Spiro-heterocyclic compound, preparation method therefor and pharmaceutical use thereof

Abstract

The present disclosure relates to a spiro-heterocyclic compound, a preparation method therefor, and the pharmaceutical use thereof. Specifically, the present disclosure relates to a spiro-heterocyclic compound as represented by general formula (I), a preparation method therefor, a pharmaceutical composition containing the compound, and the use thereof as a therapeutic agent, in particular, the use as a PRMT5 inhibitor and the use for treating and / or preventing cancers.

Description

Spiro heterocyclic compounds, preparation method thereof and application thereof in medicine TECHNICAL FIELD

[0001] The present disclosure belongs to the field of medicine, and relates to a spiro heterocyclic compound, a preparation method thereof and application thereof in medicine. In particular, the present disclosure relates to a spiro heterocyclic compound represented by general formula (I), a preparation method thereof and a pharmaceutical composition containing the compound, and the use of the compound as a PRMT5 inhibitor and for treating and / or preventing cancer. BACKGROUND

[0002] Arginine methylation, as a form of post-translational modification widely existing in mammalian cells, is mainly controlled by protein arginine methyltransferases (PRMTs). The PRMT family has 9 members in total, which can be divided into three categories according to their catalytic activity and product types: 1) Type I includes PRMT1, PRMT2, PRMT3, PRMT4 and PRMT8; 2) Type II includes PRMT5 and PRMT7; 3) Type III includes only PRMT7.

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

[0004] In about 15% of human cancers, homozygous deletion of the chromosome 9p21 (chr9p21) locus occurs, and the frequency of gene deletion in glioblastoma multiforme is as high as more than 50%. The chr9p21 locus includes the CDKN2A gene, which, as an important tumor suppressor gene, encodes the key tumor suppressor p19-ARF and p16-INK4a. The chr9p21 gene deletion often involves the co-deletion of genes near CDKN2A. Therefore, the methionine adenosyltransferase (MTAP) gene located within 100 kb of CDKN2A is homozygously deleted in up to 80%-90% of CDKN2A-deleted tumors.

[0005] MTAP is a key enzyme in the methionine compensation pathway in the "methionine cycle", which metabolizes the byproduct 5-methylthioadenosine (MTA) of polyamine synthesis, regenerating methionine and adenine. Therefore, tumor cells with MTAP gene deletion will cause a large accumulation of intracellular / extracellular MTA, which specifically binds to the PRMT5-SAM binding pocket as a specific PRMT5 competitive inhibitor, thereby inhibiting PRMT5 activity. Studies have shown that PRMT5 is a synthetic lethal gene in MTAP-deleted cells, and PRMT5 inhibitors are expected to become a new generation of targeted drugs for the treatment of MTAP-deleted tumors.

[0006] Currently, there are various mechanisms of PRMT5 inhibitors being developed in clinical trials. The first generation of PRMT5 inhibitors is mostly PRMT5 substrate competitive or SAM competitive inhibitors, which can kill MTAP-deleted tumor cells while also inhibiting the proliferation of normal cells. Hematotoxicity is the main dose-limiting toxicity of the first generation of PRMT5 inhibitors.

[0007] Therefore, the development of a selective PRMT5-MTA complex inhibitor that specifically inhibits the proliferation of MTAP gene-deleted tumor cells while effectively avoiding PTMR5 wild-type mediated related dose-limiting toxicities is an urgent medical need. SUMMARY

[0008] The purpose of the present disclosure is to provide a compound of general formula (X) or a pharmaceutically acceptable salt thereof:

[0009] wherein:

[0010] The ring in which X and Y are located is a pyrrole ring, is a single bond or a double bond, and X is NR a , Y is CR b ; or, X is CR b , Y is NR a ;

[0011] R a is selected from the group consisting of a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, an alkoxyalkyl group, a cycloalkyl group, and a cycloalkylalkyl group;

[0012] R b is selected from the group consisting of a hydrogen atom, a halogen, an alkyl group, a haloalkyl group, a hydroxyalkyl group, an alkoxy group, a haloalkoxy group, a cyano group, a cycloalkyl group, and a heterocyclic group;

[0013] Z is CR 2a or N;

[0014] Q is CR 2b or N;

[0015] G is CR2c or N;

[0016] E is CR 2d or N;

[0017] A 1 , A 2 , and A 3 are the same or different and each independently N or CR 1 ;

[0018] R 1 , R 2a , R 2b , R 2c , and R 2d are the same or different and each independently selected from the group consisting of a hydrogen atom, halogen, alkenyl, alkynyl, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, hydroxyl, cyano, nitro, amino, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, -(CH2) t NR 14 R 15 , -(CH2) t 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 each of said alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl is independently optionally substituted with one or more R 0 ;

[0019] p is 1 or 2;

[0020] n is 0, 1, 2, 3, or 4;

[0021] each R 3the same or different, and each independently selected from the group consisting of a hydrogen atom, halogen, alkenyl, alkynyl, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, aminoalkyl, hydroxyl, cyano, nitro, amino, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, -(CH2) t NR 14 R 15 , -(CH2) t 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 , -NR 17 S(O) v R 16 , oxo, and =CR 18 R 19 ; wherein each of said alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl is independently optionally substituted with one or more R 0 ;

[0022] m is 0 or 1 ;

[0023] R 4 is selected from the group consisting of a hydrogen atom, halogen, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, hydroxyl, cyano, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl;

[0024] R 5a , R 5b , and R 5c are the same or different, and each independently selected from the group consisting of a hydrogen atom, halogen, alkenyl, alkynyl, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, aminoalkyl, hydroxyl, cyano, nitro, amino, -(CH2) t OR 16 , -(CH2) t NR 14 R 15 , -S(O) v R 16 , -C(O)NR 14 R 15 , -C(O)R16 -C(O)OR 16 -NR 17 C(O)R 16 -S(O) v NR 14 R 15 -NR 17 S(O) v R 16 , cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl; wherein each of said alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl is independently optionally substituted with one or more R 6 ;

[0025] or, R 5b and R 5c together with the atom to which they are attached form a cycloalkyl or heterocyclyl, each of which is independently optionally substituted with one or more R 6 ;

[0026] or, R 5a , R 5b and R 5c together with the atom to which they are attached form a cycloalkyl or heterocyclyl, each of which is independently optionally substituted with one or more R 6 ;

[0027] R 6 are the same or different and each is independently selected from the group consisting of halogen, alkenyl, alkynyl, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, aminoalkyl, hydroxyl, cyano, nitro, amino, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, -(CH2) t NR 14 R 15 , -(CH2) t 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 , -NR 17 S(O) v R16 , oxo, and =CR 18 R 19 ; wherein each of said alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl is independently optionally substituted with one or more R 0 ;

[0028] R 14 , R 15 , and R 16 are the same or different, and each is independently selected from the group consisting of a hydrogen atom, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, and heteroaryl; wherein each of said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R 0 ;

[0029] or, R 14 and R 15 together with the nitrogen atom to which they are attached form a heterocyclyl group optionally substituted with one or more R 0 ;

[0030] R 17 is selected from the group consisting of a hydrogen atom, alkyl, and cycloalkyl;

[0031] R 18 and R 19 are the same or different, and each is independently selected from the group consisting of a hydrogen atom, alkyl, halo, haloalkyl, hydroxyalkyl, hydroxy, alkoxy, and cycloalkyl; or, R 18 and R 19 together with the atom to which they are attached form a cycloalkyl group;

[0032] R 0 are the same or different, and each is independently selected from the group consisting of oxo, halo, hydroxy, alkenyl, alkynyl, cyano, nitro, amino, -NHalkyl, -N(alkyl)2, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, aminoalkyl, cycloalkyl, cycloalkylalkyl, cycloalkyloxy, heterocyclyl, heterocyclylalkyl, heterocyclyloxy, aryl, arylalkyl, aryloxy, heteroaryl, heteroarylalkyl, and heteroaryloxy;

[0033] t is 0, 1, or 2;

[0034] v is 0, 1, or 2.

[0035] The present disclosure provides a compound represented by general formula (XI) or a pharmaceutically acceptable salt thereof,

[0036] wherein Q, Z, G, E, R 1 , m, R5a , R 5b , and R 5c are as defined in general formula (X).

[0037] In some embodiments of the disclosure, Z is CR 2a ; Q is CR 2b ; G is CR 2c or N; E is CR 2d ; R 2a , R 2b , R 2c , and R 2d are as defined in general formula (X); in some embodiments, Z is CR 2a ; Q is CR 2b ; G is CR 2c ; E is CR 2d ; R 2a , R 2b , R 2c , and R 2d are as defined in general formula (X).

[0038] In some embodiments of the disclosure, R 2a , R 2b , R 2c , and R 2d are the same or different, and each is independently selected from the group consisting of a hydrogen atom, a halogen, a C 1-6 alkyl group, a C 1-6 haloalkyl group, a C 1-6 alkoxy group, a C 1-6 haloalkoxy group, and a cyano group; in some embodiments, R 2a , R 2b , R 2c , and R 2d are the same or different, and each is independently selected from the group consisting of a hydrogen atom, a halogen, a C 1-6 alkyl group, and a C 1-6 haloalkyl group; in some embodiments, R 2c is a hydrogen atom or a halogen; in some embodiments, R 2c is a hydrogen atom; in some embodiments, R 2d is a hydrogen atom.

[0039] In some embodiments of the disclosure, G is CR 2c ; R 2c is a hydrogen atom or a halogen; in some embodiments, G is selected from the group consisting of N, CH, and C-F; in some embodiments, G is CH.

[0040] In some embodiments of the disclosure, E is CR 2d ; R 2das defined in general formula (X); in some embodiments, E is CH.

[0041] The present disclosure aims to provide a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof:

[0042] wherein:

[0043] the ring where X and Y are located is a pyrrole ring, is a single bond or a double bond, and X is NR a , Y is CR b ; or, X is CR b , Y is NR a ;

[0044] R a is selected from a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, an alkoxyalkyl group, a cycloalkyl group, and a cycloalkylalkyl group;

[0045] R b is selected from a hydrogen atom, a halogen, an alkyl group, a haloalkyl group, a hydroxyalkyl group, an alkoxy group, a haloalkoxy group, a cyano group, a cycloalkyl group, and a heterocyclyl group;

[0046] Z is CR 2a or N;

[0047] Q is CR 2b or N;

[0048] A 1 , A 2 , and A 3 are the same or different, and each is independently N or CR 1 ;

[0049] R 1 , R 2a , R 2b , and R 2 are the same or different, and each is independently selected from a hydrogen atom, a halogen, an alkenyl group, an alkynyl group, an alkyl group, a haloalkyl group, a hydroxyalkyl group, an alkoxy group, a haloalkoxy group, an alkoxyalkyl group, a hydroxyl group, a cyano group, a nitro group, an amino 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 , -(CH2) t OR 16 , -S(O) v R 16 , -C(O)NR 14 R 15 , -C(O)R 16 , -C(O)OR 16 , -NR17 C(O)R 16 , -S(O) v NR 14 R 15 , and -NR 17 S(O) v R 16 ; wherein said alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl are each independently optionally substituted with one or more R 0 ;

[0050] m2 is 0, 1, or 2;

[0051] p is 1 or 2;

[0052] n is 0, 1, 2, 3, or 4;

[0053] each R 3 is the same or different, and each is independently selected from the group consisting of a hydrogen atom, halogen, alkenyl, alkynyl, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, aminoalkyl, hydroxy, cyano, nitro, amino, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, -(CH2) t NR 14 R 15 , -(CH2) t 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 , -NR 17 S(O) v R 16 , oxo, and =CR 18 R 19 ; wherein said alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl are each independently optionally substituted with one or more R 0 ;

[0054] m is 0 or 1;

[0055] R 4R is selected from the group consisting of hydrogen atom, halogen, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, hydroxy, cyano, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl;

[0056] R 5a , R 5b , and R 5c are the same or different and each is independently selected from the group consisting of hydrogen atom, halogen, alkenyl, alkynyl, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, aminoalkyl, hydroxy, cyano, nitro, amino, -(CH2) t OR 16 , -(CH2) t NR 14 R 15 , -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 , -NR 17 S(O) v R 16 , cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl; wherein each of said alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl is independently optionally substituted with one or more R 6 ;

[0057] or, R 5b and R 5c together with the atom to which they are attached form a cycloalkyl or heterocyclyl, each of which is independently optionally substituted with one or more R 6 ;

[0058] or, R 5a , R 5b , and R 5c together with the atom to which they are attached form a cycloalkyl or heterocyclyl, each of which is independently optionally substituted with one or more R 6 ;

[0059] R 6the same or different, and each independently selected from the group consisting of halogen, alkenyl, alkynyl, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, aminoalkyl, hydroxyl, cyano, nitro, amino, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, -(CH2) t NR 14 R 15 t OR 16 v R 16 14 R 15 16 R 16 17 C(O)R 16 v NR 14 R 15 17 S(O) v R 16 18 R 19 ; wherein said alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl are each independently optionally substituted with one or more R 0 ;

[0060] R 14 , R 15 and R 16 are the same or different, and each independently selected from the group consisting of a hydrogen atom, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl and heteroaryl; wherein said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl and heteroaryl are each independently optionally substituted with one or more R 0 ;

[0061] or, R 14 and R 15 together with the nitrogen atom to which they are attached form a heterocyclyl optionally substituted with one or more R 0 ;

[0062] R 17 is selected from the group consisting of a hydrogen atom, alkyl and cycloalkyl;

[0063] R 18 and R 19 ​​​​​​​​the same or different, and each independently selected from the group consisting of a hydrogen atom, an alkyl group, a halogen, a haloalkyl group, a hydroxyalkyl group, a hydroxyl group, an alkoxy group, and a cycloalkyl group; or, R 18 and R 19 together with the atom to which they are attached form a cycloalkyl group;

[0064] R 0 the same or different, and each independently selected from the group consisting of an oxo group, a halogen, a hydroxyl group, an alkenyl group, an alkynyl group, a cyano group, a nitro group, an amino group, -NHalkyl, -N(alkyl)2, an alkyl group, a haloalkyl group, a hydroxyalkyl group, an alkoxy group, a haloalkoxy 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;

[0065] t is 0, 1, or 2;

[0066] v is 0, 1, or 2.

[0067] In some embodiments of the disclosure, R 5a is an alkynyl group; m is 1.

[0068] In some embodiments of the disclosure, R 5a is a cyano group; R 5b and R 5c the same or different, and each independently selected from the group consisting of a hydrogen atom, a halogen, an alkenyl group, an alkynyl group, an alkyl group, a haloalkyl group, a hydroxyalkyl group, an alkoxy group, a haloalkoxy group, an alkoxyalkyl group, an aminoalkyl group, a hydroxyl group, a cyano group, a nitro group, an amino group, -(CH2) t OR 16 , -(CH2) t NR 14 R 15 , -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 , -NR 17 S(O) v R 16 , 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 alkoxy group, the alkoxyalkyl group, the cycloalkyl group, the cycloalkylalkyl group, the heterocyclyl group, the heterocyclylalkyl group, the aryl group, the arylalkyl group, the heteroaryl group, and the heteroarylalkyl group is independently optionally substituted with one or more R6 substituted; or, R 5b and R 5c and the attached atoms form a cycloalkyl or heterocyclyl, each independently optionally substituted with one or more R 6 substituted; R 6 as defined in general formula (I).

[0069] In some embodiments of the disclosure, R 5a is a hydrogen atom; R 5b and R 5c and the attached atoms form a heterocyclyl or 4- to 12-membered cycloalkyl, each independently optionally substituted with one or more R 6 substituted; R 6 as defined in general formula (I).

[0070] In some embodiments of the disclosure, R 5a , R 5b and R 5c and the attached atoms form a heterocyclyl or cycloalkyl, each independently optionally substituted with one or more R 6 substituted; R 6 as defined in general formula (I); in some embodiments, R 5a , R 5b and R 5c and the attached atoms form a bicyclic heterocyclyl or bicyclic cycloalkyl, each independently optionally substituted with one or more R 6 substituted; R 6 as defined in general formula (I); in some embodiments, R 5a , R 5b and R 5c form a 5- to 8-membered bridged cycloalkyl with the attached atoms.

[0071] In some embodiments of the disclosure, the compound described in the disclosure or a pharmaceutically acceptable salt thereof is not a compound disclosed in WO2023036974A1.

[0072] In some embodiments of the disclosure, the compound described in the disclosure or a pharmaceutically acceptable salt thereof is not a compound of:

[0073] In some embodiments of the disclosure, is R a , R b , A 1 , A 2 and A3 as defined in general formula (X).

[0074] In some embodiments of the present disclosure, is R 1 as defined in general formula (X).

[0075] In some embodiments of the present disclosure, is R 1 and m1 are as defined in general formula (II).

[0076] In some embodiments of the present disclosure, is R 1 and m1 are as defined in general formula (IV).

[0077] The present disclosure provides a compound represented by general formula (I-1) or general formula (I-2), or a pharmaceutically acceptable salt thereof,

[0078] wherein:

[0079] A 1 , A 2 , A 3 , X, Y, R 2 , R 3 , R 4 , R 5a , R 5b , R 5c , p, n, m, m2, Q and Z are as defined in general formula (I).

[0080] In some embodiments of the present disclosure, p is 1.

[0081] In some embodiments of the present disclosure, n is 0 or 1; in some embodiments, n is 1; in some embodiments, n is 0.

[0082] In some embodiments of the present disclosure, A 1 is N; in some embodiments, A 1 is CR 1 ; R 1 is as defined in general formula (I); in some embodiments, A 1 is N or CH.

[0083] In some embodiments of the present disclosure, A 2 is CR 1 ; R 1as defined in general formula (I); in some embodiments, A 2 is CH or C-F; in some embodiments, A 2 is C-F; in some embodiments, A 2 is N.

[0084] in some embodiments of the disclosure, A 3 is CR 1 ; R 1 as defined in general formula (I); in some embodiments, A 3 is CH or N; in some embodiments, A 3 is CH; in some embodiments, A 3 is N.

[0085] in some embodiments of the disclosure, A 1 is N; A 2 is CR 1 ; A 3 is CR 1 ; R 1 as defined in general formula (I); in some embodiments, A 1 is N; A 2 is CR 1 ; A 3 is CH; R 1 as defined in general formula (I); in some embodiments, A 1 is N; A 2 is C-F; A 3 is CH.

[0086] In some embodiments, the present disclosure provides a compound represented by general formula (M), general formula (M-1), or general formula (M-2), or a pharmaceutically acceptable salt thereof,

[0087] wherein:

[0088] m1 is 0, 1, or 2;

[0089] R 1 , R 2 , R 3 , R 4 , R 5a , R 5b , R 5c , m, m2, X, Y, Q and Z are as defined in general formula (I), general formula (I-1), or general formula (I-2).

[0090] The present disclosure provides a compound represented by general formula (II), general formula (II-1), or general formula (II-2), or a pharmaceutically acceptable salt thereof,

[0091] wherein:

[0092] m1 is 0, 1, or 2;

[0093] R 1 , R 2 , R 3 , R 4 , R 5a , R 5b , R 5c , m, m2, Q, and Z are as defined in general formula (I).

[0094] The present disclosure provides a compound represented by general formula (III), general formula (III-1), or general formula (III-2), or a pharmaceutically acceptable salt thereof,

[0095] wherein:

[0096] m1 is 0, 1, or 2;

[0097] R 1 , R 2 , R 3 , R 4 , R 5a , R 5b , R 5c , m, m2, Q, and Z are as defined in general formula (I).

[0098] In some embodiments of the present disclosure, R 2 is selected from a hydrogen atom, a halogen, a C 1-6 alkyl group, and a C 1-6 alkoxy group; in some embodiments, R 2 is a hydrogen atom or a halogen; in some embodiments, R 2 is a hydrogen atom or F; in some embodiments, R 2 is a hydrogen atom.

[0099] In some embodiments of the present disclosure, m2 is 0 or 1; in some embodiments, m2 is 0; in some embodiments, m2 is 1.

[0100] In some embodiments of the present disclosure, -(R 2 ) m2 is absent.

[0101] In some embodiments of the present disclosure, R 3 is selected from a hydrogen atom, a halogen, and a C 1-6 alkyl group; in some embodiments, R 3 is a hydrogen atom or a C 1-6 alkyl group; in some embodiments, R 3is a hydrogen atom or a methyl group; in some embodiments, R 3 is a hydrogen atom.

[0102] In some embodiments of the disclosure, R 4 is selected from a hydrogen atom, a halogen, and a C 1-6 alkyl group; in some embodiments, R 4 is a hydrogen atom or a C 1-6 alkyl group; in some embodiments, R 4 is a hydrogen atom or a methyl group; in some embodiments, R 4 is a hydrogen atom.

[0103] In some embodiments of the disclosure, R 2 is a hydrogen atom or a halogen; and / or R 3 is a hydrogen atom; and / or R 4 is a hydrogen atom. In some embodiments of the disclosure, R 2 is a hydrogen atom; and / or R 3 is a hydrogen atom; and / or R 4 is a hydrogen atom.

[0104] In some embodiments of the disclosure, Q is CR 2b ; R 2b is as defined in general formula (I); in some embodiments, Q is CH or C-F; in some embodiments, Q is CH; in some embodiments, Q is N.

[0105] In some embodiments of the disclosure, R 2b is selected from a hydrogen atom, a halogen, and a C 1-6 alkyl group; in some embodiments, R 2b is a hydrogen atom or a halogen; in some embodiments, R 2b is selected from a hydrogen atom, F, and CI; in some embodiments, R 2b is a hydrogen atom.

[0106] In some embodiments of the disclosure, Z is CR 2a ; R 2a is as defined in general formula (I); in some embodiments, Z is C-F or C-CF3; in some embodiments, Z is C-F; in some embodiments, Z is N.

[0107] In some embodiments of the disclosure, Q is CR 2b ; Z is CR 2a ; or, Q is CR 2b ; Z is N; or, Q is N; Z is CR 2a ; R 2a and R 2b are as defined in general formula (I); in some embodiments, Q is CR2b ; Z is N; R 2b as defined in general formula (I); in some embodiments, Q is N; Z is CR 2a ; R 2a as defined in general formula (I); in some embodiments, Q is CR 2b ; Z is CR 2a ; R 2a and R 2b as defined in general formula (I); in some embodiments, Q is CR 2b , R 2b is a hydrogen atom or a halogen; and / or Z is CR 2a , R 2a is a halogen or a C 1-6 haloalkyl; in some embodiments, Q is CH; and / or Z is CR 2a ; R 2a as defined in general formula (I); in some embodiments, Q is CH; and / or Z is CF.

[0108] In some embodiments of the present disclosure, m1 is 0 or 1; in some embodiments, m1 is 1.

[0109] The present disclosure provides a compound represented by general formula (N), general formula (N-1), or general formula (N-2), or a pharmaceutically acceptable salt thereof,

[0110] wherein:

[0111] X, Y, R 1 , R 2a , R 5a , R 5b , R 5c , and m are as defined in general formula (I).

[0112] The present disclosure provides a compound represented by general formula (IV), general formula (IV-1), or general formula (IV-2), or a pharmaceutically acceptable salt thereof,

[0113] wherein:

[0114] R 1 , R 2a , R 5a , R 5b , R 5c , and m are as defined in general formula (I).

[0115] The present disclosure provides a compound represented by general formula (V), general formula (V-1), or general formula (V-2), or a pharmaceutically acceptable salt thereof,

[0116] wherein:

[0117] R 1 , R 2a , R 5a , R 5b , R 5c and m are as defined in general formula (I).

[0118] In some embodiments of the present disclosure, R 1 is selected from a hydrogen atom, a halogen, a C 1-6 alkyl group, a C 1-6 haloalkyl group, a C 1-6 alkoxy group, a cyano group, and a 3- to 6-membered cycloalkyl group; in some embodiments, R 1 is selected from a hydrogen atom, a halogen, a C 1-6 alkyl group, and a cyano group; in some embodiments, R 1 is selected from a halogen, a C 1-6 alkyl group, and a cyano group; in some embodiments, R 1 is a hydrogen atom or a halogen; in some embodiments, R 1 is a halogen; in some embodiments, R 1 is F or CI; in some embodiments, R 1 is F.

[0119] In some embodiments of the present disclosure, R 2a is selected from a hydrogen atom, a halogen, a C 1-6 alkyl group, and a C 1-6 haloalkyl group; in some embodiments, R 2a is selected from a hydrogen atom, a halogen, and a C 1-6 alkyl group; in some embodiments, R 2a is a halogen or a C 1-6 haloalkyl group; in some embodiments, R 2a is a hydrogen atom or a halogen; in some embodiments, R 2a is a halogen; in some embodiments, R 2a is selected from a hydrogen atom, F, and CI; in some embodiments, R 2a is a hydrogen atom; in some embodiments, R 2a is F or CI; in some embodiments, R 2a is F or a trifluoromethyl group; in some embodiments, R 2a is F; in some embodiments, R 2a is a trifluoromethyl group.

