 μM respectively. After centrifuging at 1000 rpm for 1 minute, react at 25°C for 240 minutes; after the reaction is completed, first add 1 μL of MTase-Glo Reagent, after centrifuging at 1000 rpm for 1 minute, react at 25°C for 40 minutes; then add 5 μL of MTase-Glo Detection reagent, after centrifuging at 1000 rpm for 1 minute, react at 25°C for 40 minutes; finally, use the BMG instrument to read the Luminescence signal value. Set the reading of the negative control (0.5% DMSO well) as 0% inhibition rate, and the reading of the positive control (MRTX-1719 highest concentration well) as 100% inhibition rate. Use GraphPad Prism 8 software to non-linearly fit the data to a sigmoidal dose-response curve to determine the IC 50 value. The experimental results are shown in Table 1. Among them, A represents IC 50 ≤20 nM, B represents 20 nM < IC 50 ≤100 nM, C represents 100 nM < IC 50 ≤500 nM, D represents 500 nM < IC 50 ; The selectivity multiple n1 is obtained by dividing the PRTM5 IC 50 value of the compound by the RMT5-MTA IC 50 value. Among them, + represents n1 ≤ 5, ++ represents 5 < n1 < 20, +++ represents n1 ≥ 20.

[0604] Table 1 Enzyme activity test results of the compounds of the present invention

[0605] Conclusion: The compounds of this invention exhibit significant inhibitory activity against the PRMT5-MTA complex, with weak inhibition of PRMT5 and excellent selectivity.

[0606] Test Example 2: Anti-cell proliferation activity

[0607] HCT-116WT cells, HCT-116MTAP knockout cells, or LU99 cells were seeded in white 96-well plates. The plates were incubated overnight in a CO2 incubator. A 3-fold dilution of the test compound was added to the culture medium, and after mixing, the medium containing the compound was added to the cell culture plates. The final compound incubation concentration range was: 10 μM downwards in HCT-116 and LU99 cells, and 3 μM downwards in HCT-116MTAP knockout cells. DMSO-treated wells served as a compound-free control. The cells were incubated in a CO2 incubator for 7 days.

[0608] Cell viability was then assessed using CellTiter-Glo reagent (purchased from Promega). 25 μL of chemiluminescent cell viability assay reagent was added to each well of the cell plate, and the cells were incubated at room temperature for 10 minutes. The OD value of each well was then read using an EnVision multilabel analyzer (PerkinElmer).

[0609] Calculate the rate of cell proliferation inhibition by the compound based on the OD value of each well. Cell viability (%) = (Test compound well reading - Background value) / (DMSO well reading - Background value) * 100%. IC50 50 The value can be obtained by curve fitting using four parameters (obtained in the "log(inhibitor) vs. response--Variable slope" mode of GraphPad Prism).

[0610] The inhibitory activity of the compounds of this invention on the proliferation of LU99 cells is shown in Table 2-1, and the inhibitory activity on the proliferation of human colon cancer HCT-116 (WT) and HCT-116 (MTAP knockout) cells is shown in Table 2-2. Wherein, A represents IC50. 50 ≤50nM, B represents 50nM <IC 50 ≤100nM, where C represents 100nM <IC 50 ≤500nM, where D represents 500nM <IC 50 ≤2000nM, where E represents 2000nM <IC 50 The selectivity factor n2 is determined by the HCT-116(WT)IC of the compound. 50 Value divided by HCT-116 (MTAP knockout) IC 50The value is obtained, where + indicates n2 ≤ 50, ++ indicates 50 < n2 < 100, and +++ indicates n2 ≥ 100;

[0611] Table 2-1 Anti-cell proliferation activity test results of the compounds of the present invention

[0612] Table 2-2 Anti-cell proliferation activity test results of the compounds of the present invention

[0613] Conclusion: The compounds of the present invention have significant inhibitory activity against the proliferation of LU99 cells; have significant inhibitory activity against human colon cancer HCT-116 (MTAP knockout) cells, have weak inhibition against HCT-116 (WT), and have excellent selectivity.

