Polycyclic compounds, processes for their preparation and their use in medicine

Abstract

The present disclosure relates to a polycyclic compound, a process for preparing the same and the pharmaceutical uses thereof. In particular, the present disclosure relates to a polycyclic compound of general formula (I), a process for preparing the same, a pharmaceutical composition containing the polycyclic compound and the use of the polycyclic compound as a therapeutic agent, in particular as a STAT6 inhibitor or degrader and in the manufacture of a medicament for the treatment and / or prevention of a disease or disorder mediated or dependent on STAT6. Wherein the groups in general formula (I) are as defined in the specification.

Description

Technical Field

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

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

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

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

[0005] In some embodiments, this disclosure provides a compound of general formula (I) or a pharmaceutically acceptable salt thereof. in: Ring A is arbitrarily controlled by one or more R1x The replacement of the four rings; 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); L 2 Selected from bond, O, C(O), S, S(O), S(O)2, NR a C(O)NR a NR a C(O), (CR) d R f ) h 、(CR d R f ) h1 O(CR d R f ) h2 、(CR d R f ) h1 S(CR d R f ) h2 、(CR d R f ) h1 NR a (CR d R f ) h2 、(CR d R f ) h1 C(O)NR a (CR d R f ) h2 and (CR) d R f ) h1 NR a C(O)(CR d R f ) h2 ; R a Selected from hydrogen atoms, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, and cycloalkylalkyl; h, h1, and h2 are each independently 0, 1, 2, 3, 4, or 5; X 2 For N or CH; Ring B is arbitrarily controlled by one or more R 2 The three rings that were replaced; Cycloyl X is selected from cycloalkyl, heterocyclic, aryl, and heteroaryl groups; G is selected from hydrogen atom, halogen and The ring Y is selected from cycloalkyl, heterocyclic, aryl, and heteroaryl groups. 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 and Y 2 Each is independently selected from O, S, N, NR. w3 CR w4 and CR w4 R w5 ; R w0 R w1 R w2 R w4 R w5 R d R f R x R y R 1x 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) vNR 4 R 5 -NR 6 S(O)2R 3 =O, =CR 8 R 9 、-Si(R 3 3. -P(O)(OR) 3 )2、-OP(O)(R 3 )2 and -OP(O)(OR 3 )2, wherein the alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each independently and optionally composed of one or more R groups. 0 replace; R w3 The atom is selected from hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups is independently and optionally converted by one or more R atoms. 0 replace; Or, R w0 With R w3 Together with their respective attached atoms, they form a heterocyclic group or a heteroaryl group, each of which is independently and optionally influenced by one or more R atoms. C replace; Or, R w0 With R w4 Together with their respective attached atoms, they form cycloalkyl, heterocyclic, aryl, or heteroaryl groups, each of which is independently and optionally influenced by one or more R groups. C replace; Or, R w2 With R x Together with their respective attached atoms, they form cycloalkyl, heterocyclic, aryl, or heteroaryl groups, each of which is independently and optionally influenced by one or more R groups. D replace; R C and R D 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 3a -NR 4a R 5a -C(O)R 3a -C(O)OR 3a -C(O)NR 4a R 5a -C(O)NR 4a OR 3a-NR 6a C(O)R 3a -NR 6a C(O)OR 3a -NR 6a C(O)NR 4a R 5a -OC(O)R 3a -OC(O)NR 4a R 5a -S(O) v R 3a -S(O)(=NR) 7a )R 3a -S(O) v NR 4a R 5a -NR 6a S(O)2R 3a =O, =CR 8a R 9a 、-Si(R 3a 3. -P(O)(OR) 3a )2、-OP(O)(R 3a )2 and -OP(O)(OR 3a )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 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 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; Or, two Rs 2 Together with the attached atoms, they form a cycloalkyl or heterocyclic group, each of which is independently and optionally influenced by one or more R atoms. 0 replace; Or, two Rs C 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 RsD 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 and y 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; the alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl groups are each independently and optionally converted by one or more R 0 replace; R b Selected from hydrogen atoms, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, and cycloalkylalkyl; t1 is selected from integers from 0 to 10; t2 is selected from integers from 0 to 20; R 3 R 4 R 5 R 3a R 4a and R 5a 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; or R 4a and R 5a 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; or, R w3 and R 5 Together with their respective attached atoms, 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; or, R w4 and R 5Together with their respective attached atoms, 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 and R 6a They may be the same or different, and each is independently selected from hydrogen atoms, alkyl, haloalkyl, hydroxyalkyl and cycloalkyl; R 7 and R 7a They may be the same or different, and each is independently selected from hydrogen atoms, alkyl, haloalkyl, hydroxyalkyl, hydroxyl, alkoxy, haloalkoxy and cycloalkyl; R 8 R 9 R 8a and R 9a 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 a cycloalkyl or heterocyclic group; or, R 8a and R 9a Together with the attached carbon atom, they form cycloalkyl or heterocyclic groups; R 0 The same or different, and each independently selected from =O, halogen, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, aminoalkyl, hydroxy, alkenyl, alkynyl, cyano, nitro, amino, -NHalkyl, -N(alkyl)2, -C(O)Oalkyl, -C(O)OH, -C(O)NH2, -C(O)NH(alkyl), -C(O)N(alkyl)2, -C(O)halogen, -C(O)alkyl, -S(alkyl), cycloalkyl, cycloalkylalkyl, cycloalkyloxy, heterocyclic, heterocyclic alkyl, heterocyclic oxy, aryl, arylalkyl, aryloxy, heteroaryl, heteroarylalkyl, and heteroaryloxy; and v can be 0, 1, or 2.

[0006] In some embodiments, this disclosure provides a compound of formula (II) or formula (III) or a pharmaceutically acceptable salt thereof. in, Y 3 Selected from NR w3 O and S; Y 4 For N or CR w4 ; G, L x , ring X, R x , x, L 2R w0 R w2 R w3 R w4 V 2 Ring B, L, Ring A, L 1 and X 2 As defined in general formula (I).

[0007] In some embodiments, this disclosure provides a compound of general formula (IV) or a pharmaceutically acceptable salt thereof. in, It can be a single bond or a double bond; Y 3 Selected from NR w3 O and S; Ring Y, R y y, L x R x , x, L 2 R w1 R w2 R w3 R w4 R 4 R 5 Rings B, L, A, and X 2 As defined in general formula (I).

[0008] In some embodiments, this disclosure provides a compound of formula (V), formula (V-1), formula (VI) or formula (VII), or a pharmaceutically acceptable salt thereof. in, It can be a single bond or a double bond; Y 3 Selected from NR w3 O and S; The ring W is selected from cycloalkyl, heterocyclic, aryl, and heteroaryl groups; R 10 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 3a -NR 4a R 5a -C(O)R3a -C(O)OR 3a -C(O)NR 4a R 5a -C(O)NR 4a OR 3a -NR 6a C(O)R 3a -NR 6a C(O)OR 3a -NR 6a C(O)NR 4a R 5a -OC(O)R 3a -OC(O)NR 4a R 5a -S(O) v R 3a -S(O)(=NR) 7a )R 3a -S(O) v NR 4a R 5a -NR 6a S(O)2R 3a =O, =CR 8a R 9a 、-Si(R 3a 3. -P(O)(OR) 3a )2、-OP(O)(R 3a )2 and -OP(O)(OR 3a )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; d can be 0, 1, 2, 3, 4, or 5; W is selected from key, (CR) r1 R r2 )r, O, S, S(O), S(O)2, NR r C(O), C(O)NR r and NR r C(O); W 1 Selected from key, (CR) r1 R r2 ) r1 O, S, S(O), S(O)2, NR r C(O), C(O)NR r and NR r C(O); W 2 Selected from key, (CR) r1 R r2 )r2 O, S, S(O), S(O)2, NR r C(O), C(O)NR r and NR r C(O); r, r1, and r2 are each independently 0, 1, 2, 3, or 4; 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 Selected from key, (CR) m1 R m2 ) m1 O, S, S(O), S(O)2, NR m C(O), C(O)NR m and NR m C(O); M 2 Selected from key, (CR) m1 R m2 ) m2 O, S, S(O), S(O)2, NR m C(O), C(O)NR m and NR m C(O); m, m1, and m2 are each independently 0, 1, 2, 3, or 4; x1 is 0, 1, 2, 3, 4, 5 or 6; E is selected from the key, (CR) e1 R e2 ) e O, S, S(O), S(O)2, NR e C(O), C(O)NR e and NR e C(O); E 1 Selected from key, (CR) e1 R e2 ) e1 O, S, S(O), S(O)2, NR e C(O), C(O)NR e and NR e C(O); E 2 Selected from key, (CR) e1 R e2 ) e2O, S, S(O), S(O)2, NR e C(O), C(O)NR e and NR e C(O); e, e1, and e2 are each independently 0, 1, 2, 3, or 4; x2 is 0, 1, 2, 3, 4, 5 or 6; R r R m and R e They may be the same or different, and each is independently selected from hydrogen atoms, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl and cycloalkylalkyl; R r1 R r2 R m1 R m2 R e1 and R e2 The same or different, and each independently selected from hydrogen atom, halogen, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, aminoalkyl, alkenyl, alkynyl, cyano, hydroxyl, nitro, amino, -NHalkyl, -N(alkyl)2, -C(O)Oalkyl, -C(O)OH, -C(O)NH2, -C(O)NH(alkyl), -C(O)N(alkyl)2, -C(O)halogen, -C(O)alkyl, -S(alkyl), cycloalkyl, cycloalkylalkyl, cycloalkyloxy, heterocyclic, heterocyclic alkyl, heterocyclic oxy, aryl, arylalkyl, aryloxy, heteroaryl, heteroarylalkyl and heteroaryloxy; or, R r1 and R r2 Together with the attached carbon atom, they form a cycloalkyl or heterocyclic group; or, R m1 and R m2 Together with the attached carbon atom, they form a cycloalkyl or heterocyclic group; or, R e1 and R e2 Together with the attached carbon atom, they form a cycloalkyl or heterocyclic group; or, R r1 and R r2 Together they form = O; or, R m1 and R m2 Together they form = O; or, R e1 and R e2 Together they form = O; G, L x , ring X, R x x, V 2 R w0 R w2 R w3 R w4 L 2 R 0 R 4R 3a R 4a R 5a R 6a R 7a R 8a R 9a v, ring B, L, ring A, L 1 and X 2 As defined in general formula (I).

