Heterocyclic compound, preparation method therefor and pharmaceutical use thereof

Abstract

The present disclosure relates to a heterocyclic compound, a preparation method therefor and the pharmaceutical use thereof. Specifically, the present disclosure relates to a heterocyclic compound as represented by general formula (I), a preparation method therefor, a pharmaceutical composition containing the heterocyclic compound, and the use thereof as a therapeutic agent, particularly the use as a STAT6 inhibitor or degrader, and the use in the preparation of a drug for treating and / or preventing STAT6-mediated or STAT6-dependent diseases or conditions. In general formula (I), each group is as defined in the specification.

Description

A heterocyclic compound, its preparation method and its pharmaceutical application Technical Field

[0001] This disclosure pertains to the pharmaceutical field and relates to a heterocyclic compound, a method for its preparation, a pharmaceutical composition containing the heterocyclic compound, and its use as a therapeutic agent, particularly as a STAT6 inhibitor or degrader, and in the preparation of medicaments for the treatment and / or prevention of STAT6-mediated or dependent diseases or conditions. Background Technology

[0002] Type II inflammatory diseases are immune diseases primarily mediated by Th2 cells and related cytokines such as IL-4, IL-5, and IL-13, and are major pathogenic mechanisms for diseases such as asthma and atopic dermatitis (AD). Asthma is the most common chronic inflammatory lung disease, with approximately 746.4 million adults worldwide and about 63.6 million in China in 2019 (Frost & Sullivan). Atopic dermatitis, also known as eczema, has become a major contributor to the global skin disease burden. The most common characteristics of AD are itching, lichenification, and dryness. In 2019, there were approximately 390 million AD patients worldwide and about 61.5 million in China.

[0003] STAT6 belongs to the STAT (signal transducers and activators of transcription) family of transcription factors. STAT6 is mainly activated by IL-4 and IL-13, and can affect more than 80% of IL-4-regulated Th2 differentiation gene expression (Immunity. 2010 Jun 25; 32(6):852-62). The activation process of STAT6 is as follows: the binding of IL-4 / IL-13 to its receptor promotes receptor dimerization, recruits and activates JAK kinase; JAK kinase phosphorylates the intracellular terminal of the receptor, and STAT6 binds to the phosphorylated receptor through the SH2 domain, and is then phosphorylated by JAK; the phosphorylated STAT6 protein molecule forms a homodimer, enters the nucleus and activates the transcription of the target gene as a transcription factor (Expert Rev Clin Immunol. 2017 May; 13(5):425-437). STAT6 plays an important role in type II inflammatory responses. In Th2 cells, it can upregulate the expression of related inflammatory factors such as IL-4, IL-5, IL-9, and IL-13; regulate the differentiation of macrophages into M2 cells, secrete keratin, and promote epithelial damage repair; promote the switching of B cell immunoglobulin types and upregulate IgE expression. IgE can bind to receptors on the surface of mast cells and basophils, inducing allergic reactions; promote airway smooth muscle contraction and epithelial cell mucus secretion, and upregulate the expression of chemokines, further recruiting inflammatory cells (JAKSTAT.2013Oct1;2(4):e25301). Human genetic studies have found that activating mutations of STAT6 can lead to early-onset and severe allergic diseases, mainly atopic dermatitis and asthma (J Exp Med.2023May 1;220(5):e20221755).

[0004] Currently, three companies—Kymera, Recludix, and Nurix—are developing novel STAT6 inhibitors. Kymera's KT-621 is a STAT6 degrader for the treatment of diseases such as Alzheimer's disease (AD), asthma, and COPD, and is in Phase 1 clinical trials. Recludix's SH2 domain-binding inhibitor is currently in the discovery stage. Nurix's STAT6 degrader is in the discovery stage and is intended for the treatment of type 2 immune diseases. Summary of the Invention

[0005] The purpose of this disclosure is to provide a compound of general formula (M) or a pharmaceutically acceptable salt thereof.

[0006] in:

[0007] Ring A is selected from phenyl, 5-10 membered monocyclic or bicyclic heterocyclic groups, and 5-10 membered monocyclic or bicyclic heteroaryl groups;

[0008] L 1 Selected from bond, O, C(O), S, S(O), S(O)2, NR a C(O)NR a and NR a C(O);

[0009] R a Selected from hydrogen atoms, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, and cycloalkylalkyl;

[0010] X 2 For N or CH;

[0011] The ring W is selected from cycloalkyl, heterocyclic, aryl, and heteroaryl groups;

[0012] Ring B is selected from cycloalkyl, heterocyclic, aryl, and heteroaryl groups;

[0013] Cycloyl X is selected from cycloalkyl, heterocyclic, aryl, and heteroaryl groups;

[0014] G is selected from hydrogen atom, halogen and Cycloyl Y is selected from cycloalkyl, heterocyclic, aryl, and heteroaryl groups;

[0015] At least one R 2 and R w Together with their respective attached atoms, they form a cycloalkyl or heterocyclic group, each of which is independently and optionally influenced by one or more R atoms. 0 replace;

[0016] The rest of R w and R 2 , and R x R y and R 1 The same or different, and each independently selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, cyano, nitro, hydroxyl, amino, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, alkoxyalkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, -OR 3 -NR 4 R 5 -C(O)R 3 -C(O)OR 3 -C(O)NR 4 R 5 -C(O)NR 4 OR 3 -NR 6 C(O)R 3 -NR 6 C(O)OR3 -NR 6 C(O)NR 4 R 5 -OC(O)R 3 -OC(O)NR 4 R 5 -S(O) v R 3 -S(O)(=NR) 7 )R 3 -S(O) v NR 4 R 5 -NR 6 S(O)2R 3 =O, =CR 8 R 9 、-Si(R 3 3. -P(O)(OR) 3 )2、-OP(O)(R 3 )2 and -OP(O)(OR 3 )2; the alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each independently and optionally composed of one or more R groups. 0 replace;

[0017] Or, two Rs w 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. 0 replace;

[0018] Or, two Rs x 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. 0 replace;

[0019] Or, two Rs y 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. 0 replace;

[0020] Or, two Rs 1 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. 0 replace;

[0021] Or, two Rs 2 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. 0 replace;

[0022] w and n are each independently 1, 2, 3, 4, 5, 6 or 7;

[0023] x, y, and m are each independently 0, 1, 2, 3, 4, 5, 6, or 7;

[0024] L x -(L A ) t1 -;

[0025] L is -(L) B ) t2 -;

[0026] L A and L B The same or different, and each independently selected from the following groups: bond, alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, O, C(O), C(S), NR b S, S(O) and S(O)2, wherein the alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl groups are each independently and optionally selected by one or more R 0 replace;

[0027] R b Selected from hydrogen atoms, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, and cycloalkylalkyl;

[0028] t1 is selected from integers from 0 to 10;

[0029] t2 is selected from integers from 0 to 20;

[0030] R 3 R 4 and R 5 The same or different, and each independently selected from hydrogen atoms, alkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl, wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl is independently optionally selected by one or more R 0 Replace; or R 4 and R 5 Together with the attached nitrogen atom, they form a heterocyclic group or a heteroaryl group, each of which is independently and optionally influenced by one or more R atoms. 0 replace;

[0031] R 6 Selected from hydrogen atoms, alkyl groups, haloalkyl groups, hydroxyalkyl groups, and cycloalkyl groups;

[0032] R 7 Selected from hydrogen atoms, alkyl groups, haloalkyl groups, hydroxyalkyl groups, hydroxyl groups, alkoxy groups, haloalkoxy groups, and cycloalkyl groups;

[0033] R 8 and R 9They may be the same or different, and each is independently selected from hydrogen atoms, halogens, alkyl groups, haloalkyl groups, hydroxyalkyl groups, and cycloalkyl groups; or, R 8 and R 9 Together with the attached carbon atom, they form cycloalkyl or heterocyclic groups;

[0034] R 0 The same or different, and each independently selected from =O, halogen, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, aminoalkyl, hydroxy, alkenyl, alkynyl, cyano, nitro, amino, -NHalkyl, -N(alkyl)2, -C(O)Oalkyl, -C(O)OH, -C(O)NH2, -C(O)NH(alkyl), -C(O)N(alkyl)2, -C(O)halogen, -C(O)alkyl, -S(alkyl), cycloalkyl, cycloalkylalkyl, cycloalkyloxy, heterocyclic, heterocyclic alkyl, heterocyclic oxy, aryl, arylalkyl, aryloxy, heteroaryl, heteroarylalkyl and heteroaryloxy; or, two R 0 Together with the attached atoms, they form cycloalkyl or heterocyclic groups; and

[0035] v can be 0, 1, or 2.

[0036] In some embodiments, this disclosure provides a compound of general formula (I) or a pharmaceutically acceptable salt thereof.

[0037] in:

[0038] Ring A is selected from cycloalkyl, heterocyclic, aryl, and heteroaryl groups;

[0039] L 1 Selected from bond, O, C(O), S, S(O), S(O)2, NR a C(O)NR a and NR a C(O);

[0040] R a Selected from hydrogen atoms, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, and cycloalkylalkyl;

[0041] X 2 For N or CH;

[0042] Ring B is selected from cycloalkyl, heterocyclic, aryl, and heteroaryl groups;

[0043] Cycloyl X is selected from cycloalkyl, heterocyclic, aryl, and heteroaryl groups;

[0044] G is selected from hydrogen atom, halogen and Cycloyl Y is selected from cycloalkyl, heterocyclic, aryl, and heteroaryl groups;

[0045] Y represents 1 and Y 2 The ring in which it is located is either aromatic or non-aromatic;

[0046] V 1 For N or C;

[0047] V 2 For N or CR w1 ;

[0048] T is either N or C;

[0049] Y 1 and Y 2 Each is independently selected from O, S, N, NR. w3 CR w4 and CR w4 R w5 ;

[0050] R w0 R w1 R w2 R w4 R w5 R x R y R 1 and R 2 The same or different, and each independently selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, cyano, nitro, hydroxyl, amino, alkoxy, haloalkyl, hydroxyalkyl, haloalkoxy, alkoxyalkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, -OR 3 -NR 4 R 5 -C(O)R 3 -C(O)OR 3 -C(O)NR 4 R 5 -C(O)NR 4 OR 3 -NR 6 C(O)R 3 -NR 6 C(O)OR 3 -NR 6 C(O)NR 4 R 5 -OC(O)R 3 -OC(O)NR 4 R 5 -S(O) v R 3 -S(O)(=NR) 7 )R 3 -S(O) v NR 4 R5 -NR 6 S(O)2R 3 =O, =CR 8 R 9 、-Si(R 3 3. -P(O)(OR) 3 )2、-OP(O)(R 3 )2 and -OP(O)(OR 3 )2, wherein the alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each independently and optionally composed of one or more R groups. 0 replace;

[0051] R w3 The atom is selected from hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups is independently and optionally converted by one or more R atoms. 0 replace;

[0052] Or, two Rs x 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. 0 replace;

[0053] Or, two Rs y 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. 0 replace;

[0054] Or, two Rs 1 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. 0 replace;

[0055] Or, two Rs 2 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. 0 replace;

[0056] Or, R 2 With R w2 Together with their respective attached atoms, they form a cycloalkyl or heterocyclic group, each of which is independently and optionally influenced by one or more R atoms. 0 replace;

[0057] Or, R 2 With R w3 Together with their respective connected atoms, they form a heterocyclic group, each of which is independently and optionally influenced by one or more R atoms.0 Replace; or,

[0058] Or, R 2 With R w4 Together with their respective attached atoms, they form a cycloalkyl or heterocyclic group, each of which is independently and optionally influenced by one or more R atoms. 0 replace;

[0059] The condition is that at least one R 2 With R w2 R w3 Or R w4 Together with their respective attached atoms, they form a cycloalkyl or heterocyclic group, each of which is independently and optionally influenced by one or more R atoms. 0 replace;

[0060] n is 1, 2, 3, 4, 5, 6, or 7;

[0061] x, y, and m are each independently 0, 1, 2, 3, 4, 5, 6, or 7;

[0062] L x -(L A ) t1 -;

[0063] L is -(L) B ) t2 -;

[0064] L A and L B The same or different, and each independently selected from the following groups: bond, alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, O, C(O), C(S), NR b S, S(O) and S(O)2, wherein the alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl groups are each independently and optionally selected by one or more R 0 replace;

[0065] R b Selected from hydrogen atoms, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, and cycloalkylalkyl;

[0066] t1 is selected from integers from 0 to 10;

[0067] t2 is selected from integers from 0 to 20;

[0068] R 3 R 4 and R 5The same or different, and each independently selected from hydrogen atoms, alkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl, wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl is independently optionally selected by one or more R 0 Replace; or R 4 and R 5 Together with the attached nitrogen atom, they form a heterocyclic group or a heteroaryl group, each of which is independently and optionally influenced by one or more R atoms. 0 replace;

[0069] R 6 Selected from hydrogen atoms, alkyl groups, haloalkyl groups, hydroxyalkyl groups, and cycloalkyl groups;

[0070] R 7 Selected from hydrogen atoms, alkyl groups, haloalkyl groups, hydroxyalkyl groups, hydroxyl groups, alkoxy groups, haloalkoxy groups, and cycloalkyl groups;

[0071] R 8 and R 9 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, alkyl groups, haloalkyl groups, hydroxyalkyl groups, and cycloalkyl groups; or, R 8 and R 9 Together with the attached carbon atom, they form cycloalkyl or heterocyclic groups;

[0072] R 0 The same or different, and each independently selected from =O, halogen, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, aminoalkyl, hydroxy, alkenyl, alkynyl, cyano, nitro, amino, -NHalkyl, -N(alkyl)2, -C(O)Oalkyl, -C(O)OH, -C(O)NH2, -C(O)NH(alkyl), -C(O)N(alkyl)2, -C(O)halogen, -C(O)alkyl, -S(alkyl), cycloalkyl, cycloalkylalkyl, cycloalkyloxy, heterocyclic, heterocyclic alkyl, heterocyclic oxy, aryl, arylalkyl, aryloxy, heteroaryl, heteroarylalkyl and heteroaryloxy; or, two R 0 Together with the attached atoms, they form cycloalkyl or heterocyclic groups; and

[0073] v can be 0, 1, or 2.

[0074] In some embodiments, this disclosure provides a compound of general formula (I) or a pharmaceutically acceptable salt thereof.

[0075] in:

[0076] Ring A is selected from phenyl, 5-10 membered monocyclic or bicyclic heterocyclic groups, and 5-10 membered monocyclic or bicyclic heteroaryl groups;

[0077] L 1Selected from bond, O, C(O), S, S(O), S(O)2, NR a C(O)NR a and NR a C(O);

[0078] R a Selected from hydrogen atoms, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, and cycloalkylalkyl;

[0079] X 2 For N or CH;

[0080] Ring B is selected from cycloalkyl, heterocyclic, aryl, and heteroaryl groups;

[0081] Cycloyl X is selected from cycloalkyl, heterocyclic, aryl, and heteroaryl groups;

[0082] G is selected from hydrogen atom, halogen and Cycloyl Y is selected from cycloalkyl, heterocyclic, aryl, and heteroaryl groups;

[0083] Y represents 1 and Y 2 The ring in which it is located is either aromatic or non-aromatic;

[0084] V 1 For N or C;

[0085] V 2 For N or CR w1 ;

[0086] T is either N or C;

[0087] Y 1 and Y 2 Each is independently selected from O, S, N, NR. w3 CR w4 and CR w4 R w5 ;

[0088] R w0 R w1 R w2 R w4 R w5 R x R y R 1 and R 2 The same or different, and each independently selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, cyano, nitro, hydroxyl, amino, alkoxy, haloalkyl, hydroxyalkyl, haloalkoxy, alkoxyalkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, -OR 3 -NR 4 R 5 -C(O)R3 -C(O)OR 3 -C(O)NR 4 R 5 -C(O)NR 4 OR 3 -NR 6 C(O)R 3 -NR 6 C(O)OR 3 -NR 6 C(O)NR 4 R 5 -OC(O)R 3 -OC(O)NR 4 R 5 -S(O) v R 3 -S(O)(=NR) 7 )R 3 -S(O) v NR 4 R 5 -NR 6 S(O)2R 3 =O, =CR 8 R 9 、-Si(R 3 3. -P(O)(OR) 3 )2、-OP(O)(R 3 )2 and -OP(O)(OR 3 )2, wherein the alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each independently and optionally composed of one or more R groups. 0 replace;

[0089] R w3 The atom is selected from hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups is independently and optionally converted by one or more R atoms. 0 replace;

[0090] Or, two Rs x 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. 0 replace;

[0091] Or, two Rs y 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. 0 replace;

[0092] Or, two Rs1 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. 0 replace;

[0093] Or, two Rs 2 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. 0 replace;

[0094] Or, R 2 With R w2 Together with their respective attached atoms, they form a cycloalkyl or heterocyclic group, each of which is independently and optionally influenced by one or more R atoms. 0 replace;

[0095] Or, R 2 With R w3 Together with their respective connected atoms, they form a heterocyclic group, each of which is independently and optionally influenced by one or more R atoms. 0 Replace; or,

[0096] Or, R 2 With R w4 Together with their respective attached atoms, they form a cycloalkyl or heterocyclic group, each of which is independently and optionally influenced by one or more R atoms. 0 replace;

[0097] The condition is that at least one R 2 With R w2 R w3 Or R w4 Together with their respective attached atoms, they form a cycloalkyl or heterocyclic group, each of which is independently and optionally influenced by one or more R atoms. 0 replace;

[0098] n is 1, 2, 3, 4, 5, 6, or 7;

[0099] x, y, and m are each independently 0, 1, 2, 3, 4, 5, 6, or 7;

[0100] L x -(L A ) t1 -;

[0101] L is -(L) B ) t2 -;

[0102] L A and L BThe same or different, and each independently selected from the following groups: bond, alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, O, C(O), C(S), NR b S, S(O) and S(O)2, wherein the alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl groups are each independently and optionally selected by one or more R 0 replace;

[0103] R b Selected from hydrogen atoms, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, and cycloalkylalkyl;

[0104] t1 is selected from integers from 0 to 10;

[0105] t2 is selected from integers from 0 to 20;

[0106] R 3 R 4 and R 5 The same or different, and each independently selected from hydrogen atoms, alkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl, wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl is independently optionally selected by one or more R 0 Replace; or R 4 and R 5 Together with the attached nitrogen atom, they form a heterocyclic group or a heteroaryl group, each of which is independently and optionally influenced by one or more R atoms. 0 replace;

[0107] R 6 Selected from hydrogen atoms, alkyl groups, haloalkyl groups, hydroxyalkyl groups, and cycloalkyl groups;

[0108] R 7 Selected from hydrogen atoms, alkyl groups, haloalkyl groups, hydroxyalkyl groups, hydroxyl groups, alkoxy groups, haloalkoxy groups, and cycloalkyl groups;

[0109] R 8 and R 9 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, alkyl groups, haloalkyl groups, hydroxyalkyl groups, and cycloalkyl groups; or, R 8 and R 9 Together with the attached carbon atom, they form cycloalkyl or heterocyclic groups;

[0110] R 0The same or different, and each independently selected from =O, halogen, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, aminoalkyl, hydroxy, alkenyl, alkynyl, cyano, nitro, amino, -NHalkyl, -N(alkyl)2, -C(O)Oalkyl, -C(O)OH, -C(O)NH2, -C(O)NH(alkyl), -C(O)N(alkyl)2, -C(O)halogen, -C(O)alkyl, -S(alkyl), cycloalkyl, cycloalkylalkyl, cycloalkyloxy, heterocyclic, heterocyclic alkyl, heterocyclic oxy, aryl, arylalkyl, aryloxy, heteroaryl, heteroarylalkyl and heteroaryloxy; or, two R 0 Together with the attached atoms, they form cycloalkyl or heterocyclic groups; and

[0111] v can be 0, 1, or 2.

[0112] In some embodiments, this disclosure provides a compound of general formula (I-1) or a pharmaceutically acceptable salt thereof.

[0113] in,

[0114] It can be a single or double bond; and

[0115] G, L x , ring X, R x x, R w0 R w1 R w2 Y 1 Y 2 Ring B, R 2 n, L, ring A, R 1 m, L 1 and X 2 As defined in general formula (I).

[0116] In some embodiments, this disclosure provides a compound of general formula (II-1), general formula (II-2), general formula (II-3) or general formula (II-4), or a pharmaceutically acceptable salt thereof.

[0117] in,

[0118] In general formula (II-1), B 1 B 2 B 3 and B 4 One of them is C and connected to L, while the other three are the same or different, and each is independently N or CR. 2 ;

[0119] In general formulas (II-2), (II-3), and (II-4), B 1 B 3 and B 4 Whether they are the same or different, and each is independently N or CR 2 ;

[0120] It can be a single bond or a double bond;

[0121] Y is selected from C, N, and CR. w4 ;

[0122] Y 3 Selected from NR w3 O and S;

[0123] Y 4 For N or CR w4 ;

[0124] M is selected from (CR) m1 R m2 ) p O, S, S(O), S(O)2, NR m C(O), C(O)NR m and NR m C(O);

[0125] M 1 For key or (CR) m1 R m2 ) p1 ;

[0126] M 2 For key or (CR) m1 R m2 ) p2 ;

[0127] p is 0, 1, 2, 3 or 4;

[0128] p1 is 0, 1, 2, 3 or 4;

[0129] p2 is 0, 1, 2, 3 or 4;

[0130] R m Selected from hydrogen atoms, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, and cycloalkylalkyl;

[0131] R m1 and R m2The same or different, and each independently selected from hydrogen atom, halogen, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, aminoalkyl, alkenyl, alkynyl, cyano, hydroxyl, nitro, amino, -NHalkyl, -N(alkyl)2, -C(O)Oalkyl, -C(O)OH, -C(O)NH2, -C(O)NH(alkyl), -C(O)N(alkyl)2, -C(O)halogen, -C(O)alkyl, -S(alkyl), cycloalkyl, cycloalkylalkyl, cycloalkyloxy, heterocyclic, heterocyclic alkyl, heterocyclic oxy, aryl, arylalkyl, aryloxy, heteroaryl, heteroarylalkyl and heteroaryloxy; or, R m1 and R m2 Together with the attached carbon atom, they form a cycloalkyl or heterocyclic group; or, R m1 and R m2 Together they form = O; and

[0132] G, L x , ring X, R x x, R w0 R w2 R w3 R w4 Y 2 V 1 V 2 T R 2 L, ring A, R 1 m, L 1 and X 2 As defined in general formula (I).

[0133] In some embodiments, this disclosure provides a compound of formula (III-1), formula (III-2), formula (III-3) or formula (III-4), or a pharmaceutically acceptable salt thereof.

[0134] in,

[0135] In general formula (III-1), B 1 B 2 B 3 and B 5 One of them is C and connected to L, while the other three are the same or different, and each is independently N or CR. 2 ;

[0136] In general formulas (III-2), (III-3), and (III-4), B 1 B 3 and B 5 Whether they are the same or different, and each is independently N or CR 2 ;

[0137] It can be a single bond or a double bond;

[0138] Y 3 Selected from NR w3 O and S;

[0139] Y 4 For N or CR w4 ;

[0140] M is selected from (CR) m1 R m2 ) p O, S, S(O), S(O)2, NR m C(O), C(O)NR m and NR m C(O);

[0141] M 1 For key or (CR) m1 R m2 ) p1 ;

[0142] M 2 For key or (CR) m1 R m2 ) p2 ;

[0143] p is 0, 1, 2, 3 or 4;

[0144] p1 is 0, 1, 2, 3 or 4;

[0145] p2 is 0, 1, 2, 3 or 4;

[0146] R m Selected from hydrogen atoms, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, and cycloalkylalkyl;

[0147] R m1 and R m2 The same or different, and each independently selected from hydrogen atom, halogen, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, aminoalkyl, alkenyl, alkynyl, cyano, hydroxyl, nitro, amino, -NHalkyl, -N(alkyl)2, -C(O)Oalkyl, -C(O)OH, -C(O)NH2, -C(O)NH(alkyl), -C(O)N(alkyl)2, -C(O)halogen, -C(O)alkyl, -S(alkyl), cycloalkyl, cycloalkylalkyl, cycloalkyloxy, heterocyclic, heterocyclic alkyl, heterocyclic oxy, aryl, arylalkyl, aryloxy, heteroaryl, heteroarylalkyl and heteroaryloxy; or, R m1 and R m2Together with the attached carbon atom, they form a cycloalkyl or heterocyclic group; or, R m1 and R m2 Together they form = O; and

[0148] G, L x , ring X, R x x, R w0 R w3 R w4 Y 1 Y 2 V 1 V 2 T R 2 L, ring A, R 1 m, L 1 and X 2 As defined in general formula (I).

[0149] In some embodiments, this disclosure provides a compound of formula (IV-1), formula (IV-2), formula (V-1) or formula (V-2), or a pharmaceutically acceptable salt thereof.

[0150] in,

[0151] t is an integer from 0 to 10;

[0152] f is 0, 1, 2, or 3;

[0153] g can be 0, 1, 2, or 3;

[0154] Z 1 For N or CR z1 ;

[0155] Z 2 For N or CR z2 ;

[0156] R z1 and R z2 They may be the same or different, and each is independently selected from hydrogen, halogen, alkyl, cyano, hydroxyl, haloalkyl, hydroxyalkyl, alkoxy, cycloalkyl and cycloalkylalkyl;

[0157] Each R z They may be the same or different, and each is independently selected from hydrogen atoms, halogens, alkyl groups, haloalkyl groups, hydroxyalkyl groups, alkoxy groups, haloalkoxy groups, cyano groups, hydroxyl groups, =O groups, cycloalkyl groups, and heterocyclic groups; or, two R groups. z Together with their respective connected atoms, they form cycloalkyl or heterocyclic groups;

[0158] k can be 0, 1, 2, 3, 4 or 5;

[0159] L B3 Selected from: bond, alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, O, C(O), C(S), NR b S, S(O) and S(O)2, wherein the alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl groups are each independently and optionally selected by one or more R 0 replace;

[0160] In general formulas (IV-1) and (IV-2), G and L x R x x R w2 R 4 R 5 V 2 Y 3 Y 4 M, p1, p2, B 1 B 3 B 4 R 0 R b Ring A, m, R 1 L 1 and X 2 As defined in general formula (II-3) or general formula (II-4); and

[0161] In general formulas (V-1) and (V-2), G and L x R x x R 4 R 5 V 2 Y 3 Y 4 M, p1, p2, B 1 B 3 B 5 R 0 R b Ring A, m, R 1 L 1 and X 2 As defined in general formula (III-3) or general formula (III-4).

[0162] In some embodiments, this disclosure provides a compound of general formula (VI-1), general formula (VI-2), general formula (VII-1) or general formula (VII-2), or a pharmaceutically acceptable salt thereof.

[0163] in,

[0164] Q is selected from O, S, NR q and CRq1 R q2 ;

[0165] R q Selected from hydrogen atoms, alkyl groups, haloalkyl groups, hydroxyalkyl groups, cycloalkyl groups, heterocyclic groups, and cycloalkylalkyl groups;

[0166] R q1 and R q2 The same or different, and each independently selected from hydrogen, halogen, alkyl, alkenyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy, alkoxyalkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, cyano, hydroxyl, amino, and nitro; or, R q1 and R q2 Together with the attached carbon atom, they form cycloalkyl or heterocyclic groups;

[0167] m1 can be 0, 1, 2, or 3;

[0168] n1 is 0, 1, 2 or 3;

[0169] L is as defined in general formula (I); and

[0170] In general formulas (VI-1) and (VI-2), G, ring Y, and R... y y, L x , R x x, R 4 R 5 Y 3 V 2 R w1 R w2 M, p1, p2, R 2 B 1 B 3 B 4 Z 1 Z 2 f, g, R z ,k,t,L B3 and R 1 As defined in general formula (IV-1) or (IV-2); and

[0171] In general formulas (VII-1) and (VII-2), G, ring Y, and R y y, L x , R x x, R 4 R 5 Y 3 V 2 R w1 M, p1, p2, R 2 B 1B 3 B 5 Z 1 Z 2 f, g, R z ,k,t,L B3 and R 1 As defined in general formula (V-1) or (V-2).

[0172] In some embodiments, this disclosure provides a compound of general formula (N) or general formula (N-1) or a pharmaceutically acceptable salt thereof.

[0173] in,

[0174] Ring A is selected from cycloalkyl, heterocyclic, aryl, and heteroaryl groups;

[0175] n1 is 0, 1, 2 or 3;

[0176] It can be a single bond or a double bond;

[0177] Y 3 Selected from NR w3 O and S; and

[0178] G, ring Y, R y y, L x R x x, R w1 R w3 R 4 R 5 M, p1, p2, R m1 R m2 R 2 L, R 1 m, L 1 and X 2 As defined in general formula (III-2).

[0179] In some embodiments, this disclosure provides a compound of general formula (M-1), general formula (M-2), general formula (M-3) or general formula (M-4), or a pharmaceutically acceptable salt thereof.

[0180] in,

[0181] Ring A is selected from cycloalkyl, heterocyclic, aryl, and heteroaryl groups;

[0182] B 6 For N or CR B6 ;

[0183] B 7 For N or CR B7 ;

[0184] R B6 and R B7 Each is independently selected from hydrogen atoms, halogens, alkyl groups, hydroxyl groups, hydroxyalkyl groups, haloalkyl groups, cyano groups, cycloalkyl groups, and cycloalkylalkyl groups;

[0185] n² is 0, 1, 2, 3, 4, or 5; and

[0186] Ring Y, R y y, L x R x x, R 4 R 5 R w1 R w2 M, p1, p2, R 2 n1, L, R 1 m, L 1 and X 2 As defined above.

[0187] In some embodiments, this disclosure provides a compound of formula (VIII) or formula (IX) or a pharmaceutically acceptable salt thereof.

[0188] in,

[0189] f is 0, 1, 2, or 3; g is 0, 1, 2, or 3; f1 is 0, 1, 2, or 3; g1 is 0, 1, 2, or 3;

[0190] Z 1 For N or CR z1 Z 2 For N or CR z2 Z 3 For N or CR z3 Z 4 For N or CR z4 ;

[0191] R z1 R z2 R z3 and R z4 They may be the same or different, and each is independently selected from hydrogen, halogen, alkyl, cyano, hydroxyl, haloalkyl, hydroxyalkyl, alkoxy, cycloalkyl and cycloalkylalkyl;

[0192] Each R z They may be the same or different, and each is independently selected from hydrogen atoms, halogens, alkyl groups, haloalkyl groups, hydroxyalkyl groups, alkoxy groups, haloalkoxy groups, cyano groups, hydroxyl groups, =O groups, cycloalkyl groups, and heterocyclic groups; or, two R groups. z Together with their respective connected atoms, they form cycloalkyl or heterocyclic groups;

[0193] k is 0, 1, 2, 3, 4, or 5; k2 is 0, 1, 2, 3, 4, or 5; and

[0194] Ring Y, R y y, L x R x x, R w1 R 4 R 5 M, p1, p2, R 2 n1, ring A, R 1 m, L 1 and X 2 As defined in general formula (M-2).

[0195] In some embodiments, ring W is a 9-membered bicyclic heteroaryl group; in some embodiments, ring W is a 5-membered heteroaryl-phenyl group or a 5-membered heteroaryl-6-membered heteroaryl group; in some embodiments, ring W is selected from indole, benzofuranyl, benzothiopheneyl, benzoimidazolyl, benzooxazolyl, thiophenepyridyl, pyrrolo[3,2-b]pyridyl, pyrrolo[2,3,-b]pyridyl, pyrazolo[1,5-a]pyridyl, and imidazo[1,2-a]pyridyl; in some embodiments, ring W is indole.

[0196] In some implementation schemes, for *The end is connected to ring X; Y 1 Y 2 V 1 V 2 , T, R w0 R w1 R w2 , and As defined in the context.

[0197] In some implementation schemes, Selected from the following structures:

[0198] R w w is as defined in the context.

[0199] In some implementations, an R 2 With R w Together with their respective attached atoms, they form a cycloalkyl or heterocyclic group, each of which is independently and optionally influenced by one or more R atoms. 0 Replace; the rest of R 2 and R w They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6Alkyl and C(O)R 4 R 5 ;R 0 R 4 and R 5 As defined in the context; in some implementations, an R 2 With R w Together with their respective connected atoms, they form 5- to 10-membered heterocyclic groups, and the remaining R 2 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl, the rest R w They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl and C(O)R 4 R 5 ;R 4 and R 5 As defined in the context.

[0200] In some implementations, w is 1, 2, 3, or 4; in some implementations, w is 1, 2, or 3; in some implementations, w is 3.

[0201] In some embodiments, ring B is selected from phenyl, 6-membered heteroaryl, and 6-membered heterocyclic groups; in some embodiments, ring B is phenyl or 6-membered heterocyclic group; in some embodiments, ring B is phenyl or piperidinyl.

[0202] In some embodiments, ring B is phenyl or a 5- or 6-membered heteroaryl; in some embodiments, ring B is phenyl or a 6-membered heteroaryl; in some embodiments, ring B is phenyl or pyridyl; in some embodiments, ring B is phenyl.

[0203] In some implementation schemes, B 2 C is connected to L, B 1 B 3 and B 4 Whether they are the same or different, and each is independently N or CR 2 ;R 2 As defined in the context.

[0204] In some implementation schemes, B 2 C is connected to L, B 1 B 3 and B 5 Whether they are the same or different, and each is independently N or CR 2 ;R 2 As defined in the context.

[0205] In some implementation schemes, B 1 For CR 2 ;R 2As defined in the context; in some implementations, B 1 For CH or N; in some implementations, B 1 For CH or CF; in some implementations, B 1 For CH.

[0206] In some implementation schemes, B 2 For CR 2 ;R 2 As defined in the context; in some implementations, B 2 For CH or N; in some implementations, B 2 For CH.

[0207] In some implementation schemes, B 3 For CR 2 ;R 2 As defined in the context; in some implementations, B 3 For CH or N; in some implementations, B 3 For CH.

[0208] In some implementation schemes, B 4 For CR 2 ;R 2 As defined in the context; in some implementations, B 4 For CH or N; in some implementations, B 4 For CH.