[0614] Test Example 3: Kinetic solubility experiment

[0615] Take 10 μL of the DMSO stock solutions of the test compound and the control compound and add them to a 96-well plate; add 490 μL of the test medium to the 96-well plate respectively, seal the plate, and vortex for 2 minutes. The sample incubation concentration is 200 μΜ, where the proportion of DMSO is 2%. Place the 96-well plate on a shaker and incubate at 800 revolutions per minute at room temperature for 24 hours to reach dissolution equilibrium. After incubation, place the sample in a centrifuge and centrifuge at 4000 revolutions per minute at 25 °C for 10 minutes. Transfer the supernatant of the centrifuged sample to a filter plate and centrifuge at 4000 revolutions per minute for 5 minutes to filter and obtain the filtrate. The concentration of the filtrate is analyzed by LC-UV linear quantification (dilute the sample as needed). The thermodynamic solubility of the corresponding compound can be calculated based on the measured concentration of the filtrate.

[0616] The experimental results show that the solubilities of the hydrochlorides of compound A2, A3, A4, A5, A6, A8, A13a, and A16a are all greater than 90 μg / mL under pH 2.0 conditions and all greater than 60 μg / mL under pH 7.4 conditions; the solubilities of compounds B3b, B6b, B7c, and B7d are all greater than 180 μg / mL under pH 2.0 conditions and all greater than 160 μg / mL under pH 7.4 conditions.

[0617] Conclusion: The compounds of the present invention show good solubility under acidic and neutral conditions.

[0618] Test Example 4: Hepatocyte stability experiment

[0619] Prepare several 96-well sample precipitate plates, named T0, T15, T30, T60, T90, T0-MC, T90-MC, and blank matrix, respectively. Preheat the resuscitation and incubation media in a 37°C water bath. Remove the frozen hepatocytes from the liquid nitrogen container and immediately immerse them in the 37°C water bath (approximately 90 seconds). After the frozen portion has thawed and loosened, pour them into centrifuge tubes containing 40 mL of resuscitation media, gently inverting to resuspend the cells in the resuscitation media. Centrifuge at 100 × g for 5 minutes at room temperature, remove the supernatant, resuspend the hepatocytes in an appropriate volume of incubation media, and calculate cell viability using trypan blue staining. Add 198 μL of the hepatocyte suspension (0.51 × 10⁻⁶ m³ / h) to the centrifuge tubes. 6 (cells / mL) were added to the preheated incubation plate. For the culture medium control group, 198 μL of incubation medium without hepatocytes was added to the T0-MC and T120-MC incubation plates. All incubation plates were pre-incubated in a 37°C incubator for 10 minutes.

[0620] Then add 2 μL of the test sample and control compound working solution, mix well, and immediately place the incubation plate in the shaker inside the incubator and start the timer to begin the reaction. Prepare two replicate samples for each time point of each compound. The incubation conditions are 37°C, saturated humidity, and 5% CO2.

[0621] In the test system, the final concentration of the test sample was 1 μM, the final concentration of the control was 3 μM, and the final concentration of hepatocytes was 0.5 × 10⁻⁶. 6 The final concentration of total organic solvent was 0.96%, with DMSO at a final concentration of 0.1%. At the end of incubation at the corresponding time points, the incubation plate was removed, and 25 μL of the mixture of compound and control compound with cells was added to a sample plate containing 125 μL of stop solution (acetonitrile solution containing 200 ng / mL tolbutamide and labetalol). For blank sample plates, 25 μL of incubation medium without hepatocytes was added directly. After sealing all sample plates, they were shaken at 600 rpm for 10 minutes on a shaker, followed by centrifugation at 3220 × g for 20 minutes. The supernatants of the test and control samples were diluted with ultrapure water at a ratio of 1:3. All samples were analyzed by LC / MS / MS after mixing. The experimental results are shown in Table 3.