[0120] In some embodiments of the present disclosure, R 5a is a hydrogen atom or a cyano group; in some embodiments, R 5a is a hydrogen atom; in some embodiments, R5a is a cyano group.

[0121] The present disclosure provides a compound represented by the general formula (VI), (VI-1) or (VI-2), or a pharmaceutically acceptable salt thereof,

[0122] wherein:

[0123] R 5b , R 5c and m are as defined in the general formula (I).

[0124] The present disclosure provides a compound represented by the general formula (VII), (VII-1) or (VII-2), or a pharmaceutically acceptable salt thereof,

[0125] wherein:

[0126] R 5b , R 5c and m are as defined in the general formula (I).

[0127] In some embodiments of the present disclosure, R 5a is selected from a hydrogen atom, a halogen, a C 2-6 alkyl group, a cyano group and a C 2-6 alkynyl group; in some embodiments, R 5a is selected from a halogen, a C 2-6 alkyl group, a cyano group and a C 2-6 alkynyl group; in some embodiments, R 5a is selected from a hydrogen atom, a cyano group and a C 2-6 alkynyl group; R 5a is selected from a C 2-6 alkynyl group, a halogen and a C 2-6 alkyl group; in some embodiments, R 5a is a C 2-6 alkynyl group or a C 2-6 alkyl group; in some embodiments, R 5a is a cyano group or a C 2-6 alkynyl group; in some embodiments, R 5a is a cyano group or In some embodiments, R 5a is a cyano group; in some embodiments, R 5a is a C 2-6 alkynyl group; in some embodiments, R 5a is In some embodiments, R 5a is selected from a hydrogen atom, F, ethyl, cyano,

[0128] In some embodiments of the present disclosure, R 5b and R 5cWhether the atoms are the same or different, and each is independently selected from hydrogen atoms, C atoms 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy C 1-6 Alkyl and C 1-6 Halogenated alkoxy C 1-6 Alkyl; or, R 5b and R 5c Together with the attached atoms, they form 3- to 8-membered cycloalkyl or 3- to 8-membered heterocyclic groups; each of the 3- to 8-membered cycloalkyl and 3- to 8-membered heterocyclic groups is independently and optionally influenced by one or more R... 6 Replace; R 6 As defined in general formula (I); in some implementations, R 5b and R 5c It is a hydrogen atom or a carbon atom. 1-6 Alkyl; or, R 5b and R 5c Together with the attached atoms, they form 3- to 6-membered cycloalkyl or 3- to 6-membered heterocyclic groups; each of the 3- to 6-membered cycloalkyl and 3- to 6-membered heterocyclic groups is independently and optionally influenced by one or more R groups. 6 Replace; R 6 As defined in general formula (I); in some implementations, R 5b and R 5c It is a hydrogen atom or a carbon atom. 1-6 Alkyl; or, R 5b and R 5c Together with the attached atoms, it forms a 3- to 6-membered cycloalkyl group or a 3- to 6-membered heterocyclic group; in some embodiments, R 5b and R 5c It can be a hydrogen atom or a methyl group; or, R 5b and R 5c Formed together with the adjacent atoms In some implementation schemes, R 5b and R 5c Formed together with the adjacent atoms

[0129] In some implementation schemes, R 5b and R 5c Together with the attached atoms, it forms a 4- to 8-membered cycloalkyl or a 3- to 8-membered heterocyclic group; the 4- to 8-membered cycloalkyl or 3- to 8-membered heterocyclic group is optionally surrounded by one or more R 6 Replace; R 6 As defined in general formula (I); in some implementations, R 5b and R 5cwith the attached atoms form a 4- to 6-membered cycloalkyl or a 3- to 6-membered heterocyclyl; each of said 4- to 6-membered cycloalkyl and 3- to 6-membered heterocyclyl is independently optionally substituted with one or more R 6 substituted; R 6 as defined in general formula (I); in some embodiments, R 5b and R 5c with the attached atoms form a 4- to 6-membered cycloalkyl optionally substituted with one or more R 6 substituted; in some embodiments, R 5b and R 5c with the attached atoms form In some embodiments, R 5b and R 5c are hydrogen atoms.

[0130] In some embodiments of the present disclosure, R 5a is a cyano or C 2-6 alkynyl; R 5b and R 5c are hydrogen atoms or C 1-6 alkyl, or R 5b and R 5c with the attached atoms form a 3- to 6-membered cycloalkyl or a 3- to 6-membered heterocyclyl; in some embodiments, R 5a is a cyano; R 5b and R 5c are hydrogen atoms or C 1-6 alkyl, or R 5b and R 5c with the attached atoms form a 3- to 6-membered cycloalkyl or a 3- to 6-membered heterocyclyl; in some embodiments, R 5a is a cyano; R 5b and R 5c are hydrogen atoms or methyl, or R 5b and R 5c with the attached atoms form cyclopropyl, cyclobutyl, and oxetanyl; in some embodiments, selected from In some embodiments, selected from

[0131] In some embodiments of the present disclosure, R 5a is a C 2-6 alkynyl; R 5b and R 5c are hydrogen atoms or C 1-6 alkyl, or R 5b and R 5cwith the attached atoms form a 3- to 6-membered cycloalkyl or 3- to 6-membered heterocyclyl; m is 1 ; R 4 is a hydrogen atom.

[0132] In some embodiments of the disclosure, R 5a is selected from C 2-6 alkyl, halo, and C 2-6 alkyl; R 5b and R 5c with the attached atoms form a 3- to 6-membered cycloalkyl or 3- to 6-membered heterocyclyl; in some embodiments, R 5a is C 2-6 alkyl; R 5b and R 5c with the attached atoms form a 3- to 6-membered cycloalkyl or 3- to 6-membered heterocyclyl; in some embodiments, R 5a is selected from C 2-6 alkyl, halo, and C 2-6 alkyl; R 5b and R 5c with the attached atoms form In some embodiments, R 5a is R 5b and R 5c with the attached atoms form a 3- to 6-membered cycloalkyl; in some embodiments, is selected from In some embodiments, is

[0133] In some embodiments of the disclosure, R 5a is a hydrogen atom; R 5b and R 5c with the attached atoms form a 4- to 12-membered cycloalkyl or 4- to 12-membered heterocyclyl, each independently optionally substituted with one or more R 6 ; R 6 is as defined in general formula (I); in some embodiments, R 5a is a hydrogen atom; R 5b and R 5c with the attached atoms form a 4- to 8-membered cycloalkyl optionally substituted with one or more R 6 ; R 6 is as defined in general formula (I); in some embodiments, R 5a is a hydrogen atom; R 5b and R 5c with the attached atoms form a 4- to 6-membered cycloalkyl optionally substituted with one or more R 6 ;6 as defined in general formula (I); in some embodiments, R 5a is a hydrogen atom; R 5b and R 5c together with the atoms to which they are attached form a 4- to 6-membered cycloalkyl optionally substituted with one or more cyano groups; in some embodiments, R 5a is a hydrogen atom; R 5b and R 5c together with the atoms to which they are attached form a cyclobutyl group optionally substituted with one or more cyano groups; in some embodiments, is selected from

[0134] in some embodiments of the disclosure, R 5a , R 5b and R 5c together with the atoms to which they are attached form a 5- to 12-membered bicyclic cycloalkyl optionally substituted with one or more R 6 groups; R 6 is as defined in general formula (I); in some embodiments, R 5a , R 5b and R 5c together with the atoms to which they are attached form a 5- to 12-membered bicyclic cycloalkyl; in some embodiments, R 5a , R 5b and R 5c together with the atoms to which they are attached form a 5- to 8-membered bicyclic cycloalkyl; in some embodiments, R 5a , R 5b and R 5c together with the atoms to which they are attached form a 5- to 8-membered bridged cycloalkyl; in some embodiments, R 5a , R 5b and R 5c together with the atoms to which they are attached form

[0135] in some embodiments of the disclosure, R 6 are the same or different and each is independently selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, cyano, C 1-6 alkoxy and C 1-6 haloalkoxy; in some embodiments, R 6 are the same or different and each is independently selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl and cyano; in some embodiments, R 6 is cyano.

[0136] in some embodiments of the disclosure, is selected from In some embodiments, selected from In some embodiments, selected from In some embodiments, is In some embodiments, is

[0137] In some embodiments of the present disclosure, m is 1; in some embodiments, m is 0.

[0138] In some embodiments of the present disclosure, R a is a hydrogen atom or C 1-6 alkyl; in some embodiments, R a is a hydrogen atom.

[0139] In some embodiments of the present disclosure, R b is a hydrogen atom.

[0140] In some embodiments of the present disclosure, R a is a hydrogen atom; R b is a hydrogen atom.

[0141] In some embodiments of the present disclosure, the ring in which X and Y are located is a pyrrole ring, is a single bond or a double bond, and X is NH and Y is CH; or, X is CH and Y is NH; in some embodiments, the ring in which X and Y are located is a pyrrole ring, is a single bond or a double bond, X is CH and Y is NH.

[0142] In some embodiments of the present disclosure, R 14 and R 15 are the same or different, and each is independently a hydrogen atom or C 1-6 alkyl.

[0143] In some embodiments of the present disclosure, R 16 is a hydrogen atom or C 1-6 alkyl; in some embodiments, R 16 is C 1-6 alkyl.

[0144] In some embodiments of the present disclosure, R 17 is a hydrogen atom.

[0145] In some embodiments of the present disclosure, R 18 and R19 the same or different, and each independently selected from the group consisting of a hydrogen atom, a halogen, and C 1-6 alkyl; in some embodiments, R 18 and R 19 the same or different, and each independently a hydrogen atom or a halogen; in some embodiments, R 18 and R 19 is F.

[0146] In some embodiments of the disclosure, v is 0; in some embodiments, v is 1; in some embodiments, v is 2.

[0147] In some embodiments of the disclosure, t is 0 or 1; in some embodiments, t is 1; in some embodiments, t is 0.

[0148] In some embodiments of the disclosure, the compound of Formula (IV), Formula (IV-1), or Formula (IV-2), or a pharmaceutically acceptable salt thereof, wherein R 1 is a halogen; R 2a is a halogen or C 1-6 haloalkyl; is selected from the group consisting of

[0149] In some embodiments of the disclosure, the compound of Formula (IV), Formula (IV-1), or Formula (IV-2), or a pharmaceutically acceptable salt thereof, wherein R 1 is a halogen; R 2a is a halogen or C 1-6 haloalkyl; is selected from the group consisting of

[0150] In some embodiments of the disclosure, the compound of Formula (XI), or a pharmaceutically acceptable salt thereof, wherein Z is CR 2a ; Q is CR 2b ; G is CR 2c or N; E is CR 2d ; R 2a , R 2b , R 2c and R 2d the same or different, and each independently selected from the group consisting of a hydrogen atom, a halogen, C 1-6 alkyl, and C 1-6 haloalkyl; R 1 is selected from the group consisting of a hydrogen atom, a halogen, C 1-6 alkyl, and cyano; is selected from the group consisting of

[0151] In some embodiments of the present disclosure, the compound represented by the general formula (II), the general formula (II-1) or the general formula (II-2) or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from the group consisting of a hydrogen atom, a halogen, a C 1-6 alkyl group and a cyano group; m1 is 1; Z is CR 2a ; R 2a is a halogen or a C 1-6 haloalkyl group; Q is CR 2b ; R 2b is a hydrogen atom or a halogen; R 2 is a hydrogen atom or a halogen; m2 is 1; R 3 is a hydrogen atom; is selected from the group consisting of

[0152] In some embodiments of the present disclosure, the compound represented by the general formula (IV), the general formula (IV-1) or the general formula (IV-2) or a pharmaceutically acceptable salt thereof, wherein R 1 is a halogen; R 2a is a halogen or a C 1-6 haloalkyl group; R 5a is a cyano group; R 5b and R 5c are a hydrogen atom or a C 1-6 alkyl group; or, R 5b and R 5c together with the atom to which they are attached form a 3- to 6-membered cycloalkyl group or a 3- to 6-membered heterocyclic group; m is 0 or 1.

[0153] In some embodiments of the present disclosure, the compound represented by the general formula (IV), the general formula (IV-1) or the general formula (IV-2) or a pharmaceutically acceptable salt thereof, wherein R 1 is a halogen; R 2a is a halogen; R 5a is a cyano group; R 5b and R 5c are a hydrogen atom or a C 1-6 alkyl group; or, R 5b and R 5c together with the atom to which they are attached form a 3- to 6-membered cycloalkyl group or a 3- to 6-membered heterocyclic group; m is 0 or 1.

[0154] In some embodiments of the present disclosure, the compound represented by the general formula (IV), the general formula (IV-1) or the general formula (IV-2) or a pharmaceutically acceptable salt thereof, wherein R 1 is a halogen; R 2a is a C 1-6 haloalkyl group; R 5a is a cyano group; R 5b and R 5cIt is a hydrogen atom or a carbon atom. 1-6 Alkyl; or, R 5b and R 5c Together with the attached atoms, it forms a 3- to 6-membered cycloalkyl group or a 3- to 6-membered heterocyclic group; m is 0 or 1.

[0155] In some embodiments of this disclosure, the compound represented by general formula (IV), general formula (IV-1) or general formula (IV-2) or a pharmaceutically acceptable salt thereof, wherein R 1 It is a halogen; R 2a Halogen or C 1-6 Halogenated alkyl; R 5a for R 5b and R 5c Together with the attached atoms, it forms 3 to 6-membered cycloalkyl groups; m is 1.

[0156] In some embodiments of this disclosure, the compound represented by general formula (IV), general formula (IV-1) or general formula (IV-2) or a pharmaceutically acceptable salt thereof, wherein R 1 It is a halogen; R 2a It is a halogen; R 5a For hydrogen atoms; R 5b and R 5c Together with the attached atom, it forms a 4- to 6-membered cycloalkyl group optionally substituted with one or more cyano groups; m is 0 or 1.

[0157] In some embodiments of this disclosure, the compound represented by general formula (IV), general formula (IV-1) or general formula (IV-2) or a pharmaceutically acceptable salt thereof, wherein R 1 It is a halogen; R 2a It is a halogen; R 5a R 5b and R 5c Together with the attached atoms, it forms a 5- to 8-membered bicyclic cycloalkyl group; m is 0 or 1.

[0158] In some embodiments of this disclosure, the compound represented by general formula (VI), general formula (VI-1) or general formula (VI-2) or a pharmaceutically acceptable salt thereof, wherein R 5b and R 5c It is a hydrogen atom or a carbon atom. 1-6 Alkyl; or, R 5b and R 5c Together with the attached atoms, it forms a 3- to 6-membered cycloalkyl group or a 3- to 6-membered heterocyclic group; m is 0 or 1.

[0159] In some embodiments of this disclosure, the compound represented by general formula (VI), general formula (VI-1) or general formula (VI-2) or a pharmaceutically acceptable salt thereof, wherein R 5b and R 5cis a hydrogen atom or a methyl group; or, R 5b and R 5c together with the atom to which they are attached form a 3- to 6-membered cycloalkyl group; m is 1. m is 0 or 1.

[0160] In some embodiments of the disclosure, the compound of Formula (IV), Formula (IV-1), or Formula (IV-2), or a pharmaceutically acceptable salt thereof, is one wherein R 1 is a halogen; R 2a is a halogen or a C 1-6 haloalkyl group; R 5a is selected from C 2-6 alkyl, a halogen, and C 2-6 alkynyl; R 5b and R 5c together with the atom to which they are attached form a 3- to 6-membered cycloalkyl group; m is 1.

[0161] In some embodiments of the disclosure, the compound of Formula (IV), Formula (IV-1), or Formula (IV-2), or a pharmaceutically acceptable salt thereof, is one wherein R 1 is a halogen; R 2a is a halogen or a C 1-6 haloalkyl group; R 5a is selected from a halogen, C 2-6 alkyl, a cyano group, and C 2-6 alkynyl; R 5b and R 5c together with the atom to which they are attached form a 3- to 6-membered cycloalkyl group; m is 1.

[0162] In some embodiments of the disclosure, the compound of Formula (IV), Formula (IV-1), or Formula (IV-2), or a pharmaceutically acceptable salt thereof, is one wherein R 1 is a halogen; R 2a is a halogen or a C 1-6 haloalkyl group; R 5a is a cyano group or C 2-6 alkynyl; R 5b and R 5c is a hydrogen atom or a C 1-6 alkyl group; or, R 5b and R 5c together with the atom to which they are attached form a 3- to 6-membered cycloalkyl group or a 3- to 6-membered heterocyclyl group; m is 0 or 1.

[0163] In some embodiments of the disclosure, the compound of Formula (IV), Formula (IV-1), or Formula (IV-2), or a pharmaceutically acceptable salt thereof, is one wherein R 1 is a halogen; R 2a is a halogen or a C 1-6 haloalkyl group; R 5a is a C2-6 alkynyl group; R 5b and R 5c is a hydrogen atom; m is 1.

[0164] Table A lists typical compounds disclosed herein, including but not limited to:

[0165] Another aspect of this disclosure relates to a compound of general formula (XIA) or a salt thereof:

[0166] in:

[0167] R X1 It is a hydrogen atom or an amino protecting group;

[0168] R X2 It is a hydrogen atom or an amino protecting group;

[0169] R X3 It is a hydrogen atom or an amino protecting group;

[0170] Or, R X2 and R X3 Together with the attached nitrogen atom, it forms a phthalimide group or

[0171] The condition is that R X1 R X2 and R X3 They are not both hydrogen atoms;

[0172] R 1 R 5a R 5b R 5c , m, Q, Z, G and E are as defined in general formula (XI).

[0173] Another aspect of this disclosure relates to a compound of general formula (IIA), general formula (II-1A) or general formula (II-2A), or a salt thereof:

[0174] in:

[0175] R X1 It is a hydrogen atom or an amino protecting group;

[0176] R X2 It is a hydrogen atom or an amino protecting group;

[0177] R X3 It is a hydrogen atom or an amino protecting group;

[0178] Or, R X2 and RX3 forms an anthranilic acid group together with the adjacent nitrogen atom, or

[0179] provided that R X1 , R X2 and R X3 are not simultaneously hydrogen atoms;

[0180] R 1 , R 2 , R 3 , R 4 , R 5a , R 5b , R 5c , m, m1, m2, Q and Z are as defined in general formula (II), general formula (II-1) or general formula (II-2).

[0181] Another aspect of the present disclosure relates to a compound represented by general formula (IIIA), general formula (III-1A) or general formula (III-2A), or a salt thereof:

[0182] wherein:

[0183] R X1 is a hydrogen atom or an amino protecting group;

[0184] R X2 is a hydrogen atom or an amino protecting group;

[0185] R X3 is a hydrogen atom or an amino protecting group;

[0186] or, R X2 and R X3 form an anthranilic acid group together with the adjacent nitrogen atom, or

[0187] provided that R X1 , R X2 and R X3 are not simultaneously hydrogen atoms;

[0188] R 1 , R 2 , R 3 , R 4 , R 5a , R 5b , R 5c , m, m1, m2, Q and Z are as defined in general formula (III), general formula (III-1) or general formula (III-2).

[0189] Another aspect of the present disclosure relates to a compound represented by general formula (IVA), general formula (IV-1A) or general formula (IV-2A), or a salt thereof:

[0190] wherein:

[0191] R X1 is a hydrogen atom or an amino protective group;

[0192] R X2 is a hydrogen atom or an amino protective group;

[0193] R X3 is a hydrogen atom or an amino protective group;

[0194] or, R X2 and R X3 together with the nitrogen atom to which they are attached form a phthalimide group or

[0195] provided that R X1 , R X2 and R X3 are not simultaneously a hydrogen atom;

[0196] R 1 , R 2a , R 5a , R 5b , R 5c and m are as defined in general formula (IV), general formula (IV-1) or general formula (IV-2).

[0197] Another aspect of the present disclosure relates to a compound represented by general formula (VA), general formula (V-1A) or general formula (V-2A), or a salt thereof:

[0198] wherein:

[0199] R X1 is a hydrogen atom or an amino protective group;

[0200] R X2 is a hydrogen atom or an amino protective group;

[0201] R X3 is a hydrogen atom or an amino protective group;

[0202] or, R X2 and R X3 together with the nitrogen atom to which they are attached form a phthalimide group or

[0203] provided that R X1 , R X2 and R X3 are not simultaneously a hydrogen atom;

[0204] R 1 , R2a R 5a R 5b R 5c and m are as defined in General Formula (V), General Formula (V-1) or General Formula (V-2).

[0205] Another aspect of the present disclosure relates to a compound represented by General Formula (VIIA), General Formula (VII-1A) or General Formula (VII-2A) or a salt thereof:

[0206] wherein:

[0207] R X1 is a hydrogen atom or an amino protective group;

[0208] R X2 is a hydrogen atom or an amino protective group;

[0209] R X3 is a hydrogen atom or an amino protective group;

[0210] or, R X2 and R X3 together with the nitrogen atom attached thereto form a phthalimide group or

[0211] provided that R X1 , R X2 and R X3 are not simultaneously a hydrogen atom;

[0212] R 5b , R 5c and m are as defined in General Formula (VI), General Formula (VI-1) or General Formula (VI-2).

[0213] Another aspect of the present disclosure relates to a compound represented by General Formula (VIIA), General Formula (VII-1A) or General Formula (VII-2A) or a salt thereof:

[0214] wherein:

[0215] R X1 is a hydrogen atom or an amino protective group;

[0216] R X2 is a hydrogen atom or an amino protective group;

[0217] R X3 is a hydrogen atom or an amino protective group;

[0218] or, R X2 and R X3 together with the nitrogen atom attached thereto form a phthalimide group or

[0219] provided that R X1 , R X2 and R X3 are not simultaneously hydrogen atoms;

[0220] R 5b , R 5c and m are as defined in general formula (VII), general formula (VII-1) or general formula (VII-2).

[0221] In some embodiments of the disclosure, R X1 is an amino protecting group; in some embodiments, R X1 is SEM.

[0222] In some embodiments of the disclosure, R X2 is a hydrogen atom.

[0223] In some embodiments of the disclosure, R X3 is an amino protecting group; in some embodiments, R X3 is Boc.

[0224] In some embodiments of the disclosure, R X1 is an amino protecting group; R X2 is a hydrogen atom; R X3 is an amino protecting group; in some embodiments, R X1 is SEM; R X2 is a hydrogen atom; R X3 is Boc; in some embodiments, R X1 is an amino protecting group; R X2 and R X3 together with the nitrogen atom to which they are attached form a phthalimide group or In some embodiments, R X1 is SEM; R X2 and R X3 together with the nitrogen atom to which they are attached form

[0225] Table B Exemplary intermediate compounds of the disclosure include, but are not limited to:

[0226] Another aspect of the disclosure relates to a method of preparing a compound represented by general formula (XI) or a pharmaceutically acceptable salt thereof, the method comprising:

[0227] removing the amino protecting group from the compound represented by general formula (XIA) or a salt thereof to obtain the compound represented by general formula (XI) or a pharmaceutically acceptable salt thereof;

[0228] wherein:

[0229] R X1 is a hydrogen atom or an amino protecting group;

[0230] R X2 is a hydrogen atom or an amino protecting group;

[0231] R X3 is a hydrogen atom or an amino protecting group;

[0232] or, R X2 and R X3 together with the nitrogen atom to which they are attached form a phthalimido group or

[0233] provided that R X1 , R X2 and R X3 are not simultaneously a hydrogen atom;

[0234] R 1 , R 5a , R 5b , R 5c , m, Q, Z, G and E are as defined in general formula (XI).

[0235] Another aspect of the present disclosure relates to a method for producing a compound represented by general formula (II), general formula (II-1) or general formula (II-2), or a pharmaceutically acceptable salt thereof, the method comprising:

[0236] removing an amino protecting group from a compound represented by general formula (IIA), or a salt thereof, to obtain a compound represented by general formula (II), or a pharmaceutically acceptable salt thereof;

[0237] removing an amino protecting group from a compound represented by general formula (II-1A), or a salt thereof, to obtain a compound represented by general formula (II-1), or a pharmaceutically acceptable salt thereof;

[0238] removing an amino protecting group from a compound represented by general formula (II-2A), or a salt thereof, to obtain a compound represented by general formula (II-2), or a pharmaceutically acceptable salt thereof;

[0239] wherein:

[0240] R X1 is a hydrogen atom or an amino protecting group;

[0241] R X2 is a hydrogen atom or an amino protecting group;

[0242] R X3 is a hydrogen atom or an amino protecting group;

[0243] or, R X2 and RX3 Together with the attached nitrogen atom, it forms a phthalimide group or

[0244] The condition is that R X1 R X2 and R X3 They are not both hydrogen atoms;

[0245] R 1 R 2 R 3 R 4 R 5a R 5b R 5c , m, m1, m2, Q and Z are as defined in general formula (II), general formula (II-1) or general formula (II-2).