[0209] In some implementation schemes, B 5 For CR 2 ;R 2 As defined in the context; in some implementations, B 5 For CH or N; in some implementations, B 5 For CH.

[0210] In some implementation schemes, B 6 For CH or N; in some implementations, B 6 Let N be the number of elements in the array.

[0211] In some implementation schemes, B 7 For CH or N; in some implementations, B 7 For CH.

[0212] In some implementation schemes, B 6 For N; B 7 For CH.

[0213] In some implementation schemes, B 1 For CR 2 B 3 For CR2 B 4 For CR 2 ;R 2 As defined in the context; in some implementations, B 1 For CR 2 B 3 For CR 2 B 5 For CR 2 ;R 2 As defined in the context; in some implementations, B 1 For CH; B 3 For CH; B 4 For CH; in some implementations, B 1 For CH; B 3 For CH; B 5 For CH.

[0214] In some embodiments, ring X is a saturated or partially unsaturated 3- to 8-membered heterocyclic group; in some embodiments, ring X is a saturated or partially unsaturated 6-membered heterocyclic group; in some embodiments, ring X is... It can be a single bond or a double bond; in some implementations, ring X is selected from... In some implementations, ring X is In the above implementation scheme, * terminal and L x Connected, With rings W and V 2 The ring or R w2 The rings they belong to are connected.

[0215] In some implementation schemes, X 2 For CH.

[0216] In some implementations, L 1 It is a bond or NH.

[0217] In some implementation schemes, R a It is a hydrogen atom or a carbon atom. 1-6 Alkyl; in some embodiments, R a It is a hydrogen atom.

[0218] In some implementation schemes, Y 1 and Y 2 The ring is a 5-membered heteroaryl group; in some implementation schemes, Y 1 and Y 2 The ring is selected from pyrrole, furanyl, thiophene, imidazole, oxazolyl, thiazolyl, triazolyl, and pyrazolyl; in some embodiments, Y and Y 2The ring is selected from pyrrole, furanyl, thiophene, imidazolyl, and pyrazolyl; in some embodiments, Y 1 and Y 2 The ring it belongs to is pyrrole.

[0219] In some implementation schemes, Selected from R w3 With R 2 Together with their respective connected atoms, they form 5- to 10-membered heterocyclic groups; R w4 With R 2 Together with their respective connected atoms, they form 5- to 10-membered heterocyclic groups; *terminus and R w0 Connected.

[0220] In some implementation schemes, Y 1 Selected from N, O, S, CH, NH, NR w3 and CR w4 ;R w3 With R 2 Together with their respective connected atoms, they form 5- to 10-membered heterocycles; R w4 With R 2 Together with their respective connected atoms, they form 5- to 10-membered heterocyclic groups; in some implementations, Y 1 Selected from CH, N, NH, S, and O; in some embodiments, Y 1 For O or NH; in some implementations, Y 1 For O; in some implementations, Y 1 For CH.

[0221] In some implementation schemes, Y 2 Selected from S, N, O, CH and NH; in some embodiments, Y 2 It is NH or O; in some implementations, Y 2 It is NH.

[0222] In some implementation schemes, Y 3 Selected from O, S, and NH; in some embodiments, Y 3 For O or NH; in some implementations, Y 3 For O; in some implementations, Y 3 It is NH.

[0223] In some implementation schemes, Y 4 For N or CH; in some implementations, Y 4 For CH; in some implementations, Y 4 Let N be the number of elements in the array.

[0224] In some implementations, Y is C or N; in other implementations, Y is C.

[0225] In some embodiments, ring A is selected from phenyl, 5- to 20-membered heterocyclic groups, and 5- to 20-membered heteroaryl groups; in some embodiments, ring A is selected from phenyl, 9- to 15-membered heterocyclic groups, and 9- to 15-membered heteroaryl groups.

[0226] In some embodiments, ring A is selected from 6- to 20-membered monocyclic, bicyclic, or tricyclic aryl, 5- to 20-membered monocyclic, bicyclic, or tricyclic heteroaryl, 3- to 20-membered monocyclic, bicyclic, or tricyclic cycloalkyl (e.g., 13- or 14-membered tricyclic cycloalkyl), and 3- to 20-membered monocyclic, bicyclic, or tricyclic heterocyclic (e.g., 13- or 14-membered tricyclic heterocyclic).

[0227] In some embodiments, ring A is selected from 6- to 10-membered monocyclic or bicyclic aryl, 5- to 10-membered monocyclic or bicyclic heteroaryl, 11- to 20-membered tricyclic cycloalkyl (e.g., 13- or 14-membered tricyclic cycloalkyl), and 11- to 20-membered tricyclic heterocyclic (e.g., 13- or 14-membered tricyclic heterocyclic); in some embodiments, ring A is selected from phenyl, 9-membered bicyclic aryl, 9-membered bicyclic heteroaryl, and 13- or 14-membered tricyclic heterocyclic.

[0228] In some embodiments, ring A is selected from phenyl, 6-membered heteroaryl, 5-membered heteroaryl-6-membered heteroaryl, 5-membered heteroaryl-phenyl, 5-membered heterocyclic-6-membered heteroaryl, and 5-membered heterocyclic-phenyl.

[0229] In some implementation schemes, Selected from Q 1 Q 2 Q 3 and Q 4 One of them is a carbon atom and is associated with L or L B3 or Z 2 or Z 4 Connected, the other three are the same or different, and each is independently N or CR. 1 G 1 G 2 G 3 G 4 and G 5 One of them is a carbon atom and is associated with L or L B3 or Z 2 or Z 4 Connected, the other four are the same or different, and each is independently N or CR. 1 U is CH2 or C(O);

[0230] Q is selected from O, S, NR q and CR q1 R q2 ;

[0231] R q Selected from hydrogen atoms, alkyl groups, haloalkyl groups, hydroxyalkyl groups, cycloalkyl groups, heterocyclic groups, and cycloalkylalkyl groups;

[0232] R q1 and R q2 The same or different, and each independently selected from hydrogen, halogen, alkyl, alkenyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy, alkoxyalkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, cyano, hydroxyl, amino, and nitro; or, R q1 and R q2 Together with the attached carbon atom, they form a cycloalkyl or heterocyclic group; R A For R 1 ;R A1 Selected from hydrogen atoms, alkyl groups, haloalkyl groups, hydroxyalkyl groups, cycloalkyl groups, heterocyclic groups, and cycloalkylalkyl groups; R 1 As defined in the context.

[0233] In some implementation schemes, Selected from *End with L or L B3 or Z 2 or Z 4 Connected; m1 is 0, 1, 2, or 3; m2 is 0, 1, 2, 3, or 4; R 1 R A R A1 Q is as defined in the context.

[0234] In some implementation schemes, Selected from *End with L or L B3 or Z 2 or Z 4 Connected;

[0235] Where m1 is 0, 1, 2, or 3; m2 is 0, 1, 2, 3, or 4; m3 is 0, 1, 2, or 3; m4 is 0, 1, or 2; m5 is 0, 1, 2, or 3; A1 is N or CH; A2 is N or CH; d1, d2, d3, and d4 are each independently 0, 1, 2, 3, or 4; J is selected from bonds, O, (CR j1 R j2 )j、S、S(O、S(O)2、NR J C(O), C(O)NR J and NR J C(O); j is 0, 1, 2, 3 or 4; Q is selected from O, S, NR q and CR q1R q2 ;R A1 R J and R q Each is independently selected from hydrogen atoms, alkyl groups, haloalkyl groups, hydroxyalkyl groups, cycloalkyl groups, heterocyclic groups, and cycloalkylalkyl groups; R A R j1 R j2 R q1 and R q2 The same or different, and each independently selected from hydrogen, halogen, alkyl, alkenyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy, alkoxyalkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, cyano, hydroxyl, amino, and nitro; or, R j1 and R j2 Together with the attached carbon atom, they form a cycloalkyl or heterocyclic group; or, R q1 and R q2 Together with the attached carbon atom, they form cycloalkyl or heterocyclic groups.

[0236] In some implementation schemes, Selected from *End with L or L B3 or Z 2 or Z 4 The groups are connected, and the definitions of each group are as defined above.

[0237] In some implementation schemes, Selected from *End with L or L B3 or Z 2 or Z 4 The groups are connected, and the definitions of each group are as defined above.

[0238] In some implementation schemes, Selected from *End with L or L B3 or Z 2 or Z 4 Connected; R 1 m1, m2, R A R A1 Q is as defined in the context.

[0239] In some implementation schemes, Selected from

[0240] *End with L or L B3 or Z 2 or Z 4 Connected.

[0241] In some implementation schemes, Selected from *End with L or L B3 or Z 2 or Z 4 Connected. In some implementation schemes, Selected from *End with L or L B3 or Z 2 or Z 4 Connected. In some implementation schemes, Selected from

[0242] *End with L or L B3 or Z 2 or Z 4 Connected.

[0243] In some implementation schemes, A 1 Let N be the number of elements in the array.

[0244] In some implementation schemes, A 2 Let N be the number of elements in the array.

[0245] In some implementation schemes, A 1 For N, A 2 Let N be the number of elements in the array.

[0246] In some implementations, d1 and d2 are each independently 0, 1, 2, or 3; in some implementations, d1 and d2 are each independently 1, 2, or 3; in some implementations, d1 is 1 and d2 is 3; in some implementations, d1 is 3 and d2 is 1; in some implementations, d1 is 2 and d2 is 2; in some implementations, d1 is 1 and d2 is 2; in some implementations, d1 is 2 and d2 is 1; in some implementations, d1 is 1 and d2 is 1.

[0247] In some implementation schemes, R j1 and R j2 It is a hydrogen atom.

[0248] In some implementations, j is 0 or 1; in other implementations, j is 1.

[0249] In some implementations, J is selected from NH, CH2, and O; in other implementations, J is O.

[0250] In some implementation schemes, R J It is a hydrogen atom or a carbon atom. 1-6Alkyl; in some embodiments, R J It is a hydrogen atom.

[0251] In some implementations, d3 and d4 are each independently 0, 1, or 2; in some implementations, d3 and d4 are each independently 0 or 1; in some implementations, d3 is 0 and d4 is 1; in some implementations, d3 is 1 and d4 is 1.

[0252] In some implementation schemes, R q It is a hydrogen atom or a carbon atom. 1-6 Alkyl; in some embodiments, R q C 1-6 Alkyl; in some embodiments, R q It is a methyl group.

[0253] In some implementation schemes, R q1 and R q2 They may be the same or different, and each is independently a hydrogen atom or a carbon atom. 1-6 Alkyl; or, R q1 and R q2 Together with the attached carbon atom, they form a 3- to 6-membered cycloalkyl group; in some embodiments, R q1 and R q2 It is methyl; or, R q1 and R q2 Together with the attached carbon atom, they form a cyclopropyl group.

[0254] In some implementations, Q is NR q or CR q1 R q2 ;R q R q1 and R q2 As defined in the context; in some implementations, Q is NR. q ;R q C 1-6 Alkyl; in some embodiments, Q is N-methyl.

[0255] In some implementation schemes, R A Selected from hydrogen atoms, halogens and C 1-6 Alkyl; in some embodiments, R A C 1-6 Alkyl; in some embodiments, R A It is a methyl group.

[0256] In some implementation schemes, R A1 The hydrogen atom is C 1-6 Alkyl; in some embodiments, R A1 C 1-6 Alkyl; in some embodiments, RA1 It is a methyl group.

[0257] In some implementation schemes, R 1 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy groups and =O; or, two R groups. 1 Together with the adjacent carbon atoms, they form 3- to 6-membered cycloalkyl groups (e.g., two R atoms on the same carbon atom). 1 Together with the attached carbon atom, they form a cyclopropyl or cyclobutyl group; in some embodiments, R 1 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups and =O; in some embodiments, R 1 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl, C 1-6 Alkoxy and =O; in some embodiments, R 1 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl, C 1-6 Alkoxy groups and =O; or, two R groups on the same carbon atom. 1 Together with the attached carbon atom, they form a cyclopropyl group; in some embodiments, R 1 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl and C 1-6 Alkoxy; in some embodiments, R 1 They may be the same or different, and each is independently a hydrogen atom or a halogen; in some embodiments, R 1 It is a hydrogen atom.

[0258] In some implementations, m is 0, 1, 2, or 3; in some implementations, m is 0, 1, or 2; in some implementations, m is 0; in some implementations, m is 1; and in some implementations, m is 2.

[0259] In some implementations, m1 is 0, 1, or 2; in some implementations, m1 is 0 or 1; in some implementations, m1 is 0.

[0260] In some implementations, m2 is 0, 1, or 2; in some implementations, m2 is 0; in some implementations, m2 is 1; and in some implementations, m2 is 2.

[0261] In some implementations, m3 is 0, 1, or 2; in some implementations, m3 is 0 or 1; in some implementations, m3 is 0.

[0262] In some implementations, m4 is 0, 1, or 2; in some implementations, m4 is 0 or 1; in some implementations, m4 is 0.

[0263] In some implementations, m5 is 0, 1, or 2; in some implementations, m5 is 0 or 1; in some implementations, m5 is 0; in some implementations, m5 is 1; in some implementations, m5 is 2.

[0264] In some implementations, t2 is 0, 1, 2, 3, 4, 5, or 6; in some implementations, t2 is 0, 1, 2, or 3; in some implementations, t2 is 0, 1, or 2; in some implementations, t2 is 1, 2, or 3; in some implementations, t2 is 1 or 2; in some implementations, t2 is 3.

[0265] In some implementations, L is -(L B ) t2 -;L B They are the same or different, and each is independently selected from O, C(O), C 1-6 Alkylene, C 2-6 Alkyne group, 3- to 12-membered cycloalkyl group and 3- to 12-membered heterocyclic group, wherein the C 1-6 Alkylene, 3- to 12-membered cycloalkyl, and 3- to 12-membered heterocyclic groups are each independently selected from hydroxyl, halogen, C 1-6 Alkyl, C 1-6 The alkyl halogroup and =O are substituted with one or more substituents; t2 is 0, 1, 2, 3, 4, 5, or 6; in some embodiments, L is -(L B ) t2 -;L B They are the same or different, and each is independently selected from O, C(O), C 1-6 Alkylene, C 2-6 Alkyne group, 3- to 8-membered cycloalkyl group and 3- to 8-membered heterocyclic group; the C 1-6 Alkylene, 3- to 8-membered cycloalkyl, and 3- to 8-membered heterocyclic groups are each independently selected from hydroxyl, halogen, C 1-6 Alkyl, C 1-6 The alkyl halogroup and =O are substituted with one or more substituents; t2 is 0, 1, 2, 3, 4, 5, or 6; in some embodiments, L is -(L B ) t2 -;L B The same or different, and each independently selected from C 1-6Alkylene, 3- to 8-membered cycloalkyl, and 3- to 8-membered heterocyclic groups; t2 is 0, 1, 2, 3, 4, 5, or 6; in some embodiments, L is -(L B ) t2 -;L B The same or different, and each independently selected from C 1-3 Alkylene and 4- to 6-membered heterocyclic groups; t2 is 1, 2, or 3; in some embodiments, L is selected from bond, CH2, CH2CH2, CH2CH2CH2,

[0266] In some implementation schemes, L is selected from *The end is connected to a ring A or a phenyl group.

[0267] In some implementation schemes, L is selected from The * terminal is attached to ring A or a phenyl group. In some embodiments, L is selected from... The * terminal is attached to ring A or a phenyl group. In some embodiments, L is... The * terminal is attached to ring A or a phenyl group. In some embodiments, L is selected from... *The end is connected to ring A or phenyl.

[0268] In some implementations, L B3 Selected from alkyl groups, 3- to 8-membered cycloalkyl groups, and 3- to 8-membered heterocyclic groups. In some embodiments, L B3 It is a 4- to 6-membered heterocyclic group. In some embodiments, L B3 For key or * The terminal is connected to ring A or a phenyl group; f1 is 0, 1, 2, or 3; g1 is 0, 1, 2, or 3; Z 3 For N or CR z3 Z 4 For N or CR z4 ;R z3 and R z4 The same or different, and each independently selected from hydrogen, halogen, alkyl, cyano, hydroxyl, haloalkyl, hydroxyalkyl, alkoxy, cycloalkyl, and cycloalkylalkyl; k2 is 0, 1, 2, 3, 4, or 5; R z As defined in the context. In some implementations, L B3 Selected from alkyl, piperidinyl, piperazine, pyrrolidinyl, and aziridine. In some embodiments, L B3Selected from key, (include (and mixtures of the two in any proportion) and *The end is connected to ring A or phenyl.

[0269] In some implementations, L is *The end is connected to ring A or a phenyl group; and t, L B3 Z 1 Z 2 f, g, R z And k is as defined in the context. In some implementations, L is... *The end is connected to ring A or a phenyl group; and t, Z 1 Z 2 Z 3 Z 4 f, g, f1, g1, R z k and k2 are as defined in the context.

[0270] In some implementation schemes, Z 1 For N or CH; in some implementations, Z 1 Let N be the number of elements in the array.

[0271] In some implementation schemes, Z 2 For N or CH; in some implementations, Z 2 For N; in some implementations, Z 2 For CH.

[0272] In some implementation schemes, Z 1 For N; Z 2 For N; in some implementations, Z 1 CH; Z 2 For N. In some implementations, Z 1 For N; Z 2 For CH.

[0273] In some implementation schemes, Z 3 For N or CH; in some implementations, Z 3 Let N be the number of elements in the array.

[0274] In some implementation schemes, Z 4 For N or CH; in some implementations, Z 4 Let N be the number of elements in the array.

[0275] In some implementation schemes, Z 3 For N; Z 4 For N; in some implementations, Z 3 CH; Z 4 Let N be the number of elements in the array.

[0276] In some implementations, f is 0, 1, or 2; in other implementations, f is 0 or 1.

[0277] In some implementations, g is 0, 1, or 2; in other implementations, g is 0 or 1.

[0278] In some implementations, f is 1 and g is 1; in some implementations, f is 0 and g is 0; in some implementations, f is 1 and g is 0.

[0279] In some implementations, f1 is 0, 1, or 2; in other implementations, f1 is 0 or 1.

[0280] In some implementations, g1 is 0, 1, or 2; in other implementations, g1 is 0 or 1.

[0281] In some implementations, f1 is 1 and g1 is 1; in some implementations, f1 is 0 and g1 is 0; in some implementations, f1 is 1 and g1 is 0.

[0282] In some implementations, k is 0, 1, or 2; in other implementations, k is 0.

[0283] In some implementations, k2 is 0, 1, or 2; in other implementations, k2 is 0.

[0284] In some implementation schemes, R z Selected from hydrogen atoms, halogens and C 1-6 Alkyl group; or, two non-adjacent R groups. z Together with their respective connected carbon atoms, they form bridging carbon atoms. 1-3 Alkylene; or, two R atoms on the same carbon atom. z Together with the attached carbon atom, it forms a 3- to 6-membered cycloalkyl group (e.g., cyclopropyl, cyclobutyl); in some embodiments, R z Selected from hydrogen atoms, halogens, C 1-6 Alkyl and =O; in some embodiments, R z It is a hydrogen atom.

[0285] In some implementation schemes, R z1 R z2 R z3 and R z4 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl; in some embodiments, R z1 R z2 R z3 and R z4 Each is an independent hydrogen atom.

[0286] In some implementations, t is 0, 1, 2, 3, 4, or 5; in some implementations, t is 0 or 1; in some implementations, t is 0; in some implementations, t is 0, 1, 2, or 3; in some implementations, t is 0, 2, or 3; in some implementations, t is 2. In some implementations, M is selected from O, S, NR. m C(O) and C(O)NR m ;R m It is a hydrogen atom or a carbon atom. 1-6 Alkyl; in some embodiments, M is O or CH2; in some embodiments, M is O.

[0287] In some implementation schemes, M 1 Selected from the bond, CH2, CH2CH2, and CH2CH2CH2; in some embodiments, M 1 It is CH2.

[0288] In some implementation schemes, M 2 Selected from the bond, CH2, CH2CH2, and CH2CH2CH2; in some embodiments, M 2 For the bond or CH2; in some implementations, M 2 For key.

[0289] In some implementations, M is O or CH2; and / or M 1 Selected from the bond, CH2, CH2CH2 and CH2CH2CH2; and / or M 2 For a bond or CH2.

[0290] In some implementations, p is 0 or 1; in other implementations, p is 1.

[0291] In some implementations, p1 is 0, 1, 2, or 3; in some implementations, p1 is 0; in some implementations, p1 is 1; in some implementations, p1 is 2; and in some implementations, p1 is 3.

[0292] In some implementations, p2 is 0, 1, 2, or 3; in some implementations, p2 is 0, 1, or 2; in some implementations, p2 is 0 or 1; in some implementations, p2 is 0.

[0293] In some implementations, p1 is 0, 1, 2, or 3; p2 is 0, 1, 2, or 3; in some implementations, p1 is 0, 1, 2, or 3; p2 is 0 or 1; in some implementations, p1 is 1; p2 is 0; in some implementations, p1 is 2; p2 is 0; in some implementations, p1 is 3; p2 is 0; in some implementations, p1 is 0; p2 is 0; in some implementations, p1 is 2; p2 is 1; in some implementations, p1 is 0; p2 is 1; in some implementations, p1 is 1; p2 is 1.

[0294] In some implementation schemes, R m1 and R m2 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl and C 1-6 Haloalkyl; or, R m1 and R m2 Together with the attached carbon atom, they form a 3- to 6-membered cycloalkyl group; in some embodiments, R m1 and R m2 It is a hydrogen atom or a carbon atom. 1-6 Alkyl group; or, R on the same carbon atom m1 and R m2 Together with the attached carbon atom, it forms a 3- to 6-membered cycloalkyl group (e.g., cyclopropyl, cyclobutyl); in some embodiments, R m1 and R m2 It is a hydrogen atom; or, R on the same carbon atom. m1 and R m2 Together with the attached carbon atom, they form a cyclopropyl group; in some embodiments, R m1 and R m2 It is a hydrogen atom.

[0295] In some implementation schemes, R m It is a hydrogen atom or a carbon atom. 1-6 Alkyl (e.g., methyl); in some embodiments, R m It is a hydrogen atom.

[0296] In some implementation schemes, R w0 For C(O)NR 4 R 5 ;R 4 and R 5 As defined in the context; in some implementations, R w0 Selected from In some implementation schemes, R w0 for

[0297] In some implementation schemes, R 4 and R5 Whether the atoms are the same or different, and each is independently selected from hydrogen atoms, C atoms 1-6 Alkyl and 3- to 6-membered cycloalkyl; or, R 4 and R 5 Together with the attached nitrogen atom, they form a 3- to 8-membered heterocyclic group; in some embodiments, R 4 and R 5 They may be the same or different, and each is independently selected from hydrogen, methyl, ethyl, propyl, and cyclopropyl; or, R 4 and R 5 Together with the attached nitrogen atom, it forms In some implementation schemes, R 4 and R 5 Each independently is C 1-6 Alkyl; in some embodiments, R 4 and R 5 It is a methyl group.

[0298] In some implementation schemes, V 1 The answer is C.

[0299] In some implementations, T stands for C.

[0300] In some implementation schemes, V 1 C is C; T is C.

[0301] In some implementation schemes, V 1 N is N; T is C.

[0302] In some implementation schemes, V 1 C is C; T is N.

[0303] In some implementation schemes, V 2 For CR w1 ;R w1 As defined in the context; in some implementations, V 2 For N or CR w1 ;R w1 Selected from hydrogen atoms, halogens and C 1-6 Alkyl; in some embodiments, V 2 For N or CF; in some implementations, V 2 For CF; in some implementations, V 2 Let N be the number of elements in the array.

[0304] In some implementation schemes, R w1 Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl and C 1-6 Haloalkoxy; in some embodiments, R w1Selected from hydrogen atoms, halogens and C 1-6 Alkyl; in some embodiments, R w1 For halogen; in some implementations, R w1 It is F.

[0305] In some implementation schemes, R w2 Selected from hydrogen atoms, halogens and C 1-6 Alkyl; or, R w2 and R 2 Together with their respective connected atoms, they form 5- to 10-membered heterocyclic groups; in some implementations, R w2 For hydrogen atoms, or, R w2 and R 2 Together with their respective connected atoms, they form 5 to 9-membered heterocyclic groups; in some implementations, R w2 For hydrogen atoms, or, R w2 and R 2 Together with their respective connected atoms, they form a 6-membered heterocyclic group.

[0306] In some implementation schemes, R w2 Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl and C 1-6 Haloalkoxy; in some embodiments, R w2 Selected from hydrogen atoms, halogens and C 1-6 Alkyl; in some embodiments, R w2 It is a hydrogen atom.

[0307] In some implementation schemes, R w3 It is a hydrogen atom or a carbon atom. 1-6 Alkyl; or, R w3 and R 2 Together with their respective connected atoms, they form 5- to 10-membered heterocyclic groups; in some implementations, R w3 For hydrogen atoms, or, R w3 and R 2 Together with their respective connected atoms, they form 6- to 9-membered heterocyclic groups; in some implementations, R w3 For hydrogen atoms, or, R w3 and R 2 Together with their respective connected atoms, they form a 6-membered heterocyclic group.

[0308] In some implementation schemes, R w3 It is a hydrogen atom or a carbon atom. 1-6 Alkyl; in some embodiments, R w3 It is a hydrogen atom.

[0309] In some implementation schemes, Rw4 Selected from hydrogen atoms, halogens and C 1-6 Alkyl; or, R w4 and R 2 Together with their respective connected atoms, they form 5- to 10-membered heterocyclic groups; in some implementations, R w4 For hydrogen atoms, or, R w4 and R 2 Together with their respective connected atoms, they form 6- to 9-membered heterocyclic groups; in some implementations, R w4 For hydrogen atoms, or, R w4 and R 2 Together with their respective connected atoms, they form a 7-membered heterocyclic group.

[0310] In some implementation schemes, R w4 Selected from hydrogen atoms, halogens and C 1-6 Alkyl; in some embodiments, R w4 It is a hydrogen atom.

[0311] In some implementation schemes, R w5 Selected from hydrogen atoms, halogens and C 1-6 Alkyl; in some embodiments, R w5 It is a hydrogen atom.

[0312] In some implementations, n is 1, 2, 3, or 4; in some implementations, n is 1 or 2; in some implementations, n is 1; and in some implementations, n is 2.

[0313] In some implementations, n1 is 0, 1, or 2; in some implementations, n1 is 0; in some implementations, n1 is 0 or 1; in some implementations, n1 is 1.

[0314] In some implementations, n2 is 0, 1, or 2; in other implementations, n2 is 0.

[0315] In some implementations, an R 2 With R w2 R w3 Or R w4 Together with their respective connected atoms, they form 5- to 10-membered heterocyclic groups; the remaining R 2 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl and C 1-6 Halogenated alkoxy groups; in some embodiments, an R 2 With R w2 R w3 Or R w4Together with their respective connected atoms, they form 5 to 9-membered heterocyclic groups; the remaining R 2 For hydrogen atoms; in some implementations, an R 2 With R w2 R w3 Or R w4 Together with their respective connected atoms, they form 6- or 7-membered heterocyclic groups; the remaining R 2 For hydrogen atoms; in some implementations, an R 2 With R w2 Together with their respective connected atoms, they form a 6- or 7-membered heterocyclic group, and the remaining R 2 If present, it is selected from hydrogen atoms and halogens (e.g., F).

[0316] In some implementation schemes, R 2 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl and C 1-6 Haloalkoxy; in some embodiments, R 2 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl and C 1-6 Alkoxy; in some embodiments, R 2 It is a hydrogen atom or a halogen (e.g., F); in some embodiments, R 2 It is a hydrogen atom.

[0317] In some implementation schemes, R B6 and R B7 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl; in some embodiments, R B6 For hydrogen atoms; in some implementations, R B7 It is a hydrogen atom.

[0318] In some implementation schemes, R x They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl and C 1-6 Haloalkoxy; in some embodiments, R x They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl; in some embodiments, R x It is a hydrogen atom.

[0319] In some implementations, x is 0 or 1; in other implementations, x is 0.

[0320] In some implementations, L x -(L A ) t1 -;L A They may be the same or different, and each is independently selected from NH, C(O), C 1-6 Alkylene, 3- to 8-membered cycloalkyl, and 3- to 8-membered heterocyclic groups; t1 is 0, 1, 2, 3, 4, or 5; in some embodiments, L x -(L A ) t1 -;L A They may be the same or different, and each is independently selected from C(O) and C. 1-6 Alkylene, 3- to 6-membered cycloalkyl, and 3- to 6-membered heterocyclic groups; t1 is 0, 1, 2, or 3; in some embodiments, L x -(L A ) t1 -;L A They may be the same or different, and each is independently selected from NH, C(O) and C. 1-6 Alkylene; t1 is 0, 1, 2 or 3.

[0321] In some implementations, L x Selected from * The terminal is connected to G or ring Y.

[0322] In some implementations, L x Selected from * The terminal is connected to G or ring Y.

[0323] In some implementations, L x Selected from In some implementations, L x for * The terminal is connected to G or ring Y.

[0324] In some implementations, t1 is 0, 1, 2, 3, 4 or 5; in some implementations, t1 is 0, 1, 2 or 3; in some implementations, t1 is 0, 1 or 2; in some implementations, t1 is 2; in some implementations, t1 is 3.

[0325] In some embodiments, ring Y is a 5- to 10-membered heteroaryl group; in some embodiments, ring Y is a 5-membered heteroaryl group; in some embodiments, ring Y is selected from pyrazolyl, triazolyl, pyridinyl, pyrimidinyl, pyridoneyl, imidazolyl, thiazolyl, oxazolyl, pyrroleyl, thiophenyl, isoxazolyl, and furanyl; in some embodiments, ring Y is pyrazolyl or triazolyl; in some embodiments, ring Y is pyrazolyl; in some embodiments, ring Y is selected from... In some implementation schemes, ring Y is In some implementation schemes, ring Y is

[0326] In some implementation schemes, R y They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups and 3- to 6-membered cycloalkyl groups; in some embodiments, R y They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl and C 1-6 Haloalkoxy; in some embodiments, R y They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl; in some embodiments, R y It is a hydrogen atom or a halogen (e.g., F); in some embodiments, R y It is a hydrogen atom.

[0327] In some implementations, y is 0 or 1; in some implementations, y is 0; in some implementations, y is 1.

[0328] In some implementations, G is a hydrogen atom or Ring Y, R y and y as defined in the context; in some implementations, G is a hydrogen atom or Cycloyl Y is a 5-membered heteroaryl group; R y They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl; y is 0 or 1; in some embodiments, G is a hydrogen atom; in some embodiments, G is selected from hydrogen atoms,

[0329] In some implementations, G or Selected from hydrogen atoms,

[0330] In some implementations, G or Selected from hydrogen atoms, In some implementations, G or Selected from In some implementations, G is selected from hydrogen atoms, In some implementations, G or for

[0331] In some implementation schemes, for Or a mixture of the two in any proportion; in some embodiments, for In some implementation schemes, for

[0332] In some implementation schemes, R b It is a hydrogen atom or a carbon atom. 1-6 Alkyl; in some embodiments, R b It is a hydrogen atom.

[0333] In some implementation schemes, R 3 It is a hydrogen atom or a carbon atom. 1-6 alkyl.

[0334] In some implementation schemes, R 6 It is a hydrogen atom.

[0335] In some implementation schemes, R 8 and R 9 They may be the same or different, and each is independently a hydrogen atom or a halogen.

[0336] In some implementation schemes, R 7 Selected from hydrogen atoms, C 1-6 Alkyl, hydroxyl and C 1-6 Alkyl group.

[0337] In some implementation schemes, R 0 Same or different, and each independently selected from =O, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6Halogenated alkoxy and cyano groups; in some embodiments, R 0 They may be the same or different, and each is independently selected from halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups.

[0338] In some embodiments, the compound represented by general formula (IV-1) or a pharmaceutically acceptable salt thereof,

[0339] in,

[0340] G is H or Cycloyl Y is a 5-membered heteroaryl group; R y They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl; y is 0 or 1; L x -(L A ) t1 -;L A Same or different, and each

[0341] Independently selected from NH, C(O), C 1-6 Alkylene, 3- to 8-membered cycloalkyl and 3- to 8-membered heterocyclic groups; t1 is 0, 1, 2, 3, 4 or 5; It can be a single or double bond; R x They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl; x is 0 or 1; V 2 For N or CR w1 ;R w1 Selected from hydrogen atoms, halogens and C 1-6 Alkyl; R w2 Selected from hydrogen atoms, halogens and C 1-6 Alkyl; Y 3 Selected from O, S and NH; R 4 and R 5 Whether the atoms are the same or different, and each is independently selected from hydrogen atoms, C atoms 1-6 Alkyl and 3- to 6-membered cycloalkyl; or, R 4 and R 5 Together with the attached nitrogen atom, they form a 3- to 8-membered heterocyclic group; M is O or CH2; p1 is 0, 1, 2, or 3; p2 is 0, 1, or 2; B 1 B 3 and B 4 Whether they are the same or different, and each is independently N or CR 2 ;R 2 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl and C 1-6 Alkoxy; Z 1 For N or CH; Z 2For N or CH; f is 0, 1 or 2; g is 0, 1 or 2; t is 0, 1, 2, 3, 4 or 5; L B3 For key or *End is connected to ring A; Z 3 For N or CH; Z 4 For N or CH; f1 is 0, 1, or 2; g1 is 0, 1, or 2; R z Selected from hydrogen atoms, halogens, C 1-6 Alkyl group and =O; k is 0, 1, or 2; k2 is 0, 1, or 2; Selected from *End and L B3 Connected; Q is NR q or CR q1 R q2 ;R q It is a hydrogen atom or a carbon atom. 1-6 Alkyl; R q1 and R q2 They may be the same or different, and each is independently a hydrogen atom or a carbon atom. 1-6 Alkyl; or, R q1 and R q2 Together with the attached carbon atom, they form 3- to 6-membered cycloalkyl groups; R A C 1-6 Alkyl; R A1 C 1-6 Alkyl; R 1 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl and C 1-6 Alkoxy group; m1 is 0, 1, or 2; m2 is 0, 1, or 2; L 1 For bond or NH; X 2 For CH.