[0009] In some implementations, L 2 For (CR) d R f ) h or (CR) d R f ) h1 O(CR d R f ) h2 h, h1, h2, R d and R f As defined in general formula (I); in some implementations, L 2 For (CR) d R f ) h h, R d and R f As defined in general formula (I); in some implementations, L 2 Selected from ligands, CH2, CH2CH2, CH2CH2CH2, CH2O, and OCH2; in some embodiments, L 2 For key.

[0010] In some implementation schemes, R d and R f 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 d and R f It is a hydrogen atom.

[0011] In some implementations, h is 0, 1, 2, or 3; in some implementations, h is 0 or 1; in some implementations, h is 0.

[0012] In some implementations, h1 and h2 are each independently 0, 1, 2 or 3; in some implementations, h1 and h2 are each independently 0 or 1; in some implementations, h1 is 1 and h2 is 0; in some implementations, h1 is 0 and h2 is 1.

[0013] In some implementation schemes, ring B is or Ring D1 is phenyl or a 5- or 6-membered heteroaryl group; ring D2 is selected from 5- to 8-membered cycloalkyl groups, 5- to 8-membered heterocyclic groups, phenyl groups, and 5- or 6-membered heteroaryl groups; Z 1 Selected from C, N and CR z1 Z 2 For N or CR z2 Z 9 Selected from C, N, and CH; R z1 and R z2 They may be the same or different, and each is independently selected from hydrogen, halogen, alkyl, cyano, hydroxyl, haloalkyl, hydroxyalkyl, alkoxy, cycloalkyl, and cycloalkylalkyl; f is 0, 1, 2, or 3; g is 0, 1, 2, or 3; n1 is 0, 1, 2, 3, or 4; n2 is 0, 1, 2, 3, or 4; n3 is 0, 1, 2, 3, or 4; R 2 As defined in general formula (I).

[0014] In some embodiments, ring D1 is selected from phenyl, pyridinyl, pyrimidinyl, thiophene, and pyrazolyl; in some embodiments, ring D1 is phenyl or pyridine; in some embodiments, ring D1 is phenyl.

[0015] In some embodiments, ring D2 is selected from 5- to 7-membered cycloalkyl, 5- to 7-membered heterocyclic and 5-membered heteroaryl; in some embodiments, ring D2 is 5 or 6-membered cycloalkyl or 5 or 6-membered heterocyclic; in some embodiments, ring D2 is 5 or 6-membered heterocyclic.

[0016] In some implementation schemes, ring B is selected from... , , , and B 1 B 2 B 5 and B 6 One of them is C and is related to R. w2 The rings are connected, and the other three are the same or different, and each is independently either N or CR. 2 Z 4 Z 5 and Z 6 One of them is C and is related to R. w2 The rings they belong to are connected, and the other two are the same or different, and each is independently selected from O, S, N, NR. 2c and CR 2 In some implementation schemes, ring B is selected from... , , , and * Connect to L; B 1 B 2 and B 5Whether they are the same or different, and each is independently N or CR 2 Z 4 and Z 6 They are the same or different, and each is independently selected from O, S, N, NR. 2c and CR 2 In the above implementation plan, Z 8 Selected from O, S, N, NR 2c CR 2 CR 2 CR 2 CR 2 =CR 2 NCR 2 N=CR 2 CR 2 N and CR 2 =N;B 3 For N or C; B 4 For N or C; Z 1 Selected from C, N and CR z1 Z 2 For N or CR z2 ;R z1 and R z2 They may be the same or different, and each is independently selected from hydrogen, halogen, alkyl, cyano, hydroxyl, haloalkyl, hydroxyalkyl, alkoxy, cycloalkyl, and cycloalkylalkyl; Z 3 For N or C; Z 7 For N or C; Z 9 For N or C; f is 0, 1, 2 or 3; g is 0, 1, 2 or 3; J is selected from bonds, (CR 2a R 2b ) q O, S, S(O), S(O)2, NR 2c C(O), C(O)NR 2c and NR 2c C(O); J 1 Selected from key, (CR) 2a R 2b ) q1 O, S, S(O), S(O)2, NR 2c C(O), C(O)NR 2c and NR 2c C(O); J 2 Selected from key, (CR) 2a R 2b ) q2 O, S, S(O), S(O)2, NR 2c C(O), C(O)NR 2c and NR 2cC(O); n1 is 0, 1, 2, 3 or 4; q, q1 and q2 are each independently 0, 1, 2, 3 or 4; R 2c Selected from hydrogen atoms, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, and cycloalkylalkyl; R 2a and R 2b The same or different, and each independently selected from hydrogen atom, halogen, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, aminoalkyl, alkenyl, alkynyl, cyano, hydroxyl, nitro, amino, -NHalkyl, -N(alkyl)2, -C(O)Oalkyl, -C(O)OH, -C(O)NH2, -C(O)NH(alkyl), -C(O)N(alkyl)2, -C(O)halogen, -C(O)alkyl, -S(alkyl), oxo, cycloalkyl, cycloalkylalkyl, cycloalkyloxy, heterocyclic, heterocyclic alkyl, heterocyclic oxy, aryl, arylalkyl, aryloxy, heteroaryl, heteroarylalkyl and heteroaryloxy; or, R 2a and R 2b Together with the attached carbon atom, they form a cycloalkyl or heterocyclic group; or, R 2a and R 2b Together form = O; R 2 As defined in general formula (I).

[0017] In some implementation schemes, ring B is or In some implementation schemes, ring B is... or * Connect to L; B 1 B 2 B 5 and B 6 One of them is C and is related to R. w2 The rings are connected, and the other three are the same or different, and each is independently either N or CR. 2 Z 1 For N or CR z1 Z 2 For N or CR z2 ;R z1 and R z2 The same or different, and each independently selected from hydrogen atom, halogen, alkyl, cyano, hydroxyl, haloalkyl, hydroxyalkyl, alkoxy, cycloalkyl and cycloalkylalkyl; f is 0, 1, 2 or 3; g is 0, 1, 2 or 3; J is selected from bond, (CR 2a R 2b ) q O, S, S(O), S(O)2, NR 2c C(O), C(O)NR 2c and NR 2c C(O); J 1 Selected from key, (CR)2a R 2b ) q1 O, S, S(O), S(O)2, NR 2c C(O), C(O)NR 2c and NR 2c C(O); J 2 Selected from key, (CR) 2a R 2b ) q2 O, S, S(O), S(O)2, NR 2c C(O), C(O)NR 2c and NR 2c C(O); n1 is 0, 1, 2, 3 or 4; q, q1 and q2 are each independently 0, 1, 2, 3 or 4; R 2c Selected from hydrogen atoms, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, and cycloalkylalkyl; R 2a and R 2b The same or different, and each independently selected from hydrogen atom, halogen, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, aminoalkyl, alkenyl, alkynyl, cyano, hydroxyl, nitro, amino, -NHalkyl, -N(alkyl)2, -C(O)Oalkyl, -C(O)OH, -C(O)NH2, -C(O)NH(alkyl), -C(O)N(alkyl)2, -C(O)halogen, -C(O)alkyl, -S(alkyl), oxo, cycloalkyl, cycloalkylalkyl, cycloalkyloxy, heterocyclic, heterocyclic alkyl, heterocyclic oxy, aryl, arylalkyl, aryloxy, heteroaryl, heteroarylalkyl and heteroaryloxy; or, R 2a and R 2b Together with the attached carbon atom, they form a cycloalkyl or heterocyclic group; or, R 2a and R 2b Together form = O; R 2 As defined in general formula (I); in some implementations, ring B is or * The terminal is connected to L; in some implementations, ring B is or * Connect to L; B 1 B 2 and B 5 Whether they are the same or different, and each is independently N or CR 2 J, J 1 J 2 Z 1 Z 2 f, g, R 2 And n1 as defined above; in some implementations, ring B is or * The terminal is connected to L; in some implementations, ring B is or * Connected to L; q1, q2, B 1 B 2 B 5 J, Z 1 Z 2 f and g are as defined above.

[0018] In some implementation schemes, ring B is selected from... , , and ;R 2d For R 2 * The terminal is connected to L; In some embodiments of this disclosure, ring B is or * Connect to L; R 2d For R 2 ;q1, q2, J, B 1 B 2 B 5 Z 1 Z 2 R 2 And n1 as defined above; in some implementations, ring B is or * Connect to L; R 2d For R 2 ;q1, q2, J, Z 1 Z 2 R 2 n1 and n2 are as defined above.

[0019] In some implementation schemes, ring B is selected from... , , , , , , , , , , , , , , , , , , , , , , , , 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and * The terminal is connected to L; where n2 is 0, 1, 2, and 3; R 2 As defined above.

[0020] In some implementation schemes, ring B is selected from... , , , , , , , , and * The terminal is connected to L; where n2 is 0, 1, 2, and 3; R 2 As defined above.

[0021] In some implementation schemes, ring B is selected from... , , , , , , , , , , , , ... , , , , , , , , ... , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and * The terminal is connected to L.

[0022] In some implementation schemes, ring B is selected from... , , , , , , , 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and * The terminal is connected to L.

[0023] In some implementation schemes, ring B is selected from... , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and * The terminal is connected to L.

[0024] In some implementation schemes, ring B is selected from... , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and * The terminal is connected to L.

[0025] In some implementations, J is O or CH2; in some implementations, J is O; in some implementations, J is CH2.

[0026] In some implementation schemes, J 1 Selected from the bond, CH2, CH2CH2, and CH2CH2CH2; in some embodiments, J 1 For the bond or CH2; in some implementations, J 1 For key.

[0027] In some implementation schemes, J 2 Selected from the bond, CH2, CH2CH2, and CH2CH2CH2; in some embodiments, J 2 For the bond, CH2 or CH2CH2; in some implementations, J 2 For the bond or CH2; in some implementations, J 2 It is CH2.

[0028] In some implementations, J is O or CH2; and / or J 1 For bond or CH2; and / or J 2 J is a bond or CH2; in some implementations, J is O; J 1 For key; J 2 J is CH2; in some implementations, J is O; J 1 CH2; J 2 It is O.

[0029] In some embodiments of this disclosure, q is 0 or 1; in other embodiments, q is 1.

[0030] In some embodiments of this disclosure, q1 and q2 are each independently 0, 1, or 2; in other embodiments, q1 and q2 are each independently 0 or 1.

[0031] In some implementations, q1 is 0 or 1; q2 is 0, 1 or 2; in some implementations, q1 is 0; q2 is 1; in some implementations, q1 is 0; q1 is 2; in some implementations, q1 is 1; q2 is 1; in some implementations, q1 is 1; q2 is 0; in some implementations, both q1 and q2 are 0.