[0246] Another aspect of this disclosure relates to a method for preparing compounds of general formula (III), general formula (III-1) or general formula (III-2) or pharmaceutically acceptable salts thereof, the method comprising:

[0247] The compound of general formula (IIIA) or its salt is deamino protected to obtain the compound of general formula (III) or its pharmaceutically usable salt;

[0248] The compound of general formula (III-1A) or its salt is deamino protected to obtain the compound of general formula (III-1) or its pharmaceutically usable salt;

[0249] The compound of general formula (III-2A) or its salt is deamino protected to obtain the compound of general formula (III-2) or its pharmaceutically usable salt;

[0250] in:

[0251] R X1 It is a hydrogen atom or an amino protecting group;

[0252] R X2 It is a hydrogen atom or an amino protecting group;

[0253] R X3 It is a hydrogen atom or an amino protecting group;

[0254] Or, R X2 and R X3 Together with the attached nitrogen atom, it forms a phthalimide group or

[0255] The condition is that R X1 R X2 and R X3 They are not both hydrogen atoms;

[0256] R 1 , R 2 , R 3 , R 4 , R 5a , R 5b , R 5c , m, m1, m2, Q and Z are as defined in general formula (III), general formula (III-1) or general formula (III-2).

[0257] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (IV), general formula (IV-1) or general formula (IV-2), or a pharmaceutically acceptable salt thereof, the method comprising:

[0258] removing an amino protecting group from a compound represented by general formula (IVA), or a salt thereof, to obtain a compound represented by general formula (IV), or a pharmaceutically acceptable salt thereof;

[0259] removing an amino protecting group from a compound represented by general formula (IV-1A), or a salt thereof, to obtain a compound represented by general formula (IV-1), or a pharmaceutically acceptable salt thereof;

[0260] removing an amino protecting group from a compound represented by general formula (IV-2A), or a salt thereof, to obtain a compound represented by general formula (IV-2), or a pharmaceutically acceptable salt thereof;

[0261] wherein:

[0262] R X1 is a hydrogen atom or an amino protecting group;

[0263] R X2 is a hydrogen atom or an amino protecting group;

[0264] R X3 is a hydrogen atom or an amino protecting group;

[0265] or, R X2 and R X3 together with the nitrogen atom to which they are attached form a phthalimide group or

[0266] provided that R X1 , R X2 and R X3 are not simultaneously a hydrogen atom;

[0267] R 1 , R 2a , R 5a , R 5b , R 5c and m are as defined in general formula (IV), general formula (IV-1) or general formula (IV-2).

[0268] Another aspect of the present disclosure relates to a method for producing a compound represented by General Formula (V), General Formula (V-1) or General Formula (V-2), or a pharmaceutically acceptable salt thereof, the method comprising:

[0269] removing an amino protecting group from the compound represented by General Formula (VA), or a salt thereof, to obtain a compound represented by General Formula (V), or a pharmaceutically acceptable salt thereof;

[0270] removing an amino protecting group from the compound represented by General Formula (V-1A), or a salt thereof, to obtain a compound represented by General Formula (V-1), or a pharmaceutically acceptable salt thereof;

[0271] removing an amino protecting group from the compound represented by General Formula (V-2A), or a salt thereof, to obtain a compound represented by General Formula (V-2), or a pharmaceutically acceptable salt thereof;

[0272] wherein:

[0273] R X1 is a hydrogen atom or an amino protecting group;

[0274] R X2 is a hydrogen atom or an amino protecting group;

[0275] R X3 is a hydrogen atom or an amino protecting group;

[0276] or, R X2 and R X3 together with the nitrogen atom to which they are attached form a phthalimide group or

[0277] provided that R X1 , R X2 and R X3 are not simultaneously a hydrogen atom;

[0278] R 1 , R 2a , R 5a , R 5b , R 5c and m are as defined in General Formula (V), General Formula (V-1) or General Formula (V-2).

[0279] Another aspect of the present disclosure relates to a method for producing a compound represented by General Formula (VI), General Formula (VI-1) or General Formula (VI-2), or a pharmaceutically acceptable salt thereof, the method comprising:

[0280] removing an amino protecting group from the compound represented by General Formula (VIA), or a salt thereof, to obtain a compound represented by General Formula (VI), or a pharmaceutically acceptable salt thereof;

[0281] The compound represented by General Formula (VI-1A) or a salt thereof is deprotected from an amino protecting group to obtain a compound represented by General Formula (VI-1) or a pharmaceutically acceptable salt thereof.

[0282] The compound represented by General Formula (VI-2A) or a salt thereof is deprotected from an amino protecting group to obtain a compound represented by General Formula (VI-2) or a pharmaceutically acceptable salt thereof.

[0283] wherein:

[0284] R X1 is a hydrogen atom or an amino protecting group;

[0285] R X2 is a hydrogen atom or an amino protecting group;

[0286] R X3 is a hydrogen atom or an amino protecting group;

[0287] or, R X2 and R X3 together with the nitrogen atom to which they are attached form a phthalimido group or

[0288] provided that R X1 , R X2 and R X3 are not simultaneously a hydrogen atom;

[0289] R 5b , R 5c and m are as defined in General Formula (VI), General Formula (VI-1) or General Formula (VI-2).

[0290] Another aspect of the present disclosure relates to a method for producing a compound represented by General Formula (VII), General Formula (VII-1) or General Formula (VII-2), or a pharmaceutically acceptable salt thereof, the method comprising:

[0291] The compound represented by General Formula (VIIA) or a salt thereof is deprotected from an amino protecting group to obtain a compound represented by General Formula (VII) or a pharmaceutically acceptable salt thereof.

[0292] The compound represented by General Formula (VII-1A) or a salt thereof is deprotected from an amino protecting group to obtain a compound represented by General Formula (VII-1) or a pharmaceutically acceptable salt thereof.

[0293] The compound represented by General Formula (VII-2A) or a salt thereof is deprotected from an amino protecting group to obtain a compound represented by General Formula (VII-2) or a pharmaceutically acceptable salt thereof.

[0294] wherein:

[0295] R X1 is a hydrogen atom or an amino protecting group;

[0296] R X2 is a hydrogen atom or an amino protecting group;

[0297] R X3 is a hydrogen atom or an amino protecting group;

[0298] or, R X2 and R X3 together with the nitrogen atom to which they are attached form a phthalimide group or

[0299] provided that R X1 , R X2 and R X3 are not simultaneously a hydrogen atom;

[0300] R 5b , R 5c and m are as defined in general formula (VII), general formula (VII-1) or general formula (VII-2).

[0301] In some embodiments of the present disclosure, in the methods of preparing general formula (XI), general formula (II), (II-1), (II-2), (III), (III-1), (III-2), (IV), (IV-1), (IV-2), (V), (V-1), (V-2), (VI), (VI-1), (VI-2), (VII), (VII-1), (VII-2), R X1 is an amino protecting group; R X2 is a hydrogen atom; R X3 is an amino protecting group; in some embodiments, R X1 is SEM; R X2 is a hydrogen atom; R X3 is Boc; in some embodiments, R X1 is an amino protecting group; R X2 and R X3 together with the nitrogen atom to which they are attached form a phthalimide group or In some embodiments, R X1 is SEM; R X2 and R X3 together with the nitrogen atom to which they are attached form

[0302] In some embodiments of the present disclosure, the process for preparing a compound of Formula (XI), (II), (II-1), (II-2), (III), (III-1), (III-2), (IV), (IV-1), (IV-2), (V), (V-1), (V-2), (VI), (VI-1), (VI-2), (VII), (VII-1), (VII-2), wherein the deprotection of the amino protecting group is carried out under acidic conditions; when one of R X1 X2 X3 and R X3 is SEM, the reaction can be carried out under acidic conditions first, and then under the action of ammonia; the reagents that provide acidic conditions include, but are not limited to, hydrogen chloride, a 1,4-dioxane solution of hydrogen chloride, a 1,4-dioxane solution of hydrochloric acid, trifluoroacetic acid, formic acid, acetic acid, hydrochloric acid, concentrated sulfuric acid, methanesulfonic acid, nitric acid, phosphoric acid, p-toluenesulfonic acid, Me3SiCl, and TMSOTf; in some embodiments, trifluoroacetic acid.

[0303] In some embodiments, the process for preparing a compound of Formula (XI), (II), (II-1), (II-2), (III), (III-1), (III-2), (IV), (IV-1), (IV-2), (V), (V-1), (V-2), (VI), (VI-1), (VI-2), (VII), (VII-1), (VII-2) 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.

[0304] Another aspect of the present disclosure relates to a pharmaceutical composition comprising a compound of Formula (X), (XI), (I), (I-1), (I-2), (M), (M-1), (M-2), (II), (II-1), (II-2), (III), (III-1), (III-2), (N), (N-1), (N-2), (IV), (IV-1), (IV-2), (V), (V-1), (V-2), (VI), (VI-1), (VI-2), (VII), (VII-1), (VII-2), or a pharmaceutically acceptable salt thereof, as shown in Table A, and one or more pharmaceutically acceptable carriers, diluents, or excipients.

[0305] The present disclosure further relates to the use of a compound of Formula (X), (XI), (I), (I-1), (I-2), (M), (M-1), (M-2), (II), (II-1), (II-2), (III), (III-1), (III-2), (N), (N-1), (N-2), (IV), (IV-1), (IV-2), (V), (V-1), (V-2), (VI), (VI-1), (VI-2), (VII), (VII-1), (VII-2), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, in the manufacture of a medicament for the treatment and / or prevention of a MTAP-deficient and / or MTA-accumulating disease.

[0306] The present disclosure further relates to the use of a compound of Formula (X), (XI), (I), (I-1), (I-2), (M), (M-1), (M-2), (II), (II-1), (II-2), (III), (III-1), (III-2), (N), (N-1), (N-2), (IV), (IV-1), (IV-2), (V), (V-1), (V-2), (VI), (VI-1), (VI-2), (VII), (VII-1), (VII-2), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, in the manufacture of a medicament for the treatment and / or prevention of a MTAP-deficient and / or MTA-accumulating disease.

[0307] The present disclosure further relates to the use of a compound of Formula (X), (XI), (I), (I-1), (I-2), (M), (M-1), (M-2), (II), (II-1), (II-2), (III), (III-1), (III-2), (N), (N-1), (N-2), (IV), (IV-1), (IV-2), (V), (V-1), (V-2), (VI), (VI-1), (VI-2), (VII), (VII-1), (VII-2), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, in the manufacture of a medicament for the treatment and / or prevention of a MTAP-deficient and / or MTA-accumulating disease.

[0308] The present disclosure further relates to the use of a compound of Formula (X), (XI), (I), (I-1), (I-2), (M), (M-1), (M-2), (II), (II-1), (II-2), (III), (III-1), (III-2), (N), (N-1), (N-2), (IV), (IV-1), (IV-2), (V), (V-1), (V-2), (VI), (VI-1), (VI-2), (VII), (VII-1), (VII-2), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, in the manufacture of a medicament for the treatment and / or prevention of a disease or disorder mediated by PRMT5.

[0309] The present disclosure further relates to the use of a compound of Formula (X), (XI), (I), (I-1), (I-2), (M), (M-1), (M-2), (II), (II-1), (II-2), (III), (III-1), (III-2), (N), (N-1), (N-2), (IV), (IV-1), (IV-2), (V), (V-1), (V-2), (VI), (VI-1), (VI-2), (VII), (VII-1), (VII-2), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, in the manufacture of a medicament for the treatment and / or prevention of a disease or disorder mediated by PRMT5.

[0310] The present disclosure further relates to a method of inhibiting PRMT5 comprising administering to a patient in need thereof a compound of Formula (X), (XI), (I), (I-1), (I-2), (M), (M-1), (M-2), (II), (II-1), (II-2), (III), (III-1), (III-2), (N), (N-1), (N-2), (IV), (IV-1), (IV-2), (V), (V-1), (V-2), (VI), (VI-1), (VI-2), (VII), (VII-1), (VII-2), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

[0311] The present disclosure further relates to a method of inhibiting a PRMT5-MTA complex comprising administering to a patient in need thereof a compound of Formula (X), (XI), (I), (I-1), (I-2), (M), (M-1), (M-2), (II), (II-1), (II-2), (III), (III-1), (III-2), (N), (N-1), (N-2), (IV), (IV-1), (IV-2), (V), (V-1), (V-2), (VI), (VI-1), (VI-2), (VII), (VII-1), (VII-2) as shown in Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

[0312] The present disclosure further relates to a method of treating and / or preventing a MTAP deficiency and / or MTA accumulation disease comprising administering to a patient in need thereof a compound of Formula (X), (XI), (I), (I-1), (I-2), (M), (M-1), (M-2), (II), (II-1), (II-2), (III), (III-1), (III-2), (N), (N-1), (N-2), (IV), (IV-1), (IV-2), (V), (V-1), (V-2), (VI), (VI-1), (VI-2), (VII), (VII-1), (VII-2) as shown in Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

[0313] The present disclosure further relates to a method of treating and / or preventing a PRMT5-mediated disease or disorder comprising administering to a patient in need thereof a compound of Formula (X), (XI), (I), (I-1), (I-2), (M), (M-1), (M-2), (II), (II-1), (II-2), (III), (III-1), (III-2), (N), (N-1), (N-2), (IV), (IV-1), (IV-2), (V), (V-1), (V-2), (VI), (VI-1), (VI-2), (VII), (VII-1), (VII-2) as shown in Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

[0314] The present disclosure further relates to a method of treating and / or preventing cancer comprising administering to a patient in need thereof a compound of Formula (X), (XI), (I), (I-1), (I-2), (M), (M-1), (M-2), (II), (II-1), (II-2), (III), (III-1), (III-2), (N), (N-1), (N-2), (IV), (IV-1), (IV-2), (V), (V-1), (V-2), (VI), (VI-1), (VI-2), (VII), (VII-1), (VII-2) and Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

[0315] The present disclosure further relates to a compound of Formula (X), (XI), (I), (I-1), (I-2), (M), (M-1), (M-2), (II), (II-1), (II-2), (III), (III-1), (III-2), (N), (N-1), (N-2), (IV), (IV-1), (IV-2), (V), (V-1), (V-2), (VI), (VI-1), (VI-2), (VII), (VII-1), (VII-2) and Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use as a medicament.

[0316] The present disclosure further relates to a compound of Formula (X), (XI), (I), (I-1), (I-2), (M), (M-1), (M-2), (II), (II-1), (II-2), (III), (III-1), (III-2), (N), (N-1), (N-2), (IV), (IV-1), (IV-2), (V), (V-1), (V-2), (VI), (VI-1), (VI-2), (VII), (VII-1), (VII-2) and Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use as a PRMT5 inhibitor.

[0317] The present disclosure further relates to a compound of Formula (X), (XI), (I), (I-1), (I-2), (M), (M-1), (M-2), (II), (II-1), (II-2), (III), (III-1), (III-2), (N), (N-1), (N-2), (IV), (IV-1), (IV-2), (V), (V-1), (V-2), (VI), (VI-1), (VI-2), (VII), (VII-1), (VII-2) and Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use as a PRMT5-MTA complex inhibitor.

[0318] The present disclosure further relates to a compound of general formula (X), (XI), (I), (I-1), (I-2), (M), (M-1), (M-2), (II), (II-1), (II-2), (III), (III-1), (III-2), (N), (N-1), (N-2), (IV), (IV-1), (IV-2), (V), (V-1), (V-2), (VI), (VI-1), (VI-2), (VII), (VII-1), (VII-2) as shown in Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use in the inhibition of PRMT5.

[0319] The present disclosure further relates to a compound of general formula (X), (XI), (I), (I-1), (I-2), (M), (M-1), (M-2), (II), (II-1), (II-2), (III), (III-1), (III-2), (N), (N-1), (N-2), (IV), (IV-1), (IV-2), (V), (V-1), (V-2), (VI), (VI-1), (VI-2), (VII), (VII-1), (VII-2) as shown in Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use in the inhibition of PRMT5-MTA complex.

[0320] The present disclosure further relates to a compound of general formula (X), (XI), (I), (I-1), (I-2), (M), (M-1), (M-2), (II), (II-1), (II-2), (III), (III-1), (III-2), (N), (N-1), (N-2), (IV), (IV-1), (IV-2), (V), (V-1), (V-2), (VI), (VI-1), (VI-2), (VII), (VII-1), (VII-2) as shown in Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use in the treatment and / or prevention of MTAP-deficient and / or MTA-accumulating diseases.

[0321] The present disclosure further relates to a compound of general formula (X), (XI), (I), (I-1), (I-2), (M), (M-1), (M-2), (II), (II-1), (II-2), (III), (III-1), (III-2), (N), (N-1), (N-2), (IV), (IV-1), (IV-2), (V), (V-1), (V-2), (VI), (VI-1), (VI-2), (VII), (VII-1), (VII-2) as shown in Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use in the treatment and / or prevention of a disease or disorder mediated by PRMT5.

[0322] The present disclosure further relates to a compound of general formula (X), (XI), (I), (I-1), (I-2), (M), (M-1), (M-2), (II), (II-1), (II-2), (III), (III-1), (III-2), (N), (N-1), (N-2), (IV), (IV-1), (IV-2), (V), (V-1), (V-2), (VI), (VI-1), (VI-2), (VII), (VII-1), (VII-2) as shown in Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use in the treatment and / or prevention of cancer.

[0323] In some embodiments, the disease or disorder mediated by PRMT5 described in the present disclosure is cancer.

[0324] In some embodiments, the MTAP-deficient and / or MTA-accumulating disease described in the present disclosure is cancer.

[0325] In some embodiments, the cancer described herein is selected from lung cancer (e.g., non-small cell lung cancer), renal cancer, liver cancer (e.g., hepatocellular carcinoma), head and neck cancer, esophageal cancer (also known as esophagus cancer), lymphoma (e.g., 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 multiforme, colorectal cancer (e.g., colon cancer and rectal cancer), malignant peripheral nerve sheath tumor (MPNST), melanoma, gastric cancer, pancreatic cancer, cholangiocarcinoma, bladder cancer, breast cancer, ovarian cancer, vaginal cancer, cervical cancer, endometrial cancer, prostate cancer, testicular cancer, seminoma, myeloma (e.g., multiple myeloma), leukemia (e.g., acute leukemia, chronic leukemia, myelogenous leukemia, myelofibrosis, erytholeukemia), acoustic neuroma, basal cell carcinoma, brain cancer, bronchial cancer, sarcoma (e.g., chondrosarcoma, soft tissue sarcoma, fibrosarcoma, leiomyosarcoma, liposarcoma, lymphangiosarcoma, myxosarcoma, osteogenic sarcoma, rhabdomyosarcoma, Ewing’s tumor), choriocarcinoma, craniopharyngioma, cystadenocarcinoma, hemangioendothelioma, ependymoma, epithelial carcinoma, glioma, astrocytic carcinoma, hemangioblastoma, medulloblastoma, meningioma, mesothelioma, neuroblastoma, bone cancer, nasopharyngeal cancer, oral cancer, laryngeal cancer, thyroid cancer, retinoblastoma, skin cancer, squamous cell carcinoma (e.g., head and neck squamous cell carcinoma), synovioma, sweat gland carcinoma, and myelodysplastic syndrome.

[0326] In some embodiments, the cancer described herein is selected from lung cancer, renal cancer, liver cancer, head and neck cancer, esophageal cancer, lymphoma, glioblastoma, glioblastoma multiforme, colorectal cancer, malignant peripheral nerve sheath tumor (MPNST), melanoma, gastric cancer, pancreatic cancer, cholangiocarcinoma, bladder cancer, breast cancer, ovarian cancer, vaginal cancer, cervical cancer, endometrial cancer, prostate cancer, testicular cancer, seminoma, myeloma, leukemia, acoustic neuroma, brain cancer, bronchial cancer, sarcoma, choriocarcinoma, craniopharyngioma, cystadenocarcinoma, hemangioendothelioma, ependymoma, epithelial carcinoma, glioma, astrocytic carcinoma, hemangioblastoma, medulloblastoma, meningioma, rhabdomyosarcoma, mesothelioma, neuroblastoma, bone cancer, nasopharyngeal cancer, oral cancer, laryngeal cancer, thyroid cancer, retinoblastoma, skin cancer, squamous cell carcinoma, synovioma, sweat gland carcinoma, and myelodysplastic syndrome.

[0327] In some embodiments, the cancer described herein is selected from ovarian cancer, lymphoma, pancreatic cancer, bladder cancer, gastric cancer, colorectal cancer, cholangiocarcinoma, mesothelioma, malignant peripheral nerve sheath tumor (MPNST), glioblastoma multiforme, and lung cancer.

[0328] In some embodiments, the cancer is a lymphoma; in some embodiments, the cancer is a non-Hodgkin's lymphoma or a Hodgkin's lymphoma; in some embodiments, the cancer is a non-Hodgkin's lymphoma; in some embodiments, the cancer is a Hodgkin's lymphoma.

[0329] In some embodiments, the cancer of the present disclosure is a MTAP-associated cancer.

[0330] In some embodiments, the cancer of the present disclosure is a Hematologic Malignancies.

[0331] In some embodiments, the lymphoma of the present disclosure is selected from the group consisting of diffuse large B-cell lymphoma (DLBCL), non-Hodgkin's lymphoma, or Hodgkin's lymphoma.

[0332] In some embodiments, the lung cancer of the present disclosure is a non-small cell lung cancer.

[0333] In some embodiments, the myeloma of the present disclosure is a multiple myeloma.

[0334] The active compounds can be prepared into a form suitable for administration by any of the appropriate routes and, as a general guide, the active compounds of the present disclosure are in some embodiments in unit dosage form, or in a form that the patient can self-administer in a single dose.

[0335] The expression of a unit dose of the compound or composition of the present disclosure can be a tablet, a capsule, a cachet, a vial of liquid, a vial of powder, a granule, a lozenge, a suppository, a reconstituted powder, or a liquid preparation. In some embodiments, the unit dose of the pharmaceutical composition is 0.001 mg to 1000 mg; in some embodiments, a suitable unit dose can be 0.1 to 1000 mg.

[0336] The pharmaceutical composition of the present disclosure can contain one or more excipients in addition to the active compound, which are selected from the group consisting of fillers (diluents), binders, wetting agents, disintegrants, or excipients, etc. Depending on the method of administration, the composition can contain 0.1 to 99% by weight of the active compound.

[0337] In certain embodiments, the pharmaceutical composition contains 0.01-99.99% of the foregoing compound, or a pharmaceutically acceptable salt thereof, or an isotopically- substituted variant thereof, based on the total weight of the composition. In certain embodiments, the pharmaceutical composition contains 0.1-99.9% of the foregoing compound, or a pharmaceutically acceptable salt thereof, or an isotopically- substituted variant thereof. In certain embodiments, the pharmaceutical composition contains 0.5-99.5% of the foregoing compound, or a pharmaceutically acceptable salt thereof, or an isotopically- substituted variant thereof. In certain embodiments, the pharmaceutical composition contains 1-99% of the foregoing compound, or a pharmaceutically acceptable salt thereof, or an isotopically- substituted variant thereof. In certain embodiments, the pharmaceutical composition contains 2-98% of the foregoing compound, or a pharmaceutically acceptable salt thereof, or an isotopically- substituted variant thereof.

[0338] In certain embodiments, the pharmaceutical composition contains 0.01-99.99% of a pharmaceutically acceptable excipient, based on the total weight of the composition. In certain embodiments, the pharmaceutical composition contains 0.1-99.9% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition contains 0.5-99.5% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition contains 1-99% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition contains 2-98% of a pharmaceutically acceptable excipient.

[0339] The pharmaceutically acceptable salts of the compounds described in the present disclosure can be selected from inorganic or organic salts.

[0340] The pharmaceutical compositions containing active ingredients can be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Compositions intended for oral use can be prepared according to any method known in the art for the manufacture of pharmaceutical compositions, and such compositions can contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations.

[0341] Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients can be inert excipients, granulating agents, disintegrating agents, binding agents, and lubricating agents. The tablets can be uncoated or they can be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over an extended period of time. Examples of coating agents include polymeric substances such as hydroxypropylmethylcellulose, hydroxypropylcellulose, and ethylcellulose, and waxes.