[0622] Table 3 Results of hepatocyte stability test of the compounds of the present invention

[0623] Conclusion: The compounds of this invention exhibit good stability in human and mouse hepatocytes.

[0624] Test Example 5: Plasma Protein Binding Rate Experiment

[0625] The protein binding rates of the compounds of this invention in CD-1 mouse and human plasma were evaluated using a balanced dialysis method. 796 μL of blank plasma from humans and CD-1 mice (plasma purchased from Bioreclamation IVT) was collected and added to either the working solution of the test compound or warfarin working solution to bring the final concentration of both the test compound and warfarin in the plasma sample to 2 μM. The samples were thoroughly mixed. The final concentration of the organic phase DMSO was 0.5%. 50 μL of the plasma sample containing the test compound and warfarin was transferred to a sample receiving plate, and the corresponding volume of blank plasma or buffer was immediately added to bring the final volume of each sample well to 100 μL, with a plasma:dialysis buffer volume ratio of 1:1. Stop solution was then added to these samples; this sample will be used as the T0 sample for recovery and stability determination. The plasma sample containing the test compound and warfarin was added to the administration end of each dialysis well, and blank dialysis buffer was added to the receiving end of the corresponding dialysis well. The dialysis plate was then sealed with a breathable membrane and placed in a humidified 5% CO2 incubator at 37°C and 100 rpm for 4 hours with shaking. After dialysis, 50 μL of the dialysis buffer sample and the dialysis plasma sample were transferred to a new sample receiving plate. The corresponding volume of blank plasma or buffer was added to the samples to make a final volume of 100 μL per well, with a plasma:dialysis buffer volume ratio of 1:1. All samples were analyzed by LC / MS / MS after protein precipitation, and the free concentration of compounds was calculated.

[0626] Conclusion: The compounds of this invention exhibit appropriate ratios of free drug concentrations in the plasma of different species, demonstrating good drug-like properties.

[0627] Test Example 6: Mouse PK Study

[0628] Six female BALB / c mice were divided into two groups of three. The intravenous (iv) group received 5% DMA + 50% PEG400 + 45% (5% glucose aqueous solution) as the solvent; the oral (po) group received 5% DMA + 95% (20% Captisol aqueous solution) as the solvent.

[0629] Whole blood was collected at 5 min (IV group only), 15 min, 30 min, 1 h, 2 h, 4 h, 8 h, and 24 h after drug administration. The whole blood was placed in anticoagulant tubes containing EDTA-K2 and centrifuged to prepare plasma. The concentration of the test substance molecules in the plasma was quantitatively detected by LC-MS / MS, and the pharmacokinetic parameters were calculated using Phoenix WinNonlin.

[0630] The experimental results are shown in Table 4. Note: CL represents the clearance rate, Vdss represents the distribution volume, and T... 1 / 2 The half-life, AUC 0-last C represents the area under the whole blood concentration-time curve from 0 to the last quantifiable time point.max To reach peak concentration; F represents bioavailability.

[0631] Table 4. Mouse PK test results of the compounds of the present invention.

[0632] Table 4 (continued) Mouse PK test results of the compounds of this invention

[0633] Conclusion: The compounds of this invention exhibited high oral exposure and oral bioavailability in mouse pharmacokinetic studies, demonstrating favorable pharmacokinetic properties.

[0634] Test Example 7: In vivo drug efficacy

[0635] BALB / c Nude mice, 6-8 weeks old, weighing 16-20 grams, female. Human non-small cell lung cancer LU99 cells (1:1 mixed with Matrigel) were subcutaneously inoculated into the right posterior dorsal region of each mouse. Tumors were inoculated when the average volume reached 100-200 mm². 3 Mice were randomly divided into groups of six. Oral administration via gavage began on the day of grouping, once or twice daily, using a solvent of 5% DMSO + 10% Solutol + 85% double-distilled water. The solvent control group (Vehicle) received the same oral gavage solution.