[0032] In some implementation schemes, Z 1 Selected from C, N, and CH; in some implementations, Z 1 For N or CH; in some implementations, Z 1 For N; in some implementations, Z 1 The answer is C.

[0033] In some implementation schemes, Z 2 For N or CH; in some implementations, Z 2 CH; in some implementations, Z 2 Let N be the number of elements in the array.

[0034] In some implementation schemes, Z 1 For N; Z 2 CH; in some implementations, Z 1 For N; Z 2 Let N be the number of elements in the array.

[0035] In some implementation schemes, R z1 and R z2 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl; in some embodiments, R z1 and R z2 Each is an independent hydrogen atom.

[0036] In some implementations, f is 0 or 1; in other implementations, f is 1.

[0037] In some implementations, g is 0 or 1; in other implementations, g is 1.

[0038] In some implementations, f is 1; g is 1.

[0039] In some implementations, n1 is 0, 1, or 2; in some implementations, n1 is 0 or 1; in some implementations, n1 is 0; in some implementations, n1 is 2.

[0040] In some implementations, n2 is 0, 1, or 2; in some implementations, n2 is 0 or 1; in some implementations, n2 is 0; in some implementations, n2 is 1; in some implementations, n2 is 2.

[0041] In some implementations, n3 is 0, 1, or 2; in some implementations, n3 is 0 or 1; in some implementations, n3 is 0.

[0042] In some implementation schemes, Z 5 C and R w2 The rings are connected, Z 4 and Z 6 Whether they are the same or different, and each is independently N or CR 2 ;R 2 As defined above.

[0043] In some implementation schemes, B 6 C and R w2 Connected to the ring, B 1 B 2 and B 5 Whether they are the same or different, and each is independently N or CR 2 ;R 2 As defined above.

[0044] In some implementation schemes, B 1 For CR 2 ;R 2 As defined above; in some implementations, B 1 Selected from N, CH, CF and C-Cl; in some embodiments, B 1 For CH.

[0045] In some implementation schemes, B 2 For CR 2 ;R 2 As defined above; in some implementations, B 2Selected from N, CH, CF and C-Cl; in some embodiments, B 2 For CH.

[0046] In some implementation schemes, B 3 C; in some implementations, B 3 Let N be the number of elements in the array.

[0047] In some implementation schemes, B 4 C; in some implementations, B 4 Let N be the number of elements in the array.

[0048] In some implementation schemes, B 3 C; B 4 C; in some implementations, B 3 For N; B 4 The answer is C.

[0049] In some implementation schemes, B 5 For CR 2 ;R 2 As defined in the context; in some implementations, B 5 Selected from N, CH, CF and C-Cl; in some embodiments, B 5 For CH.

[0050] In some implementation schemes, B 6 For CR 2 ;R 2 As defined in the context; in some implementations, B 6 Selected from N, CH, CF and C-Cl; in some embodiments, B 6 For CH.

[0051] In some implementation schemes, B 1 For CR 2 B 2 For CR 2 B 5 For CR 2 In some implementation schemes, B 1 For N; B 2 For CR 2 B 5 For CR 2 In some implementation schemes, B 1 For CR 2 B 2 For N; B 5 For CR 2 In some implementation schemes, B 1 For CR 2 B 2 For CR 2 B5 For N; in some implementations, B 1 For N; B 2 For CR 2 B 5 For N; R 2 As defined above; in some implementations, B 1 For CH; B 2 For CH; B 5 For CH; in some implementations, B 1 For CH; B 2 For N; B 5 For CH.

[0052] In some implementation schemes, R 2 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy and oxo groups; or, two R groups. 2 Together with the attached atoms, they form 3- to 6-membered cycloalkyl groups and 3- to 6-membered heterocyclic 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 Haloalkyl, C 1-6 Alkoxy and C 1-6 Haloalkoxy; in some embodiments, R 2 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl and C 1-6 Alkoxy; in some embodiments, R 2 It is a hydrogen atom or a halogen; in some implementations, R 2 Selected from hydrogen atoms, F and Cl; in some embodiments, R 2 It is a hydrogen atom.

[0053] In some implementations, two R 2 Together with the adjacent atoms, they form 3- to 6-membered cycloalkyl groups and 3- to 6-membered heterocyclic groups; in some embodiments, two R atoms on the same carbon atom 2 Together with the attached carbon atom, they form a 3- to 6-membered cycloalkyl group; in some embodiments, two non-adjacent R atoms... 2 Connected to form a bridge C 1-3 Alkylene; in some embodiments, two non-adjacent Rs 2 They connect to form a bridge CH2CH2.

[0054] In some implementation schemes, R 2dThey may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy and oxo groups; or, two R groups. 2d Together with the attached atoms, they form a 3- to 6-membered cycloalkyl group or a 3- to 6-membered heterocyclic group; in some embodiments, R 2d It is a hydrogen atom; or, two R atoms. 2d Together with the attached atoms, they form a 3- to 6-membered cycloalkyl group or a 3- to 6-membered heterocyclic group; in some embodiments, R 2d It is a hydrogen atom; or, two non-adjacent R atoms. 2d Connected to form a bridge C 1-3 Alkylene; in some embodiments, R 2d For hydrogen atoms; in some implementations, two non-adjacent R atoms 2d Connected to form a bridging CH2 or CH2CH2; in some implementations, two non-adjacent R... 2d They connect to form a bridge CH2.

[0055] In some implementation schemes, R 2a and R 2b They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl and C 1-6 Haloalkyl; or, R 2a and R 2b Together with the attached carbon atom, they form a 3- to 6-membered cycloalkyl group; in some embodiments, R 2a and R 2b For hydrogen atoms; or, R 2a and R 2b Together with the attached carbon atom, they form a cyclopropyl group; in some embodiments, R 2a and R 2b It is a hydrogen atom.

[0056] In some implementation schemes, R 2c It is a hydrogen atom or a carbon atom. 1-6 Alkyl; in some embodiments, R 2c It is a hydrogen atom.

[0057] In some implementation schemes, Z 3 For N; in some implementations, Z 3 The answer is C.

[0058] In some implementation schemes, Z 7 For N; in some implementations, Z 7 The answer is C.

[0059] In some implementation schemes, Z3 For N; in some implementations, Z 7 The answer is C.

[0060] In some implementation schemes, Z 3 C; in some implementations, Z 7 The answer is C.

[0061] In some implementation schemes, Z 4 Selected from S, O, N, NH and CH; in some embodiments, Z 4 It can be N or S.

[0062] In some implementation schemes, Z 6 Selected from S, O, N, NH and CH; in some embodiments, Z 6 For CH.

[0063] In some implementation schemes, Z 8 The ring is a 5-membered heteroaryl group; in some implementation schemes, Z 8 The ring is a 6-membered heteroaryl or phenyl; in some embodiments, Z 8 The ring it belongs to is a 6-membered heteroaryl group.

[0064] In some implementation schemes, Z 8 Selected from S, O, N, NH and CH; in some embodiments, Z 8 For CH or N; in some implementations, Z 8 Let N be the number of elements in the array.

[0065] In some implementation schemes, Z 9 C; in some implementations, Z 9 For N; in some implementations, Z 9 For CH.

[0066] In some implementation schemes, Z 1 For N; Z 9 For CH.

[0067] In some implementation schemes, Z 1 CH; Z 9 For CH.

[0068] In some implementation schemes, Z 1 For N; Z 9 The answer is C.

[0069] In some implementation schemes, Z 1 For C; Z 9 The answer is C.

[0070] In some implementations, W is O or CH2; in other implementations, W is CH2.

[0071] In some implementation schemes, W 1 (CH2) r1 ;r1 as defined above; in some implementations, W 1 Selected from the bond, CH2 and CH2CH2; in some embodiments, W 1 For the bond or CH2; in some implementations, W 1 For key.

[0072] In some implementation schemes, W 2 (CH2) r2 r2 is as defined above; in some implementations, W 2 Selected from the bond, CH2 and CH2CH2; in some embodiments, W 2 For the bond or CH2; in some implementations, W 2 As key; in some implementations, W 2 It is CH2.

[0073] In some implementations, r1 and r2 are each independently 0, 1, or 2; in some implementations, r1 and r2 are each independently 0 or 1; in some implementations, r1 is 0; in some implementations, r2 is 1; in some implementations, r1 is 0; r2 is 0; in some implementations, r1 is 0; r2 is 1; in some implementations, r1 is 0; r2 is 2.

[0074] In some implementations, M is O or CH2; in other implementations, M is O.

[0075] In some implementation schemes, M 1 Selected from the bond, CH2, CH2CH2, and CH2CH2CH2; in some embodiments, M 1 It is CH2 or CH2CH2; in some implementations, M 1 It is CH2.

[0076] In some implementation schemes, M 2 Selected from the bond, CH2, CH2CH2, and CH2CH2CH2; in some embodiments, M 2 For the bond or CH2; in some implementations, M 2 For key.

[0077] In some implementations, m is 0 or 1; in other implementations, m is 1.

[0078] In some implementations, m1 and m2 are each independently 0, 1, or 2; in other implementations, m1 and m2 are each independently 0 or 1.

[0079] In some implementations, m1 is 0, 1, or 2; 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 1; m2 is 1.

[0080] In some implementations, E is O or CH2; in other implementations, E is CH2.

[0081] In some implementation schemes, E 1 Selected from the bond, CH2 and CH2CH2; in some embodiments, E 1 For the bond or CH2; in some implementations, E 1 For key.

[0082] In some implementation schemes, E 2 Selected from the bond, CH2 and CH2CH2; in some embodiments, E 2 For the bond or CH2; in some implementations, E 2 For key; in some implementations, E 2 It is CH2.

[0083] In some implementations, e is 0 or 1; in other implementations, e is 1.

[0084] In some implementations, e1 and e2 are each independently 0, 1, or 2; in some implementations, e1 and e2 are each independently 0 or 1; in some implementations, e1 is 0; in some implementations, e2 is 1; in some implementations, e1 is 0; e2 is 0; in some implementations, e1 is 0; e2 is 1.