[0342] Oral preparations can also be provided in the form of soft gelatin capsules in which the active ingredient is mixed with an inert solid diluent or in which the active ingredient is mixed with a water-soluble or oil-soluble carrier.

[0343] Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, dispersing agents or wetting agents. The aqueous suspensions can also contain one or more preservatives, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, depending on the desire.

[0344] Oil suspensions can be formulated by suspending the active ingredients in a vegetable oil, or a mineral oil. The oil suspensions can contain a thickening agent. Sweetening agents and flavoring agents can be added to provide a palatable oral preparation. These compositions can be preserved by the addition of an anti-oxidant.

[0345] The pharmaceutical compositions of this disclosure can also be in the form of oil-in- water emulsions. The oily phase can be a vegetable oil or a mineral oil or a mixture of these. Suitable emulsifying agents can be naturally-occurring phosphatides, such as soybean phoshatide, and lecithin. The emulsions can also contain sweetening agents, flavoring agents, preservatives and antioxidants.

[0346] The pharmaceutical compositions of this disclosure can be in the form of a sterile injectable aqueous or oleaginous suspension. For this purpose, any of the injectable

[0347] The pharmaceutical compositions of this disclosure can be in the form of a sterile injectable aqueous or oleaginous suspension. For this purpose, any of the injectable

[0348] The compounds of this disclosure can be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols.

[0349] The compounds of this disclosure can be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols.

[0350] 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 activity of the specific compound used, the patient's age, the patient's weight, the patient's health status, the patient's behavior, the patient's diet, the timing of administration, the route of administration, the rate of excretion, the combination of drugs, the severity of the disease, etc.; in addition, the optimal treatment mode, such as the treatment pattern, the daily dosage of the compound, or the type of medicinal salt can be validated based on conventional treatment protocols.

[0351] Terminology Explanation

[0352] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0353] 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., C2). 1-20 Alkyl group). The alkyl group, in some embodiments, is an alkyl group having 1 to 12 carbon atoms (i.e., C12). 1-12 Alkyl groups, in some embodiments having 1 to 6 carbon atoms (i.e., C164 ... 1-6Non-limiting examples include: methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, s-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 isomers thereof, and the like. Alkyl groups can be substituted or unsubstituted, and when substituted can be substituted at any available attachment point with one or more substituents selected from deuterium atoms, halogens, alkoxy groups, haloalkyl groups, haloalkoxy groups, cycloalkyloxy groups, heterocyclyloxy groups, hydroxy groups, hydroxyalkyl groups, cyano groups, amino groups, nitro groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups, in some embodiments.

[0354] The term "alkylene" refers to a divalent alkyl group, wherein alkyl is as defined above, 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 term "alkylene" refers to a divalent alkyl group, wherein alkyl is as defined above, 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 1-12 The term "alkylene" refers to a divalent alkyl group, wherein alkyl is as defined above, 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 1-6alkylene). Non-limiting examples include: -CH2-, -CH(CH3)-, -C(CH3)2-, -CH2CH2-, -CH(CH2CH3)-, -CH2CH(CH3)-, -CH2C(CH3)2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, and the like. An alkylene group can be substituted or unsubstituted, and when substituted can be substituted at any available attachment point with, in some embodiments, one or more of a deuterium atom, a halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

[0355] The term“alkenyl” refers to an alkyl group that contains at least one carbon-carbon double bond, wherein the definition of alkyl is as described above, having from 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12) carbon atoms (i.e., C 2-12 alkenyl). In some embodiments, the alkenyl group has from 2 to 6 carbon atoms (i.e., C 2-6 alkenyl). Non-limiting examples include: ethenyl, propenyl, isopropenyl, butenyl, and the like. An alkenyl group can be substituted or unsubstituted, and when substituted can be substituted at any available attachment point with, in some embodiments, one or more of a deuterium atom, alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

[0356] The term“alkynyl” refers to an alkyl group that contains at least one carbon-carbon triple bond, wherein the definition of alkyl is as described above, having from 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12) carbon atoms (i.e., C 2-12 alkynyl). In some embodiments, the alkynyl group has from 2 to 6 carbon atoms (i.e., C 2-6 alkynyl). Non-limiting examples include: ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. An alkynyl group can be substituted or unsubstituted, and when substituted can be substituted at any available attachment point with, in some embodiments, one or more of a deuterium atom, alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

[0357] The term "alkoxy" refers to -0-(alkyl), wherein alkyl is defined above. Non-limiting examples include methoxy, ethoxy, propyloxy, and butyloxy, and the like. The alkoxy group can be substituted or non-substituted, and when substituted, it can be substituted at any available attachment point with one or more substituents selected from, in some embodiments, deuterium atom, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

[0358] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic all- carbon ring (i.e., monocyclic cycloalkyl) or a multicyclic system (i.e., multicyclic 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 has, 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).

[0359] Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, and cyclooctyl, and the like.

[0360] The multicyclic cycloalkyl groups include spirocycloalkyl, fused cycloalkyl, and bridged cycloalkyl.

[0361] The bicyclic cycloalkyl groups include monosprio cycloalkyl, bicyclofused cycloalkyl, and bicyclobridged cycloalkyl.

[0362] The term "spirocycloalkyl" refers to a polycyclic ring system sharing one carbon atom between rings (referred to as a spiro atom), which can contain one or more double bonds within the rings, or which can contain one or more heteroatoms selected from nitrogen, oxygen, and sulfur within the rings (said nitrogen can optionally be oxidized, i.e., form a nitro oxide; said sulfur can optionally be oxidized, i.e., form a sulfoxide or sulfone, but not -O-O-, -O-S-, or -S-S-), provided that at least one fully carbon ring is present and the point of attachment is on the fully carbon ring, having from 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., 5- to 20-membered spirocycloalkyl). The spirocycloalkyl groups have, in some embodiments, from 6 to 14 ring atoms (i.e., 6- to 14-membered spirocycloalkyl), and in some embodiments, from 7 to 10 ring atoms (i.e., 7- to 10-membered spirocycloalkyl). The spirocycloalkyl groups include mono- and polyspirocycloalkyl groups (such as dispirocycloalkyl groups and the like), and in some embodiments are mono- or dispirocycloalkyl groups, and in some embodiments are 3 / 4-, 3 / 5-, 3 / 6-, 4 / 4-, 4 / 5-, 4 / 6-, 5 / 3-, 5 / 4-, 5 / 5-, 5 / 6-, 5 / 7-, 6 / 3-, 6 / 4-, 6 / 5-, 6 / 6-, 6 / 7-, 7 / 5-, or 7 / 6- spirocycloalkyl groups. Non-limiting examples include: which can be at any position; and the like.

[0363] The term "fused cycloalkyl" refers to a polycyclic ring system sharing two adjacent carbon atoms between the rings, which is a monocyclic cycloalkyl fused with one or more monocyclic cycloalkyl groups, or a monocyclic cycloalkyl fused with one or more of heterocyclyl, aryl, or heteroaryl, wherein the point of attachment is on the monocyclic cycloalkyl group, which can contain one or more double bonds within its 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., 5- to 20-membered fused cycloalkyl). The fused cycloalkyl group has, in some embodiments, 6 to 14 ring atoms of fused cycloalkyl (i.e., 6- to 14-membered fused cycloalkyl), and in some embodiments, 7 to 10 ring atoms of fused cycloalkyl (i.e., 7- to 10-membered fused cycloalkyl). The fused cycloalkyl group includes bicyclic and polycyclic fused cycloalkyl groups (such as tricyclic, tetracyclic, etc.), and in some embodiments, is a bicyclic or tricyclic fused cycloalkyl group, and in some embodiments, is a 3 / 4-, 3 / 5-, 3 / 6-, 4 / 4-, 4 / 5-, 4 / 6-, 5 / 3-, 5 / 4-, 5 / 5-, 5 / 6-, 5 / 7-, 6 / 3-, 6 / 4-, 6 / 5-, 6 / 6-, 6 / 7-, 7 / 5-, or 7 / 6 bicyclic fused cycloalkyl group. Non-limiting examples include:

[0364] which can have the point of attachment at any position;

[0365] and the like.

[0366] The term "bridged cycloalkyl" refers to an all-carbon polycyclic ring system sharing two non-adjacent carbon atoms between the rings, which can contain one or more double bonds within its 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 group has, in some embodiments, 6 to 14 carbon atoms of bridged cycloalkyl (i.e., 6- to 14-membered bridged cycloalkyl), and in some embodiments, 7 to 10 carbon atoms of bridged cycloalkyl (i.e., 7- to 10-membered bridged cycloalkyl). The bridged cycloalkyl group includes bicyclic and polycyclic bridged cycloalkyl groups (such as tricyclic, tetracyclic, etc.), and in some embodiments, is a bicyclic or tricyclic bridged cycloalkyl group. Non-limiting examples include: which can have the point of attachment at any position.

[0367] Cycloalkyl groups can be substituted or non-substituted, and when substituted can be substituted at any available attachment point with substituents selected from one or more of a deuterium atom, a halogen, an alkyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a cycloalkyloxy group, a heterocyclyloxy group, a hydroxy 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, in some embodiments.

[0368] The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic heterocyclic ring (i.e., monocyclic heterocyclyl) or a polycyclic heterocyclic ring system (i.e., polycyclic heterocyclyl) having at least one (e.g., 1, 2, 3, or 4) heteroatom within the ring selected from the group consisting of nitrogen, oxygen, and sulfur (said nitrogen can optionally be oxidized, i.e., form a nitro oxide; said sulfur can optionally be oxidized, i.e., form a sulfoxide or sulfone, but not -O-O-, -O-S-, or -S-S-), and having from 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 heterocyclyl). In some embodiments, the heterocyclyl group has from 3 to 12 ring atoms (i.e., 3- to 12-membered heterocyclyl); in some embodiments, from 3 to 8 ring atoms (i.e., 3- to 8-membered heterocyclyl); in some embodiments, from 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).

[0369] Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl, dihydropyrrolyl, dihydrofuranyl, tetrahydropyranyl, 1,2,3,6-tetrahydropyridinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and the like.

[0370] Polycyclic heterocyclyl groups include spiroheterocyclyl, fused heterocyclyl, and bridged heterocyclyl groups.

[0371] The term "spiroheterocyclyl" refers to a polycyclic heterocyclic ring system which shares one atom (referred to as a spiro atom) between rings, which can contain one or more double bonds within the ring, and which contains at least one (e.g., 1, 2, 3, or 4) heteroatom within the ring selected from nitrogen, oxygen, and sulfur (said nitrogen can optionally be oxidized, i.e., form a nitro oxide; said sulfur can optionally be oxidized, i.e., form a sulfoxide or sulfone, but not -0-0-, -0-S-, or -S-S-), provided that at least one monocyclic heterocyclyl is contained and the point of attachment is on the monocyclic heterocyclyl, 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., 5- to 20-membered spiroheterocyclyl). The spiroheterocyclyl in some embodiments has 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 spiroheterocyclyl includes mono- and polyspiroheterocyclyl (e.g., dispiroheterocyclyl, etc.), in some embodiments is a monosprioheterocyclyl or dispiroheterocyclyl, in some embodiments is a 3 / 4-, 3 / 5-, 3 / 6-, 4 / 4-, 4 / 5-, 4 / 6-, 5 / 3-, 5 / 4-, 5 / 5-, 5 / 6-, 5 / 7-, 6 / 3-, 6 / 4-, 6 / 5-, 6 / 6-, 6 / 7-, 7 / 5-, or 7 / 6 monosprioheterocyclyl. Non-limiting examples include:

[0372] etc.

[0373] The term "heteroaromatic" refers to a monocyclic or bicyclic ring system sharing adjacent atoms between the rings, which rings can contain one or more double bonds, and which rings contain at least one (e.g., 1, 2, 3, or 4) heteroatom selected from nitrogen, oxygen, and sulfur (said nitrogen can optionally be oxidized, i.e., form a nitro oxide; said sulfur can optionally be oxidized, i.e., form a sulfoxide or sulfone, but not -0-0-, -0-S-, or -S-S-), which is a monocyclic heteroaromatic group fused to one or more monocyclic heteroaromatic groups, or a monocyclic heteroaromatic group fused to one or more of a cycloalkyl, aryl, or heteroaryl group, wherein the point of attachment is on the monocyclic heteroaromatic group, 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., 5- to 20-membered fused heteroaromatic). The fused heteroaromatic group in some embodiments has 6 to 14 ring atoms (i.e., 6- to 14-membered fused heteroaromatic), in some embodiments 7 to 10 ring atoms (i.e., 7- to 10-membered fused heteroaromatic); in some embodiments 7 to 9 ring atoms (i.e., 7- to 9-membered fused heteroaromatic); in some embodiments 8 or 9 ring atoms (i.e., 8- or 9-membered fused heteroaromatic). The fused heteroaromatic group includes bicyclic and polycyclic fused heteroaromatic groups (such as tricyclic fused heteroaromatic groups, tetracyclic fused heteroaromatic groups, and the like), in some embodiments a bicyclic fused heteroaromatic group or a tricyclic fused heteroaromatic group, in some embodiments a 3 / 4-, 3 / 5-, 3 / 6-, 4 / 4-, 4 / 5-, 4 / 6-, 5 / 3-, 5 / 4-, 5 / 5-, 5 / 6-, 5 / 7-, 6 / 3-, 6 / 4-, 6 / 5-, 6 / 6-, 6 / 7-, 7 / 5-, or 7 / 6 bicyclic fused heteroaromatic group. Non-limiting examples include:

[0374] etc.

[0375] The term "bridged heterocyclyl" refers to a polycyclic heterocyclic ring system that shares two non-adjacent atoms between the rings, which can contain one or more double bonds within the rings, and which contains at least one (e.g., 1, 2, 3, or 4) heteroatom(s) selected from nitrogen, oxygen, and sulfur (said nitrogen can optionally be oxidized, i.e., form a nitro oxide; said sulfur can optionally be oxidized, i.e., form a sulfoxide or sulfone, but not -0-0-, -0-S-, or -S-S-) within the rings, having from 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., 5- to 20-membered bridged heterocyclyl). The bridged heterocyclyl groups in some embodiments have from 6 to 14 ring atoms (i.e., 6- to 14-membered bridged heterocyclyl), and in some embodiments have from 7 to 10 ring atoms (i.e., 7- to 10-membered bridged heterocyclyl). Depending on the number of rings comprising the ring system, the bridged heterocyclyl groups can be bicyclic or polycyclic (e.g., tricyclic, tetracyclic, etc.), and in some embodiments are bicyclic or tricyclic. Non-limiting examples include:

[0376]

[0377] The heterocyclyl groups can be substituted or non-substituted, and when substituted, can be substituted at any available point of attachment, with one or more substituents in some embodiments selected from deuterium, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, oxo, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

[0378] ​The term "aryl" refers to a monocyclic all-carbon aromatic ring having a conjugated pi-electron system (i.e., monocyclic aryl) or a polycyclic aromatic ring system (i.e., polycyclic aryl) having 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 aryl). The aryl group in some embodiments has 6 to 10 ring atoms (i.e., 6- to 10-membered aryl) or 10 to 14 ring atoms (i.e., 10- to 14-membered aryl); in some embodiments, the aryl group has 11 to 13 ring atoms (i.e., 11- to 13-membered aryl); in some embodiments, the aryl group has 12 ring atoms (i.e., 12-membered aryl). The monocyclic aryl group is exemplified by phenyl. The polycyclic aryl group is exemplified by, without limitation: naphthyl, anthryl, phenanthryl, and the like. The polycyclic aryl group also includes phenyl or naphthyl fused with one or more heterocyclyl or cycloalkyl groups, where the point of attachment is on the phenyl 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 aryl group or a tricyclic aryl group), non-limiting examples of which include: and the like.

[0379] The aryl group can be substituted or unsubstituted, and when substituted, it can be substituted at any available point of attachment, the substituents in some embodiments being selected from one or more of a deuterium 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.

[0380] The term "heteroaryl" refers to a monocyclic heteroaryl ring (i.e., monocyclic heteroaryl) or a polycyclic heteroaryl ring system (i.e., polycyclic heteroaryl) having a conjugated π-electron system, containing at least one (e.g., 1, 2, 3 or 4) heteroatoms selected from nitrogen, oxygen and sulfur (the nitrogen may optionally be oxidized, i.e., to form nitrogen oxides; the sulfur may optionally be oxidized, i.e., to form sulfoxides or sulfones, but excluding -OO-, -OS- or -SS-), having 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., 5 to 22-membered heteroaryl). The heteroaryl group is, in some embodiments, a heteroaryl group having 5 to 10 ring atoms (i.e., a 5 to 10-membered heteroaryl group) or a heteroaryl group having 9 to 14 ring atoms (i.e., a 9 to 14-membered heteroaryl group); in some embodiments, a heteroaryl group having 11 or 12 ring atoms (i.e., an 11 or 12-membered heteroaryl group); in some embodiments, a heteroaryl group having 11 ring atoms (i.e., an 11-membered heteroaryl group); in some embodiments, a heteroaryl group having 5 or 6 ring atoms (i.e., a 5 or 6-membered heteroaryl group); and in some embodiments, a 5-membered heteroaryl group.

[0381] Non-limiting examples of the aforementioned monocyclic heteroaryl groups include: furanyl, thiopheneyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, furazonyl, pyrroleyl, N-alkylpyrroleyl, pyridyl, pyrimidinyl, pyridoneyl, N-alkylpyridone (e.g.) (etc.), pyrazinyl, pyridazinyl, etc.

[0382] The polycyclic heteroaryl group (in some embodiments, a 9- to 14-membered heteroaryl group) includes, non-limiting examples, indole, indazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, phthalazinyl, benzimidazolyl, benzothiophene, quinazolinyl, benzothiazolyl, carbazole, etc. The polycyclic heteroaryl group also includes a monocyclic heteroaryl group fused with one or more aryl 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 heteroaryl ring system. The polycyclic heteroaryl group also includes a monocyclic heteroaryl group fused with one or more cycloalkyl or heterocyclic groups, wherein the connection point is on the monocyclic heteroaryl ring, and in this case, the number of ring atoms continues to represent the number of ring atoms in the polycyclic heteroaryl ring system (in some embodiments, a bicyclic or tricyclic heteroaryl group). Non-limiting examples include: wait.

[0383] Heteroaryl groups can be substituted or non-substituted, and when substituted, can be substituted at any available attachment point with substituents selected from one or more of a deuterium atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl group in some embodiments.

[0384] The term "amino protecting group" refers to a readily removed group of atoms introduced on an amino group to keep the amino group unchanged while other parts of the molecule are reacted. Non-limiting examples include (trimethylsilyl)ethoxymethyl, tetrahydropyranyl, tert-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), formylmethoxycarbonyl (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.

[0385] The term "hydroxy protecting group" refers to a readily removed group of atoms introduced on a hydroxy group to block or protect the hydroxy group while other functional groups of the compound are reacted. Non-limiting examples include trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), tert-butyldimethylsilyl (TBS), tert-butyldimethylsilyl (TBDMS), tert-butyldiphenylsilyl (TBDPS), methyl, tert-butyl, allyl, benzyl, methoxymethyl (MOM), ethoxyethyl, 2-tetrahydropyranyl (THP), formyl, acetyl, benzoyl, p-nitrobenzoyl, (trimethylsilyl)ethoxymethyl (SEM), and the like.

[0386] The term "cycloalkyloxy" refers to cycloalkyl-O-, wherein cycloalkyl is as defined above.

[0387] The term "heterocyclyloxy" refers to heterocyclyl-O-, wherein heterocyclyl is as defined above.

[0388] The term "aryloxy" refers to aryl-O-, wherein aryl is as defined above.

[0389] The term "heteroaryloxy" refers to heteroaryl-O-, wherein heteroaryl is as defined above.

[0390] The term "cycloalkylalkyl" refers to an alkyl group substituted with one or more cycloalkyl groups, wherein alkyl and cycloalkyl are as defined above.

[0391] The term "heterocyclylalkyl" refers to an alkyl group substituted with one or more heterocyclyl groups, wherein alkyl and heterocyclyl are as defined above.

[0392] The term "arylalkyl" means an alkyl group substituted with one or more aryl groups, wherein alkyl and aryl are as defined above; for example -CH2Ph.

[0393] The term "heteroarylalkyl" means an alkyl group substituted with one or more heteroaryl groups, wherein alkyl and heteroaryl are as defined above.

[0394] The term "alkylthio" means an alkyl-S- group, wherein alkyl is as defined above.

[0395] The term "haloalkyl" means an alkyl group substituted with one or more halogen groups, wherein alkyl is as defined above.

[0396] The term "haloalkoxy" means an alkoxy group substituted with one or more halogen groups, wherein alkoxy is as defined above; for example -OCF3.

[0397] The term "deuteroalkyl" means an alkyl group substituted with one or more deuterium atoms, wherein alkyl is as defined above; for example -CD3.

[0398] The term "hydroxyalkyl" means an alkyl group substituted with one or more hydroxyl groups, wherein alkyl is as defined above; for example -CH2OH.

[0399] The term "deuteroalkoxy" means an alkoxy group substituted with one or more deuterium atoms, wherein alkoxy is as defined above; for example -OCD3.

[0400] The term "alkoxyalkyl" means an alkyl group substituted with one or more alkoxy groups, wherein alkyl and alkoxy are as defined above; for example -CH2OCH3.

[0401] The term "haloalkoxyalkyl" means an alkyl group substituted with one or more haloalkoxy groups, wherein alkyl and haloalkoxy are as defined above; for example -CH2OCHF2.

[0402] The term "aminoalkyl" means an alkyl group substituted with one or more amino groups, wherein alkyl is as defined above; for example -CH2NH2.

[0403] The term "methylene" means =CH2.

[0404] The term "halogen" means fluorine, chlorine, bromine, or iodine.

[0405] The term "hydroxyl" means -OH.

[0406] The term "mercapto" means -SH.

[0407] The term "amino" means -NH2.

[0408] The term "cyano" means -CN.

[0409] The term "nitro" means -NO2.

[0410] The term "oxo" or "oxo group" refers to "=O".

[0411] The term "carbonyl" refers to C=O.

[0412] The term "carboxyl group" refers to -C(O)OH.

[0413] The term "carboxylic acid ester group" 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.

[0414] The compounds disclosed herein can exist in specific stereoisomer forms. The term "stereoisomer" refers to isomers with the same structure but different spatial arrangements of atoms. These include cis and trans (or Z and E) isomers, (-)- and (+)- isomers, (R)- and (S)- enantiomers, diastereomers, (D)- and (L)- isomers, tautomers, blocked isomers, conformational isomers, and mixtures thereof (such as racemic mixtures and mixtures of diastereomers). Substituents in the compounds disclosed herein may contain additional asymmetric atoms. All such stereoisomers and mixtures thereof are included within the scope of this 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. This disclosure discloses certain isomers of compounds that can be prepared by asymmetric synthesis or with chiral auxiliaries, or, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), by forming a salt of the diastereomer with a suitable optically active acid or base, followed by diastereomer resolution using conventional methods known in the art to obtain the pure isomer. Furthermore, the separation of enantiomers and diastereomers is typically performed by chromatography.

[0415] In the chemical structure of the compounds described in this disclosure, the bonds... This indicates that the configuration is not specified; that is, if chiral isomers exist in the chemical structure, the bond... It can be Or simultaneously include Two configurations. For all carbon-carbon double bonds, even if only one configuration is named, both the Z-type and E-type are included.

[0416] The compounds of the present disclosure can exist in different tautomeric forms, and all such forms are included within the scope of the present disclosure. The term “tautomers” or “tautomeric forms” refers to structural isomers that exist in equilibrium and are readily converted from one isomeric form to another isomeric form. It includes all possible tautomers, i.e. in the form of a single isomer or in the form of a mixture of said tautomers in any ratio. Non-limiting examples include: keto-enol, imine-enamine, lactam-lactim, and the like.

[0417] For example, a compound is understood to include either or both tautomers of the following two structures:

[0418] All tautomeric forms are within the scope of the present disclosure, and the naming of the compounds does not exclude any tautomer.

[0419] The compounds of the present disclosure include all suitable isotopic variations of the compounds. The term “isotopic variations” means the replacement of at least one atom with an atom having the same atomic number but an atomic mass different from the predominant atomic mass of the atom. Examples of isotopes that can be present in the compounds of the present disclosure include stable and radioactive isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulphur, fluorine, chlorine, bromine, and iodine, such as 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, in some embodiments, deuterium.

[0420] Deuterated drugs have advantages of reducing side effects, increasing drug stability, enhancing efficacy, prolonging drug biological half-life, etc. compared to non-deuterated drugs. All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are included within the scope of the present disclosure. Each available hydrogen atom attached to a carbon atom can be independently replaced with a deuterium atom, wherein the replacement of deuterium can be partial or complete, partial replacement of deuterium means that at least one hydrogen is replaced with at least one deuterium.

