HETEOARYL COMPOUNDS AND METHODS FOR PREPARING THEM

Abstract

The invention relates to a heteroaryl compound and a method for preparing it. Specifically, the invention proposes a heteroaryl compound with a general formula (I), a method for preparing it, and a pharmaceutical composition containing it.

Description

Heteroaryl compounds, preparation methods thereof and their use in medicine Technical Field

[0001] The present disclosure relates to the field of medicine and relates to heteroaryl compounds, methods for preparing the same, and their use in medicine. In particular, the present disclosure relates to heteroaryl compounds represented by general formula (I), methods for preparing the same, pharmaceutical compositions containing the same, and their use as PRMT5 inhibitors and for treating and / or preventing cancer. Background Art

[0002] Arginine methylation, a post-translational modification widely found in mammalian cells, is primarily controlled by protein arginine methyltransferases (PRMTs). The PRMT family consists of nine members, which can be divided into three categories based on their catalytic activity and product types: 1) Type I, which includes PRMT1, PRMT2, PRMT3, PRMT4, and PRMT8; 2) Type II, which includes PRMT5 and PRMT7; and 3) Type III, which includes only PRMT7.

[0003] Protein methylarginine transferase 5 (PRMT5), an important type II arginine methyltransferase, regulates various physiological functions in mammalian cells by symmetrically dimethylating arginine residues on histones and non-histone proteins, including epigenetic modification of the genome, regulation of RNA splicing, DNA repair, regulation of Treg cell gene expression, and antigen presentation methylation. Studies have shown that PRMT5 overexpression plays a key role in proliferative diseases, metabolic diseases, hematological disorders, and various cancers.

[0004] Homozygous deletions of the chromosome 9p21 (chr9p21) locus occur in approximately 15% of human cancers, with a frequency exceeding 50% in glioblastoma multiforme. The chr9p21 locus encompasses the CDKN2A gene, an important tumor suppressor gene encoding the key tumor suppressors p19-ARF and p16-INK4a. Losses of chr9p21 frequently involve co-deletions of nearby genes. Specifically, the gene encoding methylthioadenosine phosphorylase (MTAP), located within 100 kb of CDKN2A, is homozygous deleted in up to 80%–90% of CDKN2A-deficient tumors.

[0005] MTAP, a key enzyme in the methionine compensation pathway of the methionine cycle, metabolizes 5-methylthioadenosine (MTA), a byproduct of polyamine synthesis, to regenerate methionine and adenine. Therefore, tumor cells lacking the MTAP gene experience significant accumulation of MTA inside and outside the cells. MTA acts as a specific competitive inhibitor of PRMT5, specifically binding to the PRMT5-SAM binding pocket and thereby inhibiting PRMT5 activity. Studies have shown that PRMT5 is a synthetic lethal gene in MTAP-deficient cells, and PRMT5 inhibitors are expected to become a new generation of targeted drugs for the treatment of MTAP-deficient tumors.

[0006] Currently, PRMT5 inhibitors with various mechanisms are in clinical development. First-generation PRMT5 inhibitors are mostly PRMT5 substrate-competitive or SAM-competitive inhibitors. While killing MTAP-deficient tumor cells, they also inhibit the proliferation of normal cells. Hematotoxicity is the primary dose-limiting toxicity of current first-generation PRMT5 inhibitors.

[0007] Therefore, developing a selective PRMT5-MTA complex inhibitor that can specifically inhibit the proliferation of tumor cells with MTAP gene deletion while effectively avoiding the dose-limiting toxicity mediated by wild-type PTMR5 has become an urgent medical need.

[0008] Patent applications for disclosed PRMT5-MTA inhibitor compounds include WO2021050915A1, WO2022192745A1, WO2023202626A1, WO2023174250A1, WO2024027703A1, WO2024114635A1, WO2024008176A1, WO2023098439A1, WO2023125540A1, CN116178347A, WO2021163344A1, WO2022115377A1, WO2022132914A1, WO2022169948A1 and WO2022026892A1.

[0009] Summary of the Invention

[0010] The purpose of the present disclosure is to provide a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof:

[0011] in:

[0012] Ring A is an aryl group or a heteroaryl group;

[0013] R 0is selected from the group consisting of a hydrogen atom, an alkyl group, a haloalkyl group, a deuterated alkyl group, a hydroxyalkyl group, an alkoxy group, a haloalkoxy group, a deuterated alkoxy group, an alkoxyalkyl group, an aminoalkyl group, a cycloalkyl group, a cycloalkylalkyl group, a heterocyclyl group, and a heterocyclylalkyl group;

[0014] R 1 Selected from -(CR 1a R 1b )r-NH2、

[0015] R 1a and R 1b are the same or different and are each independently selected from a hydrogen atom, a deuterium atom, a halogen, a hydroxyl group, a cyano group, an amino group, an alkyl group, a haloalkyl group, a deuterated alkyl group, a hydroxyalkyl group, an alkoxy group, a haloalkoxy group, a deuterated alkoxy group, and a cycloalkyl group;

[0016] or R on the same carbon atom 1a and R 1b Together they form =O;

[0017] or R 1a and R 1b Together with the attached carbon atom, they form a cycloalkyl or heterocyclyl group, which is optionally substituted with one or more R;

[0018] Ring B is a cycloalkyl or heterocyclyl group, and the cycloalkyl or heterocyclyl group is optionally substituted by one or more R;

[0019] Ring C is a nitrogen-containing heterocyclic group, which is optionally substituted by one or more R;

[0020] L is selected from a bond, an alkylene group, O, S(O) v NR a 、C(O),NR a C(O) and C(O)NR a ;

[0021] R a is selected from the group consisting of a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, and a cycloalkylalkyl group;

[0022] R 2 is selected from tricyclic cycloalkyl, tricyclic heterocyclyl, tricyclic aryl and tricyclic heteroaryl, wherein the tricyclic cycloalkyl, tricyclic heterocyclyl, tricyclic aryl and tricyclic heteroaryl are each independently optionally substituted by one or more R 4 replace;

[0023] Each R 3 and R 4are the same or different and are each independently selected from a deuterium atom, a halogen, a hydroxyl group, a cyano group, a nitro group, an amino group, an alkenyl group, an alkynyl group, an alkyl group, a haloalkyl group, a deuterated alkyl group, a hydroxyalkyl group, an alkoxy group, a haloalkoxy group, a deuterated alkoxy group, an alkoxyalkyl group, an aminoalkyl group, a cycloalkyl group, a cycloalkylalkyl group, a cycloalkyloxy group, a heterocyclyl group, a heterocyclylalkyl group, a heterocyclyloxy group, an aryl group, an arylalkyl group, a heteroaryl group, a heteroarylalkyl group, a -(CH2) t NR 14 R 15 、-OR 16 、-S(O) v R 16 、-C(O)NR 14 R 15 、-C(O)R 16 、-C(O)OR 16 、-NR 17 C(O)R 16 、-S(O) v NR 14 R 15 and -NR 17 S(O) v R 16 wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkyloxy, heterocyclyl, heterocyclylalkyl, heterocyclyloxy, aryl, arylalkyl, heteroaryl and heteroarylalkyl are each independently optionally substituted with one or more R;

[0024] Alternatively, two R on the same atom 4 Together they form =O;

[0025] Or, two R 4 With R 2 The above and the ring atoms to which they are attached together form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, which is optionally substituted with one or more R;

[0026] X 1 CR 5a or N;

[0027] X 2 CR 5b or N;

[0028] X 3 CR 5 or N;

[0029] R 5a 、R 5b and R 5are the same or different and are each independently selected from a hydrogen atom, a deuterium atom, a halogen, a hydroxyl group, a cyano group, an amino group, an alkenyl group, an alkynyl group, an alkyl group, a haloalkyl group, a deuterated alkyl group, a hydroxyalkyl group, an alkoxy group, a haloalkoxy group, a deuterated alkoxy group, an alkoxyalkyl group, an aminoalkyl group, a cycloalkyl group, a cycloalkylalkyl group, a heterocyclyl group, a heterocyclylalkyl group, an aryl group, an arylalkyl group, a heteroaryl group, a heteroarylalkyl group, -(CH2) t NR 14 R 15 、-OR 16 、-C(O)NR 14 R 15 、-C(O)R 16 、-C(O)OR 16 and -NR 17 C(O)R 16 wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl are each independently optionally substituted with one or more R;

[0030] R 14 、R 15 and R 16 are the same or different at each occurrence and are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, and heteroaryl; wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, and heteroaryl groups is independently optionally substituted with one or more R;

[0031] or R 14 and R 15 Together with the nitrogen atom to which it is attached, it forms a heterocyclic group, which is optionally substituted with one or more R;

[0032] R 17 is the same or different at each occurrence and is independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group, and a cycloalkylalkyl group;

[0033] R is the same or different at each occurrence and is each independently selected from the group consisting of oxo, a deuterium atom, a halogen, a hydroxyl group, an alkenyl group, an alkynyl group, a cyano group, a nitro group, an amino group, -NHalkyl, -N(alkyl), an alkyl group, a haloalkyl group, a deuterated alkyl group, a hydroxyalkyl group, an alkoxy group, a haloalkoxy group, a deuterated alkoxy group, an alkoxyalkyl group, an aminoalkyl group, a cycloalkyl group, a cycloalkylalkyl group, a cycloalkyloxy group, a heterocyclyl group, a heterocyclylalkyl group, a heterocyclyloxy group, an aryl group, an arylalkyl group, an aryloxy group, a heteroaryl group, a heteroarylalkyl group, and a heteroaryloxy group;

[0034] m is 0, 1, 2, 3 or 4;

[0035] r is 0, 1, 2, or 3;

[0036] v is 0, 1, or 2; and

[0037] t is 0, 1, 2, or 3.

[0038] In some embodiments of the present disclosure, the compounds represented by general formula (I), general formula (II), general formula (III), general formula (III-1), general formula (III-2), general formula (IV) or pharmaceutically acceptable salts thereof are not all the compounds disclosed in WO2024027703A1 and WO2023202626A1.

[0039] In some embodiments of the present disclosure, the compound represented by formula (I), formula (II), formula (III), formula (III-1), formula (III-2) or formula (IV) or a pharmaceutically acceptable salt thereof is not the following structure:

[0040] In some embodiments of the present disclosure, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, wherein ring A is a 6- to 10-membered aryl group or a 5- to 10-membered heteroaryl group; in some embodiments, ring A is a 5- to 10-membered heteroaryl group; in some embodiments, ring A is a 5- or 6-membered heteroaryl group; in some embodiments, ring A is a 5-membered heteroaryl group; in some embodiments, ring A is a triazolyl group or a pyrazolyl group; in some embodiments, ring A is a pyrazolyl group.

[0041] In some embodiments of the present disclosure, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, wherein for R 3a is selected from the group consisting of a hydrogen atom, an alkenyl group, an alkynyl group, an alkyl group, a haloalkyl group, a deuterated alkyl group, a hydroxyalkyl group, an alkoxyalkyl group, an aminoalkyl group, a cycloalkyl group, a cycloalkylalkyl group, a heterocyclyl group, a heterocyclylalkyl group, an aryl group, an arylalkyl group, a heteroaryl group, and a heteroarylalkyl group; wherein each of the alkyl group, the alkenyl group, the alkynyl group, the cycloalkyl group, the cycloalkylalkyl group, the heterocyclyl group, the heterocyclylalkyl group, an aryl group, an arylalkyl group, a heteroaryl group, and a heteroarylalkyl group is independently optionally substituted with one or more R groups; and A is N or CR 3b ; R 3b is a hydrogen atom or R 3 ; R and R 3 As defined in formula (I); in some embodiments, for In some embodiments, for In some embodiments, for * is connected to L.

[0042] In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, wherein each R 3 are the same or different and are each independently selected from deuterium atoms, halogens, hydroxyl groups, cyano groups, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 deuterated alkyl and 3 to 8 membered cycloalkyl; in some embodiments, each R 3 The same or different, and each independently is C 1-6 Alkyl or C 1-6 deuterated alkyl; in some embodiments, each R 3 The same or different, and each independently selected from C 1-6 Alkyl, C 1-6 Haloalkyl and C 1-6 deuterated alkyl; in some embodiments, each R 3 are the same or different and are each independently selected from halogen, C 1-6 Alkyl and C 1-6 haloalkyl; in some embodiments, each R 3 The same or different, and each independently halogen or C 1-6 Alkyl; In some embodiments, R 3 C 1-6 Alkyl; in some embodiments, R 3 C 1-6 deuterated alkyl; in some embodiments, R 3 is methyl or trideuterated methyl; in some embodiments, R 3 is methyl; in some embodiments, R 3 It is a trideuterated methyl group.

[0043] In some embodiments of the present disclosure, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, wherein m is 1.

[0044] In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, wherein R 3 C 1-6 Alkyl or C 1-6 deuterated alkyl; and m is 1; in some embodiments, R 3 C 1-6 deuterated alkyl; and m is 1.

[0045] In some embodiments of the present disclosure, in the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, L is a bond.

[0046] In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, wherein R 1 For-(CR 1a R 1b )r-NH2;R 1a 、R 1b and r are as defined in Formula (I); in some embodiments, R 1 It is -CH2-NH2.

[0047] In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, wherein r is 1 or 2; in some embodiments, r is 1.

[0048] In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, wherein ring B is a 3- to 6-membered cycloalkyl group or a 3- to 6-membered heterocyclic group; in some embodiments, ring B is selected from cyclopropyl, cyclobutyl and oxetanyl.

[0049] In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, wherein R 1 for Ring B is as defined in Formula (I); in some embodiments, R 1 Selected from

[0050] In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, wherein ring C is a 3-6 membered nitrogen-containing heterocyclic group; in some embodiments, ring C is an azetidinyl group; in some embodiments, ring C is

[0051] In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, wherein R 1 for Ring C is as defined in Formula (I); in some embodiments, R 1 for

[0052] In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from -CH2-NH2,

[0053] In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, wherein X 2 CR 5b ; R 5bAs defined in formula (I); in some embodiments, X 2 For CH.

[0054] In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, wherein R 5b Selected from hydrogen atoms, deuterium atoms, halogens, cyano groups, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Deuterated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 deuterated alkoxy and 3 to 6 membered cycloalkyl; in some embodiments, R 5b Selected from hydrogen atom, halogen, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 alkoxy and 3 to 6 membered cycloalkyl; in some embodiments, R 5b Selected from hydrogen atoms, halogens and C 1-6 Alkyl; in some embodiments, R 5b A hydrogen atom.

[0055] In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, wherein X 3 CR 5 ; R 5 As defined in formula (I); in some embodiments, X 3 For CH.

[0056] In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, wherein X 1 CR 5a or N; X 2 CR 5b ;X 3 CR 5 ; R 5a 、R 5b and R 5 As defined in formula (I); in some embodiments, X 1 CR 5a ;X 2 CR 5b ;X 3 CR 5 ; R 5a 、R 5b and R 5 As defined in formula (I); in some embodiments, X 1 CH; X 2 CH; X 3 CR5 ; R 5 As defined in formula (I); in some embodiments, X 1 CH; X 2 CH; X 3 is CH; in some embodiments, X 1 CH; X 2 CH; X 3 is CH or C-CN; in some embodiments, X 1 CH; X 2 CH; X 3 It is C-CN.

[0057] In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, wherein R 0 A hydrogen atom or C 1-6 Alkyl; in some embodiments, R 0 A hydrogen atom.

[0058] In some embodiments of the present disclosure, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof is a compound represented by general formula (II) or a pharmaceutically acceptable salt thereof:

[0059] in:

[0060] R 3a is selected from the group consisting of hydrogen, alkenyl, alkynyl, alkyl, haloalkyl, deuterated alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl are each independently optionally substituted with one or more R;

[0061] A is N or CR 3b ;

[0062] R 3b is a hydrogen atom or R 3 ;

[0063] X 1 , R, R 1a 、R 1b 、R 2 、R 3 and R 5 As defined in general formula (I).

[0064] In some embodiments of the present disclosure, the compound represented by the general formula (I) or the general formula (II) or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (III) or a pharmaceutically acceptable salt thereof:

[0065] in:

[0066] Ring D is selected from bicyclic cycloalkyl, bicyclic heterocyclyl, bicyclic aryl and bicyclic heteroaryl;

[0067] R 4b and R 4c are the same or different and are each independently a hydrogen atom or R 4 ;

[0068] j is 0, 1, 2, or 3;

[0069] A.X 1 、R 1a 、R 1b 、R 3a 、R 4 and R 5 As defined in general formula (II).

[0070] In some embodiments of the present disclosure, the compound represented by the general formula (I), general formula (II) or general formula (III) or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (III-1) or general formula (III-2) or a pharmaceutically acceptable salt thereof:

[0071] in:

[0072] Ring D, A, X 1 、R 1a 、R 1b 、R 3a 、R 4 、R 4b 、R 4c 、R 5 and j are as defined in formula (III).

[0073] In some embodiments of the present disclosure, the compound represented by the general formula (III), general formula (III-1) or general formula (III-2) or a pharmaceutically acceptable salt thereof, wherein ring D is a 7- to 9-membered bicyclic heterocyclic group; in some embodiments, ring D is an 8- or 9-membered bicyclic heterocyclic group; in some embodiments, ring D is an 8-membered bicyclic heterocyclic group;

[0074] In some embodiments, Ring D is selected from n is 0, 1, or 2 (in some embodiments, 0 or 1); p is 1, 2, or 3 (in some embodiments, 1); q is 1 or 2 (in some embodiments, 1); a is 1 or 2 (in some embodiments, 2); b is 1 or 2 (in some embodiments, 1);

[0075] In some embodiments, Ring D is selected from n is 0, 1, or 2 (in some embodiments, 0 or 1); p is 1, 2, or 3 (in some embodiments, 1); q is 1 or 2 (in some embodiments, 1);

[0076] In some embodiments, Ring D is selected from a is 1 or 2 (in some embodiments, 2); b is 1 or 2 (in some embodiments, 1); n is 0, 1 or 2 (in some embodiments, 0 or 1); p is 1, 2 or 3 (in some embodiments, 1); q is 1 or 2 (in some embodiments, 1); in some embodiments, ring D is selected from n is 0, 1, or 2 (in some embodiments, 0 or 1); p is 1, 2, or 3 (in some embodiments, 1); q is 1 or 2 (in some embodiments, 1); in some embodiments, ring D is n is 0, 1 or 2 (in some embodiments 0 or 1, in some embodiments 1); in some embodiments, ring D is selected from In some embodiments, Ring D is selected from In some embodiments, Ring D is selected from In some embodiments, Ring D is selected from In some embodiments, Ring D is selected from In some embodiments, Ring D is selected from In some embodiments, Ring D is In some embodiments, Ring D is * end is connected to the side close to the cyano group, and R 4 It can be substituted at any substitutable position on ring D.

[0077] In some embodiments of the present disclosure, the compound represented by formula (I), formula (II), formula (III), formula (III-1) or formula (III-2) or a pharmaceutically acceptable salt thereof, wherein R 1a and R 1b are the same or different and are each independently selected from hydrogen atoms, deuterium atoms, halogens, C 1-6 Alkyl and C 1-6 haloalkyl; or R on the same carbon atom1a and R 1b Together form =0; in some embodiments, R 1a and R 1b are the same or different and are each independently a hydrogen atom or a deuterium atom; or R on the same carbon atom 1a and R 1b Together form =0; in some embodiments, R 1a and R 1b are the same or different and are each independently a hydrogen atom or a deuterium atom; in some embodiments, R 1a and R 1b is a hydrogen atom; in some embodiments, R 1a and R 1b is a deuterium atom; in some embodiments, R on the same carbon atom 1a and R 1b Together they form =O.

[0078] In some embodiments of the present disclosure, the compound represented by formula (I), formula (II), formula (III), formula (III-1) or formula (III-2) or a pharmaceutically acceptable salt thereof, wherein X 1 CR 5a ; R 5a As defined in formula (I); in some embodiments, X 1 CR 5a ; R 5a Selected from hydrogen atoms, halogens and C 1-6 Alkyl; in some embodiments, X 1 For CH.

[0079] In some embodiments of the present disclosure, the compound represented by formula (I), formula (II), formula (III), formula (III-1) or formula (III-2) or a pharmaceutically acceptable salt thereof, wherein R 5a Selected from hydrogen atoms, deuterium atoms, halogens, cyano groups, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Deuterated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 deuterated alkoxy and 3 to 6 membered cycloalkyl; in some embodiments, R 5a Selected from hydrogen atom, halogen, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 alkoxy and 3 to 6 membered cycloalkyl; in some embodiments, R 5a Selected from hydrogen atoms, halogens and C 1-6 Alkyl; in some embodiments, R5a A hydrogen atom.

[0080] In some embodiments of the present disclosure, the compound represented by formula (I), formula (II), formula (III), formula (III-1) or formula (III-2) or a pharmaceutically acceptable salt thereof, wherein A is CR 3b ; R 3b As defined in formula (II); in some embodiments, A is CR 3b ; R 3b Selected from hydrogen atoms, halogens and C 1-6 Alkyl; in some embodiments, A is CH.

[0081] In some embodiments of the present disclosure, the compound represented by formula (I), formula (II), formula (III), formula (III-1) or formula (III-2) or a pharmaceutically acceptable salt thereof, wherein R 3 Selected from deuterium atoms, halogen, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 deuterated alkyl and 3 to 8 membered cycloalkyl; in some embodiments, R 3 Halogen or C 1-6 Alkyl; in some embodiments, R 3 C 1-6 alkyl.

[0082] In some embodiments of the present disclosure, the compound represented by the general formula (I), general formula (II), general formula (III), general formula (III-1) or general formula (III-2) or a pharmaceutically acceptable salt thereof, wherein R 3b Selected from hydrogen atom, deuterium atom, halogen, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 deuterated alkyl and 3 to 8 membered cycloalkyl; in some embodiments, R 3b Selected from hydrogen atoms, halogens and C 1-6 Alkyl; in some embodiments, R 3b A hydrogen atom or C 1-6 Alkyl; in some embodiments, R 3b A hydrogen atom.

[0083] In some embodiments of the present disclosure, the compound represented by the general formula (II), general formula (III), general formula (III-1) or general formula (III-2) or a pharmaceutically acceptable salt thereof, wherein X 1 is CH; and / or A is CH.

[0084] In some embodiments of the present disclosure, the compound represented by the general formula (I) or the general formula (II) or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (IV) or a pharmaceutically acceptable salt thereof:

[0085] in:

[0086] R 2 、R 3a and R 5 As defined in general formula (II).

[0087] In some embodiments of the present disclosure, the compound represented by the general formula (I), general formula (II) or general formula (IV) or a pharmaceutically acceptable salt thereof, wherein R 2 is a 10- to 14-membered tricyclic aryl or a 9- to 14-membered tricyclic heteroaryl, wherein the 10- to 14-membered tricyclic aryl and the 9- to 14-membered tricyclic heteroaryl are each independently optionally substituted by one or more R 4 Replacement; R 4 As defined in formula (I); in some embodiments, R 2 is a 10- to 14-membered tricyclic aryl group, wherein the 10- to 14-membered tricyclic aryl group is optionally substituted by one or more R 4 Replacement; R 4 As defined in formula (I); in some embodiments, R 2 is a 9- to 14-membered tricyclic heteroaryl group; wherein the 9- to 14-membered tricyclic heteroaryl group is optionally substituted by one or more R 4 Replacement; R 4 As defined in formula (I); in some embodiments, R 2 is an 11- to 13-membered tricyclic aryl group, wherein the 11- to 13-membered tricyclic aryl group is optionally substituted by one or more R 4 Replacement; R 4 As defined in general formula (I).

[0088] In some embodiments of the present disclosure, the compound represented by the general formula (I), general formula (II) or general formula (IV) or a pharmaceutically acceptable salt thereof, wherein R 2 Selected from In some embodiments, R 2 Selected from

[0089] Where: M is selected from CR 4 R 4 , O, S and NR m ; R mis selected from the group consisting of a hydrogen atom, an alkyl group, a haloalkyl group, a deuterated alkyl group, a hydroxyalkyl group, an alkoxyalkyl group, an aminoalkyl group, a cycloalkyl group, a cycloalkylalkyl group, a heterocyclic group, and a heterocyclylalkyl group; Q 1 , Q 2 and Q 3 are the same or different and are each independently selected from a bond, O, S(O) v , CR 4d R 4e , C(O) and NR 4f ; R 4a 、R 4b 、R 4c 、R 4d and R 4e are the same or different and are each independently a hydrogen atom or R 4 ; or, R 4d and R 4e Together with the attached carbon atom, they form a cycloalkyl or heterocyclyl group, which is optionally substituted with one or more R;

[0090] R 4f is selected from the group consisting of a hydrogen atom, an alkyl group, a haloalkyl group, a deuterated alkyl group, a hydroxyalkyl group, an alkoxyalkyl group, an aminoalkyl group, a cycloalkyl group, a cycloalkylalkyl group, a heterocyclyl group, and a heterocyclylalkyl group;

[0091] R 6 、R 7 、R 8 、R 9 、R 10 、R 11 and R 12 are the same or different and are each independently a hydrogen atom or R 4 ; or R 6 and R 7 Together with the attached carbon atom, it forms a cycloalkyl or heterocyclic group, which is optionally substituted with one or more R; or R 8 and R 9 Together with the carbon atom to which it is attached, it forms a cycloalkyl or heterocyclic group, wherein the cycloalkyl or heterocyclic group is optionally substituted with one or more R; or R on the same carbon atom 6 and R 7 Together form =O; or R on the same carbon atom 8 and R 9 Together they form =O; n is 0, 1, 2, 3 or 4; p is 1, 2, 3, 4, 5 or 6; q is 0, 1, 2, 3 or 4; x is 0, 1, 2, 3, 4 or 5; x1 is 1, 2, 3, 4 or 5; y is 0, 1, 2, 3 or 4; a is 0, 1, 2, 3 or 4; b is 0, 1, 2, 3 or 4; R 4 , R and v are as defined in the general formula (I).