[0636] Daily monitoring of animal health and mortality is conducted. Routine checks include observing the impact of tumor growth and drug treatment on daily behavior, such as activity levels, food and water intake (visual assessment only), weight changes (measured twice weekly or every other day), physical signs, or other abnormalities. Tumor diameter is measured three times weekly, tumor volume (V) is calculated, and the tumor growth inhibition rate (TGI, used to evaluate the antitumor efficacy of the compound) is calculated. The calculation formula is:

[0637] V = 0.5L × W 2 L and W represent the long and short diameters of the tumor, respectively;

[0638] TGI(%) = [(1 - (mean tumor volume at the end of treatment in a certain treatment group - mean tumor volume at the beginning of treatment in that treatment group)) / (mean tumor volume at the end of treatment in the solvent control group - mean tumor volume at the beginning of treatment in the solvent control group)] × 100%.

[0639] At the end of the experiment, the mice were euthanized and the tumors were removed. The tumors were then weighed quickly after removal.

[0640] During the administration process, the mice showed no significant change in body weight and good tolerance. The specific experimental results are shown in Table 5.

[0641] Table 5. In vivo efficacy results of compound LU99 in human tumor xenograft model (CDX) mice.

[0642] Conclusion: The compounds of this invention exhibit significant antitumor effects in the LU99 CDX model, and are well tolerated and safe in mice.

Claims

1. A compound of formula (IIA-1), its stereoisomers, or a pharmaceutically acceptable salt thereof, in, Ring A is selected from one or more R. a The following groups are substituted: phenyl, naphthyl, and 5-10 membered heteroaryl groups; R a2 Selected from -C 0-4 Alkyl-NR3-OR4, -C 0-4 Alkyl-NR3-N(R3)2, -C 0-4 Alkyl-ON(R3)2 and -C 0-4 Alkyl-ON=C(R3)2; R b Selected from CH3, CF3, CD3 and cyclopropyl; R c Selected from H, D, F, Cl, Br, I, OCH3, SCH3, NHCH3, N(CH3)2, CN, and the following groups optionally substituted with one or more R: C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 Cycloalkyl, 3-6 membered heterocyclic alkyl; R3 is selected from H, CN, -COR, and the following groups optionally substituted with one or more R groups: C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3- 10 Cycloalkyl, 3-10-membered heterocycloalkyl, phenyl, -CH2-phenyl, 5-6-membered heteroaryl and -CH2-5-6-membered heteroaryl; R4 is selected from H, CN, and the following groups optionally substituted with one or more R groups: C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-10 Cycloalkyl and 3-10 membered heterocyclic alkyl groups; Each R a The following groups are independently selected from H, D, F, Cl, Br, I, OR3, SR3, N(R3)2, CN, -COR3, -NR3COR4, and optionally substituted with one or more R groups: C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, phenyl and 5-6 membered heteroaryl; Each R is independently selected from H, D, F, Cl, Br, I, OH, NH2, CN, =O, and the following groups optionally substituted by one or more F: C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, C 1-4 Alkylthio, C 1-4 Alkylamino, C 3-8 Cycloalkyl and 3-8 membered heterocyclic alkyl groups; m is selected from 0, 1, and 2.

2. The compound according to claim 1, its stereoisomers, or pharmaceutically acceptable salts thereof, wherein, Each R is independently selected from H, D, F, Cl, Br, I, OH, NH2, CN, =O, CH3, CF3, CD3, CH2CH3, OCH3, OCF3, OCD3, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

3. The compound according to claim 1, its stereoisomers, or a pharmaceutically acceptable salt thereof, wherein, Each R a The groups are independently selected from H, D, F, Cl, Br, I, =O, OH, NH2, CN, CH3, CF3, CD3, CH2CH3, OCH3, OCF3, OCD3, cyclopropyl and -COCH3, respectively.

4. The compound according to claim 1, its stereoisomers, or a pharmaceutically acceptable salt thereof, wherein, R b Selected from methyl groups optionally substituted with one or more F or D atoms; further, R b Selected from CH3 and CD3.