[0421] When a position of a compound of the disclosure is specifically designated as "deuterium" or "D", that position shall be understood to have an abundance of deuterium that is at least 1000 times greater than the natural abundance of deuterium, which is 0.015% (i.e., at least 15% incorporation of deuterium). In some embodiments, the abundance of deuterium at each designated deuterium atom is at least 1000 times greater than the natural abundance of deuterium (i.e., at least 15% incorporation of deuterium). In some embodiments, the abundance of deuterium at each designated deuterium atom is at least 2000 times greater than the natural abundance of deuterium (i.e., at least 30% incorporation of deuterium). In some embodiments, the abundance of deuterium at each designated deuterium atom is at least 3000 times greater than the natural abundance of deuterium (i.e., at least 45% incorporation of deuterium). In some embodiments, the abundance of deuterium at each designated deuterium atom is at least 3340 times greater than the natural abundance of deuterium (i.e., at least 50.1% incorporation of deuterium). In some embodiments, the abundance of deuterium at each designated deuterium atom is at least 3500 times greater than the natural abundance of deuterium (i.e., at least 52.5% incorporation of deuterium). In some embodiments, the abundance of deuterium at each designated deuterium atom is at least 4000 times greater than the natural abundance of deuterium (i.e., at least 60% incorporation of deuterium). In some embodiments, the abundance of deuterium at each designated deuterium atom is at least 4500 times greater than the natural abundance of deuterium (i.e., at least 67.5% incorporation of deuterium). In some embodiments, the abundance of deuterium at each designated deuterium atom is at least 5000 times greater than the natural abundance of deuterium (i.e., at least 75% incorporation of deuterium). In some embodiments, the abundance of deuterium at each designated deuterium atom is at least 5500 times greater than the natural abundance of deuterium (i.e., at least 82.5% incorporation of deuterium). In some embodiments, the abundance of deuterium at each designated deuterium atom is at least 6000 times greater than the natural abundance of deuterium (i.e., at least 90% incorporation of deuterium). In some embodiments, the abundance of deuterium at each designated deuterium atom is at least 6333.3 times greater than the natural abundance of deuterium (i.e., at least 95% incorporation of deuterium). In some embodiments, the abundance of deuterium at each designated deuterium atom is at least 6466.7 times greater than the natural abundance of deuterium (i.e., at least 97% incorporation of deuterium). In some embodiments, the abundance of deuterium at each designated deuterium atom is at least 6600 times greater than the natural abundance of deuterium (i.e., at least 99% incorporation of deuterium). In some embodiments, the abundance of deuterium at each designated deuterium atom is at least 6633.3 times greater than the natural abundance of deuterium (i.e., at least 99.5% incorporation of deuterium).

[0422] "Optionally" or "optional" means that the subsequently described event or circumstance can or can not occur, and encompasses the two instances of the event or circumstance occurring and not occurring. For example, "alkyl optionally substituted with halogen or cyano" includes the instances of alkyl being substituted with halogen or cyano and the instance of alkyl not being substituted with halogen and cyano.

[0423] "Substitution" or "substituted" refers to one or more hydrogen atoms in a group, in some embodiments 1 to 6, and in some embodiments 1 to 3 hydrogen atoms, which are independently substituted by the corresponding number of substituents. Those skilled in the art can determine possible or impossible substitutions without much effort (through experimentation or theory). For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom having an unsaturated bond (such as an alkene).

[0424] "Pharmaceutical composition" means a mixture containing one or more of the compounds described herein or their pharmaceutically acceptable salts, along with other chemical components, such as pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to a living organism, thereby promoting the absorption of the active ingredient and its biological activity.

[0425] "Pharmacologically acceptable salt" refers to the salt of the compounds disclosed herein, which may be selected from inorganic or organic salts. Such salts are safe and effective when used in mammals and possess the expected biological activity. They can be prepared separately during the final isolation and purification of the compound, or 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 both inorganic and organic acids.

[0426] For the purposes of pharmaceuticals or pharmacologically active agents, the term "therapeutic effective amount" refers to the amount of a drug or agent sufficient to achieve or at least partially achieve the intended effect. The determination of the therapeutic effective amount varies from person to person, depending on the recipient's age and general condition, as well as the specific active substance. The appropriate therapeutic effective amount in a given case can be determined by a person skilled in the art based on routine testing.

[0427] As used herein, the term "pharmaceutically acceptable" means that these compounds, materials, compositions, and / or dosage forms are suitable for contact with patient tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, within reasonable medical judgment, have a reasonable benefit / risk ratio, and are effective for their intended use.

[0428] As used herein, the singular forms of “a,” “an,” and “the” include plural references, and vice versa, unless the context clearly indicates otherwise.

[0429] When the term "about" is applied to parameters such as pH, concentration, and temperature, it indicates that the parameter can vary by ±10%, and in some embodiments within ±5%. As those skilled in the art will understand, when a parameter is not critical, figures are typically given for illustrative purposes only and not as limitations. Attached Figure Description

[0430] Figure 1 is the effect of compound 12 on tumor volume of Lu99 transplanted tumor in NUNU nude mice in Test Example 4.

[0431] Figure 2 is the effect of compound 12 on body weight of NUNU nude mice with Lu99 transplanted tumor in Test Example 4. DETAILED DESCRIPTION

[0432] The present disclosure is further described below in connection with the following examples, which are not meant to limit the scope of the present disclosure.

[0433] EXAMPLES

[0434] The structure of the compound is determined by nuclear magnetic resonance (NMR) or / and mass spectrometry (MS). The NMR shift (δ) is given in units of 10 -6 (ppm). The NMR is determined by using a Bruker AVANCE NEO 500M NMR spectrometer, and the determination solvent is deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), deuterated methanol (CD3OD), and the internal standard is tetramethylsilane (TMS).

[0435] The MS is determined by using Agilent 1200 / 1290 DAD-6110 / 6120 Quadrupole MS liquid chromatography-mass spectrometer (manufacturer: Agilent, MS model: 6110 / 6120 Quadrupole MS); waters ACQuity UPLC-QD / SQD (manufacturer: waters, MS model: waters ACQuity Qda Detector / waters SQ Detector); THERMO Ultimate 3000-Q Exactive (manufacturer: THERMO, MS model: THERMO Q Exactive).

[0436] The high performance liquid chromatography (HPLC) analysis uses Agilent HPLC 1200 DAD, Agilent HPLC 1200 VWD, and Waters HPLC e2695-2489 high performance liquid chromatograph.

[0437] The chiral HPLC analysis determination uses Agilent 1260 DAD high performance liquid chromatograph.

[0438] The high performance liquid preparation uses Waters 2545-2767, Waters 2767-SQ Detecor2, Shimadzu LC-20AP, and Gilson GX-281 preparative chromatograph.

[0439] Chiral prep used Shimadzu LC-20AP preparative chromatograph.

[0440] CombiFlash rapid preparation instrument used Combiflash Rf200 (TELEDYNE ISCO).

[0441] Thin layer chromatography silica gel plate used Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate, the specification of silica gel plate used in thin layer chromatography (TLC) was 0.15mm-0.2mm, the specification of product used in thin layer chromatography separation and purification was 0.4mm-0.5mm.

[0442] Silica gel column chromatography generally used Yantai Huanghai silica gel 200-300 mesh silica gel as carrier.

[0443] Determination of average inhibition rate and IC 50 of kinase used NovoStar microplate reader (Germany BMG company).

[0444] Known starting materials of the present disclosure can be synthesized according to methods known in the art or purchased from ABCR GmbH&Co.KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, Daejung Chemicals and the like.

[0445] Unless otherwise specified in the examples, the reactions were carried out under argon or nitrogen atmosphere.

[0446] Argon or nitrogen atmosphere refers to that the reaction bottle is connected to an argon or nitrogen balloon with a volume of about 1L.

[0447] Hydrogen atmosphere refers to that the reaction bottle is connected to a hydrogen balloon with a volume of about 1L.

[0448] Pressurized hydrogenation reaction used Parr 3916EKX type hydrogenation instrument and Qinglan QL-500 type hydrogen generator or HC2-SS type hydrogenation instrument.

[0449] Hydrogenation reaction was usually vacuumed, filled with hydrogen, and repeated for 3 times.

[0450] Microwave reaction used CEM Discover-S 908860 type microwave reactor.

[0451] Unless otherwise specified in the examples, solution refers to aqueous solution.

[0452] Unless otherwise specified in the examples, the temperature of the reaction was room temperature.

[0453] The reaction process in the examples was monitored using thin-layer chromatography (TLC). The developing solvent used in the reaction, the eluent system for column chromatography used to purify the compounds, and the developing solvent system for TLC included: A: dichloromethane / methanol system, B: n-hexane / ethyl acetate. The volume ratio of the solvent was adjusted according to the polarity of the compounds, and small amounts of basic or acidic reagents such as triethylamine and acetic acid could also be added for adjustment.

[0454] Example 1

[0455] (S)-1-((2-((5-amino-6-fluoro-1H-pyrrolo[3,2-b]pyridin-2-yl)methyl)-5-fluoro-2',3-dioxospiro[isoindoline-1,3'-pyrrolidin]-1'-yl)methyl)cyclopropane-1-carboxylon

[0456] first step

[0457] (S)-(2-((1'-((1-cyanocyclopropyl)methyl)-5-fluoro-2',3-dioxospiro[isoindoline-1,3'-pyrrolidine]-2-yl)methyl)-6-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-b]pyridin-5-yl)tert-butyl carbamate 1b

[0458] Methyl (S)-2-((5-((tert-butoxycarbonyl)amino)-6-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-b]pyridin-2-yl)methyl)-5-fluoro-3-oxo-1-(2-oxoethyl)isoindoline-1-carboxylic acid methyl ester 1a (30 mg, 46 μmol), was prepared using the Intermediate method described on page 66 of the specification in patent application "WO2023036974". The compound was prepared by the method disclosed in BS. 1-(aminomethyl)cyclopropylformonitrile hydrochloride (9 mg, 68 μmol, Shanghai Titan) was dissolved in 1,2-dichloroethane (2 mL), triethylamine (7 mg, 69 μmol) was added, and the mixture was stirred for 30 minutes. Then, sodium triacetoxyborohydride (20 mg, 94 μmol) was added, and the mixture was stirred for 16 hours. The reaction solution was diluted with dichloromethane and washed successively with saturated sodium bicarbonate solution and saturated sodium chloride solution. The organic phase was separated, dried with anhydrous sodium sulfate, filtered to remove the desiccant, and concentrated under reduced pressure to obtain the crude title compound 1b (27 mg). The product was used directly in the next reaction without purification.

[0459] MS m / z(ESI): 693.7 [M+1].

[0460] Second step (S)-1-((2-((5-amino-6-fluoro-1H-pyrrolo[3,2-b]pyridin-2-yl)methyl)-5-fluoro- 2',3-dioxospiro[isoindoline-1,3'-pyrrolidin]-1'-yl)methyl)cyclopropane-1-carbonitrile 1

[0461] The crude compound 1b (27 mg, 39 μmol) was dissolved in dichloromethane (3 mL), trifluoroacetic acid (3 mL) was added, the reaction was stirred for 1 h, the reaction solution was concentrated under reduced pressure, the residue was dissolved in acetonitrile (2 mL), ammonia water (0.5 mL) was added, the reaction was stirred at 40 °C for 2 h, then it was cooled to room temperature and stirred for 16 h, the reaction solution was concentrated under reduced pressure, the residue was purified by high performance liquid preparative chromatography (Waters-2545, column: Welch Xtimate C18, 30 x 150 mm, 5 μm; mobile phase: water phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 40%-60%, flow rate: 30 mL / min) to give the title compound 1 (2.4 mg, yield: 18%).

[0462] MS m / z (ESI): 463.5 [M+1].

[0463] 1 H NMR (500 MHz, DMSO-d6): δ 10.70 (s, 1H), 7.66-7.59 (m, 2H), 7.55-7.50 (m, 1H), 7.35 (d, 1H), 6.15 (d, 1H), 5.61 (s, 1H), 5.50 (d, 1H), 5.41 (q, 1H), 5.33-5.31 (m, 1H), 5.15-5.04 (m, 1H), 4.40 (dd, 1H), 3.92-3.87 (m, 1H), 3.66-3.58 (m, 1H), 3.57-3.47 (m, 1H), 2.02-1.96 (m, 2H), 1.48-1.44 (m, 1H), 1.15-1.00 (m, 2H).

[0464] Example 2

[0465] (S)-1-((2-((5-amino-6-fluoro-1H-pyrrolo[3,2-b]pyridin-2-yl)methyl)-5-fluoro- 2',3-dioxospiro[isoindoline-1,3'-pyrrolidin]-1'-yl)methyl)cyclobutane-1-carbonitrile 2

[0466] First step

[0467] 1-(azidomethyl)cyclobutane-1-carbonitrile 2b

[0468] Dissolve (1-cyanocyclobutyl)methyl methanesulfonate 2a (340 mg, 1.79 mmol) in N,N-dimethylformamide (3 mL), add sodium azide (116 mg, 1.78 mmol), stir the reaction at 120 °C for 16 h, after the reaction is cooled to room temperature, dilute with ethyl acetate, wash with water (30 mL x 3), separate the organic phase, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain the crude title compound 2b (230 mg). The product is used directly in the next reaction without purification.

[0469] Second step

[0470] 1-(aminomethyl)cyclobutane-1-carbonitrile 2c

[0471] Dissolve the crude compound 2b (230 mg, 1.69 mmol) in methanol (5 mL), add 10% palladium-carbon (200 mg), replace with hydrogen, stir the reaction for 16 h, filter the reaction, and concentrate the filtrate under reduced pressure to obtain the crude title compound 2c (120 mg). The product is used directly in the next reaction without purification.

[0472] Third step

[0473] (S)-(2-((1'-((1-cyanocyclobutyl)methyl)-5-fluoro-2',3-dioxospiro[isoindoline-1,3'-pyrrolidin]-2-yl)methyl)-6-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-b]pyridin-5-yl)carbamic acid tert-butyl ester 2d

[0474] Dissolve compound 1a (30 mg, 46 µmol) and the crude compound 2c (10 mg, 91 µmol) in 1,2-dichloroethane (2 mL), add sodium triacetoxyborohydride (17 mg, 80 µmol) and sodium cyanoborohydride (5 mg, 80 µmol), stir the reaction for 16 h, dilute the reaction with dichloromethane, wash sequentially with saturated sodium bicarbonate solution and saturated sodium chloride solution, separate the organic phase, dry over anhydrous sodium sulfate, remove the drying agent by filtration, and concentrate the filtrate under reduced pressure to obtain the crude title compound 2d (32 mg). The product is used directly in the next reaction without purification.

[0475] MS m / z (ESI): 707.4 [M+1].

[0476] Fourth step

[0477] (S)-1-((2-((5-amino-6-fluoro-1H-pyrrolo[3,2-b]pyridin-2-yl)methyl)-5-fluoro-2',3-dioxospiro[isoindoline-1,3'-pyrrolidin]-1'-yl)methyl)cyclobutane-1-carbonitrile 2

[0478] The crude compound 2d (32 mg, 45 μmol) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (0.5 mL) was added, the reaction was stirred for 1 h, the reaction solution was concentrated under reduced pressure, the residue was dissolved in acetonitrile (2 mL), ammonia water (0.5 mL) was added, the reaction was carried out at 40 °C for 2 h, the reaction solution was concentrated under reduced pressure after being reduced to room temperature, and the residue was purified by high performance liquid preparative chromatography (Waters-2545, column: Welch Xtimate C18, 30 x 150 mm, 5 μm; mobile phase: water phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 35%-60%, flow rate: 30 mL / min) to obtain the title compound 2 (2 mg, yield: 10.5%).

[0479] MS m / z (ESI): 477.5 [M+1].

[0480] 1 H NMR (500 MHz, DMSO-d6) δ 10.68 (s, 1H), 7.63-7.57 (m, 2H), 7.52 (t, 1H), 7.35 (d, 1H), 6.11 (s, 1H), 5.50 (s, 2H), 5.03 (d, 1H), 4.27 (d, 1H), 3.88-3.77 (m, 2H), 3.64-3.56 (m, 2H), 2.45-2.37 (m, 2H), 2.31-2.25 (m, 1H), 2.23-2.17 (m, 1H), 2.13-2.06 (m, 1H), 2.01-1.95 (m, 1H).

[0481] Example 3

[0482] (S)-2-((5-amino-6-fluoro-1H-pyrrolo[3,2-b]pyridin-2-yl)methyl)-1'-(cyclobutylmethyl)-5-fluorospiro[isoindoline-1,3'-pyrrolidine]-2',3-dione 3

[0483] The title compound 3 (8 mg, yield: 46.1%) was prepared by using the synthetic route in Example 2, third step to fourth step, and replacing the third step raw material compound 2c with cyclobutylmethylamine (Shanghai Bide).

[0484] MS m / z (ESI): 452.4 [M+1].

[0485] 1H NMR (500 MHz, DMSO-d6) δ 10.70 (s, 1H), 7.61 - 7.55 (m, 2H), 7.52 (td, 1H), 7.37 (d, 1H), 6.09 (s, 1H), 5.51 (s, 2H), 5.02 (d, 1H), 4.22 (d, 1H), 3.72 (q, 1H), 3.42 (dq, 2H), 3.23 (dd, 1H), 2.40 - 2.29 (m, 2H), 2.11 - 1.97 (m, 3H), 1.93 - 1.80 (m, 2H), 1.74 (q, 1H), 1.65 (p, 1H).

[0486] Example 4

[0487] (S)-3-(2-((5-amino-6-fluoro-lH-pyrrolo[3,2-b]pyridin-2-yl)methyl)-5-fluoro-2',3- dioxospiro[isoindoline-l,3'-pyrrolidin]-l'-yl)-2,2-dimethylpropanenitrile 4

[0488] The title compound 4 (2.2 mg, yield: 10.9%) was prepared by using the synthetic route in Example 2, third to fourth steps, replacing the third step starting material compound 2c with 3-amino-2,2-dimethylpropanenitrile (Shanghai Leyen).

[0489] MS m / z (ESI): 465.4 [M+1].

[0490] 1 H NMR (500 MHz, DMSO-d6): δ 11.37 (s, 1H), 7.81 (s, 1H), 7.68 (dd, 1H), 7.61 - 7.51 (m, 2H), 7.18 (d, 1H), 6.98 (s, 2H), 6.64 (s, 1H), 6.26 (s, 1H), 5.31 (t, 1H), 4.95 (d, 1H), 4.44 (dd, 1H), 4.04 (dt, 1H), 2.00 (t, 2H), 1.32 (s, 3H), 1.27 (s, 3H).

[0491] Example 5

[0492] (S)-3-((2-((5-amino-6-fluoro-lH-pyrrolo[3,2-b]pyridin-2-yl)methyl)-5-fluoro-2',3- dioxospiro[isoindoline-l,3'-pyrrolidin]-l'-yl)methyl)cyclobutan-l-carbonitrile 5

[0493] (1R,3s)-3-(((S)-2-((5-amino-6-fluoro-1H-pyrrolo[3,2-b]pyridin-2-yl)methyl)-5-fluoro- 2',3-dioxospiro[isoindoline-1,3'-pyrrolidin]-1'-yl)methyl)cyclobutane-1-carbonitrile 5-p1

[0494] (1R,3r)-3-(((S)-2-((5-amino-6-fluoro-1H-pyrrolo[3,2-b]pyridin-2-yl)methyl)-5-fluoro- 2',3-dioxospiro[isoindoline-1,3'-pyrrolidin]-1'-yl)methyl)cyclobutane-1-carbonitrile 5-p2

[0495] Using the synthetic route in Example 2, third to fourth steps, replacing the third step starting material compound 2c with 3-(aminomethyl)cyclobutane-1-carbonitrile (prepared using the method disclosed in the description of patent application “WO2018141842” on page 60, Intermediate 27), the crude title compound 5 (20 mg) was prepared and purified by high performance liquid preparative chromatography (Waters-2545, column: Welch Xtimate C18, 30 x 150 mm, 5 μm; mobile phase: water phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 35% - 60%, flow rate: 30 mL / min) to give the title compound (2.9 mg, yield: 14.3%), (2.8 mg, yield: 13.8%).

[0496] Compound 5:

[0497] MS m / z (ESI): 477.4 [M+1].

[0498] Single configuration compound (shorter retention time): (2.9 mg, yield: 14.3%).

[0499] MS m / z (ESI): 477.4 [M+1].

[0500] HPLC analysis: retention time 1.00 min, purity: 99% (column: ACQUITY C18, 1.7 μm, 2.1 x 50 mm; mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10% - 95%).

[0501] 1H NMR (500 MHz, CD3OD): δ 7.58-7.53 (m, 2H), 7.45-7.40 (m, 2H), 6.28 (s, 1H), 5.02-4.88 (m, 2H), 4.72-4.68 (m, 2H), 3.82-3.77 (m, 1H), 3.59-3.57 (m, 1H), 3.19-3.14 (m, 1H), 2.68-2.61 (m, 1H), 2.54-2.42 (m, 4H), 2.23-2.20 (m, 1H), 2.13-2.05 (m, 3H).

[0502] Single configuration compound (longer retention time): (2.8 mg, yield: 13.8%).

[0503] MS m / z (ESI): 477.4 [M+1].

[0504] HPLC analysis: Retention time 1.01 min, purity: 98% (column: ACQUITY C18, 1.7 pm, 2.1 x 50 mm; mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10-95%).

[0505] 1 H NMR (500 MHz, CD3OD): δ 7.58-7.52 (m, 2H), 7.46-7.40 (m, 2H), 6.26 (s, 1H), 5.05-5.03 (m, 2H), 4.63-4.60 (m, 2H), 3.83-3.78 (m, 1H), 3.59-3.55 (m, 1H), 3.52-3.46 (m, 1H), 2.92-2.86 (m, 1H), 2.65-2.59 (m, 1H), 2.53-2.41 (m, 4H), 2.23-2.14 (m, 3H).

[0506] Example 6

[0507] (S)-3-((2-((5-amino-6-fluoro-lH-pyrrolo[3,2-b]pyridin-2-yl)methyl)-5-fluoro-2',3- dioxospiro[isoindoline-l,3'-pyrrolidin]-l'-yl)methyl)oxetane-3-carbonitrile 6

[0508] The title compound 6 was prepared by following the synthetic route of Example 2, first to fourth steps, replacing the first step starting material compound 2a with (3-cyanooxetan-3-yl)methyl methanesulfonate (prepared by following the procedure disclosed in Compound 31 of the specification page 97 of the patent application “WO2024112899”), in the third step, replacing the starting material compound 2c with aminoacetonitrile (Jiangsu Aikang), in the fourth step, replacing the starting material compound 3a with compound 6 (3 mg, yield: 14.8%).

[0509] MS m / z (ESI): 423.2 [M+1].

[0510] 1 H NMR (500 MHz, DMSO-d6) δ 10.71 (d, 1H), 7.66 (dd, 1H), 7.61 (dd, 1H), 7.55 (td, 1H), 7.37 (d, 1H), 6.12 (d, 1H), 5.51 (s, 2H), 5.01 (d, 1H), 4.50 (d, 2H), 4.31 (d, 1H), 3.85 (dt, 1H), 3.60 (td, 1H), 2.50 - 2.42 (m, 2H).

[0511] Example 7

[0512] (S)-2-(2-((5-amino-6-fluoro-1H-pyrrolo[3,2-b]pyridin-2-yl)methyl)-5-fluoro-2',3- dioxospiro[isoindoline-1,3'-pyrrolidin]-1'-yl)acetonitrile 7

[0513] The title compound 7 was prepared by following the synthetic route of Example 2, third to fourth steps, replacing the third step starting material compound 2c with aminoacetonitrile (Jiangsu Aikang), in the fourth step, replacing the starting material compound 3a with compound 6 (12 mg, yield: 18.5%).

[0514] MS m / z (ESI): 423.2 [M+1].

[0515] 1 H NMR (500 MHz, DMSO-d6) δ 10.71 (d, 1H), 7.66 (dd, 1H), 7.61 (dd, 1H), 7.55 (td, 1H), 7.37 (d, 1H), 6.12 (d, 1H), 5.51 (s, 2H), 5.01 (d, 1H), 4.50 (d, 2H), 4.31 (d, 1H), 3.85 (dt, 1H), 3.60 (td, 1H), 2.50 - 2.42 (m, 2H).

