Tetracyclic compound, preparation method therefor and pharmaceutical uses thereof

Abstract

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

Description

A tetralone compound, a preparation method thereof and a medical use thereof TECHNICAL FIELD

[0001] The present disclosure belongs to the field of medicine, and relates to a tetralone compound, a preparation method thereof, a pharmaceutical composition containing the tetralone compound, and a use of the tetralone compound as a therapeutic agent, in particular, a use as a STAT6 inhibitor or degrader and a use in preparing a medicament for treating and / or preventing a STAT6-mediated or dependent disease or disorder. BACKGROUND

[0002] Type 2 inflammatory diseases are immune diseases mediated by Th2 cells and related cytokines such as IL-4, IL5, IL-13, etc., and are the main pathogenic mechanisms of asthma and atopic dermatitis (AD) and the like. Asthma is the most common chronic inflammatory disease of the lungs, and there were about 746.4 million adult patients worldwide in 2019, and about 63.6 million patients in China (Frost & Sullivan). Atopic dermatitis, also known as eczema, has become a major factor in the global burden of skin diseases, and the most common features of AD are itching, lichenification, and dryness. There were about 390 million AD patients worldwide in 2019, and about 61.5 million patients in China.

[0003] STAT6 belongs to the STAT (signal transducers and activators of transcription) transcription factor family. STAT6 is mainly activated by IL-4 and IL-13, and can affect the expression of more than 80% of IL-4-regulated Th2 differentiation genes (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 end of the receptor, STAT6 binds to the phosphorylated receptor through the SH2 domain, and is then phosphorylated by JAK; the phosphorylated STAT6 protein molecules form homodimers, enter the nucleus as transcription factors to activate the transcription of target genes (Expert Rev Clin Immunol. 2017 May; 13(5): 425-437). STAT6 plays an important role in type 2 inflammatory response, and can up-regulate the expression of related inflammatory factors such as IL-4, IL-5, IL-9 and IL-13 in Th2 cells; can regulate the differentiation of macrophages to M2, secrete keratin, promote epithelial damage repair; can promote B cell immunoglobulin class switching, up-regulate IgE expression, IgE can bind to the surface receptors of mast cells and basophils, induce allergic reactions; and promote airway smooth muscle contraction and epithelial cell mucus secretion, and up-regulate the expression of chemotactic factors, further recruit inflammatory cells (JAKSTAT. 2013 Oct 1; 2(4): e25301). Human genetic studies have found that activating mutations of STAT6 can cause early-onset, severe allergic diseases, mainly atopic dermatitis and asthma (J Exp Med. 2023 May 1; 220(5): e20221755).

[0004] Currently, there are three companies, Kymera, Recludix and Nurix, developing new STAT6 inhibitors. KT-621 developed by Kymera is a STAT6 degrader for the treatment of AD, asthma, COPD and other diseases, and is in clinical phase 1. The inhibitor developed by Recludix binds to the SH2 domain, and is currently in the discovery stage. The STAT6 degrader developed by Nurix is in the discovery stage for the treatment of type 2 immune diseases. SUMMARY

[0005] The purpose of the present disclosure is to provide a compound represented by general formula (M) or a pharmaceutically acceptable salt thereof,

[0006] wherein:

[0007] Ring A is optionally substituted by one or more R 1The replacement of the four rings;

[0008] R 1 The same or different, and each independently selected from 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;

[0009] 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;

[0010] L 1 Selected from bond, O, C(O), S, S(O), S(O)2, NR a C(O)NRa and NR a C(O);

[0011] R a Selected from hydrogen atoms, alkyl groups, haloalkyl groups, cycloalkyl groups, and cycloalkylalkyl groups;

[0012] X 2 For N or CH;

[0013] The ring W is selected from cycloalkyl, heterocyclic, aryl, and heteroaryl groups;

[0014] Cycloyl X is selected from cycloalkyl, heterocyclic, aryl, and heteroaryl groups;

[0015] Ring B is selected from cycloalkyl, heterocyclic, aryl, and heteroaryl groups;

[0016] G is selected from hydrogen atom, halogen and

[0017] Cycloyl Y is selected from cycloalkyl, heterocyclic, aryl, and heteroaryl groups;

[0018] R w R x R y 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 -NR6 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, each independently optionally substituted with one or more R 0 ;

[0019] or, R w and R 2 together with the atom to which each is attached form a cycloalkyl or heterocyclyl, each independently optionally substituted with one or more R 0 ;

[0020] or, two R x together with the atom to which they are attached form a cycloalkyl or heterocyclyl, each independently optionally substituted with 0 one or more R ;

[0021] or, two R y together with the atom to which they are attached form a cycloalkyl or heterocylyl, each independently optionally substituted with one or more R 0 ;

[0022] or, two R 2 together with the atom to which they are attached form a cycloalkyl or heteroeyclyl, each independently optionally substituted with one or more R 0 ;

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

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

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

[0026] L A and L B are the same or different, and are each independently selected from the group consisting of a bond, alkylene, alkenylene, alkynylene, cycloalkyl, heterocyclyl, aryl, heteroaryl, O, C(O), C(S), NR bS, 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 groups, haloalkyl groups, cycloalkyl groups, and cycloalkylalkyl groups;

[0028] t1 is an integer from 0 to 10;

[0029] t2 is an integer 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, hydroxyl groups, alkoxy groups, haloalkoxy groups, and cycloalkyl groups;

[0033] 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;

[0034] R 0the same or different, and each is independently selected from =0, halo, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, aminoalkyl, hydroxyl, alkenyl, alkynyl, cyano, nitro, amino, -NHalkyl, -N(alkyl)2, -C(0)Oalkyl, -C(0)OH, -C(0)NH2, -C(0)NH(alkyl), -C(0)N(alkyl)2, -C(0)halo, -C(0)alkyl, -S(alkyl), cycloalkyl, cycloalkylalkyl, cycloalkyloxy, heterocyclyl, heterocyclylalkyl, heterocyclyloxy, aryl, arylalkyl, aryloxy, heteroaryl, heteroarylalkyl, and heteroaryloxy; or, two R 0 and the attached atoms together form a cycloalkyl or heterocyclyl; and

[0035] v is 0, 1, or 2.

[0036] In some embodiments, the present disclosure provides a compound of Formula (I), or a pharmaceutically acceptable salt thereof,

[0037] wherein:

[0038] Ring A is a tetracyclic ring optionally substituted with one or more R 1

[0039] R 1 the same or different, and each is independently selected from halo, alkyl, alkenyl, alkynyl, cyano, nitro, hydroxyl, amino, alkoxy, haloalkyl, hydroxyalkyl, haloalkoxy, alkoxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR 3 , -NR 4 R 5 , -C(0)R 3 , -C(0)OR 3 , -C(0)NR 4 R 5 , -C(0)NR 4 OR 3 , -NR 6 C(0)R 3 , -NR 6 C(0)OR 3 , -NR 6 C(0)NR 4 R 5 , -OC(0)R 3 , -OC(0)NR 4 R 5 , -S(0) v R 3 , -S(0)(=NR 7 )R 3 , -S(0) 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;

[0040] 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;

[0041] 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);

[0042] R a Selected from hydrogen atoms, alkyl groups, haloalkyl groups, cycloalkyl groups, and cycloalkylalkyl groups;

[0043] X 2 For N or CH;

[0044] Y represents 1 and Y 2 The ring in which it is located is either aromatic or non-aromatic;

[0045] V 1 For N or C;

[0046] V 2 For N or CR w1 ;

[0047] T is either N or C;

[0048] Y 1 Selected from O, S, N, NR w3 CR w4 and CR w4 R w5 ;

[0049] Y 2 Selected from O, S, N, NR w6 CR w7 and CRw7 R w8 ;

[0050] Cycloyl X is selected from cycloalkyl, heterocyclic, aryl, and heteroaryl groups;

[0051] Ring B is selected from cycloalkyl, heterocyclic, aryl, and heteroaryl groups;

[0052] G is selected from hydrogen atom, halogen and

[0053] Cycloyl Y is selected from cycloalkyl, heterocyclic, aryl, and heteroaryl groups;

[0054] R w0 R w1 R w2 R w4 R w5 R w7 R w8 R x R y and R 2 The same or different, and each independently selected from hydrogen atom, halogen, alkyl, alkenyl, alkoxy, haloalkyl, hydroxyalkyl, haloalkoxy, alkoxyalkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, cyano, nitro, hydroxyl, amino, -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(R3 )3, -P(O)(OR 3 )2, -OP(O)(R 3 )2, and -OP(O)(OR 3 )2, each independently optionally substituted with one or more R 0 ;

[0055] R w3 and R w6 are the same or different, and each is independently selected from the group consisting of a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group, each independently optionally substituted with one or more R 0 ;

[0056] or R w2 and R 2 together with the atom to which each is attached form a cycloalkyl group or a heterocyclyl group, each independently optionally substituted with one or more R 0 ;

[0057] or R w3 and R 2 together with the atom to which each is attached form a heterocyclyl group, optionally substituted with one or more R 0 ;

[0058] or R w4 and R 2 together with the atom to which each is attached form a cycloalkyl group or heterocyclyl group, each independently optionally substituted with one or more R 0 ;

[0059] or R w6 and R 2 together with the atom to which each is attached form a heterocyclyl group optionally substituted with one or more R 0 ;

[0060] or R w7 and R 2 together with the atom to which each is attached form a cycloalkyl group or heterocyclyl group, each independently optionally substituted with one or more R 0 ;

[0061] or two R x together with the atom to which each is attached form a cycloalkyl group or hetrocyclyl group, each independently optionally substituted with one or more R 0 ;

[0062] 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;

[0063] 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;

[0064] x, y, and n are each independently 0, 1, 2, 3, 4, 5, 6, or 7;

[0065] L x -(L A ) t1 -;

[0066] L is -(L) B ) t2 -;

[0067] 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;

[0068] R b Selected from hydrogen atoms, alkyl groups, haloalkyl groups, cycloalkyl groups, and cycloalkylalkyl groups;

[0069] t1 is selected from integers from 0 to 10;

[0070] t2 is selected from integers from 0 to 20;

[0071] 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;

[0072] R 6selected from the group consisting of hydrogen atom, alkyl, haloalkyl, hydroxyalkyl, and cycloalkyl;

[0073] R 7 selected from the group consisting of hydrogen atom, alkyl, haloalkyl, hydroxy, alkoxy, haloalkoxy, and cycloalkyl;

[0074] R 8 and R 9 are the same or different, and each is independently selected from the group consisting of hydrogen atom, halogen, alkyl, haloalkyl, hydroxyalkyl, and cycloalkyl; or, R 8 and R 9 together with the carbon atom to which they are attached form a cycloalkyl or heterocyclyl group;

[0075] R 0 are the same or different, and each is independently selected from the group consisting of =0, halogen, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, aminoalkyl, hydroxy, alkenyl, alkynyl, cyano, nitro, hydroxy, 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, heterocyclyl, heterocyclylalkyl, heterocyclyloxy, aryl, arylalkyl, aryloxy, heteroaryl, heteroarylalkyl, and heteroaryloxy; or, two R 0 together with the atom to which they are attached form a cycloalkyl or heterocyclyl group; and

[0076] v is 0, 1, or 2.

[0077] In some embodiments, the present disclosure provides a compound of Formula (I-1) or a pharmaceutically acceptable salt thereof,

[0078] wherein:

[0079] is a single or double bond; and

[0080] 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, L 1 and X 2 are as defined in Formula (I).

[0081] In some embodiments, the present disclosure provides a compound represented by general formula (II-1), general formula (II-2), general formula (II-3), or general formula (II-4), or a pharmaceutically acceptable salt thereof,

[0082] wherein,

[0083] In general formula (II-1), B 1 , B 2 , B 3 , B 4 and B 5 one of them is C and is connected with L, and the other four are the same or different, and each is independently N or CR 2 ;

[0084] In general formula (II-2) and general formula (II-3), B 1 , B 2 , B 4 and B 5 are the same or different, and each is independently N or CR 2 ;

[0085] In general formula (II-4), n1 is 0, 1, 2, 3, or 4;

[0086] In general formula (II-3) and general formula (II-4), is a single bond or a double bond; and

[0087] G, L x , ring X, R x , x, R w0 , R w1 , R w2 , Y 1 , Y 2 , V 1 , V 2 , T, R 2 , L, ring A and X 2 are as defined in general formula (I).

[0088] In some embodiments, the present disclosure provides a compound represented by general formula (III-1), general formula (III-2), general formula (III-3), general formula (III-4), or general formula (III-5), or a pharmaceutically acceptable salt thereof,

[0089] wherein,

[0090] B 1 , B 2 , B 4 and B5 the same or different and each independently N or CR 2

[0091] is a single or double bond;

[0092] Y 1 is selected from O, S and NH;

[0093] Y 2 is selected from O, S and NH;

[0094] Y 3 is N or CH;

[0095] M is selected from a bond, (CR m1 R m2 ) m , O, S, S(O), S(O)2, NR m , C(O), C(O)NR m and NR m C(O);

[0096] M 1 is a bond or (CR m1 R m2 ) m1 ;

[0097] M 2 is a bond or (CR m1 R m2 ) m2 ;

[0098] m is 0, 1, 2, 3 or 4;

[0099] m1 is 0, 1, 2, 3 or 4;

[0100] m2 is 0, 1, 2, 3 or 4;

[0101] R m is selected from a hydrogen atom, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl and cycloalkylalkyl;

[0102] R m1 and R m2 ​the same or different, and each is independently selected from the group consisting of a hydrogen atom, halogen, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, aminoalkyl, alkenyl, alkynyl, cyano, nitro, hydroxyl, 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, heterocyclyl, heterocyclylalkyl, heterocyclyloxy, aryl, arylalkyl, aryloxy, heteroaryl, heteroarylalkyl, and heteroaryloxy; or, R m1 and R m2 together with the carbon atom to which they are attached form a cycloalkyl or heterocyclyl; or, R m1 and R m2 together form =O; and

[0103] G, L x , R x , x, R w0 , V 2 , R w2 , R 2 , L, ring A, and X 2 are as defined in general formula (I).

[0104] In some embodiments, the present disclosure provides a compound of general formula (IV-1), general formula (IV-2), general formula (IV-3), general formula (IV-4), general formula (IV-5), general formula (IV-6), general formula (IV-7), and general formula (IV-8), or a pharmaceutically acceptable salt thereof,

[0105] wherein,

[0106] n1 is 0, 1, 2, 3, or 4;

[0107] n2 is 0, 1, 2, or 3;

[0108] Y 1 is selected from O, S, and NH;

[0109] Y 2 is selected from O, S, and NH;

[0110] t is an integer from 0 to 10;

[0111] f is 0, 1, 2, or 3;

[0112] g is 0, 1, 2, or 3;

[0113] Z 1 is N or CRz1 ;

[0114] Z 2 is N or CR z2 ;

[0115] R z1 and R z2 are the same or different and each is independently selected from the group consisting of a hydrogen atom, halogen, alkyl, cyano, hydroxyl, haloalkyl, hydroxyalkyl, alkoxy, cycloalkyl, and cycloalkylalkyl;

[0116] each R z is the same or different and each is independently selected from the group consisting of a hydrogen atom, halogen, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, cyano, hydroxyl, =0, cycloalkyl, and heterocyclyl; or, two R z and the atom to which each is attached together form a cycloalkyl or heterocyclyl;

[0117] k is 0, 1, 2, 3, 4, or 5; and

[0118] ring Y, R y , y, L x , R x , x, R w1 , R w2 , M, m1, m2, R 2 , R 4 , R 5 and ring A are as defined in Formula (III-1), Formula (III-2), Formula (III-3), Formula (III-4), or Formula (III-5).

[0119] In some embodiments, the present disclosure provides a compound of Formula (V-1) or a pharmaceutically acceptable salt thereof,

[0120] wherein,

[0121] Y 1 is N or CR w4 ;

[0122] Y 2 is selected from the group consisting of O, S, and NR w6 ;

[0123] is a single bond or a double bond; and

[0124] G, L x , R x , x, V 2 , R w2 , R w4 , R w6 , R 4, R 5 , R 2 , n, ring B, L, ring A, and X 2 as defined in general formula (I).

[0125] In some embodiments, the present disclosure provides a compound represented by general formula (V-2) or a pharmaceutically acceptable salt thereof,

[0126] wherein,

[0127] Y 1 is selected from O, S, and NR w3 ;

[0128] Y 2 is N or CR w7 ;

[0129] is a single bond or a double bond; and

[0130] G, L x , R x , x, V 2 , R w2 , R w3 , R w7 , R 4 , R 5 , R 2 , n, ring B, L, ring A, and X 2 as defined in general formula (I).

[0131] In some embodiments, the present disclosure provides a compound represented by general formula (VI) or a pharmaceutically acceptable salt thereof,

[0132] wherein,

[0133] Y 2 is selected from O, S, and NR w6 ;

[0134] n1 is 0, 1, 2, 3, or 4;

[0135] is a single bond or a double bond; and

[0136] ring Y, R y , y, L x , R x , x, R w1 , R w2 , R w6 , R 4 , R 5 , R 2 , L, ring A, and X 2 as defined in general formula (I).

[0137] In some embodiments, this disclosure provides a compound of general formula (VII) or a pharmaceutically acceptable salt thereof.

[0138] in,

[0139] Y 2 Selected from O, S and NR w6 ;

[0140] n2 is 0, 1, 2 or 3;

[0141] It can be a single bond or a double bond;

[0142] m1 can be 0, 1, 2, 3 or 4;

[0143] m2 can be 0, 1, 2, 3 or 4;

[0144] M is as defined in general formula (III-5); and

[0145] Ring Y, R y y, L x R x x, R w1 R w6 R 4 R 5 R 2 L, ring A and X 2 As defined in general formula (I).

[0146] In some embodiments, this disclosure provides a compound of general formula (VIII) or a pharmaceutically acceptable salt thereof.

[0147] in,

[0148] Y 2 Selected from O, S and NR w6 ;

[0149] It can be a single bond or a double bond;

[0150] m1 can be 0, 1, 2, 3 or 4;

[0151] m2 can be 0, 1, 2, 3 or 4;

[0152] B 6 and B 7 Each can be either N or CH independently;

[0153] n4 is 0, 1, 2, 3, or 4; and

[0154] Ring Y, R yy, L x R x x, R w1 R w6 R 4 R 5 R 2 L, ring A and X 2 As defined in general formula (I).

[0155] In some implementations, ring A is optionally controlled by one or more R... 1 The replacement of the 16-20 yuan Fourth Ring Road; R 1 As defined in the context; in some implementations, ring A is optionally bounded by one or more R 1 The replacement of the 17-yuan Fourth Ring Road; R 1 As defined in the context.

[0156] In some implementations, ring A is *Ends and L, Z 2 Or (CH2)t linked; ring C is fused with ring D; ring D is fused with ring E; ring E is fused with ring F; ring E and ring H are spiro-linked; ring C is selected from phenyl, 5- or 6-membered heterocyclic and 5- or 6-membered heteroaryl; ring D is phenyl or 5- or 6-membered heteroaryl; ring E is 5 to 10-membered cycloalkyl or 5 to 10-membered heterocyclic; ring F is 4 to 10-membered cycloalkyl or 4 to 10-membered heterocyclic; ring H is 4 to 10-membered cycloalkyl or 4 to 10-membered heterocyclic; and ring C, ring D, ring E, ring F and ring H are each independently and optionally separated by one or more R 1 Replace, R 1 As defined in the context.

[0157] In some implementations, ring A is selected from the following structures: *Ends and L, Z 2 Or (CH2)t linked; ring C is selected from phenyl, 5 or 6-membered heterocyclic and 5 or 6-membered heteroaryl; ring E is 5 to 10-membered cycloalkyl or 5 to 10-membered heterocyclic, and ring C and ring E are each independently optionally separated by one or more R 1 Replace, R 1 As defined in the context; a1 and a2 are each independently 0, 1, 2, 3, or 4; A1 is N or CR. a1 A2 is N or CR a2 A3 is N or CR a3 A4 represents N or CR a4 A5 represents N or CR. a5 A6 is N or CR a6 A7 is N or C; A8 is N or C; R a1and R a2 Each is independently selected from hydrogen atoms, halogens, alkyl groups, haloalkyl groups, cyano groups, hydroxyl groups, and hydroxyalkyl groups; R a3 R a4 R a5 and R a6 The same or different, and each independently selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy, alkoxyalkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, cyano, hydroxyl, amino, and nitro; a3 is 0, 1, 2, 3, or 4; R 1x 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; 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; or, two Rs 1xtogether with the atoms to which they are attached form a cycloalkyl or heterocyclyl, each independently optionally substituted with one or more R 0 , R 0 , R 3 , R 9 , R 2 are as defined above.

[0158] In some embodiments, ring A is selected from the following structures: together with the atoms to which they are attached form a cycloalkyl or heterocyclyl, each independently optionally substituted with one or more R 1 , R 1 are as defined above and below; a1and a2are each independently 0, 1, 2, 3, or 4; A1is N or CR a1 ; A2is N or CR a2 ; A3is N or CR a3 ; A4is N or CR a4 ; A5is N or CR a5 ; A6is N or CR a6 ; A7is N or C; A8is N or C; R a1 and R a2 are each independently selected from the group consisting of a hydrogen atom, a halogen, an alkyl, a haloalkyl, a cyano, a hydroxyl, and a hydroxyalkyl; R a3 , R a4 , R a5 , and R a6 are the same or different and are each independently selected from the group consisting of a hydrogen atom, a halogen, an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a hydroxyalkyl group, a haloalkyl group, a haloalkoxy group, an alkoxyalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, a heteroaryl group, a cyano group, a hydroxyl group, an amino group, and a nitro group.

[0159] In some embodiments, ring C is a 5-membered heterocyclyl or a 5-membered heteroaryl, and ring C is optionally substituted with one or more R 1 , R 1 are as defined above and below.

[0160] In some embodiments, ring E is a 5- to 8-membered heterocyclyl, and ring E is optionally substituted with one or more R 1 , R 1 are as defined above and below; in some embodiments, ring E is a 5- or 6-membered heterocyclyl, and ring E is optionally substituted with one or more R R 1 , R 1 are as defined above and below; in some embodiments, ring E is a 5- to 6-membered heterocyclyl or a 5- to 6-membered cycloalkyl, and ring E is optionally substituted with one or more R R 1Replace, R 1 As defined in the context; in some embodiments, ring E is a 5-membered heterocyclic group or a 5-membered cycloalkyl group, and ring E is optionally surrounded by one or more R groups. 1 Replace, R 1 As defined in the context; in some embodiments, ring E is a 5-membered heterocyclic group or a 5-membered cycloalkyl group.

[0161] In some implementations, ring A is selected from the following structures:

[0162] *Ends and L, Z 2 Or (CH2)t connected together; where Q is selected from O, S, NR q and CR q1 R q2 a1 and a2 are each independently 0, 1, 2, 3, or 4; A1 is N or CR. a1 A2 is N or CR a2 A3 is N or CR a3 A4 represents N or CR a4 A5 represents N or CR. a5 A6 is N or CR a6 J is selected from bond, O, (CR) j1 R j2 ) u S, S(O), S(O)2, NR J C(O), C(O)NR J and NR J C(O); J 1 Selected from bond, O, (CR) j1 R j2 ) p S, S(O), S(O)2, NR J C(O), C(O)NR J and NR J C(O); J 2 Selected from bond, O, (CR) j1 R j2 ) q S, S(O), S(O)2, NR J C(O), C(O)NR J and NR J C(O);

[0163] J 3 Selected from O, S, S(O), S(O)2, NR J C(O), C(O)NR J NR J C(O), (CR)j1 R j2 ) k1 and (CR) j1 R j2 ) k3 W J (CR j1 R j2 ) k4 ;

[0164] J 4 Selected from O, S, S(O), S(O)2, NR J C(O), C(O)NR J NR J C(O), (CR) j1 R j2 ) k2 and (CR) j1 R j2 ) k5 W J (CR j1 R j2 ) k6 ;

[0165] W J Selected from O, S, S(O), S(O)2, NR J C(O), C(O)NR J and NR J C(O);

[0166] k1 and k2 are each independently 1, 2, 3 or 4;

[0167] k3, k4, k5, and k6 are each independently 0, 1, 2, or 3;

[0168] u, p, and q are each independently 0, 1, 2, 3, or 4; R a1 and R a2 Each is independently selected from hydrogen atoms, halogens, alkyl groups, haloalkyl groups, cyano groups, hydroxyl groups, and hydroxyalkyl groups; R q R J and R A1 Each is independently selected from hydrogen atoms, alkyl groups, haloalkyl groups, hydroxyalkyl groups, cycloalkyl groups, heterocyclic groups, and cycloalkylalkyl groups; R q1 R q2 R j1 R j2 R a3 R a4 R a5 R a6 and R AThe 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; or, R j1 and R j2 Together with the adjacent atoms, they form a cycloalkyl or heterocyclic group; a3 is 0, 1, 2, 3, or 4; R 1x 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; 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; or, two Rs 1xtogether with the attached atoms form a cycloalkyl or heterocyclyl, each independently optionally substituted with one or more R 0 ; and v, R 0 , R 3 - R 9 as defined above.

[0169] In some embodiments, ring A is selected from the following structures: * terminus is attached to L, Z 2 ; wherein Q is selected from O, S, NR q , and CR q1 R q2 ; a1and a2are each independently 0, 1, 2, 3, or 4; A1is N or CR a1 ; A2is N or CR a2 ; A3is N or CR a3 ; A4is N or CR a4 ; A5is N or CR a5 ; A6is N or CR a6 ; J is selected from a bond, O, (CR j1 R j2 ) u , S, S(O), S(O)2, NR J , C(O), C(O)NR J , and NR J C(O); J 1 is a bond or (CR j1 R j2 ) p ; J 2 is a bond or (CR j1 R j2 ) q ; u, p, and q are each independently 0, 1, 2, 3, or 4; R a1 , and R a2 are each independently selected from a hydrogen atom, halogen, alkyl, haloalkyl, cyano, hydroxyl, and hydroxyalkyl; R q , R J , and R A1 are each independently selected from a hydrogen atom, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, and cycloalkylalkyl; R q1 , R q2 , R j1 , R j2 , R a3 , R a4 , R a5 , R a6 , and R Athe same or different, and each is independently selected from the group consisting of a hydrogen atom, a halogen, an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a hydroxyalkyl group, a haloalkyl group, a haloalkoxy group, an alkoxyalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, a heteroaryl group, a cyano group, a hydroxyl group, an amino group, and a nitro group; or, R q1 and R q2 together with the carbon atom to which they are attached form a cycloalkyl group or a heterocyclyl group; or, R j1 and R j2 together with the carbon atom to which they are attached form a cycloalkyl group or a heterocyclyl group.

[0170] In some embodiments, ring A is selected from the following structures: In some embodiments, ring A is In some embodiments, ring A is In some embodiments, the * end is attached to L, Z 2 or (CH2)t; a4 is 0, 1, or 2; and J, J 3 , J 4 , p, q, Q, R A1 , R A , A1, A2, and R 1x are as defined above.

[0171] In some embodiments, ring A is selected from the following structures: In some embodiments, the * end is attached to L, Z 2 or (CH2)t; p, q, Q, A1, and A2 are as defined above and below.

[0172] In some embodiments, ring A is selected from the following structures: In some embodiments, the * end is attached to L, Z 2 or (CH2)t.