5. The compound according to claim 1, its stereoisomers, or pharmaceutically acceptable salts thereof, wherein, Each R c The methyl groups are independently selected from H, D, F and optionally substituted with one or more R.

6. The compound according to claim 1, its stereoisomers, or a pharmaceutically acceptable salt thereof, wherein, R3 is selected from H, CN, COOCH3, COOCH2CH3, -COOC(CH3)3, COCH3, COCH2CH3, COCH=CH2, and optionally the following groups substituted with one or more Rs: methyl, ethyl, propyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, oxacyclobutyl, aziridine, pyrrolyl, piperidinyl, Oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, pyrroleyl, triazolyl and -CH2-phenyl; further, R3 is selected from H, CH3, CHF2, CF3, CD3, CH2CH3, CH2CHF2, CH2CF3 and CD2CD3.

7. The compound according to claim 1, its stereoisomers, or a pharmaceutically acceptable salt thereof, wherein, R4 is selected from C, which is arbitrarily replaced by one or more R's. 1-4 Alkyl; further, R4 is selected from H, CH3, CH2CH3, CHF2, CF3, CD3, CH2CHF2, CH2CF3 and CD2CD3.

8. The compound according to claim 1, its stereoisomers, or pharmaceutically acceptable salts thereof, wherein, R a2 Selected from 9. The compound according to claim 1, its stereoisomers, or a pharmaceutically acceptable salt thereof, wherein, Structural unit Selected from n is selected from 0, 1, 2, 3, and 4; furthermore, structural units Selected from Furthermore, structural units Selected from 10. The compound according to claim 1, its stereoisomers, or pharmaceutically acceptable salts thereof, wherein, Structural unit Selected from Furthermore, structural units Selected from 11. The compound according to any one of claims 1 to 10, its stereoisomers, or its pharmaceutically acceptable salts, wherein the compound is selected from: in, R a R a2 R b R c As defined in any one of claims 1 to 10.

12. The compounds shown in Table A and / or Table A1, their stereoisomers, or pharmaceutically acceptable salts thereof.

13. Compounds of formula (IIB), their stereoisomers, or pharmaceutically acceptable salts thereof, in, Selected from single and double bonds; X and Y are selected separately from O and S, respectively; L 21 Selected from bonds, CO, CS, SO, SO2 and optionally R L21 The following groups are substituted: C 1-4 Alkyl, C 2-4 alkenyl, C 2- 4-Alynyl group, C 1-4 Alkoxy, C 1-4 Alkylthio, C 1-4 Alkylamino, C 3-8 Cycloalkyl and 3-8 membered heterocyclic alkyl groups; L 22 Selected from bonds, CO, CS, SO, SO2 and optionally R L22 The following groups are substituted: C 1-4 Alkyl, C 2-4 alkenyl, C 2- 4-Alynyl group, C 3-8 Cycloalkyl and 3-8 membered heterocyclic alkyl groups; L 23 Selected from bonds, CO, CS, SO, SO2 and optionally R L23 The following groups are substituted: C 1-4 Alkyl, C 2-4 alkenyl, C 2- 4-Alynyl group, C 3-8 Cycloalkyl and 3-8 membered heterocyclic alkyl groups; R 21 Selected from R 21a R 21b R 21c The following groups are independently selected from H, D, F, Cl, Br, I, OH, NH2, CN, SF5, and optionally substituted with one or more R groups: C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, C 1-4 Alkylthio, C 1-4 Alkylamino, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, phenyl, naphthyl and 5-10 membered heteroaryl; Or, R 21a With R 21b Connected together, they form a C that can be arbitrarily replaced by one or more Rs. 3-8 cycloalkyl or 3-8 membered heterocyclic alkyl; R 23 Selected from H and SF5; Ring C is selected from Among them, ring C2 is connected to L3; Ring C1 is selected from one or more Rs. c The following groups are substituted: phenyl, 5-6 membered heteroaryl and 5-8 membered heterocyclic alkyl; Ring C2 is selected from one or more Rs. c The following groups are substituted: 5-6 membered heteroaryl and 5-8 membered heterocyclic alkyl; Ring D is selected from one or more R. d The following groups are substituted: phenyl and 5-6 membered heteroaryl groups; Each R L21 Each R L22 Each R L23 Each R c Each R d The following groups are selected independently from H, D, F, Cl, Br, I, =O, OH, NH2, CN, SF5, and optionally substituted with one or more of the following groups by R: C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, C 1-4 Alkylthio, C 1-4 Alkylamino, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, phenyl, naphthyl and 5-10 membered heteroaryl; Or 2 Rs d Connected together, or 2 Rs c Linked together, they independently form the following groups, optionally substituted with one or more R groups: C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, phenyl, naphthyl and 5-10 membered heteroaryl; Each R is independently selected from H, D, F, Cl, Br, I, OH, NH2, CN, =O, COCH3, and the following groups optionally substituted by one or more F: C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, C 1-4 Alkylthio, C 1-4 Alkylamino, C 3-8 Cycloalkyl and 3-8 membered heterocyclic alkyl groups; t is selected from 0, 1, 2 and 3.