[0092] In some embodiments of the present disclosure, the compound represented by the general formula (I), general formula (II) or general formula (IV) or a pharmaceutically acceptable salt thereof, wherein R 2 Selected from In some embodiments, R 2 Selected from In some embodiments, R 2 for

[0093] Where: Q 1 , Q 2 and Q 3 are the same or different and are each independently selected from a bond, O, S(O) v , CR 4d R 4e , C(O) and NR 4f ; R 4a 、R 4b 、R 4c 、R 4d and R 4e are the same or different and are each independently a hydrogen atom or R 4 ; or, R 4d and R 4e Together with the attached carbon atom, they form a cycloalkyl or heterocyclyl group, which is optionally substituted with one or more R;

[0094] R 4f is selected from the group consisting of a hydrogen atom, an alkyl group, a haloalkyl group, a deuterated alkyl group, a hydroxyalkyl group, an alkoxyalkyl group, an aminoalkyl group, a cycloalkyl group, a cycloalkylalkyl group, a heterocyclyl group, and a heterocyclylalkyl group;

[0095] R 6 、R 7 、R 8 、R 9 、R 10 、R 11 and R 12 are the same or different and are each independently a hydrogen atom or R 4 ; or R 6 and R 7 Together with the attached carbon atom, it forms a cycloalkyl or heterocyclic group, which is optionally substituted with one or more R; or R 8 and R 9 Together with the carbon atom to which it is attached, it forms a cycloalkyl or heterocyclic group, wherein the cycloalkyl or heterocyclic group is optionally substituted with one or more R; or R on the same carbon atom 6 and R 7 Together form =O; or R on the same carbon atom 8and R 9 Together they form =O; n is 0, 1, 2, 3 or 4; p is 1, 2, 3, 4, 5 or 6; q is 0, 1, 2, 3 or 4; x is 0, 1, 2, 3, 4 or 5; x1 is 1, 2, 3, 4 or 5; y is 0, 1, 2, 3 or 4; R 4 , R and v are as defined in the general formula (I).

[0096] In some embodiments of the present disclosure, the compound represented by the general formula (I), general formula (II), general formula (III), general formula (III-1), general formula (III-2) or general formula (IV) or a pharmaceutically acceptable salt thereof, wherein each R 4 are the same or different and are each independently selected from deuterium atoms, halogens, hydroxyl groups, cyano groups, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Deuterated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 deuterated alkoxy, 3 to 8 membered cycloalkyl, 3 to 8 membered cycloalkyloxy, 3 to 8 membered heterocyclyl, and 3 to 8 membered heterocyclyloxy; in some embodiments, each R 4 are the same or different and are each independently selected from halogen, cyano, C 1-6 Alkyl and C 1-6 haloalkyl; in some embodiments, each R 4 are the same or different and are each independently selected from halogen, C 1-6 Alkyl and C 1-6 haloalkyl; in some embodiments, R 4 is halogen or cyano; in some embodiments, R 4 is selected from F, Cl and cyano; in some embodiments, R 4 is F or cyano.

[0097] In some embodiments of the present disclosure, the compound represented by the general formula (I), general formula (II) or general formula (IV) or a pharmaceutically acceptable salt thereof, wherein R 4a It is a cyano group.

[0098] In some embodiments of the present disclosure, the compound represented by the general formula (III), general formula (III-1) or general formula (III-2) or a pharmaceutically acceptable salt thereof, wherein j is 0 or 1; in some embodiments, j is 0.

[0099] In some embodiments of the present disclosure, the compound represented by the general formula (I), general formula (II) or general formula (IV) or a pharmaceutically acceptable salt thereof, wherein R6 、R 7 、R 8 and R 9 are the same or different and are each independently selected from hydrogen, halogen and C 1-6 Alkyl; in some embodiments, R 6 、R 7 、R 8 and R 9 are each independently a hydrogen atom.

[0100] In some embodiments of the present disclosure, the compound represented by the general formula (I), general formula (II) or general formula (IV) or a pharmaceutically acceptable salt thereof, wherein R 10 、R 11 and R 12 are each independently a hydrogen atom.

[0101] In some embodiments of the present disclosure, the compound represented by formula (I), formula (II) or formula (IV) or a pharmaceutically acceptable salt thereof, wherein x is 0 or 1; in some embodiments, x is 1; in some embodiments, x is 0.

[0102] In some embodiments of the present disclosure, the compound represented by formula (I), formula (II) or formula (IV) or a pharmaceutically acceptable salt thereof, wherein x1 is 1 or 2; in some embodiments, x1 is 1.

[0103] In some embodiments of the present disclosure, the compound represented by general formula (I), general formula (II) or general formula (IV) or a pharmaceutically acceptable salt thereof, wherein y is 0 or 1; in some embodiments, y is 1; in some embodiments, y is 0.

[0104] In some embodiments of the present disclosure, the compound represented by formula (I), formula (II) or formula (IV) or a pharmaceutically acceptable salt thereof, wherein M is selected from NH, O and S; in some embodiments, M is O.

[0105] In some embodiments of the present disclosure, the compound represented by general formula (I), general formula (II) or general formula (IV) or a pharmaceutically acceptable salt thereof, wherein a is 1 or 2; in some embodiments, a is 2.

[0106] In some embodiments of the present disclosure, the compound represented by formula (I), formula (II) or formula (IV) or a pharmaceutically acceptable salt thereof, wherein b is 1 or 2; in some embodiments, b is 1.

[0107] In some embodiments of the present disclosure, the compound represented by formula (I), formula (II) or formula (IV) or a pharmaceutically acceptable salt thereof, wherein a is 2 and b is 1.

[0108] In some embodiments of the present disclosure, the compound represented by the general formula (I), general formula (II) or general formula (IV) or a pharmaceutically acceptable salt thereof, wherein R m A hydrogen atom or C 1-6 Alkyl; in some embodiments, R m A hydrogen atom.

[0109] In some embodiments of the present disclosure, the compound represented by formula (I), formula (II) or formula (IV) or a pharmaceutically acceptable salt thereof, wherein Q 1 is selected from CH2, O and a bond; in some embodiments, Q 1 is O or a bond; in some embodiments, Q 1 is O; in some embodiments, Q 1 is the key.

[0110] In some embodiments of the present disclosure, the compound represented by formula (I), formula (II) or formula (IV) or a pharmaceutically acceptable salt thereof, wherein Q 2 is selected from CH2, O and a bond; in some embodiments, Q 2 is O or a bond; in some embodiments, Q 2 is O; in some embodiments, Q 2 is the key.

[0111] In some embodiments of the present disclosure, the compound represented by formula (I), formula (II) or formula (IV) or a pharmaceutically acceptable salt thereof, wherein Q 1 is a key or O; Q 2 is O; in some embodiments, Q 1 O;Q 2 is O; in some embodiments, Q 1 is the key; Q 2 It is O.

[0112] In some embodiments of the present disclosure, the compound represented by formula (I), formula (II) or formula (IV) or a pharmaceutically acceptable salt thereof, wherein Q 3 It is O.

[0113] In some embodiments of the present disclosure, the compound represented by the general formula (I), general formula (II) or general formula (IV) or a pharmaceutically acceptable salt thereof, wherein R 2 Selected from In some embodiments, R 2 Selected from In some embodiments, R 2 Selected from in:

[0114] n is 0, 1, or 2 (in some embodiments, 0 or 1); p is 1, 2, or 3 (in some embodiments, 1); q is 1 or 2 (in some embodiments, 1); a is 1 or 2 (in some embodiments, 2); b is 1 or 2 (in some embodiments, 1); R 4b and R 4c are the same or different and are each independently selected from hydrogen atoms, deuterium atoms, halogens, hydroxyl groups, cyano groups, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Deuterated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 deuterated alkoxy, 3- to 8-membered cycloalkyl, 3- to 8-membered cycloalkyloxy, 3- to 8-membered heterocyclyl, and 3- to 8-membered heterocyclyloxy.

[0115] In some embodiments of the present disclosure, the compound represented by the general formula (I), general formula (II) or general formula (IV) or a pharmaceutically acceptable salt thereof, wherein R 2 Selected from In some embodiments, R 2 Selected from In some embodiments, R 2 for In some embodiments, R 2 for

[0116] wherein: n is 0, 1, or 2 (in some embodiments, 0 or 1); p is 1, 2, or 3 (in some embodiments, 1); q is 1 or 2 (in some embodiments, 1); R 4b and R 4c are the same or different and are each independently selected from hydrogen atoms, deuterium atoms, halogens, hydroxyl groups, cyano groups, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Deuterated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 Alkoxy, C1-6 Halogenated alkoxy, C 1-6 deuterated alkoxy, 3- to 8-membered cycloalkyl, 3- to 8-membered cycloalkyloxy, 3- to 8-membered heterocyclyl, and 3- to 8-membered heterocyclyloxy.

[0117] In some embodiments of the present disclosure, the compound represented by formula (I), formula (II), formula (III), formula (III-1), formula (III-2) or formula (IV) or a pharmaceutically acceptable salt thereof, wherein R 4b Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 haloalkyl; in some embodiments, R 4b Selected from halogen, C 1-6 Alkyl and C 1-6 haloalkyl; in some embodiments, R 4b is halogen; in some embodiments, R 4b is F or Cl; in some embodiments, R 4b For F.

[0118] In some embodiments of the present disclosure, the compound represented by formula (I), formula (II), formula (III), formula (III-1), formula (III-2) or formula (IV) or a pharmaceutically acceptable salt thereof, wherein R 4c is a hydrogen atom or a halogen; in some embodiments, R 4c is a hydrogen atom; in some embodiments, R 4c is halogen; in some embodiments, R 4c It is a hydrogen atom or Cl.

[0119] In some embodiments of the present disclosure, the compound represented by the general formula (I), general formula (II) or general formula (IV) or a pharmaceutically acceptable salt thereof, wherein R 4d and R 4e are the same or different and are each independently selected from hydrogen atom, halogen, C 1-6 Alkyl and C 1-6 haloalkyl; in some embodiments, R 4d and R 4e A hydrogen atom.

[0120] In some embodiments of the present disclosure, the compound represented by the general formula (I), general formula (II) or general formula (IV) or a pharmaceutically acceptable salt thereof, wherein R 4f A hydrogen atom or C 1-6 Alkyl; in some embodiments, R 4f A hydrogen atom.

[0121] In some embodiments of the present disclosure, the compound represented by formula (I), formula (II), formula (III), formula (III-1), formula (III-2) or formula (IV) or a pharmaceutically acceptable salt thereof, wherein p is 1, 2 or 3; in some embodiments, p is 1 or 2; in some embodiments, p is 1.

[0122] In some embodiments of the present disclosure, the compound represented by formula (I), formula (II), formula (III), formula (III-1), formula (III-2) or formula (IV) or a pharmaceutically acceptable salt thereof, wherein q is 1 or 2; in some embodiments, q is 1.

[0123] In some embodiments of the present disclosure, the compound represented by formula (I), formula (II), formula (III), formula (III-1), formula (III-2) or formula (IV) or a pharmaceutically acceptable salt thereof, wherein n is 0, 1 or 2; in some embodiments, n is 0 or 1; in some embodiments, n is 0; in some embodiments, n is 1.

[0124] In some embodiments of the present disclosure, the compound represented by the general formula (I), general formula (II) or general formula (IV) or a pharmaceutically acceptable salt thereof, wherein R 2 Selected from In some embodiments, R 2 Selected from In some embodiments, R 2 Selected from In some embodiments, R 2 Selected from In some embodiments, R 2 Selected from In some embodiments, R 2 Selected from In some embodiments, R 2 Selected from In some embodiments, R 2 Selected from In some embodiments, R 2 Selected from In some embodiments, R 2 Selected from In some embodiments, R 2 Selected from In some embodiments, R 2 Selected from In some embodiments, R 2 Selected from In some embodiments, R 2 Selected from In some embodiments, R 2 for In some embodiments, R 2 for In some embodiments, R 2 for In some embodiments, R 2 for

[0125] In some embodiments of the present disclosure, the compound represented by formula (I), formula (II), formula (III), formula (III-1), formula (III-2) or formula (IV) or a pharmaceutically acceptable salt thereof, wherein R 3a are the same or different and are each independently selected from hydrogen atom, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 deuterated alkyl and 3 to 8 membered cycloalkyl; in some embodiments, R 3a Selected from C 1-6 Alkyl, C 1-6 Haloalkyl and C 1-6 deuterated alkyl; in some embodiments, R 3a C 1-6 Alkyl or C 1-6 deuterated alkyl; in some embodiments, R 3a C 1-6 deuterated alkyl; in some embodiments, R 3a is methyl or trideuterated methyl; in some embodiments, R 3a is methyl; in some embodiments, R 3a It is a trideuterated methyl group.

[0126] In some embodiments of the present disclosure, the compound represented by formula (I), formula (II), formula (III), formula (III-1), formula (III-2) or formula (IV) or a pharmaceutically acceptable salt thereof, wherein R 5 Selected from hydrogen atoms, deuterium atoms, halogens, cyano groups, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Deuterated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 deuterated alkoxy, 3 to 6 membered cycloalkyl, and 3 to 6 membered heterocyclyl; in some embodiments, R 5 Selected from hydrogen atom, halogen, cyano, C 1-6 alkyl, 3 to 6 membered cycloalkyl and 3 to 6 membered heterocyclyl; in some embodiments, R 5 is selected from hydrogen, halogen, and cyano; in some embodiments, R 5 is cyano; in some embodiments, R 5 A hydrogen atom.

[0127] In some embodiments of the present disclosure, the compound represented by formula (I), formula (II), formula (III), formula (III-1), formula (III-2) or formula (IV) or a pharmaceutically acceptable salt thereof, wherein R 14 、R 15 and R 16 are the same or different at each occurrence and are independently selected from hydrogen atoms, C 1-6 alkyl and 3 to 6 membered cycloalkyl; in some embodiments, R 14 、R 15 and R 16 is the same or different at each occurrence and is independently a hydrogen atom or a C 1-6 Alkyl; in some embodiments, R 14 and R 15 A hydrogen atom or C 1-6 Alkyl; in some embodiments, R 14 and R 15 is a hydrogen atom; in some embodiments, R 16 C 1-6 alkyl.

[0128] In some embodiments of the present disclosure, the compound represented by formula (I), formula (II), formula (III), formula (III-1), formula (III-2) or formula (IV) or a pharmaceutically acceptable salt thereof, wherein R 17 A hydrogen atom or C 1-6 Alkyl; in some embodiments, R 17A hydrogen atom.

[0129] In some embodiments of the present disclosure, the compound represented by the general formula (I), general formula (II), general formula (III), general formula (III-1), general formula (III-2) or general formula (IV) or a pharmaceutically acceptable salt thereof, wherein R is the same or different at each occurrence and is independently selected from an oxo group, a deuterium atom, a halogen, a cyano group, an amino group, -NH alkyl, -N(alkyl)2, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 haloalkoxy, 3 to 6 membered cycloalkyl, and 3 to 6 membered heterocyclyl; in some embodiments, R is the same or different at each occurrence and is independently selected from halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy and C 1-6 In some embodiments, R is the same or different at each occurrence and is independently selected from halogen, C 1-6 Alkyl and C 1-6 Halogenated alkyl.

[0130] In some embodiments of the present disclosure, the compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof, wherein R 1a and R 1b is a hydrogen atom; R 3a C 1-6 Alkyl or C 1-6 Deuterated alkyl; X 1 is CH; A is CH; R 5 is a hydrogen atom; R 2 Selected from n is 0 or 1; p is 1; q is 1; a is 2; b is 1; R 4b is halogen; R 4c is a hydrogen atom or a halogen.

[0131] In some embodiments of the present disclosure, the compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof, wherein R 1a and R 1b is a hydrogen atom; R 3a C 1-6 Deuterated alkyl; X 1 CR 5a ; R 5a Selected from hydrogen atoms, halogens and C 1-6 Alkyl; A is CR 3b ; R 3b Selected from hydrogen atoms, halogens and C 1-6Alkyl; R 5 is selected from hydrogen, halogen and cyano; R 2 Selected from n is 0, 1 or 2; p is 1, 2 or 3; q is 1 or 2; a is 1 or 2; b is 1 or 2; R 4b is halogen; R 4c is a hydrogen atom or a halogen.

[0132] In some embodiments of the present disclosure, the compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof, wherein R 1a and R 1b are the same or different and are each independently a hydrogen atom or a deuterium atom; R 3a C 1-6 Alkyl or C 1-6 Deuterated alkyl; X 1 CR 5a ; R 5a Selected from hydrogen atoms, halogens and C 1-6 Alkyl; A is CR 3b ; R 3b Selected from hydrogen atoms, halogens and C 1-6 Alkyl; R 5 is selected from hydrogen, halogen and cyano; R 2 Selected from n is 0, 1 or 2; p is 1, 2 or 3; q is 1 or 2; R 4b is halogen; R 4c A hydrogen atom.

[0133] In some embodiments of the present disclosure, the compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof, wherein R 1a and R 1b are the same or different and are each independently a hydrogen atom or a deuterium atom; R 3a C 1-6 Deuterated alkyl; X 1 CR 5a ; R 5a Selected from hydrogen atoms, halogens and C 1-6 Alkyl; A is CR 3b ; R 3b Selected from hydrogen atoms, halogens and C 1-6 Alkyl; R 5 is a hydrogen atom; R 2 Selected from n is 0, 1 or 2; p is 1, 2 or 3; q is 1 or 2; R 4b is halogen; R 4c A hydrogen atom.

[0134] In some embodiments of the present disclosure, the compound represented by the general formula (III), the general formula (III-1) or the general formula (III-2) or a pharmaceutically acceptable salt thereof, wherein R 1a and R 1b is a hydrogen atom; R 3a C 1-6 Alkyl or C 1-6 Deuterated alkyl; R 5 is a hydrogen atom; X 1 is CH; A is CH; R 4b is halogen; R 4c is a hydrogen atom or a halogen; Ring D is selected from j is 0; the * end is connected to the side close to the cyano group.

[0135] In some embodiments of the present disclosure, the compound represented by the general formula (III), the general formula (III-1) or the general formula (III-2) or a pharmaceutically acceptable salt thereof, wherein R 1a and R 1b is a hydrogen atom; R 3a C 1-6 Deuterated alkyl; R 5 is selected from hydrogen, halogen and cyano; X 1 CR 5a ; R 5a Selected from hydrogen atoms, halogens and C 1-6 Alkyl; A is CR 3b ; R 3b Selected from hydrogen atoms, halogens and C 1-6 Alkyl; R 4b is halogen; R 4c is a hydrogen atom or a halogen; Ring D is selected from The * end is connected to the side close to the cyano group; n is 0, 1 or 2; p is 1, 2 or 3; q is 1 or 2; a is 1 or 2; b is 1 or 2; j is 0.

[0136] In some embodiments of the present disclosure, the compound represented by the general formula (III), the general formula (III-1) or the general formula (III-2) or a pharmaceutically acceptable salt thereof, wherein R 1a and R 1b are the same or different and are each independently a hydrogen atom or a deuterium atom; R 3a C 1-6 Alkyl or C 1-6 Deuterated alkyl; R 5 is selected from hydrogen, halogen and cyano; X 1 CR 5a ; R 5a Selected from hydrogen atoms, halogens and C 1-6 Alkyl; A is CR 3b ; R 3b Selected from hydrogen atoms, halogens and C1-6 Alkyl; R 4b is halogen; R 4c is a hydrogen atom; Ring D is selected from n is 0, 1 or 2; p is 1, 2 or 3; q is 1 or 2; R 4 Selected from halogen, C 1-6 Alkyl and C 1-6 Haloalkyl; j is 0 or 1; the * end is connected to the side close to the cyano group, and R 4 It can be substituted at any substitutable position on ring D.

[0137] In some embodiments of the present disclosure, the compound represented by the general formula (III), the general formula (III-1) or the general formula (III-2) or a pharmaceutically acceptable salt thereof, wherein R 1a and R 1b is a hydrogen atom; R 3a C 1-6 Deuterated alkyl; R 5 is a hydrogen atom; X 1 is CH; A is CH; R 4b is halogen; R 4c is a hydrogen atom; Ring D is selected from n is 0 or 1; p is 1; q is 1 or 2; j is 0; and the * end is connected to the side close to the cyano group.

[0138] In some embodiments of the present disclosure, the compound represented by the general formula (IV) or a pharmaceutically acceptable salt thereof, wherein R 3a C 1-6 Alkyl or C 1-6 Deuterated alkyl; R 5 is a hydrogen atom; R 2 Selected from n is 0; p is 1; q is 1; a is 2; b is 1; R 4b is halogen; R 4c In some embodiments of the present disclosure, the compound represented by the general formula (IV) or a pharmaceutically acceptable salt thereof, wherein R 3a C 1-6 Deuterated alkyl; R 5 is a hydrogen atom; R 2 Selected from n is 0, 1 or 2; p is 1, 2 or 3; q is 1 or 2; a is 1 or 2; b is 1 or 2; R 4b is halogen; R 4c is a hydrogen atom or a halogen.

[0139] In some embodiments of the present disclosure, the compound represented by the general formula (IV) or a pharmaceutically acceptable salt thereof, wherein R 3a C 1-6 Alkyl or C 1-6 Deuterated alkyl; R 5 is selected from hydrogen, halogen and cyano; R 2 Selected from n is 0, 1 or 2; p is 1, 2 or 3; q is 1 or 2; R 4b is halogen; R 4c A hydrogen atom.

[0140] In some embodiments of the present disclosure, the compound represented by the general formula (IV) or a pharmaceutically acceptable salt thereof, wherein R 3a C 1-6 Deuterated alkyl; R 5 is a hydrogen atom; R 2 Selected from n is 0, 1 or 2; p is 1, 2 or 3; q is 1 or 2; R 4b is halogen; R 4c A hydrogen atom.

[0141] In some embodiments of the present disclosure, the compound represented by the general formula (IV) or a pharmaceutically acceptable salt thereof, wherein R 3a C 1-6 Deuterated alkyl; R 5 is a hydrogen atom; R 2 for n is 0, 1 or 2; q is 1 or 2; R 4b is halogen; R 4c is a hydrogen atom or a halogen.

[0142] Table A Typical compounds of the present disclosure include, but are not limited to:

[0143] Another aspect of the present disclosure relates to a compound represented by general formula (IA) or a salt thereof:

[0144] in:

[0145] R w1 is a hydrogen atom or an amino protecting group;

[0146] R w2 is a hydrogen atom or an amino protecting group; provided that, Rw1 and R w2 At least one of them is an amino protecting group;

[0147] Or, R w1 and R w2 Together with the nitrogen atom to which it is attached, it forms a phthalimide group (i.e., R w1 and R w2 Together with the attached nitrogen atom, );

[0148] Ring A, L, X 1 、X 2 、X 3 、R 0 、R 1a 、R 1b 、R 2 、R 3 , m and r are as defined in formula (I). Another aspect of the present disclosure relates to a compound represented by formula (IIA) or a salt thereof:

[0149] in:

[0150] R w1 is a hydrogen atom or an amino protecting group;

[0151] R w2 is a hydrogen atom or an amino protecting group; provided that, R w1 and R w2 At least one of them is an amino protecting group;

[0152] Or, R w1 and R w2 Together with the nitrogen atom to which it is attached, it forms a phthalimide group (i.e., R w1 and R w2 Together with the attached nitrogen atom, );

[0153] A.X 1 、R 1a 、R 1b 、R 2 、R 3a and R 5 As defined in general formula (II).

[0154] Another aspect of the present disclosure relates to a compound represented by general formula (IIIA) or a salt thereof:

[0155] in:

[0156] R w1 is a hydrogen atom or an amino protecting group;

[0157] Rw2 is a hydrogen atom or an amino protecting group; provided that, R w1 and R w2 At least one of them is an amino protecting group;

[0158] Or, R w1 and R w2 Together with the nitrogen atom to which it is attached, it forms a phthalimide group (i.e., R w1 and R w2 Together with the attached nitrogen atom, );

[0159] Ring D, A, X 1 、R 1a 、R 1b 、R 3a 、R 4 、R 4b 、R 4c 、R 5 and j are as defined in formula (III).

[0160] Another aspect of the present disclosure relates to a compound represented by formula (III-1A) or formula (III-2A) or a salt thereof:

[0161] in:

[0162] R w1 is a hydrogen atom or an amino protecting group;

[0163] R w2 is a hydrogen atom or an amino protecting group; provided that, R w1 and R w2 At least one of them is an amino protecting group;

[0164] Or, R w1 and R w2 Together with the nitrogen atom to which it is attached, it forms a phthalimide group (i.e., R w1 and R w2 Together with the attached nitrogen atom, );

[0165] Ring D, A, X 1 、R 1a 、R 1b 、R 3a 、R 4 、R 4b 、R 4c 、R 5 and j are as defined in the general formula (III-1) or (III-2).

[0166] Another aspect of the present disclosure relates to a compound represented by general formula (IVA) or a salt thereof:

[0167] in:

[0168] R w1 is a hydrogen atom or an amino protecting group;

[0169] R w2 is a hydrogen atom or an amino protecting group; provided that, R w1 and R w2 At least one of them is an amino protecting group;

[0170] Or, R w1 and R w2 Together with the nitrogen atom to which it is attached, it forms a phthalimide group (i.e., R w1 and R w2 Together with the attached nitrogen atom, );

[0171] R 2 、R 3a and R 5 As defined in general formula (IV).

[0172] Table B Typical intermediate compounds disclosed herein include, but are not limited to:

[0173] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, the method comprising:

[0174] Removing the amino protecting group from the compound represented by the general formula (IA) or a salt thereof to obtain the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof;

[0175] in:

[0176] R w1 is a hydrogen atom or an amino protecting group;

[0177] R w2 is a hydrogen atom or an amino protecting group; provided that, R w1 and R w2 At least one of them is an amino protecting group;

[0178] Or, R w1 and R w2 Together with the nitrogen atom to which it is attached, it forms a phthalimide group (i.e., R w1 and R w2 Together with the attached nitrogen atom, );

[0179] R1 For-(CR 1a R 1b )r-NH2;

[0180] Ring A, L, X 1 、X 2 、X 3 、R 0 、R 1a 、R 1b 、R 2 、R 3 , m and r are as defined in the general formula (I).