[0173] In some embodiments, ring A is selected from the following structures: ​​ *end is attached to L, Z 2 or (CH2)t.

[0174] In some embodiments, ring A is selected from

[0175] *end is attached to L, Z 2 or (CH2)t.

[0176] In some embodiments, ring A is *end is attached to L, Z 2 or (CH2)t.

[0177] In some embodiments, ring A is *end is attached to L, Z 2 or (CH2)t.

[0178] In some embodiments, ring A is *end is attached to L, Z 2 or (CH2)t.

[0179] In some embodiments, ring A is *end is attached to L, Z 2 or (CH2)t.

[0180] In some embodiments, ring A is selected from the following structures: *end is attached to L, Z 2 or (CH2)t.

[0181] In some embodiments, J is CH2or O; in some embodiments, J is O.

[0182] In some embodiments, J 1 is selected from bond, CH2, CH2CH2, and CH2CH2CH2; in some embodiments, J 1 is selected from bond, CH2, and CH2CH2; in some embodiments, J 1 is CH2.

[0183] In some embodiments, J 2 is selected from bond, CH2, CH2CH2, and CH2CH2 CH2; in some embodiments, J 2 is selected from bond, CH2, and CH2CH2; in some embodiments, is bond. 2

[0184] In some embodiments, J 3 ​is selected from O, CH2, CH2CH2, OCH2, and CH2O; in some embodiments, J 3 is O or CH2.

[0185] in some embodiments, J 4 is selected from O, CH2, CH2CH2, OCH2, and CH2O; in some embodiments, J 4 is O or CH2.

[0186] in some embodiments, J 3 is CH2, J 4 is CH2; in some embodiments, J 3 is O, J 4 is CH2; in some embodiments, J 3 is CH2, J 4 is O; in some embodiments, J 3 is O, J 4 is O.

[0187] in some embodiments, W J is O.

[0188] in some embodiments, k1 is 1 or 2; in some embodiments, k1 is 1.

[0189] in some embodiments, k2 is 1 or 2; in some embodiments, k2 is 1.

[0190] in some embodiments, k3, k4, k5, and k6 are each independently 0 or 1.

[0191] in some embodiments, a1 and a2 are each independently 0 or 1; in some embodiments, a1 and a2 are 1.

[0192] in some embodiments, a3 is 0 or 1; in some embodiments, a3 is 0.

[0193] in some embodiments, a4 is 0 or 1; in some embodiments, a4 is 0.

[0194] in some embodiments, R 1x are the same or different, and each is independently selected from a hydrogen atom, a halogen, a C 1-6 alkyl group, a C 1-6 alkoxy group, a C 1-6 hydroxyalkyl group, a C 1-6 haloalkyl group, and an oxo group; or, two R 1x and the attached atoms together form a 3- to 6-membered cycloalkyl group; in some embodiments, R 1x are the same or different, and each is independently selected from a hydrogen atom, a haloge1-6 alkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, and C 1-6 haloalkyl; in some embodiments, R 1x are the same or different, and each is independently selected from the group consisting of a hydrogen atom, a halogen, and C 1-6 alkyl; in some embodiments, R 1x is a hydrogen atom; in some embodiments, R 1x is oxo; in some embodiments, two R 1x and the attached carbon atom together form a cyclopropyl group.

[0195] in some embodiments, R A is selected from the group consisting of a hydrogen atom, a halogen, and C 1-6 alkyl; in some embodiments, R A is C 1-6 alkyl; in some embodiments, R A is a methyl group.

[0196] in some embodiments, R A1 is selected from the group consisting of a hydrogen atom, C 1-6 alkyl, and 3- to 6-membered cycloalkyl; in some embodiments, R A1 is C 1-6 alkyl or 3- to 6-membered cycloalkyl; in some embodiments, R A1 is C 1-6 alkyl; in some embodiments, R A1 is a methyl or cyclopropyl group; in some embodiments, R A1 is a methyl group.

[0197] in some embodiments, R J is a hydrogen atom or C 1-6 alkyl.

[0198] in some embodiments, R q is a hydrogen atom or C 1-6 alkyl; in some embodiments, R q is C 1-6 alkyl; in some embodiments, R q is a methyl group.

[0199] in some embodiments, R q1 and R q2 are the same or different, and each is independently a hydrogen atom or C 1-6 alkyl; alternatively, R q1 and R q2 and the attached carbon atom together form a 3- to 6-membered cycloalkyl group (e.g., cyclopropyl, cyclobutyl); in some embodiments, R q1 and Rq2 is methyl; or, R q1 and R q2 together with the carbon atom to which they are attached form a cyclopropyl group.

[0200] In some embodiments, Q is NR q or CR q1 R q2 ; R q , R q1 and R q2 are as defined above and below; in some embodiments, Q is NR q ; R q is C 1-6 alkyl; in some embodiments, Q is N-methyl.

[0201] In some embodiments, A1is N or CH; in some embodiments, A1is N.

[0202] In some embodiments, A2is N or CH; in some embodiments, A2is N.

[0203] In some embodiments, A1is N; A2is N.

[0204] In some embodiments, u is 0, 1, or 2; in some embodiments, u is 1.

[0205] In some embodiments, p and q are each independently 0, 1, or 2; in some embodiments, p and q are each independently 0 or 1.

[0206] In some embodiments, p is 1, q is 0; in some embodiments, p is 2, q is 0; in some embodiments, p is 1, q is 1.

[0207] In some embodiments, A3is CR a3 ; R a3 is as defined above and below; in some embodiments, A3is N or CH; in some embodiments, A3is CH.

[0208] In some embodiments, A4is CR a4 ; R a4 is as defined above and below; in some embodiments, A4is N or CH; in some embodiments, A4is CH.

[0209] In some embodiments, A5is CR a5 ; R a5 is as defined above and below; in some embodiments, A5is N or CH; in some embodiments, A5is CH.

[0210] In some embodiments, A6is CR a6 ; R a6 is as defined above and below; in some embodiments, A6is N or CH; in some embodiments, A6is CH.

[0211] In some embodiments, A7is C.

[0212] In some embodiments, A8is C.

[0213] In some embodiments, R a1 is a hydrogen atom.

[0214] In some embodiments, R a2 is a hydrogen atom.

[0215] In some embodiments, R a3 , R a4 , R a5 , and R a6 are the same or different, and each is independently selected from a hydrogen atom, a halogen, a C 1-6 alkyl group, a C 1-6 alkoxy group, a C 1-6 hydroxyalkyl group, and a C 1-6 haloalkyl group; in some embodiments, R a3 , R a4 , R a5 , and R a6 are the same or different, and each is independently selected from a hydrogen atom, a halogens, and a C 1-6 alkyl group; in some embodiments, R a3 , R a4 , R a5 , and R a6 are each independently a hydrogen atom.

[0216] In some embodiments, R j1 and R j2 are the same or different, and each is independently selected from a hydrogen atom, a halogene, a C 1-6 alkyl group, a C 1-6 alkoxy group, a C 1-6 hydroxyalkyl group, and a C 1-6 haloalkyl group; in some embodiments, R j1 and R j2 are the same or different, and each is independently selected from a hydrogen atom, a halogene, and a C 1-6 alkyl group; in some embodiments, R j1 and R j2 are hydrogen atoms.

[0217] In some embodiments, the present disclosure provides a compound represented by General Formula (XI), General Formula (XI-1), or General Formula (XI-2), or a pharmaceutically acceptable salt thereof,

[0218] wherein,

[0219] n1 is 0, 1, 2, 3, or 4;

[0220] R A1 is selected from the group consisting of a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclyl group, and a cycloalkylalkyl group;

[0221] R 1x are the same or different, and each is independently selected from the group consisting of a hydrogen atom, a halogen, an alkyl group, an alkenyl group, an alkynyl group, a cyano group, a nitro group, a hydroxyl group, an amino group, an alkoxy group, a haloalkyl group, a hydroxyalkyl group, a haloalkoxy group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group;

[0222] a4 is 0, 1, or 2; and

[0223] ring Y, R y , y, L x , R x , x, R w1 , R w2 , R 4 , R 5 , R 2 , and L are as defined in general formula (I).

[0224] In some embodiments, the present disclosure provides a compound represented by general formula (XII), general formula (XII-1), or general formula (XII-2), or a pharmaceutically acceptable salt thereof,

[0225] wherein,

[0226] n2 is 0, 1, 2, or 3;

[0227] b8 and b9 are each independently 0, 1, or 2;

[0228] R A1 is selected from the group consisting of a hydrogen atom, an alkyl group, a

[0229] R 1x are the same or different, and each is independently selected from the group consisting of a

[0230] a4 is 0, 1, or 2; and

[0231] M, m1, m2, R m1 , and R m2 are as defined in general formula (III-5); and

[0232] Ring Y, R y , y, L x , R x , x, R w1 , R 4 , R 5 and R 2 are as defined in general formula (I).

[0233] In some embodiments, b8and b9are each independently 0 or 1; in some embodiments, b8and b9are 1.

[0234] In some embodiments, L is -(L B ) t2 -; L B are the same or different, and each is independently selected from O, C(O), C 1-6 alkylene, C 2-6 alkynyl, 3- to 12-membered cycloalkyl, and 3- to 12-membered heterocyclyl, each of which C 1-6 alkylene, 3- to 12-membered cycloalkyl, and 3- to 12-membered heterocyclyl is independently optionally substituted with one or more substituents selected from hydroxy, halo, C 1-6 alkyl, C 1-6 haloalkyl, and =O; and t2 is 0, 1, 2, 3, 4, 5, or 6; in some embodiments, L is -(L B ) t2 -; L B are the same or different, and each is independently selected from O, C(O), C6 1- alkylene, C 2-6 alkynyl, 3- to 8-membered cycloalkyl, and 3- to 8-membered heterocyclyl; each of which C 1-6 alkylene, 3- to 8-membered cycloalkyl, and 3- to8-membered heterocyclyl is independently optionally substituted with one or more substituents selected 1-6 alkyl, C 1-6 haloalkyl, and =O; and t2 is 0, 1, 2, 3, 4, 5, or 6; in some embodiments, B ) t2 -; L B are the same or different, and each is independently selected from O, C 1-6 alkylene, 3- to 12-membered cycloalkyl, and 31- to 12-membered heterocyclyl; and t2 is 0, 1, 2, or 3; in some embodiments, L is -(L B ) t2 -; L B are the same or different, and each is independently selected from C 1-6 alkylene, 3- to 8-membered cycloalkyl, and3- to 8-membered heterocyclyl; and t2 is 0, 1, 21, 3, 4, 5, or 6.

[0235] In some embodiments, L is (CH2) t or t, Z 1 , Z 2 , f, g, R z and k are as defined above and below.

[0236] In some embodiments, L is selected from the group consisting of a bond, CH2, CH2CH2, CH2CH2CH2, In some embodiments, L is selected from the group consisting of a bond, CH2, CH2CH2, CH2CH2CH2, In some embodiments, L is selected from the group consisting of a bond, CH2, CH2CH2, CH2CH2CH2, In some embodiments, L is selected from the group consisting of a bond, CH2, CH2CH2, CH2CH2CH2,

[0237] In some embodiments, L is selected from the group consisting of a bond, CH2, CH2CH2, CH2CH2CH2,

[0238] In some embodiments, L is selected from the group consisting of a bond, CH2, CH2CH2, CH2CH2CH2,

[0239] In some embodiments, L is selected from the group consisting of a bond, CH2, CH2CH2, CH2CH2CH2,

[0240] In some embodiments, L is selected from the group consisting of a bond, CH2, CH2CH2, CH2CH2CH2,

[0241] In some embodiments, L is selected from the group consisting of a bond, CH2, CH2CH2,

[0242] In some embodiments, L is selected from the group consisting of a bond, CH2, CH2CH2,

[0243] In some embodiments, L is selected from the group consisting of a bond, CH2, CH2CH2, In some embodiments, L is selected from the group consisting of a bond, CH2, CH2CH2,

[0244] In some embodiments, L is a bond.

[0245] In some embodiments, L is CH2CH2.

[0246] In some embodiments, L is selected from * is attached to ring A or N.

[0247] In some embodiments, L is * is attached to ring A or N.

[0248] In some embodiments, t2 is 0, 1, 2, 3, 4, 5, or 6; in some embodiments, t2 is 0, 1, 2, or 3; in some embodiments, t2 is 0, 1, or 2.

[0249] In some embodiments, ring W is a 9-membered bicyclic heteroaryl; in some embodiments, ring W is a 5-membered heteroaryl fused to phenyl or a 5-membered heteroaryl fused to a 6-membered heteroaryl; in some embodiments, ring W is selected from indolyl, benzofuranyl, benzothiophenyl, benzimidazolyl, benzoxazolyl, thienopyridinyl, pyrrolo[3,2-b]pyridinyl, pyrrolo[2,3,-b]pyridinyl, pyrazolo[1,5-a]pyridinyl, and imidazo[1,2-a]pyridinyl; in some embodiments, ring W is indolyl.

[0250] In some embodiments, * is attached to ring X; Y 1 , Y 2 , V 1 , V 2 , T, R w0 , R w1 , R w2 , and are as defined above and below;

[0251] In some embodiments, is selected from R w and w are as defined above and below.

[0252] In some embodiments, R w is selected from a hydrogen atom, a halogen, a C 1-6 alkyl group, and -C(O)NR 4 R 5 ; R 4 and R 5 are as defined above and below.

[0253] In some embodiments, w is 0, 1, 2, 3, or 4; in some embodiments, w is 0, 1, 2, or 3; in some embodiments, w is 2 or 3; in some embodiments, w is 2.​

[0254] In some embodiments, R w0 is -C(O)NR 4 R 5 ; R 4 and R 5 are as defined above and below; in some embodiments, R w0 is selected from In some embodiments, R w0 is selected from In some embodiments, R w0 is

[0255] In some embodiments, R w0 is a 5- or 6-membered heteroaryl optionally substituted with one or more R 0 ; R 0 is as defined in general formula (I); in some embodiments, R w0 is a 5-membered heteroaryl optionally substituted with one or more R 0 ; R 0 is as defined in general formula (I); in some embodiments, R w0 is

[0256] In some embodiments, ring B is selected from 3- to 12-membered cycloalkyl, 3- to 12-membered heterocyclyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl; in some embodiments, ring B is phenyl or 5- or 6-membered heteroaryl; in some embodiments, ring B is phenyl or 6-membered heteroaryl; in some embodiments, ring B is phenyl or pyridyl; in some embodiments, ring B is phenyl.

[0257] In some embodiments, is selected from B 1 , B 2 , B 3 , B 4 , and B 5 are the same or different and each independently N or CR 2 ; n1and R 2 are as defined above and below; the *end is attached to L.

[0258] In some embodiments, is selected from b1, b2, b3, and b4 are each independently 0, 1, 2, 3, or 4; b5 is 0, 1, 2, 3, or 4; B6 and B 7 each independently N or CH; n1 is 0, 1, 2, 3, or 4; n3 is 0, 1, 2, or 3; n5 is 0, 1, 2, or 3; n6 is 0, 1, or 2; R 2 as defined above and below; the * end is attached to L.

[0259] In some embodiments, is selected from b1, b2, b3, and b4 are each independently 0, 1, 2, 3, or 4; b5 is 0, 1, 2, 3, or 4; B 6 and B 7 each independently N or CH; n1 is 0, 1, 2, 3, or 4; n3 is 0, 1, 2, or 3; R 2 as defined above and below; the * end is attached to L.

[0260] In some embodiments, is selected from

[0261] In some embodiments, is selected from the * end is attached to L.

[0262] In some embodiments, is selected from the * end is attached to L.

[0263] In some embodiments, is selected from

[0264] In some embodiments, is selected from the * end is attached to L.

[0265] In some embodiments, is selected from the * end is attached to L.

[0266] In some embodiments, b1and b2are each independently 0, 1, or 2; in some embodiments, b1and b2are each independently 0 or 1; in some embodiments, b1and b2are 0; in some embodiments, b1and b2are 1; in some embodiments, b1is 1; b2is 0; in some embodiments, b1is 0; b2is 1.

[0267] In some embodiments, b3and b4are each independently 0, 1, or 2; in some embodiments, b3and b4are each independently 0 or 1; in some embodiments, b3and b4are 0; in some embodiments, b3is 0; b4is 0; in some embodiments, b3and b4are 1; in some embodiments, b3is 1; b4is 0; in some embodiments, b3is 0; b4is 1.

[0268] In some embodiments, b5is 1, 2, or 3; in some embodiments, b5is 1 or 2; in some embodiments, b5is 1.

[0269] In some embodiments, B 3 is C and is attached to L, B 1 , B 2 , B 4 , and B 5 are the same or different and are each independently N or CR 2 ; R 2 is as defined above and below.

[0270] In some embodiments, B 1 is CR 2 ; R 2 is as defined above and below.

[0271] In some embodiments, B 2 is CR 2 ; R 2 is as defined above and below.

[0272] In some embodiments, B 3 is CR 2 ; R 2 is as defined above and below.

[0273] In some embodiments, B 4 is CR 2 ; R 2 is as defined above and below.

[0274] In some embodiments, B 5 is CR 2 ; R 2 is as defined above and below.

[0275] In some implementation schemes, B 1 For CR 2 B 2 For CR 2 B 4 For CR 2 B 5 For CR 2 ;R 2 As defined in the context.

[0276] In some implementation schemes, B 6 For CH; in some implementations, B 6 Let N be the number of elements in the array.

[0277] In some implementation schemes, B 7 For CH; in some implementations, B 7 Let N be the number of elements in the array.

[0278] In some implementation schemes, B 6 For CH; B 7 For CH; in some implementations, B 6 For CH; B 7 For N; in some implementations, B 6 For N; B 7 For CH.

[0279] 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.

[0280] In some implementations, ring X is It can be a single bond or a double bond; in some implementations, ring X is selected from... In the above implementation scheme, * terminal and L x Connected, With ring W or R w2 The rings they belong to are connected.

[0281] In some implementation schemes, X 2 For CH; in some implementations, X 2 Let N be the number of elements in the array.

[0282] In some implementation schemes, R w6 It is a hydrogen atom or an alkyl group; in some embodiments, R w6 It is a hydrogen atom.

[0283] In some implementations, L 1 For key.

[0284] In some implementation schemes, Y 1 and Y2 The ring is a 5-membered heteroaryl group; in some implementation schemes, Y 1 and Y 2 The ring is selected from pyrrole, furanyl, imidazolyl, thiophene, oxazolyl, isoxazolyl, thiazolyl, and pyrazolyl; in some embodiments, Y 1 and Y 2 The ring it belongs to is pyrrole.

[0285] In some implementation schemes, Y 2 Selected from S, N, O, CH and NH; in some embodiments, Y 2 Selected from S, O, and NH; in some embodiments, Y 2 It is NH or O; in some implementations, Y 2 It is NH.

[0286] In some implementation schemes, Y 3 Let N be the number of elements in the array.

[0287] 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 heterocycles; 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; in some implementations, Y 1 It can be N or CH.

[0288] In some implementation schemes, Each independently selected 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 Or C(O) connected.

[0289] In some implementation schemes, R 1 They may be the same or different, and each is independently selected from halogens, C 1-6 Alkyl, C1- 6alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy and =0; in some embodiments, R 1 are the same or different and each is independently selected from halogen, C 1-6 alkyl, C 1-6 alkoxy and =0; in some embodiments, R 1 are the same or different and each is independently C 1-6 alkyl or =0.

[0290] In some embodiments, Z 1 is N or CH; in some embodiments, Z 1 is N.

[0291] In some embodiments, Z 2 is N or CH; in some embodiments, Z 2 is N.

[0292] In some embodiments, f is 0, 1 or 2; in some embodiments, f is 0 or 1.

[0293] In some embodiments, g is 0, 1 or 2; in some embodiments, g is 0 or 1.

[0294] In some embodiments, f is 1; g is 1; in some embodiments, f is 0; g is 0; in some embodiments, f is 1; g is 0.

[0295] In some embodiments, k is 0, 1 or 2; in some embodiments, k is 0.

[0296] In some embodiments, R z is selected from a hydrogen atom, halogen, C 1-6 alkyl and =0; in some embodiments, R z is a hydrogen atom.

[0297] In some embodiments, t is 0, 1, 2 or 3; in some embodiments, t is 0, 1 or 2; in some embodiments, t is 1, 2 or 3; in some embodiments, t is 2 or 3; in some embodiments, t is 2.

[0298] In some embodiments, M is selected from O, S, NR m C(O) and C(O)NR m ; R m is a hydrogen atom or C 1-6 alkyl; in some embodiments, M is selected from O, NR m C(O) and C(O)NR m ; R mis a hydrogen atom or a methyl group; in some embodiments, M is selected from O, N(methyl)C(O), and C(O)N(methyl); in some embodiments, M is O or CH2; in some embodiments, M is O; in some embodiments, M is S; in some embodiments, M is N(methyl)C(O).

[0299] In some embodiments, M 1 is (CR m1 R m2 ) m1 ; in some embodiments, M 1 is selected from a bond, CH2, CH2CH2, and CH2CH2CH2; in some embodiments, M 1 is a bond or CH2; in some embodiments, M 1 is a bond; in some embodiments, M 1 is CH2.

[0300] In some embodiments, M 2 is (CR m1 R m2 ) m2 ; in some embodiments, M 2 is selected from a bond, CH2, CH2CH2, and CH2CH2CH2; in some embodiments, M 2 is a bond or CH2; in some embodiments, M 2 is a bond; in some embodiments, M 2 is CH2.

[0301] In some embodiments, R m is a hydrogen atom or a C 1-6 alkyl group; in some embodiments, R m is a hydrogen atom or a methyl group; in some embodiments, R m is a methyl group.

[0302] In some embodiments, R m1 and R m2 are each independently selected from a hydrogen atom, a C 1-6 alkyl group, a C 1-6 haloalkyl group, and a C 1-6 hydroxyalkyl group; or, R m1 and R m2 together with the attached atoms form a 3- to 8-membered cycloalkyl group (e.g., cyclopropyl, cyclobutyl); in some embodiments, R m1 and R m2 are each independently a hydrogen atom or a C 1-6 alkyl group; or, R m1 and R m2 together with the attached atoms form a 3- to 8-membered cyclo alkyl group (e.g., cyclopropyl, cyclobutyl).together with the carbon atom to which they are attached form a cyclopropyl group; in some embodiments, R m1 and R m2 are hydrogen atoms.

[0303] In some embodiments, M 1 is (CR m1 R m2 ) m1 ; M 2 is (CR m1 R m2 ) m2 ; R m1 and R m2 are each independently a hydrogen atom or a C 1-6 alkyl group; or, R m1 and R m2 on the same carbon atom, together with the carbon atom to which they are attached, form a cyclopropyl group; m1 is 0, 1, 2, or 3; m2 is 0 or 1.

[0304] In some embodiments, R m1 and R m2 are hydrogen atoms; or, R m1 and R m2 on the same carbon atom, together with the carbon atom to which they are attached, form a cyclopropyl group; or, R m1 and R m2 are C 1-6 alkyl groups.

[0305] In some embodiments, R m1 and R m2 are hydrogen atoms; or, R m1 and R m2 on the same carbon atom, together with the carbon atom to which they are attached, form a cyclopropyl group; or, R m1 and R m2 are methyl groups.

[0306] In some embodiments, M is O; M 1 is CH2; M 2 is CH2.

[0307] In some embodiments, m1 is 0, 1, 2, or 3; in some embodiments, m1 is 0, 1, or 2; in some embodiments, m1 is 0 or 1; in some embodiments, m1 is 0; in some embodiments, m1 is 1; in some embodiments, m1 is 2; in some embodiments, m1 is 3.

[0308] In some embodiments, m2 is 0 or 1; in some embodiments, m2 is 0; in some embodiments, m2 is 1.

[0309] In some implementations, m1 is 0, 1, 2, or 3; m2 is 0 or 1; in some implementations, m1 is 1; m2 is 0; in some implementations, m1 is 2; m2 is 0; in some implementations, m1 is 3; m2 is 0; in some implementations, m1 is 0; m2 is 0; in some implementations, m1 is 2; m2 is 1; in some implementations, m1 is 0; m2 is 1; in some implementations, m1 is 1; m2 is 1.

[0310] In some implementation schemes, 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, a 3- to 8-membered heterocyclic group is formed, wherein the 3- to 8-membered heterocyclic group is optionally bonded by one or more elements selected from halogens, C, and N. 1-6 Alkyl, C 1-6 Halogenated alkyl groups and C 1-6 The alkoxy group is substituted; in some embodiments, 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; 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 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 C 1-6 Alkyl; in some embodiments, R 4 and R 5 It is a methyl group.

[0311] In some implementation schemes, V 1 The answer is C.

[0312] In some implementations, T stands for C.

[0313] 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.

[0314] In some implementation schemes, R w1 Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl groups and C 1-6 Haloalkoxy; in some embodiments, R w1 Selected from hydrogen atoms, halogens and C 1-6 Alkyl; in some embodiments, R w1 For halogen; in some implementations, R w1 It is F.

[0315] In some implementations, n is 0, 1, or 2; in some implementations, n is 1; in some implementations, n is 1 or 2.

[0316] In some implementations, n1 is 0, 1, or 2; in some implementations, n1 is 1; in some implementations, n1 is 1 or 2.

[0317] In some implementations, n2 is 0, 1, or 2; in some implementations, n2 is 0 or 1; in some implementations, n2 is 0; and in some implementations, n2 is 1.

[0318] In some implementations, n3 is 0, 1, or 2; in some implementations, n3 is 0 or 1; in some implementations, n3 is 0.

[0319] In some implementations, n4 is 0, 1, or 2; in some implementations, n4 is 0 or 1; in some implementations, n4 is 0.

[0320] In some implementations, n5 is 0 or 1; in other implementations, n5 is 0.

[0321] In some implementations, n6 is 0 or 1; in other implementations, n6 is 0.

[0322] In some implementation schemes, R2 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 and oxo groups; 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, C 1-6 Alkoxy, C 1-6 Halogenated alkyl groups 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 Each is independently selected from hydrogen atom, F, Cl, methoxy group, -OCHF2 and oxo group; in some embodiments, R 2 Each is independently selected from hydrogen, F, Cl, and methoxy groups; in some embodiments, R 2 Each is independently a hydrogen atom or a halogen; in some implementations, R 2 Each can be independently a hydrogen atom or an F atom.

[0323] 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 6- to 8-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; in some implementations, R w2 For hydrogen atoms, or, R w2 and R 2 Together with their respective connected atoms, they form a 7-membered heterocyclic group.

[0324] In some implementation schemes, R w2 Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl groups and C 1-6 Haloalkoxy; in some embodiments, R w2Selected from hydrogen atoms, halogens and C 1-6 Alkyl; in some embodiments, R w2 It is a hydrogen atom.

[0325] 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 groups and C 1-6 Haloalkoxy; in some embodiments, R x It is a hydrogen atom.

[0326] In some implementations, x is 0 or 1; in other implementations, x is 0.

[0327] 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 are the same or different, and each is independently selected from C(O), C 1-6 Alkylene and 3- to 6-membered cycloalkyl; 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; in some embodiments, L x -(L A ) t1 -;L A They are the same or different, and each is independently C(O) or C. 1-6 Alkylene; t1 is 0, 1, 2 or 3.

[0328] In some implementations, L x Selected from * The terminal is connected to G or ring Y.