[0085] In some implementation schemes, R r1 R r2 R m1 R m2 R e1 and R e2 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl and C 1-6 Haloalkyl; or, R r1 and R r2 Together with the adjacent carbon atom, they form a 3- to 6-membered cycloalkyl group; or, R m1 and R m2 Together with the adjacent carbon atom, they form a 3- to 6-membered cycloalkyl group; or, R e1 and R e2 Together with the adjacent carbon atoms, they form 3- to 6-membered cycloalkyl groups; In some implementation schemes, R r1 and R r2 For hydrogen atoms; or, Rr1 and R r2 Together with the attached carbon atom, they form a cyclopropyl group; in some embodiments, R r1 and R r2 It is a hydrogen atom; In some implementation schemes, R m1 and R m2 For hydrogen atoms; or, R m1 and R m2 Together with the attached carbon atom, they form a cyclopropyl group; in some embodiments, R m1 and R m2 It is a hydrogen atom; In some implementation schemes, R e1 and R e2 For hydrogen atoms; or, R e1 and R e2 Together with the attached carbon atom, they form a cyclopropyl group; in some embodiments, R e1 and R e2 It is a hydrogen atom.

[0086] In some implementation schemes, R r R m and R e Each is independently a hydrogen atom or a carbon atom. 1-6 Alkyl; in some embodiments, R r For hydrogen atoms; in some implementations, R m For hydrogen atoms; in some implementations, R e It is a hydrogen atom.

[0087] In some implementations, ring A is optionally controlled by one or more R... 1x The replacement of the 16-20 yuan Fourth Ring Road; R 1x As defined above; in some implementations, ring A is optionally bounded by one or more R 1x The 17-yuan Fourth Ring Road has been replaced; R 1x As defined above.

[0088] In some implementations, ring A is or * The end is connected to L; 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 spirotropically bonded; 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 1x Replace, R 1xAs defined in the context.

[0089] In some implementations, ring A is selected from the following structures: , , , , , , , , , , , , , and The ring C is selected from phenyl, 5- or 6-membered heterocyclic and 5- or 6-membered heteroaryl; the ring E is a 5- to 10-membered cycloalkyl or a 5- to 10-membered heterocyclic, and the ring C and ring E are each independently optionally separated by one or more R 1x Replace, R 1x As defined above; 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 As defined above; the * terminal is connected to L.

[0090] In some embodiments, ring C is a 5-membered heterocyclic group or a 5-membered heteroaryl group, and ring C is optionally surrounded by one or more R groups. 1x Replace, R 1x As defined above.

[0091] In some embodiments, ring E is a 5- to 8-membered heterocyclic group, and ring E is optionally surrounded by one or more R groups. 1x Replace, R 1xAs defined above; in some embodiments, ring E is a 5- to 7-membered heterocyclic group, and ring E is optionally surrounded by one or more R groups. 1x Replace, R 1x As defined above; in some embodiments, ring E is a 5- or 6-membered heterocyclic group, and ring E is optionally surrounded by one or more R groups. 1x Replace, R 1x As defined above; in some embodiments, ring E is a 5- or 6-membered heterocyclic group or a 5- or 6-membered cycloalkyl group, and ring E is optionally surrounded by one or more R groups. 1x Replace, R 1x As defined above; 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. 1x Replace, R 1x As defined above; in some embodiments, ring E is a 5- or 6-membered heterocyclic group; in some embodiments, ring E is a 5-membered heterocyclic group.

[0092] In some implementations, ring A is selected from the following structures: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and * 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 U is selected from bonds, 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); U 1 Selected from bond, O, (CR) j1 R j2 ) p1 S, S(O), S(O)2, NR J C(O), C(O)NR J and NR J C(O); U 2 Selected from bond, O, (CR) j1 R j2 ) p2 S, S(O), S(O)2, NR J C(O), C(O)NR J and NR J C(O); U 3 and U 4 Each is independently selected from O, S, S(O), S(O)2, and NR. J C(O), C(O)NR J NR J C(O), (CR) j1 R j2 ) k1 、(CR j1 R j2 ) k2 O(CR j1 R j2 ) k3 、(CR j1 R j2 ) k2 S(CR j1 R j2 ) k3 、(CR j1 Rj2 ) k2 NR J (CR j1 R j2 ) k3 、(CR j1 R j2 ) k2 C(O)(CR j1 R j2 ) k3 、(CR j1 R j2 ) k2 C(O)NR J (CR j1 R j2 ) k3 and (CR) j1 R j2 ) k2 NR J C(O)(CR j1 R j2 ) k3 k1 is 1, 2, 3, or 4; k2 and k3 are each independently 0, 1, 2, or 3; p, p1, and p2 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 attached atoms, they form a cycloalkyl or heterocyclic group; a3 is 0, 1, 2, 3, or 4; R 1x As defined above.

[0093] In some implementations, ring A is selected from... , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and * The terminal is connected to L; where Q is selected from O, S, and NR. q and CR q1 R q2 A1 is N or CR a1 A2 is N or CR a2 U is selected from bonds, 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); U 3 and U 4 Each is independently selected from O, S, S(O), S(O)2, and NR. J C(O), C(O)NR J NR J C(O), (CR) j1 R j2 ) k1、(CR j1 R j2 ) k2 O(CR j1 R j2 ) k3 、(CR j1 R j2 ) k2 S(CR j1 R j2 ) k3 、(CR j1 R j2 ) k2 NR J (CR j1 R j2 ) k3 、(CR j1 R j2 ) k2 C(O)(CR j1 R j2 ) k3 、(CR j1 R j2 ) k2 C(O)NR J (CR j1 R j2 ) k3 and (CR) j1 R j2 ) k2 NR J C(O)(CR j1 R j2 ) k3 k1 is 1, 2, 3, or 4; k2 and k3 are each independently 0, 1, 2, or 3; p, p1, and p2 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 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, Rj1 and R j2 Together with the attached atoms, they form a cycloalkyl or heterocyclic group; a4 is 0, 1, or 2; R 1x As defined above.

[0094] In some implementations, ring A is selected from the following structures: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 , , , , , , , , , , , , , , , , , , , , , , , , , , and In some implementation schemes, ring A is... or In some implementation schemes, ring A is... * The terminal is connected to L.

[0095] In some implementations, ring A is selected from... , and * The terminal is connected to L.

[0096] In some implementations, ring A is selected from... , , , and * The terminal is connected to L.

[0097] In some implementations, U is CH2 or O; in other implementations, U is O.

[0098] In some implementation schemes, U 1 Selected from the bond, CH2, CH2CH2, and CH2CH2CH2; in some embodiments, U 1 For a bond or CH2; in some implementations, U 1 For key.

[0099] In some implementation schemes, U 2 Selected from the bond, CH2, CH2CH2, and CH2CH2CH2; in some embodiments, U 2 For a bond or CH2; in some implementations, U 2 It is CH2.

[0100] In some implementation schemes, U 3 Selected from O, CH2, CH2CH2, OCH2, and CH2O; in some embodiments, U 3 It can be O or CH2.

[0101] In some implementation schemes, U 4 Selected from O, CH2, CH2CH2, OCH2, and CH2O; in some embodiments, U 4 It can be O or CH2.

[0102] In some implementation schemes, U 3 For CH2, U 4 For CH2; in some implementations, U 3 for O,U 4 For CH2; in some implementations, U 3 For CH2, U 4 For O; in some implementations, U 3 for O,U 4 It is O.

[0103] In some implementations, k1 is 1 or 2; in other implementations, k1 is 1.

[0104] In some implementations, k2 is 0, 1, or 2; in some implementations, k2 is 0 or 1; in some implementations, k2 is 0; and in some implementations, k2 is 1.

[0105] In some implementations, k3 is 0, 1, or 2; in some implementations, k3 is 0 or 1; in some implementations, k3 is 0; and in some implementations, k3 is 1.

[0106] In some implementations, k2 is 0 and k3 is 1; in some implementations, k2 is 1 and k3 is 0; in some implementations, k2 is 0 and k3 is 0.

[0107] In some implementations, a1 and a2 are each independently 0 or 1; in other implementations, a1 and a2 are 1.

[0108] In some implementations, a3 is 0 or 1; in other implementations, a3 is 0.

[0109] In some implementations, a4 is 0 or 1; in other implementations, a4 is 0.

[0110] In some implementation schemes, R 1x 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 Hydroxyalkyl, C 1-6 Halogenated alkyl and oxo group; or, two R groups. 1x Together with the attached atoms, they form a 3- to 6-membered cycloalkyl group; in some embodiments, R 1x 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 Hydroxyalkyl and C 1-6 Halogenated alkyl; in some embodiments, R 1x 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 1x For hydrogen atoms; in some implementations, R 1x For oxo groups; in some embodiments, two R groups on the same carbon atom 1x Together with the attached carbon atom, they form a cyclopropyl group.

[0111] In some implementation schemes, R A Selected from hydrogen atoms, halogens and C 1-6 Alkyl; in some embodiments, R A C 1-6 Alkyl; in some embodiments, R A It is a methyl group.

[0112] In some implementation schemes, R A1 Selected from hydrogen atoms, C 1-6 Alkyl and 3- to 6-membered cycloalkyl; in some embodiments, R A1 C 1-6 Alkyl; in some embodiments, R A1 It is a methyl group.

[0113] In some implementation schemes, R J It is a hydrogen atom or a carbon atom. 1-6 alkyl.

[0114] In some implementation schemes, R q It is a hydrogen atom or a carbon atom. 1-6 Alkyl; in some embodiments, R q C 1-6 Alkyl; in some embodiments, R q It is a methyl group.

[0115] In some implementation schemes, R q1 and R q2 They may be the same or different, and each is independently a hydrogen atom or a carbon atom. 1-6 Alkyl; or, R q1 and R q2Together with the attached carbon atom, they form a 3- to 6-membered cycloalkyl group; in some embodiments, R q1 and R q2 It is methyl; or, R q1 and R q2 Together with the attached carbon atom, they form a cyclopropyl group.

[0116] In some implementations, Q is NR q or CR q1 R q2 ;R q R q1 and R q2 As defined above; in some implementations, Q is NR. q ;R q C 1-6 Alkyl; in some embodiments, Q is N-methyl.

[0117] In some implementations, A1 is N or CH; in some implementations, A1 is N; in some implementations, A1 is CH.

[0118] In some implementations, A2 is N or CH; in other implementations, A2 is N.

[0119] In some implementations, A1 is N; A2 is N; in other implementations, A1 is CH; A2 is N.

[0120] In some implementations, p is 0, 1, or 2; in some implementations, p is 0 or 1; in some implementations, p is 1.

[0121] In some implementations, p1 and p2 are each independently 0, 1, or 2; in other implementations, p1 and p2 are each independently 0 or 1.

[0122] In some implementations, p1 is 0 and p2 is 1; in some implementations, p1 is 0 and p2 is 2; in some implementations, p1 is 1 and p2 is 1.

[0123] In some implementations, A3 is CR a3 ;R a3 As defined above; in some implementations, A3 is N or CH; in some implementations, A3 is CH.