[0342] In some embodiments, the compound represented by general formula (IV-2) or a pharmaceutically acceptable salt thereof,

[0343] in,

[0344] G is H or Cycloyl Y is a 5-membered heteroaryl group; R y They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl; y is 0 or 1; L x -(L A ) t1 -;L A They may be the same or different, and each is independently selected from NH, C(O), C 1-6 Alkylene, 3- to 8-membered cycloalkyl and 3- to 8-membered heterocyclic groups; t1 is 0, 1, 2, 3, 4 or 5; It can be a single or double bond; R x They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl; x is 0 or 1; V 2 For N or CR w1 ;R w1 Selected from hydrogen atoms, halogens and C 1-6 Alkyl; R w2 Selected from hydrogen atoms, halogens and C 1-6 Alkyl; Y 4 For N or CH; R 4 and R 5 Whether the atoms are the same or different, and each is independently selected from hydrogen atoms, C atoms 1-6 Alkyl and 3- to 6-membered cycloalkyl; or, R 4 and R 5 Together with the attached nitrogen atom, they form a 3- to 8-membered heterocyclic group; M is O or CH2; p1 is 0, 1, 2, or 3; p2 is 0, 1, or 2; B 1 B 3 and B 4 Whether they are the same or different, and each is independently N or CR 2 ;R 2 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl and C 1-6 Alkoxy; Z 1 For N or CH; Z 2 For N or CH; f is 0, 1 or 2; g is 0, 1 or 2; t is 0, 1, 2, 3, 4 or 5; L B3 For key or *End is connected to ring A; Z 3 For N or CH; Z 4 For N or CH; f1 is 0, 1, or 2; g1 is 0, 1, or 2; R z Selected from hydrogen atoms, halogens, C 1-6 Alkyl group and =O; k is 0, 1, or 2; k2 is 0, 1, or 2; Selected from *End and L B3 Connected; Q is NR q or CR q1 R q2 ;R q It is a hydrogen atom or a carbon atom. 1-6 Alkyl; R q1 and R q2 They may be the same or different, and each is independently a hydrogen atom or a carbon atom. 1-6 Alkyl; or, R q1 and R q2 Together with the attached carbon atom, they form 3- to 6-membered cycloalkyl groups; RA C 1-6 Alkyl; R A1 C 1-6 Alkyl; R 1 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl and C 1-6 Alkoxy group; m1 is 0, 1, or 2; m2 is 0, 1, or 2; L 1 For bond or NH; X 2 For CH.

[0345] In some embodiments, the compound represented by general formula (V-1) or general formula (V-2), or a pharmaceutically acceptable salt thereof,

[0346] in,

[0347] G is H or Cycloyl Y is a 5-membered heteroaryl group; R y They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl; y is 0 or 1; L x -(L A ) t1 -;L A They may be the same or different, and each is independently selected from NH, C(O), C 1-6 Alkylene, 3- to 8-membered cycloalkyl and 3- to 8-membered heterocyclic groups; t1 is 0, 1, 2, 3, 4 or 5; It can be a single or double bond; R x They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl; x is 0 or 1; V 2 For N or CR w1 ;R w1 Selected from hydrogen atoms, halogens and C 1-6 Alkyl; Y 3 Selected from O, S, and NH; Y 4 For N or CH; R 4 and R 5 Whether the atoms are the same or different, and each is independently selected from hydrogen atoms, C atoms 1-6 Alkyl and 3- to 6-membered cycloalkyl; or, R 4 and R 5 Together with the attached nitrogen atom, they form a 3- to 8-membered heterocyclic group; M is O or CH2; p1 is 0, 1, 2, or 3; p2 is 0, 1, or 2; B 1 B 3 and B 5 Whether they are the same or different, and each is independently N or CR 2 ;R 2 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms.1-6 Alkyl and C 1-6 Alkoxy; Z 1 For N or CH; Z 2 For N or CH; f is 0, 1 or 2; g is 0, 1 or 2; t is 0, 1, 2, 3, 4 or 5; L B3 For key or *End is connected to ring A; Z 3 For N or CH; Z 4 For N or CH; f1 is 0, 1, or 2; g1 is 0, 1, or 2; R z Selected from hydrogen atoms, halogens, C 1-6 Alkyl group and =O; k is 0, 1, or 2; k2 is 0, 1, or 2; Selected from *End and L B3 Connected; Q is NR q or CR q1 R q2 ;R q It is a hydrogen atom or a carbon atom. 1-6 Alkyl; R q1 and R q2 They may be the same or different, and each is independently a hydrogen atom or a carbon atom. 1-6 Alkyl; or, R q1 and R q2 Together with the attached carbon atom, they form 3- to 6-membered cycloalkyl groups; R A C 1-6 Alkyl; R A1 C 1-6 Alkyl; R 1 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl and C 1-6 Alkoxy group; m1 is 0, 1, or 2; m2 is 0, 1, or 2; L 1 For bond or NH; X 2 For CH.

[0348] In some embodiments, the compound represented by the general formula (M-2) or a pharmaceutically acceptable salt thereof,

[0349] in,

[0350] Cycloyl Y is a 5-membered heteroaryl group; R y Each is independently a hydrogen atom or a halogen; y is 0 or 1; L x for *The end is connected to ring Y; R x For hydrogen atoms; x is 0; R w1 It is a halogen; R 4 and R 5Whether the atoms are the same or different, and each is independently selected from hydrogen atoms, C atoms 1-6 Alkyl and 3- to 6-membered cycloalkyl; or, R 4 and R 5 Together with the attached nitrogen atom, it forms a 3- to 8-membered heterocyclic group; M is O; p1 is 0, 1, 2, or 3; p2 is 0, 1, 2, or 3; R 2 It can be a hydrogen atom or a halogen; n1 can be 0 or 1; L is -(L B ) t2 -;L B The same or different, and each independently selected from C 1-6 Alkylene, 3- to 8-membered cycloalkyl and 3- to 8-membered heterocyclic groups; t2 is 0, 1, 2, 3, 4, 5 or 6; Selected from * Connect to L; R A C 1-6 Alkyl; R A1 C 1-6 Alkyl; Q is NR q or CR q1 R q2 ;R q C 1-6 Alkyl; R q1 and R q2 It is methyl; or, R q1 and R q2 Together with the attached carbon atom, they form a cyclopropyl group; R 1 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl and C 1-6 Alkoxy group; m1 is 0; m2 is 0, 1, or 2; m4 is 0; m5 is 0, 1, or 2; A 1 For N; A 2 N is the constant; d1 and d2 are each independently 0, 1, 2, or 3; J is 0; d3 is 0, d4 is 1; L is 0. 1 For bond or NH; X 2 For CH.

[0351] In some embodiments, the compound represented by general formula (VIII) or a pharmaceutically acceptable salt thereof,

[0352] in,

[0353] Selected from L x for *The end is connected to ring Y; R x For hydrogen atoms; x is 0; R w1 It is a halogen; R4 and R 5 M is methyl; p1 is 1; p2 is 1; M is O; R 2 For hydrogen atoms or halogens; n1 is 0 or 1; f is 0 or 1; g is 0 or 1; f1 is 0 or 1; g1 is 0 or 1; Z 1 For N or CH; Z 2 For N or CH; Z 3 For N or CH; Z 4 For N or CH; R z For hydrogen atoms; k is 0; k2 is 0; Selected from *End and Z 4 Connected; Q is NR q or CR q1 R q2 ;R q It is a C1-6 alkyl group; R q1 and R q2 It is methyl; or, R q1 and R q2 Together with the attached carbon atom, they form a cyclopropyl group; R 1 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl and C 1-6 alkoxy group; m1 is 0; m2 is 0, 1, or 2; L 1 For bond or NH; X 2 For CH.

[0354] In some embodiments, the compound represented by the general formula (IX) or a pharmaceutically acceptable salt thereof,

[0355] in,

[0356] Selected from L x for *The end is connected to ring Y; R x For hydrogen atoms; x is 0; R w1 It is a halogen; R 4 and R 5 M is methyl; p1 is 1; p2 is 1; M is O; R 2 It can be a hydrogen atom or a halogen; n can be 1 or 0 or 1; f can be 0 or 1; g can be 0 or 1; Z 1 For N or CH; Z 2 For N or CH; R z For hydrogen atoms; k is 0; Selected from *End and Z 2 Connected; R1 Each is independently a hydrogen atom or a halogen; m4 is 0 or 1; m5 is 0, 1, or 2; A 1 For N; A 2 N is the constant; d1 and d2 are each independently 0, 1, 2, or 3; J is 0; d3 is 0, d4 is 1; L is 0. 1 For key; X 2 For CH.

[0357] This disclosure also relates to the following specific implementation plans:

[0358] 1. A compound of general formula (I) or a pharmaceutically acceptable salt thereof,

[0359] in:

[0360] Ring A is selected from cycloalkyl, heterocyclic, aryl, and heteroaryl groups;

[0361] L 1 Selected from bond, O, C(O), S, S(O), S(O)2, NR a C(O)NR a and NR a C(O);

[0362] R a Selected from hydrogen atoms, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, and cycloalkylalkyl;

[0363] X 2 For N or CH;

[0364] Ring B is selected from cycloalkyl, heterocyclic, aryl, and heteroaryl groups;

[0365] Cycloyl X is selected from cycloalkyl, heterocyclic, aryl, and heteroaryl groups;

[0366] G is selected from hydrogen atom, halogen and Cycloyl Y is selected from cycloalkyl, heterocyclic, aryl, and heteroaryl groups;

[0367] Y represents 1 and Y 2 The ring in which it is located is either aromatic or non-aromatic;

[0368] V 1 For N or C;

[0369] V 2 For N or CR w1 ;

[0370] T is either N or C;

[0371] Y 1 and Y 2Each is independently selected from O, S, N, NR. w3 CR w4 and CR w4 R w5 ;

[0372] R w0 R w1 R w2 R w4 R w5 R x R y R 1 and R 2 The same or different, and each independently selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, cyano, nitro, hydroxyl, amino, alkoxy, haloalkyl, hydroxyalkyl, haloalkoxy, alkoxyalkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, -OR 3 -NR 4 R 5 -C(O)R 3 -C(O)OR 3 -C(O)NR 4 R 5 -C(O)NR 4 OR 3 -NR 6 C(O)R 3 -NR 6 C(O)OR 3 -NR 6 C(O)NR 4 R 5 -OC(O)R 3 -OC(O)NR 4 R 5 -S(O) v R 3 -S(O)(=NR) 7 )R 3 -S(O) v NR 4 R 5 -NR 6 S(O)2R 3 =O, =CR 8 R 9 、-Si(R 3 3. -P(O)(OR) 3 )2、-OP(O)(R 3 )2 and -OP(O)(OR 3 )2, wherein the alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each independently and optionally composed of one or more R groups. 0replace;

[0373] R w3 The atom is selected from hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups is independently and optionally converted by one or more R atoms. 0 replace;

[0374] Or, two Rs x 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. 0 replace;

[0375] Or, two Rs y 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. 0 replace;

[0376] Or, two Rs 1 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. 0 replace;

[0377] Or, two Rs 2 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. 0 replace;

[0378] Or, R 2 With R w2 Together with their respective attached atoms, they form a cycloalkyl or heterocyclic group, each of which is independently and optionally influenced by one or more R atoms. 0 replace;

[0379] Or, R 2 With R w3 Together with their respective connected atoms, they form a heterocyclic group, each of which is independently and optionally influenced by one or more R atoms. 0 Replace; or,

[0380] Or, R 2 With R w4 Together with their respective attached atoms, they form a cycloalkyl or heterocyclic group, each of which is independently and optionally influenced by one or more R atoms. 0 replace;

[0381] The condition is that at least one R 2 With R w2 R w3 Or R w4Together with their respective attached atoms, they form a cycloalkyl or heterocyclic group, each of which is independently and optionally influenced by one or more R atoms. 0 replace;

[0382] n is 1, 2, 3, 4, 5, 6, or 7;

[0383] x, y, and m are each independently 0, 1, 2, 3, 4, 5, 6, or 7;

[0384] L x -(L A ) t1 -;

[0385] L is -(L) B ) t2 -;

[0386] L A and L B The same or different, and each independently selected from the following groups: bond, alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, O, C(O), C(S), NR b S, S(O) and S(O)2, wherein the alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl groups are each independently and optionally selected by one or more R 0 replace;

[0387] R b Selected from hydrogen atoms, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, and cycloalkylalkyl;

[0388] t1 is selected from integers from 0 to 10;

[0389] t2 is selected from integers from 0 to 20;

[0390] R 3 R 4 and R 5 The same or different, and each independently selected from hydrogen atoms, alkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl, wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl is independently optionally selected by one or more R 0 Replace; or R 4 and R 5 Together with the attached nitrogen atom, they form a heterocyclic group or a heteroaryl group, each of which is independently and optionally influenced by one or more R atoms. 0 replace;

[0391] R 6 Selected from hydrogen atoms, alkyl groups, haloalkyl groups, hydroxyalkyl groups, and cycloalkyl groups;

[0392] R 7Selected from hydrogen atoms, alkyl groups, haloalkyl groups, hydroxyalkyl groups, hydroxyl groups, alkoxy groups, haloalkoxy groups, and cycloalkyl groups;

[0393] R 8 and R 9 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, alkyl groups, haloalkyl groups, hydroxyalkyl groups, and cycloalkyl groups; or, R 8 and R 9 Together with the attached carbon atom, they form cycloalkyl or heterocyclic groups;

[0394] R 0 The same or different, and each independently selected from =O, halogen, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, aminoalkyl, hydroxy, alkenyl, alkynyl, cyano, nitro, amino, -NHalkyl, -N(alkyl)2, -C(O)Oalkyl, -C(O)OH, -C(O)NH2, -C(O)NH(alkyl), -C(O)N(alkyl)2, -C(O)halogen, -C(O)alkyl, -S(alkyl), cycloalkyl, cycloalkylalkyl, cycloalkyloxy, heterocyclic, heterocyclic alkyl, heterocyclic oxy, aryl, arylalkyl, aryloxy, heteroaryl, heteroarylalkyl and heteroaryloxy; or, two R 0 Together with the attached atoms, they form cycloalkyl or heterocyclic groups; and

[0395] v can be 0, 1, or 2.

[0396] 2. The compound of general formula (I) according to embodiment 1, or a pharmaceutically acceptable salt thereof, is a compound of general formula (III-2) or a pharmaceutically acceptable salt thereof:

[0397] in,

[0398] B 1 B 3 and B 5 Whether they are the same or different, and each is independently N or CR 2 ;

[0399] M is selected from (CR) m1 R m2 ) p O, S, S(O), S(O)2, NR m C(O), C(O)NR m and NR m C(O);

[0400] M 1 For key or (CR) m1 R m2 ) p1 ;

[0401] M2 For key or (CR) m1 R m2 ) p2 ;

[0402] p is 0, 1, 2, 3 or 4;

[0403] p1 is 0, 1, 2, 3 or 4;

[0404] p2 is 0, 1, 2, 3 or 4;

[0405] R m Selected from hydrogen atoms, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, and cycloalkylalkyl;

[0406] R m1 and R m2 The same or different, and each independently selected from hydrogen atom, halogen, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, aminoalkyl, alkenyl, alkynyl, cyano, hydroxyl, nitro, amino, -NHalkyl, -N(alkyl)2, -C(O)Oalkyl, -C(O)OH, -C(O)NH2, -C(O)NH(alkyl), -C(O)N(alkyl)2, -C(O)halogen, -C(O)alkyl, -S(alkyl), cycloalkyl, cycloalkylalkyl, cycloalkyloxy, heterocyclic, heterocyclic alkyl, heterocyclic oxy, aryl, arylalkyl, aryloxy, heteroaryl, heteroarylalkyl and heteroaryloxy; or, R m1 and R m2 Together with the attached carbon atom, they form a cycloalkyl or heterocyclic group; or, R m1 and R m2 Together they form = O; and

[0407] G, L x , ring X, R x x, R w0 Y 1 Y 2 V 1 V 2 T R 2 L, ring A, R 1 m, L 1 and X 2 As defined in Implementation Scheme 1.

[0408] 3. A compound of general formula (I) or a pharmaceutically acceptable salt thereof according to embodiment 1 or 2, wherein the compound is of general formula (N) or general formula (N-1) or a pharmaceutically acceptable salt thereof.

[0409] in,

[0410] Ring A is selected from cycloalkyl, heterocyclic, aryl, and heteroaryl groups;

[0411] n1 is 0, 1, 2 or 3;

[0412] It can be a single bond or a double bond;

[0413] Y 3 Selected from NR w3 O and S; and

[0414] G, ring Y, R y y, L x R x x, R w1 R w3 R 4 R 5 M, p1, p2, R m1 R m2 R 2 L, R 1 m, L 1 and X 2 As defined in Implementation Scheme 2.

[0415] 4. A compound of general formula (I) according to embodiment 1 or 2, or a pharmaceutically acceptable salt thereof, which is a compound of general formula (V-1) or general formula (V-2) or a pharmaceutically acceptable salt thereof.

[0416] in,

[0417] Y 3 Selected from NR w3 O and S;

[0418] Y 4 For N or CR w4 ;

[0419] It can be a single bond or a double bond;

[0420] t is an integer from 0 to 10;

[0421] f is 0, 1, 2, or 3;

[0422] g can be 0, 1, 2, or 3;

[0423] Z 1 For N or CR z1 ;

[0424] Z 2 For N or CR z2 ;

[0425] Rz1 and R z2 They may be the same or different, and each is independently selected from hydrogen, halogen, alkyl, cyano, hydroxyl, haloalkyl, hydroxyalkyl, alkoxy, cycloalkyl and cycloalkylalkyl;

[0426] Each R z They may be the same or different, and each is independently selected from hydrogen atoms, halogens, alkyl groups, haloalkyl groups, hydroxyalkyl groups, alkoxy groups, haloalkoxy groups, cyano groups, hydroxyl groups, =O groups, cycloalkyl groups, and heterocyclic groups; or, two R groups. z Together with their respective connected atoms, they form cycloalkyl or heterocyclic groups;

[0427] k can be 0, 1, 2, 3, 4 or 5;

[0428] L B3 Selected from: bond, alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, O, C(O), C(S), NR b S, S(O) and S(O)2, wherein the alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl groups are each independently and optionally selected by one or more R 0 Replace; and

[0429] G, L x R x x, R 4 R 5 V 2 R w3 R w4 M, p1, p2, B 1 B 3 B 5 R 0 R b Ring A, m, R 1 L 1 and X 2 As defined in Implementation Scheme 2.

[0430] 5. A compound of general formula (I) according to any one of embodiments 1 to 4, or a pharmaceutically acceptable salt thereof, wherein Y 3 Selected from O, S, and NH; for example, Y 3 It can be NH or O;

[0431] and / or Y 4 For example, Y. 4 For CH.

[0432] 6. A compound of general formula (I) according to any one of embodiments 1 to 3 and 5, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of general formula (M-2) or a pharmaceutically acceptable salt thereof.

[0433] in,

[0434] Ring A is selected from cycloalkyl, heterocyclic, aryl, and heteroaryl groups;

[0435] n1 is 0, 1, 2, or 3; and

[0436] Ring Y, R y y, L x R x x, R w1 R 4 R 5 M, p1, p2, R 2 L, R 1 m, L 1 and X 2 As defined in Implementation Scheme 2.

[0437] 7. A compound of general formula (I) according to any one of embodiments 1 to 6, wherein the compound is a compound of general formula (VIII) or general formula (IX) or a pharmaceutically acceptable salt thereof.

[0438] in,

[0439] f is 0, 1, 2, or 3; g is 0, 1, 2, or 3; f1 is 0, 1, 2, or 3; g1 is 0, 1, 2, or 3;

[0440] Z 1 For N or CR z1 Z 2 For N or CR z2 Z 3 For N or CR z3 Z 4 For N or CR z4 ;

[0441] R z1 R z2 R z3 and R z4 They may be the same or different, and each is independently selected from hydrogen, halogen, alkyl, cyano, hydroxyl, haloalkyl, hydroxyalkyl, alkoxy, cycloalkyl and cycloalkylalkyl;

[0442] Each R z They may be the same or different, and each is independently selected from hydrogen atoms, halogens, alkyl groups, haloalkyl groups, hydroxyalkyl groups, alkoxy groups, haloalkoxy groups, cyano groups, hydroxyl groups, =O groups, cycloalkyl groups, and heterocyclic groups; or, two R groups. z Together with their respective connected atoms, they form cycloalkyl or heterocyclic groups;

[0443] k is 0, 1, 2, 3, 4, or 5; k2 is 0, 1, 2, 3, 4, or 5; and

[0444] Ring Y, R y y, L x R x x, R w1 R 4 R 5 M, p1, p2, R 2 n1, ring A, R 1 m, L 1 and X 2 As defined in Implementation Scheme 6.

[0445] 8. A compound of general formula (I) according to any one of embodiments 1 to 7, or a pharmaceutically acceptable salt thereof, wherein ring A is selected from 6 to 20-membered monocyclic, bicyclic or tricyclic aryl, 5 to 20-membered monocyclic, bicyclic or tricyclic heteroaryl, 3 to 20-membered monocyclic, bicyclic or tricyclic cycloalkyl and 3 to 20-membered monocyclic, bicyclic or tricyclic heterocyclic groups; for example, ring A is selected from 6 to 10-membered monocyclic or bicyclic aryl, 5 to 10-membered monocyclic or bicyclic heteroaryl, 11 to 20-membered tricyclic cycloalkyl and 11 to 20-membered tricyclic heterocyclic groups; or, for example, ring A is selected from phenyl, 9-membered bicyclic aryl, 9-membered bicyclic heteroaryl and 13 or 14-membered tricyclic heterocyclic groups;

[0446] and / or R 1 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy groups and =O; or, two R groups. 1 Together with the adjacent carbon atoms, they form 3- to 6-membered cycloalkyl groups;

[0447] And / or m is 0, 1, 2 or 3.

[0448] 9. A compound of general formula (I) according to any one of embodiments 1 to 8, wherein... Selected from Where, * end and L or L B3 or Z 2 or Z 4 Connected; m1 is 0, 1, 2, or 3; m2 is 0, 1, 2, 3, or 4; m3 is 0, 1, 2, or 3; m4 is 0, 1, or 2; m5 is 0, 1, 2, or 3; A1 is N or CH; A2 is N or CH; d1, d2, d3, and d4 are each independently 0, 1, 2, 3, or 4; J is selected from bonds, O, (CR j1 R j2 )j、S、S(O、S(O)2、NR JC(O), C(O)NR J and NR J C(O); j is 0, 1, 2, 3 or 4; Q is selected from O, S, NR q and CR q1 R q2 ;R A1 R J and R q Each is independently selected from hydrogen atoms, alkyl groups, haloalkyl groups, hydroxyalkyl groups, cycloalkyl groups, heterocyclic groups, and cycloalkylalkyl groups; R A R j1 R j2 R q1 and R q2 The same or different, and each independently selected from hydrogen, halogen, alkyl, alkenyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy, alkoxyalkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, cyano, hydroxyl, amino, and nitro; or, R j1 and R j2 Together with the attached carbon atom, they form a cycloalkyl or heterocyclic group; or, R q1 and R q2 Together with the attached carbon atom, they form cycloalkyl or heterocyclic groups;

[0449] For example, Selected from Where, * end and L or L B3 or Z 2 or Z 4 Connected.

[0450] 10. A compound of general formula (I) or a pharmaceutically acceptable salt thereof according to any one of embodiments 1 to 3, 5, 6, 8 and 9, wherein L is -(L B ) t2 -;L B They are the same or different, and each is independently selected from O, C(O), C 1-6 Alkylene, C 2-6 Alkyne group, 3- to 8-membered cycloalkyl group and 3- to 8-membered heterocyclic group, wherein C 1-6 Alkylene, 3- to 8-membered cycloalkyl, and 3- to 8-membered heterocyclic groups are each independently selected from hydroxyl, halogen, C 1-6 Alkyl, C 1-6 The alkyl halogroup and =O are substituted with one or more substituents; t2 is 0, 1, 2, 3, 4, 5, or 6; for example, L is selected from... Among them, the * end is connected to ring A.

[0451] 11. A compound of general formula (I) according to any one of embodiments 2 to 10, or a pharmaceutically acceptable salt thereof, wherein M is O or CH2; for example, M is O;

[0452] And / or p1 is 0, 1, 2 or 3; p2 is 0, 1, 2 or 3; for example, p1 is 1; p2 is 1.

[0453] 12. A compound of general formula (I) according to any one of embodiments 1 to 11, or a pharmaceutically acceptable salt thereof, wherein R 4 and R 5 Whether the atoms are the same or different, and each is independently selected from hydrogen atoms, C atoms 1-6 Alkyl and 3- to 6-membered cycloalkyl; or, R 4 and R 5 Together with the attached nitrogen atom, they form 3 to 8-membered heterocyclic groups; for example, R 4 and R 5 Each independently is C 1-6 Alkyl groups; for example, R 4 and R 5 It is a methyl group.

[0454] 13. A compound of general formula (I) according to any one of embodiments 1 to 12, or a pharmaceutically acceptable salt thereof, wherein R w1 Selected from hydrogen atoms, halogens and C 1-6 Alkyl; for example, R w1 It is a halogen.

[0455] 14. A compound of general formula (I) according to any one of embodiments 1 to 13, or a pharmaceutically acceptable salt thereof, wherein R 2 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl and C 1-6 Alkyl groups; for example, R 2 It can be a hydrogen atom or a halogen.

[0456] 15. A compound of general formula (I) according to any one of embodiments 1 to 14, wherein L x -(L A ) t1 -;L A They may be the same or different, and each is independently selected from NH, C(O) and C. 1-6 Alkylene; t1 is 0, 1, 2 or 3; for example, L x Selected from Among them, the * end is connected to G or ring Y.

[0457] 16. A compound of general formula (I) according to any one of embodiments 1 to 15, or a pharmaceutically acceptable salt thereof, wherein ring Y is a 5-membered heteroaryl group; R yThey may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl; y is 0 or 1; for example, Selected from

[0458] Group A: Typical compounds disclosed herein include, but are not limited to:

[0459] On the other hand, this disclosure provides a compound of general formula (IV-1A) or general formula (IV-2A) or a salt thereof.

[0460] in,

[0461] R L It is a hydrogen atom or an amino protecting group; and

[0462] G, L x , R x x, R 4 R 5 Y 3 Y 4 V 2 R w2 M, p1, p2, B 1 B 3 B 4 Z 1 f, g, R z And k is as defined in general formula (IV-1) or (IV-2).

[0463] This disclosure provides a compound of general formula (V-1A) or general formula (V-2A) or a salt thereof.

[0464] in,

[0465] R L It is a hydrogen atom or an amino protecting group; and

[0466] G, L x , R x x, R 4 R 5 Y 3 Y 4 V 2 M, p1, p2, B 1 B 3 B 5 Z 1 f, g, R z And k is as defined in general formula (V-1) or (V-2).

[0467] This disclosure provides a compound of general formula (VI-2A) or a salt thereof.

[0468] in,

[0469] R L It is a hydrogen atom or an amino protecting group; and

[0470] Ring Y, R y y, L x R x x, R 4 R 5 R w1 R w2 M, p1, p2, R 2 n1, Z 1 f, g, R z And k is as defined in general formula (VI-2).

[0471] This disclosure provides a compound of general formula (VII-2A) or a salt thereof.

[0472] in,

[0473] R L It is a hydrogen atom or an amino protecting group; and

[0474] Ring Y, R y y, L x R x x, R 4 R 5 R w1 M, p1, p2, R 2 n1, Z 1 f, g, R zAnd k is as defined in general formula (VII-2).

[0475] In some implementation schemes, R L It is a hydrogen atom or Boc; in some implementations, R L For hydrogen atoms; in some implementations, R L For Boc.

[0476] This disclosure provides a compound of general formula (V-1a) or a salt thereof.

[0477] in,

[0478] G, L x R x x R 4 R 5 V 2 Y 3 Y 4 M, p1, p2, B 1 B 3 B 5 Z 1 f, g, R z And k is as defined in general formula (V-1).

[0479] This disclosure provides a compound of general formula (VII-2a) or a salt thereof.

[0480] in,

[0481] Ring Y, R y y, L x R x x, R 4 R 5 M, p1, p2, R w1 R 2 n1, Z 1 f, g, R z And k is as defined in general formula (VII-2).

[0482] Typical intermediate compounds disclosed herein include, but are not limited to:

[0483] Another aspect of this disclosure relates to a method for preparing a compound of general formula (VIII) or a pharmaceutically acceptable salt thereof, the method comprising:

[0484] The compound of general formula (VII-2a) or its salt undergoes a reductive amination reaction with the compound of general formula (VIIIB) or its salt to give the compound of general formula (VIII) or its pharmaceutically usable salt.

[0485] in,

[0486] Z 2 CH; Z 3 Let N be N; and

[0487] Ring Y, R y y, L x R x x, R w1 R 4 R 5 M, p1, p2, R 2 n1, Z 1 Z 4 f, g, f1, g1, R z k, k2, ring A, R 1 m, L 1 and X 2 As defined in general formula (VIII).

[0488] Another aspect of this disclosure relates to a method for preparing a compound of general formula (IX) or a pharmaceutically acceptable salt thereof, the method comprising:

[0489] The compound of general formula (VII-2a) or its salt undergoes a reductive amination reaction with the compound of general formula (IXB) or its salt to give the compound of general formula (IX) or its pharmaceutically usable salt.

[0490] in,

[0491] Z 2 For CH;

[0492] Selected from *End and Z 2 Connected; A1 is N; and A2, J, d1, d2, d3, d4, m4, m5, ring Y, R y y, L x R x x, R w1 R 4 R 5 M, p1, p2, R 2 n1, Z 1 f, g, R z , k, R 1 L 1 and X 2 As defined above.

[0493] In some embodiments, the reductive amination reaction occurs in the presence of a reducing agent; in some embodiments, the reductive amination reaction occurs under acidic conditions and in the presence of a reducing agent; in some embodiments, the reagents providing the acidic conditions include, but are not limited to, Lewis acids such as acetic acid, glacial acetic acid, TiCl4, Ti(i-PrO)3, and BF3·Et2O; furthermore, the acidic environment may also be generated during the reaction, for example, by reacting amine hydrochloride or trifluoroacetate with sodium acetate to generate acetic acid in situ.

[0494] In some embodiments, the reducing agent includes, but is not limited to, sodium borohydride acetate, sodium triacetoxyborohydride, sodium borohydride, lithium borohydride, sodium cyanoborohydride, sodium acetylborohydride, and sodium triacetoxyborohydride; in some embodiments, the reducing agent is sodium triacetoxyborohydride.

[0495] In some embodiments, the above preparation method is carried out in a solvent, including but not limited to: 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, and mixtures thereof.

[0496] Another aspect of this disclosure relates to a pharmaceutical composition comprising a compound of the formulas (M), (I), (I-1), (II-1), (II-2), (II-3), (II-4), (III-1), (III-2), (III-3), (III-4), (IV-1), (IV-2), (V-1), (V-2), (VI-1), (VI-2), (VII-1), (VII-2), (N), (N-1), (M-1), (M-2), (M-3), (M-4), (VIII), (IX) or shown in this disclosure, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients.

[0497] This disclosure further relates to the use of compounds of the above general formulas (M), (I), (I-1), (II-1), (II-2), (II-3), (II-4), (III-1), (III-2), (III-3), (III-4), (IV-1), (IV-2), (V-1), (V-2), (VI-1), (VI-2), (VII-1), (VII-2), (N), (N-1), (M-1), (M-2), (M-3), (M-4), (VIII), (IX) or those shown in this disclosure, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising them, in the preparation of a medicament for inhibiting or degrading STAT6.

[0498] This disclosure further relates to the use of the compounds of the above general formulas (M), (I), (I-1), (II-1), (II-2), (II-3), (II-4), (III-1), (III-2), (III-3), (III-4), (IV-1), (IV-2), (V-1), (V-2), (VI-1), (VI-2), (VII-1), (VII-2), (N), (N-1), (M-1), (M-2), (M-3), (M-4), (VIII), (IX) or those shown in this disclosure, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising them, in the preparation of a medicament for regulating the ubiquitination and degradation of STAT6 protein in a subject.

[0499] This disclosure further relates to the use of the compounds of the above general formulas (M), (I), (I-1), (II-1), (II-2), (II-3), (II-4), (III-1), (III-2), (III-3), (III-4), (IV-1), (IV-2), (V-1), (V-2), (VI-1), (VI-2), (VII-1), (VII-2), (N), (N-1), (M-1), (M-2), (M-3), (M-4), (VIII), (IX) or those shown in this disclosure, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising them, in the preparation of medicaments for the treatment and / or prevention of diseases or conditions mediated or dependent on STAT6.