[0329] In some implementations, L x Selected from In some implementations, L x Selected from In some implementations, L x Selected from In some implementations, L x Selected from In some implementations, L x Selected from In some implementations, L x for In the above implementation scheme, the * terminal is connected to G or ring Y.

[0330] 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.

[0331] In some embodiments, ring Y is a 5- to 10-membered heteroaryl group; in some embodiments, ring Y is a 5- or 6-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, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, pyrroleyl, thiopheneyl, and furanyl; in some embodiments, ring Y is selected from pyrazolyl, triazolyl, pyridinyl, pyrimidinyl, pyridoneyl, imidazolyl, thiazolyl, oxazolyl, pyrroleyl, thiopheneyl, isoxazolyl, and furanyl; in some embodiments, ring Y is pyrazolyl or triazolyl; in some embodiments, ring Y is selected from... In some implementation schemes, ring Y is selected from In some implementation schemes, ring Y is selected from In some implementation schemes, ring Y is selected from In some implementation schemes, ring Y is In some implementation schemes, ring Y is In the above implementation plan, With L x Connected.

[0332] 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 1-6Alkoxy, 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 Halogenated alkyl groups and 3- to 6-membered cycloalkyl groups (e.g., cyclopropyl); 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 groups 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 They may be the same or different, and each is independently selected from hydrogen, F, Cl, methyl, difluoromethyl, and cyclopropyl; in some embodiments, R y They may be the same or different, and each is independently selected from hydrogen atoms, F, and methyl; in some embodiments, R y They may be the same or different, and each is independently a hydrogen atom or a halogen; in some embodiments, R y They may be the same or different, and each is independently a hydrogen atom or F; in some implementations, R y It is a hydrogen atom.

[0333] In some implementations, y is 0 or 1; in some implementations, y is 1; in some implementations, y is 0.

[0334] In some implementations, G is H or Ring Y, R y And y as defined in the context; in some implementations, G is H or The ring Y is a 5- to 10-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, C 1-6 Halogenated alkyl and 3- to 6-membered cycloalkyl; y is 0 or 1; in some embodiments, 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; in some embodiments, G is a hydrogen atom; in some embodiments, G is selected from hydrogen atoms, In some implementations, G is selected from hydrogen atoms, In some implementations, G is

[0335] In some implementations, G or Each independently selected In some implementations, G or Each independently selected

[0336] In some implementations, G or Each independently selected

[0337] In some implementations, G or Each independently selected In some implementations, G or Each independently selected In some implementations, G or Each independently In some implementations, G or Each independently In some implementations, G or Each independently

[0338] In some implementation schemes, for In some implementation schemes, In some implementation schemes,

[0339] In some implementation schemes, R a It is a hydrogen atom.

[0340] 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.

[0341] In some implementation schemes, R 3 It is a hydrogen atom or a carbon atom. 1-6 alkyl.

[0342] In some implementation schemes, R 6 It is a hydrogen atom.

[0343] 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.

[0344] In some implementation schemes, R 7 Selected from hydrogen atoms, C 1-6 Alkyl, hydroxyl and C 1-6 Alkyl group. In some embodiments, R 0 Same or different, and each independently selected from =O, halogen, C 1-6 Alkyl, C 1- 6-Hydroalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated 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; in some embodiments, R 0 C 1-6 Alkyl; in some embodiments, R 0 It is a methyl group.

[0345] In some embodiments, the compound represented by general formula (IV-2) 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; 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; It can be a single or double bond; R x For hydrogen atoms; 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 2 Selected from S, O 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 3 to 8-membered heterocyclic groups; R 2 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6Alkyl and C 1-6 Alkyl group; n1 is 0, 1, or 2; t is 0, 1, 2, or 3; ring A is selected from... *Terminal and (CH2) t Connected.

[0346] In some embodiments, the compound represented by general formula (IV-2) or a pharmaceutically acceptable salt thereof, wherein the ring Y is L x Selected from It can be a single or double bond; R x Y is a hydrogen atom; 2 For NH or O; R 4 and R 5 C 1-6 Alkyl; R w1 It is a halogen; R w2 For hydrogen atoms; 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 group; n1 is 0, 1, or 2; t is 2 or 3; ring A is *Terminal and (CH2) t Connected.

[0347] In some embodiments, the compound represented by general formula (V-1) or a pharmaceutically acceptable salt thereof, wherein, Where G is L x for *The terminal is connected to G; It can be a single or double bond; R x For hydrogen atoms; V 2 For N or CR w1 ;R w1 It is a halogen; R w2 Y is a hydrogen atom; 1 For N or CH; Y 2 For NH or O; 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 nitrogen atom attached thereto, they form 3 to 8-membered heterocyclic groups; Selected from * Connect to L; 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 group; n1 is 0, 1, or 2; n3 is 0, 1, or 2; b1 and b2 are each independently 0 or 1; b3 and b4 are each independently 0 or 1; b5 is 1 or 2; B 6 and B 7 Each is independently N or CH; L is -(L B ) t2 -;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- The alkyl group is substituted with one or more of the 6-haloalkyl groups and the =O group; t2 is 0, 1, 2, 3, 4, 5, or 6; ring A is selected from... * Connect to L; X 2 It can be N or CH.

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

[0349] The ring Y is a 5- to 10-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, C 1-6 Halogenated alkyl groups and 3- to 6-membered cycloalkyl groups; 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; R x For hydrogen atoms; x is 0 or 1; It is a double bond; R w1 It is a halogen; R w2 For hydrogen atoms; R 4 and R 5 Whether the atoms are the same or different, and each is independently selected from hydrogen atoms, C atoms 1-6Alkyl 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; Y 2 For NH;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 group; n1 is 0, 1, or 2; 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- The alkyl group is substituted with one or more substituents in the 6-haloalkyl group and the =O group; t2 is 0, 1, 2, 3, 4, 5 or 6; ring A is * Connect to L; X 2 For CH.

[0350] In some embodiments, the compound represented by general formula (VII) or a pharmaceutically acceptable salt thereof, wherein,

[0351] The ring Y is a 5- to 10-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, C 1-6 Halogenated alkyl groups and 3- to 6-membered cycloalkyl groups; 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; R x For hydrogen atoms; x is 0 or 1; It is a double bond; R w1 It is a halogen; 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; Y 2 NH; M is selected from O, S, NR m C(O) and C(O)NRm ;R m It is a hydrogen atom or a carbon atom. 1-6 Alkyl; R m1 and R m2 Each is independently 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 adjacent carbon atom, they form a cyclopropyl group; m1 is 0, 1, 2, or 3; m2 is 0 or 1; 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 group; n2 is 0, 1 or 2; 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 by one or more substituents; t2 is 0, 1, 2, 3, 4, 5, or 6; ring A is * Connect to L; X 2 For CH.

[0352] In some embodiments, the compound represented by general formula (XI), general formula (XI-1), or general formula (XI-2), or a pharmaceutically acceptable salt thereof, wherein,

[0353] The ring Y is a 5- to 10-membered heteroaryl group; R y Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and 3- to 6-membered cycloalkyl groups; 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; R x For hydrogen atoms; x is 0 or 1; R w1 It is a halogen; R w2 For hydrogen atoms; 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, C1-6 Halogenated alkyl groups and C 1-6 Haloalkoxy; n1 is 0, 1, or 2; or, R w2 and R 2 Together with their respective connected atoms, they form 6- to 8-membered heterocyclic groups; 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, a 3- to 8-membered heterocyclic group is formed, wherein the 3- to 8-membered heterocyclic group is optionally bonded by one or more elements selected from halogens, C, and N. 1-6 Alkyl, C 1-6 Halogenated alkyl groups and C 1-6 The alkoxy group is substituted; 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 by one or more substituents; t2 is 0, 1, 2, 3, 4, 5 or 6; R A1 C 1-6 Alkyl; R 1x It represents a hydrogen atom; a4 represents 0, 1, or 2.

[0354] In some embodiments, the compound represented by general formula (XI), general formula (XI-1), or general formula (XI-2), or a pharmaceutically acceptable salt thereof, wherein,

[0355] The ring Y is a 5- to 10-membered heteroaryl group; R y Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and 3- to 6-membered cycloalkyl groups; 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; R x For hydrogen atoms; x is 0 or 1; R w1 It is a halogen; R w2 For hydrogen atoms; R 4and 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; 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 group; n1 is 0, 1, or 2; 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 by one or more substituents; t2 is 0, 1, 2, 3, 4, 5 or 6; R A1 C 1-6 Alkyl; R 1x It represents a hydrogen atom; a4 represents 0, 1, or 2.

[0356] In some embodiments, the compound represented by general formula (XII), general formula (XII-1) or general formula (XII-2), or a pharmaceutically acceptable salt thereof, wherein,

[0357] The ring Y is a 5- to 10-membered heteroaryl group; R y Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and 3- to 6-membered cycloalkyl groups; 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; R x For hydrogen atoms; x is 0 or 1; R w1 It is a halogen; 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; R 2They 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; n2 is 0, 1, or 2; 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; R m1 and R m2 Each is independently 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 adjacent carbon atom, they form a cyclopropyl group; m1 is 0, 1, 2, or 3; m2 is 0 or 1; b8 and b9 are each independently 0 or 1; R A1 C 1-6 Alkyl; R 1x It represents a hydrogen atom; a4 represents 0, 1, or 2.

[0358] This disclosure also relates to the following specific implementation plans:

[0359] 1. A compound of general formula (I) or a pharmaceutically acceptable salt thereof,

[0360] in:

[0361] Ring A is arbitrarily controlled by one or more R 1 The replacement of the four rings;

[0362] R 1 The same or different, and each independently selected from 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;

[0363] 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;

[0364] 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);

[0365] R a Selected from hydrogen atoms, alkyl groups, haloalkyl groups, cycloalkyl groups, and cycloalkylalkyl groups;

[0366] X 2 For N or CH;

[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 Selected from O, S, N, NR w3 CR w4 and CR w4 Rw5 ;

[0372] Y 2 Selected from O, S, N, NR w6 CR w7 and CR w7 R w8 ;

[0373] Cycloyl X is selected from cycloalkyl, heterocyclic, aryl, and heteroaryl groups;

[0374] Ring B is selected from cycloalkyl, heterocyclic, aryl, and heteroaryl groups;

[0375] G is selected from hydrogen atom, halogen and

[0376] Cycloyl Y is selected from cycloalkyl, heterocyclic, aryl, and heteroaryl groups;

[0377] R w0 R w1 R w2 R w4 R w5 R w7 R w8 R x R y and R 2 The same or different, and each independently selected from hydrogen atom, halogen, alkyl, alkenyl, alkoxy, haloalkyl, hydroxyalkyl, haloalkoxy, alkoxyalkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, cyano, nitro, hydroxyl, amino, -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 NR4 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;

[0378] R w3 and R w6 The same or different, and each independently selected from hydrogen atoms, alkyl, alkenyl, ynyl, haloalkyl, 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;

[0379] Or, R w2 and R 2 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;

[0380] Or, R w3 and R 2 Together with their respective connected atoms, they form a heterocyclic group, which is optionally influenced by one or more R atoms. 0 replace;

[0381] Or, R w4 and R 2 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;

[0382] Or, R w6 and R 2 Together with their respective connected atoms, they form a heterocyclic group, which is optionally influenced by one or more R atoms. 0 replace;

[0383] Or, R w7 and R 2 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;

[0384] 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;

[0385] 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;

[0386] 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;

[0387] x, y, and n are each independently 0, 1, 2, 3, 4, 5, 6, or 7;

[0388] L x -(L A ) t1 -;

[0389] L is -(L) B ) t2 -;

[0390] 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;

[0391] R b Selected from hydrogen atoms, alkyl groups, haloalkyl groups, cycloalkyl groups, and cycloalkylalkyl groups;

[0392] t1 is selected from integers from 0 to 10;

[0393] t2 is selected from integers from 0 to 20;

[0394] 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 5Together 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;

[0395] R 6 Selected from hydrogen atoms, alkyl groups, haloalkyl groups, hydroxyalkyl groups, and cycloalkyl groups;

[0396] R 7 Selected from hydrogen atoms, alkyl groups, haloalkyl groups, hydroxyl groups, alkoxy groups, haloalkoxy groups, and cycloalkyl groups;

[0397] 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;

[0398] 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, hydroxy, 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

[0399] v can be 0, 1, or 2.

[0400] 2. The compound of general formula (I) according to embodiment 1, or a pharmaceutically acceptable salt thereof, is a compound of general formula (II-2) or a pharmaceutically acceptable salt thereof.

[0401] in,

[0402] B 1 B 2 B 4 and B 5 Whether they are the same or different, and each is independently N or CR 2 ;and

[0403] G, L x , ring X, R x x, R w0 R w2Y 1 Y 2 V 1 V 2 T R 2 L, ring A and X 2 As defined in Implementation Scheme 1.

[0404] 3. 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 (III-1), general formula (III-2), general formula (III-3), general formula (III-4) or general formula (III-5) or a pharmaceutically acceptable salt thereof.

[0405] in,

[0406] B 1 B 2 B 4 and B 5 Whether they are the same or different, and each is independently N or CR 2 ;

[0407] It can be a single bond or a double bond;

[0408] Y 1 Selected from O, S and NH;

[0409] Y 2 Selected from O, S and NH;

[0410] Y 3 For N or CH;

[0411] M is selected from the bond, (CR) m1 R m2 ) m O, S, S(O), S(O)2, NR m C(O), C(O)NR m and NR m C(O);

[0412] M 1 For key or (CR) m1 R m2 ) m1 ;

[0413] M 2 For key or (CR) m1 R m2 ) m2 ;

[0414] m can be 0, 1, 2, 3, or 4;

[0415] m1 can be 0, 1, 2, 3 or 4;

[0416] m2 can be 0, 1, 2, 3 or 4;

[0417] R m Selected from hydrogen atoms, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, and cycloalkylalkyl;

[0418] 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, nitro, hydroxyl, 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

[0419] G, L x R x x, R w0 V 2 R w2 R 2 L, ring A and X 2 As defined in Implementation Scheme 1.

[0420] 4. A compound of general formula (I) according to any one of embodiments 1 to 3, wherein the compound is a compound of general formula (VI) or a pharmaceutically acceptable salt thereof.

[0421] in,

[0422] Y 2 Selected from O, S and NR w6 ;

[0423] n1 is 0, 1, 2, 3 or 4;

[0424] It can be a single or double bond; and

[0425] Ring Y, R y y, L x R x x, Rw1 R w2 R w6 R 4 R 5 R 2 L, ring A and X 2 As defined in Implementation Scheme 1.

[0426] 5. A compound of general formula (I) according to any one of embodiments 1 to 4, wherein the compound is a compound of general formula (VII) or a pharmaceutically acceptable salt thereof.

[0427] in,

[0428] Y 2 Selected from O, S and NR w6 ;

[0429] n2 is 0, 1, 2 or 3;

[0430] It can be a single bond or a double bond;

[0431] m1 can be 0, 1, 2, 3 or 4;

[0432] m2 can be 0, 1, 2, 3 or 4;

[0433] M is as defined in Implementation Scheme 3; and

[0434] Ring Y, R y y, L x R x x, R w1 R w6 R 4 R 5 R 2 L, ring A and X 2 As defined in Implementation Scheme 1.

[0435] 6. A compound of general formula (I) according to any one of embodiments 1 to 5, or a pharmaceutically acceptable salt thereof, wherein ring A is selected from...

[0436] *The end is connected to L; ring C is selected from phenyl, 5- or 6-membered heterocyclic and 5- or 6-membered heteroaryl; ring E is 5- to 10-membered cycloalkyl or 5- to 10-membered heterocyclic, and ring C and ring E are each independently optionally separated by one or more R 1 Replace, R 1 As defined in Implementation Scheme 1; a1 and a2 are each independently 0, 1, 2, 3 or 4; A1 is N or CR a1 A2 is N or CRa2 A3 is N or CR a3 A4 represents N or CR a4 A5 represents N or CR. a5 A6 is N or CR a6 A7 is N or C; A8 is N or C; R a1 and R a2 Each is independently selected from hydrogen atoms, halogens, alkyl groups, haloalkyl groups, cyano groups, hydroxyl groups, and hydroxyalkyl groups; R a3 R a4 R a5 and R a6 The same or different, and each independently selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy, alkoxyalkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, cyano, hydroxyl, amino, and nitro; a3 is 0, 1, 2, 3, or 4; R 1x 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)(R3 )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; or, two Rs 1x 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; and v, R 0 R 3 -R 9 As defined in Implementation Scheme 1.

[0437] 7. A compound of general formula (I) according to any one of embodiments 1 to 6, or a pharmaceutically acceptable salt thereof, wherein ring A is selected from... * The terminal is connected to L; where Q is selected from O, S, and NR. q and CR q1 R q2 a1 and a2 are each independently 0, 1, 2, 3, or 4; A1 is N or CR. a1 A2 is N or CR a2 A3 is N or CR a3 A4 represents N or CR a4 A5 represents N or CR. a5 A6 is N or CR a6 J is selected from bond, O, (CR) j1 R j2 ) u S, S(O), S(O)2, NR J C(O), C(O)NR J and NR J C(O); J 1 Selected from bond, O, (CR) j1 R j2 ) p S, S(O), S(O)2, NR J C(O), C(O)NR J and NR J C(O); J 2 Selected from bond, O, (CR) j1 R j2 ) q S, S(O), S(O)2, NR J C(O), C(O)NR J and NR JC(O); J 3 Selected from O, S, S(O), S(O)2, NR J C(O), C(O)NR J NR J C(O), (CR) j1 R j2 ) k1 and (CR) j1 R j2 ) k3 W J (CR j1 R j2 ) k4 ;

[0438] J 4 Selected from O, S, S(O), S(O)2, NR J C(O), C(O)NR J NR J C(O), (CR) j1 R j2 ) k2 and (CR) j1 R j2 ) k5 W J (CR j1 R j2 ) k6 ;

[0439] W J Selected from O, S, S(O), S(O)2, NR J C(O), C(O)NR J and NR J C(O);

[0440] k1 and k2 are each independently 1, 2, 3 or 4;

[0441] k3, k4, k5, and k6 are each independently 0, 1, 2, or 3;

[0442] u, p, and q are each independently 0, 1, 2, 3, or 4; R a1 and R a2 Each is independently selected from hydrogen atoms, halogens, alkyl groups, haloalkyl groups, cyano groups, hydroxyl groups, and hydroxyalkyl groups; R q R J and R A1 Each is independently selected from hydrogen atoms, alkyl groups, haloalkyl groups, hydroxyalkyl groups, cycloalkyl groups, heterocyclic groups, and cycloalkylalkyl groups; R q1 R q2 R j1 R j2 R a3 R a4R a5 R a6 and R A 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; or, R j1 and R j2 Together with the adjacent atoms, they form a cycloalkyl or heterocyclic group; a3 is 0, 1, 2, 3, or 4; R 1x 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; or, two Rs 1x 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; and v, R 0 and R 3 -R 9 As defined in Implementation Scheme 1;

[0443] For example, ring A is selected from the following structures: * The end is connected to L; for example, ring A is * The terminal is connected to L.

[0444] 8. A compound of general formula (I) according to any one of embodiments 1 to 7, 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 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 by one or more substituents; and t2 is 0, 1, 2, 3, 4, 5, or 6; for example, L is selected from the bond, CH2, CH2CH2, CH2CH2CH2, * The end is connected to ring A.

[0445] 9. A compound of general formula (I) according to any one of embodiments 1 to 3, 6 to 8, or a pharmaceutically acceptable salt thereof, wherein R w0 -C(O)NR 4 R 5 ;R 4 and R 5As defined in Implementation Scheme 1; for example, R w0 Selected from

[0446] 10. The compound of general formula (I) according to any one of embodiments 1 to 3, 6 to 9, or a pharmaceutically acceptable salt thereof, wherein V 2 For N or CR w1 ;R w1 Selected from hydrogen atoms, halogens and C 1-6 Alkyl; for example, V 2 For CF.

[0447] 11. The compound of general formula (I) according to any one of embodiments 1 to 4, 6 to 10, or a pharmaceutically acceptable salt thereof, wherein 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; for example, R w2 For hydrogen atoms, or, R w2 and R 2 Together with their respective connected atoms, they form 6 to 8-membered heterocyclic groups.

[0448] 12. A compound of general formula (I) according to any one of embodiments 1 to 11, 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, C 1-6 Alkoxy, C 1-6 Halogenated alkyl groups and C 1-6 Halogenated alkoxy groups; for example, R 2 Each can be a hydrogen atom or a halogen.

[0449] 13. The compound of general formula (I) according to any one of embodiments 1 to 12, 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), 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; for example, L x Selected from * The terminal is connected to G or ring Y.

[0450] 14. The compound of general formula (I) according to any one of embodiments 1 to 3, 6 to 13, or a pharmaceutically acceptable salt thereof, wherein G is H or The ring Y is a 5- to 10-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, C 1-6 Haloalkyl and 3- to 6-membered cycloalkyl; y is 0 or 1; for example, G is selected from hydrogen atoms,

[0451] 15. A compound of general formula (I) according to any one of embodiments 3 to 14, or a pharmaceutically acceptable salt thereof, wherein 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; and / or M 1 For (CR) m1 R m2 ) m1 M 2 For (CR) m1 R m2 ) m2 ;R m1 and R m2 Each is independently 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 adjacent carbon atom, they form a cyclopropyl group; m1 is 0, 1, 2, or 3; and m2 is 0 or 1;

[0452] For example, M is O; and / or M 1 CH2; and / or M 2 It is CH2.

[0453] Table A lists typical compounds disclosed herein, including but not limited to:

[0454] In another aspect, this disclosure provides a compound of general formula (X) or a salt thereof.

[0455] in,

[0456] R L1 and R L2 Each is independently protected by a hydrogen atom or an amino group;

[0457] Ring A is as defined above, and the * end is connected to R. L2 Connected.

[0458] In some implementation schemes, R L1 For hydrogen atoms; R L2 It is an amino protecting group; in some embodiments, R L1 For hydrogen atoms; R L2 For Boc; in some implementations, R L1 For hydrogen atoms; R L2 For hydrogen atoms; in some implementations, R L1 It is an amino protecting group; R L2 It is an amino protecting group; in some embodiments, R L1 For PBM; R L2 For Boc. In some implementations, R L2 For hydrogen atoms; in some implementations, R L2 For Boc.

[0459] This disclosure, in another aspect, provides a compound of general formula (VIB) or a salt thereof.

[0460] in,

[0461] R L It is a leaving group;

[0462] R 2 n1, L, ring A and X 2 As defined in general formula (VI).

[0463] This disclosure, in another aspect, provides a compound or a salt thereof represented by general formula (XIB), general formula (XI-1B) or general formula (XI-2B).

[0464] in,

[0465] R LIt is a leaving group;

[0466] R 2 n1, L, R 1x a4 and R A1 As defined in general formula (XI), general formula (XI-1), or general formula (XI-2). In another aspect, this disclosure provides a compound or a salt thereof represented by general formula (XIIA).

[0467] in,

[0468] Ring Y, R y y, L x R x x, R w1 R 4 R 5 R 2 n2, M, m1, m2, R m1 R m2 b8 and b9 are as defined in general formula (XII).

[0469] Table B discloses intermediate compounds including, but not limited to:

[0470] Another aspect of this disclosure relates to a method for preparing a compound of general formula (VI) or a pharmaceutically acceptable salt thereof, comprising:

[0471] A compound of general formula (VIA) or a salt thereof undergoes a coupling reaction with a compound of general formula (VIB) or a salt thereof to obtain a compound of general formula (VI) or a pharmaceutically usable salt thereof;

[0472] in:

[0473] R P for Or -B(OH)2;

[0474] R L It is a leaving group;

[0475] Ring Y, R y y, L x R x x Rw1 R w2 Y 2 R 4 R 5 R 2 n1, L, ring A and X 2 As defined in general formula (VI).

[0476] Another aspect of this disclosure relates to a method for preparing compounds of general formula (XI), general formula (XI-1), general formula (XI-2) or pharmaceutically acceptable salts thereof, comprising:

[0477] The compound represented by general formula (XIA) or its salt undergoes a coupling reaction with the compound represented by general formula (XIB) or its salt to obtain the compound represented by general formula (XI) or its pharmaceutically usable salt.

[0478] The compound represented by general formula (XIA) or its salt undergoes a coupling reaction with the compound represented by general formula (XI-1B) or its salt to give the compound represented by general formula (XI-1) or its pharmaceutically usable salt.

[0479] The compound represented by general formula (XIA) or its salt undergoes a coupling reaction with the compound represented by general formula (XI-2B) or its salt to give the compound represented by general formula (XI-2) or its pharmaceutically usable salt.

[0480] in:

[0481] R P for Or -B(OH)2;

[0482] R L It is a leaving group;

[0483] Ring Y, R y y, L x R x x, R w1 R w2 R 4 R 5 R 2 n1, L, R 1x a4 and R A1 As defined in general formula (XI), general formula (XI-1) or general formula (XI-2).

[0484] Another aspect of this disclosure relates to a method for preparing compounds of general formula (XII), general formula (XII-1), general formula (XII-2), or pharmaceutically acceptable salts thereof, comprising:

[0485] The compound represented by general formula (XIIA) or its salt undergoes a reductive amination reaction with the compound represented by general formula (XIIB) or its salt to give the compound represented by general formula (XII) or its pharmaceutically usable salt.

[0486] The compound represented by general formula (XIIA) or its salt undergoes a reductive amination reaction with the compound represented by general formula (XII-1B) or its salt to give the compound represented by general formula (XII-1) or its pharmaceutically usable salt.

[0487] The compound represented by general formula (XIIA) or its salt undergoes a reductive amination reaction with the compound represented by general formula (XII-2B) or its salt to give the compound represented by general formula (XII-2) or its pharmaceutically usable salt.

[0488] in:

[0489] R L2 It is a hydrogen atom;

[0490] Ring Y, R y y, L x R x x, R w1 R 4 R 5 M, m1, m2, R m1 R m2 R 2 n2, b8, b9, R 1x a4 and R A1 As defined in general formula (XII), general formula (XII-1) or general formula (XII-2).

[0491] In some implementation schemes, R L For halogen; in some implementations, R L For I or Br; in some implementations, R L It is Br.

[0492] In some implementation schemes, R P for

[0493] In some embodiments, the coupling reaction is carried out under alkaline conditions and with the aid of a metal catalyst; the metal catalyst includes, but is not limited to, methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II); the reagent providing the alkaline conditions includes organic and inorganic bases, the organic bases including, but not limited to, triethylamine, N,N-diisopropylethylamine, n-butyllithium, diisopropylaminolithium, potassium acetate, sodium tert-butoxide, potassium tert-butoxide, tetrabutylammonium fluoride, tetrahydrofuran solution of tetrabutylammonium fluoride, or 1,8-diazabicycloundec-7-ene; the inorganic bases include, but are not limited to, sodium hydride, potassium phosphate, sodium carbonate, sodium acetate, potassium acetate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, cesium fluoride, and potassium hydroxide; in some embodiments, the reagent providing the alkaline conditions is potassium phosphate.

[0494] In some embodiments, the reductive amination reaction is carried out 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.

[0495] 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 cyanoborohydride or sodium triacetoxyborohydride.

[0496] In some embodiments, the coupling reaction or reductive amination reaction 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.