14. The compound of claim 13, its stereoisomer, or a pharmaceutically acceptable salt thereof, wherein, Each R is independently selected from H, D, F, Cl, Br, I, OH, NH2, CN, =O, CH3, CF3, CD3, CH2CH3, OCH3, OCF3, OCD3, cyclopropyl and COCH3.

15. The compound according to claim 13, its stereoisomers, or pharmaceutically acceptable salts thereof, wherein, L 21 Selected from the key and optionally by one or more R L21 The following groups are substituted: C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 Alkyne group; further, L 21 Selected from CH2 and CD2.

16. The compound according to claim 13, its stereoisomers, or pharmaceutically acceptable salts thereof, wherein, R 21a R 21b R 21c The following groups are independently selected from H, D, F, Cl, Br, I, OH, NH2, CN, and optionally substituted with one or more R groups: C 1-4 Alkyl, C 1- 4-alkoxy group, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, phenyl, and 5-6 membered heteroaryl; furthermore, R 21a R 21b R 21c Each of the following is independently selected from H, D, F, Cl, Br, I, OH, NH2, CN, CH3, CF3, CD3, CH2CH3, CH2CF3, CH2CH2CH3, CH(CH3)2, CH2CH(CH3)2, OCH3, OCF3, OCD3, -COCH3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, 17. The compound of claim 13, its stereoisomers, or pharmaceutically acceptable salts thereof, wherein, Structural unit Selected from Furthermore, structural units Selected from 18. The compound according to claim 13, its stereoisomers, or pharmaceutically acceptable salts thereof, wherein, L 22 Selected from CH2.

19. The compound according to claim 13, its stereoisomers, or pharmaceutically acceptable salts thereof, wherein, L 23 Selected from key.

20. The compound of claim 13, its stereoisomer, or a pharmaceutically acceptable salt thereof, wherein, Ring D is selected from one or more R. d The following groups may be substituted: phenyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, thiazolyl; furthermore, ring D may be selected from phenyl.

21. The compound according to claim 13, its stereoisomers, or pharmaceutically acceptable salts thereof, wherein, Structural unit Selected from T1, T2, T3, and T4 are each independently selected from N and CR. d and CR 23 Furthermore, structural units Selected from 22. The compound of claim 13, its stereoisomers, or pharmaceutically acceptable salts thereof, wherein, Structural unit Selected from Furthermore, structural units Selected from 23. The compound of formula (IIB) according to any one of claims 13 to 22, its stereoisomers or pharmaceutically acceptable salts thereof, selected from: in, Rings D, X, Y, L 21 R 21 R 23 R c t is as defined in any one of claims 13 to 22.

24. The compounds shown in Table B and / or Table B1, their stereoisomers, or pharmaceutically acceptable salts thereof.

25. The use of the compound of any one of claims 1 to 24, its stereoisomer, or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating diseases related to PRMT5 inhibitors.

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