[0181] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (II) or a pharmaceutically acceptable salt thereof, the method comprising:

[0182] Removing the amino protecting group from the compound represented by general formula (IIA) or a salt thereof to obtain the compound represented by general formula (II) or a pharmaceutically acceptable salt thereof;

[0183] in:

[0184] R w1 is a hydrogen atom or an amino protecting group;

[0185] R w2 is a hydrogen atom or an amino protecting group; provided that, R w1 and R w2 At least one of them is an amino protecting group;

[0186] Or, R w1 and R w2 Together with the nitrogen atom to which it is attached, it forms a phthalimide group (i.e., R w1 and R w2 Together with the attached nitrogen atom, );

[0187] A.X 1 、R 1a 、R 1b 、R 2 、R 3a and R 5 As defined in general formula (II).

[0188] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (III) or a pharmaceutically acceptable salt thereof, the method comprising:

[0189] Removing the amino protecting group from the compound represented by general formula (IIIA) or a salt thereof to obtain the compound represented by general formula (III) or a pharmaceutically acceptable salt thereof;

[0190] in:

[0191] R w1 is a hydrogen atom or an amino protecting group;

[0192] R w2 is a hydrogen atom or an amino protecting group; provided that, R w1 and R w2 At least one of them is an amino protecting group;

[0193] Or, R w1 and R w2 Together with the nitrogen atom to which it is attached, it forms a phthalimide group (i.e., R w1 and R w2 Together with the attached nitrogen atom, );

[0194] Ring D, A, X 1 、R 1a 、R 1b 、R 3a 、R 4 、R 4b 、R 4c 、R 5 and j are as defined in formula (III).

[0195] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (III-1) or a pharmaceutically acceptable salt thereof, the method comprising:

[0196] Removing the amino protecting group from the compound represented by the general formula (III-1A) or a salt thereof to obtain the compound represented by the general formula (III-1) or a pharmaceutically acceptable salt thereof;

[0197] in:

[0198] R w1 is a hydrogen atom or an amino protecting group;

[0199] R w2 is a hydrogen atom or an amino protecting group; provided that, R w1 and R w2 At least one of them is an amino protecting group;

[0200] Or, R w1 and R w2 Together with the nitrogen atom to which it is attached, it forms a phthalimide group (i.e., R w1 and R w2 Together with the attached nitrogen atom, );

[0201] Ring D, A, X 1 、R 1a 、R 1b 、R3a 、R 4 、R 4b 、R 4c 、R 5 and j are as defined in the general formula (III-1).

[0202] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (III-2) or a pharmaceutically acceptable salt thereof, the method comprising:

[0203] Removing the amino protecting group from the compound represented by the general formula (III-2A) or a salt thereof to obtain the compound represented by the general formula (III-2) or a pharmaceutically acceptable salt thereof;

[0204] in:

[0205] R w1 is a hydrogen atom or an amino protecting group;

[0206] R w2 is a hydrogen atom or an amino protecting group; provided that, R w1 and R w2 At least one of them is an amino protecting group;

[0207] Or, R w1 and R w2 Together with the nitrogen atom to which it is attached, it forms a phthalimide group (i.e., R w1 and R w2 Together with the attached nitrogen atom, );

[0208] Ring D, A, X 1 、R 1a 、R 1b 、R 3a 、R 4 、R 4b 、R 4c 、R 5 and j are as defined in the general formula (III-2).

[0209] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (IV) or a pharmaceutically acceptable salt thereof, the method comprising:

[0210] Removing the amino protecting group from the compound represented by the general formula (IVA) or a salt thereof to obtain the compound represented by the general formula (IV) or a pharmaceutically acceptable salt thereof;

[0211] in:

[0212] R w1 is a hydrogen atom or an amino protecting group;

[0213] Rw2 is a hydrogen atom or an amino protecting group; provided that, R w1 and R w2 At least one of them is an amino protecting group;

[0214] Or, R w1 and R w2 Together with the nitrogen atom to which it is attached, it forms a phthalimide group (i.e., R w1 and R w2 Together with the attached nitrogen atom, );

[0215] R 2 、R 3a and R 5 As defined in general formula (IV).

[0216] Another aspect of the present disclosure relates to a method for preparing compounds represented by general formula (III-1) and general formula (III-2) or pharmaceutically acceptable salts thereof, the method comprising:

[0217] The compound represented by general formula (III) or a pharmaceutically acceptable salt thereof is resolved to obtain the compound represented by general formula (III-1) and general formula (III-2) or a pharmaceutically acceptable salt thereof;

[0218] in:

[0219] Ring D, A, X 1 、R 1a 、R 1b 、R 3a 、R 4 、R 4b 、R 4c 、R 5 and j are as defined in the general formula (III-1) or (III-2).

[0220] Another aspect of the present disclosure relates to a pharmaceutical composition comprising a compound of the present disclosure represented by Formula (I), Formula (II), Formula (III), Formula (III-1), Formula (III-2), Formula (IV) and Table A, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

[0221] The present disclosure further relates to the use of compounds represented by formula (I), formula (II), formula (III), formula (III-1), formula (III-2), formula (IV) and Table A or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, in the preparation of PRMT5 inhibitors.

[0222] The present disclosure further relates to the use of compounds represented by formula (I), formula (II), formula (III), formula (III-1), formula (III-2), formula (IV) and Table A or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, in the preparation of PRMT5-MTA complex inhibitors.

[0223] The present disclosure further relates to the use of compounds represented by formula (I), formula (II), formula (III), formula (III-1), formula (III-2), formula (IV) and Table A or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, in the preparation of medicaments for treating and / or preventing MTAP deficiency and / or MTA accumulation diseases.

[0224] The present disclosure further relates to the use of compounds shown in Formula (I), Formula (II), Formula (III), Formula (III-1), Formula (III-2), Formula (IV) and Table A or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, in the preparation of drugs for treating and / or preventing diseases or conditions mediated by PRMT5.

[0225] The present disclosure further relates to the use of compounds represented by formula (I), formula (II), formula (III), formula (III-1), formula (III-2), formula (IV) and Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, in the preparation of medicaments for treating and / or preventing cancer.

[0226] The present disclosure further relates to a method for inhibiting PRMT5, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I), formula (II), formula (III), formula (III-1), formula (III-2), formula (IV) and Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

[0227] The present disclosure further relates to a method for inhibiting the PRMT5-MTA complex, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I), formula (II), formula (III), formula (III-1), formula (III-2), formula (IV), and Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

[0228] The present disclosure further relates to a method for treating and / or preventing MTAP deficiency and / or MTA accumulation diseases, comprising administering to a patient in need thereof a therapeutically effective amount of a compound represented by formula (I), formula (II), formula (III), formula (III-1), formula (III-2), formula (IV), and Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

[0229] The present disclosure further relates to a method for treating and / or preventing a disease or condition mediated by PRMT5, comprising administering to a patient in need thereof an effective inhibitory amount of a compound of formula (I), formula (II), formula (III), formula (III-1), formula (III-2), formula (IV) and Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

[0230] The present disclosure further relates to a method for treating and / or preventing cancer, comprising administering to a patient in need thereof a therapeutically effective amount of a compound represented by formula (I), formula (II), formula (III), formula (III-1), formula (III-2), formula (IV), and Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

[0231] The present disclosure further relates to a compound represented by formula (I), formula (II), formula (III), formula (III-1), formula (III-2), formula (IV) and Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use as a drug.

[0232] The present disclosure further relates to a compound shown in general formula (I), general formula (II), general formula (III), general formula (III-1), general formula (III-2), general formula (IV) and Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, which is used as a PRMT5 inhibitor.

[0233] The present disclosure further relates to a compound shown in general formula (I), general formula (II), general formula (III), general formula (III-1), general formula (III-2), general formula (IV) and Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, which is used as a PRMT5-MTA complex inhibitor.

[0234] The present disclosure further relates to a compound shown in Formula (I), Formula (II), Formula (III), Formula (III-1), Formula (III-2), Formula (IV) and Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use in inhibiting PRMT5.

[0235] The present disclosure further relates to a compound shown in Formula (I), Formula (II), Formula (III), Formula (III-1), Formula (III-2), Formula (IV) and Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for inhibiting the PRMT5-MTA complex.

[0236] The present disclosure further relates to a compound shown in general formula (I), general formula (II), general formula (III), general formula (III-1), general formula (III-2), general formula (IV) and Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for treating and / or preventing MTAP deficiency and / or MTA accumulation diseases.

[0237] The present disclosure further relates to a compound shown in Formula (I), Formula (II), Formula (III), Formula (III-1), Formula (III-2), Formula (IV) and Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for treating and / or preventing a disease or condition mediated by PRMT5.

[0238] The present disclosure further relates to a compound shown in general formula (I), general formula (II), general formula (III), general formula (III-1), general formula (III-2), general formula (IV) and Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, which is used for treating and / or preventing cancer.

[0239] In some embodiments, the disease or condition mediated by PRMT5 described herein is cancer.

[0240] In some embodiments, the MTAP-deficient and / or MTA-accumulating disease described herein is cancer.

[0241] In some embodiments, the cancer described in the present disclosure is selected from lung cancer (such as non-small cell lung cancer), kidney cancer, liver cancer (such as hepatocellular carcinoma), head and neck cancer, esophageal cancer (also known as esophageal cancer), lymphoma (such as diffuse large B-cell lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, mantle cell lymphoma, lymphoid malignancies of T-cell or B-cell origin, follicular lymphoma), glioblastoma, glioblastoma, colorectal cancer (such as colon cancer and rectal cancer), malignant peripheral nerve sheath tumor (MPN NST (also called malignant peripheral nerve sheath tumor), melanoma, gastric cancer, pancreatic cancer, bile duct cancer, bladder cancer, breast cancer, ovarian cancer, vaginal cancer, cervical cancer, endometrial cancer, prostate cancer, testicular cancer, seminoma, myeloma (such as multiple myeloma), leukemia (such as acute leukemia, chronic leukemia, myelofibrosis, erythroleukemia), acoustic neuroma, basal cell carcinoma, brain cancer, bronchial cancer, sarcoma (such as chondrosarcoma, soft tissue sarcoma, fibrosarcoma, smooth muscle sarcoma, liposarcoma, lymphangiosarcoma, myxosarcoma, osteogenic sarcoma, rhabdomyosarcoma, Ewing's tumor), choriocarcinoma, craniopharyngioma, cystadenocarcinoma, hemangioendothelioma, ependymoma, epithelial carcinoma, glioma, astrocytoma, hemangioblastoma, medulloblastoma, meningioma, mesothelioma, neuroblastoma, bone cancer, nasopharyngeal cancer, oral cancer, laryngeal cancer, thyroid cancer, retinoblastoma, skin cancer, squamous cell carcinoma (such as head and neck squamous cell carcinoma), synovia, sweat gland carcinoma, and myeloblastoma In some embodiments, the cancer is selected from ovarian cancer, lymphoma, pancreatic cancer, bladder cancer, gastric cancer, colorectal cancer, bile duct cancer, mesothelioma, malignant peripheral nerve sheath tumor (MPNST), glioblastoma, and lung cancer; In some embodiments, the cancer is selected from lung cancer, mesothelioma, malignant peripheral nerve sheath tumor (MPNST), and pancreatic cancer; In some embodiments, the cancer is selected from liver cancer, breast cancer, skin cancer, bladder cancer, pancreatic cancer, and head and neck cancer.

[0242] In some embodiments, the cancer described herein is an MTAP-associated cancer.

[0243] In some embodiments, the lung cancer described herein is non-small cell lung cancer.

[0244] In another aspect, the cancer of the present disclosure is selected from the group consisting of:

[0245] Heart: sarcomas (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma, and teratoma;

[0246] Lung: bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, enchondromatous hamartoma, mesothelioma;

[0247] Gastrointestinal: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, viperoma), small intestine (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large intestine (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma);

[0248] Genitourinary tract: Kidney (adenocarcinoma, Wilms tumor, lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenomatous tumor, lipoma);

[0249] Liver: liver cancer (hepatocellular carcinoma), bile duct cancer, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma;

[0250] Biliary tract: gallbladder cancer, ampullary cancer, bile duct cancer;

[0251] Bone: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell chordoma, osteochronfroma (osteocartilaginous exostosis), benign enchondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma, and giant cell tumor;

[0252] Nervous system: skull (osteomas, hemangiomas, granulomas, xanthomas, osteitis deformans), meninges (meningiomas, meningiosarcoma, gliomatosis), brain (astrocytomas, medulloblastomas, gliomas, ependymomas, germ cell tumors, glioblastoma multiforme, oligodendrogliomas, neurothecomas (e.g., malignant peripheral nerve sheath tumors), retinoblastomas, congenital tumors), spinal neurofibromas, meningiomas, gliomas, sarcomas);

[0253] Gynecological: Uterus (endometrial cancer), cervix (cervical cancer, pre-tumor cervical dysplasia), ovary (ovarian cancer (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa-thecal cell tumor, Sertoli-Leydig cell tumor, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonic rhabdomyosarcoma), fallopian tube (carcinoma);

[0254] Hematological: Blood (myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma);

[0255] Skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, hydatidiform mole, lipoma, hemangioma, dermatofibroma, keloid, psoriasis;

[0256] and adrenal glands: neuroblastoma.

[0257] In certain embodiments, the cancer is diffuse large B-cell lymphoma (DLBCL).

[0258] The active compound can be formulated into a form suitable for administration by any appropriate route, and the compositions of the present disclosure can be formulated using one or more pharmaceutically acceptable carriers by conventional methods. Thus, the active compound of the present disclosure can be formulated into various dosage forms for oral administration, injection (e.g., intravenous, intramuscular or subcutaneous), inhalation or insufflation. The compounds of the present disclosure can also be formulated into dosage forms such as tablets, hard or soft capsules, aqueous or oily suspensions, emulsions, injections, dispersible powders or granules, suppositories, lozenges or syrups.

[0259] As a general guide, the active compound is, in some embodiments, in a unit dosage form, or in a form that a patient can self-administer as a single dose. A unit dosage form of a compound or composition of the present disclosure can be a tablet, capsule, cachet, bottled solution, powder, granule, lozenge, suppository, reconstituted powder, or liquid formulation. Suitable unit dosage forms can range from 0.1 to 1000 mg.

[0260] The pharmaceutical composition of the present disclosure may contain one or more excipients in addition to the active compound, selected from the following ingredients: fillers (diluents), binders, wetting agents, disintegrants or excipients, etc. Depending on the administration method, the composition may contain 0.1 to 99% by weight of the active compound.

[0261] In some embodiments, the unit dose of the pharmaceutical composition is 0.001 mg-1000 mg.

[0262] In certain embodiments, the pharmaceutical composition contains 0.01-99.99% of the aforementioned compound or its pharmaceutically acceptable salt or its isotopic substitution, based on the total weight of the composition. In certain embodiments, the pharmaceutical composition contains 0.1-99.9% of the aforementioned compound or its pharmaceutically acceptable salt or its isotopic substitution. In certain embodiments, the pharmaceutical composition contains 0.5%-99.5% of the aforementioned compound or its pharmaceutically acceptable salt or its isotopic substitution. In certain embodiments, the pharmaceutical composition contains 1%-99% of the aforementioned compound or its pharmaceutically acceptable salt or its isotopic substitution. In certain embodiments, the pharmaceutical composition contains 2%-98% of the aforementioned compound or its pharmaceutically acceptable salt or its isotopic substitution.

[0263] In certain embodiments, the pharmaceutical composition comprises 0.01% to 99.99% of a pharmaceutically acceptable excipient, based on the total weight of the composition. In certain embodiments, the pharmaceutical composition comprises 0.1% to 99.9% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition comprises 0.5% to 99.5% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition comprises 1% to 99% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition comprises 2% to 98% of a pharmaceutically acceptable excipient.

[0264] Tablets contain the active ingredient in admixture with nontoxic, pharmaceutically acceptable excipients suitable for tablet preparation. These excipients may include inert excipients, granulating agents, disintegrants, binders, and lubricants. Tablets may be uncoated or coated using known techniques that mask the taste of the drug or delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained-release effect over a longer period of time.

[0265] Oral formulations may also be provided in soft gelatin capsules wherein the active ingredient is mixed with an inert solid diluent or with a water-soluble carrier or oil-soluble vehicle.

[0266] Aqueous suspensions contain the active substance in admixture with excipients suitable for the preparation of aqueous suspensions. Such excipients are suspending agents, dispersing agents, or wetting agents. Aqueous suspensions may also contain one or more preservatives, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents.

[0267] Oil suspensions can be prepared by suspending the active ingredient in a vegetable oil or mineral oil. The oil suspension may contain a thickener. The above-mentioned sweeteners and flavoring agents may be added to provide a palatable preparation. These compositions may be preserved by adding antioxidants.

[0268] The pharmaceutical compositions of the present disclosure may also be in the form of oil-in-water emulsions. The oil phase may be a vegetable oil, a mineral oil, or a mixture thereof. Suitable emulsifiers may be naturally occurring phospholipids, and the emulsion may also contain sweeteners, flavorings, preservatives, and antioxidants. Such formulations may also contain demulcents, preservatives, colorants, and antioxidants.

[0269] The pharmaceutical compositions disclosed herein may be in the form of sterile injectable aqueous solutions. Acceptable vehicles or solvents that may be used include water, Ringer's solution, and isotonic sodium chloride solution. Sterile injectable formulations may be sterile injectable oil-in-water microemulsions in which the active ingredient is dissolved in an oil phase. The injectable solution or microemulsion may be administered into the patient's bloodstream via local, bolus injection. Alternatively, the solution or microemulsion may be administered in a manner that maintains a constant circulating concentration of the disclosed compound. To maintain this constant concentration, a continuous intravenous drug delivery device may be used. An example of such a device is the Deltec CADD-PLUS™ 5400 intravenous pump.

[0270] Pharmaceutical compositions of the present disclosure may be in the form of sterile water for injection or oil suspensions for intramuscular and subcutaneous administration. The suspensions may be prepared using suitable dispersants or wetting agents and suspending agents as described above according to known techniques. Sterile injectable formulations may also be sterile injectable solutions or suspensions prepared in parenteral, nontoxic diluents or solvents. In addition, sterile fixed oils may be conveniently used as solvents or suspension media. For this purpose, any blended fixed oil may be used. In addition, fatty acids may also be used to prepare injections.

[0271] The disclosed compounds can be administered in the form of suppositories for rectal administration. These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at ordinary temperatures but liquid in the rectum and will therefore melt in the rectum to release the drug.

[0272] The compounds of the present disclosure can be administered by preparing water-suspended dispersible powders and granules by adding water. These pharmaceutical compositions can be prepared by mixing the active ingredient with a dispersing or wetting agent, a suspending agent, or one or more preservatives.

[0273] As is well known to those skilled in the art, the dosage of a drug depends on a variety of factors, including but not limited to the following: the activity of the specific compound used, the age of the patient, the weight of the patient, the health status of the patient, the behavior of the patient, the diet of the patient, the time of administration, the mode of administration, the rate of excretion, the combination of drugs, the severity of the disease, etc.; in addition, the optimal treatment method such as the mode of treatment, the daily dosage of the compound or the type of pharmaceutically acceptable salt can be verified according to traditional treatment regimens.

[0274] Terminology

[0275] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0276] The term "alkyl" refers to a saturated straight-chain or branched aliphatic hydrocarbon group having 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) carbon atoms (i.e., C 1-20 The alkyl group, in some embodiments, has an alkyl group of 1 to 12 carbon atoms (i.e., C 1-12 alkyl), in some embodiments an alkyl group having 1 to 6 carbon atoms (i.e., C 1-6Non-limiting examples include: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2 ,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched-chain isomers thereof. The alkyl group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment, and the substituents are, in some embodiments, selected from one or more of a D atom, a halogen, an alkoxy group, a haloalkyl group, a haloalkoxy group, a cycloalkyloxy group, a heterocyclyloxy group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group.

[0277] The term "alkylene" refers to a divalent alkyl group, wherein alkyl is as defined above, having from 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) carbon atoms (i.e., C 1-20 The alkylene group, in some embodiments, has an alkylene group of 1 to 12 carbon atoms (i.e., C 1-12 alkylene), in some embodiments an alkylene group having 1 to 6 carbon atoms (i.e., C 1-6Alkylene). Non-limiting examples include: -CH2-, -CH(CH3)-, -C(CH3)2-, -CH2CH2-, -CH(CH2CH3)-, -CH2CH(CH3)-, -CH2C(CH3)2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, etc. Alkylene can be substituted or unsubstituted. When substituted, it can be substituted at any available point of attachment. In some embodiments, the substituent is selected from one or more of D atoms, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

[0278] The term "alkenyl" refers to an alkyl group containing at least one carbon-carbon double bond in the molecule, wherein alkyl is as defined above and has 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12) carbon atoms (i.e., C 2-12 The alkenyl group, in some embodiments, has 2 to 6 carbon atoms (i.e., C 2-6 Alkenyl). Non-limiting examples include: ethenyl, propenyl, isopropenyl, butenyl, etc. Alkenyl can be substituted or unsubstituted. When substituted, it can be substituted at any available point of attachment. In some embodiments, the substituent is selected from one or more of D atoms, alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

[0279] The term "alkynyl" refers to an alkyl group containing at least one carbon-carbon triple bond in the molecule, wherein alkyl is as defined above and has 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12) carbon atoms (i.e., C 2-12 The alkynyl group, in some embodiments, has 2 to 6 carbon atoms (i.e., C 2-6 Alkynyl). Non-limiting examples include: ethynyl, propynyl, butynyl, pentynyl, hexynyl, etc. Alkynyl can be substituted or unsubstituted. When substituted, it can be substituted at any available point of attachment. The substituents are, in some embodiments, selected from one or more of D atoms, alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

[0280] The term "alkoxy" refers to -O-(alkyl), wherein alkyl is as defined above. Non-limiting examples include methoxy, ethoxy, propoxy, and butoxy. Alkoxy groups may be substituted or unsubstituted. When substituted, they may be substituted at any available point of attachment, with the substituents being selected, in some embodiments, from one or more of a D atom, a halogen, an alkoxy group, a haloalkyl group, a haloalkoxy group, a cycloalkyloxy group, a heterocyclyloxy group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group.

[0281] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic all-carbon ring (i.e., monocyclic cycloalkyl) or polycyclic ring system (i.e., polycyclic cycloalkyl) having 3 to 20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., 3 to 20-membered cycloalkyl). The cycloalkyl group includes, in some embodiments, 3 to 12 ring atoms (i.e., 3 to 12-membered cycloalkyl), in some embodiments, 3 to 8 ring atoms (i.e., 3 to 8-membered cycloalkyl), and in some embodiments, 3 to 6 ring atoms (i.e., 3 to 6-membered cycloalkyl).

[0282] Non-limiting examples of the monocyclic cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl and cyclooctyl.

[0283] The polycyclic cycloalkyl group includes: spirocycloalkyl group, fused cycloalkyl group and bridged cycloalkyl group.

[0284] Bicyclic cycloalkyl groups include monospirocycloalkyl groups, bicyclic fused cycloalkyl groups and bicyclic bridged cycloalkyl groups.

[0285] The term "spiroalkyl" refers to a polycyclic ring system having a common carbon atom (called a spiro atom) between the rings, which may contain one or more double bonds within the ring, or one or more heteroatoms selected from nitrogen, oxygen and sulfur within the ring (the nitrogen may be optionally oxidized, i.e., to form nitrogen oxides; the sulfur may be optionally oxoed, i.e., to form sulfoxides or sulfones, but excluding -OO-, -OS- or -SS-), provided that it contains at least one all-carbon ring and the point of attachment is on the all-carbon ring, and has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (i.e., a 5- to 20-membered spiroalkyl). The spiroalkyl group has, in some embodiments, 6 to 14 ring atoms (i.e., a 6- to 14-membered spiroalkyl group), and in some embodiments, 7 to 10 ring atoms (i.e., a 7- to 10-membered spiroalkyl group). The spirocycloalkyl includes monospirocycloalkyl and polyspirocycloalkyl (such as bispirocycloalkyl, etc.), in some embodiments monospirocycloalkyl or bispirocycloalkyl, in some embodiments 3 yuan / 4 yuan, 3 yuan / 5 yuan, 3 yuan / 6 yuan, 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 3 yuan, 5 yuan / 4 yuan, 5 yuan / 5 yuan, 5 yuan / 6 yuan, 5 yuan / 7 yuan, 6 yuan / 3 yuan, 6 yuan / 4 yuan, 6 yuan / 5 yuan, 6 yuan / 6 yuan, 6 yuan / 7 yuan, 7 yuan / 5 yuan or 7 yuan / 6 yuan monospirocycloalkyl. Non-limiting examples include:

[0286] Its connection point can be at any position;

[0287] Taking the ring D of the present disclosure as an example, non-limiting examples of monospirocycloalkyl groups also include wait.

[0288] The term "fused cycloalkyl" refers to a polycyclic ring system that shares two adjacent carbon atoms between the rings, which is a monocyclic cycloalkyl fused to one or more monocyclic cycloalkyls, or a monocyclic cycloalkyl fused to one or more heterocyclyls, aryls, or heteroaryls, wherein the point of attachment is on the monocyclic cycloalkyl, which may contain one or more double bonds within the ring, and has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., a 5- to 20-membered fused cycloalkyl). The fused cycloalkyl, in some embodiments, has 6 to 14 ring atoms (i.e., a 6- to 14-membered fused cycloalkyl), and in some embodiments, has 7 to 10 ring atoms (i.e., a 7- to 10-membered fused cycloalkyl). The fused cycloalkyl includes bicyclic fused cycloalkyl and polycyclic fused cycloalkyl (such as tricyclic fused cycloalkyl, tetracyclic fused cycloalkyl, etc.), in some embodiments bicyclic fused cycloalkyl or tricyclic fused cycloalkyl, in some embodiments 3 yuan / 4 yuan, 3 yuan / 5 yuan, 3 yuan / 6 yuan, 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 3 yuan, 5 yuan / 4 yuan, 5 yuan / 5 yuan, 5 yuan / 6 yuan, 5 yuan / 7 yuan, 6 yuan / 3 yuan, 6 yuan / 4 yuan, 6 yuan / 5 yuan, 6 yuan / 6 yuan, 6 yuan / 7 yuan, 7 yuan / 5 yuan or 7 yuan / 6 yuan bicyclic fused cycloalkyl. Non-limiting examples include:

[0289] , whose connection points can be at any position; Taking the ring D of the present disclosure as an example, non-limiting examples of bicyclic fused cycloalkyl groups also include wait.