[0500] This disclosure further relates to the aforementioned general formulas (M), (I), (I-1), (II-1), (II-2), (II-3), (II-4), (III-1), (III-2), (III-3), (III-4), (IV-1), (IV-2), (V-1), (V-2), (VI-1), (VI-2), (VII-1), (VII-2), (N), (N-1), (M-1), (M-2), (M-3), and (M... -4) Use of compounds of general formula (VIII), general formula (IX) or those disclosed herein, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising thereof, in the preparation of medicaments for the treatment and / or prevention of cancer, inflammatory diseases (e.g., type 2 inflammatory diseases), autoimmune diseases, neurodegenerative diseases, viral diseases, genetic diseases, hormone-related diseases, metabolic diseases, organ transplant-related diseases, immunodeficiency diseases, destructive bone diseases, proliferative diseases, infectious diseases, diseases related to cell death, thrombin-induced platelet aggregation, liver diseases, pathological immune conditions involving T-cell activation, cardiovascular diseases, or central nervous system diseases;In some implementations, the preparation is intended for the treatment and / or prevention of asthma, eosinophilic asthma (EA), atopic dermatitis (AD), chronic obstructive pulmonary disease (COPD), urticaria, nodular prurigo, esophagitis, eosinophilic esophagitis, bronchitis, diabetes, atherosclerosis, gout, arthritis, gouty arthritis, osteoarthritis, systemic lupus erythematosus, polychondritis, colitis, conjunctivitis, allergic rhinitis, chronic rhinitis with nasal polyps, rheumatoid arthritis, juvenile arthritis, scleroderma, Wegener's granulomatosis, dermatomyositis, hepatitis, myasthenia gravis, Stevens-Johnson syndrome, inflammatory bowel disease, ulcerative colitis, Crohn's disease, irritable bowel syndrome, celiac disease, periodontitis, kidney disease, glomerular disease, alcoholic liver disease, multiple sclerosis, endocrine ophthalmopathy, Graves' disease, sarcoidosis, alveolitis, chronic allergic pneumonia, systemic sclerosis, primary biliary cirrhosis, and other conditions. Uveitis, Sjögren's syndrome, interstitial pulmonary fibrosis, psoriatic arthritis, systemic juvenile idiopathic arthritis, cold and heat protein-related periodic arthritis syndrome, nephritis, vasculitis, cystitis, glomerulonephritis, chronic granulomatous disease, endometriosis, pancreatitis, acute lung injury, acute respiratory distress syndrome, allergic reactions, sinusitis, pulmonary hypertension, cataracts, thyroiditis, appendicitis, allergies, cervicitis, cholangitis, cholecystitis, conjunctivitis, cystitis. Uses in medications for dacryoadenitis, dermatitis, dermatomyositis, encephalitis, encephalomyelitis, endocarditis, endometritis, upper gastritis, gastroenteritis, allergic purpura, idiopathic thrombocytopenic purpura (ITP), Graves' disease, ankylosing spondylitis, anaphylactic shock, hidradenitis suppurativa, interstitial lung disease, laryngitis, mastitis, meningitis, myelitis, myocarditis, myositis, nephritis, oophoritis, orchitis, osteitis, otitis media, mumps, pneumonia, polymyositis, or prostatitis.

[0501] This disclosure also relates to a method for regulating the ubiquitination and degradation of STAT6 protein in a subject, comprising administering to a desired patient a compound of the above general formula (M), general formula (I), general formula (I-1), general formula (II-1), general formula (II-2), general formula (II-3), general formula (II-4), general formula (III-1), general formula (III-2), general formula (III-3), general formula (III-4), general formula (IV-1), general formula (IV-2), general formula (V-1), general formula (V-2), general formula (VI-1), general formula (VI-2), general formula (VII-1), general formula (VII-2), general formula (N), general formula (N-1), general formula (M-1), general formula (M-2), general formula (M-3), general formula (M-4), general formula (VIII), general formula (IX) or the compound shown in this disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the thereof.

[0502] This disclosure also relates to a method of inhibiting or degrading STAT6 in a subject, comprising administering to a desired patient a compound of the above general formula (M), general formula (I), general formula (I-1), general formula (II-1), general formula (II-2), general formula (II-3), general formula (II-4), general formula (III-1), general formula (III-2), general formula (III-3), general formula (III-4), general formula (IV-1), general formula (IV-2), general formula (V-1), general formula (V-2), general formula (VI-1), general formula (VI-2), general formula (VII-1), general formula (VII-2), general formula (N), general formula (N-1), general formula (M-1), general formula (M-2), general formula (M-3), general formula (M-4), general formula (VIII), general formula (IX) or the compound shown in this disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the thereof.

[0503] This disclosure also relates to a method of treating and / or preventing diseases or conditions mediated or dependent on STAT6, comprising administering to a desired patient a compound of the above general formula (M), general formula (I), general formula (I-1), general formula (II-1), general formula (II-2), general formula (II-3), general formula (II-4), general formula (III-1), general formula (III-2), general formula (III-3), general formula (III-4), general formula (IV-1), general formula (IV-2), general formula (V-1), general formula (V-2), general formula (VI-1), general formula (VI-2), general formula (VII-1), general formula (VII-2), general formula (N), general formula (N-1), general formula (M-1), general formula (M-2), general formula (M-3), general formula (M-4), general formula (VIII), general formula (IX) or the compound shown in this disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the thereof.

[0504] This disclosure also relates to a method for treating and / or preventing cancer, inflammatory diseases (e.g., type 2 inflammatory disease), autoimmune diseases, neurodegenerative diseases, viral diseases, genetic diseases, hormone-related diseases, metabolic diseases, organ transplant-related diseases, immunodeficiency diseases, destructive bone diseases, proliferative diseases, infectious diseases, diseases related to cell death, thrombin-induced platelet aggregation, liver diseases, pathological immune conditions involving T cell activation, cardiovascular diseases, or central nervous system diseases, comprising administering the above general formulas (M), (I), (I-1), (II-1), (II-2), and (II-3) to the desired patient. Formulas II-3, II-4, III-1, III-2, III-3, III-4, IV-1, IV-2, V-1, V-2, VI-1, VI-2, VII-1, VII-2, N, N-1, M-1, M-2, M-3, M-4, VIII, IX, or compounds of the present disclosure or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the thereof, in some embodiments,Treatment and / or prevention of asthma, eosinophilic asthma (EA), atopic dermatitis (AD), chronic obstructive pulmonary disease (COPD), urticaria, nodular prurigo, esophagitis, eosinophilic esophagitis, bronchitis, diabetes, atherosclerosis, gout, arthritis, gouty arthritis, osteoarthritis, systemic lupus erythematosus, polychondritis, colitis, conjunctivitis, allergic rhinitis, chronic rhinitis with nasal polyps, rheumatoid arthritis, scleroderma, Wegener's granulomatosis, dermatomyositis, hepatitis, myasthenia gravis, Stevens-Johnson syndrome, inflammatory bowel disease, ulcerative colitis, Crohn's disease, irritable bowel syndrome, celiac disease, periodontitis, kidney disease, glomerular disease, alcoholic liver disease, multiple sclerosis, endocrine ophthalmopathy, Graves' disease, sarcoidosis, alveolitis, chronic allergic pneumonia, systemic sclerosis, primary biliary cirrhosis, uveitis, Sjögren's syndrome. Syndrome, interstitial pulmonary fibrosis, psoriatic arthritis, systemic juvenile idiopathic arthritis, cold and heat protein-related periodic arthritis syndrome, nephritis, vasculitis, cystitis, glomerulonephritis, chronic granulomatous disease, endometriosis, pancreatitis, acute lung injury, acute respiratory distress syndrome, allergic reactions, sinusitis, pulmonary hypertension, cataracts, thyroiditis, appendicitis, allergies, cervicitis, cholangitis, cholecystitis, conjunctivitis, cystitis Dacryoadenitis, dermatitis, dermatomyositis, encephalitis, encephalomyelitis, endocarditis, endometritis, upper gastritis, gastroenteritis, allergic purpura, idiopathic thrombocytopenic purpura (ITP), Graves' disease, ankylosing spondylitis, anaphylactic shock, hidradenitis suppurativa, interstitial lung disease, laryngitis, mastitis, meningitis, myelitis, myocarditis, myositis, nephritis, oophoritis, orchitis, osteitis, otitis media, mumps, pneumonia, polymyositis, or prostatitis.

[0505] This disclosure further relates to a compound of the above general formula (M), general formula (I), general formula (I-1), general formula (II-1), general formula (II-2), general formula (II-3), general formula (II-4), general formula (III-1), general formula (III-2), general formula (III-3), general formula (III-4), general formula (IV-1), general formula (IV-2), general formula (V-1), general formula (V-2), general formula (VI-1), general formula (VI-2), general formula (VII-1), general formula (VII-2), general formula (N), general formula (N-1), general formula (M-1), general formula (M-2), general formula (M-3), general formula (M-4), general formula (VIII), general formula (IX) or the compound shown in this disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the thereof, which is used as a medicament.

[0506] This disclosure further relates to a compound of the above general formula (M), general formula (I), general formula (I-1), general formula (II-1), general formula (II-2), general formula (II-3), general formula (II-4), general formula (III-1), general formula (III-2), general formula (III-3), general formula (III-4), general formula (IV-1), general formula (IV-2), general formula (V-1), general formula (V-2), general formula (VI-1), general formula (VI-2), general formula (VII-1), general formula (VII-2), general formula (N), general formula (N-1), general formula (M-1), general formula (M-2), general formula (M-3), general formula (M-4), general formula (VIII), general formula (IX) or the compound shown in this disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the thereof, which is used as a medicament for regulating the ubiquitination and degradation of STAT6 protein in a subject.

[0507] This disclosure further relates to a compound of the above general formula (M), general formula (I), general formula (I-1), general formula (II-1), general formula (II-2), general formula (II-3), general formula (II-4), general formula (III-1), general formula (III-2), general formula (III-3), general formula (III-4), general formula (IV-1), general formula (IV-2), general formula (V-1), general formula (V-2), general formula (VI-1), general formula (VI-2), general formula (VII-1), general formula (VII-2), general formula (N), general formula (N-1), general formula (M-1), general formula (M-2), general formula (M-3), general formula (M-4), general formula (VIII), general formula (IX) or the compound shown in this disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising thereof, which is used as a medicament for treating and / or preventing diseases or conditions mediated or dependent on STAT6.

[0508] This disclosure further relates to compounds of the above general formulas (M), (I), (I-1), (II-1), (II-2), (II-3), (II-4), (III-1), (III-2), (III-3), (III-4), (IV-1), (IV-2), (V-1), (V-2), (VI-1), (VI-2), (VII-1), (VII-2), (N), (N-1), (M-1), (M-2), (M-3), (M-4), (VIII), (IX) or those shown in this disclosure, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising thereof, for the purpose of modulating STAT6 protein ubiquitination and degradation in a subject.

[0509] This disclosure further relates to compounds of the above general formulas (M), (I), (I-1), (II-1), (II-2), (II-3), (II-4), (III-1), (III-2), (III-3), (III-4), (IV-1), (IV-2), (V-1), (V-2), (VI-1), (VI-2), (VII-1), (VII-2), (N), (N-1), (M-1), (M-2), (M-3), (M-4), (VIII), (IX) or those shown in this disclosure, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising thereof, for use in inhibiting or degrading STAT6 in a subject.

[0510] This disclosure further relates to compounds of the above general formulas (M), (I), (I-1), (II-1), (II-2), (II-3), (II-4), (III-1), (III-2), (III-3), (III-4), (IV-1), (IV-2), (V-1), (V-2), (VI-1), (VI-2), (VII-1), (VII-2), (VIII), (IX) or those shown in this disclosure, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising thereof, for the treatment and / or prevention of diseases or conditions mediated or dependent on STAT6.

[0511] This disclosure further relates to the aforementioned general formulas (M), (I), (I-1), (II-1), (II-2), (II-3), (II-4), (III-1), (III-2), (III-3), (III-4), (IV-1), (IV-2), (V-1), (V-2), (VI-1), (VI-2), (VII-1), (VII-2), (VIII), and (IX). The compound or pharmaceutically acceptable salt thereof shown in this disclosure, or a pharmaceutical composition comprising the compound, is used to treat and / or prevent cancer, inflammatory diseases (e.g., type 2 inflammatory disease), autoimmune diseases, neurodegenerative diseases, viral diseases, genetic diseases, hormone-related diseases, metabolic diseases, organ transplant-related diseases, immunodeficiency diseases, destructive bone diseases, proliferative diseases, infectious diseases, diseases related to cell death, thrombin-induced platelet aggregation, liver diseases, pathological immune conditions involving T cell activation, cardiovascular diseases, or central nervous system diseases.In some implementations, it is used to treat and / or prevent asthma, eosinophilic asthma (EA), atopic dermatitis (AD), chronic obstructive pulmonary disease (COPD), urticaria, nodular prurigo, esophagitis, eosinophilic esophagitis, bronchitis, diabetes, atherosclerosis, gout, arthritis, gouty arthritis, osteoarthritis, systemic lupus erythematosus, polychondritis, colitis, conjunctivitis, allergic rhinitis, chronic rhinitis with nasal polyps, rheumatoid arthritis, juvenile arthritis, scleroderma, Wegener's granulomatosis, dermatomyositis, hepatitis, myasthenia gravis, Stevens-Johnson syndrome, inflammatory bowel disease, ulcerative colitis, Crohn's disease, irritable bowel syndrome, celiac disease, periodontitis, kidney disease, glomerular disease, alcoholic liver disease, multiple sclerosis, endocrine eye disease, Graves' disease, sarcoidosis, alveolitis, chronic allergic pneumonia, systemic sclerosis, and primary biliary cirrhosis. Uveitis, Sjögren's syndrome, interstitial pulmonary fibrosis, psoriatic arthritis, systemic juvenile idiopathic arthritis, cold and heat protein-related periodic arthritis syndrome, nephritis, vasculitis, cystitis, glomerulonephritis, chronic granulomatous disease, endometriosis, pancreatitis, acute lung injury, acute respiratory distress syndrome, allergic reactions, sinusitis, pulmonary hypertension, cataracts, thyroiditis, appendicitis, allergies, cervicitis, cholangitis, cholecystitis, conjunctivitis. Cystitis, dacryoadenitis, dermatitis, dermatomyositis, encephalitis, encephalomyelitis, endocarditis, endometritis, upper gastritis, gastroenteritis, allergic purpura, idiopathic thrombocytopenic purpura (ITP), Graves' disease, ankylosing spondylitis, anaphylactic shock, hidradenitis suppurativa, interstitial lung disease, laryngitis, mastitis, meningitis, myelitis, myocarditis, myositis, nephritis, oophoritis, orchitis, osteitis, otitis media, mumps, pneumonia, polymyositis, and prostatitis.

[0512] In some embodiments, the diseases or conditions mediated or dependent on STAT6 as described in this disclosure are selected from cancer, inflammatory diseases (e.g., type 2 inflammatory disease), autoimmune diseases, neurodegenerative diseases, viral diseases, genetic diseases, hormone-related diseases, metabolic diseases, organ transplant-related diseases, immunodeficiency diseases, destructive bone diseases, proliferative diseases, infectious diseases, diseases related to cell death, thrombin-induced platelet aggregation, liver diseases, pathological immune conditions involving T cell activation, cardiovascular diseases, or central nervous system diseases; in some embodiments, the diseases or conditions mediated or dependent on STAT6 as described in this disclosure are selected from cancer, inflammatory diseases (e.g., type 2 inflammatory disease), autoimmune diseases, neurodegenerative diseases, viral diseases, genetic diseases, hormone-related diseases, metabolic diseases, organ transplant-related diseases, immunodeficiency diseases, destructive bone diseases, proliferative diseases, infectious diseases, cell death-related diseases, thrombin-induced platelet aggregation, liver diseases, pathological immune conditions involving T cell activation, cardiovascular diseases, or central nervous system diseases; in some embodiments, the diseases or conditions mediated or dependent on STAT6 as described in this disclosure are selected from cancer, inflammatory diseases (e.g., type 2 inflammatory disease), autoimmune diseases, neurodegenerative diseases, viral diseases, genetic diseases, hormone-related diseases, metabolic diseases, organ transplant-related diseases, organ transplant-related diseases, immunodeficiency diseases, organ transplant-related ... STAT6-mediated or dependent diseases or conditions are selected from asthma, eosinophilic asthma (EA), atopic dermatitis (AD), chronic obstructive pulmonary disease (COPD), urticaria, nodular prurigo, esophagitis, eosinophilic esophagitis, bronchitis, diabetes, atherosclerosis, gout, arthritis, gouty arthritis, osteoarthritis, systemic lupus erythematosus, polychondritis, colitis, conjunctivitis, allergic rhinitis, chronic rhinitis with nasal polyps, rheumatoid arthritis, juvenile arthritis, scleroderma, Wegener's granulomatosis, dermatomyositis, hepatitis, myasthenia gravis, Stevens-Johnson syndrome. Combination syndrome, inflammatory bowel disease, ulcerative colitis, Crohn's disease, irritable bowel syndrome, celiac disease, periodontitis, kidney disease, glomerular disease, alcoholic liver disease, multiple sclerosis, endocrine ophthalmopathy, Graves' disease, sarcoidosis, alveolitis, chronic allergic pneumonia, systemic sclerosis, primary biliary cirrhosis, uveitis, Sjögren's syndrome, interstitial pulmonary fibrosis, psoriatic arthritis, systemic juvenile idiopathic arthritis, cold and heat protein-related periodic arthritis syndrome, nephritis, vasculitis, cystitis, glomerulonephritis, chronic granulomatous disease, endometriosis, pancreatitis, acute lung injury, acute respiratory distress syndrome. Obsessive-compulsive syndrome, allergic reactions, sinusitis, pulmonary hypertension, cataracts, thyroiditis, appendicitis, allergies, cervicitis, cholangitis, cholecystitis, conjunctivitis, cystitis, dacryocystitis, dermatitis, dermatomyositis, encephalitis, encephalomyelitis, endocarditis, endometritis, upper gastritis, gastroenteritis, allergic purpura, idiopathic thrombocytopenic purpura (ITP), Graves' disease, ankylosing spondylitis, anaphylactic shock, hidradenitis suppurativa, interstitial lung disease, laryngitis, mastitis, meningitis, myelitis, myocarditis, myositis, nephritis, oophoritis, orchitis, osteitis, otitis media, mumps, pneumonia, polymyositis, and prostatitis.

[0513] In some implementation schemes, cancer includes, but is not limited to, benign or malignant tumors, solid tumors, fluid-filled tumors, brain cancer, kidney cancer, liver cancer (hepatocellular carcinoma), adrenal cancer, bladder cancer, breast cancer, gastric tumors, ovarian cancer, colon cancer, rectal cancer, prostate cancer, pancreas cancer, lung cancer, vaginal cancer, cervical cancer, testicular cancer, genitourinary tract cancer, esophageal cancer, larynx cancer, skin cancer, bone or thyroid cancer, sarcoma cancer, glioblastoma cancer, neuroblastoma cancer, multiple myeloma cancer, gastrointestinal cancer, especially colorectal cancer (colon cancer or colorectal cancer), adenoma cancer, neck and head cancer, and epidermal cancer. Proliferative disorders, psoriasis, benign prostatic hyperplasia, tumors, epithelial tumors, adenomas, adenocarcinomas, pancreatic ductal carcinoma, keratoacanthoma, epidermoid carcinoma, large cell carcinoma, non-small cell lung cancer, uveal melanoma, lymphoma, Hodgkin's and non-Hodgkin's cancers, breast cancer, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, IL-1-driven disease, MyD88-driven disease, indolent multiple myeloma, smoking or hematologic malignancies (including leukemia, diffuse large B-cell lymphoma), DLBCL, ABC DLBCL, chronic lymphocytic leukemia (CLL), chronic lymphocytic lymphoma, primary exudative lymphoma, Burkitt lymphoma / leukemia, acute lymphoblastic leukemia, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, Waldenström macroglobulinemia (WM), splenic marginal zone lymphoma, multiple myeloma, plasmacytoma, and intraangiocarcinoma (intravascular large B-cell lymphoma); in some implementations, the cancer to be treated is selected from glioma, breast cancer, prostate cancer, head and neck squamous cell carcinoma, cutaneous melanoma, ovarian cancer, malignant peripheral nerve schwannoma (MPNST), and pancreatic cancer. In some implementations, the cancer is selected from glioma, breast cancer, prostate cancer, head and neck squamous cell carcinoma, cutaneous melanoma, ovarian cancer, malignant peripheral nerve healthy tumor (MPNST), pancreatic cancer, and non-small cell carcinoma.

[0514] In some implementations, the cancer is selected from solid tumors (e.g., prostate cancer, kidney cancer, liver cancer, pancreatic cancer, stomach cancer, breast cancer, lung cancer, head and neck cancer, thyroid cancer, glioblastoma, Kaposi's sarcoma, Castleman's disease, uterine leiomyosarcoma, melanoma, etc.), hematologic malignancies (e.g., lymphoma, leukemia such as acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), or multiple myeloma), and skin cancers such as cutaneous T-cell lymphoma (CTCL) and cutaneous B-cell lymphoma.

[0515] In some implementations, the neurodegenerative diseases include, but are not limited to, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, and neurodegenerative diseases caused by cerebral ischemia and trauma.

[0516] In some implementations, the cardiovascular diseases include, but are not limited to, restenosis, cardiac hypertrophy, atherosclerosis, myocardial infarction, ischemic stroke, congestive heart failure, angina pectoris, post-angioplasty restenosis, post-angioplasty restenosis, post-coronary artery bypass grafting restenosis, post-coronary artery bypass grafting restenosis, stroke, transient ischemic attack, peripheral artery occlusive disease, pulmonary embolism, and deep vein thrombosis.

[0517] In some embodiments, the asthma includes intrinsic (non-allergic) asthma and extrinsic (allergic) asthma, mild asthma, moderate asthma, severe asthma, bronchial asthma, exercise-induced asthma, occupational asthma, and asthma induced or exacerbated by bacterial or viral infection; in some embodiments, the asthma is eosinophilic asthma (EA).

[0518] In some embodiments, the urticaria described in this disclosure is chronic urticaria or acute urticaria; in some embodiments, the urticaria described in this disclosure is chronic urticaria.

[0519] In some embodiments, the urticaria described in this disclosure is chronic spontaneous urticaria (CSU) or chronic inducible urticaria; in some embodiments, the urticaria described in this disclosure is chronic spontaneous urticaria. In some embodiments, the multiple sclerosis described in this disclosure is relapsing-remitting multiple sclerosis (RMS).

[0520] In some embodiments, the allergy described in this disclosure is an allergy to plant pollen, latex, drugs, food, insect venom, animal hair, animal dander, dust mites, or cockroach calyxes, etc.

[0521] In some implementations, the diabetes described in this disclosure is type 1 diabetes.

[0522] In some implementations, the thyroiditis is Hashimoto's thyroiditis or autoimmune thyroiditis.

[0523] In some implementations, the bronchitis includes, but is not limited to, acute bronchitis, peanut bronchitis, catarrhal bronchitis, croup bronchitis, chronic bronchitis, or smoke-like bronchitis.

[0524] The active compound can be formulated into a form suitable for administration via any appropriate route, in some embodiments in the form of a unit dose or in a form that a patient can self-administer as a single dose. The unit dose of the disclosed compound or composition can be expressed as tablets, capsules, sachets, bottled liquids, powders, granules, lozenges, suppositories, regenerated powders, or liquid formulations. In some embodiments, the unit dose of the pharmaceutical composition is 0.001 mg to 1000 mg. In some embodiments, a suitable unit dose may be 0.1 to 1000 mg.

[0525] In addition to the active compound, the pharmaceutical compositions disclosed herein may contain one or more excipients selected from the following: fillers (diluents), binders, wetting agents, disintegrants, or excipients. Depending on the method of administration, the composition may contain 0.1 to 99% by weight of the active compound.

[0526] In some embodiments, the pharmaceutical composition contains 0.01-99.99% of the aforementioned compound or its pharmaceutically acceptable salt or isotopic substitution, based on the total weight of the composition. In some embodiments, the pharmaceutical composition contains 0.1-99.9% of the aforementioned compound or its pharmaceutically acceptable salt or isotopic substitution. In some embodiments, the pharmaceutical composition contains 0.5%-99.5% of the aforementioned compound or its pharmaceutically acceptable salt or isotopic substitution. In some embodiments, the pharmaceutical composition contains 1%-99% of the aforementioned compound or its pharmaceutically acceptable salt or isotopic substitution. In some embodiments, the pharmaceutical composition contains 2%-98% of the aforementioned compound or its pharmaceutically acceptable salt or isotopic substitution.

[0527] In some embodiments, the pharmaceutical composition contains 0.01% to 99.99% pharmaceutically acceptable excipients based on the total weight of the composition. In some embodiments, the pharmaceutical composition contains 0.1% to 99.9% pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical composition contains 0.5% to 99.5% pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical composition contains 1% to 99% pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical composition contains 2% to 98% pharmaceutically acceptable excipients.

[0528] The pharmaceutically acceptable salts of the compounds described in this disclosure may be selected from inorganic or organic salts.

[0529] Pharmaceutical compositions containing active ingredients may be in forms suitable for oral administration, such as tablets, sugar lozenges, tablets, aqueous or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Oral compositions may be prepared according to any method known in the art for preparing pharmaceutical compositions, and such compositions may contain one or more ingredients selected from sweeteners, flavoring agents, coloring agents, and preservatives to provide an appealing and palatable pharmaceutical formulation.

[0530] Tablets contain an active ingredient and non-toxic, pharmaceutically acceptable excipients suitable for tablet preparation, used for mixing. These excipients may be inert excipients, granulating agents, disintegrants, binders, and lubricants. These tablets may be uncoated or coated using known techniques that mask the taste of the drug or delay disintegration and absorption in the gastrointestinal tract, thus providing sustained release over a longer period.

[0531] Oral formulations can also be provided using 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 carrier or an oil solvent.

[0532] Aqueous suspensions contain active substances and excipients suitable for preparing aqueous suspensions for mixing. These excipients are suspending agents, dispersing agents, or wetting agents. Aqueous suspensions may also contain one or more preservatives, one or more coloring agents, one or more flavoring agents, and one or more sweeteners.

[0533] Oil suspensions are formulated by suspending the active ingredient in vegetable or mineral oil. Oil suspensions may contain thickeners. Sweeteners and flavoring agents mentioned above may be added to provide palatable formulations. These compositions may be preserved by adding antioxidants.

[0534] The pharmaceutical compositions disclosed herein may also be in the form of an oil-in-water emulsion. The oil phase may be vegetable oil, mineral oil, or a mixture thereof. Suitable emulsifiers may be naturally occurring phospholipids, and the emulsion may also contain sweeteners, flavoring agents, preservatives, and antioxidants. Such formulations may also contain modifiers, preservatives, colorants, and antioxidants.

[0535] The pharmaceutical compositions disclosed herein may be in the form of sterile injectable aqueous solutions. Acceptable solvents or media that can be used include water, Ringer's solution, and isotonic sodium chloride solution. The sterile injectable formulation may be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in the oil phase, which can be injected into the patient's bloodstream via local large-volume injection. Alternatively, the solution and microemulsion are preferably administered in a manner that maintains a constant circulating concentration of the compounds disclosed herein. To maintain such a constant concentration, a continuous intravenous delivery device may be used. An example of such a device is the Deltec CADD-PLUS™ 5400 intravenous infusion pump.

[0536] The pharmaceutical compositions disclosed herein may be in the form of sterile injectable aqueous or oil suspensions for intramuscular and subcutaneous administration. These suspensions may be formulated using suitable dispersants or wetting agents and suspending agents according to known techniques. The sterile injectable formulations may also be sterile injectable solutions or suspensions prepared in parenteral acceptable non-toxic diluents or solvents. Furthermore, sterile fixative oils can be conveniently used as solvents or suspension media. Any blended fixative oil may be used for this purpose. Additionally, fatty acids may also be used to prepare injectable formulations.

[0537] The disclosed compounds can be administered in suppository form for rectal administration. These pharmaceutical compositions can be prepared by mixing the drug with a suitable, non-irritating excipient that is solid at normal temperatures but liquid in the rectum, and thus dissolves in the rectum to release the drug.

[0538] 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.

[0539] Terminology Explanation

[0540] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0541] 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 ... 1-6Alkyl groups). Non-limiting examples include: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2 3-Dimethylpentyl, 2,4-Dimethylpentyl, 2,2-Dimethylpentyl, 3,3-Dimethylpentyl, 2-Ethylpentyl, 3-Ethylpentyl, n-Octyl, 2,3-Dimethylhexyl, 2,4-Dimethylhexyl, 2,5-Dimethylhexyl, 2,2-Dimethylhexyl, 3,3-Dimethylhexyl, 4,4-Dimethylhexyl, 2-Ethylhexyl, 3-Ethylhexyl, 4-Ethylhexyl, 2-Methyl-2-Ethylpentyl, 2-Methyl-3-Ethylpentyl, n-Nonyl, 2-Methyl-2-Ethylhexyl, 2-Methyl-3-Ethylhexyl, 2,2-Diethylpentyl, n-Decyl, 3,3-Diethylhexyl, 2,2-Diethylhexyl, and their various branched isomers, etc. Alkyl groups can be substituted or unsubstituted, and when substituted, they can be substituted at any usable connection point. In some embodiments, the substituents are selected from one or more of deuterium, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0542] The term "alkylene" refers to a divalent alkyl group, wherein the alkyl group, as defined above, has 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 Alkylene). The alkylene is, in some embodiments, an alkylene having 1 to 10 carbon atoms (i.e., C10). 1-10 Alkylenes), in some embodiments having 1 to 8 carbon atoms (i.e., C164-C ... 1-8 Alkylenes), in some embodiments having 2 to 7 carbon atoms (i.e., C164-C ... 2-7 Alkylenes or alkylenes having 1, 2 or 3 carbon atoms (i.e., C14) 1-6Alkylenes. Non-limiting examples include: -CH2-, -CH(CH3)-, -C(CH3)2-, -CH2CH2-, -CH(CH2CH3)-, -CH2CH(CH3)-, -CH2C(CH3)2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, etc. Alkylenes can be substituted or unsubstituted, and when substituted, they can be substituted at any usable linking point. In some embodiments, the substituent is selected from one or more of deuterium, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0543] The term "bridged alkylene" refers to an alkylene ring formed by the connection of two non-adjacent atoms, as defined above. Non-limiting examples include: bridged ethylene (-CH2CH2-) and bridged methylene (-CH2-).

[0544] The term "alkenyl" refers to an alkyl group in which the molecule contains at least one carbon-carbon double bond, wherein the alkyl group is defined as described above and has 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12) carbon atoms (i.e., C atoms). 2-12 Alkenyl). The alkenyl group, in some embodiments, has 2 to 6 carbon atoms (i.e., C). 2-6 Alkenyl). Non-limiting examples include vinyl, propenyl, isopropenyl, butenyl, etc. Alkenyl groups can be substituted or unsubstituted, and when substituted, they can be substituted at any usable linker. In some embodiments, the substituent is selected from one or more of deuterium, alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0545] The term "alkynyl" refers to an alkyl group in a molecule that contains at least one carbon-carbon triple bond, wherein the alkyl group is defined as described above and has 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12) carbon atoms (i.e., C64, C74, C84, C9 ... 2-12 The alkynyl group (in some embodiments) has 2 to 6 carbon atoms (i.e., C12). 2-6 (Alynyl). Non-limiting examples include: ethynyl, propynyl, butynyl, pentyynyl, hexynyl, etc. The alkynyl group can be substituted or unsubstituted, and when substituted, it can be substituted at any usable linker. In some embodiments, the substituent is selected from one or more of deuterium, alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0546] The term "alkoxy" refers to -O-(alkyl), where alkyl is defined as described above. Non-limiting examples include methoxy, ethoxy, propoxy, and butoxy, etc. Alkoxy groups can be substituted or unsubstituted, and when substituted, they can be substituted at any usable linker. In some embodiments, the substituent is selected from one or more of deuterium, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0547] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic carbocyclic (i.e., monocyclic cycloalkyl) or polycyclic system (i.e., polycyclic cycloalkyl) having 3 to 20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., 3 to 20 membered cycloalkyl). The cycloalkyl group is described in some embodiments as having 3 to 12 ring atoms (i.e., 3 to 12 membered cycloalkyl), in some embodiments as having 11 to 20 ring atoms (i.e., 11 to 20 membered cycloalkyl), in some embodiments as having 3 to 8 ring atoms (i.e., 3 to 8 membered cycloalkyl), and in some embodiments as having 3 to 6 ring atoms (i.e., 3 to 6 membered cycloalkyl).

[0548] Non-limiting examples of the monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclohepttrienyl, and cyclooctyl.

[0549] The polycyclic alkyl groups include: spirocyclic alkyl groups, fused cyclic alkyl groups, and bridged cyclic alkyl groups.

[0550] The term "spirocycloalkyl" refers to a polycyclic system in which rings share a single carbon atom (called a spiro atom), and the ring may contain one or more double bonds, or one or more heteroatoms selected from nitrogen, oxygen, and sulfur (the nitrogen may optionally be oxidized to form nitrogen oxides; the sulfur may optionally be oxidized to form sulfoxides or sulfones, but excluding -OO-, -OS-, or -SS-), provided that it contains at least one full carbon ring with a bonding point on that full carbon ring, having 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., 5 to 20-membered spirocycloalkyl). In some embodiments, the spirocycloalkyl is a spirocycloalkyl with 6 to 14 ring atoms (i.e., 6 to 14-membered spirocycloalkyl), and in some embodiments, it is a spirocycloalkyl with 7 to 10 ring atoms (i.e., 7 to 10-membered spirocycloalkyl). The spirocyclic alkyl group includes monospirocyclic alkyl and polyspirocyclic alkyl (such as bispirocyclic alkyl, etc.), and in some embodiments is a monospirocyclic alkyl or bispirocyclic alkyl group, and in some embodiments is a 3-membered / 4-membered, 3-membered / 5-membered, 3-membered / 6-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 3-membered, 5-membered / 4-membered, 5-membered / 5-membered, 5-membered / 6-membered, 5-membered / 7-membered, 6-membered / 3-membered, 6-membered / 4-membered, 6-membered / 5-membered, 6-membered / 6-membered, 6-membered / 7-membered, 7-membered / 5-membered or 7-membered / 6-membered monospirocyclic alkyl group. Non-limiting examples include:

[0551] Its connection point can be anywhere;

[0552] wait.

[0553] The term "fused cycloalkyl" refers to a polycyclic system in which two adjacent carbon atoms are shared between rings. This system is a monocyclic cycloalkyl group fused with one or more monocyclic cycloalkyl groups, or a monocyclic cycloalkyl group fused with one or more heterocyclic, aryl, or heteroaryl groups, wherein the bonding point is on the monocyclic cycloalkyl group, which may contain one or more double bonds 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). In some embodiments, the fused cycloalkyl group has 6 to 14 ring atoms (i.e., 6 to 14-membered fused cycloalkyl), and in some embodiments, it has 7 to 10 ring atoms (i.e., 7 to 10-membered fused cycloalkyl). The fused cyclic alkyl group includes bicyclic fused cyclic alkyl groups and polycyclic fused cyclic alkyl groups (such as tricyclic fused cyclic alkyl groups, tetracyclic fused cyclic alkyl groups, etc.). In some embodiments, it is a bicyclic fused cyclic alkyl group or a tricyclic fused cyclic alkyl group. In some embodiments, it is a 3-membered / 4-membered, 3-membered / 5-membered, 3-membered / 6-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 3-membered, 5-membered / 4-membered, 5-membered / 5-membered, 5-membered / 6-membered, 5-membered / 7-membered, 6-membered / 3-membered, 6-membered / 4-membered, 6-membered / 5-membered, 6-membered / 6-membered, 6-membered / 7-membered, 7-membered / 5-membered, or 7-membered / 6-membered bicyclic fused cyclic alkyl group. Non-limiting examples include:

[0554] Its connection point can be anywhere; wait.