[0497] Another aspect of this disclosure relates to a pharmaceutical composition comprising the general formulas (M), (I), (I-1), (II-1), (II-2), (II-3), (II-4), (III-1), (III-2), (III-3), (III-4), (III-5), (IV-1), (IV-2), (IV-3), and (IV-4) described above. Compounds of formulas (IV-5), (IV-6), (IV-7), (IV-8), (V-1), (V-2), (VI), (VII), (VIII), (XI), (XI-1), (XI-2), (XII), (XII-1), (XII-2) or those shown in Table A, or pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

[0498] 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), (III-5), (IV-1), (IV-2), (IV-3), (IV-4), (IV-5), (IV-6), (IV-7), (IV-8), (V-1), (V-2), (VI), (VII), (VIII), (XI), (XI-1), (XI-2), (XII), (XII-1), (XII-2), or those shown in Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising them, in the preparation of a medicament for inhibiting or degrading STAT6.

[0499] 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), (III-5), (IV-1), (IV-2), (IV-3), (IV-4), (IV-5), and (IV-6). Use of compounds of formulas (IV-7), (IV-8), (V-1), (V-2), (VI), (VII), (VIII), (XI), (XI-1), (XI-2), (XII), (XII-1), (XII-2) or those shown in Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising thereof, in the preparation of a medicament for regulating the ubiquitination and degradation of STAT6 protein in a subject.

[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), (III-5), (IV-1), (IV-2), (IV-3), (IV-4), (IV-5), (IV-6), and (IV-5). Use of compounds of formulas IV-7, IV-8, V-1, V-2, VI, VII, VIII, XI, XI-1, XI-2, XII, XII-1, XII-2 or Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising them, in the preparation of a medicament for the treatment and / or prevention of diseases or conditions mediated or dependent on STAT6.

[0501] 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), (III-5), (IV-1), (IV-2), (IV-3), (IV-4), (IV-5), (IV-6), (IV-7), (IV-8), (V-1), (V-2), (VI), (VII), (VIII), (XI), and (XI... -1), the use of compounds of general formula (XI-2), general formula (XII), general formula (XII-1), general formula (XII-2) or Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising thereof, in the preparation of medicines 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, scleroderma, juvenile arthritis, 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.

[0502] This disclosure also relates to a method for regulating the ubiquitination and degradation of STAT6 protein in a subject, comprising administering the above general formulas (M), (I), (I-1), (II-1), (II-2), (II-3), (II-4), (III-1), (III-2), (III-3), (III-4), (III-5), (IV-1), (IV-2), and (IV-5) to the desired patient. Compounds of formulas IV-3, (IV-4), (IV-5), (IV-6), (IV-7), (IV-8), (V-1), (V-2), (VI), (VII), (VIII), (XI), (XI-1), (XI-2), (XII), (XII-1), (XII-2), or those shown in Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising them.

[0503] 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 (III-5), general formula (IV-1), general formula (IV-2), general formula (IV-3), general formula (IV-4), general formula (IV-5), general formula (IV-6), general formula (IV-7), general formula (IV-8), general formula (V-1), general formula (V-2), general formula (VI), general formula (VII), general formula (VIII), general formula (XI), general formula (XI-1), general formula (XI-2), general formula (XII), general formula (XII-1), general formula (XII-2), or Table A, 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 diseases or conditions mediated or dependent on STAT6, comprising administering the above-described formulas (M), (I), (I-1), (II-1), (II-2), (II-3), (II-4), (III-1), (III-2), (III-3), (III-4), (III-5), (IV-1), and (IV-2) to a desired patient. Compounds of general formulas (IV-3), (IV-4), (IV-5), (IV-6), (IV-7), (IV-8), (V-1), (V-2), (VI), (VII), (VIII), (XI), (XI-1), (XI-2), (XII), (XII-1), (XII-2), or those shown in Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising them.

[0505] 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), (II-3), (II-4), and (II-5) to the desired patient. Compounds of formulas (I-1), (III-2), (III-3), (III-4), (III-5), (IV-1), (IV-2), (IV-3), (IV-4), (IV-5), (IV-6), (IV-7), (IV-8), (V-1), (V-2), (VI), (VII), (VIII), (XI), (XI-1), (XI-2), (XII), (XII-1), (XII-2), or those shown in Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising them, 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, juvenile arthritis, 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, 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 Lacrimal gland inflammation, 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.

[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 (III-5), general formula (IV-1), general formula (IV-2), general formula (IV-3), general formula (IV-4), general formula (IV-5), general formula (IV-6), general formula (IV-7), general formula (IV-8), general formula (V-1), general formula (V-2), general formula (VI), general formula (VII), general formula (VIII), general formula (XI), general formula (XI-1), general formula (XI-2), general formula (XII), general formula (XII-1), general formula (XII-2) or Table A, or a pharmaceutically usable salt thereof, or a pharmaceutical composition comprising the thereof, which is used as a medicament.

[0507] This disclosure further relates to a 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 (III-5), general formula (IV-1), general formula (IV-2), general formula (IV-3), general formula (IV-4), general formula (IV-5), general formula (IV- 6) Compounds of formulas (IV-7), (IV-8), (V-1), (V-2), (VI), (VII), (VIII), (XI), (XI-1), (XI-2), (XII), (XII-1), (XII-2) or those shown in Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising them, used as a drug for regulating the ubiquitination and degradation of STAT6 protein in a subject.

[0508] This disclosure further relates to one of the above-mentioned general formulas (M), (I), (I-1), (II-1), (II-2), (II-3), (II-4), (III-1), (III-2), (III-3), (III-4), (III-5), (IV-1), (IV-2), (IV-3), (IV-4), (IV-5), and (IV-6). Compounds of formulas (IV-7), (IV-8), (V-1), (V-2), (VI), (VII), (VIII), (XI), (XI-1), (XI-2), (XII), (XII-1), (XII-2) or shown in Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising them, used as medicines for the treatment and / or prevention of diseases or conditions mediated or dependent on STAT6.

[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), (III-5), (IV-1), (IV-2), (IV-3), (IV-4), (IV-5), (IV-6), (IV-7), (IV-8), (V-1), (V-2), (VI), (VII), (VIII), (XI), (XI-1), (XI-2), (XII), (XII-1), (XII-2), or those shown in Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising thereof, for the purpose of modulating STAT6 protein ubiquitination and degradation 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), (III-5), (IV-1), (IV-2), (IV-3), (IV-4), (IV-5), (IV-6), (IV-7), (IV-8), (V-1), (V-2), (VI), (VII), (VIII), (XI), (XI-1), (XI-2), (XII), (XII-1), (XII-2), or those shown in Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising thereof, for use in inhibiting or degrading STAT6 in a subject.

[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), (III-5), (IV-1), (IV-2), (IV-3), (IV-4), (IV-5), and (IV-6). Compounds of formulas (IV-7), (IV-8), (V-1), (V-2), (VI), (VII), (VIII), (XI), (XI-1), (XI-2), (XII), (XII-1), (XII-2) or shown in Table A, 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.

[0512] 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), (III-5), (IV-1), (IV-2), (IV-3), (IV-4), (IV-5), (IV-6), (IV-7), (IV-8), (V-1), (V-2), (VI), (VII), (VIII), (XI), and so on. Compounds of formula (XI-1), general formula (XI-2), general formula (XII), general formula (XII-1), general formula (XII-2) or Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising thereof, 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, 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, scleroderma, juvenile arthritis, 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.

[0513] 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.

[0514] 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.

[0515] In some embodiments, 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. In some embodiments, the neurodegenerative disease includes, but is not limited to, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), 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 can 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 can 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 can be used for this purpose. Additionally, fatty acids can 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., C14-C6 ... 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). In some embodiments, the cycloalkyl group has 3 to 12 ring atoms (i.e., 3 to 12-membered cycloalkyl), in some embodiments it has 3 to 8 ring atoms (i.e., 3 to 8-membered cycloalkyl), and in some embodiments it has 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: Its connection point can be anywhere; wait.

[0551] 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: Its connection point can be anywhere; wait.

[0552] 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.

[0553] 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.

[0554] 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 4 to 12 ring atoms (i.e., a 4 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 8 ring atoms (i.e., a 4 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).

[0555] Non-limiting examples of the monocyclic heterocyclic group include: pyrrolidinyl, tetrahydropyranyl, 1,2,3,6-tetrahydropyridyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, and homopiperazinyl, etc.

[0556] The polycyclic heterocyclic groups include spirocyclic heterocyclic groups, fused heterocyclic groups, and bridged heterocyclic groups.

[0557] 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: wait.

[0558] 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: wait.

[0559] 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: wait.

[0560] 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.

[0561] 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: wait.

[0562] 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.

[0563] 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).

[0564] 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.

[0565] 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.

[0566] 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.

[0567] The term "tetracyclic" refers to a polycyclic ring system having four rings containing 0 to 5 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 15 to 24 (e.g., 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24) ring atoms (i.e., 15 to 24-membered tetracyclic). Each monocyclic ring in the tetracyclic is independently selected from saturated rings, partially unsaturated rings, and aromatic rings, and the monocyclic rings may be joined together in a fused, bridged, or helical manner; in some embodiments, the tetracyclic is a 16 to 20-membered tetracyclic; in some embodiments, the tetracyclic is a 17-membered tetracyclic; non-limiting examples of "tetracyclic" include, but are not limited to: wait.

[0568] 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.

[0569] 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.

[0570] 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.

[0571] 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.

[0572] 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.

[0573] The term "cycloalkyloxy" refers to -O-cycloalkyl, where the cycloalkyl is as defined above.

[0574] The term "heterocyclic oxygen group" refers to an -O-heterocyclic group, wherein the heterocyclic group is as defined above.

[0575] The term "aryloxy group" refers to -O-aryl, where the aryl group is as defined above.

[0576] The term "heteroaryloxy" refers to -O-heteroaryl, where the heteroaryl is as defined above.

[0577] 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.

[0578] 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.

[0579] 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.

[0580] The term "haloalkoxy" refers to an alkoxy group that is substituted by one or more halogens, wherein the alkoxy group is as defined above.

[0581] 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.

[0582] The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0583] The term "hydroxyl group" refers to -OH.

[0584] The term "thiol" refers to -SH.

[0585] The term "amino" refers to -NH2.

[0586] The term "cyano" refers to -CN.

[0587] The term "nitro" refers to -NO2.

[0588] The term "oxo" or "oxo group" refers to "=O".

[0589] The term "carbonyl" refers to C=O.

[0590] The term "alkylthio" refers to -S-alkyl, where the alkyl group is as defined above.

[0591] The term "haloalkylthio" refers to an alkylthio group that is replaced by one or more halogens, wherein the alkylthio group is as defined above.

[0592] The term "cycloalkylthio" refers to -S-cycloalkyl, where the cycloalkyl group is as defined above.

[0593] The term "heterocyclic thio" refers to a -S-heterocyclic group, where the heterocyclic group is as defined above.

[0594] 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.

[0595] The term "leaving group," or simply leaving group, refers to an atom or functional group that breaks off from a larger molecule in a chemical reaction. It is used in nucleophilic substitution and elimination reactions. In a nucleophilic substitution reaction, the reactant attacked by the nucleophile is called the substrate, and the atom or group of atoms that breaks off with a pair of electrons from the substrate molecule is called the leaving group. Groups that readily accept electrons and have a strong ability to accept negative charges are desirable leaving groups. The smaller the pKa of the conjugate acid of the leaving group, the easier it is for the leaving group to break off from other molecules. This is because a smaller pKa of the conjugate acid means that the corresponding leaving group does not need to combine with other atoms, and its tendency to exist as an anion (or an electrically neutral leaving group) is enhanced. Common leaving groups include, but are not limited to, halogens, methanesulfonyl groups, -OTs, -OTf, or -OH.

[0596] 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.

[0597] 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 Or simultaneously include and Two configurations. For all carbon-carbon double bonds, even if only one configuration is named, both the Z-type and E-type are included. No configuration is specified, meaning it can be Z configuration, E configuration, or both configurations.

[0598] In the chemical structure of the compounds described in this disclosure, the bonds attached to the stereoisomer centers of the compounds are... or The relative configuration of the stereoisomer center can be indicated by adding Rel before the compound name; for example, compound 122g-1 is a mixture of 122g-1-1 and 122g-1-2.

[0599] 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:

[0600] 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:

[0601] All tautomers are within the scope of this disclosure, and the naming of compounds does not exclude any tautomers.

[0602] 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.

[0603] 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.

[0604] 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.

[0605] 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.

[0606] 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.

[0607] "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 will 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.

[0608] "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).

[0609] "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.

[0610] "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.

[0611] 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.

[0612] As used herein, the singular forms of “a,” “an,” and “the” include plural references, and vice versa, unless the context clearly indicates otherwise.

[0613] When the term "about" is applied to parameters such as pH, concentration, temperature, etc., it indicates that the parameter can vary by ±10%, and sometimes even within ±5% in some embodiments. 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

[0614] The following embodiments are used to further describe this disclosure, but these embodiments are not intended to limit the scope of this disclosure.

[0615] Example

[0616] 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).

[0617] MS measurements were performed using an Agilent 1200 / 1290DAD-6110 / 6120 Quadrupole MS liquid chromatography-mass spectrometry system (manufacturer: Agilent, MS model: 6110 / 6120 Quadrupole MS);

[0618] waters ACQuity UPLC-QD / SQD (manufacturer: waters, MS model: waters ACQuity Qda Detector / waters SQ Detector);

[0619] THERMO Ultimate 3000-Q Exactive (Manufacturer: THERMO, MS Model: THERMO Q Exactive).

[0620] 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.

[0621] Chiral HPLC analysis was performed using an Agilent 1260DAD high-performance liquid chromatograph.

[0622] High performance liquid chromatography (HPLC) was performed using Waters 2545-2767, Waters 2767-SQ Detecor2, Shimadzu LC-20AP, and Gilson GX-281 preparative chromatographs.

[0623] Chiral preparation was performed using a Shimadzu LC-20AP preparative chromatograph.

[0624] The CombiFlash rapid preparation system uses a CombiFlash Rf200 (TELEDYNE ISCO).

[0625] 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.

[0626] Silica gel column chromatography generally uses Yantai Huanghai silica gel with a mesh size of 200-300 as the carrier.

[0627] Mean inhibition rate of kinases and IC 50 The values ​​were determined using a NovoStar microplate reader (BMG GmbH, Germany).

[0628] 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.

[0629] Unless otherwise specified in the examples, all reactions can be carried out under an argon or nitrogen atmosphere.

[0630] Argon or nitrogen atmosphere refers to a reaction flask connected to an argon or nitrogen gas balloon with a volume of approximately 1L.

[0631] A hydrogen atmosphere refers to a reaction vessel connected to a hydrogen balloon with a volume of approximately 1L.

[0632] The pressurized hydrogenation reaction was performed using a Parr 3916EKX hydrogenator and a Qinglan QL-500 hydrogen generator or an HC2-SS hydrogenator.

[0633] The hydrogenation reaction is usually carried out under vacuum, filled with hydrogen gas, and repeated 3 times.

[0634] The microwave reaction was performed using a CEM Discover-S 908860 microwave reactor.

[0635] Unless otherwise specified in the examples, "solution" refers to an aqueous solution.

[0636] Unless otherwise specified in the examples, the reaction temperature is room temperature.

[0637] 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.

[0638] Example 1

[0639] 6-(1-(3-(1H-1,2,3-triazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-4-(4-(2-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-1H,6H-spiro[furano[3,2-f]indazole-5,4'-piperidin]-1'-yl)ethyl)phenyl)-7-fluoro-N,N-dimethyl-1H-indole-2-carboxamide1

[0640] first step

[0641] 1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxoborhecyclopentan-2-yl)-3,6-dihydropyridin-1(2H)-yl)-3-(1H-1,2,3-triazol-1-yl)prop-1-one 1c

[0642] 3-(1H-1,2,3-triazol-1-yl)propionic acid 1a (1 g, 7.09 mmol, Shanghai Biotech) was dissolved in dry pyridine (10 mL), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.04 g, 10.64 mmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxoborhexacyclopentan-2-yl)-1,2,3,6-tetrahydropyridine 1b (1.6 g, 7.65 mmol) were added. The mixture was stirred for 16 hours, 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 1c (1.6 g, yield: 70%).

[0643] MS m / z(ESI):333.0[M+1].

[0644] Step 2

[0645] 2-(4-Bromobenzyl)-1,3-dioxapentane 1e

[0646] 4-Bromophenylacetaldehyde 1d (10 g, 50.24 mmol, Shanghai Shaoyuan), ethylene glycol (3 mL, 55 mmol), and p-toluenesulfonic acid monohydrate (950 mg, 4.99 mmol) were dissolved in toluene (150 mL) and refluxed at 120 °C for 16 hours. The reaction solution was cooled to room temperature and washed successively with saturated sodium bicarbonate solution, water, and saturated sodium chloride solution to separate the organic phase. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to give the title compound 1e (6 g, yield: 49%).

[0647] MS m / z(ESI):242.9[M+1].

[0648] Step 3

[0649] 2-(4-((1,3-dioxacyclopent-2-yl)methyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaboranecyclopentane 1f

[0650] Compound 1e (6.00 g, 24.7 mmol), pinacol diborate (6.97 g, 27.44 mmol), potassium acetate (4.8 g, 49.40 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (212 mg, 0.26 mmol) were mixed in 1,4-dioxane (60 mL), purged with nitrogen, and stirred at 100 °C for 6 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 B to give title compound 1f (5 g, yield: 70%).

[0651] MS m / z(ESI):291.1[M+1].

[0652] Step 4

[0653] 1-(5-bromo-2-fluoro-4-(methoxymethoxy)phenyl)ethane-1-one 1h

[0654] 1 g (1 g, 4.29 mmol, Shanghai Bide) of 1-(5-bromo-2-fluoro-4-hydroxyphenyl)ethane-1-one was dissolved in N,N-dimethylformamide (20 mL). Sodium hydride (257 mg, 6.42 mmol, 60% purity) was added in portions under ice bath conditions. After stirring for 30 minutes while maintaining the temperature, chloromethyl methyl ether (414 mg, 5.15 mmol) was added dropwise. The mixture was allowed to return to room temperature naturally and stirred for 2 hours. The reaction mixture was poured into ice water and extracted with ethyl acetate (30 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 B to give the title compound 1h (830 mg, yield: 70%).

[0655] MS m / z(ESI):276.9[M+1].

[0656] Step 5

[0657] 5-Bromo-6-(methoxymethoxy)-3-methyl-1H-indazole 1i

[0658] Compound 1h (800 mg, 2.89 mmol) was mixed with hydrazine hydrate (10 mL) and refluxed for 24 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to give the title compound 1i (470 mg, yield: 60%).

[0659] MS m / z(ESI):271.1[M+1].

[0660] Step 6

[0661] 3-(5-bromo-6-(methoxymethoxy)-3-methyl-1H-indazol-1-yl)-1-(4-methoxybenzyl)piperidine-2,6-dione

[0662] Compound 1i (450 mg, 1.66 mmol) was dissolved in tetrahydrofuran (10 mL). Potassium tert-butoxide (280 mg, 2.49 mmol) was added at 0 °C under a nitrogen atmosphere. The mixture was stirred for 1 hour while maintaining the temperature. 3-Bromo-1-[(4-methoxyphenyl)methyl]piperidine-2,6-dione (518 mg, 1.66 mmol, Shanghai Leyan) was added, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched with saturated ammonium chloride solution in an ice bath. Extraction was performed with ethyl acetate (15 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 B to give title compound 1j (330 mg, yield: 60%). MS m / z (ESI): 502.2 [M+1].

[0663] Step 7

[0664] 3-(5-bromo-6-hydroxy-3-methyl-1H-indazol-1-yl)-1-(4-methoxybenzyl)piperidine-2,6-dione 1k

[0665] Compound 1j (300 mg, 0.6 mmol) was dissolved in dichloromethane (5 mL), and a 4M solution of 1,4-dioxane in hydrogen chloride (5 mL) was added. The mixture was stirred for 3 hours, and the reaction solution was concentrated under reduced pressure. Ethyl acetate (10 mL) was added to the residue, and the mixture was washed with saturated sodium bicarbonate aqueous solution to separate the organic phase. The organic phase was dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude title compound 1k (240 mg). The product was used directly in the next reaction without purification.

[0666] MS m / z(ESI):458.1[M+1].

[0667] Step 8

[0668] 4-(((5-bromo-1-(1-(4-methoxybenzyl)-2,6-dioxopiperidin-3-yl)-3-methyl-1H-indazol-6-yl)oxy)methyl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester 1l

[0669] The crude compound 1k (240 mg, 0.52 mmol) was dissolved in N,N-dimethylformamide (10 mL), and 4-(chloromethyl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (127 mg, 0.55 mmol, prepared according to the method disclosed in the literature "Journal of Medicinal Chemistry, 2013, vol. 56, #22, p. 9275-9295") and potassium carbonate (144 mg, 1.04 mmol) 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 with eluent system A to give the title compound 1l (340 mg, yield: 90%). MS m / z (ESI): 653.2 [M+1].

[0670] Step 9

[0671] 1-(1-(4-methoxybenzyl)-2,6-dioxopiperidin-3-yl)-3-methyl-2',3'-dihydro-1H,1'H,6H-spiro[furano[3,2-f]indazole-5,4'-pyridine]-1'-carboxylic acid tert-butyl ester 1m

[0672] Compound 1l (300 mg, 0.46 mmol) was dissolved in N,N-dimethylformamide (5 mL), and sodium formate (50 mg, 0.74 mmol), sodium acetate (96 mg, 1.17 mmol), palladium acetate (11 mg, 0.05 mmol), and tetraethylammonium chloride (119 mg, 0.72 mmol) were added. The mixture was reacted at 75 °C for 12 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 the title compound 1m (147 mg, yield: 56%).

[0673] MS m / z(ESI): 573.3 [M+1].

[0674] Step 10

[0675] 1-(1-(4-methoxybenzyl)-2,6-dioxopiperidin-3-yl)-3-methyl-1H,6H-spiro[furano[3,2-f]indazole-5,4'-piperidin]-1'-carboxylic acid tert-butyl ester 1n

[0676] Compound 1m (100 mg, 0.17 mmol) was dissolved in a mixed solvent of tetrahydrofuran and methanol (10 mL) (V / V = 1:2), and 10% palladium on carbon hydrogenation catalyst (11 mg) and palladium hydroxide (14 mg) were added. The mixture was purged with hydrogen and stirred at 70 °C for 16 hours. After the reaction solution cooled to room temperature, it was filtered, and the filtrate was concentrated under reduced pressure to give crude title compound 1n (73 mg). The product was used directly in the next reaction without purification.

[0677] MS m / z(ESI): 575.3 [M+1].

[0678] Step 11

[0679] 3-(3-methyl-1H,6H-spiro[furano[3,2-f]indazole-5,4'-piperidin]-1-yl)piperidin-2,6-dione 1o

[0680] The crude compound 1n (73 mg, 0.13 mmol) was dissolved in toluene (5 mL), and methanesulfonic acid (125 mg, 1.3 mmol) was added. The mixture was heated to 120 °C and stirred for 3 hours. After the reaction solution was cooled to room temperature, it was concentrated under reduced pressure. 5% sodium bicarbonate solution (5 mL) was added, and the mixture was extracted with ethyl acetate (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 1o (40 mg). The product was used directly in the next reaction without purification.

[0681] MS m / z(ESI): 355.2 [M+1].

[0682] Step Twelve

[0683] 1q of methyl 2-azido-3-(4-bromo-2-chloro-5-fluorophenyl)acrylate

[0684] Sodium methoxide (907 mg, 16.8 mmol) was dissolved in methanol (20 mL). A methanol solution of 4-bromo-2-chloro-5-fluorobenzaldehyde 1p (2 g, 8.42 mmol, Shanghai Biotech) and ethyl 2-azidoacetate (4.34 g, 33.7 mmol) in 30 mL was added dropwise at -10 °C. The mixture was allowed to return to room temperature naturally and then stirred for 12 hours. The reaction mixture was then poured into a saturated ammonium chloride aqueous solution at 0 °C, filtered, and the filter cake was washed with water and dried to obtain the crude title compound 1q (1.5 g). This product was used directly in the next reaction without purification.

[0685] MS m / z(ESI): 333.9 [M+1].

[0686] Step Thirteen

[0687] methyl 6-bromo-4-chloro-7-fluoro-1H-indole-2-carboxylate 1r

[0688] The crude compound 1q (1.5 g, 4.50 mmol) was dissolved in xylene (50 mL) and refluxed for 5 hours. After the reaction solution was cooled to room temperature, it was filtered and the filter cake was dried to obtain the crude title compound 1r (1.0 g). The product was used directly in the next step of the reaction without purification.

[0689] MS m / z(ESI): 305.9 [M+1].

[0690] Step Fourteen

[0691] 6-Bromo-4-chloro-7-fluoro-1H-indole-2-carboxylic acid 1S

[0692] The crude compound 1r (1.0 g, 3.3 mmol) was dissolved in tetrahydrofuran (10 mL), methanol (5 mL), and water (5 mL). Lithium hydroxide monohydrate (693 mg, 16.5 mmol) was added, and the mixture was stirred for 16 hours. The reaction solution was diluted with water, and the pH was adjusted to about 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 1s (900 mg). The product was used directly in the next step of the reaction without purification.

[0693] MS m / z(ESI):291.9[M+1].

[0694] Step 15

[0695] 6-Bromo-4-chloro-7-fluoro-N,N-dimethyl-1H-indole-2-carboxamide 1t

[0696] The crude compound 1s (800 mg, 2.27 mmol) was dissolved in N,N-dimethylformamide (10 mL), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (370 mg, 2.66 mmol), 1-hydroxybenzotriazole (460 mg, 3.41 mmol), N,N-diisopropylethylamine (147 mg, 11.37 mmol), and dimethylamine hydrochloride (278 mg, 3.40 mmol, Shanghai Bide) were added. The mixture was stirred for 3 hours. Water was added to the reaction solution to dilute the solution, and the precipitated solid was filtered. The filter cake was washed with water and dried to obtain the crude title compound 1t (650 mg). The product was used directly in the next reaction without purification.

[0697] MS m / z(ESI): 318.9 [M+1].

[0698] Step Sixteen

[0699] 6-(1-(3-(1H-1,2,3-triazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-4-chloro-7-fluoro-N,N-dimethyl-1H-indole-2-carboxamide 1u

[0700] Crude compound 1t (600 mg, 1.88 mmol), compound 1c (0.62 g, 1.87 mmol), 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (206 mg, 281 μmol), and anhydrous potassium carbonate (780 mg, 5.65 mmol) were dissolved in 1,4-dioxane (10 mL) and water (3 mL). The mixture was purged with nitrogen and stirred at 80 °C for 16 hours. After the reaction mixture was cooled to room temperature, it was diluted with water and extracted with dichloromethane (10 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 with eluent system A to give title compound 1u (400 mg, yield: 48%).

[0701] MS m / z(ESI):445.2[M+1].

[0702] Step Seventeen

[0703] 4-(4-((1,3-dioxacyclopent-2-yl)methyl)phenyl)-6-(1-(3-(1H-1,2,3-triazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-7-fluoro-N,N-dimethyl-1H-indole-2-carboxamide 1v

[0704] Compound 1u (200 mg, 0.45 mmol), compound 1f (196 mg, 0.67 mmol), potassium phosphate (191 mg, 0.9 mmol), and methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (38 mg, 45 μmol) were mixed in 1,4-dioxane (10 mL) and water (2 mL), purged with nitrogen, and stirred at 80 °C for 6 hours. 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 A to give title compound 1v (150 mg, yield: 58%).