[0290] The term "bridged cycloalkyl" refers to a full carbon polycyclic ring system that shares two carbon atoms that are not directly connected between the rings, which may contain one or more double bonds within the ring and has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) carbon atoms (i.e., 5 to 20-membered bridged cycloalkyl). The bridged cycloalkyl, in some embodiments, has a bridged cycloalkyl of 6 to 14 carbon atoms (i.e., 6 to 14-membered bridged cycloalkyl), and in some embodiments, has a bridged cycloalkyl of 7 to 10 carbon atoms (i.e., 7 to 10-membered bridged cycloalkyl). The bridged cycloalkyl includes bicyclic bridged cycloalkyl and polycyclic bridged cycloalkyl (e.g., tricyclic bridged cycloalkyl, tetracyclic bridged cycloalkyl, etc.), and in some embodiments, is a bicyclic bridged cycloalkyl or a tricyclic bridged cycloalkyl. Non-limiting examples include:

[0291] The connection point can be at any position. Taking the ring D of the present disclosure as an example, non-limiting examples of bicyclic bridged cycloalkyl groups also include wait.

[0292] The cycloalkyl group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment, with the substituents in some embodiments being selected from one or more of a D atom, a halogen, an alkyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a cycloalkyloxy group, a heterocyclyloxy group, a hydroxyl group, a hydroxyalkyl group, an oxo group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group.

[0293] The number of rings in the "tricyclic cycloalkyl" ring system is 3, and the point of attachment is on the all-carbon ring. 2 For example, non-limiting examples of "tricyclic cycloalkyl" include wait.

[0294] The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic heterocycle (i.e., a monocyclic heterocyclyl) or a polycyclic heterocyclic ring system (i.e., a polycyclic heterocyclyl) containing at least one (e.g., 1, 2, 3, or 4) heteroatoms selected from nitrogen, oxygen, and sulfur (the nitrogen may be optionally oxidized, i.e., to form nitrogen oxides; the sulfur may be optionally oxoed, i.e., to form sulfoxides or sulfones, but excluding -OO-, -OS-, or -SS-) in the ring, and having 3 to 20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., a 3- to 20-membered heterocyclyl). The heterocyclyl group has, in some embodiments, 3 to 12 ring atoms (i.e., 3 to 12-membered heterocyclyl); in some embodiments, 3 to 8 ring atoms (i.e., 3 to 8-membered heterocyclyl); in some embodiments, 3 to 6 ring atoms (i.e., 3 to 6-membered heterocyclyl); in some embodiments, 5 or 6 ring atoms (i.e., 5 or 6-membered heterocyclyl).

[0295] Non-limiting examples of the monocyclic heterocyclic group include pyrrolidinyl, dihydropyrrolyl, dihydrofuranyl, tetrahydropyranyl, 1,2,3,6-tetrahydropyridinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl and homopiperazinyl.

[0296] The polycyclic heterocyclic group includes spiroheterocyclic groups, fused heterocyclic groups and bridged heterocyclic groups. The term "spiroheterocyclic group" refers to a polycyclic heterocyclic ring system in which the rings share one atom (called a spiro atom), which may contain one or more double bonds in the ring and at least one (e.g., 1, 2, 3 or 4) heteroatoms selected from nitrogen, oxygen and sulfur (the nitrogen may be optionally oxidized to form nitrogen oxides; the sulfur may be optionally oxoed to form sulfoxides or sulfones, but does not include -OO-, -OS- or -SS-), provided that it contains at least one monocyclic heterocyclic group and the point of attachment is on the monocyclic heterocyclic group, which has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (i.e., a 5- to 20-membered spiroheterocyclic group). The spiroheterocyclyl group has, in some embodiments, 6 to 14 ring atoms (i.e., 6- to 14-membered spiroheterocyclyl), in some embodiments 7 to 10 ring atoms (i.e., 7- to 10-membered spiroheterocyclyl); in some embodiments 7 to 9 ring atoms (i.e., 7- to 9-membered spiroheterocyclyl); in some embodiments 7 or 8 ring atoms (i.e., 7- or 8-membered spiroheterocyclyl). The spiro heterocyclic group includes a monospiro heterocyclic group and a polyspiro heterocyclic group (such as a bispiro heterocyclic group, etc.), in some embodiments a monospiro heterocyclic group or a bispiro heterocyclic group, in some embodiments a 3-membered / 4-membered, 3-membered / 5-membered, 3-membered / 6-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 3-membered, 5-membered / 4-membered, 5-membered / 5-membered, 5-membered / 6-membered, 5-membered / 7-membered, 6-membered / 3-membered, 6-membered / 4-membered, 6-membered / 5-membered, 6-membered / 6-membered, 6-membered / 7-membered, 7-membered / 5-membered or 7-membered / 6-membered monospiro heterocyclic group. Non-limiting examples include:

[0297] etc.; Taking the ring D of the present disclosure as an example, non-limiting examples of the monospiro heterocyclic group also include wait.

[0298] The term "fused heterocyclyl" refers to a polycyclic heterocyclic ring system that shares two adjacent atoms between the rings, which may contain one or more double bonds within the ring and at least one (e.g., 1, 2, 3, or 4) heteroatom selected from nitrogen, oxygen, and sulfur (the nitrogen may be optionally oxidized, i.e., to form a nitrogen oxide; the sulfur may be optionally oxidized, i.e., to form a sulfoxide or sulfone, but excluding -OO-, -OS-, or -SS-), which is a monocyclic heterocyclyl fused to one or more monocyclic heterocyclyls, or a monocyclic heterocyclyl fused to one or more cycloalkyl, aryl, or heteroaryl groups, wherein the point of attachment is on the monocyclic heterocyclyl, and has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., a 5- to 20-membered fused heterocyclyl). The fused heterocyclyl group has, in some embodiments, 6 to 14 ring atoms (i.e., 6- to 14-membered fused heterocyclyl), in some embodiments, 7 to 10 ring atoms (i.e., 7- to 10-membered fused heterocyclyl); in some embodiments, 7 to 9 ring atoms (i.e., 7- to 9-membered fused heterocyclyl); in some embodiments, 8 or 9 ring atoms (i.e., 8 or 9-membered fused heterocyclyl). The fused heterocyclic group includes bicyclic and polycyclic fused heterocyclic groups (such as tricyclic fused heterocyclic groups, tetracyclic fused heterocyclic groups, etc.), in some embodiments, bicyclic fused heterocyclic groups or tricyclic fused heterocyclic groups, in some embodiments, 3-membered / 4-membered, 3-membered / 5-membered, 3-membered / 6-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 3-membered, 5-membered / 4-membered, 5-membered / 5-membered, 5-membered / 6-membered, 5-membered / 7-membered, 6-membered / 3-membered, 6-membered / 4-membered, 6-membered / 5-membered, 6-membered / 6-membered, 6-membered / 7-membered, 7-membered / 5-membered or 7-membered / 6-membered bicyclic fused heterocyclic groups. Non-limiting examples include:

[0299] etc.; Taking the ring D of the present disclosure as an example, non-limiting examples of the bicyclic fused heterocyclic group also include wait.

[0300] The term "bridged heterocyclyl" refers to a polycyclic heterocyclic ring system that shares two atoms that are not directly connected between the rings, which may contain one or more double bonds within the ring and at least one (e.g., 1, 2, 3, or 4) heteroatom selected from nitrogen, oxygen, and sulfur (the nitrogen may be optionally oxidized, i.e., to form nitrogen oxides; the sulfur may be optionally oxoed, i.e., to form sulfoxides or sulfones, but excluding -OO-, -OS-, or -SS-), having 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., a 5- to 20-membered bridged heterocyclyl). In some embodiments, the bridged heterocyclyl has 6 to 14 ring atoms (i.e., a 6- to 14-membered bridged heterocyclyl), and in some embodiments, has 7 to 10 ring atoms (i.e., a 7- to 10-membered bridged heterocyclyl). According to the number of constituent rings, it can be divided into bicyclic bridged heterocyclic groups and polycyclic bridged heterocyclic groups (such as tricyclic bridged heterocyclic groups, tetracyclic bridged heterocyclic groups, etc.), and in some embodiments, it is a bicyclic bridged heterocyclic group or a tricyclic bridged heterocyclic group. Non-limiting examples include:

[0301] etc.; Taking the ring D of the present disclosure as an example, non-limiting examples of the bicyclic bridged heterocyclic group also include wait.

[0302] “Bicyclic heterocyclyl” includes bicyclic fused heterocyclyl, monospiro heterocyclyl and bicyclic bridged heterocyclyl, in some embodiments, 7- to 9-membered bicyclic heterocyclyl, in some embodiments, 8- or 9-membered bicyclic heterocyclyl, in some embodiments, 8-membered bicyclic heterocyclyl; taking ring D of the present disclosure as an example, non-limiting examples of “bicyclic heterocyclyl” include:

[0303] The number of rings in the "tricyclic heterocyclyl" ring system is 3, and the point of attachment is on the monocyclic heterocycle. 2 For example, non-limiting examples of "tricyclic heterocyclyl" include wait.

[0304] The heterocyclyl group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment, and the substituents are, in some embodiments, selected from one or more of a D atom, a halogen, an alkyl, an alkoxy, a haloalkyl, a haloalkoxy, a cycloalkyloxy, a heterocyclyloxy, a hydroxyl, a hydroxyalkyl, an oxo, a cyano, an amino, a nitro, a cycloalkyl, a heterocyclyl, an aryl, and a heteroaryl.

[0305] The term "aryl" refers to a monocyclic all-carbon aromatic ring (i.e., monocyclic aromatic group) or a polycyclic aromatic ring system (i.e., polycyclic aromatic group) having a conjugated π electron system, which has 6 to 22 (e.g., 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, or 22) ring atoms (i.e., 6 to 22-membered aromatic group). In some embodiments, the aryl group has 6 to 10 ring atoms (i.e., 6 to 10-membered aromatic group) or 10 to 14 ring atoms (i.e., 10 to 14-membered aromatic group); in some embodiments, the aryl group has 11 to 13 ring atoms (i.e., 11 to 13-membered aromatic group); in some embodiments, the aryl group has 12 ring atoms (i.e., 12-membered aromatic group). The monocyclic aromatic group is, for example, phenyl. Non-limiting examples of the polycyclic aromatic group include: naphthyl, anthracenyl, phenanthrenyl, etc. The polycyclic aromatic group also includes a phenyl group fused with one or more heterocyclic groups or cycloalkyl groups, or a naphthyl group fused with one or more heterocyclic groups or cycloalkyl groups, wherein the connection point is on the phenyl group or naphthyl group, and in this case, the number of ring atoms continues to represent the number of ring atoms in the polycyclic aromatic ring system (in some embodiments, a bicyclic aromatic group or a tricyclic aromatic group), non-limiting examples include:

[0306] Taking ring D of the present application as an example, non-limiting examples of “bicyclic aryl” also include: wait.

[0307] The number of rings in the "tricyclic aryl" ring system is 3, and the point of attachment is on the phenyl or naphthyl group. In some embodiments, the tricyclic aryl group has 10 to 14 ring atoms (i.e., 10- to 14-membered tricyclic aryl); in some embodiments, the tricyclic aryl group has 11 to 13 ring atoms (i.e., 11- to 13-membered tricyclic aryl); in some embodiments, the tricyclic aryl group has 12 ring atoms (i.e., 12-membered tricyclic aryl); 2 For example, non-limiting examples of "tricyclic aryl" include: wait.

[0308] Aryl groups can be substituted or unsubstituted. When substituted, they can be substituted at any available point of attachment, and the substituents are, in some embodiments, selected from one or more of D atoms, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, oxo, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

[0309] The term "heteroaryl" refers to a monocyclic heteroaromatic ring (i.e., a monocyclic heteroaryl) or a polycyclic heteroaromatic ring system (i.e., a polycyclic heteroaryl) having a conjugated π electron system, which contains at least one (e.g., 1, 2, 3, or 4) heteroatom selected from nitrogen, oxygen, and sulfur (the nitrogen may be optionally oxidized, i.e., to form a nitrogen oxide; the sulfur may be optionally oxidized, i.e., to form a sulfoxide or sulfone, but excluding -OO-, -OS-, or -SS-), and has 5 to 22 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, or 22) ring atoms (i.e., a 5- to 22-membered heteroaryl). The heteroaryl group, in some embodiments, has 5 to 10 ring atoms (i.e., a 5- to 10-membered heteroaryl) or a heteroaryl group having 9 to 14 ring atoms (i.e., a 9- to 14-membered heteroaryl); in some embodiments, the heteroaryl group has 11 or 12 ring atoms (i.e., an 11- or 12-membered heteroaryl); in some embodiments, the heteroaryl group has 11 ring atoms (i.e., an 11-membered heteroaryl); in some embodiments, the heteroaryl group has 5 or 6 ring atoms (i.e., a 5- or 6-membered heteroaryl), and in some embodiments, a 5-membered heteroaryl.

[0310] The monocyclic heteroaryl groups include, but are not limited to, furyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, furazanyl, pyrrolyl, N-alkylpyrrolyl, pyridyl, pyrimidinyl, pyridonyl, N-alkylpyridone (e.g. etc.), pyrazinyl, pyridazinyl, etc.

[0311] The polycyclic heteroaryl (in some embodiments, a 9- to 14-membered heteroaryl), non-limiting examples include: indolyl, indazolyl, quinolyl, isoquinolyl, quinoxalinyl, phthalazinyl, benzimidazolyl, benzothiophenyl, quinazolinyl, benzothiazolyl, carbazolyl, etc. The polycyclic heteroaryl also includes a monocyclic heteroaryl fused with one or more aromatic groups, wherein the connection point is on the aromatic ring, and in this case, the number of ring atoms continues to represent the number of ring atoms in the polycyclic heteroaromatic ring system. The polycyclic heteroaryl also includes a monocyclic heteroaryl fused with one or more cycloalkyl or heterocyclic groups, wherein the connection point is on the monocyclic heteroaromatic ring, and in this case, the number of ring atoms continues to represent the number of ring atoms in the polycyclic heteroaromatic ring system (in some embodiments, a bicyclic heteroaryl or a tricyclic heteroaryl). Non-limiting examples include:

[0312] Taking ring D of the present application as an example, non-limiting examples of “bicyclic heteroaryl” also include: wait.

[0313] The number of rings in the "tricyclic heteroaryl" ring system is 3, and the point of attachment is on the monocyclic heteroaryl ring. "Tricyclic heteroaryl" in some embodiments has a tricyclic heteroaryl with 9 to 14 ring atoms (i.e., a 9- to 14-membered tricyclic heteroaryl); in some embodiments has 11 or 12 ring atoms (i.e., an 11- or 12-membered tricyclic heteroaryl); in some embodiments has 11 ring atoms (i.e., a 12-membered tricyclic heteroaryl). 2 For example, non-limiting examples of "tricyclic heteroaryl" include: wait.

[0314] The heteroaryl group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment, with the substituents in some embodiments being selected from one or more of a D atom, a halogen, an alkyl, an alkoxy, a haloalkyl, a haloalkoxy, a cycloalkyloxy, a heterocyclyloxy, a hydroxyl, a hydroxyalkyl, a cyano, an amino, a nitro, a cycloalkyl, a heterocyclyl, an aryl, and a heteroaryl group.

[0315] The term "amino protecting group" refers to a group that is easily removed and introduced onto an amino group in order to keep the amino group unchanged while reacting other parts of the molecule. Non-limiting examples include: (trimethylsilyl)ethoxymethyl, tetrahydropyranyl, tert-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz), methyloxycarbonyl (Fmoc), allyloxycarbonyl (Alloc), trimethylsilylethoxycarbonyl (Teoc), methoxycarbonyl, ethoxycarbonyl, phthaloyl (Pht), p-toluenesulfonyl (Tos), trifluoroacetyl (Tfa), trityl (Trt), 2,4-dimethoxybenzyl (DMB), acetyl, benzyl, allyl, p-methoxybenzyl, and the like.

[0316] The term "cycloalkyloxy" refers to a cycloalkyl-O- group in which cycloalkyl is as defined above.

[0317] The term "heterocyclyloxy" refers to a heterocyclyl-O- group in which heterocyclyl is as defined above.

[0318] The term "aryloxy" refers to an aryl-O- group in which the aryl group is as defined above.

[0319] The term "heteroaryloxy" refers to a heteroaryl-O- group in which heteroaryl is as defined above.

[0320] The term "cycloalkylalkyl" refers to an alkyl group substituted with one or more cycloalkyl groups, wherein alkyl and cycloalkyl are as defined above.

[0321] The term "heterocyclylalkyl" refers to an alkyl group substituted by one or more heterocyclyl groups, wherein alkyl and heterocyclyl are as defined above.

[0322] The term "arylalkyl" refers to an alkyl group substituted with one or more aryl groups, wherein alkyl and aryl are as defined above; for example, -CH2Ph.

[0323] The term "heteroarylalkyl" refers to an alkyl group substituted with one or more heteroaryl groups, wherein alkyl and heteroaryl are as defined above. The term "alkylthio" refers to an alkyl-S- group, wherein alkyl is as defined above.

[0324] The term "haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.

[0325] The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein alkoxy is as defined above; for example, -OCF3.

[0326] The term "deuterated alkyl" refers to an alkyl group substituted with one or more deuterium atoms, wherein alkyl is as defined above; for example, -CD3.

[0327] The term "hydroxyalkyl" refers to an alkyl group substituted with one or more hydroxy groups, wherein alkyl is as defined above; for example, -CH2OH.

[0328] The term "deuterated alkoxy" refers to an alkoxy group substituted with one or more deuterium atoms, wherein alkoxy is as defined above; for example, -OCD3.

[0329] The term "alkoxyalkyl" refers to an alkyl group substituted with one or more alkoxy groups, wherein alkyl and alkoxy are as defined above; for example, -CH2OCH3.

[0330] The term "aminoalkyl" refers to an alkyl group substituted with one or more amino groups, wherein alkyl is as defined above; for example, -CH2NH2.

[0331] The term "methylidene" refers to =CH2.

[0332] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0333] The term "hydroxy" refers to -OH.

[0334] The term "mercapto" refers to -SH.

[0335] The term "amino" refers to -NH2.

[0336] The term "cyano" refers to -CN.

[0337] The term "nitro" refers to -NO2.

[0338] The term "oxo" or "oxo" refers to "=0".

[0339] The term "carbonyl" refers to C=O.

[0340] The term "carboxy" refers to -C(O)OH.

[0341] The term "carboxylate" refers to -C(O)O(alkyl), -C(O)O(cycloalkyl), (alkyl)C(O)O-, or (cycloalkyl)C(O)O-, where alkyl and cycloalkyl are as defined above.

[0342] The compounds of the present invention may exist in specific stereoisomeric forms. The term "stereoisomer" refers to isomers with identical structures but different arrangements of atoms in space. It includes cis and trans (or Z and E) isomers, (-)- and (+)-isomers, (R)- and (S)-enantiomers, diastereomers, (D)- and (L)-isomers, tautomers, atropisomers, conformers and mixtures thereof (such as racemates, mixtures of diastereomers). The substituents in the compounds of the present invention may have additional asymmetric atoms. All of these stereoisomers and their mixtures are included within the scope of the present disclosure. Optically active (-)- and (+)-isomers, (R)- and (S)-enantiomers and (D)- and (L)-isomers can be prepared by chiral synthesis, chiral reagents or other conventional techniques. An isomer of a compound disclosed herein can be prepared by asymmetric synthesis or chiral auxiliary, or, when the molecule contains a basic functional group (e.g., amino) or an acidic functional group (e.g., carboxyl), by forming a diastereomeric salt with an appropriate optically active acid or base, followed by diastereomeric resolution by conventional methods known in the art to obtain the pure isomer. Furthermore, separation of enantiomers and diastereomers is typically accomplished by chromatography.

[0343] The configuration of atropisomers can be described using the nomenclature (M)- and (P)- to describe the relative positions of substituents (see WO2022192745A1 and J. Med. Chem. 2022, 65, 3, 1749–1766).

[0344] Non-limiting examples of atropisomers include: 5-p1 and 5-p2

[0345] In the chemical structures of the compounds disclosed herein, the bond Indicates that the configuration is not specified, that is, if chiral isomers exist in the chemical structure, the bond Can be or include both For all carbon-carbon double bonds, even if only one configuration is named, both the Z and E configurations are included.

[0346] The compounds of the present disclosure may exist in different tautomeric forms, and all such forms are included within the scope of the present disclosure. The term "tautomer" or "tautomeric form" refers to a structural isomer that exists in equilibrium and is easily converted from one isomeric form to another isomeric form. It includes all possible tautomers, i.e., existing in the form of a single isomer or in the form of a mixture of any proportions of the tautomers. Non-limiting examples include: keto-enol, imine-enamine, lactam-lactim, etc.

[0347] For example, a compound is understood to include either or both tautomers of the following structures:

[0348] All tautomeric forms are within the scope of the present disclosure, and the naming of compounds does not exclude any tautomer.

[0349] The compounds of the present disclosure include all suitable isotopic derivatives of the compounds thereof. The term "isotopic derivative" refers to a compound in which at least one atom is replaced by an atom having the same atomic number but a different atomic mass. Examples of isotopes that can be introduced into the compounds of the present disclosure include stable and radioactive isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine, and iodine, for example, 2 H (deuterium, D), 3 H (tritium, T), 11 C. 13 C. 14 C. 15 N. 17 O. 18 O. 32 p、 33 p、 33 S. 34 S. 35 S. 36 S. 18 F. 36 Cl, 82 Br, 123 I. 124 I. 125 I. 129 I and 131 I, etc., in some embodiments, deuterium.

[0350] Compared to non-deuterated drugs, deuterated drugs have advantages such as reduced toxic side effects, increased drug stability, enhanced efficacy, and prolonged biological half-life. All isotopic variations of the compounds disclosed herein, whether radioactive or not, are encompassed by the present disclosure. Each available hydrogen atom attached to a carbon atom can be independently replaced with a deuterium atom, where the deuterium replacement can be partial or complete. Partial deuterium replacement refers to the replacement of at least one hydrogen atom with at least one deuterium atom.

[0351] Compounds of the present disclosure, when a position is specifically designated as "deuterium" or "D," are understood to have an abundance of deuterium at that position that is at least 1000 times greater than the natural abundance of deuterium (which is 0.015%) (i.e., at least 15% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 1000 times greater than the natural abundance of deuterium (i.e., at least 15% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 2000 times greater than the natural abundance of deuterium (i.e., at least 30% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 3000 times greater than the natural abundance of deuterium (i.e., at least 45% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 3340 times greater than the natural abundance of deuterium (i.e., at least 50.1% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 3500 times greater than the natural abundance of deuterium (i.e., at least 52.5% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 4000 times greater than the natural abundance of deuterium (i.e., at least 60% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 4500 times greater than the natural abundance of deuterium (i.e., at least 67.5% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 5000 times greater than the natural abundance of deuterium (i.e., at least 75% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 5500 times greater than the natural abundance of deuterium (i.e., at least 82.5% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 6000 times greater than the natural abundance of deuterium (i.e., at least 90% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 6333.3 times greater than the natural abundance of deuterium (i.e., at least 95% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 6466.7 times greater than the natural abundance of deuterium (i.e., at least 97% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 6600 times greater than the natural abundance of deuterium (i.e., at least 99% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 6633.3 times greater than the natural abundance of deuterium (ie, at least 99.5% deuterium incorporation).

[0352] "Optional" or "optionally" means that the event or circumstances described subsequently may but need not occur, and includes both situations in which the event or circumstances occur and do not occur. For example, "alkyl optionally (optionally) substituted with halogen or cyano" includes both situations in which the alkyl is substituted with halogen or cyano and situations in which the alkyl is not substituted with halogen and cyano.

[0353] "Substitution" or "substituted" means that one or more hydrogen atoms, in some embodiments 1 to 6, and in some embodiments 1 to 3 hydrogen atoms, in a group are independently replaced by a corresponding number of substituents. One skilled in the art will be able to determine (by experiment or theory) whether substitution is possible or not without undue effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom with an unsaturated bond (such as an alkene).

[0354] A "pharmaceutical composition" refers to a mixture containing one or more compounds described herein, or pharmaceutically acceptable salts thereof, and other chemical components, as well as other components such as pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitating absorption of the active ingredients and thereby exerting their biological activity.

[0355] "Pharmaceutically acceptable salts" refer to salts of the compounds of the present disclosure, which may be selected from inorganic or organic salts. Such salts are safe and effective for use in mammals and possess the desired biological activity. They can be prepared during the final isolation and purification of the compound, or separately by reacting a suitable group with a suitable base or acid. Bases commonly used to form pharmaceutically acceptable salts include inorganic bases, such as sodium hydroxide and potassium hydroxide, and organic bases, such as ammonia. Acids commonly used to form pharmaceutically acceptable salts include inorganic acids and organic acids.

[0356] With respect to a drug or pharmacologically active agent, the term "therapeutically effective amount" refers to an amount of the drug or agent sufficient to achieve, or at least partially achieve, the desired effect. The determination of a therapeutically effective amount varies from person to person, depending on the age and general condition of the recipient, as well as the specific active substance. The appropriate therapeutically effective amount in each individual case can be determined by those skilled in the art through routine experimentation.

[0357] The term "pharmaceutically acceptable" as used herein refers to compounds, materials, compositions and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with patient tissues without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit / risk ratio, and effective for the intended use.