[0124] In some implementations, A4 is CR a4 ;R a4 As defined above; in some implementations, A4 is N or CH; in some implementations, A4 is CH.

[0125] In some implementations, A5 is CRa5 ;R a5 As defined above; in some implementations, A5 is N or CH; in some implementations, A5 is CH.

[0126] In some implementations, A6 is CR a6 ;R a6 As defined above; in some implementations, A6 is N or CH; in some implementations, A6 is CH.

[0127] In some implementations, A7 is C.

[0128] In some implementations, A8 is C.

[0129] In some implementation schemes, R a1 It is a hydrogen atom.

[0130] In some implementation schemes, R a2 It is a hydrogen atom.

[0131] In some implementation schemes, R a3 R a4 R a5 and R a6 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 Hydroxyalkyl and C 1-6 Halogenated alkyl; in some embodiments, R a3 R a4 R a5 and R a6 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 a3 R a4 R a5 and R a6 Each is an independent hydrogen atom.

[0132] In some implementation schemes, R j1 and R j2 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 Hydroxyalkyl and C 1-6 Haloalkyl; or, R j1 and R j2 Together with the attached carbon atom, they form a 3- to 6-membered cycloalkyl group; in some embodiments, R j1 and R j2 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 j1 and R j2 It is a hydrogen atom.

[0133] In some implementation schemes, V 2 For CR w1 ;R w1 As defined in the context; in some implementations, 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.

[0134] 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.

[0135] In some implementation schemes, R w2 Selected from hydrogen atoms, halogens and C 1-6 Alkyl; R x Selected from hydrogen atoms, halogens, C 1-6 Alkyl and oxo groups; or, R w2 With R x Together with their respective attached atoms, they form 5- to 8-membered cycloalkyl or 5- to 8-membered heterocyclic groups; in some embodiments, R w2 For hydrogen atoms; R x It can be a hydrogen atom or an oxo group; or, R w2 With R x Together with their respective attached atoms, they form 5- to 7-membered cycloalkyl or 5- to 7-membered heterocyclic groups; in some embodiments, R w2 For hydrogen atoms; R x For hydrogen atoms; or, R w2 With R x Together with their respective connected atoms, they form a 6- or 7-membered heterocyclic group; in some embodiments, R w2 For hydrogen atoms; R x It is a hydrogen atom.

[0136] In some implementation schemes, R w2 Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Alkoxy, C1-6 Halogenated alkyl groups and C 1-6 Haloalkoxy; in some embodiments, R w2 Selected from hydrogen atoms, halogens and C 1-6 Alkyl; in some embodiments, R w2 It is a hydrogen atom.

[0137] 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 Haloalkyl, C 1-6 Haloalkoxy and oxo groups; in some embodiments, R x Selected from hydrogen atoms, halogens, C 1-6 Alkyl and oxo groups; in some embodiments, R x It is a hydrogen atom or an oxo group; in some embodiments, R x It is a hydrogen atom.

[0138] In some implementations, x is 0, 1, or 2; in some implementations, x is 0 or 1; in some implementations, x is 0; and in some implementations, x is 1.

[0139] In some implementations, x1 is 0, 1, or 2; in some implementations, x1 is 0 or 1; in some implementations, x1 is 0.

[0140] In some implementations, x2 is 0, 1, or 2; in some implementations, x2 is 0 or 1; in some implementations, x2 is 0.

[0141] In some embodiments, ring X is a 5- or 6-membered monocyclic heterocyclic group or a 9- or 12-membered bicyclic heterocyclic group; in some embodiments, ring X is a saturated or partially unsaturated 6-membered heterocyclic group; in some embodiments, ring X is a saturated or partially unsaturated 9- or 10-membered bicyclic heterocyclic group; in some embodiments, ring X is... ; It can be a single bond or a double bond; in some implementations, ring X is selected from... , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and In some implementation schemes, ring X is... ;*end and L x Connected, With L 2 Connected.

[0142] In some implementation schemes, Selected from , and In some implementation schemes, for E, E 1 E 2 e1, e2, R x x, x2 and As defined above; in some implementation schemes, Selected from , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and ;R x For hydrogen atoms or R x With R w2 Together with their respective attached atoms, they form 5- to 8-membered cycloalkyl or 5- to 8-membered heterocyclic groups; in some embodiments, Selected from , and ;R x For hydrogen atoms or R x With R w2 Together with their respective attached atoms, they form 5- to 8-membered cycloalkyl or 5- to 8-membered heterocyclic groups; in some embodiments, Selected from , , and ;*end and L x Connected, With L 2 Connected.

[0143] In some implementation schemes, R w3 It is a hydrogen atom or a carbon atom. 1-6 Alkyl; or, R w3 and R w0 Together with their respective attached atoms, they form 5- to 8-membered heterocyclic groups or 6-membered heteroaryl groups; the 5- to 8-membered heterocyclic groups and the 6-membered heteroaryl groups are each independently selected independently from halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -NR 4a R5a The oxo group is substituted by one or more substituents; R 4a and R 5a 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 4a and R 5a Together with the nitrogen atom attached to it, they form 3 to 8-membered heterocyclic groups.

[0144] In some implementation schemes, R w3 It is a hydrogen atom or a carbon atom. 1-6 Alkyl; in some embodiments, R w3 It is a hydrogen atom.

[0145] In some implementation schemes, R w4 Selected from hydrogen atoms, halogens and C 1-6 Alkyl; R w0 -C(O)NR 4 R 5 Or, R w4 With R w0 Together with their respective attached atoms, they form 5- to 8-membered heterocyclic groups, phenyl groups, or 6-membered heteroaryl groups, wherein each of the 5- to 8-membered heterocyclic groups, phenyl groups, and 6-membered heteroaryl groups is independently selected independently from halogens, C... 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -NR 4a R 5a The oxo group is substituted by one or more substituents; 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; or, R w4 and R 5 Together with their respective connected atoms, they form 5- to 8-membered heterocyclic groups; R 4a and R 5a 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 4a and R 5a Together with the nitrogen atom attached to it, they form 3 to 8-membered heterocyclic groups.

[0146] In some implementation schemes, R w4 Selected from hydrogen atoms, halogens and C 1-6 Alkyl; R 4 and R 5Whether the atoms are the same or different, and each is independently selected from hydrogen atoms, C atoms 1-6 Alkyl and 3- to 6-membered cycloalkyl; or, R 4 and R 5 Together with the attached nitrogen atom, they form a 3- to 8-membered heterocyclic group; or, R w4 and R 5 Together with their respective connected atoms, they form 5- to 8-membered heterocyclic groups; in some implementations, R w4 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 1-6 Alkyl and 3- to 6-membered cycloalkyl; or, R 4 and R 5 Together with the attached nitrogen atom, they form a 4- to 6-membered heterocyclic group; or, R 4 and R 5 Together with the nitrogen atom attached to it, they form a 6-membered heterocyclic group.

[0147] In some implementation schemes, R w4 Selected from hydrogen atoms, halogens and C 1-6 Alkyl; in some embodiments, R w4 It is a hydrogen atom.

[0148] In some implementation schemes, R w5 Selected from hydrogen atoms, halogens and C 1-6 Alkyl; in some embodiments, R w5 It is a hydrogen atom.

[0149] In some implementation schemes, R w0 -C(O)NR 4 R 5 ;R 4 and R 5 As defined in general formula (I); in some implementations, R w0 Selected from , , and In some implementation schemes, R w0 for .

[0150] 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, they form a 3- to 8-membered heterocyclic group; in some embodiments, R 4and 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 , or 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.

[0151] In some implementation schemes, R 4 It is a hydrogen atom or a carbon atom. 1-6 Alkyl; in some embodiments, R 4 C 1-6 Alkyl; in some embodiments, R 4 It is a methyl group.

[0152] In some implementation schemes, R 5 With R w4 Together with their respective attached atoms, they form a 5- to 8-membered heterocyclic group, wherein the 5- to 8-membered heterocyclic group is optionally selected from halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 One or more substituents in the haloalkoxy group are substituted; in some embodiments, R 5 With R w4 Together with their respective connected atoms, they form 5- to 8-membered heterocyclic groups; in some implementations, R 5 With R w4 Together with their respective connected atoms, they form a 6-membered heterocyclic group.

[0153] In some implementation schemes, R 4 C 1-6 Alkyl; R 5 With R w4 Together with their respective connected atoms, they form 5- to 8-membered heterocyclic groups; in some implementations, R 4 Methyl; R 5 With R w4 Together with their respective connected atoms, they form a 6-membered heterocyclic group.

[0154] In some implementation schemes, for W, r1, and r2 are as defined above; in some implementations, or Selected from CH2, CH2CH2, CH2CH2CH2 CH2OCH2, CH2CH2CH2CH2 , and The * terminal is connected to N; in some implementations, or CH2CH2; * is connected to N.

[0155] In some implementation schemes, R 4a and R 5a 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 4a and R 5a Together with the attached nitrogen atom, they form a 3- to 8-membered heterocyclic group; in some embodiments, R 4a and R 5a They may be the same or different, and each is independently selected from hydrogen, methyl, ethyl, propyl, and cyclopropyl; or, R 4a and R 5a Together with the attached nitrogen atom, it forms , or In some implementation schemes, R 4a and R 5a C 1-6 Alkyl; in some embodiments, R 4a and R 5a It is a methyl group.

[0156] In some embodiments, ring W is selected from 5- to 8-membered heterocyclic groups, phenyl groups, and 6-membered heteroaryl groups; in some embodiments, ring W is a 5- to 8-membered heterocyclic group or a 6-membered heteroaryl group; in some embodiments, ring W is a 5- to 7-membered heterocyclic group or a pyridyl group; in some embodiments, ring W is a 6-membered heterocyclic group.

[0157] In some implementation schemes, R 10 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, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -NR 4a R 5a and oxygen group; R 4a and R 5a 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 4a and R 5a Together with the attached nitrogen atom, they form a 3- to 8-membered heterocyclic group; in some embodiments, R10 Whether the atoms are the same or different, and each is independently selected from hydrogen atoms, C atoms 1-6 Alkyl, -N(C) 1-6 alkyl)2 and oxo group; in some embodiments, R 10 Whether the atoms are the same or different, and each is independently selected from hydrogen atoms, C atoms 1-6 Alkyl and oxo groups.

[0158] In some implementations, d is 0, 1, 2, or 3; in some implementations, d is 0, 1, or 2; in some implementations, d is 1 or 2; in some implementations, d is 2.