[0705] MS m / z(ESI): 573.3 [M+1].

[0706] Step 18

[0707] 6-(1-(3-(1H-1,2,3-triazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-7-fluoro-N,N-dimethyl-4-(4-(2-oxoethyl)phenyl)-1H-indole-2-carboxamide 1w

[0708] Compound 1v (150 mg, 0.40 mmol) was dissolved in formic acid (2 mL), and the mixture was stirred at 40 °C for 2 hours. After the reaction solution was cooled to room temperature, it was concentrated under reduced pressure to obtain crude title compound 1w (150 mg). The product was not purified and was directly used for the next reaction.

[0709] MS m / z(ESI): 529.2 [M+1].

[0710] Step 19

[0711] 6-(1-(3-(1H-1,2,3-triazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-4-(4-(2-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-1H,6H-spiro[furano[3,2-f]indazole-5,4'-piperidin]-1'-yl)ethyl)phenyl)-7-fluoro-N,N-dimethyl-1H-indole-2-carboxamide1

[0712] Crude compound 1w (50 mg, 95 μmol) and compound 1o (34 mg, 95 μmol) were dissolved in 1,2-dichloroethane (10 mL) and dimethyl sulfoxide (1 mL). Acetic acid (12 mg, 0.20 mmol) and potassium acetate (20 mg, 0.20 mmol) were added, and the mixture was stirred for 1 hour. Sodium cyanoborohydride (18 mg, 0.28 mmol) was added, and the mixture was stirred for another 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by preparative high performance liquid chromatography (Waters-2545, column: Boston Phlex Prep C18, C18, 30 × 150 mm, 5 μm; mobile phase: aqueous phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 30-55%, flow rate: 30 mL / min) to give title compound 1 (10 mg, yield: 12%).

[0713] MS m / z(ESI): 867.4 [M+1].

[0714] Example 2

[0715] 6-(1-(3-(1H-1,2,3-triazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-4-(4-(2-((4aR)-8-(2,6-dioxopiperidin-3-yl)-10-methyl-9-oxo-1,2,4a,5,9,10-hexahydro-8H-imidazo[4',5':4,5]benzo[1,2-b]pyrazino[1,2-d][1,4]oxazin-3(4H)-yl)ethyl)phenyl)-7-fluoro-N,N-dimethyl-1H-indole-2-carboxamide 2

[0716] first step

[0717] 1-Bromo-5-fluoro-2-(methoxymethoxy)-4-nitrobenzene 2b

[0718] 2-Bromo-4-fluoro-5-nitrophenol 2a (10.0 g, 42.37 mmol, Shanghai Biotech) was dissolved in dichloromethane (150 mL), and N,N-diisopropylethylamine (16.43 g, 12.7 mmol) was added under ice bath conditions. Bromomethyl methyl ether (5.82 g, 9.32 mmol) was added dropwise, and the mixture was stirred at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system A to give title compound 2b (9.49 g, yield: 80%).

[0719] Step 2

[0720] 5-Bromo-4-(methoxymethoxy)-N-methyl-2-nitroaniline 2c

[0721] Compound 2b (9.49 g, 33.89 mmol) was added to a 2 M methylaminetetrahydrofuran solution (51 mL), and the mixture was stirred at 15 °C for 10 minutes. The reaction solution was diluted with water and extracted with ethyl acetate (150 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 to obtain the crude title compound 2c (8.38 g). The product was used directly in the next reaction without purification.

[0722] MS m / z(ESI):292.0[M+1].

[0723] Step 3

[0724] 5-Bromo-4-(Methoxymethoxy)-N 1 -Methylphenyl-1,2-diamine 2d

[0725] The crude compound 2c (8.38 g, 28.79 mmol) was dissolved in ethanol (100 mL) and water (50 mL), and iron powder (8.04 g, 143.94 mmol) and ammonium chloride (7.70 g, 143.94 mmol) were added. The mixture was stirred at 85 °C for 2 hours. After cooling to room temperature, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was diluted with water and extracted with ethyl acetate (150 mL × 2). The organic phases were combined and washed successively with saturated sodium bicarbonate solution and saturated sodium chloride solution. The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system A to give the title compound 2d (5.26 g, yield: 70%).

[0726] MS m / z(ESI):262.0[M+1].

[0727] Step 4

[0728] 6-Bromo-5-(methoxymethoxy)-1-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one 2e

[0729] Compound 2d (5.26 g, 20.14 mmol) was dissolved in acetonitrile (100 mL), and N,N'-carbonyldiimidazole (6.53 g, 40.29 mol) was added. The mixture was purged with nitrogen and stirred at 80 °C for 6 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure. The residue was diluted with water and filtered. The filter cake was washed with water and dried to obtain the crude title compound 2e (4.74 g). This product was used directly in the next reaction without purification.

[0730] MS m / z(ESI):288.1[M+1].

[0731] Step 5

[0732] 3-(5-bromo-6-(methoxymethoxy)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-1-(4-methoxybenzyl)piperidine-2,6-dione 2f

[0733] The crude compound 2e (4.74 g, 16.51 mmol) was dissolved in N,N-dimethylformamide (60 mL), and sodium hydride (858 mg, 21.46 mmol, 60% purity) was added under ice bath conditions. After stirring for 1 hour while maintaining the temperature, 3-bromo-1-(4-methoxybenzyl)piperidine-2,6-dione (6.18 g, 19.81 mmol, Shanghai Bide) was added, and the reaction was allowed to proceed at room temperature for 16 hours. The reaction mixture was poured into ice water and extracted with ethyl acetate (80 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 elution system A to give the title compound 2f (1.71 g, yield: 20%).

[0734] MS m / z(ESI): 519.1 [M+1].

[0735] Step 6

[0736] (3R)-3-(hydroxymethyl)-4-(1-(1-(4-methoxybenzyl)-2,6-dioxopiperidin-3-yl)-6-(methoxymethoxy)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)piperazine-1-carboxylic acid benzyl ester 2g

[0737] Compound 2f (800 mg, 8.47 mmol) and (3R)-3-(hydroxymethyl)piperazine-1-carboxylic acid benzyl ester (425 mg, 1.70 mmol, Shanghai Bide) were dissolved in 1,4-dioxane (15 mL), and cesium carbonate (1.01 g, 3.09 mmol) and methanesulfonic acid [(R)-2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl](2'-amino-1,1'-biphenyl-2-yl)palladium(II) (153 mg, 0.15 mmol) were added. Nitrogen was purged, and the reaction was carried out at 110 °C for 16 hours. After cooling to room temperature, the reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using elution system A to give 2 g (796 mg, yield: 75%) of the title compound.

[0738] MS m / z(ESI): 688.7 [M+1].

[0739] Step 7

[0740] (3R)-4-(6-hydroxy-1-(1-(4-methoxybenzyl)-2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro

[0741] -1H-Benzo[d]imidazol-5-yl)-3-(hydroxymethyl)piperazine-1-carboxylic acid benzyl ester 2h

[0742] 2 g (796 mg, 1.16 mmol) of the compound was dissolved in 10 mL of dichloromethane, and 5 mL of a 4 M hydrogen chloride solution of 1,4-dioxane was added. The mixture was stirred for 2 hours. The reaction mixture was quenched with saturated sodium bicarbonate solution, extracted with dichloromethane (30 mL × 2), and the organic phases were combined. The mixture was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give crude title compound 2 h (745 mg). The product was used directly in the next reaction without purification.

[0743] MS m / z(ESI): 644.6 [M+1].

[0744] Step 8

[0745] (4aR)-8-(1-(4-methoxybenzyl)-2,6-dioxopiperidin-3-yl)-10-methyl-9-oxo-1,2,4a,5,9,10-hexahydro-8H-imidazo[4',5':4,5]benzo[1,2-b]pyrazino[1,2-d][1,4]oxazine-3(4H)-carboxylic acid benzyl ester 2i

[0746] The crude compound 2h (745 mg, 1.16 mmol) and triphenylphosphine (424 mg, 1.74 mmol) were dissolved in tetrahydrofuran (15 mL), and diisopropyl azodicarboxylate (351 mg, 1.74 mmol) was added under a nitrogen atmosphere. 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 elution system A to give the title compound 2i (362 mg, yield: 50%).

[0747] MS m / z(ESI): 626.6 [M+1].

[0748] Step 9

[0749] 1-(4-methoxybenzyl)-3-((R)-10-methyl-9-oxo-1,2,3,4,4a,5,9,10-octahydro-8H-imidazo[4',5':4,5]benzo[1,2-b]pyrazino[1,2-d][1,4]oxazin-8-yl)piperidin-2,6-dione 2j

[0750] Compound 2i (362 mg, 0.58 mmol) was dissolved in methanol (10 mL), and 10% palladium on carbon hydrogenation catalyst (62 mg) was added. The mixture was purged with hydrogen and stirred for 2 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain crude title compound 2j (284 mg). The product was used directly in the next step of the reaction without purification.

[0751] MS m / z(ESI): 492.5 [M+1].

[0752] Step 10

[0753] 3-((R)-10-methyl-9-oxo-1,2,3,4,4a,5,9,10-octahydro-8H-imidazo[4',5':4,5]benzo[1,2-b]pyrazino[1,2-d][1,4]oxazin-8-yl)piperidin-2,6-dione 2k

[0754] The crude compound 2j (150 mg, 0.31 mmol) was dissolved in toluene (5 mL), and methanesulfonic acid (2 mL) was added. The mixture was heated to 120 °C and reacted for 1 hour. After the reaction solution was cooled to room temperature, it was concentrated under reduced pressure. The residue was purified by high performance liquid chromatography (Waters-2545, column: Boston Phlex Prep C18, 30 × 150 mm, 5 μm; mobile phase: aqueous phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 25-55%, flow rate: 30 mL / min) to give the title compound 2k (45 mg, yield: 40%).

[0755] MS m / z(ESI): 372.3 [M+1].

[0756] Step 11

[0757] 6-(1-(3-(1H-1,2,3-triazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-4-(4-(2-((4aR)-8-(2,6-dioxopiperidin-3-yl)-10-methyl-9-oxo-1,2,4a,5,9,10-hexahydro-8H-imidazo[4',5':4,5]benzo[1,2-b]pyrazino[1,2-d][1,4]oxazin-3(4H)-yl)ethyl)phenyl)-7-fluoro-N,N-dimethyl-1H-indole-2-carboxamide 2

[0758] Compound 1w (30 mg, 0.06 mmol) and compound 2k (21 mg, 0.06 mmol) were dissolved in 1,2-dichloroethane (5 mL), and sodium triacetoxyborohydride (25 mg, 0.12 mmol) was added. The mixture was heated to 30 °C and reacted for 16 hours. After the reaction solution cooled to room temperature, it was quenched with water, extracted with dichloromethane (5 mL × 3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative high-performance liquid chromatography (HPLC) (instrument: Waters-2545, column: Welch Xtimate, Prep 30 × 250 mm; 5 μm; C18, mobile phase: water (10 mM ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 35%-50%, flow rate: 30 mL / min) to give title compound 2 (15 mg, yield: 30%).

[0759] MS m / z(ESI): 884.9 [M+1].

[0760] Example 3

[0761] 6-(1-(3-(1H-1,2,3-triazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-4-(4-(2-((4aS)-8-(2,6-dioxopiperidin-3-yl)-10-methyl-9-oxo-1,2,4a,5,9,10-hexahydro-8H-imidazo[4',5':4,5]benzo[1,2-b]pyrazino[1,2-d][1,4]oxazin-3(4H)-yl)ethyl)phenyl)-7-fluoro-N,N-dimethyl-1H-indole-2-carboxamide 3

[0762] Using steps six to eleven of the synthetic route in Example 2, the starting compound (3R)-3-(hydroxymethyl)piperazine-1-carboxylic acid benzyl ester in step six was replaced with (3S)-3-(hydroxymethyl)piperazine-1-carboxylic acid benzyl ester (Shanghai Bide) to obtain title compound 3 (13 mg, yield: 25%).

[0763] MS m / z(ESI): 884.9 [M+1].

[0764] Example 4

[0765] 6-(1-(3-(1H-1,2,3-triazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-4-(4-(2-((4aR)-8-(2,6-dioxopiperidin-3-yl)-10-methyl-1,2,4a,5-tetrahydro-8H-pyrazino[1',2':4,5][1,4]oxazino[3,2-f]indazole-3(4H)-yl)ethyl)phenyl)-7-fluoro-N,N-dimethyl-1H-indole-2-carboxamide 4

[0766] Using steps six through eleven of the synthetic route in Example 2, the starting compound 2f in step six was replaced with compound 1j to obtain the title compound 4 (17 mg, yield: 35%).

[0767] MS m / z(ESI): 868.9 [M+1].

[0768] Example 5

[0769] 6-(1-(3-(1H-1,2,3-triazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-4-(4-(2-((4aS)-8-(2,6-dioxopiperidin-3-yl)-10-methyl-1,2,4a,5-tetrahydro-8H-pyrazino[1',2':4,5][1,4]oxazino[3,2-f]indazole-3(4H)-yl)ethyl)phenyl)-7-fluoro-N,N-dimethyl-1H-indole-2-carboxamide 5

[0770] Using steps six to eleven of the synthetic route in Example 2, the starting material 2f in step six was replaced with compound 1j, and (3R)-3-(hydroxymethyl)piperazine-1-carboxylic acid benzyl ester was replaced with (3S)-3-(hydroxymethyl)piperazine-1-carboxylic acid benzyl ester (Shanghai Bide) to obtain title compound 5 (13 mg, yield: 26%).

[0771] MS m / z(ESI): 868.9 [M+1].

[0772] Example 6

[0773] 6-(1-(3-(1H-1,2,3-triazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-4-(4-(2-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-2-oxo-2,3-dihydro-1H,6H-spiro[benzofurano[5,6-d]imidazol-7,4'-piperidin]-1'-yl)ethyl)phenyl)-7-fluoro-N,N-dimethyl-1H-indole-2-carboxamide 6

[0774] Using steps seven through nineteen of the synthetic route in Example 1, the starting compound 1j in step seven was replaced with compound 2f to obtain title compound 6 (13 mg, yield 15%).

[0775] MS m / z(ESI): 883.4 [M+1].

[0776] Example 7

[0777] 2-(1-(3-(1H-1,2,3-triazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-9-(2-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-1H,6H-spiro[furano[3,2-f]indazole-5,4'-piperidin]-1'-yl)ethyl)-3-fluoro-N,N-dimethyl-4,6-dihydrobenzo[6,7]oxaheptanecyclo[3,4,5-cd]indole-5-carboxamide 7

[0778] first step

[0779] 2-(4-bromo-3-(methoxymethoxy)phenyl)methyl acetate 7b

[0780] 2-(4-bromo-3-hydroxyphenyl)acetic acid methyl ester 7a (1 g, 4.10 mmol, Shanghai Leyan) was dissolved in N,N-dimethylformamide (20 mL). Sodium hydride (246 mg, 6.15 mmol, 60% purity) was added in portions under ice bath conditions. The mixture was stirred for 30 minutes while maintaining the temperature. Chloromethyl ether (414 mg, 5.15 mmol) was then added dropwise. The mixture was slowly brought to room temperature and stirred for 2 hours. The reaction mixture was quenched in ice water and extracted with ethyl acetate (30 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 B to give the title compound 7b (944 mg, yield: 80%).

[0781] Step 2

[0782] 2-(3-(methoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxoborhexacyclopent-2-yl)phenyl)methyl acetate 7c

[0783] Compound 7b (900 mg, 3.12 mmol), pinacol diborate (1.19 g, 4.68 mmol), 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (23 mg, 31 μmmol), and potassium acetate (612 mg, 6.24 mmol) were mixed in 1,4-dioxane (20 mL), purged with nitrogen, and heated to 100 °C for 2 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 B to give the title compound 7c (682 mg, yield: 65%).

[0784] MS m / z(ESI): 337.2 [M+1].

[0785] Step 3

[0786] methyl 4-bromo-6-chloro-7-fluoro-1H-indole-2-carboxylate 7e

[0787] 2-Bromo-4-chloro-5-fluorobenzaldehyde 7d (29 g, 122.2 mmol, Shanghai Haohong) was dissolved in methanol (100 mL). A methanol solution of sodium methoxide (88 g, 488 mmol) was added in portions (200 mL) at -60 °C, followed by dropwise addition of ethyl diazonate (63 g, 488 mmol). The mixture was stirred and kept at the temperature for 1 hour, then allowed to return to room temperature and reacted for another 12 hours. The reaction solution was cooled to 0 °C, filtered, and the filter cake was dried. The crude product was dispersed in xylene (150 mL) and reacted at 160 °C for 2 hours. The temperature was then lowered to 0 °C, filtered, and the filter cake was dried to obtain the crude title compound 7e (3.6 g). The product was used directly in the next reaction without purification.

[0788] MS m / z(ESI): 306.0 [M+1].

[0789] Step 4

[0790] 4-Bromo-6-chloro-7-fluoro-3-formyl-1H-indole-2-carboxylic acid methyl ester 7f

[0791] Phosphorus oxychloride (26 mL) was slowly added dropwise to N-methylformamide (37 mL). After stirring for 1 hour, a solution of crude compound 7e (2.5 g, 8.16 mmol) in 1,2-dichloroethane (30 mL) was added dropwise. The mixture was heated to 90 °C and reacted for 4 hours. After the reaction solution was cooled to room temperature, it was poured into ice water and 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 to obtain crude title compound 7f (700 mg). The product was used directly in the next reaction without purification.

[0792] MS m / z(ESI): 333.9 [M+1].

[0793] Step 5

[0794] 7g of methyl 4-bromo-3-(((tert-butyldimethylsilyl)oxy)methyl)-6-chloro-7-fluoro-1H-indole-2-carboxylate

[0795] The crude compound 7f (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 solution was quenched with saturated ammonium chloride solution. The mixture was extracted with ethyl acetate (15 mL × 2), and the organic phases were combined and concentrated under reduced pressure. The resulting crude product was dissolved in dichloromethane (10 mL), and imidazole (0.28 g, 4.11 mmol) and tert-butyldimethylchlorosilane (0.38 g, 2.52 mmol) were added. The mixture was stirred for 12 hours, and water was added to the reaction solution. The mixture was extracted with dichloromethane (15 mL × 2), and the organic phases were combined. The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude title compound 7f (0.83 g). The product was used directly in the next reaction without purification.

[0796] MS m / z(ESI):450.0[M+1].

[0797] Step 6

[0798] 4-Bromo-3-(((tert-butyldimethylsilyl)oxy)methyl)-6-chloro-7-fluoro-1H-indole-2-carboxylic acid 7h

[0799] 7 g (0.67 g, 1.49 mmol) of the crude compound was dissolved in tetrahydrofuran (6 mL), water (1.5 mL), and methanol (1.5 mL). Lithium hydroxide monohydrate (274 mg, 6.53 mmol) was added, and the mixture was stirred at 40 °C for 12 hours. After the reaction solution was cooled to room temperature, the pH was adjusted to approximately 4 with 2 M dilute hydrochloric acid. The solution was extracted with dichloromethane (15 mL × 2), and the organic phases were combined. The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude title compound 7h (0.63 g). The product was used directly in the next reaction without purification.

[0800] MS m / z(ESI):436.0[M+1].

[0801] Step 7

[0802] 4-Bromo-3-(((tert-butyldimethylsilyl)oxy)methyl)-6-chloro-7-fluoro-N,N-dimethyl-1H-indole-2-carboxamide 7i

[0803] The crude compound 7h (0.62 g, 1.42 mmol) and dimethylamine hydrochloride (0.26 g, 3.19 mmol) were dissolved in N,N-dimethylformamide (2 mL). N,N-diisopropylethylamine (2.06 g, 16 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate (967 mg, 2.54 mmol) were added sequentially at 0 °C. The mixture was stirred at room temperature for 2 hours. The reaction solution was poured into water, and a solid precipitated. The solid was filtered, and the filter cake was dried to obtain the crude title compound 7i (0.63 g). The product was used directly in the next reaction without purification.

[0804] MS m / z(ESI):463.1[M+1].

[0805] Step 8

[0806] 2-(4-(3-(((tert-butyldimethylsilyl)oxy)methyl)-6-chloro-2-(dimethylaminocarbonyl)-7-fluoro-1H-indol-4-yl)-3-(methoxymethoxy)phenyl)methyl acetate 7j

[0807] Crude compound 7i (0.63 g, 1.36 mmol), compound 7c (0.55 g, 1.63 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloromethane complex (0.1 g, 0.12 mmol) were dissolved in 1,4-dioxane (10 mL) and water (2 mL). The mixture was purged with nitrogen and reacted at 90 °C for 3 hours. After cooling to room temperature, water was added, and the mixture was extracted with ethyl acetate (10 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 using eluent system B to give title compound 7j (0.75 g, yield: 93%). MS m / z (ESI): 593.2 [M+1].

[0808] Step 9

[0809] 2-(4-(6-chloro-2-(dimethylaminocarbonyl)-7-fluoro-3-(hydroxymethyl)-1H-indol-4-yl)-3-hydroxyphenyl)methyl acetate 7k

[0810] Compound 7j (0.7 g, 1.18 mmol) was dissolved in dichloromethane (5 mL), and a 1,4-dioxane solution of 4M hydrogen chloride (2 mL) was added. The mixture was stirred for 5 hours, and the reaction solution was concentrated under reduced pressure to obtain the crude title compound 7k (0.46 g). The product was used directly in the next reaction without purification.

[0811] MS m / z(ESI):435.1[M+1].

[0812] Step 10

[0813] 2-(2-chloro-5-(dimethylaminocarbonyl)-3-fluoro-4,6-dihydrobenzo[6,7]oxaheptane[3,4,5-cd]indol-9-yl)methyl acetate 7l

[0814] The crude compound 7k (0.4 g, 0.92 mmol) was dissolved in tetrahydrofuran (5 mL), and triphenylphosphine (306 mg, 1.17 mmol) and diethyl azodicarbonate (191 mg, 1.09 mmol) were added sequentially at 0 °C. The mixture was stirred at room temperature for 2 hours, and the reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system B to obtain the title compound 7l (0.30 g, yield: 78.4%).

[0815] MS m / z(ESI):417.1[M+1].

[0816] Step 11

[0817] 2-(2-(1-(3-(4H-1,2,3-triazol-4-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)methyl acetate 7m

[0818] Compound 7l (0.30 g, 0.72 mmol), compound 1c (0.24 g, 0.72 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 mixed in 1,4-dioxane (10 mL) and water (2 mL). The mixture was purged with nitrogen and stirred at 80 °C for 6 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 using eluent system B to give the title compound 7m (0.31 g, yield: 73%).

[0819] MS m / z(ESI): 587.2 [M+1].

[0820] Step Twelve

[0821] 2-(1-(3-(1H-1,2,3-triazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-3-fluoro-9-(2-hydroxyethyl)-

[0822] N,N-Dimethyl-4,6-dihydrobenzo[6,7]oxaheptane[3,4,5-cd]indole-5-carboxamide 7n

[0823] Compound 7m (0.30 g, 0.51 mmol) was dissolved in tetrahydrofuran (5 mL), and lithium borohydride (22 mg, 1.02 mmol) was added under ice bath conditions. The reaction mixture was allowed to return to room temperature for 16 hours. The reaction solution was poured into ice water and extracted with ethyl acetate (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give crude title compound 7n (0.2 g). The product was used directly in the next reaction without purification.

[0824] MS m / z(ESI): 559.2 [M+1].

[0825] Step Thirteen

[0826] 2-(1-(3-(1H-1,2,3-triazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-3-fluoro-N,N-dimethyl-9-(2-oxoethyl)-4,6-dihydrobenzo[6,7]oxaheptanecyclo[3,4,5-cd]indole-5-carboxamide 7o

[0827] The crude compound 7n (0.2 g, 0.36 mmol) was dissolved in dichloromethane (5 mL), and Dess-Martin oxidant (168 mg, 0.4 mmol) was added under ice bath conditions. The mixture was stirred and kept at the same temperature for 2 hours. Saturated sodium bicarbonate solution was added to the reaction mixture, and the mixture was extracted with dichloromethane (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was purified by silica gel column chromatography using eluent system A to give the title compound 7o (0.13 g, 65%).

[0828] MS m / z(ESI): 557.2 [M+1].

[0829] Step Fourteen

[0830] 2-(1-(3-(1H-1,2,3-triazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-9-(2-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-1H,6H-spiro[furano[3,2-f]indazole-5,4'-piperidin]-1'-yl)ethyl)-3-fluoro-N,N-dimethyl-4,6-dihydrobenzo[6,7]oxaheptanecyclo[3,4,5-cd]indole-5-carboxamide 7

[0831] Compound 7o (50 mg, 0.09 mmol) and compound 1o (31.8 mg, 0.09 mmol) were dissolved in 1,2-dichloroethane (10 mL) and dimethyl sulfoxide (1 mL). Acetic acid (12 mg, 0.2 mmol) and potassium acetate (20 mg, 0.2 mmol) were added, and the mixture was stirred for 1 hour. Sodium cyanoborohydride (18 mg, 0.28 mmol) was added, and the mixture was stirred for another 16 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative high performance liquid chromatography (Waters-2545, column: Boston Phlex Prep C18, 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 give title compound 7 (9 mg, yield: 11%).

[0832] MS m / z(ESI): 895.4 [M+1].

[0833] Example 8

[0834] 6-(1-(3-(1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-4-(4-(2-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H,7H-spiro[furano[3,2-g]indazole-6,4'-piperidin]-1'-yl)ethyl)phenyl)-7-fluoro-N,N-dimethyl-1H-indole-2-carboxamide 8

[0835] first step

[0836] 6-Bromo-7-methoxy-1H-indazole 8b

[0837] 4-Bromo-2-fluoro-3-methoxybenzaldehyde 8a (9 g, 38.62 mmol, Shanghai Biotech) was dissolved in ethylene glycol dimethyl ether (100 mL), and 85% hydrazine hydrate (16 g, 271.67 mmol) was added. The reaction mixture was reacted at 100 °C for 48 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system B to give the title compound 8b (950 mg, yield: 10.8%).

[0838] MS m / z(ESI):227.1[M+1].

[0839] Step 2

[0840] 6-Bromo-3-iodo-7-methoxy-1H-indazole 8c

[0841] Compound 8b (1.10 g, 4.84 mmol) was dissolved in N,N-dimethylformamide (15 mL), and N-iodosuccinimide (1.42 g, 6.30 mmol, Shanghai Titan) was added. The mixture was stirred for 3 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 8c (1.41 g, yield: 82.4%).

[0842] MS m / z(ESI): 353.0 [M+1].

[0843] Step 3

[0844] 6-Bromo-3-iodo-7-methoxy-1-methyl-1H-indazole 8d

[0845] Compound 8c (1.41 g, 4.0 mmol) was dissolved in N,N-dimethylformamide (15 mL), and potassium carbonate (1.10 g, 8.0 mmol, Sinopharm) and methyl iodide (1.13 g, 8.0 mmol, Shanghai Titan) were added. The reaction mixture was reacted at room temperature for 3 hours. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to give the title compound 8d (900 mg, yield: 61.3%).

[0846] MS m / z(ESI): 367.1 [M+1].