[0358] As used herein, the singular form "a," "an," and "the" include plural references and vice versa unless the context clearly dictates otherwise.

[0359] When the term "about" is applied to a parameter such as pH, concentration, temperature, etc., it indicates that the parameter can vary by ±10%, and in some embodiments, within ±5%. As will be understood by those skilled in the art, when a parameter is not critical, a number is generally given for illustrative purposes only and is not limiting.

[0360] Synthesis method of the disclosed compound

[0361] In order to achieve the purpose of this disclosure, the present disclosure adopts the following technical solutions:

[0362] Option 1

[0363] The present invention discloses a method for preparing a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, comprising the following steps:

[0364] The compound represented by general formula (IA) or a salt thereof is subjected to the action of a deprotecting agent to remove the amino protecting group to obtain the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof;

[0365] in:

[0366] R w1 is a hydrogen atom or an amino protecting group;

[0367] R w2 is a hydrogen atom or an amino protecting group; provided that, R w1 and R w2 At least one of them is an amino protecting group;

[0368] Or, R w1 and R w2 Together with the nitrogen atom to which it is attached, it forms a phthalimide group (i.e., R w1 and R w2 Together with the attached nitrogen atom, );

[0369] R 1 For-(CR 1a R 1b )r-NH2;

[0370] Ring A, L, X 1 、X 2 、X 3 、R 0 、R 1a 、R 1b 、R 2 、R 3 , m and r are as defined in the general formula (I).

[0371] Option 2

[0372] The present invention discloses a method for preparing a compound represented by general formula (II) or a pharmaceutically acceptable salt thereof, comprising the following steps:

[0373] The compound represented by general formula (IIA) or a salt thereof is subjected to the action of a deprotecting agent to remove the amino protecting group to obtain the compound represented by general formula (II) or a pharmaceutically acceptable salt thereof;

[0374] in:

[0375] R w1 is a hydrogen atom or an amino protecting group;

[0376] R w2 is a hydrogen atom or an amino protecting group; provided that, R w1 and R w2 At least one of them is an amino protecting group;

[0377] Or, R w1 and R w2 Together with the nitrogen atom to which it is attached, it forms a phthalimide group (i.e., R w1 and R w2 Together with the attached nitrogen atom, );

[0378] A.X 1 、R 1a 、R 1b 、R 2 、R 3a and R 5 As defined in general formula (II).

[0379] Option 3

[0380] The present invention discloses a method for preparing a compound represented by general formula (III) or a pharmaceutically acceptable salt thereof, comprising the following steps:

[0381] The compound represented by general formula (IIIA) or a salt thereof is subjected to the action of a deprotecting agent to remove the amino protecting group to obtain the compound represented by general formula (III) or a pharmaceutically acceptable salt thereof;

[0382] in:

[0383] R w1 is a hydrogen atom or an amino protecting group;

[0384] R w2 is a hydrogen atom or an amino protecting group; provided that, R w1 and R w2 At least one of them is an amino protecting group;

[0385] Or, R w1 and R w2 Together with the nitrogen atom to which it is attached, it forms a phthalimide group (i.e., R w1 and R w2 Together with the attached nitrogen atom, );

[0386] Ring D, A, X 1 、R 1a 、R1b 、R 3a 、R 4 、R 4b 、R 4c 、R 5 and j are as defined in formula (III).

[0387] Option 4

[0388] The present invention discloses a method for preparing a compound represented by general formula (III-1) or a pharmaceutically acceptable salt thereof, comprising the following steps:

[0389] The compound represented by general formula (III-1A) or a salt thereof is subjected to the action of a deprotecting agent to remove the amino protecting group to obtain the compound represented by general formula (III-1) or a pharmaceutically acceptable salt thereof;

[0390] in:

[0391] R w1 is a hydrogen atom or an amino protecting group;

[0392] R w2 is a hydrogen atom or an amino protecting group; provided that, R w1 and R w2 At least one of them is an amino protecting group;

[0393] Or, R w1 and R w2 Together with the nitrogen atom to which it is attached, it forms a phthalimide group (i.e., R w1 and R w2 Together with the attached nitrogen atom, );

[0394] Ring D, A, X 1 、R 1a 、R 1b 、R 3a 、R 4 、R 4b 、R 4c 、R 5 and j are as defined in the general formula (III-1).

[0395] Plan 5

[0396] The present invention discloses a method for preparing a compound represented by general formula (III-2) or a pharmaceutically acceptable salt thereof, comprising the following steps:

[0397] The compound represented by general formula (III-2A) or a salt thereof is subjected to the action of a deprotecting agent to remove the amino protecting group to obtain the compound represented by general formula (III-2) or a pharmaceutically acceptable salt thereof;

[0398] in:

[0399] R w1 is a hydrogen atom or an amino protecting group;

[0400] R w2 is a hydrogen atom or an amino protecting group; provided that, R w1 and R w2 At least one of them is an amino protecting group;

[0401] Or, R w1 and R w2 Together with the nitrogen atom to which it is attached, it forms a phthalimide group (i.e., R w1 and R w2 Together with the attached nitrogen atom, );

[0402] Ring D, A, X 1 、R 1a 、R 1b 、R 3a 、R 4 、R 4b 、R 4c 、R 5 and j are as defined in the general formula (III-2).

[0403] Plan 6

[0404] The present invention discloses a method for preparing a compound represented by general formula (IV) or a pharmaceutically acceptable salt thereof, comprising the following steps:

[0405] The compound represented by general formula (IVA) or a salt thereof is subjected to the action of a deprotecting agent to remove the amino protecting group to obtain the compound represented by general formula (IV) or a pharmaceutically acceptable salt thereof;

[0406] in:

[0407] R w1 is a hydrogen atom or an amino protecting group;

[0408] R w2 is a hydrogen atom or an amino protecting group; provided that, R w1 and R w2 At least one of them is an amino protecting group;

[0409] Or, R w1 and R w2 Together with the nitrogen atom to which it is attached, it forms a phthalimide group (i.e., R w1 and R w2 Together with the attached nitrogen atom, );

[0410] R 2 、R3a and R 5 As defined in general formula (IV).

[0411] Plan 7

[0412] The present invention discloses a method for preparing the compounds represented by general formula (III-1) and general formula (III-2) or pharmaceutically acceptable salts thereof, which comprises the following steps:

[0413] The compound represented by general formula (III) or a pharmaceutically acceptable salt thereof is resolved to obtain the compound represented by general formula (III-1) and general formula (III-2) or a pharmaceutically acceptable salt thereof;

[0414] in:

[0415] Ring D, A, X 1 、R 1a 、R 1b 、R 3a 、R 4 、R 4b 、R 4c 、R 5 and j are as defined in the general formula (III-1) or (III-2).

[0416] In the above synthetic schemes 1 to 6, the amino protecting group is Boc in some embodiments.

[0417] In the above-mentioned synthesis schemes 1 to 6, when R w1 and R w2 Together with the connected nitrogen atom, a phthalimide group is formed. The reaction of removing the amino protecting group can be carried out under the action of a deprotecting agent such as hydrazine, hydrazine hydrate, sodium borohydride or concentrated HCl, and in some embodiments, hydrazine hydrate is used.

[0418] In some embodiments, the above reaction is carried out in a solvent, and the solvent used includes but is not limited to: N-methylpyrrolidone, ethylene glycol dimethyl ether, acetic acid, methanol, ethanol, acetonitrile, n-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide, 1,4-dioxane, water, N,N-dimethylformamide, N,N-dimethylacetamide, 1,2-dibromoethane and mixtures thereof. BRIEF DESCRIPTION OF THE DRAWINGS

[0419] FIG1 shows the efficacy data of compound 2-p1 against Lu99 xenograft tumors in NUNU nude mice.

[0420] FIG2 shows the effect of compound 2-p1 on the body weight of NUNU nude mice. DETAILED DESCRIPTION

[0421] The present disclosure is further described below with reference to the following embodiments, but these embodiments are not intended to limit the scope of the present disclosure.

[0422] Example

[0423] The structures of the compounds were determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). -6 The unit of ppm is given. NMR measurements were performed using a Bruker AVANCE NEO 500M NMR spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD), and tetramethylsilane (TMS) was used as the internal standard.

[0424] MS was measured using an Agilent 1200 / 1290 DAD-6110 / 6120 Quadrupole MS liquid chromatography-mass spectrometer (manufacturer: Agilent, MS model: 6110 / 6120 Quadrupole MS); a Waters ACQuity UPLC-QD / SQD (manufacturer: Waters, MS model: Waters ACQuity Qda Detector / Waters SQ Detector); and a THERMO Ultimate 3000-Q Exactive (manufacturer: THERMO, MS model: THERMO Q Exactive).

[0425] High performance liquid chromatography (HPLC) analysis was performed using Agilent HPLC 1200DAD, Agilent HPLC 1200VWD and Waters HPLC e2695-2489 high performance liquid chromatographs.

[0426] Chiral HPLC analysis was performed using an Agilent 1260DAD high performance liquid chromatograph.

[0427] High performance liquid chromatography (HPLC) was performed using Waters 2545-2767, Waters 2767-SQ Detecor2, Shimadzu LC-20AP, and Gilson GX-281 preparative chromatographs.

[0428] Chiral preparations were performed using a Shimadzu LC-20AP preparative chromatograph.

[0429] The CombiFlash rapid preparation instrument used was Combiflash Rf200 (TELEDYNE ISCO).

[0430] The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate. The specification of the silica gel plate used in thin layer chromatography (TLC) is 0.15mm~0.2mm, and the specification used for thin layer chromatography separation and purification products is 0.4mm~0.5mm.

[0431] Silica gel column chromatography generally uses Yantai Huanghai 200-300 mesh silica gel as the carrier.

[0432] Average kinase inhibition rate and IC 50 The values ​​were determined using a NovoStar microplate reader (BMG, Germany).

[0433] The known starting materials disclosed herein can be synthesized by methods known in the art, or can be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, Darui Chemicals, and other companies.

[0434] Unless otherwise specified in the examples, all reactions can be carried out under an argon atmosphere or a nitrogen atmosphere.

[0435] Argon atmosphere or nitrogen atmosphere means that the reaction bottle is connected to an argon or nitrogen balloon with a capacity of about 1 L.

[0436] Hydrogen atmosphere means that the reaction bottle is connected to a hydrogen balloon with a capacity of about 1L.

[0437] The pressurized hydrogenation reaction uses a Parr 3916EKX hydrogenator and a Qinglan QL-500 hydrogen generator or an HC2-SS hydrogenator.

[0438] The hydrogenation reaction is usually carried out by evacuating the chamber and filling it with hydrogen, and the operation is repeated three times.

[0439] A CEM Discover-S 908860 microwave reactor was used for the microwave reaction.

[0440] Unless otherwise specified in the examples, the solution refers to an aqueous solution.

[0441] Unless otherwise specified in the examples, the reaction temperature is room temperature, 20°C to 30°C.

[0442] The reaction progress in the examples was monitored by thin layer chromatography (TLC). The developing solvent used in the reaction, the eluent system for column chromatography used to purify the compound, and the developing solvent system for thin layer chromatography included: A: dichloromethane / methanol system, B: n-hexane / ethyl acetate. The volume ratio of the solvents was adjusted according to the polarity of the compound, and a small amount of alkaline or acidic reagents such as triethylamine and acetic acid could also be added for adjustment.

[0443] Example 1

[0444] 5-(4-(4-(Aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-6-fluoro-1,2,2a,8a-tetrahydrobenzo[b]cyclobutano[e][1,4]dioxane-4-carbonitrile 1

[0445] (M)-(2aS,8aR)-5-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-6-fluoro-1,2,2a,8a-tetrahydrobenzo[b]cyclobutano[e][1,4]dioxane-4-carbonitrile 1-p1

[0446] (M)-(2aR,8aS)-5-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-6-fluoro-1,2,2a,8a-tetrahydrobenzo[b]cyclobutano[e][1,4]dioxane-4-carbonitrile 1-p2

[0447] (P)-(2aS,8aR)-5-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-6-fluoro-1,2,2a,8a-tetrahydrobenzo[b]cyclobutano[e][1,4]dioxane-4-carbonitrile 1-p3

[0448] (P)-(2aR,8aS)-5-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-6-fluoro-1,2,2a,8a-tetrahydrobenzo[b]cyclobutano[e][1,4]dioxane-4-carbonitrile 1-p4

[0449] first step

[0450] 2-(2-Bromo-4,6-difluorophenoxy)cyclobutan-1-one 1c

[0451] 2-Bromo-4,6-difluorophenol 1b (473 g, 2.04 mol, Jiangsu Aikang) was dissolved in N,N-dimethylformamide (3000 mL). Sodium carbonate (997.14 g, 9.41 mol) and 2-bromocyclobutan-1-one 1a (410.08 g, 2.34 mol, prepared using the method disclosed for Intermediate I-07A on page 53 of the specification of patent application "WO2018013770") were added, and the mixture was stirred at 80°C for 2 hours. The reaction mixture was cooled to room temperature, filtered, and the filter cake was washed with 4000 mL of ethyl acetate. The filtrate was collected and added with 4000 mL of water. The organic phase was separated and the aqueous phase was extracted once with 500 mL of ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered to remove the desiccant, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent System B to obtain the title compound 1c (260 g, 46% yield).

[0452] MS m / z(ESI):276.9[M+1].

[0453] Step 2

[0454] 2-(2-Bromo-4,6-difluorophenoxy)cyclobutan-1-ol 1d

[0455] Compound 1c (240 g, 822.92 mmol) was dissolved in tetrahydrofuran (1500 mL), cooled to -70°C, and a 1 M solution of lithium tri-sec-butylborohydride in tetrahydrofuran (905 mL) was added dropwise. The temperature was maintained and stirred for 1 hour. 500 mL of water was added dropwise to quench the mixture. 500 mL of 1% sodium hydroxide solution was then added, and the mixture was extracted with ethyl acetate (500 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered to remove the desiccant, and concentrated under reduced pressure to give the crude title compound 1d (272 g), which was used directly in the next step without purification.

[0456] MS m / z(ESI):278.9[M+1].

[0457] Step 3

[0458] 4-Bromo-6-fluoro-1,2,2a,8a-tetrahydrobenzo[b]cyclobutane[e][1,4]dioxane 1e

[0459] Compound 1d (272 g, 779.71 mmol) was dissolved in dimethyl sulfoxide (2700 mL), and cesium carbonate (762.13 g, 2.34 mol) was added. The mixture was heated to 120°C and stirred for 1 hour. The reaction mixture was cooled to room temperature, water was added, and extraction was performed with ethyl acetate (500 mL x 2). The organic phases were combined, washed sequentially with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered to remove the desiccant, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent System B to obtain the title compound 1e (201 g, yield: 69.7%).

[0460] MS m / z(ESI):258.9[M+1].

[0461] Step 4

[0462] 6-Fluoro-1,2,2a,8a-tetrahydrobenzo[b]cyclobutane[e][1,4]dioxane-4-carbonitrile 1f

[0463] Compound 1e (5.45 g, 21 mmol) was dissolved in N,N-dimethylacetamide (50 mL), and zinc cyanide (4.94 g, 42 mmol), zinc powder (1.44 g, 22.1 mmol) and tetrakis(triphenylphosphine)palladium (1.2 g, 1.05 mmol) were added. The atmosphere was replaced with nitrogen and heated to 100°C for 16 hours. The reaction solution was cooled to room temperature, diluted with ethyl acetate and filtered. The filtrate was washed with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered to remove the desiccant, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent System B to give the title compound 1f (3.52 g, yield: 81.5%).

[0464] MS m / z(ESI):206.2[M+1].

[0465] Step 5

[0466] 6-Fluoro-5-iodo-1,2,2a,8a-tetrahydrobenzo[b]cyclobutane[e][1,4]dioxane-4-carbonitrile 1g

[0467] Compound 1f (2.32 g, 11.3 mmol) was dissolved in tetrahydrofuran (80 mL), cooled to -78°C, and a 2 M solution of lithium diisopropylamide in tetrahydrofuran (6.3 mL) was added dropwise. After stirring for 30 minutes, a solution of iodine (3.0 g, 11.8 mmol) in tetrahydrofuran (10 mL) was added, and the reaction was stirred for 30 minutes. A saturated sodium sulfite solution and an aqueous sodium bicarbonate solution were added to the reaction solution to quench the reaction. The layers were separated, and the aqueous phase was extracted with ethyl acetate (50 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered to remove the desiccant, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent System B to give the title compound 1g (1.5 g, yield: 40%).

[0468] Step 6

[0469] 6-Fluoro-5-(1-methyl-1H-pyrazol-5-yl)-1,2,2a,8a-tetrahydrobenzo[b]cyclobutano[e][1,4]dioxane-4-carbonitrile 1i

[0470] 1-Methyl-1H-pyrazole-5-boronic acid pinacol ester 1h (1.78 g, 8.5 mmol, Nanjing Yaoshi) and compound 1g (1.42 g, 4.28 mmol) were dissolved in water (6 mL) and 1,4-dioxane (30 mL), and sodium carbonate (909 mg, 8.6 mmol) and 1,1'-bis(di-tert-butylphosphino)ferrocenepalladium dichloride (292 mg, 428.29 μmol) were added. The atmosphere was replaced with nitrogen and heated to 85°C for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in dichloromethane and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to give the title compound 1i (1.22 g, yield: 99%).

[0471] MS m / z(ESI):286.0[M+1].

[0472] Step 7

[0473] 5-(4-Bromo-1-methyl-1H-pyrazol-5-yl)-6-fluoro-1,2,2a,8a-tetrahydrobenzo[b]cyclobutano[e][1,4]dioxane-4-carbonitrile 1j

[0474] Compound 1i (1.22 g, 4.3 mmol) was dissolved in acetonitrile (20 mL), and N-bromosuccinimide (837 mg, 4.7 mmol) was added. The reaction was stirred for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent System B to give the title compound 1j (1.55 g, yield: 99%).

[0475] MS m / z(ESI):364.0[M+1].

[0476] Step 8

[0477] 5-(4-(4-((1,3-dioxoisoindolin-2-yl)methyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-6-fluoro-1,2,2a,8a-tetrahydrobenzo[b]cyclobutano[e][1,4]dioxane-4-carbonitrile

[0478] Under nitrogen atmosphere, compound 1j (1.27 g, 2.94 mmol), 2-((4-oxo-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydrophthalazin-1-yl)methyl)isoindoline-1,3-dione 1k (1.27 g, 2.94 mmol, according to the literature "Journal of Medicinal Chemistry, 2022, vol. 65, #3, p. 1749-1766” prepared by the method disclosed in “Chemistry, 2022, vol. 65, #3, p. 1749-1766”), 1,1'-bis(di-tert-butylphosphino)ferrocenepalladium dichloride (1.95 g, 2.94 mmol), sodium bicarbonate (495 mg, 5.89 mmol) were dissolved in 1,4-dioxane (25 mL) and water (5 mL), stirred at 80° C. for 4 hours, and the reaction solution was concentrated under reduced pressure. The residue was dissolved in dichloromethane and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system A to obtain the title compound 11 (973 mg, yield: 56.1%).

[0479] MS m / z(ESI):589.2[M+1].

[0480] Steps 9 to 10

[0481] 5-(4-(4-(Aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-6-fluoro-1,2,2a,8a-tetrahydrobenzo[b]cyclobutano[e][1,4]dioxane-4-carbonitrile 1

[0482] (M)-(2aS,8aR)-5-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-6-fluoro-1,2,2a,8a-tetrahydrobenzo[b]cyclobutano[e][1,4]dioxane-4-carbonitrile 1-p1

[0483] (M)-(2aR,8aS)-5-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-6-fluoro-1,2,2a,8a-tetrahydrobenzo[b]cyclobutano[e][1,4]dioxane-4-carbonitrile 1-p2

[0484] (P)-(2aS,8aR)-5-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-6-fluoro-1,2,2a,8a-tetrahydrobenzo[b]cyclobutano[e][1,4]dioxane-4-carbonitrile 1-p3

[0485] (P)-(2aR,8aS)-5-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-6-fluoro-1,2,2a,8a-tetrahydrobenzo[b]cyclobutano[e][1,4]dioxane-4-carbonitrile 1-p4

[0486] Compound 11 (973 mg, 1.65 mmol) was dissolved in ethanol (15 mL), and hydrazine hydrate (780 mg, 13.2 mmol, 85% purity) was added. The mixture was stirred at 80°C for 2 hours. The reaction solution was concentrated under reduced pressure, and dichloromethane / methanol (V:V=5:1) was added to the residue. After stirring for 10 minutes, the mixture was filtered and the filtrate was concentrated under reduced pressure to obtain crude compound 1 (760 mg). Compound 1 was purified by preparative HPLC (Waters-2545, column: YMC Triart-Exrs, Prep 30*150 mm, 5 μm; mobile phase: aqueous phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 30%-42%, flow rate: 30 mL / min) to obtain two components, component A (180 mg, yield: 24.5%) and component B (180 mg, yield: 24.5%).

[0487] Component A: short retention time

[0488] MS m / z(ESI):459.1[M+1].

[0489] HPLC analysis: retention time 1.01 minutes, purity: 99% (chromatographic column: C18, 1.7 μm, 2.1*50 mm; mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%).

[0490] 1H NMR (500MHz, DMSO-d6): δ12.44(s,1H),8.26(s,1H),8.18(d,1H),7.75(dd,1H),7.70 (s,1H),7.59(d,1H),4.96-4.92(m,2H),3.76(d,2H),3.75(s,3H),2.24-2.15(m,6H).

[0491] Component B: long retention time

[0492] MS m / z(ESI):459.1[M+1].

[0493] HPLC analysis: retention time 1.04 minutes, purity: 96% (chromatographic column: C18, 1.7 μm, 2.1*50 mm; mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%).

[0494] 1 H NMR (500MHz, DMSO-d6): δ12.43(s,1H),8.24(s,1H),8.15(d,1H),7.74(s,1H),7.67(dd, 1H),7.59(d,1H),4.96-4.90(m,2H),3.79-3.78(m,5H),2.25-2.13(m,4H),1.95(s,2H).

[0495] Component A (100 mg) was separated by chiral column (Shimadzu LC-20AP, chromatographic column: Daicel CHIRALPAK IE, 20*250 mm, 10 μm; mobile phase A: n-hexane, mobile phase B: ethanol (0.5% ammonia methanol solution), gradient ratio: A:B 55:45, flow rate: 20 mL / min) to give the title compounds 1-p4 (30 mg, 30%) and 1-p1 (32 mg, 32%).

[0496] Single configuration compound 1-p4 (shorter retention time in component A): (30 mg, 30%).

[0497] Chiral HPLC analysis: retention time 13.511 minutes, purity: 99% (chromatographic column: CHIRALPAK IE 150*4.6 mm, 5 μm; mobile phase: n-hexane and ethanol (containing 0.1% diethylamine), gradient ratio: A:B 50:50, flow rate: 1.0 mL / min).

[0498] 1H NMR (500MHz, DMSO-d6): δ12.45(s,1H),8.26(s,1H),8.18(d,1H),7.75(dd,1H),7.71 (s,1H),7.59(d,1H),4.97-4.91(m,2H),3.78(d,2H),3.75(s,3H),2.25-2.15(m,6H).

[0499] Single configuration compound 1-p1 (longer retention time in component A): (32 mg, 32%).

[0500] Chiral HPLC analysis: retention time 17.880 minutes, purity: 98% (chromatographic column: CHIRALPAK IE 150*4.6 mm, 5 μm; mobile phase: n-hexane and ethanol (containing 0.1% diethylamine), gradient ratio: A:B 50:50, flow rate: 1.0 mL / min).

[0501] 1 H NMR (500MHz, DMSO-d6): δ12.45(s,1H),8.26(s,1H),8.18(d,1H),7.75(dd, 1H),7.71(s,1H),7.59(d,1H),4.97-4.91(m,2H),3.78(d,2H),3.75(s,3H), 2.25-2.15(m,6H).

[0502] Component B (100 mg) was separated by chiral column (Shimadzu LC-20AP, chromatographic column: Daicel CHIRALPAK IE, 20*250 mm, 10 μm; mobile phase A: n-hexane, mobile phase B: ethanol (0.5% ammonia methanol solution), gradient ratio: A:B 40:60, flow rate: 20 mL / min) to give the title compounds 1-p3 (28 mg, 28%) and 1-p2 (30 mg, 30%).

[0503] Single configuration compound 1-p3 (shorter retention time in component B): (28 mg, 28%).

[0504] Chiral HPLC analysis: retention time 13.120 minutes, purity: 99% (chromatographic column: CHIRALPAK IE 150*4.6 mm, 5 μm; mobile phase: n-hexane and ethanol (containing 0.1% diethylamine), gradient ratio: A:B 50:50, flow rate: 1.0 mL / min).

[0505] 1H NMR (500MHz, DMSO-d6): δ12.44(s,1H),8.24(s,1H),8.15(d,1H),7.74(s,1H),7. 67(dd,1H),7.58(d,1H),4.96-4.90(m,2H),3.80-3.77(m,5H),2.25-2.13(m,4H).

[0506] Single configuration compound 1-p2 (longer retention time in component B): (30 mg, 30%).

[0507] Chiral HPLC analysis: retention time 23.466 minutes, purity: 99% (chromatographic column: CHIRALPAK IE 150*4.6 mm, 5 μm; mobile phase: n-hexane and ethanol (containing 0.1% diethylamine), gradient ratio: A:B 50:50, flow rate: 1.0 mL / min).

[0508] 1 H NMR (500MHz, DMSO-d6): δ12.44(s,1H),8.24(s,1H),8.15(d,1H),7.74(s,1H),7. 67(dd,1H),7.58(d,1H),4.96-4.90(m,2H),3.80-3.77(m,5H),2.25-2.13(m,4H).