[0555] The term "bridged cycloalkyl" refers to a fully carbon polycyclic system sharing two non-directly linked carbon atoms between rings, which may contain one or more double bonds 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). In some embodiments, the bridged cycloalkyl is a bridged cycloalkyl with 6 to 14 carbon atoms (i.e., 6 to 14-membered bridged cycloalkyl), and in some embodiments, it is a bridged cycloalkyl with 7 to 10 carbon atoms (i.e., 7 to 10-membered bridged cycloalkyl). The bridged cycloalkyl includes bicyclic bridged cycloalkyl and polycyclic bridged cycloalkyl (e.g., tricyclic bridged cycloalkyl, tetracyclic bridged cycloalkyl, etc.), and in some embodiments, it is a bicyclic or tricyclic bridged cycloalkyl. Non-limiting examples include: Its connection point can be anywhere.

[0556] The cycloalkyl group can be substituted or unsubstituted. When substituted, it can be substituted at any usable connection point. In some embodiments, the substituent is selected from one or more of the following: deuterium, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, alkylthio, haloalkylthio, cycloalkylthio, heterocyclic thio, heterocyclic oxy, hydroxy, hydroxyalkyl, oxo, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0557] The term "heterocyclic group" refers to a saturated or partially unsaturated monocyclic heterocycle (i.e., monocyclic heterocyclic group) or polycyclic heterocyclic system (i.e., polycyclic heterocyclic group) 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-), and having 3 to 20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (i.e., 3 to 20 membered heterocyclic groups). In some embodiments, a heterocyclic group having 3 to 12 ring atoms (i.e., a 3 to 12-membered heterocyclic group); in some embodiments, a heterocyclic group having 3 to 8 ring atoms (i.e., a 3 to 8-membered heterocyclic group); in some embodiments, a heterocyclic group having 4 to 6 ring atoms (i.e., a 4 to 6-membered heterocyclic group); in some embodiments, a heterocyclic group having 3 to 6 ring atoms (i.e., a 3 to 6-membered heterocyclic group); in some embodiments, a heterocyclic group having 5 or 6 ring atoms (i.e., a 5 or 6-membered heterocyclic group); in some embodiments, a heterocyclic group having 6 ring atoms (i.e., a 6-membered heterocyclic group); in some embodiments, a heterocyclic group having 11 to 20 ring atoms (i.e., an 11 to 20-membered heterocyclic group); in some embodiments, a heterocyclic group having 13 or 14 ring atoms (i.e., a 13 or 14-membered heterocyclic group); in some embodiments, a heterocyclic group having 14 ring atoms (i.e., a 14-membered heterocyclic group).

[0558] Non-limiting examples of the monocyclic heterocyclic group include: pyrrolidinyl, tetrahydropyranyl, 1,2,3,6-tetrahydropyridyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, and homopiperazinyl, etc.

[0559] The polycyclic heterocyclic groups include spirocyclic heterocyclic groups, fused heterocyclic groups, and bridged heterocyclic groups.

[0560] The term "spiroheterocyclic group" refers to a polycyclic heterocyclic system in which rings share a single atom (called a spiro atom), which may contain one or more double bonds and at least one (e.g., 1, 2, 3, or 4) heteroatoms selected from nitrogen, oxygen, and sulfur (the nitrogen may optionally be oxidized to form nitrogen oxides; the sulfur may optionally be oxidized to form sulfoxides or sulfones, but excluding -OO-, -OS-, or -SS-), provided that at least one monocyclic heterocyclic group is present and the bonding point is on the monocyclic heterocyclic group, which has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., 5 to 20-membered spiroheterocyclic groups). The spiroheterocyclic group has 6 to 14 ring atoms in some embodiments (i.e., 6 to 14-membered spiroheterocyclic groups), and 7 to 11 ring atoms in some embodiments (i.e., 7 to 11-membered spiroheterocyclic groups). The spiroheterocyclic group includes monospirocyclic and polyspirocyclic groups (such as bispirocyclic groups), and in some embodiments is a monospirocyclic or bispirocyclic group, and in some embodiments is a 3-membered / 4-membered, 3-membered / 5-membered, 3-membered / 6-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 3-membered, 5-membered / 4-membered, 5-membered / 5-membered, 5-membered / 6-membered, 5-membered / 7-membered, 6-membered / 3-membered, 6-membered / 4-membered, 6-membered / 5-membered, 6-membered / 6-membered, 6-membered / 7-membered, 7-membered / 5-membered, or 7-membered / 6-membered monospirocyclic group. Non-limiting examples include:

[0561] wait.

[0562] The term "fused heterocyclic group" refers to a polycyclic heterocyclic system in which two adjacent atoms are shared between rings. The ring may contain one or more double bonds and at least one (e.g., 1, 2, 3, or 4) heteroatoms selected from nitrogen, oxygen, and sulfur (the nitrogen may optionally be oxidized to form nitrogen oxides; the sulfur may optionally be oxidized to form sulfoxides or sulfones, but excluding -OO-, -OS-, or -SS-). It is a monocyclic heterocyclic group fused with one or more monocyclic heterocyclic groups, or a monocyclic heterocyclic group fused with one or more cycloalkyl, aryl, or heteroaryl groups, wherein the bonding point is on the monocyclic heterocyclic 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 heterocyclic groups). The fused heterocyclic group is, in some embodiments, a fused heterocyclic group having 6 to 14 ring atoms (i.e., a 6 to 14-membered fused heterocyclic group), and in some embodiments, a fused heterocyclic group having 7 to 10 ring atoms (i.e., a 7 to 10-membered fused heterocyclic group). The fused heterocyclic group includes bicyclic and polycyclic fused heterocyclic groups (such as tricyclic fused heterocyclic groups, tetracyclic fused heterocyclic groups, etc.), and in some embodiments is a bicyclic or tricyclic fused heterocyclic group, and in some embodiments is a 3-membered / 4-membered, 3-membered / 5-membered, 3-membered / 6-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 3-membered, 5-membered / 4-membered, 5-membered / 5-membered, 5-membered / 6-membered, 5-membered / 7-membered, 6-membered / 3-membered, 6-membered / 4-membered, 6-membered / 5-membered, 6-membered / 6-membered, 6-membered / 7-membered, 7-membered / 5-membered, or 7-membered / 6-membered bicyclic fused heterocyclic group. Non-limiting examples include:

[0563] wait.

[0564] The term "bridged heterocyclic group" refers to a polycyclic heterocyclic system in which two non-directly connected atoms are shared between the rings. The rings may contain one or more double bonds, and the rings contain at least one (e.g., 1, 2, 3, or 4) heteroatoms selected from nitrogen, oxygen, and sulfur (the nitrogen may optionally be oxidized to form nitrogen oxides; the sulfur may optionally be oxidized to form sulfoxides or sulfones, but excluding -OO-, -OS-, or -SS-), having 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., 5 to 20-membered bridged heterocyclic groups). In some embodiments, the bridged heterocyclic group has 6 to 14 ring atoms (i.e., 6 to 14-membered bridged heterocyclic groups), and in some embodiments, it has 7 to 10 ring atoms (i.e., 7 to 10-membered bridged heterocyclic groups). Based on the number of constituent rings, heterocyclic groups can be classified into bicyclic bridged heterocyclic groups and multicyclic bridged heterocyclic groups (such as tricyclic bridged heterocyclic groups, tetracyclic bridged heterocyclic groups, etc.). In some embodiments, they are bicyclic bridged heterocyclic groups or tricyclic bridged heterocyclic groups. Non-limiting examples include:

[0565] wait.

[0566] The heterocyclic group can be substituted or unsubstituted. When substituted, it can be substituted at any usable connection point. In some embodiments, the substituent is selected from one or more of the following: deuterium, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, alkylthio, haloalkylthio, cycloalkylthio, heterocyclic thio, hydroxy, hydroxyalkyl, oxo, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0567] The term "aryl" refers to a monocyclic all-carbon aromatic ring (i.e., monocyclic aryl) or a polycyclic aromatic ring system (i.e., polycyclic aryl) having a conjugated π-electron system, having 6 to 14 (e.g., 6, 7, 8, 9, 10, 11, 12, 13, or 14) ring atoms (i.e., 6 to 14-membered aryl). In some embodiments, the aryl group has 6 to 10 ring atoms (i.e., 6 to 10-membered aryl). The monocyclic aryl group is, for example, phenyl. Non-limiting examples of the polycyclic aryl group include naphthyl, anthraceneyl, phenanthrene, etc. The polycyclic aryl group further includes fusion of the phenyl group with one or more heterocyclic groups or cycloalkyl groups, or fusion of the naphthyl group with one or more heterocyclic groups or cycloalkyl groups, wherein the bonding point 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, non-limiting examples including:

[0568] wait.

[0569] The aryl group can be substituted or unsubstituted. When substituted, it can be substituted at any usable connection point. In some embodiments, the substituent is selected from one or more of the following: deuterium, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxyl, alkylthio, haloalkylthio, cycloalkylthio, heterocyclic thio, hydroxyalkyl, oxo, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0570] 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 15 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15) ring atoms (i.e., 5 to 15-membered heteroaryl). In some embodiments, the heteroaryl has 5 to 10 ring atoms (i.e., 5 to 10-membered heteroaryl), and in some embodiments, it has 5 or 6 ring atoms (i.e., 5 or 6-membered heteroaryl).

[0571] 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.

[0572] Non-limiting examples of the polycyclic heteroaryl groups include: indolyl, indazole, quinolinyl, isoquinolinyl, quinoxalinyl, phthalazinyl, benzimidazolyl, benzothiophene, quinazolinyl, benzothiazolyl, carbazole, etc. The polycyclic heteroaryl groups also include monocyclic heteroaryl groups fused with one or more aryl groups, wherein the connecting 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 groups also include monocyclic heteroaryl groups fused with one or more cycloalkyl or heterocyclic groups, wherein the connecting 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. Non-limiting examples include: wait.

[0573] The heteroaryl group can be substituted or unsubstituted. When substituted, it can be substituted at any usable connection point. In some embodiments, the substituent is selected from one or more of the following: deuterium, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxyl, alkylthio, haloalkylthio, cycloalkylthio, heterocyclic thio, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0574] The aforementioned cycloalkyl, heterocyclic, aryl, and heteroaryl groups include residues derived from removing one hydrogen atom from a parent ring atom, or residues derived from removing two hydrogen atoms from the same ring atom or two different ring atoms of the parent ring, i.e., "cycloalkylene", "heterocyclicene", "arylene", and "heteroarylene". Non-limiting examples include: wait.

[0575] When a polycyclic system is divalent, and the monocyclic ring connected to the parent ring is a heterocyclic ring, then the polycyclic system is a heterocyclic base, for example... The *terminus is connected to the parent compound, therefore it belongs to a heterocyclic group; when the monocyclic ring connected to the parent compound is a cycloalkyl group, then the polycyclic system is a cycloalkyl group, for example... The *terminus is attached to the parent compound, therefore it belongs to the cycloalkyl group; when the monocyclic ring attached to the parent compound is a heteroaryl group, then the polycyclic system is a heteroaryl group, for example... The *terminus is connected to the parent compound, therefore it belongs to the heteroaryl group; when the single ring connected to the parent compound is aryl, then the polycyclic system is aryl (except for the case where the ring connected to the parent compound is aryl, and all other single rings are either heteroaryl or aryl, and at least one single ring is heteroaryl; in this case, it belongs to the heteroaryl group). For example... The *terminus is connected to the parent compound, therefore it belongs to the aryl group. And... Although the *terminus is connected to the parent compound, it belongs to the heteroaryl group.

[0576] The term "cycloalkylalkyl" refers to an alkyl group that is substituted by one or more cycloalkyl groups, wherein the cycloalkyl and alkyl groups are as defined above.

[0577] The term "heterocyclic alkyl" refers to an alkyl group that is substituted by one or more heterocyclic groups, wherein the heterocyclic group and the alkyl group are as defined above.

[0578] The term "arylalkyl" refers to an alkyl group that is substituted with one or more aryl groups, wherein the aryl and alkyl groups are as defined above.

[0579] The term "heteroarylalkyl" refers to an alkyl group that is substituted by one or more heteroaryl groups, wherein the heteroaryl and alkyl groups are as defined above.

[0580] The term "cycloalkyloxy" refers to -O-cycloalkyl, where the cycloalkyl is as defined above.

[0581] The term "heterocyclic oxygen group" refers to an -O-heterocyclic group, wherein the heterocyclic group is as defined above.

[0582] The term "aryloxy group" refers to -O-aryl, where the aryl group is as defined above.

[0583] The term "heteroaryloxy" refers to -O-heteroaryl, where the heteroaryl is as defined above.

[0584] The term "aminoalkyl" refers to an alkyl group that is substituted with one or more amino groups, wherein the alkyl group is as defined above.

[0585] The term "alkoxyalkyl" refers to an alkyl group that is substituted with one or more alkoxy groups, wherein the alkoxy groups and alkyl groups are as defined above.

[0586] The term "halogenated alkyl" refers to an alkyl group that has been substituted with one or more halogens, wherein the alkyl group is as defined above.

[0587] The term "haloalkoxy" refers to an alkoxy group that is substituted by one or more halogens, wherein the alkoxy group is as defined above.

[0588] The term "hydroxyalkyl" refers to an alkyl group that is replaced by one or more hydroxyl groups, wherein the alkyl group is as defined above.

[0589] The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0590] The term "hydroxyl group" refers to -OH.

[0591] The term "thiol" refers to -SH.

[0592] The term "amino" refers to -NH2.

[0593] The term "cyano" refers to -CN.

[0594] The term "nitro" refers to -NO2.

[0595] The term "oxo" or "oxo group" refers to "=O".

[0596] The term "carbonyl" refers to C=O.

[0597] The term "alkylthio" refers to -S-alkyl, where the alkyl group is as defined above.

[0598] The term "haloalkylthio" refers to an alkylthio group that is replaced by one or more halogens, wherein the alkylthio group is as defined above.

[0599] The term "cycloalkylthio" refers to -S-cycloalkyl, where the cycloalkyl group is as defined above.

[0600] The term "heterocyclic thio" refers to a -S-heterocyclic group, where the heterocyclic group is as defined above.

[0601] The term "amino protecting group" refers to a group that is easily removed from the amino group, introduced onto the amino group to ensure that the amino group remains unchanged during reactions at other sites of the molecule. Non-limiting examples include: (trimethylsilyl)ethoxymethyl (SEM), tetrahydropyranyl, tert-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz), methoxycarbonyl (Fmoc), allyloxycarbonyl (Alloc), trimethylsilylethoxycarbonyl (Teoc), methoxycarbonyl, ethoxycarbonyl, phthaloyl (Pht), p-toluenesulfonyl (Tos), tert-butylsulfinyl, trifluoroacetyl (Tfa), trichloroacetyl, triphenylmethyl (Trt), 2,4-dimethoxybenzyl (DMB), p-methoxybenzyl (PMB), acetyl, benzyl, allyl, p-methoxybenzyl, etc.

[0602] 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 an isomer of a compound, which 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.

[0603] 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.

[0604] In the chemical structure of the compounds described in this disclosure, the bonds... Indicates forward or reverse.

[0605] The compounds disclosed herein may exist in various tautomer forms, and all such forms are included within the scope of this disclosure. The terms "tautomer" or "tautomer form" refer to a structural isomer that exists in equilibrium and readily transforms from one isomer to another. This includes all possible tautomers, i.e., existing as a single isomer or as a mixture of said tautomers in any proportion. Non-limiting examples include: keto-enols, imine-enamines, lactam-lactamimides, etc. Examples of lactam-lactamimide equilibrium are shown below:

[0606] When referring to the pyrazolyl group, it should be understood to include any one or a mixture of two tautomers of the following two structures:

[0607] All tautomers are within the scope of this disclosure, and the naming of compounds does not exclude any tautomers.

[0608] The compounds disclosed herein may comprise transisomers. The term "transisomer" refers to a conformational stereoisomer resulting from restricted or significantly slowed rotation around a single bond in a molecule (as a result of steric interactions with other parts of the molecule and asymmetric substituents at the ends of the single bond), whose interconversion is slow enough to allow separation and isolation under predetermined conditions. For example, some compounds of this disclosure may exist as mixtures of transisomers (e.g., equal-proportion mixtures, mixtures enriched with one transisomer, etc.) or as a purified transisomer.

[0609] The compounds disclosed herein, or pharmaceutically acceptable salts thereof, include solvates (e.g., hydrates, non-aqueous solvates) or non-solvents of the compounds thereof or pharmaceutically acceptable salts thereof.

[0610] The compounds disclosed herein include all suitable isotopic derivatives thereof. The term "isotopic derivative" refers to a compound in which at least one atom is replaced by an atom having the same atomic number but a different atomic mass. Examples of isotopes that may be introduced into the compounds of this disclosure include stable and radioactive isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine, and iodine, for example, […]. 2 H (deuterium, D) 3 H (tritium, T) 11 C 13 C 14 C 15 N、 17 O、 18 O、 32 p、 33 p、 33 S, 34 S,35 S, 36 S, 18 F, 36 Cl、 82 Br、 123 I, 124 I, 125 I, 129 I and 131 In some implementations, I is deuterium.

[0611] Compared to undeuterated drugs, deuterated drugs offer advantages such as reduced toxicity, increased drug stability, enhanced efficacy, and prolonged biological half-life. All isotopic variations of the compounds disclosed herein, regardless of radioactivity, are included within the scope of this disclosure. Each available hydrogen atom bonded to a carbon atom can be independently replaced by a deuterium atom, wherein the deuterium substitution can be partial or complete; partial deuterium substitution refers to the replacement of at least one hydrogen atom with at least one deuterium atom.

[0612] When a site is specifically designated as deuterium D, the site should be understood as having a deuterium abundance of at least 1,000 times greater than the natural abundance of deuterium (which is 0.015%) (i.e., at least 15% deuterium incorporation). The compounds in the examples having a natural abundance greater than deuterium can be at least 1000 times abundant deuterium (i.e., at least 15% deuterium doping), at least 2000 times abundant deuterium (i.e., at least 30% deuterium doping), at least 3000 times abundant deuterium (i.e., at least 45% deuterium doping), at least 3340 times abundant deuterium (i.e., at least 50.1% deuterium doping), at least 3500 times abundant deuterium (i.e., at least 52.5% deuterium doping), at least 4000 times abundant deuterium (i.e., at least 60% deuterium doping), or at least 4500 times abundant deuterium (i.e., at least 67.5% deuterium doping). The abundance of deuterium is at least 5000 times (i.e., at least 75% deuterium doping), at least 5500 times (i.e., at least 82.5% deuterium doping), at least 6000 times (i.e., at least 90% deuterium doping), at least 6333.3 times (i.e., at least 95% deuterium doping), at least 6466.7 times (i.e., at least 97% deuterium doping), at least 6600 times (i.e., at least 99% deuterium doping), at least 6633.3 times (i.e., at least 99.5% deuterium doping), or higher.

[0613] "Optional" or "optional" means that the event or situation described below may but is not necessarily to occur; it includes both the possibility that the event or situation may occur or not occur. For example, "C that is optionally substituted with a halogen or cyano group..." 1-6 "Alkyl" includes cases where the alkyl group is substituted with a halogen or cyano group and cases where the alkyl group is not substituted with a halogen or cyano group.

[0614] "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).

[0615] "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.

[0616] "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.

[0617] 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.

[0618] As used herein, the singular forms of “a,” “an,” and “the” include plural references, and vice versa, unless the context clearly indicates otherwise.

[0619] When the term "about" is applied to parameters such as pH, concentration, temperature, etc., 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. Detailed Implementation

[0620] The following embodiments are used to further describe this disclosure, but these embodiments are not intended to limit the scope of this disclosure.

[0621] Example

[0622] The structure of the compound was determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts (δ) were expressed in 10⁻¹⁰ ohms.-6 The unit (ppm) is given. NMR determination was performed using a Bruker AVANCE-400 NMR spectrometer or a Bruker AVANCE NEO 500M. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD). The internal standard was tetramethylsilane (TMS).

[0623] MS measurements were performed using an Agilent 1200 / 1290DAD-6110 / 6120 Quadrupole MS LC-MS system (manufacturer: Agilent, MS model: 6110 / 6120 Quadrupole MS). Other instruments used included: a waters ACQuity UPLC-QD / SQD system (manufacturer: waters, MS model: waters ACQuity Qda Detector / waters SQ Detector); and a THERMO Ultimate 3000-Q Exactive system (manufacturer: THERMO, MS model: THERMO Q Exactive).

[0624] High-performance liquid chromatography (HPLC) analysis was performed using an Agilent HPLC 1200DAD, an Agilent HPLC 1200VWD, and a Waters HPLC e2695-2489 HPLC system.

[0625] Chiral HPLC analysis was performed using an Agilent 1260DAD high-performance liquid chromatograph.

[0626] High performance liquid chromatography (HPLC) was performed using Waters 2545-2767, Waters 2767-SQ Detecor2, Shimadzu LC-20AP, and Gilson GX-281 preparative chromatographs.

[0627] Chiral preparation was performed using a Shimadzu LC-20AP preparative chromatograph.

[0628] The CombiFlash rapid preparation system uses a CombiFlash Rf200 (TELEDYNE ISCO).

[0629] Thin-layer chromatography silica gel plates are Yantai Huanghai HSGF254 or Qingdao GF254. The silica gel plates used in thin-layer chromatography (TLC) have a diameter of 0.15 mm to 0.2 mm, and the diameter of the silica gel plates used for thin-layer chromatography separation and purification products is 0.4 mm to 0.5 mm.

[0630] Silica gel column chromatography generally uses Yantai Huanghai silica gel with a mesh size of 200-300 as the carrier.

[0631] Mean inhibition rate of kinases and IC 50 The values ​​were determined using a NovoStar microplate reader (BMG GmbH, Germany).

[0632] The known starting materials disclosed herein can be synthesized using or in accordance with methods known in the art, or can be purchased from companies such as ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, and Darui Chemicals.

[0633] Unless otherwise specified in the examples, all reactions can be carried out under an argon or nitrogen atmosphere.

[0634] Argon or nitrogen atmosphere refers to a reaction flask connected to an argon or nitrogen gas balloon with a volume of approximately 1L.

[0635] A hydrogen atmosphere refers to a reaction vessel connected to a hydrogen balloon with a volume of approximately 1L.

[0636] The pressurized hydrogenation reaction was performed using a Parr 3916EKX hydrogenator and a Qinglan QL-500 hydrogen generator or an HC2-SS hydrogenator.

[0637] The hydrogenation reaction is usually carried out under vacuum, filled with hydrogen gas, and repeated 3 times.

[0638] The microwave reaction was performed using a CEM Discover-S 908860 microwave reactor.

[0639] Unless otherwise specified in the examples, "solution" refers to an aqueous solution.

[0640] Unless otherwise specified in the examples, the reaction temperature is room temperature.

[0641] 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 system, and D: dichloromethane / ethyl acetate system. 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.

[0642] Example 1

[0643] 2-(1-(3-(1H-1,2,3-triazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-9-(4-(2-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)ethyl)piperazin-1-yl)-3-fluoro-N,N-dimethyl-4,6-dihydrobenzo[6,7]oxaheptanecyclo[3,4,5-cd]indole-5-carboxamide 1

[0644] first step

[0645] 4-(4-bromo-3-(methoxymethoxy)phenyl)piperazine-1-carboxylic acid tert-butyl ester 1b

[0646] 1-Bromo-4-iodo-2-(methoxymethoxy)benzene 1a (5 g, 14.58 mmol, Shanghai Haohong) and tert-butyloxycarbonylpiperazine (4.1 g, 22.01 mmol, Shanghai Bide) were dispersed in dimethyl sulfoxide (20 mL). Cuprous iodide (278 mg, 1.76 mmol) and L-proline (336 mg, 2.92 mmol) were added sequentially to the above system. The mixture was heated to 80 °C for 3 hours under a nitrogen atmosphere. After cooling to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography using eluent system A to give the title compound 1b (3.1 g).

[0647] MS m / z(ESI):401.1[M+1].

[0648] Step 2

[0649] 4-(3-(methoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxoborhexacyclopentan-2-yl)phenyl)piperazine-1-carboxylic acid tert-butyl ester 1c

[0650] Compound 1b (0.5 g, 1.25 mmol) was dispersed in 1,4-dioxane (15 mL), followed by the addition of pinacol diborate (0.35 g, 1.38 mmol), potassium acetate (366 mg, 3.73 mmol), and 1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (45 mg, 0.06 mmol). The mixture was purged with nitrogen three times and heated to 100 °C for 16 hours. The mixture was then concentrated under reduced pressure to obtain the title compound 1c (1.36 g), which was used directly in the next reaction without purification. MS m / z (ESI): 449.2 [M+1].

[0651] Step 3

[0652] 1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxoborhexacyclopentan-2-yl)-3,4-dihydropyridin-1(2H)-yl)-3-(1H-1,2,3-triazol-1-yl)prop-1-one 1f

[0653] 1d of 3-(1H-1,2,3-triazol-1-yl)propionic acid (1g, 7.14mmol, Shanghai Haohong) and 1e of 5-(4,4,5,5-tetramethyl-1,3,2-dioxoborhexacyclopentan-2-yl)-1,2,3,4-tetrahydropyridine hydrochloride (1.9g, 7.74mmol, Beijing Bailingwei) were dispersed in N,N-dimethylformamide (10mL). 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (3.5g, 9.21mmol) and diisopropylethylamine (4.6g, 35.59mmol) were added sequentially to the above system, and the mixture was stirred for 12 hours. Water was added, and the mixture was extracted with ethyl acetate. The organic phases were combined, washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography with eluent system A to give the title compound 1f (1.6 g).

[0654] MS m / z(ESI): 332.2 [M+1].

[0655] Step 4

[0656] 2-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)acetaldehyde 1i

[0657] 1 g (1 g, 2.96 mmol, Shanghai Haohong) of 3-(4-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidin-2,6-dione and 1 h (0.64 g, 3.85 mmol, Beijing Bailingwei) were dispersed in ethylene glycol dimethyl ether (10 mL). Then, di[2-(2,4-difluorophenyl)-5-trifluoromethylpyridine][2-2'] was added sequentially to the above system. The reaction mixture consisted of [bi(4-tert-butylpyridine)]iridium di(hexafluorophosphate) (0.33 g, 295.92 μmol), [4,4'-bis(1,1-dimethylethyl)-2,2'-bipyridine]nickel(II) dichloride (0.06 g, 148.24 μmol), tris(trimethylsilyl)silane (0.74 g, 2.97 mmol), and 2,6-dimethylpyridine (0.63 g, 5.92 mmol). The reaction was carried out under nitrogen atmosphere and blue light irradiation for 12 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography using eluent system A to obtain a crude product. This crude product was dissolved in 5 mL of dichloromethane, and 1 mL of 1,4-dioxane solution of hydrogen chloride was added. The mixture was stirred for 1 hour and concentrated under reduced pressure to the level of the title compound 1i (110 mg).

[0658] MS m / z(ESI):302.1[M+1].

[0659] Step 5

[0660] methyl 4-bromo-6-chloro-7-fluoro-1H-indole-2-carboxylate 1k

[0661] 2-Bromo-4-chloro-5-fluorobenzaldehyde 1j (29 g, 122.2 mmol, Shanghai Haohong) was dissolved in 100 mL of methanol and cooled to -60 °C. Sodium methoxide solution (88 g, 488 mmol) was added in portions, followed by dropwise addition of ethyl diazonate (63 g, 488 mmol). The reaction was carried out at this temperature for 1 hour, then allowed to rise naturally to room temperature, and the reaction was continued with stirring for 12 hours. The mixture was cooled to 0 °C, filtered, and the filter cake was dried. The resulting crude product was dispersed in 150 mL of xylene and reacted at 160 °C for 2 hours. The mixture was then cooled to 0 °C, filtered, and the filter cake was dried to give the title compound 1k (3.6 g).

[0662] MS m / z(ESI):308.0[M+1].

[0663] Step 6

[0664] 1l of methyl 4-bromo-6-chloro-7-fluoro-3-formyl-1H-indole-2-carboxylate

[0665] Phosphorus oxychloride (26 mL) was slowly added dropwise to N-methylformamide (37 mL), and the mixture was stirred for 1 h. Then, a solution of compound 1k (2.5 g, 8.16 mmol) dissolved in 1 mL of 1,2-dichloroethane was added dropwise to the above system. The mixture was reacted at 90 °C for 4 h, cooled to room temperature, and then poured into 100 mL of ice water. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give the title compound 1l (700 mg).

[0666] MS m / z(ESI): 336.0 [M+1].

[0667] Step 7

[0668] 4-Bromo-3-(((tert-butyldimethylsilyl)oxy)methyl)-6-chloro-7-fluoro-1H-indole-2-carboxylic acid methyl ester 1m

[0669] Compound 1L (0.7 g, 2.09 mmol) was dissolved in methanol (6 mL), and sodium borohydride (118 mg, 3.12 mmol) was added in portions. The mixture was stirred for 1 hour, and the reaction was quenched with acetone. Water was added, and the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product. The crude product was then dissolved in 10 mL of dichloromethane, and imidazole (0.28 g, 4.11 mmol) was added, followed by tert-butyldimethylchlorosilane (0.38 g, 2.52 mmol). The mixture was reacted at room temperature for 12 hours. Water was added, and the mixture was extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give the title compound 1M (0.83 g).

[0670] MS m / z(ESI):452.0[M+1].

[0671] Step 8

[0672] 4-Bromo-3-(((tert-butyldimethylsilyl)oxy)methyl)-6-chloro-7-fluoro-1H-indole-2-carboxylic acid 1n

[0673] Compound 1m (0.67 g, 1.49 mmol) was dissolved in a mixed solvent of 6 mL tetrahydrofuran, 1.5 mL water and 1.5 mL methanol. Lithium hydroxide (274 mg, 6.53 mmol) was added, and the mixture was stirred at 40 °C for 12 hours. The pH was adjusted to 4 with 2 M dilute hydrochloric acid, extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give the title compound 1n (0.63 g).

[0674] MS m / z(ESI):438.0[M+1].

[0675] Step 9

[0676] 4-Bromo-3-(((tert-butyldimethylsilyl)oxy)methyl)-6-chloro-7-fluoro-N,N-dimethyl-1H-indole-2-carboxamide

[0677] 1o

[0678] Compound 1n (0.62 g, 1.42 mmol) and dimethylamine hydrochloride (0.26 g, 3.19 mmol) were dissolved in 2 mL of N,N-dimethylformamide. 3.7 mL of diisopropylethylamine and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate (967 mg, 2.54 mmol) were added sequentially to the above system. The mixture was stirred at 0 °C for 2 hours. The reaction solution was poured into water, filtered, and the filter cake was dried to obtain the title compound 1o (0.63 g).

[0679] MS m / z(ESI):465.1[M+1].

[0680] Step 10

[0681] tert-butyl 4-(4-(3-(((tert-butyldimethylsilyl)oxy)methyl)-6-chloro-2-(dimethylaminocarbonyl)-7-fluoro-1H-indol-4-yl)-3-(methoxymethoxy)phenyl)piperazine-1-carboxylic acid tert-butyl ester 1p

[0682] Compound 1o (0.63 g, 1.36 mmol), compound 1c (0.7 g, 1.56 mmol), and the [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloromethane complex (0.1 g, 0.12 mmol) were dissolved in 10 mL of 1,4-dioxane, and 2 mL of water were added. The mixture was reacted at 90 °C for 3 hours under a nitrogen atmosphere. After cooling to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography using eluent system B to give the title compound 1p (0.79 g).

[0683] MS m / z(ESI): 705.2 [M+1].

[0684] Step 11

[0685] tert-butyl 4-(4-(6-chloro-2-(dimethylaminocarbonyl)-7-fluoro-3-(hydroxymethyl)-1H-indol-4-yl)-3-hydroxyphenyl)piperazine-1-carboxylic acid tert-butyl ester 1q

[0686] Compound 1p (0.49 g, 0.70 mmol) was dissolved in 5 mL of dichloromethane, and 2 mL of a 1,4-dioxane solution of hydrogen chloride was added. The mixture was stirred for 5 hours, and then concentrated under reduced pressure to obtain the crude product. The crude product was dispersed in 5 mL of tetrahydrofuran, and di-tert-butyl dicarbonate (180 mg, 0.83 mmol) and 0.5 mL of triethylamine were added to the above system. The mixture was stirred for 12 hours, and then concentrated to obtain the title compound 1q (0.4 g).

[0687] MS m / z(ESI): 547.2 [M+1].

[0688] Step Twelve

[0689] 4-(2-chloro-5-(dimethylaminocarbonyl)-3-fluoro-4,6-dihydroxybenzo[6,7]oxaheptane[3,4,5-cd]indol-9-yl)piperazine-1-carboxylic acid tert-butyl ester 1r

[0690] Compound 1q (0.4 g, 0.73 mmol) was dissolved in 5 mL of tetrahydrofuran. Triphenylphosphine (306 mg, 1.17 mmol) and diethyl azodicarbonate (191 mg, 1.09 mmol) were added sequentially to the above system at 0 °C. The mixture was stirred at room temperature for 2 hours, concentrated under reduced pressure, and the residue was purified by column chromatography using eluent system B to obtain the title compound 1r (0.31 g).

[0691] MS m / z(ESI): 529.2 [M+1].