[0847] Step 4

[0848] 6-Bromo-3-iodo-1-methyl-1H-indazole-7-phenol 8e

[0849] Compound 8d (900 mg, 2.45 mmol) was dissolved in N,N-dimethylformamide (10 mL), and sodium ethanethiol (2.06 g, 24.52 mmol, Shanghai Titan) was added. The reaction mixture was reacted at 80 °C for 30 min. The reaction solution was cooled to room temperature, 50 mL of water was added, and the mixture was extracted with ethyl acetate (50 mL × 3). The aqueous phases were combined, the pH was adjusted to 6-7 with 1 M hydrochloric acid, and the mixture was extracted with ethyl acetate (50 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 the title compound 8e (800 mg, yield: 92.4%).

[0850] MS m / z(ESI): 353.0 [M+1].

[0851] Step 5

[0852] 8g of 4-(bromomethyl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester

[0853] 8f of 4-(hydroxymethyl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (50 g, 234.44 mmol, prepared according to the method disclosed in the literature "Journal of Medicinal Chemistry, 2013, vol. 56, #22, p. 9275-9295") was dissolved in dichloromethane (500 mL), and triphenylphosphine (79.93 g, 304.74 mmol) and carbon tetrabromide (101.07 g, 304.77 mmol) were added under ice bath. The reaction mixture was stirred for 30 minutes while maintaining the temperature. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to give 8 g (64 g, yield: 98.8%) of the title compound. MS m / z (ESI): 220.0 [M-55].

[0854] Step 6

[0855] 4-(((6-bromo-3-iodo-1-methyl-1H-indazol-7-yl)oxy)methyl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester 8h

[0856] Compound 8e (20 g, 56.66 mmol) and compound 8 g (16.43 g, 59.49 mmol) were dissolved in N,N-dimethylformamide (200 mL), and potassium carbonate (15.66 g, 113.31 mmol) was added. The mixture was stirred for 0.5 h, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to give the title compound 8h (26.8 g, yield: 86.2%).

[0857] MS m / z(ESI):492.1[M-55].

[0858] Step 7

[0859] 4-(((3-(2,6-bis(benzyloxy)pyridin-3-yl)-6-bromo-1-methyl-1H-indazol-7-yl)oxy)methyl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester 8i

[0860] Compound 8h (10 g, 18.24 mmol) was dissolved in 1,4-dioxane (200 mL) and water (40 mL), and 2,6-bisbenzyloxypyridine-3-boronic acid pinacol ester (11.41 g, 27.34 mmol, Shanghai Bide), 1,1-bis(diphenylphosphine)ferrocene palladium dichloride (1.33 g, 1.82 mmol), and potassium carbonate (5.04 g, 36.48 mmol) were added. The mixture was purged with nitrogen and reacted at 90 °C for 3 h. The reaction solution was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate (50 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 with eluent system B to give the title compound 8i (7 g, yield: 83.9%). MS m / z (ESI): 711.6 [M+1].

[0861] Step 8

[0862] 3-(2,6-bis(benzyloxy)pyridin-3-yl)-1-methyl-2',3'-dihydro-1H,1'H,7H-spiro[furano[3,2-g]indazole-6,4'-pyridine]-1'-carboxylic acid tert-butyl ester 8j

[0863] Compound 8i (10 g, 14.05 mmol) was dissolved in 1,4-dioxane (300 mL), and sodium formate (1.91 g, 28.08 mmol), sodium acetate (2.30 g, 28.04 mmol), bis(tert-butylphosphine)palladium (1.07 g, 2.09 mmol), and tetraethylammonium chloride (4.65 g, 28.06 mmol) were added. The reaction mixture was reacted at 95 °C for 8 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system B to give the title compound 8j (5.5 g, yield: 62.05%).

[0864] MS m / z(ESI): 631.6 [M+1].

[0865] Step 9

[0866] 3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H,7H-spiro[furano[3,2-g]indazole-6,4'-piperidin]-1'-carboxylic acid tert-butyl ester 8k

[0867] Compound 8j (5.50 g, 8.72 mmol) was dissolved in tetrahydrofuran (70 mL) and methanol (30 mL), and 10% palladium on carbon (2.78 g) and palladium hydroxide (3.67 g) were added. The reaction was carried out at 70 °C for 48 hours under a hydrogen atmosphere at 30 atm. 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 8k (3.5 g). The product was used directly in the next reaction without purification.

[0868] MS m / z(ESI): 455.6 [M+1].

[0869] Step 10

[0870] 3-(1-Methyl-1H,7H-spiro[furano[3,2-g]indazole-6,4'-piperidine]-3-yl)piperidine-2,6-dione hydrochloride 8l

[0871] The crude compound 8k (5.2 g, 11.44 mmol) was dissolved in dichloromethane (100 mL), and a 1,4-dioxane solution of 4M hydrogen chloride (10 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 8l (4.46 g). The product was used directly in the next reaction without purification.

[0872] MS m / z(ESI): 355.1 [M+1].

[0873] Step 11

[0874] 6-Chloro-7-fluoro-4-(4-(2-hydroxyethyl)phenyl)-N,N-dimethyl-1H-indole-2-carboxamide 8o

[0875] 4-Bromo-6-chloro-7-fluoro-N,N-dimethyl-1H-indole-2-carboxamide 8m (1g, 3.13mmol, prepared by the method disclosed in intermediate C on page 1098 of patent application "WO2025049820") was dissolved in 1,4-dioxane (15mL) and water (3mL). 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxoborhexacyclopentan-2-yl)phenyl)ethyl-1-ol 8n (933mg, 3.76mmol, Shanghai Bide), 1,1-bis(diphenylphosphine)ferrocene palladium dichloride (227mg, 310μmol), and potassium carbonate (650mg, 4.70mmol) were added. The mixture was purged with nitrogen and reacted at 100°C for 2 hours. The reaction solution was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate (20 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 with eluent system B to give the title compound 8o (900 mg, yield: 79.7%).

[0876] MS m / z(ESI): 361.3 [M+1].

[0877] Step Twelve

[0878] 6-(1-(3-(1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-7-fluoro-4-(4-(2-hydroxyethyl)phenyl)-N,N-dimethyl-1H-indole-2-carboxamide 8p

[0879] Compound 8o (300 mg, 831 μmol) was dissolved in 1,4-dioxane (15 mL) and water (3 mL), and 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 (303 mg, 915 μmol, prepared by the method disclosed in intermediate N on page 1114 of patent application "WO2025049820") and methanesulfonic acid (2-dicyclohexylphosphino-2',4', 6'-Triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (70 mg, 83 μmol), potassium phosphate (353 mg, 1.66 mmol), nitrogen purging, reaction at 100 °C for 2.5 h. The reaction solution was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate (15 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 A to give the title compound 8p (390 mg, yield: 88.5%).

[0880] MS m / z(ESI): 530.4 [M+1].

[0881] Step Thirteen

[0882] 4-(6-(1-(3-(1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-2-(dimethylaminocarbonyl)-7-fluoro-1H-indole-4-yl)phenethyl methanesulfonate 8q

[0883] Compound 8p (150 mg, 283 μmol) was dissolved in dichloromethane (5 mL), and N,N-diisopropylethylamine (55 mg, 425 μmol) and methanesulfonyl chloride (39 mg, 340 μmol) were added. The mixture was stirred for 1 hour, water was added to the reaction solution, and the mixture was extracted with dichloromethane (10 mL × 2). The organic phases were combined and washed successively with saturated sodium bicarbonate solution and saturated sodium chloride solution. The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude title compound 8q (160 mg). The product was used directly in the next reaction without purification.

[0884] MS m / z(ESI): 608.5 [M+1].

[0885] Step Fourteen

[0886] 6-(1-(3-(1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-4-(4-(2-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H,7H-spiro[furano[3,2-g]indazole-6,4'-piperidin]-1'-yl)ethyl)phenyl)-7-fluoro-N,N-dimethyl-1H-indole-2-carboxamide 8

[0887] Compound 8q (50 mg, 82 μmol) was dissolved in N,N-dimethylacetamide (2 mL), and N,N-diisopropylethylamine (32 mg, 247 μmol) and compound 8l (30 mg, 77 μmol) were added. The mixture was stirred at 100 °C for 3 hours. After the reaction solution was cooled to room temperature, it was filtered. The filtrate 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 give title compound 8 (12 mg, yield: 16.8%).

[0888] MS m / z(ESI): 866.7 [M+1].

[0889] 1H NMR (500MHz, DMSO-d6): δ12.19(d,1H),10.89(s,1H),7.73(dd,1H),7.61(d,2H),7.44(d,1H),7.39(d ,2H),7.21(d,2H),7.01(dd,2H),6.87(s,1H),6.24–6.14(m,2H),5.33(t,1H),4.62(s,2H),4.42–4.3 7(m,3H),4.36–4.30(m,2H),4.09(s,2H),3.66(t,1H),3.60(t,1H),3.24(s,1H),3.20-3.07(m,2H),2 .99(s,6H),2.86(t,2H),2.73–2.53(m,2H),2.34-2.23(m,4H),2.21–2.07(m,4H),2.05–1.93(m,4H).

[0890] Example 9

[0891] 6-(1-(3-(1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-4-(4-(2-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H,6H-spiro[furano[2,3-f]indazole-7,4'-piperidin]-1'-yl)ethyl)phenyl)-7-fluoro-N,N-dimethyl-1H-indole-2-carboxamide 9

[0892] first step

[0893] 6-Bromo-3-iodo-5-methoxy-1H-indazole 9b

[0894] 6-Bromo-5-methoxy-1H-indazole 9a (25 g, 110.10 mmol, Shanghai Bide) was dissolved in N,N-dimethylformamide (400 mL), and 1-iodopyrrolidine-2,5-dione (27.50 g, 122.23 mmol, Shanghai Bide) was added. The mixture was stirred for 2 hours. The reaction solution was concentrated under reduced pressure, and dichloromethane (400 mL) was added. After stirring for 1 hour, the mixture was filtered. The filtrate was concentrated under reduced pressure to obtain the crude title compound 9b (35 g). The product was used directly in the next reaction without purification.

[0895] MS m / z(ESI): 353.1 [M+1].

[0896] Step 2

[0897] 6-Bromo-3-iodo-5-methoxy-1-methyl-1H-indazole 9c

[0898] Compound 9b (35 g, 99.16 mmol) was dissolved in N,N-dimethylformamide (500 mL), and iodomethane (16.90 g, 119.06 mmol) and cesium carbonate (70 g, 214.84 mmol) were added. The mixture was stirred for 3 hours. Ethyl acetate (200 mL) was added to the reaction solution, and the mixture was filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system D to give the title compound 9c (16 g, yield: 43.9%).

[0899] MS m / z(ESI): 367.2 [M+1].

[0900] Step 3

[0901] 6-Bromo-3-iodo-1-methyl-1H-indazole-5-phenol 9d

[0902] Compound 9c (32 g, 87.20 mmol) was dissolved in dichloromethane (300 mL), and a 2M boron tribromide solution in dichloromethane (299.4 mL) was added at 0 °C. The reaction mixture was reacted at 30 °C for 12 hours. The reaction solution was cooled to room temperature (0 °C), quenched with methanol, and concentrated under reduced pressure. The residue was slurried with saturated sodium bicarbonate solution, filtered, and the filter cake was washed with water, dried, and then slurried with dichloromethane. After filtration and drying, the crude title compound 9d (24.4 g) was obtained. The product was used directly in the next reaction without purification.

[0903] MS m / z(ESI): 353.1 [M+1].

[0904] Step 4

[0905] 4-(((6-bromo-3-iodo-1-methyl-1H-indazol-5-yl)oxy)methyl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester 9e

[0906] Compound 9d (12.80 g, 36.26 mmol) and compound 8 g (11.80 g, 42.73 mmol) were dissolved in N,N-dimethylformamide (200 mL), and potassium carbonate (9.84 g, 71.20 mmol) was added. The mixture was stirred for 0.5 h, and the reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to give title compound 9e (19 g, yield: 97.33%).

[0907] MS m / z(ESI):492.3[M-55].

[0908] Step 5

[0909] 4-(((3-(2,6-bis(benzyloxy)pyridin-3-yl)-6-bromo-1-methyl-1H-indazol-5-yl)oxy)methyl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester 9f

[0910] Compound 9e (13.70 g, 24.99 mmol) was dissolved in 1,4-dioxane (150 mL) and water (30 mL), and 2,6-bisbenzyloxypyridine-3-boronic acid pinacol ester (12.51 g, 29.98 mmol, Shanghai Bide), 1,1-bis(diphenylphosphine)ferrocene palladium dichloride (1.82 g, 2.49 mmol), and potassium carbonate (6.90 g, 49.92 mmol) were added. The mixture was purged with nitrogen and reacted at 100 °C for 2.5 h. The reaction solution was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate (50 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 with eluent system B to give the title compound 9f (16.4 g, yield: 92.2%).

[0911] MS m / z(ESI): 711.5 [M+1].

[0912] Step 6

[0913] 9g of 3-(2,6-bis(benzyloxy)pyridin-3-yl)-1-methyl-2',3'-dihydro-1H,1'H,6H-spiro[furano[2,3-f]indazole-7,4'-pyridine]-1'-carboxylic acid tert-butyl ester

[0914] Compound 9f (16.40 g, 23.04 mmol) was dissolved in N,N-dimethylformamide (150 mL), and sodium formate (2.50 g, 36.76 mmol), sodium acetate (4.91 g, 59.85 mmol), palladium acetate (569 mg, 2.53 mmol), and tetraethylammonium chloride (6.10 g, 36.81 mmol) were added. The reaction mixture was reacted at 75 °C for 12 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system B to give the title compound 9f (9.1 g, yield: 62.6%).

[0915] MS m / z(ESI): 631.8 [M+1].

[0916] Step 7

[0917] 3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H,6Hspiro[furano[2,3-f]indazole-7,4'-piperidin]-1'-carboxylic acid tert-butyl ester 9h

[0918] 9 g (1.50 g, 2.38 mmol) of the compound was dissolved in a mixed solvent of tetrahydrofuran (15 mL) and methanol (30 mL), and 10% palladium on carbon (380 mg) and palladium hydroxide (500 mg) were added. The mixture was purged with hydrogen and reacted at 70 °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 9h (870 mg, yield: 24.2%). The product was used directly in the next reaction without purification.

[0919] MS m / z(ESI): 455.6 [M+1].

[0920] Step 8

[0921] 3-(1-Methyl-1H,6H-spiro[furano[2,3-f]indazole-7,4'-piperidine]-3-yl)piperidine-2,6-dione hydrochloride 9i

[0922] Compound 9h (870 mg, 1.91 mmol) was dissolved in dichloromethane (10 mL), and a 1,4-dioxane solution of 4M hydrogen chloride (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 9i (750 mg). The product was used directly in the next reaction without purification.

[0923] MS m / z(ESI): 355.1 [M+1].

[0924] Step 9

[0925] 6-(1-(3-(1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-7-fluoro-N,N-dimethyl-4-(4-(2-oxoethyl)phenyl)-1H-indole-2-carboxamide 9m

[0926] Compound 8p (50 mg, 94 μmol) was dissolved in dichloromethane (2 mL), and Dys-Martin oxidant (60 mg, 141 μmol) was added under ice bath conditions. The mixture was stirred and kept at the same temperature for 12 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, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude title compound 9m (39 mg). The product was used directly in the next reaction without purification.

[0927] MS m / z(ESI): 528.5 [M+1].

[0928] Step 10

[0929] 6-(1-(3-(1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-4-(4-(2-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H,6H-spiro[furano[2,3-f]indazole-7,4'-piperidin]-1'-yl)ethyl)phenyl)-7-fluoro-N,N-dimethyl-1H-indole-2-carboxamide 9

[0930] Compound 9m (39 mg, 74 μmol) and compound 9i (30 mg, 77 μmol) were dissolved in 1,2-dichloroethane (10 mL). Sodium triacetoxyborohydride (16 mg, 74 μmol) was added under ice bath conditions. The mixture was stirred and kept at the same temperature for 1.5 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, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. 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 give title compound 9 (10 mg, yield: 15.7%).

[0931] MS m / z(ESI): 866.7 [M+1].

[0932] 1 H NMR (500MHz, DMSO-d6): δ12.20(d,1H),10.85(s,1H),7.73(dd,1H),7.61(dd,2H),7.52(d,1H),7.46–7.36(m, 3H),7.20(s,1H),7.04(dd,1H),6.92(s,1H),6.87(q,1H),6.66(s,1H),6.20(dt,1H),6.18–6.14(m,1H),5.33 (t,1H),4.43–4.28(m,4H),4.28-4.24(m,1H),4.23(t,1H),3.95(s,3H),3.66(t,1H),3.60(t,1H),3.23-3.18 (m,2H),2.99(s,6H),2.86(t,2H),2.69–2.53(m,4H),2.32-2.25(m,2H),2.17–2.07(m,4H),2.05–1.95(m,4H).

[0933] Example 10

[0934] 6-(1-(3-(1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-4-(4-(2-((4aR)-8-(2,6-dioxopiperidin-3-yl)-10-methyl-9-oxo-1,2,4a,5,9,10-hexahydro-8H-imidazo[4',5':4,5]benzo[1,2-b]pyrazino[1,2-d][1,4]oxazin-3(4H)-yl)ethyl)phenyl)-7-fluoro-N,N-dimethyl-1H-indole-2-carboxamide 10

[0935] first step

[0936] 4,5-Difluoro-N-methyl-2-nitroaniline 10b

[0937] 1,2,4-trifluoro-5-nitrobenzene 10a (20 g, 113 mmol) was dissolved in ethanol (60 mL), and 30% methylamine methanol solution (23.34 g, 225.87 mmol) was added under ice bath conditions. The mixture was allowed to return to room temperature naturally with stirring for 2 hours. Water was added to the reaction solution, and the mixture was stirred for 0.5 hours. The mixture was then filtered, and the filter cake was slurried with 100 mL of ethyl acetate / petroleum ether (V:V = 1:4). The mixture was filtered again, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system B to give the title compound 10b (3 g, yield: 14.1%).

[0938] MS m / z(ESI): 189.1 [M+1].

[0939] Step 2

[0940] (R)-4-(2-fluoro-5-(methylamino)-4-nitrophenyl)-3-(hydroxymethyl)piperazine-1-carboxylic acid tert-butyl ester 10c

[0941] Compound 10b (750 mg, 3.99 mmol) was dissolved in acetonitrile (30 mL), and (R)-3-hydroxymethylpiperazine-1-carboxylic acid tert-butyl ester (948 mg, 4.38 mmol, Shanghai Bide) and cesium carbonate (4.54 g, 13.95 mmol) were added. The mixture was stirred at 40 °C for 0.5 h. After the reaction solution cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate (20 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 10c (1.53 g). The product was used directly in the next reaction without purification.

[0942] MS m / z(ESI): 385.4 [M+1].

[0943] Step 3

[0944] (R)-9-(methylamino)-8-nitro-1,2,4a,5-tetrahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine-3(4H)-carboxylic acid tert-butyl ester 10d

[0945] The crude compound 10c (1.53 g, 3.98 mmol) was dissolved in dimethyl sulfoxide (15 mL), and cesium carbonate (4.54 g, 13.93 mmol) was added. The mixture was stirred at 120 °C for 2 hours. After the reaction solution cooled to room temperature, water was added, and a solid precipitated. The solid was filtered, and the filter cake was washed with water and dried to obtain the crude title compound 10d (1.4 g). The product was used directly in the next reaction without purification.

[0946] MS m / z(ESI): 365.4 [M+1].

[0947] Step 4

[0948] (R)-8-amino-9-(methylamino)-1,2,4a,5-tetrahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine-3(4H)-carboxylic acid tert-butyl ester 10e

[0949] The crude compound 10d (1.40 g, 3.84 mmol) was dissolved in ethanol (50 mL) and water (10 mL), and iron powder (1.07 g, 19.21 mmol) and ammonium chloride (1.03 g, 19.21 mmol) were added. The mixture was stirred at 85 °C for 1 hour. After the reaction solution was cooled to room temperature, it was filtered. Saturated sodium bicarbonate solution was added to the filtrate, and the mixture was extracted with dichloromethane (20 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 10e (970 mg). The product was used directly in the next reaction without purification.

[0950] MS m / z(ESI): 335.4 [M+1].

[0951] Step 5

[0952] (R)-10-methyl-9-oxo-1,2,4a,5,9,10-hexahydro-8H-imidazo[4',5':4,5]benzo[1,2-b]pyrazino[1,2-d][1,4]oxazine-3(4H)-carboxylic acid tert-butyl ester 10f

[0953] The crude compound 10e (970 mg, 2.90 mmol) was dissolved in acetonitrile (30 mL), and N,N'-carbonyldiimidazole (941 mg, 5.80 mmol) was added. The mixture was purged with nitrogen and stirred at 80 °C for 10 hours. After the reaction solution cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate (15 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 using eluent system A to give the title compound 10f (1 g, yield: 95.6%).

[0954] MS m / z(ESI): 361.3 [M+1].

[0955] Step 6

[0956] (4aR)-8-(1-(4-methoxybenzyl)-2,6-dioxopiperidin-3-yl)-10-methyl-9-oxo-1,2,4a,5,9,10-hexahydro-8H-imidazo[4',5':4,5]benzo[1,2-b]pyrazino[1,2-d][1,4]oxazine-3(4H)-carboxylic acid tert-butyl ester 10g

[0957] Compound 10f (500 mg, 1.39 mmol) was dissolved in N,N-dimethylformamide (15 mL), and sodium hydride (58 mg, 1.53 mmol, 60% purity) was added at 0 °C. The mixture was stirred for 0.5 h while maintaining the temperature. Then, 3-bromo-1-(4-methoxybenzyl)piperidine-2,6-dione (520 mg, 1.66 mmol, Shanghai Bide) was added. The mixture was allowed to return to room temperature and stirred for 16 h. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system A to give the title compound 10 g (100 mg, yield: 12.2%).

[0958] MS m / z(ESI): 592.5 [M+1].

[0959] Step 7

[0960] 3-((R)-10-methyl-9-oxo-1,2,3,4,4a,5,9,10-octahydro-8H-imidazo[4',5':4,5]benzo[1,2-b]pyrazino[1,2-d][1,4]oxazin-8-yl)piperidine-2,6-dione 10h

[0961] 10 g (100 mg, 169 μmol) of the compound was dissolved in 10 mL of trifluoroacetic acid, and 4 mL of trifluoromethanesulfonic acid was added. The mixture was stirred at 70 °C for 2 hours. After the reaction solution was cooled to room temperature, it was concentrated under reduced pressure. 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 40%-60%, flow rate: 30 mL / min) to give the title compound 10h (31 mg, yield: 50%).

[0962] MS m / z(ESI): 372.3 [M+1].

[0963] Step 8

[0964] 6-(1-(3-(1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-4-(4-(2-((4aR)-8-(2,6-dioxopiperidin-3-yl)-10-methyl-9-oxo-1,2,4a,5,9,10-hexahydro-8H-imidazo[4',5':4,5]benzo[1,2-b]pyrazino[1,2-d][1,4]oxazin-3(4H)-yl)ethyl)phenyl)-7-fluoro-N,N-dimethyl-1H-indole-2-carboxamide 10

[0965] Compound 9m (45 mg, 85 μmol) and compound 10h (31 mg, 85 μmol) were dissolved in 1,2-dichloroethane (10 mL) and dimethyl sulfoxide (0.5 mL). Sodium acetate (14 mg, 171 μmol) was added, and the mixture was stirred for 0.5 hours. Then, sodium triacetoxyborohydride (36 mg, 171 μmol) was added, and the mixture was stirred for 16 hours. The reaction solution was 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 give title compound 10 (16 mg, yield: 21.2%).

[0966] MS m / z(ESI): 883.4 [M+1].

[0967] 1H NMR(500MHz,DMSO)δ12.18(d,1H),11.03(s,1H),7.71(dd,1H),7.58(dd,2H),7.48-7.3 1(m,3H),7.02(dd,1H),6.82(d,2H),6.58(d,1H),6.26-6.08(m,2H),5.22(dd,1H),4.47 -4.27(m,4H),4.23(dd,1H),3.96-3.75(m,2H),3.61(dt,3H),3.27(s,4H),3.24-2.92(m ,10H),2.87-2.83(m,3H),2.63(qd,4H),2.41-2.18(m,3H),1.97(ddd,1H),1.84(t,1H).

[0968] Example 11

[0969] 6-(1-(3-(1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-4-(4-(2-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-3H,7H-spiro[furano[3,2-e]indazole-8,4'-piperidin]-1'-yl)ethyl)phenyl)-7-fluoro-N,N-dimethyl-1H-indole-2-carboxamide 11-p1

[0970] 6-(1-(3-(1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-4-(4-(2-(2-(2,6-dioxopiperidin-3-yl)-1-methyl-2H,7H-spiro[furano[3,2-e]indazole-8,4'-piperidin]-1'-yl)ethyl)phenyl)-7-fluoro-N,N-dimethyl-1H-indole-2-carboxamide 11-p2

[0971] first step

[0972] 3-Methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-5-phenol 11b

[0973] 3-Methyl-1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxoboronacyclopentan-2-yl)-1H-indazole 11a (9 g, 26.59 mmol, prepared by the method disclosed in Example 2 on page 8 of patent application “CN104610229B”), sodium perborate tetrahydrate (12.07 g, 78.38 mmol) was dissolved in tetrahydrofuran (100 mL) and water (100 mL), and reacted at 50 °C for 2 hours. After the reaction solution was cooled to room temperature, it 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 title compound 11b (5.1 g, yield: 83.4%).

[0974] MS m / z(ESI):233.2[M+1].

[0975] Step 2

[0976] 4-Bromo-3-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-5-phenol 11c

[0977] Compound 11b (1.50 g, 6.46 mmol) was dissolved in tetrahydrofuran (30 mL), and N-bromosuccinimide (1.15 g, 6.46 mmol) 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 11c (1.55 g, yield: 77.1%).

[0978] MS m / z(ESI): 311.2 [M+1].

[0979] Step 3

[0980] 4-(((4-bromo-3-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)oxy)methyl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester 11d

[0981] Compound 11c (1.55 g, 4.98 mmol) and compound 8 g (2.06 g, 7.47 mmol) were dissolved in N,N-dimethylformamide (20 mL), and potassium carbonate (1.38 g, 9.96 mmol) was added. The mixture was stirred for 0.5 h, and the reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to give title compound 11d (2.4 g, yield: 95.1%).

[0982] MS m / z(ESI): 506.3 [M+1].

[0983] Step 4

[0984] 1-Methyl-3-(tetrahydro-2H-pyran-2-yl)-3H,7H-spiro[furano[3,2-e]indazole-8,4'-piperidine]-1'-carboxylic acid tert-butyl ester 11e

[0985] Compound 11d (500 mg, 987 μmol) was dissolved in toluene (30 mL), and tri-n-butyltin hydride (458 mg, 1.58 mmol) and azobisisobutyronitrile (32 mg, 197 μmol) were added. The mixture was purged with nitrogen and reacted at 90 °C for 16 hours. After cooling the reaction solution to room temperature, 10% potassium fluoride solution was added, and the mixture was extracted with ethyl acetate (15 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 11e (380 mg, yield: 90%).

[0986] MS m / z(ESI):428.4[M+1].