[0509] Example 2

[0510] 5-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-(methyl-d3)-1H-pyrazol-5-yl)-6-fluoro-1,2,2a,8a-tetrahydrobenzo[b]cyclobutano[e][1,4]dioxane-4-carbonitrile 2

[0511] (M)-(2aS,8aR)-5-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-(methyl-d3)-1H-pyrazol-5-yl)-6-fluoro-1,2,2a,8a-tetrahydrobenzo[b]cyclobutano[e][1,4]dioxane-4-carbonitrile 2-p1

[0512] (M)-(2aR,8aS)-5-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-(methyl-d3)-1H-pyrazol-5-yl)-6-fluoro-1,2,2a,8a-tetrahydrobenzo[b]cyclobutano[e][1,4]dioxane-4-carbonitrile 2-p2

[0513] (P)-(2aS,8aR)-5-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-(methyl-d3)-1H-pyrazol-5-yl)-6-fluoro-1,2,2a,8a-tetrahydrobenzo[b]cyclobutano[e][1,4]dioxane-4-carbonitrile 2-p3

[0514] (P)-(2aR,8aS)-5-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-(methyl-d3)-1H-pyrazol-5-yl)-6-fluoro-1,2,2a,8a-tetrahydrobenzo[b]cyclobutano[e][1,4]dioxane-4-carbonitrile 2-p4

[0515] first step

[0516] 6-Fluoro-5-(1-(methyl-d3)-1H-pyrazol-5-yl)-1,2,2a,8a-tetrahydrobenzo[b]cyclobutano[e][1,4]dioxane-4-carbonitrile 2b

[0517] 1-(Methyl-d3)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole 2a (3 g, 14.2 mmol, prepared by the method disclosed in Example 25 on page 178 of the specification of patent application "WO2019079469") and compound 1g (2.4 g, 7.25 mmol) were dissolved in water (8 mL) and 1,4-dioxane (40 mL). L), sodium carbonate (1.6 g, 15.1 mmol) and 1,1'-bis(di-tert-butylphosphino)ferrocenepalladium dichloride (470 mg, 718.9 μmol) were added, the atmosphere was replaced with nitrogen, and the mixture was heated to 85°C for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in dichloromethane and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent System B to obtain the title compound 2b (2 g, yield: 99%).

[0518] MS m / z(ESI):289.0[M+1].

[0519] Step 2

[0520] 5-(4-Bromo-1-(methyl-d3)-1H-pyrazol-5-yl)-6-fluoro-1,2,2a,8a-tetrahydrobenzo[b]cyclobutano[e][1,4]dioxane-4-carbonitrile 2c

[0521] Compound 2b (1.9 g, 6.6 mmol) was dissolved in acetonitrile (40 mL), and N-bromosuccinimide (1.3 g, 7.25 mmol) was added. The reaction was stirred for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent System B to give the title compound 2c (2.1 g, yield: 86.7%).

[0522] MS m / z(ESI):367.2[M+1].

[0523] Step 3

[0524] 5-(4-(4-((1,3-dioxoisoindolin-2-yl)methyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-(methyl-d3)-1H-pyrazol-5-yl)-6-fluoro-1,2,2a,8a-tetrahydrobenzo[b]cyclobutano[e][1,4]dioxane-4-carbonitrile 2d

[0525] Under nitrogen atmosphere, compound 2c (1.5 g, 4.08 mmol), compound 1k (1.8 g, 4.17 mmol), 1,1'-bis(di-tert-butylphosphino)ferrocenepalladium dichloride (2.7 g, 4 mmol) and sodium bicarbonate (686 mg, 8.17 mmol) were dissolved in 1,4-dioxane (20 mL) and water (4 mL). The mixture was stirred at 80°C for 4 hours. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in dichloromethane and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent System A to give the title compound 2d (760 mg, yield: 31.4%).

[0526] MS m / z(ESI):592.2[M+1].

[0527] Steps 4 and 5

[0528] 5-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-(methyl-d3)-1H-pyrazol-5-yl)-6-fluoro-1,2,2a,8a-tetrahydrobenzo[b]cyclobutano[e][1,4]dioxane-4-carbonitrile 2

[0529] (M)-(2aS,8aR)-5-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-(methyl-d3)-1H-pyrazol-5-yl)-6-fluoro-1,2,2a,8a-tetrahydrobenzo[b]cyclobutano[e][1,4]dioxane-4-carbonitrile 2-p1

[0530] (M)-(2aR,8aS)-5-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-(methyl-d3)-1H-pyrazol-5-yl)-6-fluoro-1,2,2a,8a-tetrahydrobenzo[b]cyclobutano[e][1,4]dioxane-4-carbonitrile 2-p2

[0531] (P)-(2aS,8aR)-5-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-(methyl-d3)-1H-pyrazol-5-yl)-6-fluoro-1,2,2a,8a-tetrahydrobenzo[b]cyclobutano[e][1,4]dioxane-4-carbonitrile 2-p3

[0532] (P)-(2aR,8aS)-5-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-(methyl-d3)-1H-pyrazol-5-yl)-6-fluoro-1,2,2a,8a-tetrahydrobenzo[b]cyclobutano[e][1,4]dioxane-4-carbonitrile 2-p4

[0533] Compound 2d (760 mg, 1.28 mmol) was dissolved in ethanol (15 mL), and hydrazine hydrate (605 mg, 10.2 mmol, 85% purity) was added. The mixture was stirred at 80° C. for 2 hours. The reaction solution was concentrated under reduced pressure, and dichloromethane / methanol (V:V=5:1) was added to the residue. After stirring for 10 minutes, the mixture was filtered and the filtrate was concentrated under reduced pressure to obtain crude compound 2 (590 mg). Compound 2 was purified by preparative HPLC (Waters-2545, column: YMC Triart-Exrs, Prep 30*150 mm, 5 μm; mobile phase: aqueous phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 30%-42%, flow rate: 30 mL / min) to obtain two fractions, fraction A (short retention time, 130 mg, yield: 22%) and fraction B (long retention time, 130 mg, yield: 22%).

[0534] Component A (130 mg) was separated by chiral column (Gilson-281, chromatographic column: CHIRALPAK IE, 20*250 mm, 5 μm; mobile phase A: n-hexane, mobile phase B: ethanol (0.5% 7 M ammonia methanol solution), gradient ratio: A:B 50:50, flow rate: 15 mL / min) to give the title compounds 2-p4 (30 mg, 23%) and 2-p1 (30 mg, 23%).

[0535] Single configuration compound 2-p4 (shorter retention time in component A) (30 mg, 23%).

[0536] Chiral HPLC analysis: retention time 13.617 minutes, purity: 99% (chromatographic column: CHIRALPAK IG 150*4.6 mm, 5 μm; mobile phase: n-hexane and ethanol (containing 0.1% diethylamine), gradient ratio: A:B 50:50, flow rate: 1.0 mL / min).

[0537] MS m / z(ESI):462.1[M+1].

[0538] 1 H NMR (500MHz, CD3OD): δ8.30(d,1H),8.15(s,1H),7.77(d,1H),7.70(dd,1H),7.33(d,1H),4.11-4.00(m,2H),3.34-3.32(m,2H),2.37-2.17(m,4H).

[0539] Single configuration compound 2-p1 (longer retention time in component A): (30 mg, 23%).

[0540] Chiral HPLC analysis: retention time 18.128 minutes, purity: 98% (chromatographic column: CHIRALPAK IE 150*4.6 mm, 5 μm; mobile phase: n-hexane and ethanol (containing 0.1% diethylamine), gradient ratio: A:B 50:50, flow rate: 1.0 mL / min).

[0541] MS m / z(ESI):462.1[M+1].

[0542] 1 H NMR (500MHz, DMSO-d6): δ12.44(s,1H),8.25(s,1H),8.19-8.17(m,1H),7.76-7.74(m,1H),7.71-7.7 0(m,1H),7.60-7.58(m,1H),4.97-4.90(m,2H),3.80-3.73(m,2H),2.26-2.13(m,4H),1.91(brs,2H).

[0543] Component B (130 mg) was separated by chiral column (Gilson-281, chromatographic column: CHIRALPAK IE, 20*250 mm, 5 μm; mobile phase A: n-hexane, mobile phase B: ethanol (0.5% 7 M ammonia methanol solution), gradient ratio: A:B 50:50, flow rate: 15 mL / min) to give the title compounds 2-p3 (30 mg, 23%) and 2-p2 (47 mg, 36.1%).

[0544] Single configuration compound 2-p3 (shorter retention time in component B): (30 mg, 23%).

[0545] Chiral HPLC analysis: retention time 13.073 minutes, purity: 99% (chromatographic column: CHIRALPAK IE 150*4.6 mm, 5 μm; mobile phase: n-hexane and ethanol (containing 0.1% diethylamine), gradient ratio: A:B 50:50, flow rate: 1.0 mL / min).

[0546] MS m / z(ESI):462.1[M+1].

[0547] 1 H NMR (500MHz, DMSO-d6): δ12.42(s,1H),8.24(s,1H),8.15-8.14(m,1H),7.74-7.73(m,1H),7.68-7.6 6(m,1H),7.59-7.57(m,1H),4.96-4.89(m,2H),3.81-3.74(m,2H),2.26-2.11(m,4H),1.82(brs,2H).

[0548] Single configuration compound 2-p2 (longer retention time in component B): (47 mg, 36.1%).

[0549] Chiral HPLC analysis: retention time 23.504 minutes, purity: 99% (chromatographic column: CHIRALPAK IE 150*4.6 mm, 5 μm; mobile phase: n-hexane and ethanol (containing 0.1% diethylamine), gradient ratio: A:B 50:50, flow rate: 1.0 mL / min).

[0550] MS m / z(ESI):462.1[M+1].

[0551] 1 H NMR (500MHz, CD3OD): δ8.27(d,1H),8.15(s,1H),7.73(d,1H),7.68(dd,1H),7.33(d,1H),4.07-3.97(m,2H),3.38-3.34(m,2H),2.35-2.21(m,4H).

[0552] Example 3

[0553] 7-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-(methyl-d3)-1H-pyrazol-5-yl)-6-fluoro-3H-spiro[benzo[b][1,4]dioxane-2,1'-cyclopropane]-8-carbonitrile 3

[0554] (M)-7-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-(methyl-d3)-1H-pyrazol-5-yl)-6-fluoro-3H-spiro[benzo[b][1,4]dioxane-2,1'-cyclopropane]-8-carbonitrile 3-p1

[0555] (P)-7-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-(methyl-d3)-1H-pyrazol-5-yl)-6-fluoro-3H-spiro[benzo[b][1,4]dioxane-2,1'-cyclopropane]-8-carbonitrile 3-p2

[0556] MS m / z(ESI):462.1[M+1].

[0557] Example 4

[0558] 6-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-(methyl-d3)-1H-pyrazol-5-yl)-5-fluoro-3H-spiro[benzofuran-2,1'-cyclopropane]-7-carbonitrile 4

[0559] (M)-6-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-(methyl-d3)-1H-pyrazol-5-yl)-5-fluoro-3H-spiro[benzofuran-2,1'-cyclopropane]-7-carbonitrile 4-p1

[0560] (P)-6-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-(methyl-d3)-1H-pyrazol-5-yl)-5-fluoro-3H-spiro[benzofuran-2,1'-cyclopropane]-7-carbonitrile 4-p2

[0561] MS m / z(ESI):446.1[M+1].

[0562] Example 5

[0563] (R)-8-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-(methyl-d3)-1H-pyrazol-5-yl)-7-fluoro-2,3,3a,4-tetrahydro-1H-benzo[b]pyrrolo[1,2-d][1,4]oxazine-9-carbonitrile 5

[0564] (M)-(R)-8-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-(methyl-d3)-1H-pyrazol-5-yl)-7-fluoro-2,3,3a,4-tetrahydro-1H-benzo[b]pyrrolo[1,2-d][1,4]oxazine-9-carbonitrile 5-p1

[0565] (P)-(R)-8-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-(methyl-d3)-1H-pyrazol-5-yl)-7-fluoro-2,3,3a,4-tetrahydro-1H-benzo[b]pyrrolo[1,2-d][1,4]oxazine-9-carbonitrile 5-p2

[0566] first step

[0567] (R)-7-Fluoro-9-nitro-2,3,3a,4-tetrahydro-1H-benzo[b]pyrrolo[1,2-d][1,4]oxazine 5c

[0568] D-Prolinol 5a (3.4 g, 33.6 mmol, Shanghai Shaoyuan) and 2,3,5-trifluoronitrobenzene 5b (5 g, 28.2 mmol, Shanghai Bid) were dissolved in dimethyl sulfoxide (20 mL), potassium hydroxide (5.54 g, 98.7 mmol) was added, and the reaction was stirred at 65°C for 4 hours. After the reaction solution was cooled to room temperature, water was added and extracted with dichloromethane (50 mL×3). The organic phases were combined and washed with water and saturated sodium chloride solution in sequence. The organic phase was dried over anhydrous sodium sulfate and filtered. After removing the desiccant, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with elution system B to obtain the title compound 5c (5 g, yield: 74.6%).

[0569] MS m / z(ESI):239.3[M+1].

[0570] Step 2

[0571] (R)-7-Fluoro-2,3,3a,4-tetrahydro-1H-benzo[b]pyrrolo[1,2-d][1,4]oxazin-9-amine 5d

[0572] Compound 5c (1 g, 4.2 mmol) was dissolved in methanol (20 mL) and tetrahydrofuran (4 mL). 10% palladium-on-carbon hydrogenation catalyst (wet) (260 mg) was added, and the atmosphere was replaced with hydrogen. The reaction was stirred for 16 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to give the crude title compound 5d (900 mg). This product was used directly in the next step without purification. MS m / z (ESI): 223.3 [M+1].

[0573] Step 3

[0574] (R)-9-Bromo-7-fluoro-2,3,3a,4-tetrahydro-1H-benzo[b]pyrrolo[1,2-d][1,4]oxazine 5e

[0575] Cuprous bromide (744 mg, 5.18 mmol) was added to acetonitrile (10 mL) at 0°C, and tert-butyl nitrite (668.5 mg, 6.5 mmol) was added dropwise. The mixture was stirred at this temperature for 10 minutes, followed by the addition of a solution of compound 5d (900 mg, 4.3 mmol) in acetonitrile (3 mL). The mixture was returned to room temperature and stirred for 16 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent B to afford the title compound 5e (160 mg, 13.6% yield). MS m / z (ESI): 272.2 [M+1].

[0576] Step 4

[0577] (R)-7-Fluoro-2,3,3a,4-tetrahydro-1H-benzo[b]pyrrolo[1,2-d][1,4]oxazine-9-carbonitrile 5f

[0578] Compound 5e (3 g, 11 mmol) was dissolved in N,N-dimethylacetamide (50 mL), and cuprous cyanide (4.9 g, 54.7 mmol) was added. The mixture was heated to 120°C for 16 hours. The reaction solution was cooled to room temperature, diluted with ethyl acetate, and filtered. The filtrate was washed with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered to remove the desiccant, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent System B to give the title compound 5f (1 g, yield: 41.5%).

[0579] MS m / z(ESI):219.3[M+1].

[0580] Step 5

[0581] (R)-7-Fluoro-8-iodo-2,3,3a,4-tetrahydro-1H-benzo[b]pyrrolo[1,2-d][1,4]oxazine-9-carbonitrile 5g

[0582] Compound 5f (1 g, 4.6 mmol) was dissolved in tetrahydrofuran (30 mL), cooled to -78°C, and a 2 M solution of lithium diisopropylamide in tetrahydrofuran (2.5 mL) was added dropwise. After stirring for 30 minutes, a solution of iodine (1.22 g, 4.8 mmol) in tetrahydrofuran (5 mL) was added, and the reaction was stirred for 30 minutes. A saturated sodium sulfite solution and an aqueous sodium bicarbonate solution were added to the reaction solution to quench the reaction. The layers were separated, and the aqueous phase was extracted with ethyl acetate (50 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered to remove the desiccant, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent System B to give the title compound 5g (500 mg, yield: 31.8%).

[0583] MS m / z(ESI):345.2[M+1].

[0584] Step 6

[0585] (M)-(R)-8-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-(methyl-d3)-1H-pyrazol-5-yl)-7-fluoro-2,3,3a,4-tetrahydro-1H-benzo[b]pyrrolo[1,2-d][1,4]oxazine-9-carbonitrile 5-p1

[0586] (P)-(R)-8-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-(methyl-d3)-1H-pyrazol-5-yl)-7-fluoro-2,3,3a,4-tetrahydro-1H-benzo[b]pyrrolo[1,2-d][1,4]oxazine-9-carbonitrile 5-p2

[0587] Using the synthetic route in Example 2, the first step raw material compound 1g was replaced by compound 5g to obtain the title compounds 5-p1 (22 mg, yield: 14%) and 5-p2 (22 mg, yield: 14%).

[0588] Single configuration compound 5-p1 (shorter retention time) (22 mg, yield: 14%).

[0589] MS m / z(ESI):475.1[M+1].

[0590] HPLC analysis: retention time 1.19 minutes, purity: 98% (chromatographic column: C18, 1.7 μm, 2.1*50 mm; mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%).

[0591] 1H NMR (500MHz, CD3OD): δ8.29(d,1H),8.14(s,1H),7.78(dd,1H),7.74-7.70(m,1H),7.11(d,1H),4.49(dd, 1H),4.18-4.07(m,1H),3.99(dd,2H),3.69-3.54(m,3H),2.23(dt,1H),2.01(qdd,2H),1.76-1.65(m,1H).

[0592] Single configuration compound 5-p2 (longer retention time): (22 mg, yield: 14%).

[0593] MS m / z(ESI):475.1[M+1].

[0594] HPLC analysis: retention time 1.21 minutes, purity: 98% (chromatographic column: C18, 1.7 μm, 2.1*50 mm; mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%).

[0595] 1 H NMR (500MHz, CD3OD): δ8.28(d,1H),8.15(s,1H),7.81-7.64(m,2H),7.14(d,1H),4.49(d,1H),4.23-4.03( m,1H),4.00(d,2H),3.66-3.53(m,2H),3.47-3.33(m,1H),2.21(dd,1H),2.00-1.85(m,2H),1.69(ddd,1H).

[0596] Example 6

[0597] 6-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-(methyl-d3)-1H-pyrazol-5-yl)-7-fluoro-2,3,3a,9a-tetrahydro-1H-benzo[b]penta[e][1,4]dioxane-5-carbonitrile

[0598] (M)-(3aS,9aR)-6-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-(methyl-d3)-1H-pyrazol-5-yl)-7-fluoro-2,3,3a,9a-tetrahydro-1H-benzo[b]penta[e][1,4]dioxane-5-carbonitrile 6-p1

[0599] (M)-(3aR,9aS)-6-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-(methyl-d3)-1H-pyrazol-5-yl)-7-fluoro-2,3,3a,9a-tetrahydro-1H-benzo[b]penta[e][1,4]dioxane-5-carbonitrile 6-p2

[0600] (P)-(3aS,9aR)-6-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-(methyl-d3)-1H-pyrazol-5-yl)-7-fluoro-2,3,3a,9a-tetrahydro-1H-benzo[b]penta[e][1,4]dioxane-5-carbonitrile 6-p3

[0601] (P)-(3aR,9aS)-6-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-(methyl-d3)-1H-pyrazol-5-yl)-7-fluoro-2,3,3a,9a-tetrahydro-1H-benzo[b]penta[e][1,4]dioxane-5-carbonitrile 6-p4

[0602] MS m / z(ESI):476.1[M+1].

[0603] Example 7

[0604] 2-(4-(4-(Aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-(methyl-d3)-1H-pyrazol-5-yl)-4a,5,6,6a-tetrahydrocyclobutano[b]thieno[2,3-e][1,4]dioxane-3-carbonitrile 7

[0605] (4aS,6aR)-2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-(methyl-d3)-1H-pyrazol-5-yl)-4a,5,6,6a-tetrahydrocyclobutano[b]thieno[2,3-e][1,4]dioxane-3-carbonitrile 7-p1

[0606] (4aR,6aS)-2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-(methyl-d3)-1H-pyrazol-5-yl)-4a,5,6,6a-tetrahydrocyclobutano[b]thieno[2,3-e][1,4]dioxane-3-carbonitrile 7-p2

[0607] MS m / z(ESI):450.1[M+1].

[0608] Example 8

[0609] (S)-8-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-(methyl-d3)-1H-pyrazol-5-yl)-7-fluoro-2,3,3a,4-tetrahydro-1H-benzo[b]pyrrolo[1,2-d][1,4]oxazine-9-carbonitrile 8

[0610] (M)-(S)-8-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-(methyl-d3)-1H-pyrazol-5-yl)-7-fluoro-2,3,3a,4-tetrahydro-1H-benzo[b]pyrrolo[1,2-d][1,4]oxazine-9-carbonitrile 8-p1

[0611] (P)-(S)-8-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-(methyl-d3)-1H-pyrazol-5-yl)-7-fluoro-2,3,3a,4-tetrahydro-1H-benzo[b]pyrrolo[1,2-d][1,4]oxazine-9-carbonitrile 8-p2

[0612] Using the synthetic route of Example 5, replacing the first step raw material D-prolinol 5a with L-prolinol, the title compounds 8-p2 (50 mg, yield: 7.4%) and 8-p1 (50 mg, yield: 7.4%) were obtained. The single-configuration compound 8-p2 (shorter retention time) was obtained (50 mg, yield: 7.4%).

[0613] MS m / z(ESI):475.1[M+1].

[0614] HPLC analysis: retention time 1.09 minutes, purity: 98% (chromatographic column: ACQUITY C18, 1.7 μm, 2.1*50 mm; mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%).

[0615] 1 H NMR (500MHz, CD3OD): δ8.29(d,1H),8.15(s,1H),7.77(dd,1H),7.73(s,1H),7.12(d,1H),4.49(dd, 1H),4.12(dt,1H),4.03(t,2H),3.64-3.54(m,3H),2.23(dq,1H),2.06-1.95(m,2H),1.70(dq,1H).

[0616] Single configuration compound 8-p1 (longer retention time): (50 mg, yield: 7.4%).

[0617] MS m / z(ESI):475.1[M+1].

[0618] HPLC analysis: retention time 1.11 minutes, purity: 98% (chromatographic column: C18, 1.7 μm, 2.1*50 mm; mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%).

[0619] MS m / z(ESI):475.1[M+1].

[0620] 1 H NMR (500MHz, CD3OD): δ8.28(d,1H),8.16(s,1H),7.78-7.71(m,2H),7.15(d,1H),4.49(d,1H),4.10(ddd,1H ),4.07-3.96(m,2H),3.66-3.56(m,2H),3.42-3.35(m,1H),2.21(dq,1H),2.04-1.90(m,2H),1.70(dt,1H).

[0621] Example 9

[0622] (R)-9-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-(methyl-d3)-1H-pyrazol-5-yl)-8-fluoro-1,2,4a,5-tetrahydro-4H-benzo[b][1,4]oxazino[4,3-d][1,4]oxazine-10-carbonitrile 9

[0623] (M)-(R)-9-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-(methyl-d3)-1H-pyrazol-5-yl)-8-fluoro-1,2,4a,5-tetrahydro-4H-benzo[b][1,4]oxazino[4,3-d][1,4]oxazine-10-carbonitrile 9-p1

[0624] (P)-(R)-9-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-(methyl-d3)-1H-pyrazol-5-yl)-8-fluoro-1,2,4a,5-tetrahydro-4H-benzo[b][1,4]oxazino[4,3-d][1,4]oxazine-10-carbonitrile 9-p2

[0625] first step

[0626] (R)-10-Bromo-8-fluoro-1,2,4a,5-tetrahydro-4H-benzo[b][1,4]oxazino[4,3-d][1,4]oxazine 9c

[0627] (S)-Morpholin-3-ylmethanol 9a (5 g, 42.6 mmol, Shanghai Titan) and 1-bromo-2,5-difluoro-3-nitrobenzene 9b (8.4 g, 35.5 mmol, Jiangsu Aikon) were dissolved in dimethyl sulfoxide (60 mL), potassium hydroxide (7 g, 124.4 mmol) was added, and the reaction was stirred at 65°C for 4 hours. After the reaction solution was cooled to room temperature, water was added and extracted with dichloromethane (50 mL×3). The organic phases were combined and washed with water and saturated sodium chloride solution in sequence. The organic phase was dried over anhydrous sodium sulfate and filtered. After removing the desiccant, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with elution system B to give the title compound 9c (5 g, yield: 48%).

[0628] MS m / z(ESI):287.9[M+1].

[0629] Step 2

[0630] (R)-8-Fluoro-1,2,4a,5-tetrahydro-4H-benzo[b][1,4]oxazino[4,3-d][1,4]oxazine-10-carbonitrile 9d

[0631] Compound 9c (5 g, 17.2 mmol) was dissolved in N,N-dimethylacetamide (100 mL), and zinc cyanide (3.5 g, 30.2 mmol), zinc powder (1.2 g, 18.1 mmol), and tetrakistriphenylphosphine palladium (2 g, 1.7 mmol) were added. The atmosphere was replaced with nitrogen and heated to 100°C for 16 hours. The reaction solution was cooled to room temperature, diluted with ethyl acetate, and filtered. The filtrate was washed with water and a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the desiccant was removed by filtration. The residue was concentrated under reduced pressure and purified by silica gel column chromatography with eluent System B to give the title compound 9d (3.9 g, yield: 97%).

[0632] MS m / z(ESI):235.3[M+1].

[0633] Step 3

[0634] (R)-8-Fluoro-9-iodo-1,2,4a,5-tetrahydro-4H-benzo[b][1,4]oxazino[4,3-d][1,4]oxazine-10-carbonitrile 9e

[0635] Compound 9d (3.94 g, 16.8 mmol) was dissolved in tetrahydrofuran (250 mL), cooled to -78°C, and a 2 M solution of lithium diisopropylamide in tetrahydrofuran (8.4 mL) was added dropwise. After stirring for 30 minutes, a solution of iodine (4.2 g, 16.8 mmol) in tetrahydrofuran (50 mL) was added, and the reaction was stirred for 30 minutes. Saturated sodium sulfite solution and aqueous sodium bicarbonate solution were added to the reaction solution to quench the reaction. The layers were separated, and the aqueous phase was extracted with ethyl acetate (50 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered to remove the desiccant, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent System B to give the title compound 9e (1.1 g, yield: 18%).