[0692] Step Thirteen

[0693] 4-(2-(1-(3-(1H-1,2,3-triazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-5-(dimethylaminocarbonyl)-3-fluoro-4,6-dihydrobenzo[6,7]oxaheptanecyclo[3,4,5-cd]indol-9-yl)piperazine-1-carboxylic acid tert-butyl ester 1s

[0694] Compound 1r (0.31 g, 0.59 mmol), compound 1f (0.2 g, 0.60 mmol), methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl) palladium (50 mg, 0.06 mmol), and potassium phosphate (0.37 g, 1.74 mmol) were dissolved in a mixed solvent of 10 mL of 1,4-dioxane and 2 mL of water. The mixture was stirred at 80 °C for 6 hours under a nitrogen atmosphere. The mixture was then concentrated under reduced pressure, and the residue was purified by column chromatography using eluent system B to give the title compound 1s (0.21 g).

[0695] MS m / z(ESI): 698.1 [M+1].

[0696] Step Fourteen

[0697] 2-(1-(3-(1H-1,2,3-triazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-3-fluoro-N,N-dimethyl-9-(piperazin-1-yl)-4,6-dihydrobenzo[6,7]oxaheptanecyclo[3,4,5-cd]indole-5-carboxamide 1t

[0698] Compound 1s (0.21 g, 0.30 mmol) was dissolved in 5 mL of dichloromethane, and 2 mL of a 1,4-dioxane solution of hydrogen chloride was added. The mixture was stirred for 2 hours and then concentrated under reduced pressure to give the title compound 1t (0.2 g).

[0699] MS m / z(ESI):598.1[M+1].

[0700] Step 15

[0701] 2-(1-(3-(1H-1,2,3-triazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-9-(4-(2-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)ethyl)piperazin-1-yl)-3-fluoro-N,N-dimethyl-4,6-dihydrobenzo[6,7]oxaheptanecyclo[3,4,5-cd]indole-5-carboxamide 1

[0702] Compound 1t (200 mg, 0.32 mmol) and compound 1i (100 mg, 0.33 mmol) were dispersed in a mixed solvent of methanol (1 mL) and dichloromethane (2 mL). Triethylamine (90 mg, 0.89 mmol) and sodium cyanoborohydride (40 mg, 0.67 mmol) were added sequentially to the above system, and the mixture was stirred for 2 hours. The reaction was quenched with acetone, filtered, and the filtrate was purified by high performance liquid chromatography (column: ODS-BIO C18, 5 μm 30*250 mm; mobile phase: aqueous phase (0.1% ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 20%-95%) to obtain title compound 1 (36 mg, yield: 18%).

[0703] MS m / z(ESI): 883.2 [M+1].

[0704] Example 2

[0705] 10-(4-(4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-7-yl)piperazin-1-yl)piperidin-1-yl)-4,11-difluoro-5-(1-(3-(3-fluoro-1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-N,N-dimethyl-6,8-dihydro-3H-benzo[5,6]oxaheptanecyclo[4,3-e]indole-2-carboxamide 2

[0706] 10-(4-(4-(3-((R)-2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-7-yl)piperazin-1-yl)piperidin-1-yl)-4,11-difluoro-5-(1-(3-(3-fluoro-1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-N,N-dimethyl-6,8-dihydro-3H-benzo[5,6]oxaheptanecyclo[4,3-e]indole-2-carboxamide 2-1

[0707] 10-(4-(4-(3-((S)-2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-7-yl)piperazin-1-yl)piperidin-1-yl)-4,11-difluoro-5-(1-(3-(3-fluoro-1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-N,N-dimethyl-6,8-dihydro-3H-benzo[5,6]oxaheptanecyclo[4,3-e]indole-2-carboxamide 2-2

[0708] first step

[0709] 3-Bromo-5-chloro-2-fluoro-4-iodoaniline 2b

[0710] 3-Bromo-5-chloro-2-fluoroaniline 2a (45.30 g, 201.82 mmol, Shanghai Hanhong) was dissolved in acetic acid (200 mL), and N-iodosuccinimide (45.40 g, 201.79 mmol) was added. The mixture was stirred at 40 °C for 1 hour. After the reaction solution cooled to room temperature, the pH was adjusted to neutral with saturated sodium bicarbonate, and the mixture was extracted with ethyl acetate (150 mL × 3). The organic phases were combined, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to give title compound 2b (50 g, yield: 70.7%).

[0711] MS m / z(ESI): 349.8 [M+1].

[0712] Step 2

[0713] (3-Bromo-5-chloro-2-fluoro-4-iodophenyl)hydrazine 2c

[0714] Compound 2b (30 g, 85.63 mmol) was mixed with concentrated hydrochloric acid (150 mL), and an aqueous solution of sodium nitrite (6.20 g, 89.95 mmol) (15 mL) was slowly added dropwise at -5 °C. The mixture was stirred for 1 hour while maintaining the temperature. Then, a concentrated hydrochloric acid solution of stannous chloride dihydrate (58 g, 257.04 mmol) (100 mL) was added dropwise, and the mixture was stirred for 2 hours while maintaining the temperature. The pH of the reaction solution was adjusted to 9-10 with 30% sodium hydroxide solution, diluted with ethyl acetate, filtered, and the filtrate was extracted with ethyl acetate (150 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude title compound 2c (25.5 g). The product was used directly in the next reaction without purification.

[0715] MS m / z(ESI): 362.9 [M-1].

[0716] Step 3

[0717] 2-(2-(3-bromo-5-chloro-2-fluoro-4-iodophenyl)hydrazylmethylene)-N,N-dimethylpropionamide 2d

[0718] The crude compound 2c (25.50 g, 69.79 mmol) was dissolved in methanol (200 mL), and N,N-dimethyl-2-oxopropionamide (8.4 g, 72.96 mmol, Jiangsu Aikon) was added dropwise. The mixture was stirred for 4 hours. The reaction solution was concentrated under reduced pressure to obtain the crude title compound 2d (32 g). The product was used directly in the next reaction without purification.

[0719] MS m / z(ESI):462.0[M+1].

[0720] Step 4

[0721] 6-Bromo-4-chloro-7-fluoro-5-iodo-N,N-dimethyl-1H-indole-2-carboxamide 2e

[0722] The crude compound 2d (11.70 g, 25.30 mmol) was mixed with polyphosphoric acid (100 mL) and stirred at 125 °C for 1.5 h. After the reaction solution cooled to room temperature, it was poured into ice water, filtered, the filter cake was dissolved in ethyl acetate and washed with water, the organic phase was separated, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system D to give the title compound 2e (3.5 g, yield: 31.06%).

[0723] MS m / z(ESI):445.0[M+1].

[0724] Step 5

[0725] 6-Bromo-4-chloro-7-fluoro-5-formyl-N,N-dimethyl-1H-indole-2-carboxamide 2f

[0726] Compound 2e (1.8 g, 4.04 mmol) was dissolved in tetrahydrofuran (20 mL). Under a nitrogen atmosphere, a 2 M solution of magnesium isopropyl chloride in tetrahydrofuran (4.5 mL) was added dropwise at -78 °C. After stirring for 2 hours while maintaining the temperature, a solution of N,N-dimethylformamide (440 mg, 6.02 mmol) in tetrahydrofuran (2 mL) was added dropwise. The reaction was then slowly brought to room temperature and stirred for 1 hour before being quenched with water. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system D to give the title compound 2f (320 mg, yield: 22.8%).

[0727] MS m / z(ESI): 347.0 [M+1].

[0728] Step 6

[0729] 2g of 5-(4-chloro-2-(dimethylaminocarbonyl)-7-fluoro-5-formyl-1H-indol-6-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester

[0730] Compound 2f (150 mg, 431 μmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxoborhexacyclopentan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (135 mg, 436 μmol, Shanghai Bide), 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (15 mg, 20.5 μmol), and anhydrous potassium carbonate (90 mg, 651 μmol) were dissolved in 1,4-dioxane (5 mL) and water (0.5 mL). The reaction mixture was stirred at 80 °C for 5 hours under a nitrogen atmosphere. After the reaction solution was cooled to room temperature, it was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system A to give 2 g (160 mg, yield: 82.4%) of the title compound.

[0731] MS m / z(ESI): 450.1 [M+1].

[0732] Step 7

[0733] Methyl 4-fluoro-3-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)benzoate 2i

[0734] 2h of methyl 3-bromo-4-fluorobenzoate (10 g, 42.91 mmol, Shanghai Shaoyuan) and 4-piperidinone ethylene glycol (7.4 g, 51.68 mmol) were dissolved in 1,4-dioxane (100 mL). Cesium carbonate (28 g, 85.94 mmol), tris(dibenzylacetone)dipalladium (4 g, 4.37 mmol), and 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (5.4 g, 8.67 mmol) were added. The mixture was stirred at 110 °C for 16 hours under a nitrogen atmosphere. After cooling to room temperature, the reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system B to give the title compound 2i (11 g, yield: 86.8%).

[0735] MS m / z(ESI):296.2[M+1].

[0736] Step 8

[0737] Methyl 2-bromo-4-fluoro-5-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)benzoate 2j

[0738] Compound 2i (11 g, 37.25 mmol) was dissolved in tetrahydrofuran (100 mL), and N-bromosuccinimide (7.30 g, 41.01 mmol) was added. The mixture was stirred for 1 hour. The reaction solution was quenched with saturated sodium thiosulfate solution, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic phases were combined, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to give the title compound 2j (5 g, yield: 35.87%).

[0739] MS m / z(ESI): 374.1 [M+1].

[0740] Step 9

[0741] 4-Fluoro-5-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxoborhexacyclopentan-2-yl)methyl benzoate 2k

[0742] Compound 2j (2 g, 5.34 mmol), pinacol diborate (2 g, 7.88 mmol), potassium acetate (1 g, 10.19 mmol), and 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (200 mg, 273 μmol) were mixed in 1,4-dioxane (50 mL) and stirred at 100 °C for 3.5 h under a nitrogen atmosphere. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system B to give the title compound 2k (1.8 g, yield: 79.9%).

[0743] MS m / z(ESI):422.2[M+1].

[0744] Step 10 (4-fluoro-5-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxoborhecyclopentan-2-yl)phenyl)methanol 2l

[0745] Compound 2k (200 mg, 475 μmol) was dissolved in tetrahydrofuran (5 mL). Under a nitrogen atmosphere and in an ice bath, lithium borohydride (21 mg, 964 μmol) was added, and the mixture was allowed to return to room temperature with stirring for 2 hours. A saturated ammonium chloride solution was added to the reaction mixture, and the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system B to give the title compound 2l (180 mg, yield: 96.4%).

[0746] Step 11

[0747] 5-(2-(dimethylaminocarbonyl)-7-fluoro-4-(5-fluoro-2-(hydroxymethyl)-4-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)phenyl)-5-formyl-1H-indol-6-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester 2m

[0748] Compound 2 g (160 mg, 356 μmol), compound 2 l (170 mg, 432 μmol), potassium phosphate (115 mg, 542 μmol), and methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (45 mg, 53 μmol) were mixed in 1,4-dioxane (3 mL) and water (0.3 mL). The mixture was stirred at 95 °C for 5 hours under a nitrogen atmosphere. After the reaction solution was cooled to room temperature, it was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system A to give the title compound 2 m (240 mg, yield: 99.1%).

[0749] MS m / z(ESI): 681.4 [M+1].

[0750] Step Twelve

[0751] 5-(2-(dimethylaminocarbonyl)-7-fluoro-4-(5-fluoro-2-(hydroxymethyl)-4-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)phenyl)-5-(hydroxymethyl)-1H-indol-6-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl2n

[0752] Compound 2m (240 mg, 352 μmol) was dissolved in tetrahydrofuran (5 mL). Under a nitrogen atmosphere and in an ice bath, lithium borohydride (12 mg, 551 μmol) was added, and the reaction was allowed to return to room temperature with stirring for 1 hour. The reaction solution was quenched with saturated ammonium chloride solution, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system A to give the title compound 2n (170 mg, yield: 70.6%).

[0753] MS m / z(ESI): 683.4 [M+1].

[0754] Step Thirteen

[0755] 4,11-Difluoro-N,N-dimethyl-10-(4-oxopiperidin-1-yl)-5-(1,2,5,6-tetrahydropyridin-3-yl)-6,8-dihydro-3H-benzo[5,6]oxaheptanecyclo[4,3-e]indole-2-carboxamide 2o

[0756] Compound 2n (170 mg, 249 μmol) was dissolved in tetrahydrofuran (1 mL), and 50% sulfuric acid (1 mL) was added. The mixture was stirred at 70 °C for 2 hours. After the reaction solution cooled to room temperature, the pH was adjusted to >7 with 2M sodium hydroxide solution. The solution was extracted with ethyl acetate (5 mL × 3), and the organic phases were combined. The mixture was dried over saturated anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude title compound 2o (100 mg). The product was used directly in the next reaction without purification.

[0757] MS m / z(ESI): 521.3 [M+1].

[0758] Step Fourteen

[0759] 2q of methyl 3-(3-fluoro-1H-pyrazole-1-yl)propionate

[0760] 3-Fluoro-1H-pyrazole 2p (3.5 g, 40.66 mmol, Shanghai Bide) was dissolved in N,N-dimethylformamide (40 mL), and potassium carbonate (11.22 g, 81.33 mmol) and methyl 3-bromopropionate (10.19 g, 61 mmol) were added. The mixture was stirred for 16 hours, and water was added to the reaction solution. The mixture was extracted with ethyl acetate (50 mL × 2). The organic phases were combined, washed with saturated sodium chloride solution, 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 2q (6.1 g, yield: 87.1%).

[0761] MS m / z(ESI): 173.0 [M+1].

[0762] Step 15

[0763] 3-(3-Fluoro-1H-pyrazol-1-yl)propionic acid 2r

[0764] Compound 2q (6 g, 34.85 mmol) was dissolved in tetrahydrofuran (10 mL) and water (10 mL), and lithium hydroxide monohydrate (2.92 g, 69.70 mmol) was added. The mixture was stirred for 1 hour. The reaction solution was diluted with water, and the pH was adjusted to approximately 5 with 1 M hydrochloric acid solution. The mixture was filtered, and the filter cake was washed with water and dried to obtain the crude title compound 2r (5.5 g). The product was used directly in the next reaction without purification.

[0765] MS m / z(ESI):159.0[M+1].

[0766] Step Sixteen

[0767] 4,11-Difluoro-5-(1-(3-(3-fluoro-1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-N,N-dimethyl-10-(4-oxopiperidin-1-yl)-6,8-dihydro-3H-benzo[5,6]oxaheptanecyclo[4,3-e]indole-2-carboxamide 2s

[0768] Compound 2r (50 mg, 316 μmol) and compound 2o (100 mg, 192 μmol) were dissolved in N,N-dimethylformamide (2 mL), and N,N-diisopropylethylamine (75 mg, 580 μmol) and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate (110 mg, 289 μmol) were added. The mixture was stirred for 16 hours. The reaction solution was poured into water and extracted with ethyl acetate (10 mL × 2). The organic phases were combined, washed with saturated sodium chloride solution, 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 A to give the title compound 2s (120 mg, yield: 94.5%).

[0769] MS m / z(ESI): 661.5 [M+1].

[0770] Step Seventeen

[0771] 10-(4-(4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-7-yl)piperazin-1-yl)piperidin-1-yl)-4,11-difluoro-5-(1-(3-(3-fluoro-1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-N,N-dimethyl-6,8-dihydro-3H-benzo[5,6]oxaheptanecyclo[4,3-e]indole-2-carboxamide 2

[0772] 10-(4-(4-(3-((R)-2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-7-yl)piperazin-1-yl)piperidin-1-yl)-4,11-difluoro-5-(1-(3-(3-fluoro-1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-N,N-dimethyl-6,8-dihydro-3H-benzo[5,6]oxaheptanecyclo[4,3-e]indole-2-carboxamide 2-1

[0773] 10-(4-(4-(3-((S)-2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-7-yl)piperazin-1-yl)piperidin-1-yl)-4,11-difluoro-5-(1-(3-(3-fluoro-1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-N,N-dimethyl-6,8-dihydro-3H-benzo[5,6]oxaheptanecyclo[4,3-e]indole-2-carboxamide 2-2

[0774] 2t (16 mg, 44 μmol, prepared by the method disclosed in EXAMPLE 23 on page 417 of patent application “WO2025101588”) of 3-(1-methyl-7-(piperazin-1-yl)-1H-indazol-3-yl)piperidine-2,6-dione hydrochloride, and 2s (30 mg, 45 μmol) were dissolved in 1,2-dichloroethane (1 mL) and dimethyl sulfoxide (0.5 mL). Sodium acetate (11 mg, 136 μmol) was added, and the mixture was stirred for 1 hour. Then, sodium triacetoxyborohydride (29 mg, 136 μmol) was added, and the mixture was stirred for 16 hours. Saturated sodium bicarbonate solution was added to the reaction solution, and the mixture was extracted with dichloromethane (5 mL × 2). The organic phases were combined, concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography (Waters-2545, column: Welch Xtimate C18, 30*150 mm, 5 μm; mobile phase: aqueous phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 30%-60%, flow rate: 30 mL / min) to obtain title compound 2 (5 mg, yield: 11.3%), which was resolved by chiral column to obtain title compounds 2-1 and 2-2.

[0775] Compound 2:

[0776] MS m / z (ESI): 972.7 [M+1].

[0777] 1H NMR (500MHz, CDCl3): δ9.58(s,1H),7.96(s,1H),7.47(dd,1H),7.41(dd,1H),7.36(d,1H),7.15–7.07(m,3H), 7.04–6.99(m,1H),5.99(s,1H),5.73(ddd,1H),4.64(d,1H),4.49(dd,1H),4.40(t,2H),4.36(s,3H),4.32(dd ,1H),4.10(d,1H),3.97(d,1H),3.72(t,3H),3.43(s,3H),3.25(s,3H),3.14(s,3H),3.04–2.95(m,3H),2.88( t,2H),2.70(ddd,3H),2.52(td,2H),2.40(ddd,3H),2.27–2.21(m,2H),2.10(s,2H),2.03(q,2H),1.91(d,2H).

[0778] Example 3

[0779] 10-(4-(4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl)piperazin-1-yl)piperidin-1-yl)-4,11-difluoro-5-(1-(3-(3-fluoro-1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-N,N-dimethyl-6,8-dihydro-3H-benzo[5,6]oxaheptanecyclo[4,3-e]indole-2-carboxamide 3

[0780] 10-(4-(4-(3-((R)-2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl)piperazin-1-yl)piperidin-1-yl)-4,11-difluoro-5-(1-(3-(3-fluoro-1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-N,N-dimethyl-6,8-dihydro-3H-benzo[5,6]oxaheptanecyclo[4,3-e]indole-2-carboxamide 3-1

[0781] 10-(4-(4-(3-((S)-2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl)piperazin-1-yl)piperidin-1-yl)-4,11-difluoro-5-(1-(3-(3-fluoro-1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-N,N-dimethyl-6,8-dihydro-3H-benzo[5,6]oxaheptanecyclo[4,3-e]indole-2-carboxamide 3-2

[0782] Using the synthetic route in Example 2, the starting compound 2t in step seventeen was replaced with 3-(1-methyl-6-(piperazin-1-yl)-1H-indazole-3-yl)piperidine-2,6-dione hydrochloride (prepared by the method disclosed in Example 106 on page 322 of patent application "WO2023083194") to obtain title compound 3 (8 mg, yield: 18.1%), which was then resolved by chiral column chromatography to obtain title compounds 3-1 and 3-2.

[0783] Compound 3:

[0784] MS m / z(ESI): 972.7 [M+1].

[0785] 1 H NMR (500MHz, DMSO-d6): δ12.32(d,1H),10.85(s,1H),7.65(dt,1H),7.52(dd,2H),7.29–7.23(m, 1H),6.96–6.89(m,2H),6.86(s,1H),5.95–5.83(m,2H),4.53(d,3H),4.24(ddt,4H),4.01(d,1H), 3.90(s,3H),3.80(d,2H),3.68–3.51(m,4H),3.30(s,3H),3.24(s,5H),3.05(s,2H),2.96(t,1H), 2.94–2.70(m,6H),2.69–2.56(m,3H),2.40–2.23(m,3H),2.16(dd,1H),1.96(s,2H),1.67(d,2H).

[0786] Example 4

[0787] 10-(4-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluoro-5-methoxyphenyl)piperazin-1-yl)piperidin-1-yl)-4,11-difluoro-5-(1-(3-(3-fluoro-1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-N,N-dimethyl-6,8-dihydro-3H-benzo[5,6]oxaheptanecyclo[4,3-e]indole-2-carboxamide 4

[0788] 10-(4-(4-(4-((((R)-2,6-dioxopiperidin-3-yl)amino)-2-fluoro-5-methoxyphenyl)piperazin-1-yl)piperidin-1-yl)-4,11-difluoro-5-(1-(3-(3-fluoro-1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-N,N-dimethyl-6,8-dihydro-3H-benzo[5,6]oxaheptanecyclo[4,3-e]indole-2-carboxamide 4-1

[0789] 10-(4-(4-(4-(((S)-2,6-dioxopiperidin-3-yl)amino)-2-fluoro-5-methoxyphenyl)piperazin-1-yl)piperidin-1-yl)-4,11-difluoro-5-(1-(3-(3-fluoro-1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-N,N-dimethyl-6,8-dihydro-3H-benzo[5,6]oxaheptanecyclo[4,3-e]indole-2-carboxamide 4-2

[0790] Using the synthetic route in Example 2, the starting compound 2t in step seventeen was replaced with 3-((5-fluoro-2-methoxy-4-(piperazin-1-yl)phenyl)amino)piperidine-2,6-dione hydrochloride (prepared using the method disclosed in EXAMPLE 2 on page 165 of patent application "WO2022032026") to obtain title compound 4 (10 mg, yield: 22.4%), which was then resolved by chiral column chromatography to obtain title compounds 4-1 and 4-2.

[0791] Compound 4:

[0792] MS m / z(ESI): 981.7 [M+1].

[0793] 1 H NMR (500MHz, DMSO-d6): δ12.24(s,1H),10.86(s,1H),7.64(dt,1H),7.52(d,1H),7.23(dd ,1H),6.91(d,1H),6.61(d,1H),6.55(d,1H),5.96–5.80(m,2H),5.09(d,1H),4.60–4.45( m,2H),4.24(tt,3H),4.05–3.83(m,3H),3.79(s,4H),3.67–3.50(m,4H),3.13(d,6H),3.0 0–2.74(m,9H),2.68(s,4H),2.37(dt,3H),2.13(dd,1H),2.04–1.85(m,4H),1.63(d,2H).

[0794] Example 5

[0795] 10-(4-(4-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)piperazin-1-yl)piperidin-1-yl)-4,11-difluoro-5-(1-(3-(3-fluoro-1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-N,N-dimethyl-6,8-dihydro-3H-benzo[5,6]oxaheptanecyclo[4,3-e]indole-2-carboxamide 5

[0796] 10-(4-(4-(4-((S)-2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)piperazin-1-yl)piperidin-1-yl)-4,11-difluoro-5-(1-(3-(3-fluoro-1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-N,N-dimethyl-6,8-dihydro-3H-benzo[5,6]oxaheptanecyclo[4,3-e]indole-2-carboxamide 5-1

[0797] 10-(4-(4-(4-((R)-2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)piperazin-1-yl)piperidin-1-yl)-4,11-difluoro-5-(1-(3-(3-fluoro-1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-N,N-dimethyl-6,8-dihydro-3H-benzo[5,6]oxaheptanecyclo[4,3-e]indole-2-carboxamide 5-2

[0798] Using the synthetic route in Example 2, the starting compound 2t in step seventeen was replaced with 3-(2,6-difluoro-4-(piperazin-1-yl)phenyl)piperidine-2,6-dione (prepared by the method disclosed in Example 4 on page 44 of patent application "CN119431448A"). The formate salt of title compound 5 (5 mg, yield: 11%) was purified by preparative high-performance liquid chromatography (Waters-2545, column: Welch Xtimate C18, 30*150 mm, 5 μm; mobile phase: aqueous phase (0.1% formic acid) and acetonitrile, gradient ratio: acetonitrile 20%-45%, flow rate: 30 mL / min). Resolution with a chiral column yielded title compounds 5-1 and 5-2.

[0799] Compound 5:

[0800] MS m / z(ESI): 954.7 [M+1].

[0801] 1H NMR (500MHz, CDCl3): δ9.75(d,1H),8.08(s,1H),7.46(dd,1H),7.38–7.32(m,1H),7.10(t,1H),7.01(dt,1H),6.49 –6.42(m,2H),5.98(s,1H),5.73(ddd,1H),4.64(d,1H),4.48(dd,1H),4.41-4.31(m,3H),4.10(d,1H),4.03–3.93( m,2H),3.75-3.66(m,2H),3.64-3.57(m,1H),3.43(s,3H),3.33–3.16(m,6H),3.01–2.92(m,2H),2.89-2.80(m,6H) ,2.74-2.67(m,1H),2.62-2.55(m,1H),2.45-2.30(m,3H),2.20-2.13(m,1H),2.10-1.97(m,6H),1.92-1.82(m,2H).

[0802] Example 6

[0803] 2-(1-(3-(1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-9-(4-(2-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)ethyl)piperazin-1-yl)-N,N-dimethyl-4,6-dihydrobenzo[6,7]oxaheptanecyclo[3,4,5-cd]indole-5-carboxamide 6

[0804] first step

[0805] 6-Bromo-4-chloro-N,N-dimethyl-1H-indole-2-carboxamide 6b

[0806] 6-Bromo-4-chloro-1H-indole-2-carboxylic acid 6a (3.3 g, 12.02 mmol, Shanghai Shaoyuan) and dimethylamine hydrochloride (1.44 g, 14.66 mmol) were dissolved in N,N-dimethylformamide (30 mL), and N,N-diisopropylethylamine (12.7 mL) and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate (6.8 g, 17.88 mmol) were added. The mixture was stirred for 3 hours, the reaction solution was poured into water, filtered, and the filter cake was dried to obtain the crude title compound 6b (3.5 g). The product was used directly in the next reaction without purification.

[0807] MS m / z(ESI): 301.2 [M+1].

[0808] Step 2

[0809] 6-Bromo-4-chloro-3-formyl-N,N-dimethyl-1H-indole-2-carboxamide 6c

[0810] Under a nitrogen atmosphere and in an ice bath, phosphorus oxychloride (1.03 mL) was slowly added dropwise to N,N-dimethylformamide (2.77 mL), followed by a solution of crude compound 6b (3.0 g, 9.95 mmol) in N,N-dimethylformamide (4 mL). The mixture was stirred at the same temperature for 1 hour, then heated to 60 °C and reacted for 12 hours. The reaction mixture was cooled to room temperature and poured into ice water. The pH was adjusted to approximately 7 with 2 M sodium hydroxide solution. The mixture was filtered, and the filter cake was purified by silica gel column chromatography using eluent system B to obtain the title compound 6c (306 mg, yield: 9.3%).

[0811] MS m / z(ESI):329.1[M+1].

[0812] Step 3

[0813] 6-(1-(3-(1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-4-chloro-3-carboxyl-N,N-dimethyl-1H-indole-2-carboxamide 6d

[0814] Compound 6c (0.28 g, 0.85 mmol), 3-(1H-pyrazol-1-yl)-1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxoborhexacyclopentan-2-yl)-3,6-dihydropyridin-1(2H)-yl)prop-1-one (0.4 g, 1.21 mmol), were prepared using the Intermediate method described on page 1114 of patent application "WO2025049820". The [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloromethane complex (60 mg, 0.08 mmol), potassium carbonate (230 mg, 1.66 mmol), and 1,4-dioxane (15 mL) and water (2 mL) were prepared by the method disclosed in N. The reaction was carried out at 85 °C for 12 hours under a nitrogen atmosphere. After cooling to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic phases were combined, washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system A to give the title compound 6d (310 mg, yield: 80.4%).

[0815] MS m / z(ESI):454.3[M+1].

[0816] Step 4

[0817] 4-(4-(6-(1-(3-(1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-2-(dimethylaminocarbonyl)-3-formyl-1H-indol-4-yl)-3-methoxyphenyl)piperazine-1-carboxylic acid tert-butyl ester 6e

[0818] Compound 6d (30 mg, 66 μmol) and 4-(3-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxoborhexacyclopent-2-yl)phenyl)piperazine-1-carboxylic acid tert-butyl ester (30 mg, 72 μmol) were prepared using patent application "EP2952510". The product was prepared by the method disclosed in "Intermediate 1" on pages 19 and 20 of the specification in A1), methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl) palladium (10 mg, 12 μmol) and potassium phosphate (45 mg, 212 μmol) were dissolved in 1,4-dioxane (5 mL) and water (1 mL). The reaction was carried out under nitrogen atmosphere and stirred at 90 °C for 12 hours. After the reaction solution was cooled to room temperature, it was concentrated under reduced pressure to obtain the crude title compound 6e (46 mg). The product was used directly in the next reaction without purification.

[0819] MS m / z(ESI): 710.6 [M+1].

[0820] Step 5

[0821] 6-(1-(3-(1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-3-formyl-4-(2-hydroxy-4-(piperazin-1-yl)phenyl)-N,N-dimethyl-1H-indole-2-carboxamide 6f

[0822] The crude compound 6e (30 mg, 42 μmol) was dissolved in dichloromethane (6 mL). A 2M solution of boron tribromide in dichloromethane (53 mg, 211 μmol) was added under ice bath cooling. The mixture was stirred for 1 hour while maintaining the temperature, then stirred for another 16 hours at room temperature. The reaction mixture was quenched with methanol and concentrated under reduced pressure to obtain the crude title compound 6f (25 mg). This product was used directly in the next reaction without purification.

[0823] MS m / z(ESI): 596.4 [M+1].

[0824] Step 6

[0825] 6g of 4-(4-(6-(1-(3-(1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-2-(dimethylaminocarbonyl)-3-formyl-1H-indol-4-yl)-3-hydroxyphenyl)piperazine-1-carboxylic acid tert-butyl ester

[0826] The crude compound 6f (25 mg, 42 μmol) was dissolved in dichloromethane (5 mL), and triethylamine (26 mg, 257 μmol) and di-tert-butyl dicarbonate (10 mg, 46 μmol) were added. The mixture was stirred for 1 hour, and the reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system A to give the title compound 6 g (12 mg, yield: 41.09%).

[0827] MS m / z(ESI): 696.6 [M+1].

[0828] Step 7

[0829] 4-(4-(6-(1-(3-(1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-2-(dimethylaminocarbonyl)-3-(hydroxymethyl)-1H-indol-4-yl)-3-hydroxyphenyl)piperazine-1-carboxylic acid tert-butyl ester 6h

[0830] 6 g (12 mg, 17 μmol) of the compound was dissolved in methanol (3 mL), and sodium borohydride (5 mg, 132 μmol) was added. The mixture was stirred for 2 hours. The reaction solution was quenched with saturated ammonium chloride aqueous solution and extracted with dichloromethane (5 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude title compound 6h (16 mg). The product was used directly in the next reaction without purification.

[0831] MS m / z(ESI): 698.5 [M+1].

[0832] Step 8

[0833] 4-(2-(1-(3-(1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-5-(dimethylaminocarbonyl)-4,6-dihydrobenzo[6,7]oxaheptanecyclo[3,4,5-cd]indol-9-yl)piperazine-1-carboxylic acid tert-butyl ester 6i

[0834] The crude compound 6h (10 mg, 14 μmol) was dissolved in tetrahydrofuran (1 mL). Triphenylphosphine (12 mg, 46 μmol) and diisopropyl azodicarbonate (12 mg, 59 μmol) were added sequentially at 0 °C. The mixture was stirred at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system A to give the title compound 6i (10 mg, yield: 100%).

[0835] MS m / z(ESI): 579.3 [M-99].

[0836] Step 9

[0837] 2-(1-(3-(1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-N,N-dimethyl-9-(piperazin-1-yl)-4,6-dihydrobenzo[6,7]oxaheptanecyclo[3,4,5-cd]indole-5-carboxamide hydrochloride 6j

[0838] Compound 6i (10 mg, 14.7 μmol) was dissolved in dichloromethane (1 mL), and a 1,4-dioxane solution of 4 M hydrogen chloride (0.3 mL) was added. The mixture was stirred for 1 hour, and the reaction solution was concentrated under reduced pressure to obtain crude title compound 6j (9 mg). The product was used directly in the next reaction without purification.

[0839] Step 10

[0840] 2-(1-(3-(1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-9-(4-(2-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)ethyl)piperazin-1-yl)-N,N-dimethyl-4,6-dihydrobenzo[6,7]oxaheptanecyclo[3,4,5-cd]indole-5-carboxamide 6

[0841] The crude compound 6j (10 mg, 16 μmol) and 2-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)acetaldehyde (5 mg, 16.6 μmol, prepared by the method disclosed in the specification on page 430 of patent application "WO2023278759A1, intermediate X") were dissolved in dimethyl sulfoxide (1 mL) and tetrahydrofuran (2 mL). Acetic acid (10 mg, 166 μmol), potassium acetate (9 mg, 92 μmol), and sodium triacetoxyborohydride (11 mg, 52 μmol) were added, and the mixture was stirred for 16 hours. The reaction solution was quenched with acetone and filtered. The filtrate was purified by preparative high performance liquid chromatography (Waters-2545, column: Welch Xtimate C18, 30*150mm, 5μm; mobile phase: aqueous phase (10mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 30%-60%, flow rate: 30mL / min) to obtain title compound 6 (1mg, yield: 7.12%).

[0842] MS m / z(ESI): 863.2 [M-1].