[0987] Step 5

[0988] 1-Methyl-3H,7H-spiro[furano[3,2-e]indazole-8,4'-piperidine]-1'-carboxylic acid tert-butyl ester 11f

[0989] Compound 11e (340 mg, 795 μmol) was dissolved in methanol (10 mL), and p-toluenesulfonic acid monohydrate (605 mg, 3.18 mmol) was added. The mixture was stirred for 3 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate (15 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 11f (110 mg, yield: 40.2%).

[0990] MS m / z(ESI): 344.3 [M+1].

[0991] Step 6

[0992] 3-(2,6-dioxopiperidin-3-yl)-1-methyl-3H,7H-spiro[furano[3,2-e]indazole-8,4'-piperidin]-1'-carboxylic acid tert-butyl ester 11g-1

[0993] 2-(2,6-dioxopiperidin-3-yl)-1-methyl-2H,7H-spiro[furano[3,2-e]indazole-8,4'-piperidin]-1'-carboxylic acid tert-butyl ester 11g-2

[0994] Compound 11f (110 mg, 320 μmol) was dissolved in N,N-dimethylformamide (15 mL), sodium hydride (37 mg, 961 μmol, 60% purity) was added at 0 °C, and the mixture was stirred for 0.5 h while maintaining the temperature. Then, 3-bromo-1-(4-methoxybenzyl)piperidine-2,6-dione (92 mg, 480 μmol) and potassium iodide (53 mg, 320 μmol) were added, and the mixture was allowed to return to room temperature and stirred for 4 h. The reaction mixture was quenched with saturated ammonium chloride solution, and 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 with eluent system A to give a mixture of title compounds 11g-1 and 11g-2 (70 mg, yield: 48.1%).

[0995] MS m / z(ESI): 455.4 [M+1].

[0996] Step 7

[0997] 3-(1-Methyl-3H,7H-spiro[furano[3,2-e]indazole-8,4'-piperidine]-3-yl)piperidine-2,6-dione hydrochloride 11h-1

[0998] 3-(1-Methyl-2H,7H-spiro[furano[3,2-e]indazole-8,4'-piperidine]-2-yl)piperidine-2,6-dione hydrochloride 11h-2

[0999] A mixture of compounds 11g-1 and 11g-2 (70 mg, 154 μmol) was dissolved in dichloromethane (5 mL), and a 1,4-dioxane solution of 4M hydrogen chloride (2 mL) was added. The mixture was stirred for 1 hour, and the reaction solution was concentrated under reduced pressure to obtain a crude mixture of the title compounds 11h-1 and 11h-2 (59 mg). The product was used directly in the next reaction without purification.

[1000] MS m / z(ESI): 355.4 [M+1].

[1001] Step 8

[1002] 6-(1-(3-(1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-4-(4-(2-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-3H,7H-spiro[furano[3,2-e]indazole-8,4'-piperidin]-1'-yl)ethyl)phenyl)-7-fluoro-N,N-dimethyl-1H-indole-2-carboxamide 11-p1

[1003] 6-(1-(3-(1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-4-(4-(2-(2-(2,6-dioxopiperidin-3-yl)-1-methyl-2H,7H-spiro[furano[3,2-e]indazole-8,4'-piperidin]-1'-yl)ethyl)phenyl)-7-fluoro-N,N-dimethyl-1H-indole-2-carboxamide 11-p2

[1004] Compound 9m (80 mg, 152 μmol), a mixture of compounds 11h-1 and 11h-2 (59 mg, 152 μmol), was dissolved in tetrahydrofuran (10 mL) and dimethyl sulfoxide (2 mL). Sodium triacetoxyborohydride (96 mg, 455 μmol) was added, and the mixture was stirred for 16 hours. The reaction solution was 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 25%-60%, flow rate: 30 mL / min) to give the title compound (8 mg, yield: 6.1%) and (5 mg, yield: 3.8%).

[1005] Single configuration compound (shorter retention time): (8 mg, yield: 6.1%).

[1006] MS m / z(ESI): 866.2 [M+1].

[1007] HPLC analysis: Retention time 1.742 min, purity: 90% (Column: HALO) C18, 2.7 μm, 3.0 × 30 mm; Mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%). 1 H NMR (500MHz, CDCl3): δ9.62(d,1H),8.16(s,1H),7.70(t,2H),7.61–7.41(m ,4H),7.19(d,1H),7.06–6.90(m,3H),6.21(ddd,2H),5.37(d,1H),5.28–5.1 8(m,1H),4.72–4.41(m,6H),4.29(d,1H),3.79(d,1H),3.58(d,1H),3.48–3. 07(m,9H),3.01(dt,4H),2.93–2.70(m,5H),2.53–2.19(m,6H),2.03(d,3H).

[1008] Single-configuration compound (longer retention time): (5 mg, yield: 3.8%).

[1009] MS m / z(ESI): 866.2 [M+1].

[1010] HPLC analysis: Retention time 1.948 min, purity: 90% (Column: HALO) C18, 2.7 μm, 3.0 × 30 mm; Mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%). 1 H NMR (500MHz, CDCl3): δ9.50(d,1H),8.21–8.04(m,1H),7.67–7.45(m,4H),7.39 (t,2H),7.18–6.81(m,4H),6.30–6.13(m,2H),5.37(t,1H),5.23(dd,1H),4.55 (dt,4H),4.29(s,1H),3.81(t,1H),3.59(t,2H),3.45–2.99(m,9H),2.82(d,7H ),2.58–2.33(m,4H),2.34–2.15(m,2H),2.18–1.95(m,3H),1.97–1.69(m,3H).

[1011] Example 12

[1012] 6-(1-(3-(1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-4-(4-(2-((4aS)-8-(2,6-dioxopiperidin-3-yl)-10-methyl-9-oxo-1,2,4a,5,9,10-hexahydro-8H-imidazo[4',5':4,5]benzo[1,2-b]pyrazino[1,2-d][1,4]oxazin-3(4H)-yl)ethyl)phenyl)-7-fluoro-N,N-dimethyl-1H-indole-2-carboxamide 12

[1013] Using steps two through eight of the synthetic route in Example 10, the starting compound (R)-3-hydroxymethylpiperazine-1-carboxylic acid tert-butyl ester was replaced with (S)-3-hydroxymethylpiperazine-1-carboxylic acid tert-butyl ester to obtain title compound 12 (18 mg, yield: 17.9%).

[1014] MS m / z(ESI): 883.8 [M+1].

[1015] 1H NMR (500MHz, DMSO-d6): δ12.18(d,1H),11.03(s,1H),7.71(dd,1H),7.58(d,2H),7.47- 7.33(m,3H),7.02(dd,1H),6.88-6.74(m,2H),6.58(d,1H),6.25-6.10(m,2H),5.23(dd, 1H),4.47-4.27(m,4H),4.23(dd,1H),3.94-3.76(m,2H),3.61(dt,3H),3.27(s,4H),3. 24-2.93(m,10H),2.85(t,3H),2.72-2.56(m,4H),2.37-2.19(m,3H),2.02-1.79(m,2H).

[1016] Example 13

[1017] 6-(1-(3-(1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-4-(4-(2-((7aR)-3-(2,6-dioxopiperidin-3-yl)-1-methyl-7a,8,10,11-tetrahydro-3H-pyrazino[1',2':4,5][1,4]oxazino[3,2-e]indazole-9(7H)-yl)ethyl)phenyl)-7-fluoro-N,N-dimethyl-1H-indole-2-carboxamide 13

[1018] Title compound 13 was prepared by referring to the present disclosure and known technical methods.

[1019] MS m / z(ESI): 867.4 [M+1].

[1020] Example 14

[1021] 6-(1-(3-(1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-4-(4-(2-((7aS)-3-(2,6-dioxopiperidin-3-yl)-1-methyl-7a,8,10,11-tetrahydro-3H-pyrazino[1',2':4,5][1,4]oxazino[3,2-e]indazole-9(7H)-yl)ethyl)phenyl)-7-fluoro-N,N-dimethyl-1H-indole-2-carboxamide 14

[1022] Title compound 14 was prepared by referring to the present disclosure and known technical methods.

[1023] MS m / z(ESI): 867.4 [M+1].

[1024] Example 15

[1025] 6-(1-(3-(1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-4-(4-(2-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-1H,6H-spiro[furano[3,2-f]indazole-5,4'-piperidin]-1'-yl)ethyl)phenyl)-7-fluoro-N,N-dimethyl-1H-indole-2-carboxamide 15

[1026] Title compound 15 was prepared by referring to the present disclosure and known technical methods.

[1027] MS m / z(ESI): 866.4 [M+1].

[1028] Example 16

[1029] 6-(1-(3-(1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-4-(4-(2-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-2-oxo-1,2,3,6-tetrahydrospiro[benzofurano[6,7-d]imidazol-7,4'-piperidin]-1'-yl)ethyl)phenyl)-7-fluoro-N,N-dimethyl-1H-indole-2-carboxamide 16

[1030] Title compound 16 was prepared by referring to the present disclosure and known technical methods.

[1031] MS m / z(ESI): 882.4 [M+1].

[1032] Example 17

[1033] 6-(1-(3-(1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-4-(4-(2-(6-(2,6-dioxopiperidin-3-yl)-8-methyl-3,6-dihydrospiro[furano[2,3-e]indazole-2,4'-piperidin]-1'-yl)ethyl)phenyl)-7-fluoro-N,N-dimethyl-1H-indole-2-carboxamide 17

[1034] Title compound 17 was prepared by referring to the present disclosure and known technical methods.

[1035] MS m / z(ESI): 866.4 [M+1].

[1036] Example 18

[1037] 6-(1-(3-(1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-4-(4-(2-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1,6-dihydrospiro[furano[3,2-g]indazole-7,4'-piperidin]-1'-yl)ethyl)phenyl)-7-fluoro-N,N-dimethyl-1H-indole-2-carboxamide 18

[1038] Title compound 18 was prepared by referring to the methods disclosed herein and known techniques.

[1039] MS m / z(ESI): 866.4 [M+1].

[1040] Example 19

[1041] 6-(1-(3-(1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-4-(4-(4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H,7H-spiro[furano[3,2-g]indazole-6,4'-piperidin]-1'-yl)piperidin-1-yl)-3-fluorophenyl)-7-fluoro-N,N-dimethyl-1H-indole-2-carboxamide formate 19

[1042] first step

[1043] 8-(4-bromo-2-fluorophenyl)-1,4-dioxa-8-azaspiro[4.5]decane 19b

[1044] 4-Bromo-2-fluoro-1-iodobenzene 19a (1 g, 3.32 mmol, Shanghai Bide) and 4-piperidinone ethylene glycol (523 mg, 3.66 mmol, Shanghai Shaoyuan) were dissolved in toluene (5 mL). Sodium tert-butoxide (383 mg, 3.99 mmol), tris(dibenzylacetone)dipalladium (304 mg, 332 μmol), and 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (621 mg, 997 μmol) were added. The mixture was purged with nitrogen and stirred in a microwave at 130 °C for 1.5 h. After cooling to room temperature, 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 19b (580 mg, yield: 55.1%).

[1045] MS m / z(ESI): 316.1 [M+1].

[1046] Step 2

[1047] 1-(4-bromo-2-fluorophenyl)piperidin-4-one 19c

[1048] Compound 19b (550 mg, 1.74 mmol) was dissolved in tetrahydrofuran (5 mL), and 2 M sulfuric acid (5 mL) was added. The mixture was stirred at 80 °C for 16 hours. After the reaction solution cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined and washed successively with saturated sodium bicarbonate solution and saturated sodium chloride solution. The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system B to give the title compound 19c (300 mg, yield: 63.3%).

[1049] MS m / z(ESI):272.0[M+1].

[1050] Step 3

[1051] 3-(1'-(1-(4-bromo-2-fluorophenyl)piperidin-4-yl)-1-methyl-1H,7H-spiro[furano[3,2-g]indazole-6,4'-piperidin]-3-yl)piperidin-2,6-dione 19d

[1052] Compound 19c (60 mg, 220 μmol) and compound 8l (86 mg, 220 μmol) were dissolved in 1,2-dichloroethane (2 mL), and tetraethyl titanate (251 mg, 1.10 mmol) was added. The mixture was stirred at 65 °C for 2 hours, then cooled to room temperature. Sodium borohydride acetate (140 mg, 661 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 ethyl acetate (10 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 19d (30 mg, yield: 22.2%). MS m / z (ESI): 610.2 [M+1].

[1053] Step 4

[1054] 6-(1-(3-(1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-4-(4-(4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H,7H-spiro[furano[3,2-g]indazole-6,4'-piperidin]-1'-yl)piperidin-1-yl)-3-fluorophenyl)-7-fluoro-N,N-dimethyl-1H-indole-2-carboxamide formate 19

[1055] Compound 19d (30 mg, 49 μmol), 6-(1-(3-(1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-7-fluoro-N,N-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxoborhexacyclopentan-2-yl)-1H-indole-2-carboxamide 19e (26 mg, 49 μmol), were prepared according to the method described in patent application "WO2025049820". The intermediate AR, prepared by the method disclosed on page 1145 of the manual, was dissolved in 1,4-dioxane (5 mL) and water (1 mL), and methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (4 mg, 4.9 μmol) and potassium phosphate (21 mg, 98 μmol) were added. The mixture was purged with nitrogen and reacted at 80 °C for 1.5 hours. After the reaction solution was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate (5 mL × 3). 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 (0.1% formic acid) and acetonitrile, gradient ratio: acetonitrile 18%-40%, flow rate: 30 mL / min) to give title compound 19 (20 mg, yield: 43.3%).

[1056] MS m / z(ESI): 939.6 [M+1].

[1057] 1 H NMR (500MHz, DMSO-d6): δ12.21(d,1H),10.90(s,1H),8.30(s,1H),7.73(dd,1H),7.47–7.36(m,3H) ,7.19(dd,2H),7.08–6.98(m,2H),6.89(d,1H),6.24–6.13(m,2H),4.61(s,2H),4.42–4.36(m,3H),4 .33(dt,2H),4.09(s,3H),3.66(t,1H),3.59(t,2H),3.52(d,3H),3.36(s,6H),3.01–2.93(m,4H),2. 75(t,2H),2.69–2.63(m,1H),2.40–2.25(m,6H),2.20–2.11(m,1H),1.99–1.86(m,4H),1.70(t,4H).

[1058] Examples 19-p1, 19-p2

[1059] 6-(1-(3-(1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-4-(4-(4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H,7H-spiro[furano[3,2-g]indazole-6,4'-piperidin]-1'-yl)piperidin-1-yl)-3-fluorophenyl)-7-fluoro-N,N-dimethyl-1H-indole-2-carboxamide 19-1

[1060] (R)-6-(1-(3-(1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-4-(4-(4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H,7H-spiro[furano[3,2-g]indazole-6,4'-piperidin]-1'-yl)piperidin-1-yl)-3-fluorophenyl)-7-fluoro-N,N-dimethyl-1H-indole-2-carboxamide 19-p1

[1061] (S)-6-(1-(3-(1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-4-(4-(4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H,7H-spiro[furano[3,2-g]indazole-6,4'-piperidin]-1'-yl)piperidin-1-yl)-3-fluorophenyl)-7-fluoro-N,N-dimethyl-1H-indole-2-carboxamide 19-p2

[1062] Compound 19d (760 mg, 1.24 mmol) and compound 19e (700 mg, 1.31 μmol) were dissolved in 1,4-dioxane (20 mL) and water (4 mL), and methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (105 mg, 124 μmol) and potassium phosphate (528 mg, 2.49 mmol) were added. The mixture was purged with nitrogen and reacted at 80 °C for 1.5 h. After the reaction solution was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate (20 mL × 3). 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 20%-55%, flow rate: 30 mL / min) to give the title compound 19-1 (450 mg, yield: 38.5%).

[1063] Compound 19-1 (550 mg) was resolved by a chiral column (column: (S,S)-Whelk-O1, 20×250 mm, 10 μm; mobile phase A: acetonitrile, mobile phase B: ethanol, gradient ratio: A:B = 20:80, flow rate: 20 mL / min) to give title compounds 19-p1 (210 mg, yield: 38.2%) and 19-p2 (210 mg, yield: 38.2%).

[1064] Single configuration compound (shorter retention time): 19-p1 (210 mg, yield: 38.2%).

[1065] MS m / z(ESI): 939.7 [M+1].

[1066] Chiral HPLC analysis: Retention time 6.822 min, purity: 99.9% (Column: (S,S)-Whelk- 4.6 × 150 mm, 5 μm; mobile phase A: ethanol, mobile phase B: acetonitrile, gradient ratio: A:B = 80:20, flow rate: 1.0 mL / min).

[1067] 1 H NMR (500MHz, CDCl3): δ9.61(d,1H),8.20(s,1H),7.54–7.44(m,2H),7.33–7.27(m,2H),7.17(d,1H),7 .06(q,1H),7.00–6.90(m,3H),6.20(dd,1H),6.13(d,1H),4.57–4.49(m,4H),4.47(s,1H),4.26(dd,2H ),4.16(s,3H),3.77(t,1H),3.64(d,2H),3.55(t,1H),3.39(s,3H),3.20(s,3H),3.00(ddd,5H),2.79( t,2H),2.67(ddd,1H),2.57–2.45(m,2H),2.40–2.30(m,5H),2.09(td,2H),1.99(d,2H),1.83(dd,4H).

[1068] Single configuration compound (longer retention time): 19-p2 (210 mg, yield: 38.2%).

[1069] MS m / z(ESI): 939.7 [M+1].

[1070] Chiral HPLC analysis: Retention time 10.988 min, purity: 99.9% (Column: (S,S)-Whelk- 4.6 × 150 mm, 5 μm; mobile phase A: ethanol, mobile phase B: acetonitrile, gradient ratio: A:B = 80:20, flow rate: 1.0 mL / min).

[1071] 1 H NMR (500MHz, CDCl3): δ9.59(d,1H),8.15(s,1H),7.57–7.47(m,2H),7.36–7.30(m,2H),7.20(d,1H),7. 09(q,1H),7.03–6.92(m,3H),6.23(dd,1H),6.16(d,1H),4.62–4.52(m,4H),4.49(s,1H),4.28(t,2H),4 .19(s,3H),3.80(t,1H),3.67(d,2H),3.58(t,1H),3.42(s,3H),3.23(s,3H),3.03(ddd,5H),2.81(t,2H ),2.70(ddd,1H),2.60–2.47(m,2H),2.38(qd,5H),2.16–2.07(m,2H),2.06–1.99(m,2H),1.86(dd,4H).

[1072] Example 20

[1073] 6-(1-(3-(1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-4-(4-(4-((3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H,7H-spiro[furano[3,2-g]indazole-6,4'-piperidin]-1'-yl)methyl)piperidin-1-yl)-3-fluorophenyl)-7-fluoro-N,N-dimethyl-1H-indole-2-carboxamide formate 20

[1074] first step

[1075] (1-(4-bromo-2-fluorophenyl)piperidin-4-yl)methanol20b

[1076] 4-Bromo-2-fluoro-1-iodobenzene 19a (5.74 g, 19.10 mmol) and piperidin-4-ylmethanol 20a (2 g, 17.36 mmol, Shanghai Shaoyuan) were dissolved in dimethyl sulfoxide (50 mL). Cuprous iodide (661 mg, 3.47 mmol), L-proline (800 mg, 6.95 mmol), and potassium carbonate (4.79 g, 34.73 mmol) were added. The mixture was purged with nitrogen and stirred at 90 °C for 16 hours. After the reaction solution cooled to room temperature, a saturated ammonium chloride solution was added, and the mixture was extracted with ethyl acetate (50 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 the title compound 20b (690 mg, yield: 13.8%). MS m / z (ESI): 288.3 [M+1].

[1077] Step 2

[1078] 1-(4-bromo-2-fluorophenyl)piperidine-4-carboxaldehyde 20c

[1079] Compound 20b (200 mg, 694 μmol) was dissolved in dichloromethane (30 mL), and Dess-Martin oxidant (441 mg, 1.04 mmol) was added under ice bath conditions. The mixture was allowed to return to room temperature naturally with stirring for 3 hours. Saturated sodium bicarbonate solution was added to the reaction mixture, and the mixture was extracted with dichloromethane (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was purified under reduced pressure using silica gel column chromatography with eluent system B to obtain title compound 20c (140 mg, 70.5%).

[1080] MS m / z(ESI):285.9[M+1].

[1081] Step 3

[1082] 3-(1'-((1-(4-bromo-2-fluorophenyl)piperidin-4-yl)methyl)-1-methyl-1H,7H-spiro[furano[3,2-g]indazole-6,4'-piperidin]-3-yl)piperidin-2,6-dione 20d

[1083] Compound 20c (100 mg, 349 μmol) and compound 8l (124 mg, 319 μmol) were dissolved in 1,2-dichloroethane (10 mL) and dimethyl sulfoxide (8 mL). Tetraethyl titanate (370 mg, 1.75 mmol) and sodium borohydride acetate (370 mg, 1.74 mmol) were added. The mixture was stirred at 60 °C for 2 hours, then cooled to 0 °C. Sodium cyanoborohydride (12 mg, 200 μmol) was added in portions, and the mixture was stirred for 3 hours. Saturated sodium bicarbonate solution was 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 with eluent system B to give the title compound 20d (140 mg, yield: 64.2%).

[1084] MS m / z(ESI): 624.4 [M+1].

[1085] Step 4

[1086] 6-(1-(3-(1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-4-(4-(4-((3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H,7H-spiro[furano[3,2-g]indazole-6,4'-piperidin]-1'-yl)methyl)piperidin-1-yl)-3-fluorophenyl)-7-fluoro-N,N-dimethyl-1H-indole-2-carboxamide formate 20

[1087] Compound 20d (140 mg, 224 μmol) and compound 19e (120 mg, 224 μmol) were dissolved in 1,4-dioxane (20 mL) and water (2 mL). Methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (19 mg, 22 μmol) and potassium phosphate (95 mg, 448 μmol) were added. The mixture was purged with nitrogen and reacted at 80 °C for 1.5 hours. After the reaction solution was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate (5 mL × 3). 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 (0.1% formic acid) and acetonitrile, gradient ratio: acetonitrile 18%-40%, flow rate: 30 mL / min) to give title compound 20 (60 mg, yield: 26.8%).

[1088] MS m / z(ESI): 953.6 [M+1].

[1089] 1H NMR (500MHz, DMSO-d6): δ12.20(d,1H),10.89(s,1H),8.19(s,1H),7.73(dd,1H),7.47–7.36(m ,3H),7.23–7.10(m,2H),7.07–6.96(m,2H),6.89(s,1H),6.25–6.13(m,2H),4.61(s,2H),4.42– 4.23(m,5H),4.08(s,3H),3.62(dt,2H),3.46(d,2H),3.24–2.93(m,8H),2.89(d,2H),2.80–2. 57(m,5H),2.40–2.23(m,5H),2.16(dd,1H),2.05–1.84(m,6H),1.69(d,2H),1.41–1.28(m,2H).

[1090] Example 21

[1091] 6-(1-(3-(1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-4-(4-(3-((3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H,7H-spiro[furano[3,2-g]indazole-6,4'-piperidin]-1'-yl)methyl)azacyclobutane-1-yl)-3-fluorophenyl)-7-fluoro-N,N-dimethyl-1H-indole-2-carboxamide 21

[1092] Using the synthetic route in Example 20, the formate of title compound 21 was prepared by replacing the starting material compound 20a in the first step with 3-azacyclobutane methanol hydrochloride (Shanghai Bide). The formate was 30 mg, yield: 27.6%. MS m / z (ESI): 925.6 [M+1].

[1093] 1H NMR (500MHz, DMSO-d6): δ12.17(d,1H),10.89(s,1H),8.27(s,1H),7.73(dd,1H),7.45–7.33(m,3H),7.20 (d,1H),7.04–6.94(m,2H),6.86(d,1H),6.67(t,1H),6.24–6.14(m,2H),4.61(s,2H),4.41–4.29(m,5H),4 .14–4.06(m,5H),3.66(q,3H),3.59(t,1H),3.21(s,3H),3.07(s,3H),2.98(dt,3H),2.87(d,2H),2.67(dd ,3H),2.61(t,1H),2.33(dq,3H),2.28(s,1H),2.19–2.13(m,1H),2.07(t,2H),1.95(dd,2H),1.69(d,2H).

[1094] Example 22

[1095] 6-(1-(3-(1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-4-(4-(2-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H,7H-spiro[furano[3,2-g]indazole-6,4'-piperidin]-1'-yl)ethyl)-3,5-difluorophenyl)-7-fluoro-N,N-dimethyl-1H-indole-2-carboxamide 22

[1096] first step

[1097] 6-(1-(3-(1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-4-(3,5-difluoro-4-(2-hydroxyethyl)phenyl)-7-fluoro-N,N-dimethyl-1H-indole-2-carboxamide 22b

[1098] 2-(4-bromo-2,6-difluorophenyl)ethyl-1-ol 22a (140 mg, 224 μmol, prepared by the method disclosed in Example 25 on page 57 of patent application "WO2024099440"), compound 19e (150 mg, 280 μmol), were dissolved in 1,4-dioxane (10 mL) and water (2 mL). [1,1′-bis(diphenylphosphine)ferrocene]palladium(II) dichloride (41 mg, 56 μmol) and potassium carbonate (116 mg, 839 μmol) were added. The mixture was purged with nitrogen and reacted at 85 °C for 2 hours. After cooling to room temperature, the mixture was filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system B to give title compound 22b (130 mg, yield: 82%).

[1099] MS m / z(ESI): 566.5 [M+1].

[1100] Step 2

[1101] 4-(6-(1-(3-(1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-2-(dimethylaminocarbonyl)-7-fluoro-1H-indole-4-yl)-2,6-difluorophenylethyl methanesulfonate 22c

[1102] Compound 22b (65 mg, 115 μmol) and triethylamine (35 mg, 345 μmol) were dissolved in dichloromethane (5 mL). Methylsulfonyl chloride (20 mg, 172 μmol) was added under ice bath conditions. The mixture was stirred steadily for 0.5 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 and washed successively with saturated sodium bicarbonate solution and saturated sodium chloride solution. The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain crude title compound 22c (73 mg). The product was used directly in the next reaction without purification.

[1103] MS m / z(ESI): 644.5 [M+1].

[1104] Step 3

[1105] 6-(1-(3-(1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-4-(4-(2-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H,7H-spiro[furano[3,2-g]indazole-6,4'-piperidin]-1'-yl)ethyl)-3,5-difluorophenyl)-7-fluoro-N,N-dimethyl-1H-indole-2-carboxamide 22

[1106] The crude compound 22c (73 mg, 113 μmol) was dissolved in N-methylpyrrolidone (5 mL), and N,N-diisopropylethylamine (44 mg, 340 μmol), compound 8l (44 mg, 113 μmol), and sodium bromide (23 mg, 223 μmol) were added. The mixture was stirred at 100 °C for 8 hours. After the reaction solution was cooled to room temperature, it was filtered. The filtrate 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 give the title compound 22 (10 mg, yield: 9.8%).

[1107] MS m / z(ESI): 902.7 [M+1].