[0516] Example 8

[0517] (S)-2-((5-amino-6-fluoro-lH-pyrrolo[3,2-b]pyridin-2-yl)methyl)-l'-(bicyclo[l. l. l]pentan- 1 -ylmethyl)-5-fluorospiro[isoindoline-l,3'-pyrrolidine]-2',3-dione 8

[0518] The title compound 8 (5 mg, yield: 28.5%) was prepared by using the synthetic route in Example 2, third to fourth steps, replacing the third step starting material compound 2c with bicyclo[l. l. l]pentan-l -ylmethanamine hydrochloride (Eijison, Jiangsu).

[0519] MS m / z (ESI): 464.5 [M+l].

[0520] 1 H NMR (500 MHz, DMSO-d6): δ 10.70 (s, 1H), 7.65 (dd, 1H), 7.59 (dd, 1H), 7.55 (td, 1H), 7.37 (d, 1H), 6.09 (d, 1H), 5.51 (s, 2H), 5.04 (d, 1H), 4.21 (d, 1H), 3.84 (dt, 1H), 3.50 (td, 1H), 3.44 (d, 1H), 3.21 (d, 1H), 2.65 (p, 1H), 2.41 - 2.33 (m, 3H), 2.06 - 1.96 (m, 3H), 1.47 (q, 2H).

[0521] Example 9

[0522] (S)-2-((5-amino-6-fluoro-lH-pyrrolo[3,2-b]pyridin-2-yl)methyl)-5-fluoro-l'-((l-(prop- l-yn-l-yl)cyclopropyl)methyl)spiro[isoindoline-l,3'-pyrrolidine]-2',3-dione 9

[0523] First step

[0524] 1 -(azidomethyl)- 1 -(prop- 1 -yn- 1 -yl)cyclopropane 9b

[0525] (1-(prop-1-yn-1-yl)cyclopropyl)methyl methanesulfonate 9a (200 mg, 1.06 mmol, prepared by the method disclosed in Example 109 of the specification of patent application "EP2017275") was dissolved in N,N-dimethylformamide (3 mL), sodium azide (76 mg, 1.17 mmol) was added, the reaction was stirred at 90 °C for 16 hours, after the reaction was cooled to room temperature, diluted with ethyl acetate, washed with water (30 mL x 3), the organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude title compound 9b (100 mg). The product was used directly in the next reaction without purification.

[0526] Second step

[0527] (1-(prop-1-yn-1-yl)cyclopropyl)methyl methanesulfonate 9a (200 mg, 1.06 mmol, prepared by the method disclosed in Example 109 of the specification of patent application "EP2017275") was dissolved in N,N-dimethylformamide (3 mL), sodium azide (76 mg, 1.17 mmol) was added, the reaction was stirred at 90 °C for 16 hours, after the reaction was cooled to room temperature, diluted with ethyl acetate, washed with water (30 mL x 3), the organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude title compound 9b (100 mg). The product was used directly in the next reaction without purification.

[0528] MS m / z (ESI): 110.1 [M+1].

[0529] MS m / z (ESI): 110.1 [M+1].

[0530] Third step

[0531] (S)-(6-fluoro-2-((5-fluoro-2',3-dioxo-1'-((1-(prop-1-yn-1-yl)cyclopropyl)methyl)spiro[isoindoline-1,3'-pyrrolidin]-2-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-b]pyridin-5-yl)carbamic acid tert-butyl ester 9d

[0532] Compound 1a (30 mg, 46 μmol), crude compound 9c (200 mg, 183 μmol) were dissolved in 1,2-dichloroethane (15 mL), sodium cyanoborohydride (6 mg, 100 μmol), sodium methoxide (3 mg, 55 μmol) were added, the reaction was stirred at 50 °C for 3 hours, after the reaction was cooled to room temperature, concentrated under reduced pressure, the residue was purified by silica gel column chromatography with eluent system A to obtain the title compound 9d (20 mg, yield: 60.9%).

[0533] MS m / z (ESI): 706.6 [M+1].

[0534] Fourth step

[0535] (S)-2-((5-amino-6-fluoro-1H-pyrrolo[3,2-b]pyridin-2-yl)methyl)-5-fluoro-1'-((1-(prop-1-yn-1-yl)cyclopropyl)methyl)spiro[isoindoline-1,3'-pyrrolidin]-2',3-dione 9

[0536] Compound 9d (20 mg, 28 μmol) was dissolved in dichloromethane (3 mL), trifluoroacetic acid (1 mL) was added, the reaction was stirred for 1 h, and the reaction solution was concentrated under reduced pressure. The residue was dissolved in acetonitrile (5 mL), ammonia water (1 mL) was added, and the reaction was carried out at 40 °C for 2 h. After the reaction solution was cooled to room temperature, it was concentrated under reduced pressure, and the residue was purified by high performance liquid preparative chromatography (Waters-2545, column: Welch Xtimate C18, 30 x 150 mm, 5 μm; mobile phase: aqueous phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 35%-60%, flow rate: 30 mL / min) to give the title compound 9 (3.5 mg, yield: 26.7%).

[0537] MS m / z (ESI): 476.0 [M+1].

[0538] 1 H NMR (500 MHz, CD3OD): δ 7.68-7.66 (m, 1H), 7.59-7.57 (m, 1H), 7.48-7.44 (m, 1H), 7.41 (d, 1H), 6.30 (s, 1H), 5.17 (d, 1H), 4.53 (d, 1H), 4.05-4.00 (m, 1H), 3.79-3.74 (m, 1H), 3.56 (d, 1H), 3.07 (d, 1H), 2.62-2.56 (m, 1H), 2.48-2.43 (m, 1H), 2.22 (t, 1H), 2.07-2.03 (m, 1H), 1.72 (s, 3H), 1.64-1.59 (m, 1H), 0.96-0.91 (m, 2H), 0.87-0.77 (m, 2H).

[0539] Example 10

[0540] 1-((2-((5-amino-6-fluoro-1H-pyrrolo[3,2-b]pyridin-2-yl)methyl)-2',3-dioxo-5- (trifluoromethyl)spiro[isoindoline-1,3'-pyrrolidin]-1'-yl)methyl)cyclopropane-1- carbonitrile 10

[0541] First step

[0542] Methyl 2-(cyanomethyl)-5-(trifluoromethyl)benzoate 10b

[0543] Methyl 2-(bromomethyl)-5-(trifluoromethyl)benzoate 10a (4.7 g, 15.82 mmol), prepared using the method disclosed in Example 103 of the specification of patent application “WO2023244815”, was dissolved in acetonitrile (100 mL), potassium carbonate (4.37 g, 31.64 mmol), trimethylsilyl cyanide (3.13 g, 31.64 mmol) were added, the reaction was stirred at 80 °C for 16 h, after the reaction was cooled to room temperature, it was concentrated under reduced pressure, the residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 10b (1 g, yield: 26%).

[0544] MS m / z (ESI): 242.1 [M-1].

[0545] Second step

[0546] Methyl 2-(2-methoxy-2-oxoethyl)-5-(trifluoromethyl)benzoate 10c

[0547] Compound 10b (1 g, 4.11 mmol) was dissolved in methanol (6 mL), concentrated sulfuric acid (403 mg, 4.11 mmol) was added, the reaction was stirred at 80 °C for 5 days, after the reaction was cooled to room temperature, it was concentrated under reduced pressure, ice water was added to the residue, the pH was adjusted to >7 with ammonia water, the organic phase was extracted with ethyl acetate (20 mL x 3), the combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude title compound 10c (1.2 g), which was used directly in the next step without purification.

[0548] MS m / z (ESI): 277.1 [M+1].

[0549] Third step

[0550] Methyl 2-(1-bromo-2-methoxy-2-oxoethyl)-5-(trifluoromethyl)benzoate 10d

[0551] The crude compound 10c (1.2 g, 4.34 mmol) was dissolved in acetonitrile (10 mL), N-bromosuccinimide (1.5 g, 8.42 mmol), azobisisobutyronitrile (210 mg, 1.28 mmol) were added, the reaction was stirred at 80 °C for 16 h, after the reaction was cooled to room temperature, it was concentrated under reduced pressure, the residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 10d (630 mg, yield: 40.8%).

[0552] Fourth step

[0553] Methyl 2-(4-methoxybenzyl)-3-oxo-5-(trifluoromethyl)isoindoline-1-carboxylate 10e

[0554] Compound 10d (630 mg, 1.77 mmol) was dissolved in acetonitrile (25 mL), 4-methoxybenzylamine (250 mg, 1.82 mmol, Shanghai Aoyuan), sodium bicarbonate (299 mg, 3.56 mmol) were added, the reaction was stirred at 80 °C for 6 hours, after the reaction solution was cooled to room temperature, it was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude title compound 10e (650 mg), which was used directly in the next step without purification.

[0555] MS m / z (ESI): 380.2 [M+1].

[0556] Fifth step

[0557] Methyl 1-allyl-2-(4-methoxybenzyl)-3-oxo-5-(trifluoromethyl)isoindoline-1-carboxylate 10f

[0558] Compound 10e (650 mg, 1.71 mmol) was dissolved in N,N-dimethylformamide (30 mL), 3-bromopropene (621 mg, 5.13 mmol, Shanghai Titan), cesium carbonate (1.67 g, 5.12 mmol) were added, the reaction was stirred at 80 °C for 16 hours, after the reaction solution was cooled to room temperature, it was filtered, and 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 10f (300 mg, yield: 45.9%).

[0559] MS m / z (ESI): 420.3 [M+1].

[0560] Sixth step

[0561] Methyl 1-allyl-3-oxo-5-(trifluoromethyl)isoindoline-1-carboxylate 10g

[0562] Compound 10f (150 mg, 357 μmol) was dissolved in acetonitrile (10 mL) and water (5 mL), cerium ammonium nitrate (490 mg, 894 μmol, Shanghai Titan) was added, the reaction was stirred for 16 hours, water was added to the reaction solution, which was extracted with ethyl acetate (10 mL x 3), the combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system A to obtain the title compound 10g (90 mg, yield: 84%).

[0563] MS m / z (ESI): 300.2 [M+1].

[0564] Seventh step

[0565] 5-((tert-butoxycarbonyl)amino)-6-fluoro-l-((2-(trimethylsilyl)ethoxy)methyl)-lH- pyrrolo [3, 2-b] pyridine-2-carboxylic acid methyl ester 10i

[0566] Methyl 5-chloro-6-fluoro-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrrolo[3,2- b]pyridine-2-carboxylate 10h (31 g, 264.6 mmol, prepared using the method disclosed in the specification of patent application “WO2023036974” on page 55, Intermediate AV) was added to 1,4-dioxane (400 mL), followed by the addition of tert-butyl carbamate (31 g, 264.6 mmol), cesium carbonate (56.3 g, 172.8 mmol), 2-(dicyclohexylphosphino)3,6-dimethoxy-2',4',6'-triisopropyl-l,l'- biphenyl (10 g, 18.6 mmol), (2-dicyclohexylphosphino)-3,6-dimethoxy-2',4',6'- triisopropyl-l,l'-biphenyl)methanone (2'-amino-l,l'-biphenyl-2-yl)palladium(II) (8 g, 8.8 mmol), and the reaction was stirred at 80 °C for 2 h under nitrogen atmosphere. After the reaction solution was cooled to room temperature, it was filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed with saturated sodium chloride solution, and the organic phase was collected and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system B to obtain the title compound 10i (31.5 g, yield: 71.7%).

[0567] MS m / z (ESI): 440.2 [M+1].

[0568] Eighth step

[0569] tert-Butyl (6-fluoro-2-(hydroxymethyl)-l-((2-(trimethylsilyl)ethoxy)methyl)-lH- pyrrolo [3, 2-b] pyridin-5-yl)carbamate 10j

[0570] Compound 10i (29 g, 66.0 mmol) was dissolved in dichloromethane (300 mL), and the solution was cooled to 0 °C. Then, 1 M diisobutylaluminum hydride in n-hexane (268 mL) was slowly added. The reaction was stirred for 30 min at the same temperature. The reaction solution was quenched by slowly adding 2 M aqueous sodium hydroxide solution, and extracted with ethyl acetate (100 mL x 3). The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system B to obtain the title compound 10j (14 g, yield: 51.5%).

[0571] MS m / z (ESI): 440.2 [M+1].

[0572] Ninth step

[0573] tert-Butyl (2-(chloromethyl)-6-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H- pyrrolo[3,2-b]pyridin-5-yl)carbamate 10k

[0574] Compound 10j (14 g, 34.0 mmol) was dissolved in dichloromethane (200 mL), cooled to 0 °C, and sulfuric chloride (11.3 g, 95.2 mmol) was added dropwise slowly, keeping the temperature. The reaction was quenched by adding saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate (50 mL x 3), the organic phase was combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to give the title compound 10k (8.5 g, yield: 58.1%).

[0575] MS m / z (ESI): 430.2 [M+1].

[0576] Tenth step

[0577] Methyl 1-allyl-2-((5-((tert-butoxycarbonyl)amino)-6-fluoro-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-b]pyridin-2-yl)methyl)-3-oxo-5- (trifluoromethyl)isoindoline-1-carboxylate 10l

[0578] Compound 10g (90 mg, 301 μmol), compound 10k (150 mg, 349 μmol) were dissolved in N,N-dimethylformamide (30 mL), sodium iodide (10 mg, 67 μmol), cesium carbonate (196 mg, 602 μmol) were added, and the reaction was stirred at 70 °C for 3 hours. After the reaction was cooled to room temperature, it was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to give the title compound 10l (48 mg, yield: 23%).

[0579] MS m / z (ESI): 693.5 [M+1].

[0580] Eleventh step

[0581] Methyl 2-((5-((tert-butoxycarbonyl)amino)-6-fluoro-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-b]pyridin-2-yl)methyl)-3-oxo-1-(2- oxoethyl)-5-(trifluoromethyl)isoindoline-1-carboxylate 10m

[0582] Compound 10l (48 mg, 69 μmol) was dissolved in 1,4-dioxane (5 mL) and water (2 mL), potassium osmate dihydrate (0.3 mg, 0.8 μmol, Shanghai Titan), sodium periodate (46 mg, 215 μmol), 2,6-dimethylpyridine (15 mg, 140 μmol) were added, and the reaction was stirred for 16 hours. Water was added to the reaction solution, and dichloromethane (5 mL x 3) was used to extract the organic phase. The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system B to obtain the title compound 10m (20 mg, yield: 41.5%).

[0583] MS m / z (ESI): 695.5 [M+1].

[0584] Twelfth step

[0585] (2-((1'-((1-cyanocyclopropyl)methyl)-2',3-dioxo-5-(trifluoromethyl)spiro[isoindoline-1,3'-pyrrolidin]-2-yl)methyl)-6-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-b]pyridin-5-yl)carbamic acid tert-butyl ester 10n

[0586] Compound 10m (20 mg, 29 μmol), 1-(aminomethyl)cyclopropylcarbonitrile hydrochloride (12 mg, 91 μmol) were dissolved in 1,2-dichloroethane (5 mL), and after stirring for 30 minutes, sodium cyanoborohydride (7 mg, 69 μmol) was added. After stirring for 16 hours, sodium methoxide (5 mg, 92 μmol) was added, and the reaction was stirred at 50°C for 3 hours. After the reaction solution was cooled to room temperature, it was concentrated under reduced pressure. Dichloromethane / methanol (V:V=10:1) (15 mL) was added to the residue, and after stirring for 10 minutes, it was filtered. The filtrate was concentrated under reduced pressure to obtain the crude title compound 10n (20 mg). The product was used directly in the next reaction without purification.

[0587] MS m / z (ESI): 743.3 [M+1].

[0588] Thirteenth step

[0589] 1-((2-((5-amino-6-fluoro-1H-pyrrolo[3,2-b]pyridin-2-yl)methyl)-2',3-dioxo-5-(trifluoromethyl)spiro[isoindoline-1,3'-pyrrolidin]-1'-yl)methyl)cyclopropane-1-carbonitrile 10

[0590] The crude compound 10n (20 mg, 27 μmol) was dissolved in dichloromethane (3 mL), trifluoroacetic acid (1 mL) was added, the reaction was stirred for 1 h, the reaction solution was concentrated under reduced pressure, the residue was dissolved in acetonitrile (3 mL), ammonia water (1 mL) was added, and the reaction was carried out at 50 °C for 2 h. After the reaction solution was cooled to room temperature, it was concentrated under reduced pressure, and the residue was purified by high performance liquid preparative chromatography (Waters-2545, column: Welch Xtimate C18, 30 x 150 mm, 5 μm; mobile phase: aqueous phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 35%-60%, flow rate: 30 mL / min) to obtain the title compound 10 (5.6 mg, yield: 40.5%).

[0591] MS m / z (ESI): 512.9 [M+1].

[0592] 1 H NMR (500 MHz, CDCl3): δ 9.16 (s, 1H), 8.22-8.19 (m, 1H), 7.90 (d, 1H), 7.63 (d, 1H), 6.36 (s, 1H), 5.06 (d, 1H), 4.47 (d, 1H), 4.44 (s, 2H), 4.17-4.12 (m, 1H), 3.90-3.85 (m, 1H), 3.60 (d, 1H), 3.42 (d, 1H), 2.86-2.79 (m, 1H), 2.51-2.46 (m, 1H), 2.26-2.23 (m, 1H), 1.43-1.39 (m, 2H), 1.16-1.08 (m, 2H).

[0593] Example 11

[0594] (S)-2-((5-amino-6-fluoro-1H-pyrrolo[3,2-b]pyridin-2-yl)methyl)-1'-((1- ethynylcyclopropyl)methyl)-5-fluorospiro[isoindoline-1,3'-pyrrolidine]-2',3-dione 11

[0595] First step

[0596] tert-Butyl (tert-butoxycarbonyl)((1-ethynylcyclopropyl)methyl)carbamate 11b

[0597] Compound 11b (530 mg, yield: 31.3%) was obtained by dissolving (1-ethynylcyclopropyl)methanol 11a (550 mg, 5.72 mmol, Nanjing Yaoke) and bis(tert-butoxycarbonyl)amine (1.5 g, 6.90 mmol, Shanghai Shaoyuan), triphenylphosphine (1.81 g, 6.91 mmol) in tetrahydrofuran (20 mL), adding diisopropyl azodicarboxylate (1.39 g, 6.87 mmol) in an ice bath, and stirring the reaction at room temperature for 16 hours. The reaction solution 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 (530 mg, yield: 31.3%).

[0598] Second step

[0599] (1-ethynylcyclopropyl)methanamine hydrochloride 11c

[0600] Compound 11b (300 mg, 1.01 mmol) was dissolved in dichloromethane (3 mL), 4M hydrogen chloride solution in 1,4-dioxane (1.5 mL) was added, and the reaction was stirred for 2 hours. The reaction solution was concentrated under reduced pressure to obtain the crude title compound 11c (133 mg). The product was used directly in the next step without purification.

[0601] Third step

[0602] (S)-2-((5-amino-6-fluoro-1H-pyrrolo[3,2-b]pyridin-2-yl)methyl)-1'-((1-ethynylcyclopropyl)methyl)-5-fluorospiro[isoindoline-1,3'-pyrrolidin]-2',3-dione 11

[0603] The title compound 11 (15.4 mg, yield: 14.6%) was prepared by replacing the third step raw material compound 9c with compound 11c in the third to fourth steps of the synthetic route in Example 9.

[0604] MS m / z (ESI): 462.0 [M+1].

[0605] 1 H NMR (500 MHz, CDCl3): δ 9.43 (s, 1H), 7.56 (dd, 1H), 7.47 (dd, 1H), 6.46-6.27 (m, 1H), 5.37 (t, 1H), 5.05 (d, 1H), 4.60 (s, 2H), 4.42 (d, 1H), 4.06 (dt, 1H), 3.90 (td, 1H), 3.53 (d, 1H), 3.39 (d, 1H), 2.76-2.70 (m, 1H), 2.41-2.36 (m, 1H), 2.30-2.19 (m, 1H), 2.06-2.03 (m, 1H), 1.21-1.05 (m, 2H), 1.01-0.81 (m, 2H).

[0606] Example 12

[0607] (S)-2-((5-amino-6-fluoro-lH-pyrrolo[3,2-b]pyridin-2-yl)methyl)-5-fluoro-l'-((l- fluorocyclopropyl)methyl)spiro[isoindoline-l,3'-pyrrolidine]-2',3-dione 12

[0608] First Step

[0609] (S)-(6-fluoro-2-((5-fluoro-l'-((l-fluorocyclopropyl)methyl)-2',3-dioxospiro[isoindoline- 1,3'-pyrrolidine]-2-yl)methyl)-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrrolo[3,2- b]pyridin-5-yl)carbamic acid tert-butyl ester 12a

[0610] Methyl (S)-2-((5-((tert-butoxycarbonyl)amino)-6-fluoro-l-((2- (trimethylsilyl)ethoxy)methyl)-lH-pyrrolo[3,2-b]pyridin-2-yl)methyl)-5-fluoro-3-oxo- 1-(2-oxoethyl)isoindoline-1-carboxylate la (1.0 g, 1.6 mmol, prepared using the method disclosed in the specification of patent application "WO2023036974" on page 66, Intermediate BS), 1-(aminomethyl)cyclopropyl fluoride hydrochloride (255 mg, 2.0 mmol, Shanghai Titan) were dissolved in 1,2-dichloroethane (20 mL), triethylamine (315 mg, 3.1 mmol) was added, and after stirring for 30 minutes, sodium triacetoxyborohydride (660 mg, 3.1 mmol) was added, and the reaction was stirred for 16 hours. Dichloromethane was added to dilute the reaction solution, which was washed with saturated sodium bicarbonate solution and saturated sodium chloride solution in sequence, the organic phase was separated, dried over anhydrous sodium sulfate, filtered to remove the drying agent, and then concentrated under reduced pressure to obtain the crude title compound 12a (950 mg). The product was used directly in the next step without purification.

[0611] MS m / z (ESI): 686.7 [M+1].

[0612] Second Step

[0613] (S)-2-((5-amino-6-fluoro-lH-pyrrolo[3,2-b]pyridin-2-yl)methyl)-5-fluoro-l'-((l- fluorocyclopropyl)methyl)spiro

[0614] [isoindoline-l,3'-pyrrolidine]-2',3-dione 12

[0615] The crude compound 12a (1.2 g, 1.75 mmol) was dissolved in trifluoroacetic acid (10 mL) and stirred at room temperature for 1 h. The reaction solution was concentrated under reduced pressure, the residue was dissolved in acetonitrile (10 mL), and ammonia water (5 mL) was added. After the reaction was carried out at 40 °C for 1 h, it was stirred at room temperature for 16 h. The reaction solution was concentrated under reduced pressure, and the residue was purified by high performance liquid preparative chromatography (Waters-2545, column: Welch Xtimate C18, 30 x 150 mm, 5 μm; mobile phase: water phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 40%-60%, flow rate: 30 mL / min) to give the title compound 12 (380 mg, yield: 48%).

[0616] MS m / z (ESI): 456.4 [M+1].

[0617] 1 H NMR (500 MHz, DMSO-d6): δ 10.71 (s, 1H), 7.62-7.56 (m, 2H), 7.54 (td, 1H), 7.36 (d, 1H), 6.10 (s, 1H), 5.51 (s, 2H), 5.06 (d, 1H), 4.24 (d, 1H), 3.88 (dt, 1H), 3.86-3.79 (m, 1H), 3.64 (ddd, 1H), 3.57 (dd, 1H), 2.45-2.37 (m, 2H), 1.09 (dqt, 2H), 0.92-0.79 (m, 1H), 0.79-0.68 (m, 1H).

[0618] Example 13

[0619] (S)-2-((5-amino-6-fluoro-1H-pyrrolo[3,2-b]pyridin-2-yl)methyl)-5-fluoro-1'-(pent-3-yn-1-yl)spiro[isoindoline-1,3'-pyrrolidine]-2',3-dione 13

[0620] The title compound 13 (61 mg, yield: 58.3%) was prepared by using the synthetic route in Example 9, Step 3 to Step 4, and replacing the starting material compound 9c in Step 3 with 1-pent-3-yn-amine hydrochloride (prepared by the method disclosed in the literature "Journal of Organic Chemistry, 2004, vol. 69, #26, p. 9215-9223").

[0621] MS m / z (ESI): 450.0 [M+1].

[0622] 1H NMR (500 MHz, CDC13): δ 9.45 (s, 1H), 7.56-7.54 (m, 1H), 7.42-7.40 (m, 1H), 7.30-7.28 (m, 1H), 7.26-7.25 (m, 1H), 6.36 (s, 1H), 5.07-5.04 (d, 1H), 4.57 (br s, 2H), 4.43-4.40 (d, 1H), 3.92-3.87 (m, 1H), 3.78-3.66 (m, 2H), 3.52-3.47 (m, 1H), 2.74-2.70 (m, 1H), 2.57-2.53 (m, 2H), 2.39-2.34 (m, 1H), 1.81-1.80 (m, 3H).