[0843] Example 7

[0844] 11-(1-(3-(1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-7-(4-(2-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-1H-indazol-4-yl)ethyl)piperazin-1-yl)-N,N-dimethyl-1,5-dihydro-3H-benzo[6,7]oxaheptanecyclo[3,4,5-cd]indole-2-carboxamide 7

[0845] first step

[0846] 4-(4-(6-(1-(3-(1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-2-(dimethylaminocarbonyl)-3-formyl-1H-indol-4-yl)-3-(hydroxymethyl)phenyl)piperazine-1-carboxylic acid tert-butyl ester 7a

[0847] Compound 6d (60 mg, 132 μmol) and 4-(3-(hydroxymethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxoborhexacyclopentan-2-yl)phenyl)piperazine-1-carboxylic acid tert-butyl ester (66 mg, 158 μmol) were used in patent application "WO2022228489". The compound was prepared by the method disclosed in intermediate 28-4 on page 27 of the specification in A1, methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl) palladium (20 mg, 23.6 μmol) and potassium phosphate (100 mg, 471 μmol) in 1,4-dioxane (8 mL) and water (1.5 mL). The reaction was carried out under nitrogen atmosphere and stirred at 90 °C for 16 hours. After the reaction solution was cooled to room temperature, it was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system A to give title compound 7a (50 mg, yield: 53.3%).

[0848] MS m / z(ESI): 710.7 [M+1].

[0849] Step 2

[0850] 4-(4-(6-(1-(3-(1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-2-(dimethylaminocarbonyl)-3-formyl-1-(methylsulfonyl)-1H-indol-4-yl)-3-(chloromethyl)phenyl)piperazine-1-carboxylic acid tert-butyl ester 7b

[0851] Compound 7a (30 mg, 42 μmol) was dissolved in dichloromethane (5 mL), and triethylamine (26 mg, 257 μmol) and methanesulfonyl chloride (10 mg, 87 μmol) were added under ice bath conditions. The reaction mixture was allowed to return to room temperature for 0.5 hours. The reaction solution was washed with water, the organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give crude title compound 7b (34 mg). The product was used directly in the next reaction without purification.

[0852] MS m / z(ESI): 806.5 [M+1].

[0853] Step 3

[0854] 4-(4-(6-(1-(3-(1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-2-(dimethylaminocarbonyl)-3-(hydroxymethyl)-1-(methylsulfonyl)-1H-indol-4-yl)-3-(chloromethyl)phenyl)piperazine-1-carboxylic acid tert-butyl ester 7c

[0855] The crude compound 7b (34 mg, 42 μmol) was dissolved in tetrahydrofuran (2 mL), and a 2M lithium borohydride tetrahydrofuran solution (23 μL) was added. The mixture was stirred for 1 hour. The reaction solution was quenched with water, extracted with ethyl acetate (5 mL × 2), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude title compound 7c (34 mg). The product was used directly in the next reaction without purification.

[0856] MS m / z(ESI): 808.5 [M+1].

[0857] Step 4

[0858] 4-(11-(1-(3-(1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-2-(dimethylaminocarbonyl)-1-(methanesulfonyl)-1,5-dihydro-3H-benzo[6,7]oxaheptanecyclo[3,4,5-cd]indol-7-yl)piperazine-1-carboxylic acid tert-butyl ester 7d

[0859] The crude compound 7c (34 mg, 39 μmol) was dissolved in N,N-dimethylformamide (1 mL), and sodium hydride (6 mg, 150 μmol) was added. The mixture was stirred for 5 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate (5 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude title compound 7d (30 mg). The product was used directly in the next reaction without purification.

[0860] MS m / z(ESI): 772.5 [M+1].

[0861] Step 5

[0862] 4-(11-(1-(3-(1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-2-(dimethylaminocarbonyl)-1,5-dihydro-3H-benzo[6,7]oxaheptanecyclo[3,4,5-cd]indol-7-yl)piperazine-1-carboxylic acid tert-butyl ester 7e

[0863] The crude compound 7d (30 mg, 39 μmol) was dissolved in N,N-dimethylformamide (2 mL) and water (0.5 mL), and sodium hydroxide (10 mg, 250 μmol) was added. The mixture was stirred for 1 hour. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate (5 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude title compound 7d (12 mg). The product was used directly in the next reaction without purification.

[0864] MS m / z(ESI): 694.2 [M+1].

[0865] Step 6

[0866] 11-(1-(3-(1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-N,N-dimethyl-7-(piperazin-1-yl)-1,5-dihydro-3H-benzo[6,7]oxaheptanecyclo[3,4,5-cd]indole-2-carboxamide hydrochloride 7f

[0867] The crude compound 7d (12 mg, 17.29 μmol) was dissolved in dichloromethane (5 mL), and a 1,4-dioxane solution of 4M hydrogen chloride (0.5 mL) was added. The mixture was stirred for 1 hour, and the reaction solution was concentrated under reduced pressure to obtain the crude title compound 7f (11 mg). The product was used directly in the next step of the reaction without purification.

[0868] MS m / z(ESI): 594.2 [M+1].

[0869] Step 7

[0870] 11-(1-(3-(1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-7-(4-(2-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-1H-indazol-4-yl)ethyl)piperazin-1-yl)-N,N-dimethyl-1,5-dihydro-3H-benzo[6,7]oxaheptanecyclo[3,4,5-cd]indole-2-carboxamide 7

[0871] The crude compound 7f (4 mg, 6.3 μmol) and 2-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-1H-indazol-4-yl)acetaldehyde (4 mg, 14 μmol, prepared by the method disclosed in the specification on page 1131 of patent application "WO 2025049820 A1, intermediate AB") were dispersed in dimethyl sulfoxide (0.5 mL) and tetrahydrofuran (2 mL). Acetic acid (8 mg, 133 μmol), potassium acetate (4 mg, 40.7 μmol), and sodium triacetoxyborohydride (15 mg, 71 μmol) were added, and the mixture was stirred for 16 hours. The reaction was quenched with acetone, filtered, and the filtrate was purified by high performance liquid chromatography (Waters-2545, column: Welch Xtimate C18, 30*150mm, 5μm; mobile phase: aqueous phase (10mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 30%-60%, flow rate: 30mL / min) to give title compound 7 (1mg, yield: 18.2%).

[0872] MS m / z(ESI): 864.2 [M+1].

[0873] The compounds in the following examples can be obtained by referring to the methods in Examples 1-7 above.

[0874] Example 8

[0875] Title compound 8 was prepared by referring to the methods disclosed herein and known techniques.

[0876] MS m / z(ESI): 959.7 [M+1].

[0877] Example 9

[0878] 10-(4-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)piperazin-1-yl)piperidin-1-yl)-4,11-difluoro-5-(1-(3-(3-fluoro-1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-N,N-dimethyl-6,8-dihydro-3H-benzo[5,6]oxaheptane[4,3-e]indole-2-carboxamide ester 9

[0879] Using the synthetic route in Example 2, the starting compound 2t in step seventeen was replaced with 3-(3-methyl-2-oxo-5-(piperazin-1-yl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione hydrochloride (prepared using the method disclosed in Intermediate AWS on page 657 of patent application "WO2020264499"). The formate of title compound 9 was purified by preparative high-performance liquid chromatography (Waters-2545, column: Welch Xtimate C18, 30*150mm, 5μm; mobile phase: aqueous phase (0.1% formic acid) and acetonitrile, gradient ratio: acetonitrile 20%-45%, flow rate: 30mL / min) to obtain a formate of title compound 9 (5mg, yield: 10.6%).

[0880] MS m / z(ESI): 988.7 [M+1].

[0881] 1 H NMR (500MHz, CDCl3): δ9.65(d,1H),8.21(s,1H),7.47(dd,1H),7.38–7.33(m,1H),7.11(t,1H),7.01(dt,1H),6.7 4–6.67(m,2H),5.98(s,1H),5.73(ddd,1H),5.22(dd,1H),4.64(d,1H),4.49(dd,1H),4.45–4.31(m,3H),4.10(d, 1H),3.96(d,2H),3.76-3.67(m,2H),3.63-3.57(m,1H),3.51-3.37(m,6H),3.33–3.18(m,6H),3.02–2.93(m,5H), 2.91-2.82(m,3H),2.77-2.68(m,2H),2.45-2.36(m,2H),2.30-2.23(m,2H),2.16-2.09(m,2H),2.06-1.91(m,6H).

[0882] Example 10

[0883] Title compound 10 was prepared by referring to the methods disclosed herein and known techniques.

[0884] MS m / z(ESI): 958.7 [M+1].

[0885] Example 11

[0886] 10-(4-(6-(2,6-dioxopiperidin-3-yl)-5,7-difluoro-2H-spiro[benzofuran-3,4'-piperidin]-1'-yl)piperidin-1-yl)-4,11-difluoro-5-(1-(3-(3-fluoro-1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-N,N-dimethyl-6,8-dihydro-3H-benzo[5,6]oxaheptanecyclo[4,3-e]indole-2-carboxamide 11

[0887] first step

[0888] 11b of tert-butyl 4-(bromomethyl)-3,6-dihydropyridine-1(2H)-carboxylate

[0889] 10 g (46.89 mmol, Shanghai Biotech) of tert-butyl 4-(hydroxymethyl)-3,6-dihydropyridine-1(2H)-carboxylate 11a was dissolved in dichloromethane (100 mL). Triphenylphosphine (16 g, 61.00 mmol) and carbon tetrabromide (20.2 g, 60.91 mmol) were added under ice bath cooling, and the reaction was carried out for 30 minutes under ice bath conditions. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system B to give the title compound 11b (6.3 g, yield: 49%).

[0890] Step 2

[0891] 4-((2,4-difluoro-6-iodophenoxy)methyl)-3,6-dihydropyridine-1(2H)-formate tert-butyl ester 11c

[0892] Compound 11b (1.13 g, 4.09 mmol) and 2,4-difluoro-6-iodophenol (800 mg, 3.12 mmol, Bailingwei Chemical) were dissolved in N,N-dimethylformamide (20 mL), and anhydrous potassium carbonate (864 mg, 6.25 mmol) was added. The reaction mixture was reacted for 30 minutes. Saturated ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution, 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 give title compound 11c (1.0 g, yield: 71%).

[0893] MS m / z(ESI):396.0[M-55].

[0894] Step 3

[0895] 5,7-Difluoro-2',3'-dihydro-1'H,2H-spiro[benzofuran-3,4'-pyridine]-1'-carboxylic acid tert-butyl ester 11d

[0896] Compound 11c (700 mg, 1.55 mmol) was dissolved in N,N-dimethylformamide (10 mL), and palladium acetate (70 mg, 0.31 mmol), sodium formate (317 mg, 4.66 mmol), sodium acetate (382 mg, 4.65 mmol), and tetraethylammonium chloride (772 mg, 4.66 mmol) were added. The reaction mixture was reacted at 90 °C for 12 hours under a nitrogen atmosphere. The reaction solution was cooled to room temperature, and a saturated ammonium chloride solution was added. The mixture was extracted with ethyl acetate (15 mL × 3), and the organic phases were combined and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to give the title compound 11d (400 mg, yield: 80%).

[0897] MS m / z(ESI):268.0[M-55].

[0898] Step 4

[0899] 11e of tert-butyl 5,7-difluoro-2H-spiro[benzofuran-3,4'-piperidine]-1'-carboxylate

[0900] Compound 11d (700 mg, 2.17 mmol) was dissolved in methanol (10 mL), and 10% palladium on carbon (231 mg) and 20% palladium hydroxide on carbon (305 mg) were added. The mixture was purged with hydrogen and stirred for 16 hours. The reaction solution was filtered through diatomaceous earth, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system B to give the title compound 11e (350 mg, yield: 50%).

[0901] MS m / z(ESI):270.1[M-55].

[0902] Step 5

[0903] 5,7-Difluoro-6-iodo-2H-spiro[benzofuran-3,4'-piperidine]-1'-carboxylic acid tert-butyl ester 11f

[0904] Compound 11e (350 mg, 1.08 mmol) was dissolved in tetrahydrofuran (10 mL). A 2 M solution of diisopropylaminolithium in tetrahydrofuran (0.81 mL) was slowly added dropwise at -78 °C. After reacting for 2 hours, iodine (547 mg, 2.15 mmol) was added, and the mixture was slowly heated to room temperature and reacted for 3 hours. Saturated sodium thiosulfate and sodium carbonate solutions were added to the reaction mixture, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system B to give the title compound 11f (450 mg, yield: 93%). MS m / z (ESI): 396.0 [M-55].

[0905] Step 6

[0906] 11g of tert-butyl 6-(2,6-bis(benzyloxy)pyridin-3-yl)-5,7-difluoro-2H-spiro[benzofuran-3,4'-piperidine]-1'-carboxylate

[0907] Compound 11f (450 mg, 0.99 mmol) and 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxoborhexacyclopentan-2-yl)pyridine (417 mg, 0.99 mmol) were dissolved in 1,4-dioxane (10 mL) and water (2 mL), followed by the addition of [1,1'-bis(di-tert-butylphosphine)ferrocene]palladium dichloride (65 mg, 0.10 mmol) and anhydrous potassium carbonate (414 mg, 2.99 mmol). The reaction was carried out under a nitrogen atmosphere at 100 °C for 16 hours. The reaction was cooled to room temperature, water (10 mL) was added, and the mixture was extracted with ethyl acetate (15 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (10 mL × 3), 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 11 g (581 mg, yield: 95%) of the title compound.

[0908] MS m / z(ESI): 615.2 [M+1].

[0909] Step 7

[0910] 6-(2,6-dioxopiperidin-3-yl)-5,7-difluoro-2H-spiro[benzofuran-3,4'-piperidin]-1'-carboxylic acid tert-butyl ester 11h

[0911] 11 g (90 mg, 0.15 mmol) of compound was dissolved in ethyl acetate (5 mL), followed by the addition of 10% palladium on carbon (24 mg) and 20% palladium hydroxide on carbon (32 mg). The mixture was then purged with hydrogen and heated to 60 °C for 6 hours. The reaction solution was cooled to room temperature, filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system A to give the title compound 11h (40 mg, yield: 62%).

[0912] MS m / z(ESI):381.1[M-55].

[0913] Step 8

[0914] 3-(5,7-difluoro-2H-spiro[benzofuran-3,4'-piperidin]-6-yl)piperidin-2,6-dione hydrochloride 11i

[0915] Compound 11h (40 mg, 0.09 mmol) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (0.4 mL) was added dropwise under ice bath conditions. The mixture was stirred for 2 hours. The reaction solution was concentrated under reduced pressure to obtain the crude product, title compound 11i (40 mg). The product was used directly in the next reaction without purification.

[0916] MS m / z(ESI): 337.3 [M+1].

[0917] Step 9

[0918] 10-(4-(6-(2,6-dioxopiperidin-3-yl)-5,7-difluoro-2H-spiro[benzofuran-3,4'-piperidin]-1'-yl)piperidin-1-yl)-4,11-difluoro-5-(1-(3-(3-fluoro-1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-N,N-dimethyl-6,8-dihydro-3H-benzo[5,6]oxaheptanecyclo[4,3-e]indole-2-carboxamide 11

[0919] Using the synthetic route in Example 2, the starting compound 2t in step seventeen was replaced with compound 11i to obtain title compound 11 (8 mg, yield: 17.9%).

[0920] MS m / z(ESI): 981.7 [M+1].

[0921] 1 H NMR (500MHz, DMSO-d6): δ12.20(s,1H),10.95(s,1H),7.65(dt,1H),7.56–7.45(m,1H),7.2 3(dd,1H),7.15–7.08(m,1H),6.91(t,1H),5.95–5.79(m,2H),4.52(s,4H),4.21(dq,3H),3 .89(ddd,4H),3.68–3.49(m,4H),3.13(d,6H),2.99–2.70(m,7H),2.53(d,1H),2.43(d,1H) ,2.39–2.19(m,4H),2.18–2.06(m,1H),2.06–1.95(m,1H),1.95–1.82(m,4H),1.68(dd,4H).

[0922] Example 12

[0923] Title compound 12 was prepared by referring to the methods disclosed herein and known techniques.

[0924] MS m / z(ESI): 982.7 [M+1].

[0925] Example 12-1

[0926] 10-(4-((4aR)-8-(2,6-dioxopiperidin-3-yl)-7,9-difluoro-1,2,4a,5-tetrahydrobenzo[b]pyrazino[1,2-d][1,4]oxazin-3(4H)-yl)piperidin-1-yl)-4,11-difluoro-5-(1-(3-(3-fluoro-1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-N,N-dimethyl-6,8-dihydro-3H-benzo[5,6]oxaheptanecyclo[4,3-e]indole-2-carboxamide 12-1

[0927] first step

[0928] 1-Benzyl 4-(tert-butyl)(R)-2-(hydroxymethyl)piperazine-1,4-dicarboxylate 12b

[0929] (R)-3-hydroxymethylpiperazine-1-carboxylic acid tert-butyl ester 12a (3.0 g, 13.90 mmol, Shanghai Shaoyuan) was dissolved in ethyl acetate (25 mL), water (25 mL) was added, the mixture was cooled to 0 °C, sodium bicarbonate (3.5 g, 41.70 mmol) was added, and benzyl chloroformate (3.55 g, 20.80 mmol) was added dropwise. The reaction mixture was reacted for 16 hours. The reaction solution was extracted with ethyl acetate (50 mL × 3), the organic phases were 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 title compound 12b (4.3 g, yield: 88%).

[0930] MS m / z(ESI): 349.2 [M-1].

[0931] Step 2

[0932] 1-Benzyl 4-(tert-butyl)(R)-2-((2,4,6-trifluorophenoxy)methyl)piperazine-1,4-dicarboxylate 12c

[0933] 2,4,6-Trifluorophenol (700 mg, 4.7 mmol) and compound 12b (1.68 g, 4.78 mmol) were dissolved in tetrahydrofuran (50 mL). Triphenylphosphine (2.45 g, 9.34 mmol) and diisopropyl azodicarbonate (1.89 g, 9.35 mmol) were added under a nitrogen atmosphere, and the mixture was stirred for 16 hours under a nitrogen atmosphere. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system B to give the title compound 12c (2.3 g, yield: 100%).

[0934] MS m / z(ESI):425.2[M-55].

[0935] Step 3: (R)-3-((2,4,6-trifluorophenoxy)methyl)piperazine-1-carboxylic acid tert-butyl ester 12d

[0936] Compound 12c (2.3 g, 4.79 mmol) was dissolved in methanol (40 mL), and 10% palladium on carbon hydrogenation catalyst (100 mg) and 20% palladium hydroxide on carbon hydrogenation catalyst (100 mg) were added. The mixture was purged with hydrogen and stirred for 16 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude title compound 12d (1.86 g). The product was used directly in the next reaction without purification.

[0937] MS m / z(ESI): 347.2 [M+1].

[0938] Step 4

[0939] (R)-7,9-difluoro-1,2,4a,5-tetrahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine-3(4H)-tert-butyl formate 12e

[0940] The crude compound 12d (1.76 g, 5.08 mmol) was dissolved in dimethyl sulfoxide (40 mL), and sodium hydride (230 mg, 5.75 mmol, 60% purity) was added. The reaction was carried out for 30 minutes, and then the temperature was raised to 120 °C and reacted for another 30 minutes. The reaction was cooled to room temperature, and water (100 mL) was added. The mixture was extracted with ethyl acetate (50 mL × 3). The organic phases were 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 12e (340 mg, yield: 21%).

[0941] MS m / z(ESI):271.2[M-55].

[0942] Step 5

[0943] (R)-8-bromo-7,9-difluoro-1,2,4a,5-tetrahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine-3(4H)-tert-butyl formate 12f

[0944] Compound 12e (155 mg, 475 μmol) was dissolved in dichloromethane (7.5 mL), and N-bromosuccinimide (95 mg, 534 μmol) was added. The mixture was stirred for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system B to give the title compound 12f (148 mg, yield: 77%).

[0945] MS m / z(ESI):349.0[M-55].

[0946] Step 6

[0947] (4aR)-8-(2,6-bis(benzyloxy)pyridin-3-yl)-7,9-difluoro-1,2,4a,5-tetrahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine-3(4H)-tert-butyl formate 12g

[0948] Compound 12f (148 mg, 365 μmol) and 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxoborhexacyclopentan-2-yl)pyridine (155 mg, 371 μmol) were dissolved in 6.5 mL of a mixture of 1,4-dioxane and water (V / V = 10 / 3). [1,1'-bis(di-tert-butylphosphine)ferrocene]palladium dichloride (26 mg, 40 μmol) and anhydrous potassium carbonate (116 mg, 839 μmol) were added. The reaction was carried out at 100 °C for 16 hours under a nitrogen atmosphere. The reaction was cooled to room temperature, water (20 mL) was added, and the mixture was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (30 mL × 2), 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 12 g (160 mg, yield: 71%) of the title compound.

[0949] MS m / z (ESI): 616.2 [M+1].

[0950] Step 7

[0951] (4aR)-8-(2,6-dioxopiperidin-3-yl)-7,9-difluoro-1,2,4a,5-tetrahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine-3(4H)-tert-butyl formate 12h

[0952] 12 g (160 mg, 260 μmol) of the compound was dissolved in ethyl acetate (10 mL), and 30 mg (10 mg) of wet palladium on carbon and 40 mg (20 mg) of palladium hydroxide on carbon were added. The mixture was purged with hydrogen and heated to 60 °C for 16 hours. After the reaction solution cooled to room temperature, it was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude title compound 12h (113 mg). The product was used directly in the next reaction without purification.

[0953] Step 8

[0954] 3-((R)-7,9-difluoro-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazin-8-yl)piperidine-2,6-dione hydrochloride 12i

[0955] The crude compound 12h (113 mg, 258 μmol) was dissolved in dichloromethane (3 mL), and a 4M hydrogen chloride solution of 1,4-dioxane (1 mL) was added. The mixture was stirred for 2 hours. The reaction solution was concentrated under reduced pressure to obtain the crude title compound 12i (100 mg). The product was used directly in the next reaction without purification.

[0956] MS m / z(ESI): 338.2 [M+1].

[0957] Step 9

[0958] 10-(4-((4aR)-8-(2,6-dioxopiperidin-3-yl)-7,9-difluoro-1,2,4a,5-tetrahydrobenzo[b]pyrazino[1,2-d][1,4]oxazin-3(4H)-yl)piperidin-1-yl)-4,11-difluoro-5-(1-(3-(3-fluoro-1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-N,N-dimethyl-6,8-dihydro-3H-benzo[5,6]oxaheptanecyclo[4,3-e]indole-2-carboxamide 12-1

[0959] The crude title compound 12i (17 mg, 45 μmol) and compound 2s (30 mg, 45 μmol) were dissolved in 1,2-dichloroethane (1 mL) and dimethyl sulfoxide (0.5 mL). Sodium acetate (11 mg, 136 μmol) was added, and the mixture was stirred for 1 hour. Then, sodium triacetoxyborohydride (29 mg, 136 μmol) was added, and the mixture was stirred for 16 hours. Saturated sodium bicarbonate solution was added to the reaction mixture, and the mixture was extracted with dichloromethane (5 mL × 2). The organic phases were combined, concentrated under reduced pressure, and the residue was purified by preparative high-performance liquid chromatography (Waters-2545, column: Welch Xtimate C18, 30*150 mm, 5 μm; mobile phase: aqueous phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 30%-60%, flow rate: 30 mL / min) to obtain title compound 12-1 (5 mg, yield: 11.2%).

[0960] MS m / z(ESI): 982.7 [M+1].

[0961] 1H NMR (500MHz, CDCl3): δ9.68(s,1H),8.02(s,1H),7.46(dd,1H),7.38–7.32(m,1H),7.10(t,1H),7.03–6.97(m,1H), 6.42–6.35(m,1H),5.99(s,1H),5.73(ddd,1H),4.64(d,1H),4.48(dd,1H),4.43–4.29(m,4H),4.10(d,1H),4.05–3. 94(m,3H),3.70(d,2H),3.61(d,1H),3.48–3.18(m,7H),3.11(d,1H),3.02–2.89(m,4H),2.86–2.80(m,2H),2.71(dd d,1H),2.58–2.50(m,2H),2.43–2.34(m,2H),2.28–2.21(m,1H),2.21–2.13(m,2H),2.01(d,2H),1.91–1.78(m,6H).

[0962] Example 13

[0963] Title compound 13 was prepared by referring to the methods disclosed herein and known techniques.

[0964] MS m / z(ESI): 967.7 [M+1].

[0965] Example 14

[0966] Title compound 14 was prepared by referring to the methods disclosed herein and known techniques.

[0967] MS m / z(ESI): 954.7 [M+1].

[0968] Example 15

[0969] Title compound 15 was prepared by referring to the present disclosure and known technical methods.

[0970] MS m / z(ESI): 954.7 [M+1].

[0971] Example 16

[0972] Title compound 16 was prepared by referring to the present disclosure and known technical methods.

[0973] MS m / z(ESI): 941.7 [M+1].

[0974] Example 17

[0975] Title compound 17 was prepared by referring to the present disclosure and known technical methods.

[0976] MS m / z(ESI): 970.7 [M+1].

[0977] Example 18

[0978] Title compound 18 was prepared by referring to the methods disclosed herein and known techniques.

[0979] MS m / z(ESI): 940.7 [M+1].

[0980] Example 19

[0981] Title compound 19 was prepared by referring to the present disclosure and known technical methods.

[0982] MS m / z(ESI): 963.7 [M+1].

[0983] Example 20

[0984] Title compound 20 was prepared by referring to the methods disclosed herein and known techniques.

[0985] MS m / z(ESI): 936.7 [M+1].

[0986] Example 21

[0987] Title compound 21 was prepared by referring to the methods disclosed herein and known techniques.

[0988] MS m / z(ESI): 963.7 [M+1].

[0989] Example 22

[0990] Title compound 22 was prepared by referring to the present disclosure and known technical methods.

[0991] MS m / z(ESI): 964.7 [M+1].

[0992] Example 23

[0993] Title compound 23 was prepared by referring to the present disclosure and known technical methods.

[0994] MS m / z(ESI): 949.7 [M+1].

[0995] Example 24

[0996] Title compound 24 was prepared by referring to the methods disclosed herein and known techniques.

[0997] MS m / z(ESI): 955.7 [M+1].

[0998] Example 25

[0999] Title compound 25 was prepared by referring to the present disclosure and known technical methods.

[1000] MS m / z(ESI): 955.7 [M+1].

[1001] Example 26

[1002] Title compound 26 was prepared by referring to the present disclosure and known technical methods.

[1003] MS m / z(ESI): 942.7 [M+1].

[1004] Example 27

[1005] Title compound 27 was prepared by referring to the methods disclosed herein and known techniques.

[1006] MS m / z(ESI): 971.7 [M+1].

[1007] Example 28

[1008] Title compound 28 was prepared by referring to the methods disclosed herein and known techniques.

[1009] MS m / z(ESI): 941.7 [M+1].

[1010] Example 29

[1011] Title compound 29 was prepared by referring to the methods disclosed herein and known techniques.

[1012] MS m / z(ESI): 964.7 [M+1].

[1013] Example 30

[1014] Title compound 30 was prepared by referring to the methods disclosed herein and known techniques.

[1015] MS m / z(ESI): 937.7 [M+1].

[1016] Example 31

[1017] Title compound 31 was prepared by referring to the present disclosure and known technical methods.

[1018] MS m / z(ESI): 964.7 [M+1].

[1019] Example 32

[1020] Title compound 32 was prepared by referring to the present disclosure and known technical methods.

[1021] MS m / z(ESI): 965.7 [M+1].

[1022] Example 33

[1023] Title compound 33 was prepared by referring to the methods disclosed herein and known techniques.

[1024] MS m / z(ESI): 950.7 [M+1].

[1025] Example 34

[1026] 5-(1-(3-(1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-10-(4-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluoro-5-methoxyphenyl)piperazin-1-yl)piperidin-1-yl)-4-fluoro-N,N-dimethyl-3,6,8,8a,9,10,11,12-octahydropyrido[2',1':3,4][1,4]oxazaheptancyclo[5,6-e]indole-2-carboxamide 34

[1027] Title compound 34 was prepared by referring to the methods disclosed herein and known techniques.

[1028] MS m / z(ESI): 952.7 [M+1].

[1029] Example 35

[1030] 5-(1-(3-(1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-10-(4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl)piperazin-1-yl)-4-fluoro-N,N-dimethyl-3,6,8,8a,9,10,11,12-octahydropyrido[2',1':3,4][1,4]oxazaheptancyclo[5,6-e]indole-2-carboxamide 35

[1031] Title compound 35 was prepared by referring to the methods disclosed herein and known techniques.

[1032] MS m / z(ESI): 860.7 [M+1].

[1033] Example 36

[1034] 5-(1-(3-(1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-10-(4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-7-yl)piperazin-1-yl)-4-fluoro-N,N-dimethyl-3,6,8,8a,9,10,11,12-octahydropyrido[2',1':3,4][1,4]oxazaheptancyclo[5,6-e]indole-2-carboxamide 36

[1035] Title compound 36 was prepared by referring to the methods disclosed herein and known techniques.

[1036] MS m / z(ESI): 860.7 [M+1].

[1037] Example 37

[1038] 5-(1-(3-(1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-10-(4-(4-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)piperazin-1-yl)piperidin-1-yl)-4-fluoro-N,N-dimethyl-3,6,8,8a,9,10,11,12-octahydropyrido[2',1':3,4][1,4]oxazaheptancyclo[5,6-e]indole-2-carboxamide 37

[1039] Title compound 37 was prepared by referring to the methods disclosed herein and known techniques.

[1040] MS m / z(ESI): 925.7 [M+1].

[1041] Example 38

[1042] 5-(1-(3-(1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-10-(4-(3-(2,6-dioxopiperidin-3-yl)-6,7,8,10-tetrahydro-9H-isoxazo[4',5':5,6]benzo[1,2-c]azacycloheptyl-9-yl)piperidin-1-yl)-4,11-difluoro-N,N-dimethyl-6,8-dihydro-3H-benzo[5,6]oxaheptylcyclo[4,3-e]indole-2-carboxamide 38

[1043] Title compound 38 was prepared by referring to the methods disclosed herein and known techniques.

[1044] MS m / z(ESI): 926.7 [M+1].

[1045] Example 39

[1046] 10-(4-(3-(2,6-dioxopiperidin-3-yl)-6,8,9,10-tetrahydro-7H-isooxazolo[5',4':3,4]benzo[1,2-c]azacycloheptyl-7-yl)piperidin-1-yl)-4,11-difluoro-5-(1-(3-(3-fluoro-1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-N,N-dimethyl-6,8-dihydro-3H-benzo[5,6]oxaheptylcyclo[4,3-e]indole-2-carboxamide 39

[1047] Using the synthetic route in Example 2, the starting compound 2t in step seventeen was replaced with 3-(7,8,9,10-tetrahydro-6H-isoxazo[5',4':3,4]benzo[1,2-c]azacyclohept-3-yl)piperidine-2,6-dione hydrochloride (prepared by the method disclosed in Preparation Example 11 on page 75 of the specification in patent application "WO2025195363") to obtain title compound 39.

[1048] MS m / z(ESI): 944.7 [M+1].

[1049] Example 40

[1050] 10-(4-(3-(2,6-dioxopiperidin-3-yl)-6,9-dihydroisoxazolo[4,5-h]isoquinoline-8(7H)-yl)piperidin-1-yl)-4,11-difluoro-5-(1-(3-(3-fluoro-1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-N,N-dimethyl-6,8-dihydro-3H-benzo[5,6]oxaheptane[4,3-e]indole-2-carboxamide 40

[1051] Using the synthetic route in Example 2, the starting compound 2t in step seventeen was replaced with 3-(6,7,8,9-tetrahydroisoxazolo[4,5-h]isoquinoline-3-yl)piperidine-2,6-dione hydrochloride (prepared by the method disclosed in Example 18 on page 110 of the specification in patent application "WO2023088406") to obtain title compound 40.

[1052] MS m / z(ESI): 930.7 [M+1].

[1053] Biological evaluation

[1054] The following test examples further describe and explain this disclosure, but these test examples are not intended to limit the scope of this disclosure.

[1055] Test Example 1: Degradation activity test of the disclosed compounds against total STAT6 protein in THP-1 cells.

[1056] I. Experimental Objective

[1057] The purpose of this experiment was to test the degradation activity of the compound on total STAT6 protein in THP-1 cells, based on absolute DC. 50 and D max Size is used to evaluate the in vitro activity of compounds.

[1058] II. Experimental Principle

[1059] This experiment uses The TR-FRET STAT6 Total Protein Kit detects the level of intracellular STAT6 total protein after THP-1 cell lysis. This kit uses two specific antibodies for detection, one of which is conjugated to [specific antibody name missing]. TR-FRET Solar Eu, as a fluorescence resonance energy transfer (FRET) donor; another antibody conjugated with TR-FRET LA acts as a fluorescence resonance energy transfer (FRET) receptor. When two antibodies bind to different epitopes of the STAT6 protein, the TR-FRET donor and receptor approach each other close enough that laser excitation (615 nm or 620 nm) triggers FRET energy transfer to the receptor, causing it to fluoresce at a specific wavelength (665 nm). The intensity of this specific signal is proportional to the total STAT6 protein level in the cell. The degradation activity of the compound can be determined by measuring the signal value in the presence of the compound.

[1060] III. Experimental Materials

[1061] 1. Instruments

[1062] 2. Reagents and consumables

[1063] IV. Experimental Methods

[1064] On day 1, THP-1 cells were centrifuged and resuspended in RPMI 1640 complete medium containing 10% fetal bovine serum and 0.05 mM 2-mercaptoethanol. After counting, cells were seeded at 1,875,000 cells / 16 μL / well in 384-well cell culture microplates. The test compounds (final concentration range: 10,000-0.5 nM, 3-fold serial dilution, DMSO final concentration 0.25%) were added using a TECAN D300e micro-volume separator, and the cells were incubated at 37°C in a 5% CO2 cell culture incubator for 48 hours.

[1065] On the third day, first prepare 5× lysis buffer, then remove the incubated 384-well plate. Add 4 μL of 5× lysis buffer to each well and vortex at room temperature for 60 minutes to lyse. Prepare 1× detection buffer, and then prepare the premixed detection antibody pair according to the kit instructions, protecting it from light. Add 5 μL of antibody to each well of the 384-well cell culture microplate, vortex at room temperature for 2 minutes to mix, centrifuge, and incubate overnight at 25°C in the dark.

[1066] On the third day, the luminescence values ​​at 620nm and 665nm were read using an Envision microplate reader.