[1108] The compounds in the following examples were obtained using the methods described in Examples 1-22 above:

[1109] Example 29

[1110] 6-(1-(3-(1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-4-(1-(2-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H,7H-spiro[furano[3,2-g]indazole-6,4'-piperidin]-1'-yl)ethyl)-1,2,3,6-tetrahydropyridin-4-yl)-7-fluoro-N,N-dimethyl-1H-indole-2-carboxamide 29

[1111] first step

[1112] 4-(6-(1-(3-(1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-2-(dimethylaminocarbonyl)-7-fluoro-1H-indole-4-yl)-3,6-dihydropyridin-1(2H)-carboxylic acid tert-butyl ester 29b

[1113] 4-Bromo-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester 29a (118 mg, 448 μmol) and compound 19e (200 mg, 373 μmol) were dissolved in 1,4-dioxane (30 mL) and water (6 mL). 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (55 mg, 75 μmol) and potassium carbonate (129 mg, 934 μmol) were added. The mixture was purged with nitrogen and reacted at 90 °C for 5 hours. 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 A to give title compound 29b (200 mg, yield: 90.9%).

[1114] MS m / z(ESI): 591.5 [M+1].

[1115] Step 2

[1116] 6-(1-(3-(1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-7-fluoro-N,N-dimethyl-4-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole-2-carboxamide 2,2,2-trifluoroacetate 29c

[1117] Compound 29b (280 mg, 474 μmol) was dissolved in dichloromethane (20 mL), and trifluoroacetic acid (10 mL) was added. The mixture was stirred for 1 hour. The reaction solution was concentrated under reduced pressure to obtain the crude title compound 29c (280 mg). The product was used directly in the next reaction without purification.

[1118] MS m / z(ESI):491.5[M+1].

[1119] Step 3

[1120] 6-(1-(3-(1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-7-fluoro-4-(1-(2-hydroxyethyl)-1,2,3,6-tetrahydropyridin-4-yl)-N,N-dimethyl-1H-indole-2-carboxamide 29d

[1121] The crude compound 29c (280 mg, 474 μmol) was dissolved in N,N-dimethylformamide (10 mL), and 2-bromoethanol (199 mg, 1.59 mmol), N,N-diisopropylethylamine (206 mg, 1.59 mmol), potassium carbonate (220 mg, 1.59 mmol), and sodium iodide (159 mg, 1.06 mmol) were added. The mixture was stirred at 60 °C for 1.5 h. 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 29d (50 mg, yield: 19.7%).

[1122] MS m / z(ESI): 535.4 [M+1].

[1123] Step 4

[1124] 6-(1-(3-(1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-4-(1-(2-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H,7H-spiro[furano[3,2-g]indazole-6,4'-piperidin]-1'-yl)ethyl)-1,2,3,6-tetrahydropyridin-4-yl)-7-fluoro-N,N-dimethyl-1H-indole-2-carboxamide 29

[1125] Using the synthetic route in Example 8, the starting compound 8p in step thirteen was replaced with compound 29d to obtain title compound 29 (6 mg, yield: 12%).

[1126] MS m / z(ESI): 871.8 [M+1].

[1127] Example 30

[1128] 6-(1-(3-(1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-4-(1-(2-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H,7H-spiro[furano[3,2-g]indazole-6,4'-piperidin]-1'-yl)ethyl)piperidin-4-yl)-7-fluoro-N,N-dimethyl-1H-indole-2-carboxamide 30

[1129] first step

[1130] 4-(6-chloro-2-(dimethylaminocarbonyl)-7-fluoro-1H-indol-4-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester 30b

[1131] Compound 8m (360 mg, 1.13 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxoborhexacyclopentan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester 30a (453 mg, 1.46 mmol), and 1,4-dioxane (40 mL) and water (10 mL) were dissolved. 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (165 mg, 225 μmol) and potassium carbonate (389 mg, 2.82 mmol) were added, and the mixture was purged with nitrogen and reacted at 90 °C for 5 hours. 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 A to give title compound 30b (340 mg, yield: 71.5%).

[1132] MS m / z(ESI): 366.3 [M-55].

[1133] Step 2

[1134] 4-(6-chloro-2-(dimethylaminocarbonyl)-7-fluoro-1H-indol-4-yl)piperidine-1-carboxylic acid tert-butyl ester 30c

[1135] Compound 30b (310 mg, 735 μmol) was dissolved in tetrahydrofuran (10 mL), and 10% palladium on carbon hydrogenation catalyst (wet) (180 mg) was added. The mixture was purged with hydrogen and stirred for 3 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain crude title compound 30c (300 mg). The product was used directly in the next reaction without purification.

[1136] MS m / z(ESI):424.4[M+1].

[1137] Step 3

[1138] 4-(6-(1-(3-(1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-2-(dimethylaminocarbonyl)-7-fluoro-1H-indol-4-yl)piperidin-1-carboxylic acid tert-butyl ester 30d

[1139] Compound 30c (200 mg, 472 μmol) was dissolved in 1,4-dioxane (20 mL) and water (5 mL), and 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 (156 mg, 472 μmol), methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (80 mg, 94 μmol), potassium phosphate (250 mg, 1.18 mmol) was added. The mixture was purged with nitrogen and reacted at 100 °C for 5 hours. The reaction solution was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate (15 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 with eluent system A to give the title compound 30d (250 mg, yield: 89.5%).

[1140] MS m / z(ESI): 593.5 [M+1].

[1141] Step 4

[1142] 6-(1-(3-(1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-4-(1-(2-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H,7H-spiro[furano[3,2-g]indazole-6,4'-piperidin]-1'-yl)ethyl)piperidin-4-yl)-7-fluoro-N,N-dimethyl-1H-indole-2-carboxamide 30

[1143] Using the synthetic route in Example 29, the title compound 30 (3 mg, yield: 7%) was prepared by replacing the starting compound 29b in the second step with compound 30d.

[1144] MS m / z(ESI): 873.9 [M+1].

[1145] Example 31

[1146] 6-(1-(3-(1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-4-(4-(2-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H,7H-spiro[furano[3,2-g]indazole-6,4'-piperidin]-1'-yl)-1,1-difluoroethyl)phenyl)-7-fluoro-N,N-dimethyl-1H-indole-2-carboxamide 31

[1147] first step

[1148] 2-(4-Bromophenyl)-2,2-Difluoroethyltrifluoromethanesulfonate 31b

[1149] 2-(4-bromophenyl)-2,2-difluoroethane-1-ol 31a (180 mg, 759 μmol, prepared by the method disclosed in Intermediate 7 on page 34 of patent application "WO2017037595") and N,N-diisopropylethylamine (235 mg, 1.82 μmol) were dissolved in dichloromethane (10 mL). Trifluoromethanesulfonic anhydride (514 mg, 1.82 mmol) was added under ice bath conditions. The mixture was stirred at room temperature for 16 hours. Saturated sodium bicarbonate solution was added to the reaction solution, and the mixture was extracted with dichloromethane (10 mL × 2). The organic phases were combined and washed successively with saturated sodium bicarbonate solution and saturated sodium chloride solution. The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain crude title compound 31b (280 mg). The product was used directly in the next reaction without purification.

[1150] Step 2

[1151] 3-(1'-(2-(4-bromophenyl)-2,2-difluoroethyl)-1-methyl-1H,7H-spiro[furano[3,2-g]indazole-6,4'-piperidine]-3-yl)piperidine-2,6-dione 31c

[1152] The crude compound 31b (200 mg, 542 μmol) was dissolved in tetrahydrofuran (15 mL), and triethylamine (274 mg, 2.71 mmol) and compound 8l (106 mg, 271 μmol) were added. The mixture was stirred at 70 °C for 16 hours. After the reaction solution was cooled to room temperature, saturated sodium bicarbonate solution was added, and the mixture was extracted with ethyl acetate (10 mL × 2). The organic phases were combined, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system A to give the title compound 31c (50 mg, yield: 16.1%).

[1153] MS m / z(ESI): 573.4 [M+1].

[1154] Step 3

[1155] 6-(1-(3-(1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-4-(4-(2-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H,7H-spiro[furano[3,2-g]indazole-6,4'-piperidin]-1'-yl)-1,1-difluoroethyl)phenyl)-7-fluoro-N,N-dimethyl-1H-indole-2-carboxamide 31

[1156] Compound 31c (50 mg, 87 μmol) and compound 19e (46 mg, 87 μmol) were dissolved in 1,4-dioxane (10 mL) and water (1 mL). Methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (11 mg, 13 μmol) and potassium phosphate (56 mg, 264 μmol) were added. The mixture was purged with nitrogen and reacted at 90 °C for 1 hour. The reaction solution was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure, and the residue 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 31 (20mg, yield: 25.4%).

[1157] MS m / z(ESI): 902.7 [M+1].

[1158] Example 32

[1159] 6-(1-(3-(1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-4-(4-((3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H,7H-spiro[furano[3,2-g]indazole-6,4'-piperidin]-1'-yl)methyl)-3,5-difluorophenyl)-7-fluoro-N,N-dimethyl-1H-indole-2-carboxamide 32

[1160] Using the synthetic route in Example 22, the title compound 32 (28 mg, yield: 25.1%) was prepared by replacing the first-step starting compound 22a with (4-bromo-2,6-difluorophenyl)methanol (Shanghai Leyan).

[1161] MS m / z(ESI): 888.9 [M+1].

[1162] Example 33

[1163] 6-(1-(3-(1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-4-(4-(2-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H,7H-spiro[furano[3,2-g]indazole-6,4'-piperidin]-1'-yl)-7-azaspiro[3,5]non-7-yl)-3-fluorophenyl)-7-fluoro-N,N-dimethyl-1H-indole-2-carboxamide 33

[1164] (R)-6-(1-(3-(1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-4-(4-(2-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H,7H-spiro[furano[3,2-g]indazole-6,4'-piperidin]-1'-yl)-7-azaspiro[3,5]non-7-yl)-3-fluorophenyl)-7-fluoro-N,N-dimethyl-1H-indole-2-carboxamide 33-p1

[1165] (S)-6-(1-(3-(1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-4-(4-(2-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H,7H-spiro[furano[3,2-g]indazole-6,4'-piperidin]-1'-yl)-7-azaspiro[3,5]non-7-yl)-3-fluorophenyl)-7-fluoro-N,N-dimethyl-1H-indole-2-carboxamide 33-p2

[1166] first step

[1167] 7-(4-bromo-2-fluorophenyl)-7-azaspiro[3.5]non-2-ol 33b

[1168] 7-(3-Fluoro-4-iodophenyl)-7-azaspiro[3.5]non-2-ol 33c

[1169] Compound 19a (6 g, 19.94 mmol), 7-azaspiro[3.5]nonane-2-ol hydrochloride 33a (4.25 g, 23.92 mmol, Shanghai Bide) were dissolved in dimethyl sulfoxide (60 mL), and cuprous iodide (760 mg, 3.99 mmol), L-proline (918 mg, 7.98 mmol), and potassium carbonate (11.02 g, 79.74 mmol) were added. The mixture was purged with nitrogen and stirred at 60 °C for 16 hours. After the reaction solution cooled to room temperature, saturated ammonium chloride solution was added, and the mixture was extracted with ethyl acetate (50 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 with eluent system B to give a mixture of title compound 33b and compound 33c (510 mg, yield: 8.1%).

[1170] Compound 33b: MS m / z (ESI): 314.2 [M+1].

[1171] Compound 33c: MS m / z (ESI): 362.2 [M+1].

[1172] Step 2

[1173] 7-(4-bromo-2-fluorophenyl)-7-azaspiro[3.5]non-2-one 33d

[1174] 7-(3-Fluoro-4-iodophenyl)-7-azaspiro[3.5]non-2-one 33e

[1175] A mixture of compounds 33b and 33c (250 mg, 796 μmol) was dissolved in dichloromethane (10 mL). Dess-Martin oxidant (506 mg, 1.19 mmol) was added under ice bath conditions. The mixture was allowed to return to room temperature and stirred for 1 hour. Saturated sodium bicarbonate solution was added to the reaction mixture, and the mixture was extracted with dichloromethane (15 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 using eluent system B to obtain the title compound 33d (145 mg, 58.3%) and compound 33e (60 mg, 21%).

[1176] Compound 33d: MS m / z (ESI): 312.2 [M+1].

[1177] Compound 33e: MS m / z (ESI): 360.2 [M+1].

[1178] Step 3

[1179] 3-(1'-(7-(4-bromo-2-fluorophenyl)-7-azaspiro[3.5]non-2-yl)-1-methyl-1H,7H-spiro[furano[3,2-g]indazole-6,4'-piperidine]-3-yl)piperidine-2,6-dione 33f

[1180] Compound 33d (60 mg, 192 μmol) and compound 8l (75 mg, 192 μmol) were dissolved in 1,2-dichloroethane (5 mL) and dimethyl sulfoxide (1 mL). Sodium acetate (47 mg, 573 μmol) was added, and the mixture was stirred for 1 hour. Then, sodium borohydride acetate (122 mg, 576 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 (10 mL × 3). The organic phases were combined, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system A to give title compound 33f (55 mg, yield: 44%).

[1181] MS m / z(ESI): 650.4 [M+1].

[1182] Step 4

[1183] 6-(1-(3-(1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-4-(4-(2-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H,7H-spiro[furano[3,2-g]indazole-6,4'-piperidin]-1'-yl)-7-azaspiro[3,5]non-7-yl)-3-fluorophenyl)-7-fluoro-N,N-dimethyl-1H-indole-2-carboxamide 33

[1184] Compound 33f (55 mg, 84 μmol) and compound 19e (45 mg, 84 μmol) were dissolved in 1,4-dioxane (5 mL) and water (0.5 mL). Methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (11 mg, 13 μmol) and potassium phosphate (54 mg, 254 μmol) were added. The mixture was purged with nitrogen and reacted at 90 °C for 1.5 hours. The reaction solution was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure, and the residue 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 33 (27mg, yield: 32.6%).

[1185] Compound 33 was resolved by chiral column chromatography to yield the title compounds 33-p1 and 33-p2.

[1186] MS m / z(ESI): 979.7 [M+1].

[1187] Example 34

[1188] 6-(1-(3-(1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-4-(4-(2-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H,7H-spiro[furano[3,2-g]indazole-6,4'-piperidin]-1'-yl)-7-azaspiro[3,5]non-7-yl)-2-fluorophenyl)-7-fluoro-N,N-dimethyl-1H-indole-2-carboxamide 2,2,2-trifluoroacetate 34

[1189] Using the synthetic route in Example 33, the starting compound 33d in the third step was replaced with compound 33e, and purified by high performance liquid chromatography (Waters-2545, column: Welch Xtimate C18, 30×150mm, 5μm; mobile phase: aqueous phase (0.1% trifluoroacetic acid) and acetonitrile, gradient ratio: acetonitrile 25%-55%, flow rate: 30mL / min) to obtain title compound 34 (30mg, yield: 42.7%).

[1190] MS m / z(ESI): 979.9 [M+1].

[1191] Example 35

[1192] 6-(1-(3-(1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-4-(4-(6-((3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H,7H-spiro[furano[3,2-g]indazole-6,4'-piperidin]-1'-yl)methyl)-2-azaspiro[3,3]hept-2-yl)-3-fluorophenyl)-7-fluoro-N,N-dimethyl-1H-indole-2-carboxamide 35-1

[1193] 6-(1-(3-(1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-4-(4-(6-((3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H,7H-spiro[furano[3,2-g]indazole-6,4'-piperidin]-1'-yl)methyl)-2-azaspiro[3,3]hept-2-yl)-2-fluorophenyl)-7-fluoro-N,N-dimethyl-1H-indole-2-carboxamide 35-2

[1194] first step

[1195] (2-azaspiro[3.3]hept-6-yl)methanol hydrochloride 35b

[1196] 6-(hydroxymethyl)-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester 35a (1 g, 4.40 mmol, sourced from Shanghai Bide) was dissolved in dichloromethane (5 mL), and a 1,4-dioxane solution of 4M hydrogen chloride (5 mL) was added. The mixture was stirred for 2 hours, and the reaction solution was concentrated under reduced pressure to obtain crude title compound 35b (707 mg). The product was used directly in the next reaction without purification.

[1197] Step 2

[1198] (2-(4-bromo-2-fluoroph...

Claims

1. A compound of general formula (I) or a pharmaceutically acceptable salt thereof, in: Ring A is arbitrarily controlled by one or more R 1 The replacement of the four rings; R 1 The same or different, and each independently selected from 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; 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; 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); R a Selected from hydrogen atoms, alkyl groups, haloalkyl groups, cycloalkyl groups, and cycloalkylalkyl groups; X 2 For N or CH; Y represents 1 and Y 2 The ring in which it is located is either aromatic or non-aromatic; V 1 For N or C; V 2 For N or CR w1 ; T is either N or C; Y 1 Selected from O, S, N, NR w3 CR w4 and CR w4 R w5 ; Y 2 Selected from O, S, N, NR w6 CR w7 and CR w7 R w8 ; Cycloyl X is selected from cycloalkyl, heterocyclic, aryl, and heteroaryl groups; Ring B 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; R w0 R w1 R w2 R w4 R w5 R w7 R w8 R x R y and R 2 The same or different, and each independently selected from hydrogen atom, halogen, alkyl, alkenyl, alkoxy, haloalkyl, hydroxyalkyl, haloalkoxy, alkoxyalkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, cyano, nitro, hydroxyl, amino, -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 and R w6 The same or different, and each independently selected from hydrogen atoms, alkyl, alkenyl, ynyl, haloalkyl, 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 w2 and R 2 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 w3 and R 2 Together with their respective connected atoms, they form a heterocyclic group, which is optionally influenced by one or more R atoms. 0 replace; Or, R w4 and R 2 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 w6 and R 2 Together with their respective connected atoms, they form a heterocyclic group, which is optionally influenced by one or more R atoms. 0 replace; Or, R w7 and R 2 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, 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 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; x, y, and n 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 groups, haloalkyl groups, cycloalkyl groups, and cycloalkylalkyl groups; 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, 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, hydroxy, 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, is a compound of general formula (II-2) or a pharmaceutically acceptable salt thereof. in, B 1 B 2 B 4 and B 5 Whether they are the same or different, and each is independently N or CR 2 ;and G, L x , Ring X, R x , x, R w0 , R w2 , Y 1 , Y 2 , V 1 , V 2 , T, R 2 L, ring A and X 2 As defined in claim 1.

3. The compound of general formula (I) according to claim 1 or 2, wherein the compound is of general formula (III-1), general formula (III-2), general formula (III-3), general formula (III-4) or general formula (III-5) or a pharmaceutically acceptable salt thereof. in, B 1 B 2 B 4 and B 5 Whether they are the same or different, and each is independently N or CR 2 ; It can be a single bond or a double bond; Y 1 Selected from O, S and NH; Y 2 Selected from O, S and NH; Y 3 For N or CH; M is selected from the bond, (CR) m1 R m2 ) m 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 ) m1 ; M 2 For key or (CR) m1 R m2 ) m2 ; m can be 0, 1, 2, 3, or 4; m1 can be 0, 1, 2, 3 or 4; m2 can be 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, nitro, hydroxyl, 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 R x x, R w0 V 2 R w2 R 2 L, ring A and X 2 As defined in claim 1.

4. The compound of general formula (I) according to any one of claims 1 to 3, wherein it is the compound of general formula (VI) or a pharmaceutically acceptable salt thereof. in, Y 2 Selected from O, S and NR w6 ; n1 is 0, 1, 2, 3 or 4; It can be a single or double bond; and Ring Y, R y y, L x R x x, R w1 R w2 R w6 R 4 R 5 R 2 L, ring A and X 2 As defined in claim 1.

5. The compound of general formula (I) according to any one of claims 1 to 4, wherein it is the compound of general formula (VII) or a pharmaceutically acceptable salt thereof. in, Y 2 Selected from O, S and NR w6 ; n2 is 0, 1, 2 or 3; It can be a single bond or a double bond; m1 can be 0, 1, 2, 3 or 4; m2 can be 0, 1, 2, 3 or 4; M is as defined in claim 3; and Ring Y, R y y, L x R x x, R w1 R w6 R 4 R 5 R 2 L, ring A and X 2 As defined in claim 1.

6. The compound of general formula (I) according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein ring A is selected from... *The end is connected to L; ring C is selected from phenyl, 5- or 6-membered heterocyclic and 5- or 6-membered heteroaryl; ring E is 5- to 10-membered cycloalkyl or 5- to 10-membered heterocyclic, and ring C and ring E are each independently optionally separated by one or more R 1 Replace, R 1 As defined in claim 1; a1 and a2 are each independently 0, 1, 2, 3 or 4; A1 is N or CR a1 A2 is N or CR a2 A3 is N or CR a3 A4 represents N or CR a4 A5 represents N or CR. a5 A6 is N or CR a6 A7 is N or C; A8 is N or C; R a1 and R a2 Each is independently selected from hydrogen atoms, halogens, alkyl groups, haloalkyl groups, cyano groups, hydroxyl groups, and hydroxyalkyl groups; R a3 R a4 R a5 and R a6 The same or different, and each independently selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy, alkoxyalkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, cyano, hydroxyl, amino, and nitro; a3 is 0, 1, 2, 3, or 4; R 1x 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; or, two Rs 1x 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; and v, R 0 R 3 -R 9 As defined in claim 1.

7. The compound of general formula (I) according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein ring A is selected from... * The terminal is connected to L; where Q is selected from O, S, and NR. q and CR q1 R q2 a1 and a2 are each independently 0, 1, 2, 3, or 4; A1 is N or CR. a1 A2 is N or CR a2 A3 is N or CR a3 A4 represents N or CR a4 A5 represents N or CR. a5 A6 is N or CR a6 J is selected from bond, O, (CR) j1 R j2 ) u S, S(O), S(O)2, NR J C(O), C(O)NR J and NR J C(O); J 1 Selected from bond, O, (CR) j1 R j2 ) p S, S(O), S(O)2, NR J C(O), C(O)NR J and NR J C(O); J 2 Selected from bond, O, (CR) j1 R j2 ) q S, S(O), S(O)2, NR J C(O), C(O)NR J and NR J C(O); J 3 Selected from O, S, S(O), S(O)2, NR J C(O), C(O)NR J NR J C(O), (CR) j1 R j2 ) k1 and (CR) j1 R j2 ) k3 W J (CR j1 R j2 ) k4 ; J 4 selected from O, S, S(O), S(O)2, NR J , C(O), C(O)NR J , NR J C(O), (CR j1 R j2 ) k2 and (CR j1 R j2 ) k5 W J (CR j1 R j2 ) k6 ; W J Selected from O, S, S(O), S(O)2, NR J C(O), C(O)NR J and NR J C(O); k1 and k2 are each independently 1, 2, 3 or 4; k3, k4, k5, and k6 are each independently 0, 1, 2, or 3; u, p, and q are each independently 0, 1, 2, 3, or 4; R a1 and R a2 Each is independently selected from hydrogen atoms, halogens, alkyl groups, haloalkyl groups, cyano groups, hydroxyl groups, and hydroxyalkyl groups; R q R J and R A1 Each is independently selected from hydrogen atoms, alkyl groups, haloalkyl groups, hydroxyalkyl groups, cycloalkyl groups, heterocyclic groups, and cycloalkylalkyl groups; R q1 R q2 R j1 R j2 R a3 R a4 R a5 R a6 and R A 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; or, R j1 and R j2 Together with the adjacent atoms, they form a cycloalkyl or heterocyclic group; a3 is 0, 1, 2, 3, or 4; R 1x 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; or, two Rs 1x 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; and v, R 0 and R 3 -R 9 As defined in claim 1; Preferably, ring A is selected from the following structures: *The end is connected to L; more preferably, ring A is... * The terminal is connected to L.

8. The compound of formula (I) according to any one of claims 1 to 7, 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 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 group is substituted with one or more substituents in the =O group; and t2 is 0, 1, 2, 3, 4, 5 or 6; preferably, L is selected from the group consisting of the alkyl group, CH2, CH2CH2, CH2CH2CH2, ... * The end is connected to ring A.

9. The compound of general formula (I) according to any one of claims 1 to 3, 6 to 8, or a pharmaceutically acceptable salt thereof, wherein R w0 -C(O)NR 4 R 5 ;R 4 and R 5 As defined in claim 1; preferably, R w0 Selected from 10. The compound of general formula (I) according to any one of claims 1 to 3, 6 to 9, or a pharmaceutically acceptable salt thereof, wherein V 2 For N or CR w1 ;R w1 Selected from hydrogen atoms, halogens and C 1-6 Alkyl; preferably, V 2 For CF.

11. The compound of general formula (I) according to any one of claims 1 to 4, 6 to 10, or a pharmaceutically acceptable salt thereof, wherein 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 a 5- to 10-membered heterocyclic group; preferably, R w2 For hydrogen atoms, or, R w2 and R 2 Together with their respective connected atoms, they form 6 to 8-membered heterocyclic groups.

12. The compound of general formula (I) according to any one of claims 1 to 11, 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, C 1-6 Alkoxy, C 1-6 Halogenated alkyl and C 1-6 Halogenated alkoxy groups; preferably, R 2 Each can be a hydrogen atom or a halogen.

13. The compound of formula (I) according to any one of claims 1 to 12, 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), 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; preferably, L x Selected from * The terminal is connected to G or ring Y.

14. The compound of general formula (I) according to any one of claims 1 to 3, 6 to 13, or a pharmaceutically acceptable salt thereof, wherein G is H or The ring Y is a 5- to 10-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, C 1-6 Haloalkyl and 3- to 6-membered cycloalkyl; y is 0 or 1; preferably, G is selected from hydrogen atoms, 15. The compound of formula (I) according to any one of claims 3 to 14, or a pharmaceutically acceptable salt thereof, wherein 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; and / or M 1 For (CR) m1 R m2 ) m1 M 2 For (CR) m1 R m2 ) m2 ;R m1 and R m2 Each is independently 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 adjacent carbon atom, they form a cyclopropyl group; m1 is 0, 1, 2, or 3; and m2 is 0 or 1; Preferably, M is O; and / or M 1 CH2; and / or M 2 It is CH2.

16. The compound of general formula (I) according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, selected from the group consisting of: And all compounds listed in Table A of the instruction manual.

17. A compound of general formula (VIB) or a salt thereof, in, R L It is a leaving group; R 2 n1, L, ring A and X 2 As defined in claim 4.

18. A compound or a salt thereof, selected from the following compounds:

19. A method for preparing a compound of general formula (VI) according to claim 4 or a pharmaceutically acceptable salt thereof, the method comprising: A compound of general formula (VIA) or a salt thereof undergoes a coupling reaction with a compound of general formula (VIB) or a salt thereof to obtain a compound of general formula (VI) or a pharmaceutically usable salt thereof; in: R P for Or -B(OH)2; R L It is a leaving group; Ring Y, R y , y, L x , R x , x, R w1 R w2 Y 2 R 4 R 5 R 2 n1, L, ring A and X 2 As defined in claim 4.

20. A pharmaceutical composition comprising a compound of formula (I) according to any one of claims 1 to 16 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

21. Use of the compound of general formula (I) according to any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 20, in the preparation of a medicament for inhibiting or degrading STAT6.

22. Use of the compound of general formula (I) according to any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 20, in the preparation of a medicament for the treatment and / or prevention of diseases or conditions mediated or dependent on STAT6.

23. The compound of general formula (I) according to any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 20, 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. Use in pharmaceuticals; preferably in the preparation of drugs 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, scleroderma, juvenile arthritis, Wegener's granulomatosis, dermatomyositis, hepatitis, myasthenia gravis, Stevens-Johnson syndrome. Symptoms, 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 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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