[0159] In some implementations, t2 is 0, 1, 2, 3, 4, 5, or 6; in some implementations, t2 is 0, 1, 2, or 3; in some implementations, t2 is 0, 1, or 2; in some implementations, t2 is 0.

[0160] In some implementations, L is -(L B ) t2 -;L B They may be the same or different, and each is independently selected from O, NH, N(CH3), C(O), C 1-6 Alkylene, C 2-6 Alkyne group, 3- to 8-membered cycloalkyl group and 3- to 8-membered heterocyclic group; the C 1-6 Alkylene, 3- to 8-membered cycloalkyl, and 3- to 8-membered heterocyclic groups are each independently selected from hydroxyl, halogen, C 1-6 Alkyl, C 1-6 The alkyl halogroup and =O are substituted with one or more substituents; t2 is 0, 1, 2, 3, 4, 5, or 6; in some embodiments, L is -(L B ) t2 -;L B They are the same or different, and each is independently selected from O, C(O), C 1-6 Alkylene, 3- to 6-membered cycloalkyl, and 4- to 6-membered heterocyclic groups; t2 is 0, 1, 2, or 3; in some embodiments, L is selected from bond, CH2, CH2CH2, CH2CH2CH2, C(O), , , , , , and * The end is connected to ring A; in some embodiments, L is selected from bond, CH2 and C(O); in some embodiments, L is bond or CH2; in some embodiments, L is bond.

[0161] 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.

[0162] In some implementations, L x -(L A ) t1 -;L A They may be the same or different, and each is independently selected from NH, C(O), C 1-6 Alkylene, 3- to 8-membered cycloalkyl, and 3- to 8-membered heterocyclic groups; t1 is 0, 1, 2, 3, 4, or 5; in some embodiments, L x -(L A ) t1 -;L A They may be the same or different, and each is independently selected from NH, C(O) and C. 1-6 Alkylene; t1 is 0, 1, 2 or 3; in some embodiments, L x Selected from CH2, CH2CH2, , , , , , , , , , , , , , , , , , and In some implementation schemes, L x Selected from CH2, CH2CH2, , , and In some implementation schemes, L x for * The terminal is connected to G or ring Y.

[0163] 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, oxazolyl, pyrroleyl, thiophenyl, isoxazolyl, and furanyl; in some embodiments, ring Y is pyrazolyl or triazolyl; in some embodiments, ring Y is selected from... , , , , , , , , , , , , , , and In some implementation schemes, ring Y is or .

[0164] In some implementation schemes, R y They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 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 It is a hydrogen atom.

[0165] In some implementations, y is 0 or 1; in other implementations, y is 0.

[0166] In some implementations, G is H or ; Ring Y, R y And y as defined in the context; in some embodiments of this disclosure, G is ; Ring Y, R y And y as defined in the context; in some implementations, 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 group; y is 0 or 1; in some embodiments, G is a hydrogen atom; in some embodiments, G is selected from hydrogen atoms, and .

[0167] In some implementations, cycloylate Y is a 5-membered heteroaryl group; R y Selected from hydrogen atoms, halogens and C 1-6 Alkyl; y is 0 or 1; in some embodiments, G or Selected from , , , , , , , , , , , , , , , , , , , and In some implementations, G or Each independently , , or In some implementations, G or Each independently , or In some implementations, G or Each independently or In some implementations, G or Each independently .

[0168] In some implementation schemes, Y 1 and Y 2 The ring is a 5-membered heteroaryl group; in some implementation schemes, Y 1 and Y 2 The ring is selected from pyrrole, furanyl, thiophene, imidazole, oxazolyl, thiazolyl, triazolyl, and pyrazolyl; in some embodiments, Y 1 and Y 2 The ring it belongs to is pyrrole.

[0169] In some implementation schemes, Selected from , , , , , , , , , , , , , , , , , , , , , , , , , , , and ;*end and R w0 Connected; R w3 and R w4 As defined in general formula (I).

[0170] In some implementation schemes, Y 1 Selected from N, O, S, CH, NH, NR w3 and CR w4 ;R w3 and R w4 As defined in general formula (I); in some implementations, Y 1 Selected from O, S, and NH; in some embodiments, Y 1 For NR w3 or CR w4 In some implementation schemes, Y 1 For CR w4 ;R w4 As defined in general formula (I); in some implementations, Y 1 For CH.

[0171] In some implementation schemes, Y 2 Selected from S, N, O, CH and NH; in some embodiments, Y 2 For NR w3 ;R w3 As defined in general formula (I); in some implementations, Y 2 It is NH or O; in some implementations, Y 2 It is NH.

[0172] In some implementation schemes, Y 3 Selected from O, S, and NH; in some embodiments, Y 3 For NR w3 ;R w3 As defined in general formula (IV); in some implementations, Y 3 It is NH or O; in some implementations, Y 3 It is NH.

[0173] In some implementation schemes, Y 4 For CR w4 ;R w4 As defined in general formula (IV); in some implementations, Y 4For CH; in some implementations, Y 4 Let N be the number of elements in the array.

[0174] In some implementation schemes, X 2 For CH; in some implementations, X 2 Let N be the number of elements in the array.

[0175] In some implementations, L 1 For bond or NH; in some implementations, L 1 For key.

[0176] In some implementation schemes, R a It is a hydrogen atom or a carbon atom. 1-6 Alkyl; in some embodiments, R a It is a hydrogen atom.

[0177] 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.

[0178] In some implementation schemes, V 1 The answer is C.

[0179] In some implementations, T stands for C.

[0180] In some implementation schemes, V 1 C is C; T is C.

[0181] In some implementation schemes, V 1 N is N; T is C.

[0182] In some implementation schemes, V 1 C is C; T is N.

[0183] In some implementation schemes, R 3 It is a hydrogen atom or a carbon atom. 1-6 alkyl.

[0184] In some implementation schemes, R 3a It is a hydrogen atom or a carbon atom. 1-6 alkyl.

[0185] In some implementation schemes, R 6 It is a hydrogen atom.

[0186] In some implementation schemes, R 6a It is a hydrogen atom.

[0187] In some implementation schemes, R 7 Selected from hydrogen atoms, C 1-6 Alkyl, hydroxyl and C 1-6 Alkyl group.

[0188] In some implementation schemes, R 7a Selected from hydrogen atoms, C 1-6 Alkyl, hydroxyl and C 1-6 Alkyl group.

[0189] 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.

[0190] In some implementation schemes, R 8a and R 9a They may be the same or different, and each is independently a hydrogen atom or a halogen.

[0191] In some implementation schemes, R 0 Same or different, and each independently selected from O, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 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 groups.

[0192] In some implementation schemes, R C 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, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -NR 4a R 5a and oxygen group; R 4a and R 5a 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 4a and R 5a Together with the attached nitrogen atom, they form a 3- to 8-membered heterocyclic group; in some embodiments, R C Whether the atoms are the same or different, and each is independently selected from hydrogen atoms, C atoms 1-6 Alkyl, -N(C) 1-6 alkyl)2 and oxo group; in some embodiments, R C Whether the atoms are the same or different, and each is independently selected from hydrogen atoms, C atoms 1-6 Alkyl and oxo groups; in some embodiments, R C They may be the same or different, and each is independently a hydrogen atom or a carbon atom. 1-6 alkyl.

[0193] In some implementation schemes, R D 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, C 1-6 Alkoxy, C 1-6 Haloalkoxy and oxo groups; in some embodiments, R D Whether the atoms are the same or different, and each is independently selected from hydrogen atoms, C atoms 1-6 Alkyl, C 1-6 Halogenated alkyl groups and oxo groups; in some embodiments, R D It is a hydrogen atom.

[0194] In some implementation schemes, for or In some implementation schemes, for In some implementation schemes, for .

[0195] In some embodiments, the compound represented by general formula (IV) or a pharmaceutically acceptable salt thereof, wherein, for or L x for * The end is connected to ring Y; R x It is a hydrogen atom; It is a double bond; L 2 For key; R w1 It is a halogen; R w2 Y is a hydrogen atom; 3 For NH;R w4 For hydrogen atoms; R 4 and R 5 C 1-6 Alkyl; Cyclic B is or * The terminal is connected to L; J is O or CH2; q1 and q2 are each independently 0 or 1; Z 1 For N or CH; Z 2 For N or CH; R 2 n is a hydrogen atom or a halogen; n2 is 0, 1, or 2; R 2d It is a hydrogen atom; or, two non-adjacent R atoms. 2d Connected to form a bridge C 1-3 Alkylene; n1 is 0, 1, or 2; L is selected from bond, CH2, and C(O); ring A is or * Connect to L; X 2 It can be N or CH.

[0196] Group A: Typical compounds disclosed herein include, but are not limited to: , , , , , , , , , , , , , 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 , , , , , , , , , , and .

[0197] This disclosure provides a compound of general formula (IVB) or a salt thereof. in, R LP It is a leaving group; Rings B, L, A, and X 2 As defined in general formula (IV); and the * terminal is connected to L. End and R LP Connected.

[0198] In some implementation schemes, R LP For halogen; in some implementations, R LP It is Br.

[0199] Typical intermediate compounds disclosed herein include, but are not limited to: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and .

[0200] This disclosure, in another aspect, provides a method for preparing a compound of general formula (IV) or a pharmaceutically acceptable salt thereof. The compound represented by general formula (IVA) or its salt reacts with the compound represented by general formula (IVB) or its salt to give the compound represented by general formula (IV) or its pharmaceutically usable salt. in, It can be a single bond or a double bond; R T -B(OH)2 or ; R LP It is a leaving group; Ring Y, R y y, L x R x , x, L 2 Y 3 R w1 R w2 R w4 R 4 R 5 Rings B, L, A, and X 2 As defined in general formula (IV).

[0201] In some implementation schemes, R LP For halogen; in some implementations, R LP It is Br.

[0202] In some embodiments, the reaction is a coupling reaction in the preparation of the compound of general formula (IV) or its pharmaceutically acceptable salt; in some embodiments, the reaction is carried out under a metal catalyst and alkaline conditions, wherein the metal catalyst includes, but is not limited to, 1,1'-bis(diphenylphosphine)ferrocene palladium(II) chloride, and the reagent providing the alkaline conditions includes, but is not limited to, potassium phosphate.

[0203] Another aspect of this disclosure relates to a pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt thereof represented by general formula (I), general formula (II), general formula (III), general formula (IV), general formula (V), general formula (V-1), general formula (VI), general formula (VII) or group A of this disclosure, and one or more pharmaceutically acceptable carriers, diluents or excipients.