[0636] MS m / z(ESI):361.3[M+1].

[0637] Steps 4 and 5

[0638] (R)-9-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-(methyl-d3)-1H-pyrazol-5-yl)-8-fluoro-1,2,4a,5-tetrahydro-4H-benzo[b][1,4]oxazino[4,3-d][1,4]oxazine-10-carbonitrile 9

[0639] (M)-(R)-9-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-(methyl-d3)-1H-pyrazol-5-yl)-8-fluoro-1,2,4a,5-tetrahydro-4H-benzo[b][1,4]oxazino[4,3-d][1,4]oxazine-10-carbonitrile 9-p1

[0640] (P)-(R)-9-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-(methyl-d3)-1H-pyrazol-5-yl)-8-fluoro-1,2,4a,5-tetrahydro-4H-benzo[b][1,4]oxazino[4,3-d][1,4]oxazine-10-carbonitrile 9-p2

[0641] The synthetic route in Example 2 was used, and the raw material compound 1g in the first step was replaced by compound 9e to obtain the crude title compound 9 (117 mg). The crude product was separated by chiral column (Gilson-281, chromatographic column: CHIRALPAK IE, 20*250 mm, 5 μm; mobile phase A: n-hexane, mobile phase B: ethanol (0.5% 7 M ammonia methanol solution), gradient ratio: A:B 50:50, flow rate: 15 mL / min) to give the title compounds 9-p2 (15.6 mg, yield: 13.3%) and 9-p1 (15 mg, yield: 12.8%).

[0642] Single configuration compound 9-p2 (shorter retention time) (15.6 mg, yield: 13.3%).

[0643] MS m / z(ESI):491.2[M+1].

[0644] Chiral HPLC analysis: retention time: 12.342 minutes, purity: 97.6% (chromatographic column: CHIRALPAKAD-H250*4.6 mm, 5 μm; mobile phase: A: n-hexane, B: ethanol, gradient ratio: A:B 50:50, flow rate: 1.0 mL / min).

[0645] 1 H NMR (500MHz, DMSO-d6): δ12.42(s,1H),8.24-8.12(m,2H),7.80-7.66(m,2H),7.45-7. 40(m,1H),4.48-4.26(m,2H),3.87-3.64(m,6H),3.48-3.44(m,3H),2.12-1.84(m,2H).

[0646] Single configuration compound 9-p1 (longer retention time): (15 mg, yield: 12.8%).

[0647] MS m / z(ESI):491.2[M+1].

[0648] Chiral HPLC analysis: retention time: 18.774 minutes, purity: 83.2% (chromatographic column: CHIRALPAK AD-H250*4.6 mm, 5 μm; mobile phase: A: n-hexane, B: ethanol, gradient ratio: A:B 90:10, flow rate: 1.0 mL / min).

[0649] 1 H NMR (500MHz, DMSO-d6): δ12.42(s,1H),8.23-8.15(m,2H),7.86-7.67(m,2H),7.50-7. 40(m,1H),4.43-4.33(m,2H),3.88-3.61(m,6H),3.51-3.49(m,3H),2.00-1.69(m,2H).

[0650] Example 10

[0651] (S)-9-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-(methyl-d3)-1H-pyrazol-5-yl)-8-fluoro-1,2,4a,5-tetrahydro-4H-benzo[b][1,4]oxazino[4,3-d][1,4]oxazine-10-carbonitrile 10

[0652] The synthetic route in Example 9 was used to replace the first step raw material compound 9a with (R)-morpholin-3-ylmethanol (Shanghai Titan) to obtain the title compound 10 (71.6 mg, yield: 24.2%).

[0653] MS m / z(ESI):491.2[M+1].

[0654] 1 H NMR (500MHz, DMSO-d6): δ12.43(s,1H),8.24-8.15(m,2H),7.74-7.66(m,2H),7.43-7. 41(m,1H),4.50-4.20(m,2H),4.01-3.67(m,6H),3.47-3.45(m,3H),2.01-1.76(m,2H).

[0655] Example 11

[0656] (M)-(2aS,8aR)-5-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-(methyl-d3)-1H-pyrazol-5-yl)-7-chloro-6-fluoro-1,2,2a,8a-tetrahydrobenzo[b]cyclobutano[e][1,4]dioxane-4-carbonitrile 11-p3

[0657] (P)-(2aS,8aR)-5-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-(methyl-d3)-1H-pyrazol-5-yl)-7-chloro-6-fluoro-1,2,2a,8a-tetrahydrobenzo[b]cyclobutano[e][1,4]dioxane-4-carbonitrile 11-p4

[0658] first step

[0659] (2aR,8aS)-6-fluoro-5-iodo-1,2,2a,8a-tetrahydrobenzo[b]cyclobutane[e][1,4]dioxane-4-carbonitrile 11a-1

[0660] (2aS,8aR)-6-fluoro-5-iodo-1,2,2a,8a-tetrahydrobenzo[b]cyclobutane[e][1,4]dioxane-4-carbonitrile 11a-2

[0661] Compound 1g (11.6g) was separated by chiral column (Waters SFC 150, chromatographic column: 40*250mm, 10μm; mobile phase A: supercritical carbon dioxide, mobile phase B: methanol (+0.1% 7M ammonia methanol solution), gradient ratio: A:B=70:30, flow rate: 140mL / min) to obtain the title compound (5.4g, yield: 46.5%), (5.5g, yield: 47.4%).

[0662] Single configuration compound 11a-1 (shorter retention time): (5.4 g, yield: 46.5%)

[0663] Chiral HPLC analysis: retention time 1.599 minutes, purity: 99% (chromatographic column: 100*3mm, 3μm; mobile phase A: supercritical carbon dioxide, mobile phase B: methanol (+0.1% diethylamine), gradient ratio: A:B=90:10, flow rate: 1.5mL / min).

[0664] Single configuration compound 11a-2 (longer retention time): (5.5 g, yield: 47.4%)

[0665] Chiral HPLC analysis: retention time 2.274 minutes, purity: 99% (chromatographic column: 100*3mm, 3μm; mobile phase A: supercritical carbon dioxide, mobile phase B: methanol (+0.1% diethylamine), gradient ratio: A:B=90:10, flow rate: 1.5mL / min).

[0666] Step 2

[0667] (2aS,8aR)-6-fluoro-5-(1-(methyl-d3)-1H-pyrazol-5-yl)-1,2,2a,8a-tetrahydrobenzo[b]cyclobutano[e][1,4]dioxane-4-carbonitrile 11b-2

[0668] Compound 2a (7 g, 33.1 mmol) and compound 11a-2 (5.5 g, 33.2 mmol) were dissolved in water (24 mL) and 1,4-dioxane (120 mL), and sodium carbonate (3.5 g, 15.1 mmol) and 1,1'-bis(di-tert-butylphosphino)ferrocenepalladium dichloride (1.1 g, 1.7 mmol) were added. The mixture was heated to 85°C and reacted for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in dichloromethane and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 11b-2 (4.15 g, yield: 86.7%).

[0669] MS m / z(ESI):289.0[M+1].

[0670] Step 3

[0671] (2aS,8aR)-5-(4-bromo-1-(methyl-d3)-1H-pyrazol-5-yl)-6-fluoro-1,2,2a,8a-tetrahydrobenzo[b]cyclobutano[e][1,4]dioxane-4-carbonitrile 11c-2

[0672] Compound 11b-2 (4.15 g, 14.4 mmol) was dissolved in acetonitrile (70 mL), and N-bromosuccinimide (2.82 g, 15.7 mmol) was added. The mixture was heated to 50°C for 3 seconds. After the reaction solution was cooled to room temperature, saturated sodium bicarbonate solution and saturated sodium thiosulfate solution were added to quench the mixture. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate (50 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered to remove the desiccant, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 11c-2 (5.1 g, yield: 96.7%).

[0673] MS m / z(ESI):367.0[M+1].

[0674] Step 4

[0675] (2aS,8aR)-5-(4-bromo-1-(methyl-d3)-1H-pyrazol-5-yl)-7-chloro-6-fluoro-1,2,2a,8a-tetrahydrobenzo[b]cyclobutano[e][1,4]dioxane-4-carbonitrile 11d-2

[0676] Compound 11c-2 (530 mg, 1.44 mmol) was dissolved in tetrahydrofuran (10 mL), cooled to -78°C, and a 2M solution of lithium diisopropylamide in tetrahydrofuran (0.87 mL) was added dropwise. After stirring for 30 minutes, a solution of hexachloroethane (512.6 mg, 2.16 mmol) in tetrahydrofuran (2 mL) was added and the reaction was stirred for 30 minutes. A saturated sodium sulfite solution and an aqueous sodium bicarbonate solution were added to the reaction solution to quench the reaction. The layers were separated, and the aqueous phase was extracted with ethyl acetate (15 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered to remove the desiccant, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent System B to give the title compound 11d-2 (500 mg, yield: 86%).

[0677] MS m / z(ESI):401.0[M+1].

[0678] Step 5

[0679] (M)-(2aS,8aR)-5-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-(methyl-d3)-1H-pyrazol-5-yl)-7-chloro-6-fluoro-1,2,2a,8a-tetrahydrobenzo[b]cyclobutano[e][1,4]dioxane-4-carbonitrile 11-p3

[0680] (P)-(2aS,8aR)-5-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-(methyl-d3)-1H-pyrazol-5-yl)-7-chloro-6-fluoro-1,2,2a,8a-tetrahydrobenzo[b]cyclobutano[e][1,4]dioxane-4-carbonitrile 11-p4

[0681] The third to fifth steps of the synthetic route in Example 2 were adopted, and the raw material compound 2c in the third step was replaced by compound 11d-2 to obtain the title compounds 11-p3 (6 mg, yield: 4.7%) and 11-p4 (10 mg, yield: 7.9%).

[0682] Single configuration compound 11-p3 (shorter retention time) (6 mg, yield: 4.7%).

[0683] MS m / z(ESI):496.1[M+1].

[0684] HPLC analysis: retention time 1.08 minutes, purity: 98% (chromatographic column: C18, 1.7 μm, 2.1*50 mm; mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%).

[0685] 1 H NMR (500MHz, CD3OD): δ8.30(d,1H),8.16(s,1H),7.80(s,1H),7.66(d,1H),5.00(dq,1H),4.96–4.91(m,1H),4.15–4.01(m,2H),2.42–2.20(m,4H).

[0686] Single configuration compound 11-p4 (longer retention time): (10 mg, yield: 7.9%).

[0687] MS m / z(ESI):496.1[M+1].

[0688] HPLC analysis: retention time 1.11 minutes, purity: 94% (chromatographic column: C18, 1.7 μm, 2.1*50 mm; mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%).

[0689] 1 H NMR (500MHz, CD3OD): δ8.28(d,1H),8.16(s,1H),7.79(s,1H),7.63(d,1H),5.00(qt,1H),4.96–4.92(m,1H),4.13–4.00(m,2H),2.43–2.15(m,4H).

[0690] Example 12

[0691] 6-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-(methyl-d3)-1H-pyrazol-5-yl)-5-fluoro-2H-spiro[benzofuran-3,1'-cyclopropane]-7-carbonitrile 12

[0692] first step

[0693] 1-(2-(Benzyloxy)-5-fluorophenyl)cyclopropane-1-carbonitrile 12b

[0694] 2-(2-(Benzyloxy)-5-fluorophenyl)acetonitrile 12a (23.6 g, 97.8 mmol, prepared by the method disclosed in Example 13 on page 148 of the specification of patent application WO2011046771) and tetrabutylammonium bromide (1.5 g, 5.24 mmol) were mixed in N,N-dimethylformamide (DMF) (400 mL), and sodium hydride (8.22 g, 205.51 mmol, purity 60%) was added under ice bath. ), return to room temperature for 15 minutes, slowly add dropwise a solution of 1,2-dibromoethane (21 g, 111.78 mmol) in N,N-dimethylformamide (DMF) (100 mL), stir and react for 3 hours, add saturated ammonium chloride solution to quench, extract with dichloromethane (150 mL × 3), combine the organic phases, and concentrate under reduced pressure. The residue is purified by silica gel column chromatography with eluent system B to obtain the title compound 12b (25 g, yield: 95.6%).

[0695] MS m / z(ESI):268.2[M+1].

[0696] Step 2

[0697] Ethyl 1-(2-(benzyloxy)-5-fluorophenyl)cyclopropane-1-carboxylate 12c

[0698] Compound 12b (25 g, 93.5 mmol) was dissolved in ethanol (300 mL), concentrated sulfuric acid (300 mL) was added, and the mixture was reacted at 80°C for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was poured into ice water and extracted with ethyl acetate (100 mL × 3). The organic phases were combined and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system B to obtain the title compound 12c (15 g, yield: 51%).

[0699] MS m / z(ESI):315.2[M+1].

[0700] Step 3

[0701] Ethyl 1-(5-fluoro-2-hydroxyphenyl)cyclopropane-1-carboxylate 12d

[0702] Compound 12c (1 g, 3.18 mmol) was dissolved in methanol (20 mL), and palladium carbon hydrogenation catalyst (wet) (200 mg) was added. The atmosphere was replaced with hydrogen and stirred for 3 hours. The reaction solution was filtered and the filtrate was concentrated under reduced pressure to give the crude title compound 12d (650 mg), which was used directly in the next reaction without purification.

[0703] Step 4

[0704] Ethyl 1-(3-bromo-5-fluoro-2-hydroxyphenyl)cyclopropane-1-carboxylate 12e

[0705] Compound 12d (730 mg, 3.2 mmol) was dissolved in acetonitrile (20 mL), and N-bromosuccinimide (584 mg, 3.2 mmol) was added. The reaction was stirred for 2 hours. Saturated sodium sulfite solution and sodium bicarbonate aqueous solution were added to the reaction solution to quench the reaction. The layers were separated, and the aqueous phase was extracted with ethyl acetate (20 mL × 3). The organic phases were combined and dried over anhydrous sodium sulfate. The desiccant was removed by filtration and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent System B to give the title compound 12e (820 mg, yield: 83%).

[0706] MS m / z(ESI):301.2[M-1].

[0707] Step 5

[0708] 2-Bromo-4-fluoro-6-(1-(hydroxymethyl)cyclopropyl)phenol 12f

[0709] Compound 12e (820 mg, 2.7 mmol) was dissolved in tetrahydrofuran (50 mL), and a 1 M solution of lithium aluminum hydride in tetrahydrofuran (3.2 mL) was added dropwise at 0°C. The mixture was naturally stirred at room temperature for 2 hours. Water (0.2 mL) and 20% sodium hydroxide solution (0.2 mL) were added to the reaction solution in that order. The mixture was stirred for 10 minutes and filtered. The filtrate was dried over anhydrous sodium sulfate, the desiccant was removed by filtration, and the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent System B to give the title compound 12f (580 mg, yield: 82%).

[0710] MS m / z(ESI):261.0[M+1].

[0711] Step 6

[0712] 7-Bromo-5-fluoro-2H-spiro[benzofuran-3,1'-cyclopropane] 12g

[0713] Compound 12f (580 mg, 2.22 mmol) and azodicarbonyl dipiperidine (ADDP) (841 mg, 3.33 mmol) were dissolved in toluene (20 mL), the atmosphere was replaced with nitrogen, and the mixture was heated to 50°C. Tributylphosphine (675 mg, 3.33 mmol) was added and the reaction was stirred for 17 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent System B to afford the title compound 12g (540 mg, 99% yield).

[0714] Step 7

[0715] 6-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-(methyl-d3)-1H-pyrazol-5-yl)-5-fluoro-2H-spiro[benzofuran-3,1'-cyclopropane]-7-carbonitrile 12

[0716] The second to fourth steps of the synthetic route in Example 9 were adopted, and the raw material compound 9c in the second step was replaced by compound 12g to obtain the title compound 12 (102 mg, yield: 41.1%).

[0717] MS m / z(ESI):446.2[M+1].

[0718] 1 H NMR (500MHz, CD3OD): δ7.29-7.27(m,1H),8.14(s,1H),7.74-7.73(m,1H),7.70-7.68 (m,1H),7.19-7.18(m,1H),4.81-4.76(m,2H),4.03-3.96(m,2H),1.38-1.30(m,4H).

[0719] Example 13

[0720] (S)-8-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-(methyl-d3)-1H-pyrazol-5-yl)-6-chloro-7-fluoro-2,3,3a,4-tetrahydro-1H-benzo[b]pyrrolo[1,2-d][1,4]oxazine-9-carbonitrile 13

[0721] (M)-(S)-8-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-(methyl-d3)-1H-pyrazol-5-yl)-6-chloro-7-fluoro-2,3,3a,4-tetrahydro-1H-benzo[b]pyrrolo[1,2-d][1,4]oxazine-9-carbonitrile 13-p1

[0722] (P)-(S)-8-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-(methyl-d3)-1H-pyrazol-5-yl)-6-chloro-7-fluoro-2,3,3a,4-tetrahydro-1H-benzo[b]pyrrolo[1,2-d][1,4]oxazine-9-carbonitrile 13-p2

[0723] first step

[0724] (S)-7-Fluoro-8-(1-(methyl-d3)-1H-pyrazol-5-yl)-2,3,3a,4-tetrahydro-1H-benzo[b]pyrrolo[1,2-d][1,4]oxazine-9-carbonitrile 13b

[0725] Compound 13a (12.3 g, 35.7 mmol, using the synthetic route of 5 g in Example 5, replacing the first step raw material D-prolinol 5a with L-prolinol) and compound 2a (15.1 g, 71.5 mmol) were dissolved in water (40 mL) and 1,4-dioxane (200 mL), and sodium carbonate (7.6 g, 71.4 mmol) and 1,1'-bis(di-tert-butylphosphino)ferrocenepalladium dichloride (2.43 mg, 3.56 mmol) were added. The atmosphere was replaced with nitrogen and heated to 85°C for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in dichloromethane and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 13b (9 g, yield: 83%).

[0726] MS m / z(ESI):302.1[M+1].

[0727] Step 2

[0728] (S)-8-(4-Bromo-1-(methyl-d3)-1H-pyrazol-5-yl)-7-fluoro-2,3,3a,4-tetrahydro-1H-benzo[b]pyrrolo[1,2-d][1,4]oxazine-9-carbonitrile 13c

[0729] Compound 13b (9 g, 29.8 mmol) was dissolved in acetonitrile (150 mL), and N-bromosuccinimide (5.84 g, 32.8 mmol) was added. The reaction was stirred for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent System B to give the title compound 13c (8.4 g, yield: 74.0%).

[0730] MS m / z(ESI):380.0[M+1].

[0731] Step 3

[0732] (S)-8-(4-Bromo-1-(methyl-d3)-1H-pyrazol-5-yl)-6-chloro-7-fluoro-2,3,3a,4-tetrahydro-1H-benzo[b]pyrrolo[1,2-d][1,4]oxazine-9-carbonitrile 13d

[0733] Compound 13c (480 mg, 1.26 mmol) was dissolved in tetrahydrofuran (10 mL), cooled to -78°C, and a 2 M solution of lithium diisopropylamide in tetrahydrofuran (0.88 mL) was added dropwise. After stirring for 30 minutes, a solution of hexachloroethane (448 mg, 1.89 mmol) in tetrahydrofuran (2 mL) was added, and the reaction was stirred for 30 minutes. Saturated sodium sulfite solution and aqueous sodium bicarbonate solution were added to the reaction solution to quench the reaction. The layers were separated, and the aqueous phase was extracted with ethyl acetate (15 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered to remove the desiccant, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent System B to give the title compound 13d (288 mg, yield: 55%).

[0734] MS m / z(ESI):414.0[M+1].

[0735] Step 4

[0736] (S)-tert-Butyl((7-(5-(6-chloro-9-cyano-7-fluoro-2,3,3a,4-tetrahydro-1H-benzo[b]pyrrolo[1,2-d][1,4]oxazin-8-yl)-1-(methyl-d3)-1H-pyrazol-4-yl)-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)carbamate 13e

[0737] Under nitrogen atmosphere, compound 13d (54 mg, 0.131 mmol), tert-butyl ((4-oxo-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydrophthalazin-1-yl)methyl)carbamate (105 mg, 0.262 mmol, using the literature Org. Process Res.Dev.2023,27,5,954–971 disclosed method), 1,1'-bis(di-tert-butylphosphino)ferrocenedichloropalladium (18.6 mg, 0.026 mmol) and sodium carbonate (35 mg, 0.327 mmol) were dissolved in 1,4-dioxane (2 mL) and water (0.4 mL), stirred at 85 ° C. overnight, the reaction solution was concentrated under reduced pressure, the residue was dissolved in dichloromethane and filtered, and the filtrate was concentrated under reduced pressure. The obtained crude compound 13e was used directly in the next step without purification (80 mg).

[0738] MS m / z(ESI):609.2[M+1].

[0739] Step 5

[0740] (M)-(S)-8-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-(methyl-d3)-1H-pyrazol-5-yl)-6-chloro-7-fluoro-2,3,3a,4-tetrahydro-1H-benzo[b]pyrrolo[1,2-d][1,4]oxazine-9-carbonitrile 13-p1

[0741] (P)-(S)-8-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-(methyl-d3)-1H-pyrazol-5-yl)-6-chloro-7-fluoro-2,3,3a,4-tetrahydro-1H-benzo[b]pyrrolo[1,2-d][1,4]oxazine-9-carbonitrile 13-p2

[0742] Compound 13e (80 mg, 0.131 mmol) was dissolved in dichloromethane (2 mL) and trifluoroacetic acid (2 mL), and the reaction was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was purified by high-performance liquid chromatography (Waters-2545 YMC Triart-Exrs, Prep 30*150 mm, 5 μm (10 mmol / L) 30%-42%, 30 mL / min) to obtain the title compound.

[0743] Compound 13-p2 with a single configuration and short retention time: (4 mg, 6%)

[0744] HPLC analysis: retention time 0.98 minutes, purity: 90% (chromatographic column: C18, 1.7 μm, 2.1*50 mm; mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%).

[0745] 1 H NMR(500MHz,CD3OD)δ8.29(d,1H),8.17(s,1H),7.87(d,1H),7.62(dd,1H),4.69–4.61(m,1H),4.58– 4.47(m,2H),4.13(dt,1H),3.70–3.60(m,3H),2.30–2.19(m,1H),2.02(tdd,2H),1.80–1.70(m,1H).

[0746] MS m / z(ESI):509.2[M+1].

[0747] Compound 13-p1 with a single configuration and a long retention time: (4 mg, 6%)

[0748] 1H NMR(500MHz,CD3OD)δ8.27(d,1H),8.18(s,1H),7.95(d,1H),7.54(dd,1H),4.67–4.61(m,1H),4.61–4.52( m,2H),4.10(dt,1H),3.70–3.60(m,2H),3.43(dt,1H),2.28–2.19(m,2H),2.00(pd,2H),1.76–1.68(m,1H).

[0749] HPLC analysis: retention time 1.01 minutes, purity: 90% (chromatographic column: C18, 1.7 μm, 2.1*50 mm; mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%).

[0750] MS m / z(ESI):509.2[M+1].

[0751] Biological evaluation

[0752] The present disclosure is further described and explained below in conjunction with test examples, but these test examples are not intended to limit the scope of the present disclosure.

[0753] Test Example 1 Inhibitory activity of the disclosed compounds on human PRMT5 enzyme activity

[0754] 1. Experimental Materials and Instruments

[0755] 1. Recombinant human PRMT5:MEP50 protein (active motif, 31521)

[0756] 2. EPIgeneous Methyltransferase Kit (cisbio, 62SAHPEH)

[0757] 3. 96-well plate (Sangon Biotech, F610960-0010)

[0758] 4. 384-well white plate (Perkin Elmer, 6007290)

[0759] 5. 1M Tris-HCl [pH 8.5] (Sangon Biotech, B548141)

[0760] 6. Histone H4 peptide substrate (1-21) (BPS bioscience, 52014)

[0761] 7. 5′-deoxy-5′-(methylthio)adenosine (Aladdin, D168979-25mg)

[0762] 8. Tween-20 (Sangon Biotech, A100777-0500)

[0763] 9.DMSO (Sigma, D2650)

[0764] 10. Constant temperature box (Boxun Medical Biological Instrument Co., Ltd.)

[0765] 11. PHERAstar FS microplate reader (BMG Labtech)

[0766] 2. Experimental steps

[0767] PRMT5 can transfer the methyl group of S-adenosylmethionine (SAM) to the histone H4 peptide substrate (1-21), thereby generating S-adenosylhomocysteine ​​(SAH). In this experiment, the amount of SAH generated by the reaction was detected by homogeneous time-resolved fluorescence (HTRF) to evaluate the inhibitory activity of compounds against PRMT5.

[0768] 1. Standard curve drawing

[0769] Prepare the EPIgeneous Diluent Buffer in the EPIgeneous Methyltransferase kit with or without 1 μM 5'-deoxy-5'-(methylthiyl)adenosine (MTA) as sample diluent. Serially dilute the SAM and SAH standards according to the instructions, and aliquot 10 μL into each well (duplicate wells for each concentration). Add 2 μL of EPIgeneous Detection Buffer 1 to each well, centrifuge, vortex to mix, and incubate at room temperature for 10 minutes. Dilute SAH d2 Reagent 32-fold with EPIgeneous Detection Buffer 2, add 4 μL of SAH-d2 diluent to each well, centrifuge, and vortex to mix for 2 minutes. Dilute SAH Tb Cryptate Antibody 50-fold with EPIgeneous Detection Buffer 2, add 4 μL of Tb Cryptate Antibody diluent to each well, centrifuge, vortex to mix for 2 minutes, and incubate at room temperature for 60 minutes. Read the plate using a PHERAstar FS microplate reader and measure the 665 / 620 ratio. Create an xy plot of SAH concentration versus ratio to derive the calculation formula.