[0623] Example 14

[0624] (S)-2-((5-amino-6-fluoro-lH-pyrrolo[3,2-b]pyridine-2-yl)methyl)-l'-((l- ethylcyclopropyl)methyl)-5-fluorospiro[isoindoline-l,3'-pyrrolidine]-2',3-dione 14

[0625] Using the synthetic route outlined in Example 11, replacing the first step starting material compound 11a with (l-ethylcyclopropyl)methanol (prepared using the method disclosed in the literature "Journal of Organic Chemistry, 2009, vol. 74, #22, p. 8726-8732"), the title compound 14 was prepared (22 mg, yield: 21.6%).

[0626] MS m / z (ESI): 466.4 [M+1].

[0627] 1 H NMR (500 MHz, CDC13): δ 9.31 (s, 1H), 7.58-7.55 (m, 1H), 7.30 (s, 2H), 7.26 (s, 1H), 6.34-6.29 (m, 1H), 5.43-5.33 (m, 2H), 5.05 (d, 1H), 4.41 (s, 2H), 4.34 (d, 1H), 3.83 (dt, 1H), 3.71 (dd, 1H), 3.56 (d, 1H), 3.13 (d, 1H), 2.74-2.67 (m, 1H), 2.42-2.34 (m, 1H), 0.97 (t, 3H), 0.91 (t, 2H), 0.52-0.48 (m, 2H).

[0628] Example 15

[0629] 6'-((5-amino-6-fluoro-1H-pyrrolo[3,2-b]pyridin-2-yl)methyl)-3'-fluoro-1- ((1-fluorocyclopropyl)methyl)spiro[pyrrolidine-3,7'-pyrrolo[3,4-b]pyridine]- 2,5'(6'H)-dione 15

[0630] (S)-6'-((5-amino-6-fluoro-1H-pyrrolo[3,2-b]pyridin-2-yl)methyl)-3'-fluoro-1- ((1-fluorocyclopropyl)methyl)spiro[pyrrolidine-3,7'-pyrrolo[3,4-b]pyridine]- 2,5'(6'H)-dione 15-p1

[0631] (R)-6'-((5-amino-6-fluoro-1H-pyrrolo[3,2-b]pyridin-2-yl)methyl)-3'-fluoro-1- ((1-fluorocyclopropyl)methyl)spiro[pyrrolidine-3,7'-pyrrolo[3,4-b]pyridine]- 2,5'(6'H)-dione 15-p2

[0632] First step

[0633] 5-fluoro-2-(2-methoxy-2-oxoethyl)nicotinic acid methyl ester 15b

[0634] Dissolve 2-(2-ethoxy-2-oxoethyl)-5-fluoronicotinic acid 15a (10 g, 44.01 mmol, prepared by the method disclosed in Example 24 of the specification of patent application “WO2023156386”) in methanol (25 mL), slowly add concentrated sulfuric acid (10.5 g, 107.06 mmol), stir the reaction at 80 °C for 16 hours, after the reaction is reduced to room temperature, concentrate under reduced pressure, add ice water to the residue, extract with ethyl acetate (50 mL x 3), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain the crude title compound 15b (9.8 g), which is used directly in the next step without purification.

[0635] MS m / z (ESI): 277.2 [M+1].

[0636] Second step

[0637] 7-allyl-3-fluoro-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-7-carboxylic acid methyl ester 15c

[0638] Use the third to sixth steps of the synthetic route in Example 10, replace the third step starting material compound 10c with 15b, to prepare the title compound 15c (1.89 g, yield: 82.5%).

[0639] MS m / z (ESI): 251.1 [M+1].

[0640] Third step

[0641] 7-allyl-6-((5-chloro-6-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2- b]pyridin-2-yl)methyl)-3-fluoro-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-7-carboxylic acid methyl ester 15e

[0642] 5-chloro-2-(chloromethyl)-6-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2- b]pyridine 15d (3 g, 6.89 mmol, prepared by the method disclosed in Intermediate AX on page 56 of the specification of patent application “WO2023036974”), compound 15c (1.89 g, 7.55 mmol) were dissolved in N,N-dimethylformamide (30 mL), sodium iodide (113 mg, 754 µmol), cesium carbonate (4.92 g, 15.10 mmol) were added, the reaction was stirred at 80 °C for 3 hours, after the reaction solution was cooled to room temperature, water was added, ethyl acetate was extracted (50 mL x 3), the combined organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, the residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 15e (3.2 g, yield: 75%).

[0643] MS m / z (ESI): 563.3 [M+1].

[0644] Fourth step

[0645] 7-allyl-6-((5-chloro-6-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2- b]pyridin-2-yl)methyl)-3-fluoro-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-7-carboxylic acid methyl ester 15e

[0646] Compound 15e (3.19 g, 5.66 mmol) was dissolved in 1,4-dioxane (40 mL), and tert-butyl carbamate (1.33 g, 11.35 mmol), potassium phosphate (2.41 g, 11.35 mmol), (2-dicyclohexylphosphino)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl methane sulfonic acid (2-dicyclohexylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (1.03 g, 1.13 mmol) were added. The reaction was carried out at 80 °C for 2 h under nitrogen atmosphere. After the reaction solution was cooled to room temperature, it was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to give the title compound 15f (2.5 g, yield: 68.5%).

[0647] MS m / z (ESI): 644.0 [M+1].

[0648] Fifth step

[0649] 6'-((5-amino-6-fluoro-1H-pyrrolo[3,2-b]pyridin-2-yl)methyl)-3'-fluoro-1-((1- fluorocyclopropyl)methyl)spiro[pyrrolidine-3,7'-pyrrolo[3,4-b]pyridine]-2,5'(6'H)- dione 15

[0650] (S)-6'-((5-amino-6-fluoro-1H-pyrrolo[3,2-b]pyridin-2-yl)methyl)-3'-fluoro-1-((1- fluorocyclopropyl)methyl)spiro[pyrrolidine-3,7'-pyrrolo[3,4-b]pyridine]-2,5'(6'H)- dione 15-p1

[0651] (R)-6'-((5-amino-6-fluoro-1H-pyrrolo[3,2-b]pyridin-2-yl)methyl)-3'-fluoro-1-((1- fluorocyclopropyl)methyl)spiro[pyrrolidine-3,7'-pyrrolo[3,4-b]pyridine]-2,5'(6'H)- dione 15-p2

[0652] The title compound 15 (102 mg, yield: 62.6%) was prepared by using the synthetic route of Example 10, Steps eleven to thirteen, replacing the starting compound 10l of Step eleven with compound 15f, and replacing the starting compound 1-(aminomethyl)cyclopropylcarbonitrile hydrochloride of Step twelve with (1-fluorocyclopropyl)methanamine hydrochloride (Shanghai Biotech). Compound 15 was subjected to chiral preparation (ChiralPak IF, 5um, 20mm x 250mm; mobile phase A: acetonitrile, mobile phase B: ethanol (0.5% ammonia-methanol solution, 7M), gradient ratio: A:B 5:95, flow rate: 15.0 mL / min) to give the title compound (45 mg, yield: 28%) and (53 mg, yield: 32%).

[0653] Compound 15:

[0654] MS m / z (ESI): 456.9 [M+1].

[0655] 1 H NMR (500 MHz, CDC13): δ 9.22 (s, 1H), 8.57 (s, 1H), 7.84-7.82 (m, 1H), 7.28-7.25 (m, 1H), 6.37 (s, 1H), 5.06 (d, 1H), 4.46 (s, 1H), 4.43 (s, 2H), 4.14-4.09 (m, 1H), 3.89-3.82 (m, 2H), 3.75-3.68 (m, 1H), 2.67-2.52 (m, 2H), 1.21-1.15 (m, 2H), 0.80-0.76 (m, 2H).

[0656] Single configuration compound (shorter retention time): (45 mg, yield: 28%).

[0657] MS m / z (ESI): 457.4 [M+1].

[0658] Chiral HPLC analysis: Retention time 2.853 min, purity: 97.0% (Column: CHIRALPAK IF 150*4.6 mm, 5 um; Mobile phase A: Ethanol (0.1% diethylamine), Mobile phase B: Acetonitrile, Gradient ratio: A:B 95:5, Flow rate: 1.0 mL / min).

[0659] 1 H NMR (500 MHz, CDC13): δ 9.22 (s, 1H), 8.57 (s, 1H), 7.84-7.82 (m, 1H), 7.28-7.25 (m, 1H), 6.37 (s, 1H), 5.06 (d, 1H), 4.46 (s, 1H), 4.43 (s, 2H), 4.14-4.09 (m, 1H), 3.89-3.82 (m, 2H), 3.75-3.68 (m, 1H), 2.67-2.52 (m, 2H), 1.21-1.15 (m, 2H), 0.80-0.76 (m, 2H).

[0660] Single configuration compound (longer retention time): (53 mg, yield 32%).

[0661] MS m / z (ESI): 457.4 [M+1].

[0662] Chiral HPLC analysis: Retention time 5.340 min, purity: 97.5% (Chromatography column: CHIRALPAK IF 150*4.6 mm, 5 um; mobile phase A: ethanol (0.1% diethylamine), mobile phase B: acetonitrile, gradient ratio: A:B 95:5, flow rate: 1.0 mL / min).

[0663] 1 H NMR (500 MHz, CDC13): δ 9.29 (s, 1H), 8.57 (s, 1H), 7.83 (dd, 1H), 7.27 (s, 1H), 6.38 (s, 1H), 5.06 (d, 1H), 4.60 (br s, 2H), 4.46 (d, 1H), 4.15-4.11 (m, 1H), 3.89-3.82 (m, 2H), 3.76-3.68 (m, 1H), 2.67-2.61 (m, 1H), 2.57-2.52 (m, 1H), 1.21-1.15 (m, 2H), 0.79-0.76 (m, 2H).

[0664] Example 16

[0665] 2-((5-amino-6-fluoro-lH-pyrrolo[3,2-b]pyridin-2-yl)methyl)-5,6-difluoro-l'- ((l-fluorocyclopropyl)methyl)spiro[isoindoline-l,3'-pyrrolidine]-2',3-dione 16

[0666] (S)-2-((5-amino-6-fluoro-lH-pyrrolo[3,2-b]pyridin-2-yl)methyl)-5,6-difluoro-l'- ((l-fluorocyclopropyl)methyl)spiro[isoindoline-l,3'-pyrrolidine]-2',3-dione 16-p1

[0667] (R)-2-((5-amino-6-fluoro-lH-pyrrolo[3,2-b]pyridin-2-yl)methyl)-5,6-difluoro-l'- ((l-fluorocyclopropyl)methyl)spiro[isoindoline-l,3'-pyrrolidine]-2',3-dione 16-p2

[0668] First step

[0669] 1-allyl-5,6-difluoro-3-oxoisoindoline-l-carboxylate 16b

[0670] The title compound 16b (1.9 g, yield: 79%) was prepared by replacing the first starting material compound 10a with methyl 2-(bromomethyl)-4,5-difluorobenzoate 16a (prepared by the method disclosed in Example 195 of the specification of patent application “EP3957633”) in the first to sixth steps of the synthetic route in Example 10.

[0671] MS m / z (ESI): 268.2 [M+1].

[0672] Second step

[0673] 2-((5-amino-6-fluoro-1H-pyrrolo[3,2-b]pyridin-2-yl)methyl)-5,6-difluoro-1'-((1- fluorocyclopropyl)methyl)spiro[isoindoline-1,3'-pyrrolidine]-2',3-dione 16

[0674] (S)-2-((5-amino-6-fluoro-1H-pyrrolo[3,2-b]pyridin-2-yl)methyl)-5,6-difluoro-1'-((1- fluorocyclopropyl)methyl)spiro[isoindoline-1,3'-pyrrolidine]-2',3-dione 16-p1

[0675] (R)-2-((5-amino-6-fluoro-1H-pyrrolo[3,2-b]pyridin-2-yl)methyl)-5,6-difluoro-1'-((1- fluorocyclopropyl)methyl)spiro[isoindoline-1,3'-pyrrolidine]-2',3-dione 16-p2

[0676] The title compound 16 (45 mg, yield: 38.2%) was prepared by replacing the third starting material compound 15c with compound 16b in the third to fifth steps of the synthetic route in Example 15. Compound 16 was subjected to chiral preparation (Chiralpak IF, 5um, 20mm x 250mm; mobile phase A: Acetonitrile, mobile phase B: Ethanol (0.5% ammonia-methanol solution, 7M), gradient ratio: A:B 20:80, flow rate: 15.0 mL / min) to obtain the title compound (21 mg, yield: 18%) and (22 mg, yield: 18%).

[0677] Compound 16:

[0678] MS m / z (ESI): 473.9 [M+1].

[0679] 1H NMR (500 MHz, CDC13): δ 9.21 (s, 1H), 7.79 (t, 1H), 7.26 (s, 1H), 7.28 (q, 1H), 6.33 (s, 1H), 5.04 (d, 1H), 4.43 (s, 2H), 4.37 (d, 1H), 4.00-3.82 (m, 3H), 3.71-3.64 (m, 1H), 2.76-2.70 (m, 1H), 2.40-2.35 (m, 1H), 1.23-1.17 (m, 2H), 0.86-0.76 (m, 2H).

[0680] Single configuration compound (short retention time): (21 mg, yield: 18%).

[0681] MS m / z (ESI): 473.9 [M+1].

[0682] Chiral HPLC analysis: Retention time 2.408 min, purity: 98.6% (Column: CHIRALPAK IF 150 x 4.6 mm, 5 um; Mobile phase A: Ethanol (0.1% diethylamine), Mobile phase B: Acetonitrile, Gradient ratio: A:B 90:10, Flow rate: 1.0 mL / min).

[0683] 1 H NMR (500 MHz, CDC13): δ 9.21 (s, 1H), 7.79 (t, 1H), 7.26 (s, 1H), 7.28 (q, 1H), 6.33 (s, 1H), 5.04 (d, 1H), 4.43 (s, 2H), 4.37 (d, 1H), 4.00-3.82 (m, 3H), 3.71-3.64 (m, 1H), 2.76-2.70 (m, 1H), 2.40-2.35 (m, 1H), 1.23-1.17 (m, 2H), 0.86-0.76 (m, 2H).

[0684] Single configuration compound (long retention time): (22 mg, yield 18%).

[0685] MS m / z (ESI): 473.9 [M+1].

[0686] Chiral HPLC analysis: Retention time 6.143 min, purity: 99.0% (Column: CHIRALPAK IF 150 x 4.6 mm, 5 um; Mobile phase A: Ethanol (0.1% diethylamine), Mobile phase B: Acetonitrile, Gradient ratio: A:B 90:10, Flow rate: 1.0 mL / min).

[0687] 1H NMR (500 MHz, CDC13): δ 9.29 (s, 1H), 7.71-7.68 (m, 1H), 7.31 (s, 1H), 7.21-7.18 (q, 1H), 6.36 (s, 1H), 5.03 (d, 1H), 4.62 (br s, 2H), 4.39 (d, 1H), 4.00-3.82 (m, 3H), 3.71-3.64 (m, 1H), 2.76-2.70 (m, 1H), 2.41-2.36 (m, 1H), 1.24-1.17 (m, 2H), 0.86-0.75 (m, 2H).

[0688] Example 17

[0689] 2-((5-amino-6-fluoro-lH-pyrrolo[3,2-b]pyridin-2-yl)methyl)-5,7-difluoro-l'- ((l-fluorocyclopropyl)methyl)spiro[isoindoline-l,3'-pyrrolidine]-2',3-dione 17

[0690] (S)-2-((5-amino-6-fluoro-lH-pyrrolo[3,2-b]pyridin-2-yl)methyl)-5,7-difluoro-l'- ((l-fluorocyclopropyl)methyl)spiro[isoindoline-l,3'-pyrrolidine]-2',3-dione 17-p1

[0691] (R)-2-((5-amino-6-fluoro-lH-pyrrolo[3,2-b]pyridin-2-yl)methyl)-5,7-difluoro-l'- ((l-fluorocyclopropyl)methyl)spiro[isoindoline-l,3'-pyrrolidine]-2',3-dione 17-p2

[0692] The title compound 17 (58 mg, yield: 43.1%) was prepared by using the synthetic route in Example 16, replacing the first starting material compound 16a with methyl 2-(bromomethyl)-3,5-difluorobenzoate (prepared by the method disclosed in Example 4 of the specification of patent application "WO2017087607"). The compound 17 was subjected to chiral preparation (column: ChiralPak IF, 5um, 20mm x 250mm; mobile phase A: acetonitrile, mobile phase B: ethanol (0.5% ammonia-methanol solution, 7M), gradient ratio: A:B 20:80, flow rate: 15.0 mL / min) to obtain the title compound (15 mg, yield: 31%) and (13 mg, yield: 27%).

[0693] Compound 17:

[0694] MS m / z (ESI): 473.9 [M+1].

[0695] 1 H NMR (500 MHz, DMSO-de): δ 10.73 (d, 1H), 7.63 (td, 1H), 7.56 (dd, 1H), 7.37 (d, 1H), 6.19 - 6.09 (m, 1H), 5.53 (s, 2H), 5.00 (d, 1H), 4.31 (d, 1H), 3.85 - 3.74 (m, 2H), 3.68 - 3.51 (m, 2H), 2.65 - 2.55 (m, 1H), 2.41 (td, 1H), 1.05 (ddp, 2H), 0.90 - 0.79 (m, 1H), 0.72 (ddd, 1H).

[0696] Single configuration compound (short retention time): (15 mg, yield: 31%).

[0697] MS m / z (ESI): 473.9 [M+1].

[0698] Chiral HPLC analysis: Retention time 2.464 min, purity: 98.0% (Column: CHIRALPAK IF 150*4.6 mm, 5 um; Mobile phase A: Ethanol (0.1% diethylamine), Mobile phase B: Acetonitrile, Gradient ratio: A:B 90:10, Flow rate: 1.0 mL / min).

[0699] 1 H NMR (500 MHz, DMSO-de): δ 10.79 (s, 1H), 7.64 (td, 1H), 7.56 (dd, 1H), 7.41 (d, 1H), 6.14 (d, 1H), 5.64 (s, 2H), 5.00 (d, 1H), 4.32 (d, 1H), 3.79 (td, 2H), 3.64 (td, 1H), 3.57 (dd, 1H), 2.58 (ddd, 1H), 2.42 (ddd, 1H), 1.14 - 0.98 (m, 2H), 0.88 - 0.79 (m, 1H), 0.78 - 0.67 (m, 1H).

[0700] Single configuration compound (long retention time): (13 mg, yield 27%).

[0701] MS m / z (ESI): 473.9 [M+1].

[0702] Chiral HPLC analysis: Retention time 4.878 min, purity: 98.0% (Column: CHIRALPAK IF 150*4.6 mm, 5 um; Mobile phase A: Ethanol (0.1% diethylamine), Mobile phase B: Acetonitrile, Gradient ratio: A:B 90:10, Flow rate: 1.0 mL / min).

[0703] 1 H NMR (500 MHz, DMSO-d6): δ 10.82 (s, 1H), 7.63 (td, 1H), 7.56 (dd, 1H), 7.43 (d, 1H), 6.15 (d, 1H), 5.71 (s, 2H), 5.00 (d, 1H), 4.33 (d, 1H), 3.83 - 3.74 (m, 2H), 3.64 (td, 1H), 3.57 (dd, 1H), 2.58 (ddd, 1H), 2.42 (ddd, 1H), 1.11 - 1.00 (m, 2H), 0.83 (ddt, 1H), 0.72 (ddt, 1H).

[0704] Example 18

[0705] (S)-2-((5-amino-6-fluoro-lH-pyrrolo[3,2-b]pyridin-2-yl)methyl)-5-fluoro-l'-((l- methylcyclopropyl)methyl)spiro[isoindoline-l,3'-pyrrolidine]-2',3-dione

[0706] The title compound (41 mg, yield: 61.9%) was obtained by using the synthetic route in Example 1, replacing the first raw material compound 1-(aminomethyl)cyclopropylcarbonitrile hydrochloride with (1-methylcyclopropyl)methanamine hydrochloride (Shanghai Biode).

[0707] MS m / z (ESI): 451.9 [M+1].

[0708] 1 H NMR (500 MHz, CDCl3): δ 9.34 (s, 1H), 7.57-7.55 (m, 1H), 7.33-7.28 (m, 2H), 7.26 (s, 1H), 6.33 (s, 1H), 5.05 (d, 1H), 4.41 (s, 2H), 4.37 (d, 1H), 3.87-3.82 (m, 1H), 3.72-3.68 (m, 1H), 3.52 (d, 1H), 3.10 (d, 1H), 2.74-2.68 (m, 1H), 2.39-2.34 (m, 1H), 1.11 (s, 3H), 0.54-0.46 (m, 4H).

[0709] Example 19

[0710] (S)-2-((5-amino-6-fluoro-lH-pyrrolo[3,2-b]pyridin-2-yl)methyl)-l'-(cyclopropylmethyl)-5- fluorospiro[isoindoline-l,3'-pyrrolidine]-2',3-dione

[0711] The title compound was prepared by following the synthetic route in Example 1, replacing the first starting material compound 1-(aminomethyl)cyclopropylcarbonitrile hydrochloride with cyclopropylmethanamine hydrochloride (Shanghai Shaoyuan), to give the title compound (38 mg, yield: 61.1%).

[0712] MS m / z (ESI): 438.0 [M+1].

[0713] 1 H NMR (500 MHz, CDC13): δ 9.35 (s, 1H), 7.57-7.55 (m, 1H), 7.32-7.28 (m, 2H), 7.26 (s, 1H), 6.33 (s, 1H), 5.04 (d, 1H), 4.41 (s, 2H), 4.37 (d, 1H), 3.90-3.84 (m, 1H), 3.77-3.72 (m, 1H), 3.47-3.43 (m, 1H), 3.22-3.18 (m, 1H), 2.72-2.66 (m, 1H), 2.39-2.34 (m, 1H), 1.09-1.04 (m, 1H), 0.70-0.62 (m, 2H), 0.37-0.30 (m, 2H).

[0714] Comparative Example 1

[0715] (S)-2-((5-amino-6-fluoro-1H-pyrrolo[3,2-b]pyridin-2-yl)methyl)-5-fluoro-1'-((1- (fluoromethyl)cyclopropyl)methyl)spiro[isoindoline-1,3'-pyrrolidine]-2',3-dione (Example 9 in WO2023036974A1)

[0716] The title compound was prepared by following the synthetic route in Example 1, replacing the first starting material compound 1-(aminomethyl)cyclopropylcarbonitrile hydrochloride with (1-(fluoromethyl)cyclopropyl)methanamine trifluoromethanesulfonate (prepared by following the method disclosed in Example 54 of the specification in patent application “WO2022184849”), to give the title compound (35 mg, yield: 14.9%).

[0717] MS m / z (ESI): 470.4 [M+1].

[0718] 1H NMR (500 MHz, DMSO-d6): δ 10.71 (d, 1H), 7.64-7.50 (m, 3H), 7.37 (d, 1H), 6.15-6.08 (m, 1H), 5.51 (s, 2H), 5.05 (d, 1H), 4.24 (d, 1H), 3.88-3.73 (m, 2H), 3.64-3.46 (m, 2H), 2.45-2.32 (m, 2H), 2.32-2.20 (m, 2H), 2.17 (td, 1H), 2.01 (ddd, 1H), 1.78 (qt, 1H), 1.48 (dtd, 1H).

[0719] Biological evaluation

[0720] The present disclosure is further described and explained with reference to the following test examples, which are not meant to limit the scope of the present disclosure.

[0721] Test Example 1, Inhibitory activity of the compounds of the present disclosure on human PRMT5 enzyme activity

[0722] I. Experimental materials and instruments

[0723] 1. Recombinant human PRMT5: MEP50 protein (active motif, 31521)

[0724] 2. EPIgeneous Methyltransferase kit (cisbio, 62SAHPEH)

[0725] 3. 96-well plate (Sangon Biotech, F610960-0010)

[0726] 4. 384-well white plate (Perkin Elmer, 6007290)

[0727] 5. 1M Tris-HCl [pH 8.5] (Sangon Biotech, B548141)

[0728] 6. Histone H4 peptide substrate (1-21) (BPS bioscience, 52014)

[0729] 7. 5'-Deoxy-5'-(methylthio)adenosine (Aldrich, D168979-25mg)

[0730] 8. Tween-20 (Sangon Biotech, A100777-0500)

[0731] 9. DMSO (Sigma, D2650)

[0732] 10. Thermo Cycler (Bio-Rad Laboratories, Inc.)