[0204] This disclosure further relates to the use of compounds or pharmaceutically acceptable salts thereof of the present general formulas (I), (II), (III), (IV), (V), (V-1), (VI), or (VII) or group A, or pharmaceutical compositions thereof, in the preparation of medicaments for inhibiting or degrading STAT6.

[0205] This disclosure further relates to the use of compounds or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the present general formulas (I), (II), (III), (IV), (V), (V-1), (VI), or (VII) or group A, in the preparation of a medicament for regulating the ubiquitination and degradation of STAT6 protein in a subject.

[0206] This disclosure further relates to the use of compounds or pharmaceutically acceptable salts thereof represented by general formula (I), general formula (II), general formula (III), general formula (IV), general formula (V), general formula (V-1), general formula (VI) or general formula (VII) or group A, or pharmaceutical compositions thereof, in the preparation of medicaments for the treatment and / or prevention of diseases or conditions mediated or dependent on STAT6.

[0207] This disclosure further relates to compounds or pharmaceutically acceptable salts thereof of general formulas (I), (II), (III), (IV), (V), (V-1), (VI), or (VII) or group A, or pharmaceutical compositions 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, and diseases involving T. Use in medicaments for the treatment and / or prevention of asthma, atopic dermatitis (AD), chronic obstructive pulmonary disease (COPD), bronchitis, diabetes, atherosclerosis, gout, gouty arthritis, osteoarthritis, systemic lupus erythematosus, polychondritis, colitis, conjunctivitis, allergic rhinitis, rheumatoid arthritis, scleroderma, Wegener's granulomatosis, dermatomyositis, hepatitis, myasthenia gravis, Stevens-Johnson syndrome, ulcerative colitis, Crohn's disease, irritable bowel syndrome, and lactation. Celiac disease, periodontitis, kidney disease, glomerular disease, alcoholic liver disease, multiple sclerosis, endocrine ophthalmopathy, Graves' disease, sarcoidosis, alveolitis, chronic allergic pneumonia, multiple 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, myasthenia gravis, thyroiditis. Uses in medications for appendicitis, allergies, cervicitis, cholangitis, cholecystitis, conjunctivitis, cystitis, dacryoadenitis, dermatitis, dermatomyositis, encephalitis, encephalomyelitis, endocarditis, endometritis, upper gastritis, gastroenteritis, allergic purpura, hidradenitis suppurativa, interstitial lung disease, laryngitis, mastitis, meningitis, myelitis, myocarditis, myositis, nephritis, oophoritis, orchitis, osteitis, otitis media, mumps, pneumonia, polymyositis, or prostatitis.

[0208] In some embodiments, the STAT6-mediated or dependent diseases or conditions 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, and diseases involving T. Cellular activation of pathological immune status, cardiovascular disease, or central nervous system disease; in some embodiments, the STAT6-mediated or dependent diseases or conditions described in this disclosure are selected from asthma, atopic dermatitis (AD), chronic obstructive pulmonary disease (COPD), bronchitis, diabetes, atherosclerosis, gout, gouty arthritis, osteoarthritis, systemic lupus erythematosus, polychondritis, colitis, conjunctivitis, allergic rhinitis, rheumatoid arthritis, scleroderma, Wegener's granulomatosis, dermatomyositis, hepatitis, myasthenia gravis, Stevens-Johnson syndrome, ulcerative colitis, Crohn's disease, irritable bowel syndrome. Combination syndrome, celiac disease, periodontitis, kidney disease, glomerular disease, alcoholic liver disease, multiple sclerosis, endocrine ophthalmopathy, Graves' disease, sarcoidosis, alveolitis, chronic allergic pneumonia, multiple 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, myasthenia gravis, thyroiditis. Appendicitis, allergies, cervicitis, cholangitis, cholecystitis, conjunctivitis, cystitis, dacryoadenitis, dermatitis, dermatomyositis, encephalitis, encephalomyelitis, endocarditis, endometritis, upper gastritis, gastroenteritis, allergic purpura, hidradenitis suppurativa, interstitial lung disease, laryngitis, mastitis, meningitis, myelitis, myocarditis, myositis, nephritis, oophoritis, orchitis, osteitis, otitis media, mumps, pneumonia, polymyositis, and prostatitis.

[0209] In some implementations, 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, rectum, prostate cancer, pancreas cancer, lung cancer, vagina, cervix, testis cancer, genitourinary tract cancer, esophagus cancer, larynx cancer, skin cancer, bone cancer 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, epidermal hyperplasia, psoriasis, benign prostatic hyperplasia, tumors, epithelial tumors, adenoma, adenocarcinoma, pancreatic ductal carcinoma, keratoacanthoma, epidermoid carcinoma, large cell carcinoma, non-small cell lung cancer, uveal melanoma, lymphoma, Hodgkin's and non-Hodgkin's cancer, breast cancer, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, IL-1-driven disease, MyD88. Driving diseases, 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, intraangiocarcinoma); 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 sheath tumor (MPNST), and pancreatic cancer. In some embodiments, 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. 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.

[0210] 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.

[0211] In some implementations, the asthma includes endogenous (non-allergic) asthma and extrinsic (allergic) asthma, mild asthma, moderate asthma, severe asthma, bronchial asthma, exercise-induced asthma, occupational asthma, and induced asthma.

[0212] 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.

[0213] 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, the unit dose is 0.1 to 1000 mg.

[0214] 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.

[0215] 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.

[0216] 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.

[0217] The pharmaceutically acceptable salts of the compounds described in this disclosure may be selected from inorganic or organic salts.

[0218] 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.

[0219] 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.

[0220] 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.

[0221] 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.

[0222] 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.

[0223] 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.

[0224] 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 disclosed compounds. To maintain such a constant concentration, a continuous intravenous delivery device can be used. An example of such a device is the Deltec CADD-PLUS™ 5400 intravenous infusion pump.

[0225] The pharmaceutical compositions disclosed herein may be in the form of sterile injectable aqueous or oil suspensions for intramuscular and subcutaneous administration. These suspensions may be formulated using suitable dispersants or wetting agents and suspending agents according to known techniques. The sterile injectable formulations may also be sterile injectable solutions or suspensions prepared in parenteral acceptable non-toxic diluents or solvents. Furthermore, sterile fixative oils can be conveniently used as solvents or suspension media. Any blended fixative oil may be used for this purpose. Additionally, fatty acids may also be used to prepare injectable formulations.

[0226] 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.

[0227] 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.

[0228] Terminology Explanation Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0229] The term "alkyl" refers to a saturated, straight-chain or branched aliphatic hydrocarbon group having 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) carbon atoms (i.e., C2). 1-20 Alkyl group). The alkyl group, in some embodiments, is an alkyl group having 1 to 12 carbon atoms (i.e., C12). 1-12 Alkyl groups, in some embodiments having 1 to 6 carbon atoms (i.e., C164 ... 1-6 Alkyl 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 the following: D atom, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0230] 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 group, in some embodiments, is an alkylene group 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) 1-6 Alkylenes. 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 the following: D atom, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0231] 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-).

[0232] 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 the following: D atom, alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0233] 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, the alkynyl group having 2 to 6 carbon atoms, i.e., C16) is an alkynyl group with 2 to 6 carbon atoms. 2-6Alkyne group. Non-limiting examples include ethynyl, propynyl, butynyl, pentylyl, 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 the following: D atom, alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0234] 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 the following: D atom, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0235] 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) or 4 to 11 ring atoms (i.e., 4 to 11 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).

[0236] Non-limiting examples of the monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclohepttrienyl, and cyclooctyl.

[0237] The polycyclic alkyl groups include: spirocyclic alkyl, fused cyclic alkyl, and bridged cyclic alkyl.

[0238] 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.

[0239] 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. The ring 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 ternary / quaternary, ternary / pentary, ternary / hexaternary, quaternary / quaternary, quaternary / pentary, quaternary / hexaternary, pentary / pentary, pentary / pentary, pentary / pentary, pentary / hexatern ... or pentary / hexaternary bicyclic fused cyclic alkyl group. Non-limiting examples include: Its connection point can be anywhere; wait.

[0240] The term "bridged cycloalkyl" refers to a fully carbon polycyclic system in which two non-directly connected carbon atoms are shared between rings, and the ring may contain one or more double bonds and have 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 has 6 to 14 carbon atoms (i.e., 6 to 14-membered bridged cycloalkyl), and in some embodiments, it has 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.

[0241] 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: D atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, alkylthio, haloalkylthio, cycloalkylthio, heterocyclic thio, heterocyclic oxy, hydroxy, hydroxyalkyl, oxo, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0242] 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, the heterocyclic group has 5 to 15 ring atoms (i.e., a 5 to 15-membered heterocyclic group); in some embodiments, it has 3 to 12 ring atoms (i.e., a 3 to 12-membered heterocyclic group); in some embodiments, it has 4 to 12 ring atoms (i.e., a 4 to 12-membered heterocyclic group); in some embodiments, it has 3 to 8 ring atoms (i.e., a 3 to 8-membered heterocyclic group); in some embodiments, it has 4 to 8 ring atoms (i.e., a 4 to 8-membered heterocyclic group); in some embodiments, it has 4 to 6 ring atoms (i.e., a 4 to 6-membered heterocyclic group); in some embodiments, it has 3 to 6 ring atoms (i.e., a 3 to 6-membered heterocyclic group); in some embodiments, it has... Heterocyclic groups having 5 or 6 ring atoms (i.e., 5- or 6-membered heterocyclic groups); in some embodiments, heterocyclic groups having 6 ring atoms (i.e., 6-membered heterocyclic groups); in some embodiments, heterocyclic groups having 8 to 10 ring atoms (i.e., 8 to 10-membered heterocyclic groups); in some embodiments, heterocyclic groups having 9 ring atoms (i.e., 9-membered heterocyclic groups); in some embodiments, heterocyclic groups having 11 to 13 ring atoms (i.e., 11 to 13-membered heterocyclic groups); in some embodiments, heterocyclic groups having 12 ring atoms (i.e., 12-membered heterocyclic groups); in some embodiments, heterocyclic groups having 13 to 15 ring atoms (i.e., 13 to 15-membered heterocyclic groups); in some embodiments, heterocyclic groups having 14 ring atoms (i.e., 14-membered heterocyclic groups).

[0243] Non-limiting examples of the monocyclic heterocyclic group include: pyrrolidinyl, tetrahydropyranyl, 1,2,3,6-tetrahydropyridyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, and homopiperazinyl, etc.

[0244] The polycyclic heterocyclic groups include spirocyclic heterocyclic groups, fused heterocyclic groups, and bridged heterocyclic groups.