[0770] 2. Compound Detection

[0771] Reaction buffer (1×): 50 mM Tris-HCl [pH 8.5], 1 mM DTT, 0.005% Tween-20;

[0772] Compound preparation: Dilute 20 mM test compound in 100% DMSO to 1 mM as the highest drug concentration. Serially dilute this concentration three-fold with 100% DMSO in a 96-well plate for 10 concentrations, leaving blank wells with 100% DMSO. Dilute the serially diluted compound and 100% DMSO 20-fold with reaction buffer to create a 5x concentration. Mix thoroughly and set aside.

[0773] Dilute PRMT5:MEP50 to a final concentration of 12.5 nM in reaction buffer. Add 4 μL of the 12.5 nM PRMT5:MEP50 solution to each well of a 384-well plate. Add 4 μL of reaction buffer to the negative control wells. Add 2 μL of 5x concentration compound to each well. Add 2 μL of 5% DMSO to the negative control wells (no enzyme or compound) and the positive control wells (no compound). Seal the plate and centrifuge, mix by vortexing for 2 minutes, and let stand at room temperature for 20 minutes.

[0774] Prepare substrate mixed solution: Prepare a substrate mixed solution containing 1.5 μM histone H4 peptide substrate (1-21) and 2.5 μM SAM or 1.5 μM histone H4 peptide substrate (1-21), 2.5 μM SAM, and 2.5 μM MTA in reaction buffer;

[0775] 4 μL of substrate mixed solution (- / +MTA) was added to each well to initiate the reaction. The plate was sealed and centrifuged, shaken and mixed for 2 minutes, and then placed in a 37°C constant temperature incubator for 120 minutes.

[0776] Detection: Detection was performed using an EPIgeneous Methyltransferase kit. 2 μL of EPIgeneous Detection Buffer 1 was added to each well, the plate was centrifuged, vortexed to mix, and allowed to stand at room temperature for 10 minutes. SAH d2 Reagent was diluted 32-fold with EPIgeneous Detection Buffer 2, 4 μL of SAH-d2 diluent was added to each well, the plate was centrifuged, and vortexed to mix for 2 minutes. SAH Tb Cryptate Antibody was diluted 50-fold with EPIgeneous Detection Buffer 2, 4 μL of Tb Cryptate Antibody diluent was added to each well, the plate was centrifuged, vortexed to mix for 2 minutes, and allowed to stand at room temperature for 60 minutes. The plate was then read using a PHERAstar FS microplate reader and the 665 / 620 ratio was measured.

[0777] After the value was substituted into the formula for conversion, the inhibition curve was drawn using Graphpad Prism software according to the concentration of the compound and the corresponding inhibition rate, and the concentration of the compound when the inhibition rate reached 50% was calculated, that is, IC 50 value.

[0778] Table 1 IC inhibitory activity of the disclosed compounds on human PRMT5 50 value

[0779] Conclusion: The disclosed compounds have good enzyme inhibitory activity against PRMT5 (+MTA).

[0780] Test Example 2 HCT116 and HCT116 MTAP- / - cell proliferation assay

[0781] 1. Experimental Materials and Instruments

[0782] 1. HCT116 cell line (Nanjing Kebai, CBP60028)

[0783] 2. HCT116 MTAP- / - cell line (Nanjing Kebai, CBP75002)

[0784] 3.DMSO (Sigma, D2650)

[0785] 4.McCoy's 5A medium (Gibco, 16600-082)

[0786] 5. Fetal bovine serum (FBS) (Gibco, 10091148)

[0787] 6. Phosphate buffered saline (DPBS) pH 7.4 (Gibco, 14190-144)

[0788] 7.Pen strep(PS)(Gibco,15140-122)

[0789] 8.0.25% Typsin-EDTA (1×) (Gibco, 25200-072)

[0790] 9. Luminescent Cell Viability Assay (Promega, G7572)

[0791] 10. 96-well round-bottom plate (JET / JET, TCP002096)

[0792] 11. 96-well black transparent bottom cell culture plate (Xinyou Biotechnology, 060096)

[0793] 12. 1.2 mL 96-well deep-well plate, clear, sterile, square wells, V-bottom (Titan, 02089063)

[0794] 13. 15mL centrifuge tube (Titan)

[0795] 14. Biological safety cabinet (Thermo, 1300AII)

[0796] 15. Cell counter (Countstar, IC1000)

[0797] 16. Incubator (Thermo, I160)

[0798] 17. Centrifuge (Beckman Coulter, Allegra X-12 centrifuge)

[0799] 18. PHERAstar FS microplate reader (BMG Labtech)

[0800] 2. Experimental steps

[0801] 1. Cell Plating (Day 0)

[0802] a) Observe the cell status under a microscope to ensure that the cell confluence is ∼90%.

[0803] b) Discard the cell supernatant, rinse once with PBS, discard the PBS, add an appropriate amount of trypsin to digest the cells, and incubate at 37°C for 3 minutes.

[0804] c) Terminate the digestion with an equal volume of McCoy's 5A medium containing 10% FBS, collect the cell suspension, centrifuge at 300g for 3 minutes, and resuspend the cells in an appropriate amount of fresh medium.

[0805] d) Take the resuspended cell suspension and count it.

[0806] e) Dilute the cell suspension to 1e4 / mL with McCoy's 5A medium containing 10% FBS, and add 50 μL / well. For HCT116, the cell suspension should be 500 cells / well, and for HCT116 MTAP- / -, the cell suspension should be 500 cells / well.

[0807] f) Place the cell plate in an incubator at 37°C and 5% carbon dioxide overnight

[0808] 2. Adding medication (Day 1)

[0809] a) Serially dilute each compound into 9 concentration points using DMSO (starting at 10,000 μM, 3-fold dilution; different compounds may require different IC50 values ​​depending on their peak concentration). For example, in a 96-well round-bottom plate, serially dilute 5 μL of compound into 10 μL of DMSO.

[0810] b) Each compound concentration was diluted 250-fold into the corresponding volume of McCoy's 5A medium.

[0811] c) 50 μL of the diluted compound solution was added to 50 μL / well of the cell supernatant in each cell plate.

[0812] d) Place the cell plate after drug addition in an incubator at 37°C and 5% carbon dioxide.

[0813] 3. Re-digestion and plating and drug addition (Day 5)

[0814] a) Five days after drug addition, discard the drug-containing culture medium, then rinse once by adding 100 μL / well of PBS, and immediately aspirate the PBS.

[0815] b) Add 25 μL of trypsin to digest the cells, incubate at 37° C. for 3 minutes, and then add 175 μL / well of McCoy's 5A medium containing 10% FBS to terminate the digestion.

[0816] c) Use a pipette to mix the cells and re-plate them at a ratio of 1:20, i.e., pipette 10 μL of the cell suspension into a new 96-well plate (40 μL of McCoy's 5A medium containing 10% FBS was added to the new plate in advance).

[0817] d) Prepare and add the compound according to steps a) to c) in 2., 50 μL per well.

[0818] e) Place the cell plate after drug addition in an incubator at 37° C. and 5% carbon dioxide for incubation.

[0819] 4. CTG detection (Day 10)

[0820] a) Before use, equilibrate CellTiter-Glo Buffer and lyophilized CellTiter-Glo Substrate to room temperature. Mix thoroughly to make 100 mL of CellTiter-Glo Reagent (or bring the mixed CellTiter-Glo Reagent from -20°C to room temperature).

[0821] b) Remove the plate to be tested from the incubator, equilibrate to room temperature, and add 50 μL of CellTiter-Glo reagent to each well.

[0822] c) Vortex and mix for 2 minutes to fully lyse the cells.

[0823] d) Allow the sample to stand at room temperature for 28 minutes until the signal stabilizes, and then perform detection on a Pherastar FS.

[0824] Comparative Example 1 (refer to WO2022192745A1, Examples 16-90), the structure is as follows

[0825] Table 2 IC values ​​of the disclosed compounds for inhibition of HCT116 MTAP- / - cell growth 50 value

[0826] Conclusion: The disclosed compounds have a good selective inhibitory effect on the growth of HCT116 MTAP- / - cells. Compared with Comparative Example 1, the disclosed compounds have a better inhibitory effect on the growth of HCT116 MTAP- / - cells.

[0827] Test Example 3 Pharmacokinetic Evaluation

[0828] 1. Nu / Nu Mouse Experiment

[0829] 1. Abstract

[0830] Nu / Nu mice were used as test animals. The drug concentrations in the plasma of Nu / Nu mice at different times after gavage (ig) of the example compounds were determined by LC / MS / MS to study the pharmacokinetic behavior of the disclosed compounds in Nu / Nu mice and evaluate their pharmacokinetic characteristics.

[0831] 2. Experimental plan

[0832] 2.1. Investigational Drugs

[0833] Compound 1-p1, Compound 2-p1, Compound 8-p1 and Comparative Example 1.

[0834] 2.2 Experimental Animals

[0835] Thirty-six female Nu / Nu mice were equally divided into four groups and provided by Weitong Lihua Laboratory Animal Technology Co., Ltd.

[0836] 2.3 Drug preparation

[0837] A certain amount of the test compound was weighed respectively, and 5% DMSO + 20% PEG400 + 70% (10% TPGS) + 5% (1% HMPC K100LV) was added to prepare a 10 mg / mL colorless clear solution.

[0838] 2.4 Drug Administration

[0839] The dosage was 100 mg / kg and the administration volume was 10 mL / kg.

[0840] 3. Operation

[0841] Mice were administered via oral gavage. Blood (0.1 mL) was collected from the orbital cavity before and at 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 11.0, and 24.0 hours after administration. Plasma was separated by centrifugation at 10,000 rpm for 1 minute (4°C) in an EDTA-K2 anticoagulant tube. Plasma was separated within 1 hour and stored at -20°C until testing. The blood collection and centrifugation process was performed in an ice bath.

[0842] The test compound content in Nu / Nu mouse plasma was determined after administration of various compounds: 20 μL of plasma samples from Nu / Nu mice at various times after administration were added to 200 μL of acetonitrile and 25 μL of verapamil (100 ng / mL). The mixture was vortexed for 5 minutes and centrifuged at 4000 rpm for 15 minutes. 90 μL of water and 90 μL of the supernatant were vortexed for 5 minutes. 2 μL (Compound 1-p1), 2 μL (Compound 2-p1), 1 μL (Compound 8-p1), and 0.5 μL (Comparative Example 1) of the supernatant were injected for LC / MS / MS analysis.

[0843] 4. Pharmacokinetic parameter results

[0844] Table 3. Pharmacokinetic parameters of the disclosed compounds in Nu / Nu mice

[0845] Conclusion: Compared with Comparative Example 1, the compound of the present disclosure has high blood concentration, high exposure, and low clearance in Nu / Nu mice, and has pharmacokinetic advantages.

[0846] Test Example 4: Efficacy Test

[0847] 1. Experimental Purpose

[0848] The compounds of the present disclosure were evaluated for their inhibitory effects on the growth of subcutaneous xenografts of the human giant cell lung cancer cell line Lu99 in female NUNU nude mice.

[0849] 2. Experimental drugs

[0850] Compound 2-p1

[0851] A solution of 20% PEG400 + 70% (10% TPGS) + 5% DMSO + 5% (1% HPMCK100LV) was used.

[0852] 3. Experimental methods and materials

[0853] 3.1 Experimental animals and housing conditions

[0854] Experimental animals: Female NUNU nude mice were purchased from Zhejiang Weitonglihua Experimental Animal Technology Co., Ltd. (License No.: SCXK (Zhe) 2024-0001, Animal Certification No.: 20240524Abzz0619000789), weighing approximately 20-24 g at the time of purchase.

[0855] Rearing conditions: 5 animals / cage, 12 / 12 h light / dark cycle, constant temperature of 23±1°C, humidity of 50 to 60%, free access to food and water.

[0856] 3.2 Animal grouping

[0857] After NUNU nude mice were adapted to feeding, they were grouped and administered as follows:

[0858] Table 4. Animal groups and dosing regimens for in vivo efficacy experiments Note: qd means administration once a day; ig means administration by gavage.

[0859] 3.3 Experimental methods:

[0860] 0.1 ml (5×10 5 Lu99 cells (with 50% matrigel) were subcutaneously inoculated into the right upper limb of each mouse, and the average tumor volume reached 75 mm 3 Mice were randomly divided into four groups of 12 mice each based on tumor volume and body weight, as shown in Table 4. Grouping was designated D0, and oral administration began once or twice daily for 21 days, with the 21st day after dosing designated D21 (Table 5). Tumor volume and body weight of tumor-bearing mice were measured twice weekly using a vernier caliper and a balance, and the data were recorded.

[0861] 3.4 Data Statistics

[0862] All data were graphed and statistically analyzed using Excel and GraphPad Prism 10 software.

[0863] The formula for calculating tumor volume (V) is: V = 1 / 2 × a × b 2 Where a and b represent length and width respectively.

[0864] Relative tumor proliferation rate T / C (%) = (T-T0) / (C-C0) × 100 (%), where T and C are the tumor volumes of the treatment group and the control group at the end of the experiment; T0 and C0 are the tumor volumes at the beginning of the experiment.

[0865] Tumor inhibition rate TGI (%) = 100 - T / C (%).

[0866] 4. Results

[0867] The efficacy data of compound 2-p1 against Lu99 transplanted tumors in NUNU nude mice are shown in Table 5 and Figure 1.

[0868] The effect of compound 2-p1 on the body weight of NUNU nude mice is shown in Figure 2.

[0869] Table 5. Efficacy of the disclosed compounds on Lu99 transplanted tumors in NUNU nude mice Note: qd means administration once a day; d means day; ig means oral administration; SEM means standard error.

[0870] 5. Conclusion

[0871] Compound 2-p1 was administered once a day. After 21 days of administration, the tumor inhibition rate of the low-dose 50mpk / qd group was 72%, the tumor inhibition rate of the medium-dose 100mpk / qd group was 90%, and the tumor inhibition rate of the high-dose 200mpk / qd group was 95%. The administration had no effect on the weight of the mice.

Claims

1. A compound represented by general formula (I) or a pharmaceutically acceptable salt thereof: in: Ring A is an aryl group or a heteroaryl group; R 0 is selected from the group consisting of a hydrogen atom, an alkyl group, a haloalkyl group, a deuterated alkyl group, a hydroxyalkyl group, an alkoxy group, a haloalkoxy group, a deuterated alkoxy group, an alkoxyalkyl group, an aminoalkyl group, a cycloalkyl group, a cycloalkylalkyl group, a heterocyclyl group, and a heterocyclylalkyl group; R 1 Selected from -(CR 1a R 1b )r-NH2, R 1a and R 1b are the same or different and are each independently selected from a hydrogen atom, a deuterium atom, a halogen, a hydroxyl group, a cyano group, an amino group, an alkyl group, a haloalkyl group, a deuterated alkyl group, a hydroxyalkyl group, an alkoxy group, a haloalkoxy group, a deuterated alkoxy group and a cycloalkyl group; or R on the same carbon atom 1a and R 1b Together they form = O; or R 1a and R 1b Together with the attached carbon atom, they form a cycloalkyl or heterocyclyl group, which is optionally substituted with one or more R; Ring B is a cycloalkyl or heterocyclyl group, and the cycloalkyl or heterocyclyl group is optionally substituted by one or more R; Ring C is a nitrogen-containing heterocyclic group, which is optionally substituted by one or more R; L is selected from a bond, an alkylene group, O, S(O) v NR a 、C(O)、NR a C(O) and C(O)NR a ; R a is selected from the group consisting of a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, and a cycloalkylalkyl group; R 2 is selected from the group consisting of tricyclic cycloalkyl, tricyclic heterocyclyl, tricyclic aryl and tricyclic heteroaryl, wherein the tricyclic cycloalkyl, tricyclic heterocyclyl, tricyclic aryl and tricyclic heteroaryl are each independently optionally substituted by one or more R 4 replace; Each R 3 and R 4 are the same or different and are each independently selected from the group consisting of a deuterium atom, a halogen, a hydroxyl, a cyano group, a nitro group, an amino group, an alkenyl group, an alkynyl group, an alkyl group, a haloalkyl group, a deuterated alkyl group, a hydroxyalkyl group, an alkoxy group, a haloalkoxy group, a deuterated alkoxy group, an alkoxyalkyl group, an aminoalkyl group, a cycloalkyl group, a cycloalkylalkyl group, a cycloalkyloxy group, a heterocyclyl group, a heterocyclylalkyl group, a heterocyclyloxy group, an aryl group, an arylalkyl group, a heteroaryl group, a heteroarylalkyl group, a -(CH2) t NR 14 R 15 、-OR 16 、-S(O) v R 16 、-C(O)NR 14 R 15 、-C(O)R 16 、-C(O)OR 16 、-NR 17 C(O)R 16 、-S(O) v NR 14 R 15 and-NR 17 S(O) v R 16 wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkyloxy, heterocyclyl, heterocyclylalkyl, heterocyclyloxy, aryl, arylalkyl, Heteroaryl and heteroarylalkyl are each independently optionally substituted with one or more R; Or, two R on the same atom 4 Together they form = O; Or, two R 4 With R 2 The above and the ring atoms to which they are attached together form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, wherein the cycloalkyl, heterocyclyl, aryl or heteroaryl group is optionally substituted with one or more R; X 1 CR 5a or N; X 2 CR 5b or N; X 3 CR 5 or N; R 5a , R 5b and R 5 are the same or different and are each independently selected from a hydrogen atom, a deuterium atom, a halogen, a hydroxyl group, a cyano group, an amino group, an alkenyl group, an alkynyl group, an alkyl group, a haloalkyl group, a deuterated alkyl group, a hydroxyalkyl group, an alkoxy group, a haloalkoxy group, a deuterated alkoxy group, an alkoxyalkyl group, an aminoalkyl group, a cycloalkyl group, a cycloalkylalkyl group, a heterocyclyl group, a heterocyclylalkyl group, an aryl group, an arylalkyl group, a heteroaryl group, a heteroarylalkyl group, -(CH2) t NR 14 R 15 、-OR 16 、-C(O)NR 14 R 15 、-C(O)R 16 、-C(O)OR 16 and-NR 17 C(O)R 16 ; wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl are each independently optionally substituted with one or more R; R 14 , R 15 and R 16 are the same or different at each occurrence and are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl and heteroaryl; wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl and heteroaryl is optionally substituted with one or more R; or R 14 and R 15 Together with the nitrogen atom to which it is attached, it forms a heterocyclic group, which is optionally substituted with one or more R; R 17 is the same or different at each occurrence and is independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group and a cycloalkylalkyl group; R is the same or different at each occurrence and is independently selected from oxo, a deuterium atom, a halogen, a hydroxyl, an alkenyl, an alkynyl, a cyano, a nitro, an amino, -NHalkyl, -N(alkyl), alkyl, a haloalkyl, a deuterated alkyl, a hydroxyalkyl, an alkoxy, a haloalkoxy, a deuterated alkoxy, an alkoxyalkyl, an aminoalkyl, a cycloalkyl, a cycloalkylalkyl, a cycloalkyloxy, a heterocyclyl, a heterocyclylalkyl, a heterocyclyloxy, an aryl, an arylalkyl, an aryloxy, a heteroaryl, a heteroarylalkyl, and a heteroaryloxy; m is 0, 1, 2, 3 or 4; r is 0, 1, 2, or 3; v is 0, 1, or 2; and t is 0, 1, 2, or 3.

2. The compound of general formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein ring A is a 5- to 10-membered heteroaryl group; preferably, ring A is a pyrazolyl group.

3. The compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, which is a compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof: in: R 3a is selected from the group consisting of hydrogen, alkenyl, alkynyl, alkyl, haloalkyl, deuterated alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl are each independently optionally substituted with one or more R; A is N or CR 3b ; R 3b is a hydrogen atom or R 3 ; X 1 , R, R 1a , R 1b , R 2 , R 3 and R 5 As defined in claim 1.

4. A compound represented by general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein R 1a and R 1b are the same or different and are each independently a hydrogen atom or a deuterium atom; preferably, R 1a and R 1b A hydrogen atom.

5. A compound represented by general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein X 1 CR 5a ; R 5a Selected from hydrogen atoms, halogens and C 1-6 Alkyl; preferably, X 1 For CH.

6. A compound represented by general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 3 to 5, wherein A is CR 3b ; R 3b Selected from hydrogen atoms, halogens and C 1-6 Alkyl; preferably, A is CH.

7. The compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, which is a compound represented by the general formula (IV) or a pharmaceutically acceptable salt thereof: in: R 2 , R 3a and R 5 As defined in claim 3.

8. A compound represented by general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, wherein R 2 Selected from in: M is selected from CR 4 R 4 , O, S and NR m ; R m is selected from the group consisting of a hydrogen atom, an alkyl group, a haloalkyl group, a deuterated alkyl group, a hydroxyalkyl group, an alkoxyalkyl group, an aminoalkyl group, a cycloalkyl group, a cycloalkylalkyl group, a heterocyclyl group, and a heterocyclylalkyl group; Q 1 , Q 2 and Q 3 are the same or different and are each independently selected from a bond, O, S(O) v , CR 4d R 4e , C(O) and NR 4f ; R 4a , R 4b , R 4c , R 4d and R 4e are the same or different and are each independently a hydrogen atom or R 4 or, R 4d and R 4e Together with the attached carbon atom, they form a cycloalkyl or heterocyclyl group, which is optionally substituted with one or more R; R 4f is selected from the group consisting of a hydrogen atom, an alkyl group, a haloalkyl group, a deuterated alkyl group, a hydroxyalkyl group, an alkoxyalkyl group, an aminoalkyl group, a cycloalkyl group, a cycloalkylalkyl group, a heterocyclyl group, and a heterocyclylalkyl group; R 6 , R 7 , R 8 , R 9 , R 10 , R 11 and R 12 are the same or different and are each independently a hydrogen atom or R 4 ; or R 6 and R 7 Together with the attached carbon atom, it forms a cycloalkyl or heterocyclic group, which is optionally substituted with one or more R; or R 8 and R 9 Together with the carbon atom to which it is attached, it forms a cycloalkyl or heterocyclic group, wherein the cycloalkyl or heterocyclic group is optionally substituted with one or more R; or R on the same carbon atom 6 and R 7 Together they form =O; or R on the same carbon atom 8 and R 9 Together they form = O; n is 0, 1, 2, 3 or 4; p is 1, 2, 3, 4, 5 or 6; q is 0, 1, 2, 3 or 4; x is 0, 1, 2, 3, 4 or 5; x1 is 1, 2, 3, 4 or 5; y is 0, 1, 2, 3 or 4; a is 0, 1, 2, 3 or 4; b is 0, 1, 2, 3 or 4; R 4 , R and v are as defined in claim 1; Preferably, R 2 Selected from 9. A compound represented by general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 3 to 8, wherein R 3a C 1-6 Alkyl or C 1-6 deuterated alkyl; preferably, R 3a C 1-6 Deuterated alkyl.

10. The compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 9, wherein R 5 Selected from hydrogen atoms, halogens, cyano groups, C 1-6 alkyl, 3 to 6-membered cycloalkyl and 3 to 6-membered heterocyclic group; preferably, R 5 A hydrogen atom.

11. The compound represented by the general formula (I) according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof, which is selected from any one of the following compounds:

12. A compound represented by general formula (IIA) or a salt thereof: in: R w1 is a hydrogen atom or an amino protecting group; R w2 is a hydrogen atom or an amino protecting group; the condition is that R w1 and R w2 At least one of them is an amino protecting group; Or, R w1 and R w2 Together with the attached nitrogen atom, it forms a phthalimide group; A.X 1 , R 1a , R 1b , R 2 , R 3a and R 5 As defined in claim 3.

13. The compound represented by the general formula (IIA) or a salt thereof according to claim 12, which is selected from any one of the following compounds:

14. A method for preparing the compound represented by general formula (I) according to claim 3 or a pharmaceutically acceptable salt thereof, the method comprising: The compound represented by the general formula (IIA) or its salt is deprotected from the amino protecting group to obtain the compound represented by the general formula (II) or its pharmaceutically acceptable salt; in: R w1 is a hydrogen atom or an amino protecting group; R w2 is a hydrogen atom or an amino protecting group; the condition is that R w1 and R w2 At least one of them is an amino protecting group; Or, R w1 and R w2 Together with the attached nitrogen atom, it forms a phthalimide group; A.X 1 , R 1a , R 1b , R 2 , R 3a and R 5 As defined in claim 3.

15. A pharmaceutical composition comprising a compound represented by general formula (I) according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

16. Use of the compound represented by general formula (I) according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition according to claim 15 in the preparation of a PRMT5 inhibitor.

17. Use of a compound of formula (I) according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 15 in the preparation of a medicament for treating and / or preventing cancer; the cancer is preferably selected from lung cancer, kidney cancer, liver cancer, head and neck cancer, esophageal cancer, lymphoma, glioblastoma, glioblastoma, colorectal cancer, malignant peripheral nerve sheath tumor (MPNST), melanoma, gastric cancer, pancreatic cancer, bile duct cancer, bladder cancer, breast cancer, ovarian cancer, vaginal cancer, cervical cancer, endometrial cancer, prostate cancer, testicular cancer, seminoma, myeloma, leukemia, acoustic neuroma. , basal cell carcinoma, brain cancer, bronchogenic carcinoma, sarcoma, choriocarcinoma, craniopharyngioma, cystadenocarcinoma, hemangioendothelioma, ependymoma, epithelial cancer, glioma, astrocytoma, hemangioblastoma, medulloblastoma, meningioma, mesothelioma, neuroblastoma, bone cancer, nasopharyngeal carcinoma, oral cancer, laryngeal cancer, thyroid cancer, retinoblastoma, skin cancer, squamous cell carcinoma, synovioma, sweat gland carcinoma and myelodysplastic syndrome; preferably, the cancer is selected from ovarian cancer, lymphoma, pancreatic cancer, bladder cancer, gastric cancer, colorectal cancer, bile duct cancer, mesothelioma, malignant peripheral nerve sheath tumor (MPNST), glioblastoma and lung cancer.