[1067] V. Data Analysis

[1068] Calculate the ratio of acceptor to donor emission signals per well: Ratio = 665nm fluorescence signal value / 620nm fluorescence signal value × 10000. Perform curve fitting using XLfit based on the logarithmic concentration and degradation rate of the compounds, and calculate the absolute DC. 50 Value, Degradation rate (%) = 100 × (ratio) 化合物 -ratio 空白对照 ) / (ratio 溶媒对照 -ratio 空白对 照 ).

[1069] Table 1. Degradation activity of the compounds disclosed herein against total STAT6 protein in THP-1 cells.

[1070] Among them, for DC 50 DC 50 <500nM is A; DC 50 B is present in the range of 500 nM to 5000 nM; DC 50 >5000nM is C. For Dmax, Dmax>70% is A; Dmax between 50% and 70% is B; Dmax between 30% and 50% is C.

[1071] Test Examples 1-2: Degradation Activity Tests of the Disclosed Compounds on Total STAT6 Protein in THP-1 Cells

[1072] I. Experimental Objective

[1073] The purpose of this experiment was to test the degradation activity of the compound on total STAT6 protein in THP-1 cells, based on absolute DC. 50 The Dmax value is used to evaluate the in vitro activity of the compound.

[1074] II. Experimental Principle

[1075] This experiment uses The TR-FRET STAT6 Total Protein Kit detects the level of intracellular STAT6 total protein after THP-1 cell lysis. This kit uses two specific antibodies for detection, one of which is conjugated to [specific antibody name missing]. TR-FRET Solar Eu, as a fluorescence resonance energy transfer (FRET) donor; another antibody conjugated with TR-FRET LA acts as a fluorescence resonance energy transfer (FRET) receptor. When two antibodies bind to different epitopes of the STAT6 protein, the TR-FRET donor and receptor approach each other close enough that excitation of the fluorescent donor with a xenon lamp (320 or 340 nm) or laser (337 nm) triggers a resonance energy transfer (FRET) between the donor and receptor molecules, which emit a TR FRET signal at 665 nm. The signal intensity at 665 nm is proportional to the concentration of the target protein in the cell lysate. The residual energy of the Solar Eu chelate allows for signal intensity detection at 615 nm or 620 nm, which can serve as an internal standard for homogenizing the signal intensity at 665 nm. The total protein level can be determined by detecting the signal intensity at a specific wavelength and calculating the 665 nm / 615 nm ratio. The degradation activity of the compound can be determined by measuring the signal value in the presence of the compound.

[1076] III. Experimental Materials

[1077] 1. Instruments

[1078] 2. Reagents and consumables

[1079] IV. Experimental Methods

[1080] On day 1, THP-1 cells were centrifuged and resuspended in RPMI 1640 complete medium containing 10% fetal bovine serum and 0.05 mM 2-mercaptoethanol. After counting, the cells were seeded at 30,000 cells / 16 μL / well in columns 3-24 of a 384-well cell culture microplate. Columns 1 and 2 were filled with the same volume of medium as control wells. The test compound (final concentration range: 30 nM-0.001524 nM or 1-0.000051 nM, 3-fold serial dilution, DMSO final concentration 0.25%) was added using a TECAN D300e microfluidic analyzer and incubated at 37°C in a 5% CO2 cell culture incubator for 24 hours.

[1081] On the second day, first prepare 5× lysis buffer, then remove the incubated 384-well plate. Add 4 μL of 5× lysis buffer to each well and vortex at room temperature for 60 minutes. Prepare 1× detection buffer, then prepare the premixed detection antibody pair according to the kit instructions. Add 5 μL of antibody to each well of the 384-well cell culture microplate, vortex at room temperature for 2 minutes, centrifuge, and incubate overnight at 25°C in the dark.

[1082] On the third day, the total protein level can be determined by reading the luminescence values ​​at 620nm and 665nm using an Envision microplate reader and calculating the signal intensity of the 665nm / 620nm ratio.

[1083] V. Data Analysis

[1084] Calculate the ratio of acceptor to donor emission signals per well: Ratio = 665nm fluorescence signal value / 620nm fluorescence signal value × 10000. Perform curve fitting using XLfit based on the logarithmic concentration and degradation rate of the compounds, and calculate the absolute DC. 50 Value, Degradation rate (%) = 100 × (ratio) 化合物 -ratio 空白对照 ) / (ratio 溶媒对照 -ratio 空白对 照 ).

[1085] Table 1-2. Degradation activity of the compounds disclosed herein on total STAT6 protein in THP-1 cells.

[1086] Conclusion: The compound disclosed herein exhibits good degradation activity against total STAT6 protein in THP-1 cells.

[1087] Test Example 2: Inhibitory Activity Test of the Compounds Disclosed on STAT6 Phosphorylation Levels in PBMC Cells I. Experimental Objective

[1088] The purpose of this experiment was to test the inhibitory effect of the compound on STAT6 phosphorylation levels in PBMC cells, based on IC50. 50 Size is used to evaluate the in vitro activity of compounds.

[1089] II. Experimental Principle

[1090] The TR-FRET phosphorylated protein kit is based on the principle of traditional sandwich immunoassay. First, cells are pretreated by lysis. Then, a pair of specific antibodies conjugated to either a TR-FRET Solar Eu fluorescent resonance energy transfer donor or a TR-FRET LA fluorescent resonance energy transfer receptor are added to the sample. When these two antibodies bind to different epitopes of the phosphorylated protein, the donor and receptor approach each other close enough that excitation of the fluorescent donor with a xenon lamp or laser triggers resonance energy transfer (FRET) between the donor and receptor molecules, which emits a TR-FRET signal at 665 nm. The signal intensity at 665 nm is proportional to the concentration of the target protein in the cell lysate. The residual energy of the Solar Eu chelate can be detected at 615 nm or 620 nm, and this signal can be used as an internal standard for homogenizing the signal intensity at 665 nm. The level of total phosphorylated protein can be determined by detecting the signal intensity at a specific wavelength and calculating the 665 nm / 615 nm ratio.

[1091] III. Experimental Materials

[1092] 1. Instruments

[1093] 2. Reagents and consumables

[1094] IV. Experimental Methods

[1095] On day 1, frozen PBMC cells were resuspended in IMDM medium containing 10% inactivated fetal bovine serum and seeded at 50,000 cells / 14 μL / well in 384-well plates. The test compound was added to each well using an ultra-micro pipette to achieve 10 concentration points with a 3-fold serial dilution starting from 10 μM (final concentration range: 10,000-0.5 nM or 30 nM-0.001524 nM or 1-0.000051 nM, depending on the properties of different series of compounds). The plates were incubated at 37°C in a cell culture incubator with 5% CO2 for 48 hours.

[1096] On the third day, after 48 hours of incubation, 2 μL of IL-4 (final concentration 3 ng / mL) was added to each well, and the plate was placed in an incubator for 10 minutes of stimulation. After incubation, 4 μL of IL-4 was added to each well. Use the 5× lysis buffer from the TR-FRET Phospho STAT6 (Y641) Kit, and lyse at room temperature (400 rpm) for 30 minutes. Then follow the instructions... The recommended procedure for the TR-FRET Phospho STAT6(Y641) Kit is to prepare 4× premixed detection antibody pairs (detection buffer + Ab1-Solar Eu + Ab2-LA), add 5 μL of antibody per well to a 384-well cell culture microplate, mix by shaking at room temperature for 2 minutes, centrifuge, and then incubate overnight at 25°C in the dark.

[1097] On the fourth day, the level of phosphorylated protein can be determined by reading the 665nm and 620nm wavelengths using an Envision microplate reader and calculating the signal intensity of the 665nm / 620nm ratio.

[1098] V. Data Analysis

[1099] The IC50 of the compound's inhibitory activity was calculated using Xlfit software. 50 value.

[1100] Conclusion: The compound disclosed herein exhibits good inhibitory activity against STAT6 phosphorylation levels in PBMC cells.

[1101] Test Example 3: Pharmacokinetic Evaluation

[1102] I. SD Rat Experiment

[1103] 1. Abstract

[1104] Using SD rats as test animals, the plasma drug concentration of the disclosed compound at different time points after gavage (ig) administration to SD rats was determined by LC / MS / MS. The pharmacokinetic behavior of the disclosed compound in SD rats was investigated to evaluate its pharmacokinetic characteristics.

[1105] 2. Test Plan

[1106] 2.1 Test Drugs

[1107] This compound is disclosed.

[1108] 2.2 Experimental Animals

[1109] SD rats were provided by Viton Lever Laboratories. After fasting overnight, the drugs were administered via gavage.

[1110] 2.3 Drug Preparation

[1111] Weigh out a certain amount of the test compound, add 5% DMSO + 5% Tween 80 + 90% physiological saline, and prepare a colorless and clear solution of 0.2 mg / mL.

[1112] 2.4. Administration

[1113] The dosage is 2.0 mg / kg, and the administration volume is 10.0 mL / kg.

[1114] 3. Operation

[1115] Blood samples of 0.1 mL were collected from the orbital cavity before administration and at 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 11.0, and 24.0 hours after administration. The samples were placed in EDTA-K2 anticoagulant tubes and centrifuged at 10,000 rpm for 1 minute (4°C). Plasma was separated within 1 hour and stored at -20°C for analysis. The entire process, from blood collection to centrifugation, was performed under ice bath conditions. Patients ate 2 hours after administration.

[1116] The levels of the target compound in the plasma of SD rats were determined after administration of different concentrations of the drug.

[1117] Conclusion: The compound disclosed herein has a high exposure level in SD rats and exhibits pharmacokinetic advantages.

[1118] II. C57 Mouse Experiment

[1119] 1. Abstract

[1120] Using C57 mice as test animals, the plasma drug concentrations of the disclosed compound at different time points after administration by gavage (ig) / intravenous injection (iv) in C57 mice were determined by LC / MS / MS. The pharmacokinetic behavior of the disclosed compound in C57 mice was investigated to evaluate its pharmacokinetic characteristics.

[1121] 2. Test Plan

[1122] 2.1 Test Drugs

[1123] This compound is disclosed.

[1124] 2.2 Experimental Animals

[1125] C57 mice were provided by Viton Lever Laboratories. The drugs were administered via gavage and intravenous injection, respectively.

[1126] 2.3 Drug Preparation

[1127] Weigh out a certain amount of the test compound, add 5% DMSO + 5% Tween 80 + 90% physiological saline, and prepare a 0.1 mg / mL colorless clear solution (gavage administration group) and a 0.1 mg / mL colorless clear solution (intravenous injection group).

[1128] 2.4. Administration

[1129] Gavage administration group: The dosage was 2.0 mg / kg, and the administration volume was 0.2 mL / 10 g.

[1130] Intravenous administration group: The dosage was 1.0 mg / kg, and the administration volume was 0.1 mL / 10 g.

[1131] 3. Operation

[1132] In the gavage administration group: 0.1 mL of blood was collected before administration and at 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 11.0, and 24.0 hours after administration. The blood was placed in an EDTA-K2 anticoagulant tube, centrifuged at 10,000 rpm for 1 minute (4℃), and the plasma was separated within 1 hour and stored at -80℃ for analysis. The blood collection and centrifugation process was performed under ice bath conditions.

[1133] Intravenous injection group: Blood samples were collected before administration and 5 minutes after administration, and at 0.25, 0.5, 1.0, 2.0, 4.0, 8.0, 11.0 and 24 hours after administration. The treatment was the same as that of the gavage group.

[1134] The levels of the target compound in the plasma of C57 mice were determined after administration of different concentrations of the drug.

[1135] Conclusion: The compound disclosed herein exhibits high exposure levels in C57 mice and demonstrates pharmacokinetic advantages.

[1136] Test Example 4: Degradation Activity Test of the Compounds of this Disclosure on STAT6 Protein in Human Whole Blood

[1137] I. Experimental Objective

[1138] The purpose of this experiment was to test the degradation effect of the disclosed compound on STAT6 protein in human whole blood, based on DC... 50 Size is used to evaluate the in vitro activity of compounds.

[1139] II. Experimental Materials

[1140] 1. Instruments

[1141] 2. Reagents and consumables

[1142] III. Experimental Methods

[1143] On day 1, 95 μL of human whole blood was plated into each well of a 96-well U-bottom cell culture plate. The test compound was then added to each well using a micro-liquid separator. The overall dimethyl sulfoxide (DMSO) concentration was set at 0.25%, with initial compound concentrations of 100 nM, 10 nM, or 1 nM (column 2), and 3-fold or 4-fold gradients (columns 3-11). Columns 1 and 12 were treated with DMSO only as negative and positive controls, respectively. The culture plates were then incubated at 37°C in a 5% CO2 cell culture incubator for 24 hours.

[1144] On the second day, 15 minutes before the end of whole blood incubation, the anti-CD3 (CD3-Pacific Blue) antibody against PB was diluted 10-fold with complete culture medium (IMDM medium + 10% inactivated FBS), and 5 μL was added to each well of whole blood. After brief mixing, the wells were incubated in a cell culture incubator for 15 minutes. After incubation, whole blood from the 96-well cell culture plate was transferred to 2 mL deep-well plates, 1 mL of 1× lysis and fixation buffer was added, and the plates were incubated at 37°C for 20 minutes to fully lyse and fix the red blood cells. The cells were then washed three times with staining buffer. Next, 400 μL of pre-chilled permeation buffer III was added to each well, and the plates were incubated on ice for 30 minutes. After washing three times with staining buffer, add 200 μL of Alexa Fluor 647-conjugated anti-STAT6 antibody (1:125 ratio) to each well in columns 2-12, and add 200 μL of Alexa Fluor 647-conjugated isotype control antibody (1:125 ratio) to each well in column 1. Incubate overnight at 4°C in the dark.

[1145] On the third day, after centrifuging to remove the antibodies, the cells were washed twice with staining buffer and then resuspended in 200 μL of staining buffer. Subsequently, whole-plate fluorescence detection (detecting Pacific Blue and Alexa Fluor 647 fluorescence channels) was performed on a flow cytometer.

[1146] V. Data Analysis

[1147] The proportion of STAT6-positive cells and their average fluorescence intensity in the CD3-positive single-cell population were analyzed using Flowjo software. The proportion of STAT6-positive cells in the negative control group was set at approximately 0.5%.

[1148] Calculate the relative fluorescence unit, where the relative fluorescence unit = the proportion of STAT6-positive cells in CD3 cells × the average fluorescence intensity.

[1149] Calculate the degradation rate, degradation rate = (relative fluorescence units) 阳性对照 -Relative fluorescence unit 化合物 ) / (Relative fluorescence unit) 阳性对照 -Relative fluorescence unit 阴性对照The maximum degradation rate (D) of the compound is defined as the maximum degradation rate of the compound at each concentration, calculated as 100% × 100%. max ), and used XLfit to plot dose-response curves and calculate DC. 50 .

[1150] Conclusion: The compound disclosed herein exhibits good degradation activity against STAT6 protein in human whole blood.

Claims

1. A compound of general formula (I) or a pharmaceutically acceptable salt thereof, in: Ring A is selected from cycloalkyl, heterocyclic, aryl, and heteroaryl groups; L 1 is selected from the group consisting of a bond, O, C(O), S, S(O), S(O)2, NR a , C(O)NR a , and NR a C(O); R a is selected from the group consisting of a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, and a cycloalkylalkyl group; X 2 is N or CH; Ring B is selected from cycloalkyl, heterocyclic, aryl, and heteroaryl groups; Cycloyl X is selected from cycloalkyl, heterocyclic, aryl, and heteroaryl groups; G is selected from hydrogen atom, halogen and Cycloyl Y is selected from cycloalkyl, heterocyclic, aryl, and heteroaryl groups; represents Y 1 and Y 2 the ring in which Y is aromatic or non-aromatic; V 1 is N or C; V 2 is N or CR w1 ; T is either N or C; Y 1 and Y 2 are each independently selected from O, S, N, NR w3 , CR w4 and CR w4 R w5 ; R w0 R w1 R w2 R w4 R w5 R x R y R 1 and R 2 The same or different, and each independently selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, cyano, nitro, hydroxyl, amino, alkoxy, haloalkyl, hydroxyalkyl, haloalkoxy, alkoxyalkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, -OR 3 -NR 4 R 5 -C(O)R 3 -C(O)OR 3 -C(O)NR 4 R 5 -C(O)NR 4 OR 3 -NR 6 C(O)R 3 -NR 6 C(O)OR 3 -NR 6 C(O)NR 4 R 5 -OC(O)R 3 -OC(O)NR 4 R 5 -S(O) v R 3 -S(O)(=NR) 7 )R 3 -S(O) v NR 4 R 5 -NR 6 S(O)2R 3 =O, =CR 8 R 9 、-Si(R 3 3. -P(O)(OR) 3 )2、-OP(O)(R 3 )2 and -OP(O)(OR 3 )2, wherein the alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each independently and optionally composed of one or more R groups. 0 replace; R w3 The atom is selected from hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups is independently and optionally converted by one or more R atoms. 0 replace; Or, two Rs x 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. 0 replace; Or, two Rs y 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. 0 replace; Or, two Rs 1 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. 0 replace; Or, two Rs 2 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. 0 replace; Or, R 2 With R w2 Together with their respective attached atoms, they form a cycloalkyl or heterocyclic group, each of which is independently and optionally influenced by one or more R atoms. 0 replace; Or, R 2 With R w3 Together with their respective connected atoms, they form a heterocyclic group, each of which is independently and optionally influenced by one or more R atoms. 0 Replace; or, Or, R 2 With R w4 Together with their respective attached atoms, they form a cycloalkyl or heterocyclic group, each of which is independently and optionally influenced by one or more R atoms. 0 replace; The condition is that at least one R 2 With R w2 R w3 Or R w4 Together with their respective attached atoms, they form a cycloalkyl or heterocyclic group, each of which is independently and optionally influenced by one or more R atoms. 0 replace; n is 1, 2, 3, 4, 5, 6, or 7; x, y, and m are each independently 0, 1, 2, 3, 4, 5, 6, or 7; L x -(L A ) t1 -; L is -(L) B ) t2 -; L A and L B The same or different, and each independently selected from the following groups: bond, alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, O, C(O), C(S), NR b S, S(O) and S(O)2, wherein the alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl groups are each independently and optionally selected by one or more R 0 replace; R b Selected from hydrogen atoms, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, and cycloalkylalkyl; t1 is selected from integers from 0 to 10; t2 is selected from integers from 0 to 20; R 3 R 4 and R 5 The same or different, and each independently selected from hydrogen atoms, alkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl, wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl is independently optionally selected by one or more R 0 Replace; or R 4 and R 5 Together with the attached nitrogen atom, they form a heterocyclic group or a heteroaryl group, each of which is independently and optionally influenced by one or more R atoms. 0 replace; R 6 Selected from hydrogen atoms, alkyl groups, haloalkyl groups, hydroxyalkyl groups, and cycloalkyl groups; R 7 Selected from hydrogen atoms, alkyl groups, haloalkyl groups, hydroxyalkyl groups, hydroxyl groups, alkoxy groups, haloalkoxy groups, and cycloalkyl groups; R 8 and R 9 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, alkyl groups, haloalkyl groups, hydroxyalkyl groups, and cycloalkyl groups; or, R 8 and R 9 Together with the attached carbon atom, they form cycloalkyl or heterocyclic groups; R 0 The same or different, and each independently selected from =O, halogen, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, aminoalkyl, hydroxy, alkenyl, alkynyl, cyano, nitro, amino, -NHalkyl, -N(alkyl)2, -C(O)Oalkyl, -C(O)OH, -C(O)NH2, -C(O)NH(alkyl), -C(O)N(alkyl)2, -C(O)halogen, -C(O)alkyl, -S(alkyl), cycloalkyl, cycloalkylalkyl, cycloalkyloxy, heterocyclic, heterocyclic alkyl, heterocyclic oxy, aryl, arylalkyl, aryloxy, heteroaryl, heteroarylalkyl and heteroaryloxy; or, two R 0 Together with the attached atoms, they form cycloalkyl or heterocyclic groups; and v can be 0, 1, or 2.

2. The compound of general formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is of general formula (III-2) or a pharmaceutically acceptable salt thereof: in, B 1 B 3 and B 5 Whether they are the same or different, and each is independently N or CR 2 ; M is selected from (CR) m1 R m2 ) p O, S, S(O), S(O)2, NR m C(O), C(O)NR m and NR m C(O); M 1 For key or (CR) m1 R m2 ) p1 ; M 2 For key or (CR) m1 R m2 ) p2 ; p is 0, 1, 2, 3 or 4; p1 is 0, 1, 2, 3 or 4; p2 is 0, 1, 2, 3 or 4; R m Selected from hydrogen atoms, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, and cycloalkylalkyl; R m1 and R m2 The same or different, and each independently selected from hydrogen atom, halogen, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, aminoalkyl, alkenyl, alkynyl, cyano, hydroxyl, nitro, amino, -NHalkyl, -N(alkyl)2, -C(O)Oalkyl, -C(O)OH, -C(O)NH2, -C(O)NH(alkyl), -C(O)N(alkyl)2, -C(O)halogen, -C(O)alkyl, -S(alkyl), cycloalkyl, cycloalkylalkyl, cycloalkyloxy, heterocyclic, heterocyclic alkyl, heterocyclic oxy, aryl, arylalkyl, aryloxy, heteroaryl, heteroarylalkyl and heteroaryloxy; or, R m1 and R m2 Together with the attached carbon atom, they form a cycloalkyl or heterocyclic group; or, R m1 and R m2 Together they form = O; and G, L x , ring X, R x , x, R w0 , Y 1 , Y 2 , V 1 , V 2 , T, R 2 L, ring A, R 1 m, L 1 and X 2 As defined in claim 1.

3. The compound of general formula (I) according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein the compound is of general formula (N) or general formula (N-1) or a pharmaceutically acceptable salt thereof. in, Ring A is selected from cycloalkyl, heterocyclic, aryl, and heteroaryl groups; n1 is 0, 1, 2 or 3; It can be a single bond or a double bond; Y 3 Selected from NR w3 O and S; and G, ring Y, R y y, L x R x x, R w1 R w3 R 4 R 5 M, p1, p2, R m1 R m2 R 2 L, R 1 m, L 1 and X 2 As defined in claim 2.

4. The compound of general formula (I) according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein the compound is of general formula (V-1) or general formula (V-2) or a pharmaceutically acceptable salt thereof. in, Y 3 Selected from NR w3 O and S; Y 4 For N or CR w4 ; It can be a single bond or a double bond; t is an integer from 0 to 10; f is 0, 1, 2, or 3; g can be 0, 1, 2, or 3; Z 1 For N or CR z1 ; Z 2 For N or CR z2 ; R z1 and R z2 They may be the same or different, and each is independently selected from hydrogen, halogen, alkyl, cyano, hydroxyl, haloalkyl, hydroxyalkyl, alkoxy, cycloalkyl and cycloalkylalkyl; Each R z They may be the same or different, and each is independently selected from hydrogen atoms, halogens, alkyl groups, haloalkyl groups, hydroxyalkyl groups, alkoxy groups, haloalkoxy groups, cyano groups, hydroxyl groups, =O groups, cycloalkyl groups, and heterocyclic groups; or, two R groups. z Together with their respective connected atoms, they form cycloalkyl or heterocyclic groups; k can be 0, 1, 2, 3, 4 or 5; L B3 Selected from: bond, alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, O, C(O), C(S), NR b S, S(O) and S(O)2, wherein the alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl groups are each independently and optionally selected by one or more R 0 Replace; and G, L x R x x, R 4 R 5 V 2 R w3 R w4 M, p1, p2, B 1 B 3 B 5 R 0 R b Ring A, m, R 1 L 1 and X 2 As defined in claim 2.

5. The compound of general formula (I) according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein Y 3 Selected from O, S and NH; preferably, Y 3 For NH or O; and / or Y 4 It is CH or N; preferably, Y 4 For CH.

6. The compound of general formula (I) according to any one of claims 1 to 3 and 5, or a pharmaceutically acceptable salt thereof, wherein the compound is of general formula (M-2) or a pharmaceutically acceptable salt thereof. in, Ring A is selected from cycloalkyl, heterocyclic, aryl, and heteroaryl groups; n1 is 0, 1, 2, or 3; and Ring Y, R y y, L x R x x, R w1 R 4 R 5 M, p1, p2, R 2 L, R 1 m, L 1 and X 2 As defined in claim 2.

7. The compound of general formula (I) according to any one of claims 1 to 6, wherein the compound is of general formula (VIII) or general formula (IX) or a pharmaceutically acceptable salt thereof. in, f is 0, 1, 2, or 3; g is 0, 1, 2, or 3; f1 is 0, 1, 2, or 3; g1 is 0, 1, 2, or 3; Z 1 For N or CR z1 Z 2 For N or CR z2 Z 3 For N or CR z3 Z 4 For N or CR z4 ; R z1 R z2 R z3 and R z4 They may be the same or different, and each is independently selected from hydrogen, halogen, alkyl, cyano, hydroxyl, haloalkyl, hydroxyalkyl, alkoxy, cycloalkyl and cycloalkylalkyl; Each R z They may be the same or different, and each is independently selected from hydrogen atoms, halogens, alkyl groups, haloalkyl groups, hydroxyalkyl groups, alkoxy groups, haloalkoxy groups, cyano groups, hydroxyl groups, =O groups, cycloalkyl groups, and heterocyclic groups; or, two R groups. z Together with their respective connected atoms, they form cycloalkyl or heterocyclic groups; k is 0, 1, 2, 3, 4, or 5; k2 is 0, 1, 2, 3, 4, or 5; and Ring Y, R y y, L x R x x, R w1 R 4 R 5 M, p1, p2, R 2 n1, ring A, R 1 m, L 1 and X 2 As defined in claim 6.

8. The compound of general formula (I) according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein ring A is selected from 6 to 20-membered monocyclic, bicyclic or tricyclic aryl, 5 to 20-membered monocyclic, bicyclic or tricyclic heteroaryl, 3 to 20-membered monocyclic, bicyclic or tricyclic cycloalkyl and 3 to 20-membered monocyclic, bicyclic or tricyclic heterocyclic groups; preferably, ring A is selected from 6 to 10-membered monocyclic or bicyclic aryl, 5 to 10-membered monocyclic or bicyclic heteroaryl, 11 to 20-membered tricyclic cycloalkyl and 11 to 20-membered tricyclic heterocyclic groups; more preferably, ring A is selected from phenyl, 9-membered bicyclic aryl, 9-membered bicyclic heteroaryl and 13 or 14-membered tricyclic heterocyclic groups; and / or R 1 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy groups and =O; or, two R groups. 1 Together with the adjacent carbon atoms, they form 3- to 6-membered cycloalkyl groups; And / or m is 0, 1, 2 or 3.

9. The compound of formula (I) according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein, Selected from Where, * end and L or L B3 or Z 2 or Z 4 Connected; m1 is 0, 1, 2, or 3; m2 is 0, 1, 2, 3, or 4; m3 is 0, 1, 2, or 3; m4 is 0, 1, or 2; m5 is 0, 1, 2, or 3; A1 is N or CH; A2 is N or CH; d1, d2, d3, and d4 are each independently 0, 1, 2, 3, or 4; J is selected from bonds, O, (CR j1 R j2 )j、S、S(O、S(O)2、NR J C(O), C(O)NR J and NR J C(O); j is 0, 1, 2, 3 or 4; Q is selected from O, S, NR q and CR q1 R q2 ;R A1 R J and R q Each is independently selected from hydrogen atoms, alkyl groups, haloalkyl groups, hydroxyalkyl groups, cycloalkyl groups, heterocyclic groups, and cycloalkylalkyl groups; R A R j1 R j2 R q1 and R q2 The same or different, and each independently selected from hydrogen, halogen, alkyl, alkenyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy, alkoxyalkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, cyano, hydroxyl, amino, and nitro; or, R j1 and R j2 Together with the attached carbon atom, they form a cycloalkyl or heterocyclic group; or, R q1 and R q2 Together with the attached carbon atom, they form cycloalkyl or heterocyclic groups; Preferably, Selected from Where, * end and L or L B3 or Z 2 or Z 4 Connected.

10. The compound of general formula (I) according to any one of claims 1 to 3, 5, 6, 8 and 9, or a pharmaceutically acceptable salt thereof, wherein L is -(L B ) t2 -;L B They are the same or different, and each is independently selected from O, C(O), C 1-6 Alkylene, C 2-6 Alkyne group, 3- to 8-membered cycloalkyl group and 3- to 8-membered heterocyclic group, wherein C 1-6 Alkylene, 3- to 8-membered cycloalkyl, and 3- to 8-membered heterocyclic groups are each independently selected from hydroxyl, halogen, C 1-6 Alkyl, C 1-6 The alkyl halogroup and =O are substituted with one or more substituents; t2 is 0, 1, 2, 3, 4, 5 or 6; preferably, L is selected from... in, * The end is connected to ring A.

11. The compound of formula (I) according to any one of claims 2 to 10, or a pharmaceutically acceptable salt thereof, wherein M is O or CH2; preferably, M is O; And / or p1 is 0, 1, 2 or 3; p2 is 0, 1, 2 or 3; preferably, p1 is 1; p2 is 1.

12. The compound of general formula (I) according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, Where R 4 and R 5 Whether the atoms are the same or different, and each is independently selected from hydrogen atoms, C atoms 1-6 Alkyl and 3- to 6-membered cycloalkyl; or, R 4 and R 5 Together with the connected nitrogen atom, they form a 3- to 8-membered heterocyclic group; preferably, R 4 and R 5 Each independently is C 1-6 Alkyl; more preferably, R 4 and R 5 It is a methyl group.

13. The compound of formula (I) according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, wherein R w1 Selected from hydrogen atoms, halogens and C 1-6 Alkyl; preferably, R w1 It is a halogen.

14. The compound of formula (I) according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, wherein R 2 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl and C 1-6 Alkoxy; preferably, R 2 It can be a hydrogen atom or a halogen.

15. The compound of formula (I) according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, wherein L x -(L A ) t1 -;L A They may be the same or different, and each is independently selected from NH, C(O) and C. 1-6 Alkylene; t1 is 0, 1, 2 or 3; preferably, L x Selected from in, * The terminal is connected to G or ring Y.

16. The compound of general formula (I) according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, wherein ring Y is a 5-membered heteroaryl group; R y They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl; y is 0 or 1; preferably, Selected from 17. The compound of general formula (I) according to any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, selected from the group consisting of: And all compounds in group A of the product information or their pharmaceutically acceptable salts.

18. A compound of general formula (VII-2a) or a salt thereof, in, Ring Y, R y y, L x R x x, R w1 R 4 R 5 M, p1, p2, R 2 n1, Z 1 f, g, R z And k as defined in claim 7.

19. A compound or a salt thereof, selected from the following compounds: Or its salt.

20. A method for preparing a compound of general formula (VIII) or a pharmaceutically acceptable salt thereof, comprising the following steps: The compound of general formula (VII-2a) or its salt undergoes a reductive amination reaction with the compound of general formula (VIIIB) or its salt to give the compound of general formula (VIII) or its pharmaceutically usable salt. in, Z 2 CH; Z 3 Let N be the number of people in the group. Ring Y, R y y, L x R x x, R w1 R 4 R 5 M, p1, p2, R 2 n1, Z 1 Z 4 f, g, f1, g1, R z k, k2, ring A, R 1 m, L 1 and X 2 As defined in claim 7.

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

22. Use of the compound of any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of claim 21 in the preparation of a medicament for inhibiting or degrading STAT6.

23. Use of the compound of any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of claim 21 in the preparation of a medicament for the treatment and / or prevention of diseases or conditions mediated or dependent on STAT6.

24. The compound of any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 21, in the preparation of a medicament for the treatment and / or prevention of cancer, inflammatory diseases, autoimmune diseases, neurodegenerative diseases, viral diseases, genetic diseases, hormone-related diseases, metabolic diseases, organ transplant-related diseases, immunodeficiency diseases, destructive bone diseases, proliferative diseases, infectious diseases, diseases related to cell death, thrombin-induced platelet aggregation, liver diseases, pathological immune conditions involving T cell activation, cardiovascular diseases, or central nervous system diseases. Used for the treatment and / or prevention of asthma, eosinophilic asthma (EA), atopic dermatitis (AD), chronic obstructive pulmonary disease (COPD), urticaria, nodular prurigo, esophagitis, eosinophilic esophagitis, bronchitis, diabetes, atherosclerosis, gout, arthritis, gouty arthritis, osteoarthritis, systemic lupus erythematosus, polychondritis, colitis, conjunctivitis, allergic rhinitis, chronic rhinitis with nasal polyps, rheumatoid arthritis, juvenile arthritis, scleroderma, Wegener's granulomatosis, dermatomyositis, hepatitis, myasthenia gravis, Stevens-Johnson syndrome, and inflammation. Gastrointestinal disorders, ulcerative colitis, Crohn's disease, irritable bowel syndrome, celiac disease, periodontitis, kidney disease, glomerular disease, alcoholic liver disease, multiple sclerosis, endocrine ophthalmopathy, Graves' disease, sarcoidosis, alveolitis, chronic allergic pneumonia, systemic sclerosis, primary biliary cirrhosis, uveitis, Sjögren's syndrome, interstitial pulmonary fibrosis, psoriatic arthritis, systemic juvenile idiopathic arthritis, cold and heat protein-related periodic arthritis syndrome, nephritis, vasculitis, cystitis, glomerulonephritis, chronic granulomatous disease, endometriosis, pancreatitis, acute lung injury, acute respiratory distress syndrome, and so on. Uses in medications for allergic reactions, sinusitis, pulmonary hypertension, cataracts, thyroiditis, appendicitis, allergies, cervicitis, cholangitis, cholecystitis, conjunctivitis, cystitis, dacryoadenitis, dermatitis, dermatomyositis, encephalitis, encephalomyelitis, endocarditis, endometritis, upper gastritis, gastroenteritis, allergic purpura, idiopathic thrombocytopenic purpura (ITP), Graves' disease, ankylosing spondylitis, anaphylactic shock, hidradenitis suppurativa, interstitial lung disease, laryngitis, mastitis, meningitis, myelitis, myocarditis, myositis, nephritis, oophoritis, orchitis, osteitis, otitis media, mumps, pneumonia, polymyositis, or prostatitis.

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