[0733] 11. PHERAstar FS Microplate Reader (BMG Labtech)

[0734] II. Experimental Procedures

[0735] PRMT5 can transfer the methyl group of S-adenosylmethionine (SAM) to the histone H4 peptide substrate (1-21), thereby generating S-Adenosylhomocysteine (SAH). This experiment is to detect the amount of SAH generated by the reaction by the method of Homogeneous Time-Resolved Fluorescence (HTRF), to evaluate the inhibitory activity of the compound on the enzyme activity of PRMT5.

[0736] 1) Standard Curve Preparation Prepare the EPIgeneous Diluent Buffer in the EPIgeneous Methyltransferase kit into sample diluent with / without 1 μM 5'-deoxy-5'-(methylthiyl) adenosine (MTA) according to the instructions. Dilute the SAM and SAH standards in series according to the instructions, and then dispense 10 μL per well (2 replicates per concentration). Add 2 μL of EPIgeneous Detection Buffer 1 per well, centrifuge, shake well, and let stand at room temperature for 10 min. Dilute the SAH d2 reagent 32-fold with EPIgeneous Detection Buffer 2 solution, add 4 μL of SAH-d2 diluent per well, centrifuge, shake well for 2 min, and let stand at room temperature for 60 min. Dilute the SAH Tb Cryptate Antibody 50-fold with EPIgeneous Detection Buffer 2 solution, add 4 μL of Tb Cryptate Antibody diluent per well, centrifuge, shake well for 2 min, and let stand at room temperature for 60 min. After 60 min, read the plate using the PHERAstar FS microplate reader and detect the 665 / 620 ratio value. Plot the concentration of SAH against the ratio value to obtain the calculation formula.

[0737] 2) Compound Detection Reaction Buffer (1x): 50 mM Tris-HCl [pH 8.5], 1 mM DTT, 0.005% Tween-20.

[0738] Compound preparation: 20 mM test compound dissolved in 100% DMSO was diluted to 1 mM with 100% DMSO as the highest drug concentration, and this concentration of compound was diluted 3-fold serially in 100% DMSO in a 96-well plate for 10 concentration points, with 100% DMSO in the blank wells. The above serially diluted compound and 100% DMSO were diluted 20-fold with reaction buffer as 5x concentration compound, mixed well and ready for use.

[0739] PRMT5:MEP50 was diluted with reaction buffer to a final concentration of 12.5 nM, and 4 μL of 12.5 nM PRMT5:MEP50 solution was added to each well of a 384-well plate, with 4 μL of reaction buffer in the negative control wells. 2 μL of 5x concentration compound was added to each well, with 2 μL of 5% DMSO added to the negative control wells (no enzyme and no compound) and the positive control wells (no compound). After sealing the plate, centrifugation was performed in a centrifuge, and the plate was mixed by shaking for 2 min and left to stand at room temperature for 20 min.

[0740] Preparation of substrate mixture solution: a substrate mixture 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, 2.5 μM MTA was prepared with reaction buffer; 4 μL of substrate mixture solution (- / + MTA) was added to each well to start the reaction, and the plate was centrifuged after sealing, mixed by shaking for 2 min, and left to stand in a 37°C constant temperature incubator for 120 min.

[0741] Detection: detection was performed using the EPIgeneous Methyltransferase kit. 2 μL of EPIgeneous Detection Buffer 1 was added to each well, centrifuged, mixed by shaking, and left to stand at room temperature for 10 min; the SAH d2 reagent was diluted 32-fold with EPIgeneous Detection Buffer 2 solution, 4 μL of SAH-d2 diluent was added to each well, centrifuged, and mixed by shaking for 2 min; the SAH Tb Cryptate Antibody was diluted 50-fold with EPIgeneous Detection Buffer 2 solution, 4 μL of Tb Cryptate Antibody diluent was added to each well, centrifuged, and mixed by shaking for 2 min. After standing at room temperature for 60 min, the plate was read using a PHERAstar FS microplate reader, and the 665 / 620 ratio value was detected.

[0742] After the values were converted using the formula, the Graphpad Prism software was used to plot the inhibition curve according to the concentration of each compound and the corresponding inhibition rate, and the concentration of the compound at which the inhibition rate reached 50%, i.e. IC 50 value.

[0743] Table 1, IC50 of the compounds of the present disclosure for the enzyme activity inhibition activity of human PRMT5 50 Values

[0744] Conclusion: The compounds of the present disclosure have good enzyme activity inhibition activity for PRMT5(+MTA).

[0745] Test Example 2, HCT116 and HCT116 MTAP- / - cell proliferation experiment

[0746] I. Experimental materials and instruments

[0747] 1. HCT116 cell strain (Nanjing Kebai, CBP60028)

[0748] 2. HCT116 MTAP- / - cell strain (Nanjing Kebai, CBP75002)

[0749] 3. DMSO (Sigma, D2650)

[0750] 4. McCoy's 5A medium (Gibco, 16600-082)

[0751] 5. Fetal bovine serum (FBS) (Gibco, 10091148)

[0752] 6. Phosphate buffer (DPBS) PH7.4 (Gibco, 14190-144)

[0753] 7. Pen strep (PS) (Gibco, 15140-122)

[0754] 8. 0.25% Typsin-EDTA (1x) (Gibco, 25200-072)

[0755] 9, Luminescent Cell Viability Assay (Promega, G7572)

[0756] 10. 96-well round-bottom plate (JET, TCP002096)

[0757] 11. 96-well black transparent bottom cell culture plate (Xinyou Biotechnology, 060096)

[0758] 12. 1.2mL 96-well deep well plate, transparent, sterile, square well, V-bottom (Titan, 02089063)

[0759] 13, 15 mL centrifuge tubes (Titan)

[0760] 14, Biological safety cabinet (Thermo, 1300AII)

[0761] 15, Cell counter (Countstar, IC1000)

[0762] 16, Incubator (Thermo, I160)

[0763] 17, Centrifuge (Beckman coulter, Allegra X-12 centrifuge)

[0764] 18, PHERAstar FS microplate reader (BMG Labtech)

[0765] II. Experimental procedure

[0766] 1, Cell plating (Day 0)

[0767] a) Observe cell status under microscope to ensure the confluency of cells is ~90%.

[0768] b) Discard the supernatant of cells, rinse once with PBS, and discard the PBS. Add appropriate amount of trypsin to digest the cells, and let it stand for 3 minutes at 37°C.

[0769] c) Stop the digestion with equal volume of McCoy's 5A medium containing 10% FBS, and collect the cell suspension. Centrifuge at 300g for 3 minutes. Resuspend the cells with appropriate amount of fresh medium.

[0770] d) Take the resuspended cell suspension to count.

[0771] e) Dilute the cell suspension to 1e4 / mL with McCoy's 5A medium containing 10% FBS, 50 μL / well. For HCT116, 500 cells / well; for HCT116 MTAP- / -, 500 cells / well.

[0772] f) Place the cell plate in an incubator at 37°C, 5% CO2 overnight

[0773] 2, Drug addition (Day 1)

[0774] a) Dilute each compound into 9 concentration points with DMSO (starting concentration 10000 μM, 3-fold dilution; the highest concentration can be adjusted accordingly according to the IC 50 of different compounds). For example, in a 96-well round-bottom drug plate, dilute 5 μL of compound into 10 μL of DMSO in turn.

[0775] b) Each compound concentration point was diluted 250-fold into the corresponding volume of McCoy's 5A medium.

[0776] c) To each cell plate, 50 μL / well of cell supernatant, 50 μL of the diluted compound solution was added sequentially.

[0777] d) The drug-treated cell plates were incubated at 37°C in a 5% CO2incubator.

[0778] 3. Re-digest and drug (Day 5)

[0779] a) After 5 days of drug treatment, the drug-containing medium was discarded, and then PBS was added at 100 μL / well, which was immediately aspirated.

[0780] b) The cells were trypsinized by adding 25 μL trypsin, and incubated at 37°C for 3 minutes, and then the trypsinization was terminated by adding 175 μL / well of McCoy's 5A medium containing 10% FBS.

[0781] c) The cells were mixed by blowing with a syringe, and re-plated at a ratio of 1:20, i.e., 10 μL of the cell suspension was aspirated into a new 96-well plate (40 μL of McCoy's 5A medium containing 10% FBS was added to the new plate in advance).

[0782] d) The compound preparation and drug treatment were performed according to steps a) to c) in 2, and 50 μL per well.

[0783] e) The drug-treated cell plates were incubated at 37°C in a 5% CO2incubator.

[0784] 4. CTG detection (Day 10)

[0785] a) Before use, the CellTiter-Glo buffer and the freeze-dried CellTiter-Glo substrate were equilibrated to room temperature, and mixed to prepare 100 mL of CellTiter-Glo reagent (or the mixed CellTiter-Glo reagent was taken out from -20°C and equilibrated to room temperature).

[0786] b) The plate to be detected was taken out from the incubator and equilibrated to room temperature, and 50 μL of CellTiter-Glo reagent was added per well.

[0787] c) The cells were fully lysed by shaking for 2 minutes.

[0788] d) After 28 minutes of room temperature standing to stabilize the signal, detection was performed on a Pherastar FS.

[0789] Table 2, IC of the compounds of the disclosure for HCT116 MTAP- / - cell growth inhibition 50 Values

[0790] Conclusion: The compounds of the disclosure have good inhibitory effect on the growth of HCT116 MTAP- / - cells.

[0791] Test Example 3, Pharmacokinetic evaluation

[0792] I. C57 mouse test

[0793] 1. Abstract

[0794] C57 mice were used as test animals, and LC / MS / MS method was used to determine the drug concentration in the plasma of C57 mice at different time points after oral administration (i.g.) of the compounds of the examples, to study the pharmacokinetic behavior of the compounds of the disclosure in C57 mice, and to evaluate the pharmacokinetic characteristics thereof.

[0795] 2. Test plan

[0796] 2.1. Test drug

[0797] Compound 12;

[0798] The compound corresponding to the chiral HPLC analysis retention time of 2.853 minutes in 15-p1 and 15-p2;

[0799] The compound corresponding to the chiral HPLC analysis retention time of 5.340 minutes in 15-p1 and 15-p2;

[0800] The compound corresponding to the chiral HPLC analysis retention time of 2.408 minutes in 16-p1 and 16-p2;

[0801] The compound corresponding to the chiral HPLC analysis retention time of 6.143 minutes in 16-p1 and 16-p2;

[0802] The compound corresponding to the chiral HPLC analysis retention time of 2.464 minutes in 17-p1 and 17-p2;

[0803] The compound corresponding to the chiral HPLC analysis retention time of 4.878 minutes in 17-p1 and 17-p2;

[0804] Comparative Example 1.

[0805] 2.2. Test animals

[0806] C57 mice, 72, female, were divided into 8 groups on average, provided by Vantolin Experimental Animal Technology Co., Ltd. (SCXK (Beijing) 2021-0006) or Suzhou Guochen Biotechnology Co., Ltd. (Animal Use License: SYXK (Suzhou) 2020-0018).

[0807] 2.3, Drug preparation

[0808] A certain amount of test compound was weighed, and 5% DMSO + 5% Tween 80 + 90% physiological saline was added to prepare a 0.1 mg / mL colorless transparent solution.

[0809] 2.4, Drug administration

[0810] The drug dose was 2 mg / kg, and the drug volume was 20 mL / kg.

[0811] 3, Operation

[0812] Gavage administration, and at 0.25 hours, 0.5 hours, 1.0 hours, 2.0 hours, 4.0 hours, 6.0 hours, 8.0 hours, 11.0 hours, and 24.0 hours after administration, 0.1 mL of blood was collected from the orbital venous plexus into an EDTA-K2 anticoagulant tube, centrifuged at 4°C at 10,000 rpm for 2 minutes or 2,600 g for 10 minutes to separate the plasma, and stored at -80°C for testing. All processes were operated on ice and completed within 1 hour.

[0813] LC / MS / MS was used to determine the content of the test compound in the plasma of C57 mice after administration of different compounds.

[0814] 4, Pharmacokinetic parameter results

[0815] Table 3, Pharmacokinetic parameters of the compound of the present disclosure in C57 mice

[0816] Conclusion: Compared with Comparative Example 1, the compound of the present disclosure has high blood concentration, high exposure, and low clearance rate in C57 mice, and has pharmacokinetic advantages.

[0817] Test Example 4, Pharmacodynamic test

[0818] 1, Purpose of the experiment

[0819] The growth inhibition effect of the compound of the present disclosure on human giant cell lung cancer cell line Lu99 subcutaneous xenograft in female NUNU nude mice was evaluated.

[0820] 2, Experimental drugs

[0821] Compound 12

[0822] Formulated with 20% PEG400 + 70% (10% TPGS) + 5% DMSO + 5% (1% HPMCK100LV) solution.

[0823] 3. Experimental methods and experimental materials

[0824] 3.1 Experimental animals and feeding conditions

[0825] Experimental animals: NUNU nude mice, female, purchased from Beijing Vito Lihua Experimental Animal Co., Ltd. (Animal qualification certificate number: 110011251103764121), with a body weight of about 20.40-26.89 g at the time of purchase.

[0826] Feeding conditions: 6 / cage feeding, 12 / 12 hour light / dark cycle regulation, temperature 20-26℃, humidity 30-70%, free feeding and free water.

[0827] 3.2 Animal grouping

[0828] After adaptive feeding of NUNU nude mice, the grouping and drug administration scheme are as follows.

[0829] Table 4, animal grouping and drug administration scheme for in vivo efficacy experiment

[0830] Note: bid is twice a day; i.g. is intragastrically administered.

[0831] 3.3 Experimental methods:

[0832] 0.2ml (5×10 6 cells + 50% Matrigel) Lu99 cells (supplier: JCRB Cell Bank; item number: JCRB0080; with Matrigel, volume ratio 1:1) in logarithmic growth phase were subcutaneously inoculated on the right back of each mouse, and when the average tumor volume reached 120mm 3 , the mice were randomly divided into 4 groups according to tumor volume and body weight, 12 in each group, as shown in Table 4. The grouping day was set as D0, and twice a day intragastric administration was started, for a total of 17 days. The 17th day after administration was set as D17 (Table 5). The tumor volume of tumor-bearing mice and body weight were measured twice a week with a vernier caliper and a balance, respectively, and the data were recorded.

[0833] 3.4 Data statistics

[0834] All data were plotted and statistically analyzed using Excel and GraphPad Prism 10 software.

[0835] The formula for calculating the tumor volume (V) is: V = 1 / 2 × a × b 2 where a and b represent length and width, respectively.

[0836] The antitumor efficacy of the compound was evaluated by TGI (%). TGI (%) reflects the tumor growth inhibition rate. The calculation of TGI (%) is as follows: TGI (%) = (1-T / C) x 100.

[0837] 4、Results

[0838] The data of the efficacy of compound 12 on Lu99 transplanted tumor in NUNU nude mice are shown in Table 5 and Figure 1.

[0839] The effect of compound 12 on the body weight of NUNU nude mice is shown in Figure 2.

[0840] Table 5, the efficacy of the compound of the present disclosure on Lu99 transplanted tumor in NUNU nude mice

[0841] Note: bid is 2 times a day; d is day; i.g. is intragastrical administration; SEM is standard error.

[0842] 5、Conclusion

[0843] Compound 12, administered twice a day, after 17 days of administration, the tumor inhibition rate of the low-dose 30mpk / bid group was 97.4%, the tumor inhibition rate of the medium-dose 50mpk / bid group was 100.3%, and the tumor inhibition rate of the high-dose 100mpk / bid group was 102.7%, and the administration had no effect on the body weight of the mice.

Claims

1. A compound of the formula (I) or a pharmaceutically acceptable salt thereof, wherein: the ring in which X and Y are located is a pyrrole ring, is a single or double bond, and X is NR a , Y is CR b ; or, X is CR b , Y is NR a ; R a is selected from the group consisting of a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, an alkoxyalkyl group, a cycloalkyl group, and a cycloalkylalkyl group; R b selected from the group consisting of a hydrogen atom, a halogen, an alkyl group, a haloalkyl group, a hydroxyalkyl group, an alkoxy group, a haloalkoxy group, a cyano group, a cycloalkyl group, and a heterocyclyl group; Z is CR 2a or N; Q is CR 2b or N; A 1 , A 2 and A 3 are identical or different and each independently N or CR 1 ; R 1 , R 2a , R 2b and R 2 are the same or different and each is independently selected from the group consisting of a hydrogen atom, halogen, alkenyl, alkynyl, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, hydroxy, cyano, nitro, amino, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, -(CH2) t NR 14 R 15 , -(CH2) t 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 each of said alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl is independently optionally substituted with one or more R 0 ; m2 is 0, 1 or 2; p is 1 or 2; n is 0, 1, 2, 3 or 4; each R 3 are the same or different and each is independently selected from the group consisting of a hydrogen atom, halogen, alkenyl, alkynyl, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, aminoalkyl, hydroxyl, cyano, nitro, amino, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, -(CH2) t NR 14 R 15 , -(CH2) t 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 , -NR 17 S(O) v R 16 , oxo, and =CR 18 R 19 ; wherein each of said alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl is independently optionally substituted with one or more R 0 ; m is 0 or 1; R 4 selected from hydrogen atom, halogen, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, hydroxy, cyano, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl; R 5a , R 5b , and R 5c are the same or different and each is independently selected from the group consisting of a hydrogen atom, halogen, alkenyl, alkynyl, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, aminoalkyl, hydroxyl, cyano, nitro, amino, -(CH2) t OR 16 , -(CH2) t NR 14 R 15 , -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 , -NR 17 S(O) v R 16 , cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl; wherein each of said alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl is independently optionally substituted with one or more R 6 ; or R 5b and the atom to which they are attached to form a cycloalkyl or heterocyclyl, each independently optionally substituted with one or more R 5c and the atom to which they are attached to form a cycloalkyl or heterocyclyl, each independently optionally substituted with one or more R 6 substituents; Or, R 5a R 5b and R 5c Together with the attached atoms, they form a cycloalkyl or heterocyclic group, each of which is independently and optionally influenced by one or more R atoms. 6 replace; R 6 the same or different, and each is independently selected from the group consisting of halogen, alkenyl, alkynyl, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, aminoalkyl, hydroxyl, cyano, nitro, amino, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, -(CH2) t NR 14 R 15 , -(CH2) t 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 , -NR 17 S(O) v R 16 , oxo, and =CR 18 R 19 ; wherein said alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl are each independently optionally substituted with one or more R 0 ; R 14 , R 15 , and R 16 are the same or different and each is independently selected from the group consisting of a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, a cycloalkylalkyl group, a heterocyclyl group, a heterocyclylalkyl group, an aryl group, and a heteroaryl group; wherein each of said alkyl group, alkenyl group, alkynyl group, cycloalkyl group, cycloalkylalkyl group, heterocyclyl group, heterocyclylalkyl group, aryl group, and heteroaryl group is independently optionally substituted with one or more R 0 ; or R 14 and R 15 together with the nitrogen atom to which they are attached form a heterocyclyl optionally substituted with one or more R 0 substituents; R 17 selected from a hydrogen atom, an alkyl group and a cycloalkyl group; R 18 and R 19 are the same or different and each is independently selected from the group consisting of a hydrogen atom, an alkyl group, a halogen, a haloalkyl group, a hydroxyalkyl group, a hydroxyl group, an alkoxy group, and a cycloalkyl group; or, R 18 and R 19 together with the atoms to which they are attached form a cycloalkyl group; R 0 the same or different, and each independently selected from oxo, halo, hydroxyl, alkenyl, alkynyl, cyano, nitro, amino, -NHalkyl, -N(alkyl)2, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, aminoalkyl, cycloalkyl, cycloalkylalkyl, cycloalkyloxy, heterocyclyl, heterocyclylalkyl, heterocyclyloxy, aryl, arylalkyl, aryloxy, heteroaryl, heteroarylalkyl, and heteroaryloxy; t is 0, 1 or 2; v is 0, 1 or 2.

2. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, which is a compound of formula (II), formula (II-1) or formula (II-2), or a pharmaceutically acceptable salt thereof, wherein: m1 is 0, 1 or 2; R 1 , R 2 , R 3 , R 4 , R 5a , R 5b , R 5c , m, m2, Q and Z are as defined in claim 1.

3. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein R 2 is a hydrogen atom or a halogen; and / or R 3 is a hydrogen atom; and / or R 4 is a hydrogen atom.

4. The compound according to any one of claims 1 to 3, wherein Q is CR 2b , R 2b is a hydrogen atom or a halogen; and / or Z is CR 2a , R 2a is a halogen or a C 1-6 haloalkyl group; Preferably, Q is CH; and / or Z is CF.

5. The compound of Formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, which is a compound of Formula (IV), Formula (IV-1) or Formula (IV-2), or a pharmaceutically acceptable salt thereof, wherein: R 1 , R 2a , R 5a , R 5b , R 5c and m are as defined in claim 1.

6. The compound of Formula (I) or pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, wherein R 1 is halogen; preferably, R 1 is F.

7. A compound of general formula (I) as claimed in any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R 2a is halogen; preferably, R 2a is F.

8. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, wherein R 5a is cyano or C 2-6 alkyl; R 5b and R 5c are hydrogen or C 1-6 alkyl, or, R 5b and R 5c together with the atoms to which they are attached form a 3- to 6-membered cycloalkyl or 3- to 6-membered heterocyclyl. Preferably, selected from the group consisting of 9. A compound of general formula (I) as claimed in any one of claims 1 to 7, wherein R 5a is selected from C 2-6 alkynyl, halogen and C 2-6 alkyl; R 5b and R 5c together with the atoms to which they are attached form a 3- to 6-membered cycloalkyl or 3- to 6-membered heterocyclyl; preferably, is selected from 10. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, wherein R 5a is a hydrogen atom; R 5b and R 5c together with the atom to which they are attached form a 4- to 6-membered cycloalkyl group optionally substituted by one or more cyano groups; preferably, is selected from 11. The compound of Formula (I) or pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, wherein R 5a , R 5b and R 5c together with the atoms to which they are attached form a 5- to 8- membered bridged cycloalkyl; preferably, R 5a , R 5b and R 5c together with the atoms to which they are attached form a 12. The compound of Formula (I) or pharmaceutically acceptable salt thereof according to any one of claims 1 to 11, wherein selected from 13. A compound selected from any one of the following: ###0007### or a pharmaceutically acceptable salt thereof.

14. A compound of the formula (IIA) ###00010### (IIA) or a salt thereof. wherein: R X1 is a hydrogen atom or an amino protecting group; R X2 is a hydrogen atom or an amino protecting group; R X3 is a hydrogen atom or an amino protecting group; or R X2 and R X3 together with the nitrogen atom to which they are attached form a phthalimide group or provided that R X1 , R X2 , and R X3 are not simultaneously hydrogen atoms; R 1 , R 2 , R 3 , R 4 , R 5a , R 5b , R 5c , m, m1, m2, Q and Z are as defined in claim 2.

15. A compound or salt thereof selected from any one of the following:

16. A process for the preparation of a compound of formula (II) or a pharmaceutically acceptable salt thereof, which process comprises: The compound of general formula (IIA) or a salt thereof is deprotected to give a compound of general formula (II) or a pharmaceutically acceptable salt thereof; wherein: R X1 is a hydrogen atom or an amino protecting group; R X2 is a hydrogen atom or an amino protecting group; R X3 is a hydrogen atom or an amino protecting group; or R X2 and R X3 together with the nitrogen atom to which they are attached form a phthalimide group or provided that R X1 , R X2 , and R X3 are not simultaneously hydrogen atoms; R 1 , R 2 , R 3 , R 4 , R 5a , R 5b , R 5c , m, m1, m2, Q and Z are as defined in claim 2.

17. A pharmaceutical composition comprising a compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

18. Use of a compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 17, for the manufacture of a PRMT5 inhibitor.

19. Use of a compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 17, for the manufacture of a medicament for the treatment and / or prevention of a cancer; preferably the cancer is selected from the group consisting of lung cancer, renal 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, cholangiocarcinoma, 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, bronchial cancer, sarcoma, choriocarcinoma, craniopharyngioma, cystadenocarcinoma, hemangioendothelioma, ependymoma, epithelial carcinoma, glioma, astrocytic carcinoma, hemangioblastoma, medulloblastoma, meningioma, rhabdomyosarcoma, mesothelioma, neuroblastoma, bone cancer, nasopharyngeal cancer, 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 the group consisting of ovarian cancer, lymphoma, pancreatic cancer, bladder cancer, gastric cancer, colorectal cancer, cholangiocarcinoma, mesothelioma, malignant peripheral nerve sheath tumor (MPNST), glioblastoma and lung cancer.

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