[0245] 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 it contains at least one monocyclic heterocyclic group with a connecting point 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, in some embodiments, 6 to 14 ring atoms (i.e., 6 to 14-membered spiroheterocyclic groups), and in some embodiments, 7 to 11 ring atoms (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.

[0246] 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.

[0247] The term "bridged heterocyclic group" refers to a polycyclic heterocyclic system in which two non-directly bonded 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, 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-). It 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 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.

[0248] 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: D atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, alkylthio, haloalkylthio, cycloalkylthio, heterocyclic thio, hydroxy, hydroxyalkyl, oxo, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0249] 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.

[0250] 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: D atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxyl, alkylthio, haloalkylthio, cycloalkylthio, heterocyclic thio, hydroxyalkyl, oxo, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl. 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).

[0251] 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.

[0252] 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.

[0253] 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: D atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxyl, alkylthio, haloalkylthio, cycloalkylthio, heterocyclic thio, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0254] 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.

[0255] 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.

[0256] 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.

[0257] 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.

[0258] 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.

[0259] The term "cycloalkyloxy" refers to -O-cycloalkyl, where the cycloalkyl is as defined above.

[0260] The term "heterocyclic oxygen group" refers to an -O-heterocyclic group, wherein the heterocyclic group is as defined above.

[0261] The term "aryloxy group" refers to -O-aryl, where the aryl group is as defined above.

[0262] The term "heteroaryloxy" refers to -O-heteroaryl, where the heteroaryl is as defined above.

[0263] 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.

[0264] 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.

[0265] The term "haloalkyl" refers to an alkyl group that has been substituted with one or more halogens, wherein the alkyl group is as defined above.

[0266] The term "haloalkoxy" refers to an alkoxy group that is substituted by one or more halogens, wherein the alkoxy group is as defined above.

[0267] 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.

[0268] The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0269] The term "hydroxyl group" refers to -OH.

[0270] The term "thiol" refers to -SH.

[0271] The term "amino" refers to -NH2.

[0272] The term "cyano" refers to -CN.

[0273] The term "nitro" refers to -NO2.

[0274] The term "oxo" or "oxo group" refers to "=O".

[0275] The term "carbonyl" refers to C=O.

[0276] The term "alkylthio" refers to -S-alkyl, where the alkyl group is as defined above.

[0277] The term "haloalkylthio" refers to an alkylthio group that is replaced by one or more halogens, wherein the alkylthio group is as defined above.

[0278] The term "cycloalkylthio" refers to -S-cycloalkyl, where the cycloalkyl group is as defined above.

[0279] The term "heterocyclic thio" refers to a -S-heterocyclic group, where the heterocyclic group is as defined above.

[0280] The term "tricyclic" refers to a polycyclic ring system having three 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 9 to 24 ring atoms (i.e., 9 to 24-membered tricyclic), each monocycle in the tricyclic ring being independently selected from saturated rings, partially unsaturated rings, and aromatic rings, and the monocycles may be joined together in a fused, bridged, or helical manner; in some embodiments, the tricyclic ring is a 14- or 15-membered tricyclic ring; in some embodiments, the tricyclic ring is a 14-membered tricyclic ring; non-limiting examples of "tricyclic" include, but are not limited to: and wait.

[0281] 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., 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: and wait.

[0282] 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 nucleophilic substitution reactions, 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.

[0283] The disclosed compounds 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 transisomers, conformational isomers, and mixtures thereof (e.g., racemic mixtures, 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 can be prepared by chiral synthesis, chiral reagents, or other conventional techniques. R )-and( S - Enantiomers and (D )-and( L This disclosure discloses an isomer of a certain 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, and then resolving the diastereomer by conventional methods known in the art to obtain the pure isomer. Furthermore, the separation of enantiomers and diastereomers is usually accomplished by chromatography.

[0284] In the chemical structure of the compounds described in this disclosure, the bond " "" indicates that the configuration is not specified, meaning that if a chiral isomer exists in the chemical structure, the bond " "can be " "or" , or both contain " "and" "Two configurations. For all carbon-carbon double bonds, even if only one configuration is named, Z Type and E All types are included.

[0285] In the chemical structure of the compounds described in this disclosure, the bond " "or" "Indicates forward or reverse."

[0286] 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: .

[0287] 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: .

[0288] All tautomers are within the scope of this disclosure, and the naming of compounds does not exclude any tautomers.

[0289] 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 spatial 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.

[0290] 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 I In some implementation schemes, it is deuterium.

[0291] 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.

[0292] When a position is specifically designated as deuterium D, the position 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.

[0293] "Optional" or "optional" means that the event or situation described below may but is not necessarily to occur; it includes both the possibility that the event or situation may occur or not occur. For example, "C that is optionally substituted with a halogen or cyano group..." 1-6 "Alkyl" includes cases where the alkyl group is substituted with a halogen or cyano group and cases where the alkyl group is not substituted with a halogen or cyano group.

[0294] "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 improbable substitutions without much effort (through experimentation or theory). For example, an amino or hydroxyl group having free hydrogen may be unstable when combined with a carbon atom having an unsaturated bond (such as an alkene).

[0295] "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.

[0296] "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.

[0297] 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.

[0298] As used herein, the singular forms of “a,” “an,” and “the” include plural references, and vice versa, unless the context clearly indicates otherwise.

[0299] When the term "about" is applied to parameters such as pH, concentration, temperature, etc., it indicates that the parameter can vary by ±10%, and in some embodiments within ±5%. As those skilled in the art will understand, when a parameter is not critical, figures are typically given for illustrative purposes only and not as limitations. Detailed Implementation

[0300] The following embodiments are used to further describe this disclosure, but these embodiments are not intended to limit the scope of this disclosure.

[0301] Example The structure of the compound was determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shift ( ) with 10-6 The unit (ppm) is given. NMR measurements were performed using a Bruker AVANCE-400 NMR spectrometer or a Bruker AVANCE NEO 500M, with deuterated dimethyl sulfoxide (DMSO) as the solvent. d 6 ), deuterated chloroform (CDCl3), deuterated methanol (CD3OD), with tetramethylsilane (TMS) as the internal standard.

[0302] MS measurements were performed using an Agilent 1200 / 1290 DAD-6110 / 6120 Quadrupole MS liquid chromatography-mass spectrometry system (manufacturer: Agilent, MS model: 6110 / 6120 Quadrupole MS).

[0303] waters ACQuity UPLC-QD / SQD (Manufacturer: waters, MS model: waters ACQuity QdaDetector / waters SQ Detector) THERMO Ultimate 3000-Q Exactive (Manufacturer: THERMO, MS Model: THERMO QExactive) 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.

[0304] Chiral HPLC analysis was performed using an Agilent 1260 DAD high-performance liquid chromatograph.

[0305] High performance liquid chromatography (HPLC) was performed using Waters 2545-2767, Waters 2767-SQ Detecor2, Shimadzu LC-20AP, and Gilson GX-281 preparative chromatographs.

[0306] Chiral preparation was performed using a Shimadzu LC-20AP preparative chromatograph.

[0307] The CombiFlash rapid preparation system uses a CombiFlash Rf200 (TELEDYNE ISCO).

[0308] 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 size of 0.15 mm to 0.2 mm, and the size used for thin-layer chromatography separation and purification of products is 0.4 mm to 0.5 mm.

[0309] Silica gel column chromatography generally uses Yantai Huanghai silica gel with a mesh size of 200-300 as the carrier.

[0310] Mean inhibition rate of kinases and IC 50 The values ​​were determined using a NovoStar microplate reader (BMG GmbH, Germany).

[0311] 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.

[0312] Unless otherwise specified in the examples, all reactions can be carried out under an argon or nitrogen atmosphere.

[0313] Argon or nitrogen atmosphere refers to a reaction flask connected to an argon or nitrogen gas balloon with a volume of approximately 1L.

[0314] A hydrogen atmosphere refers to a reaction flask connected to a hydrogen balloon with a volume of approximately 1L.

[0315] The pressurized hydrogenation reaction was performed using a Parr 3916EKX hydrogenator and a Qinglan QL-500 hydrogen generator or an HC2-SS hydrogenator.

[0316] The hydrogenation reaction is usually carried out under vacuum, filled with hydrogen gas, and repeated 3 times.

[0317] The microwave reaction was performed using a CEM Discover-S 908860 microwave reactor.

[0318] Unless otherwise specified in the examples, "solution" refers to an aqueous solution.

[0319] Unless otherwise specified in the examples, the reaction temperature is room temperature.

[0320] 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.

[0321] Example 1 6-(1-(3-(1 H -pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-4-(4'-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1 H 6 H -spiro[furano[2,3-] f [Indazole-7,4'-piperidine]-1'-yl)-2 H -spiro[benzofuran-3,1'-cyclohexane]-6-yl)-7-fluoro- N , N -Dimethyl-1 H -Indole-2-formamide 1 first step 8-((5-bromo-2-iodophenoxy)methyl)-1,4-dioxaspiro[4.5]dec-8-ol 1c 5-Bromo-2-iodophenol 1a (4 g, 13.38 mmol, Shanghai Biotech) and 1,7,10-trioxadispiro[2.2.4] were mixed. 6 .2 3 Dodecane 1b (2.5 g, 14.69 mmol, prepared using the method disclosed in the literature "Synthetic Communications, 2003, vol. 33, #12, p. 2135-2143") dissolved in N , N - Dimethylformamide (40 mL) was added to anhydrous potassium carbonate (6.50 g, 47.03 mmol), and the mixture was stirred at 90°C for 16 hours. The reaction mixture was cooled to room temperature, ice water was added, and the mixture was extracted with methyl tert-butyl ether (50 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 silica gel column chromatography with eluent system B to give the title compound 1c (6 g, yield: 95.5%).

[0322] Step 2 8-((5-bromo-2-iodophenoxy)methyl)-1,4-dioxaspiro[4.5]dec-7-ene 1d Compound 1c (4 g, 8.53 mmol) and pyridine (2.03 g, 17.05 mmol) were dissolved in thionyl chloride (40 mL), and anhydrous potassium carbonate (6.50 g, 47.03 mmol) was added. The mixture was stirred for 10 minutes, and the reaction solution was concentrated under reduced pressure. The residue was dissolved in dichloromethane and washed successively with saturated sodium bicarbonate solution and saturated sodium chloride solution. The organic phase was separated, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to give the title compound 1d (2 g, yield: 52%).

[0323] Step 3 6-Bromo-2 H -Dispiro[benzofuran-3,1'-cyclohexane-4',2''-[1,3]dioxapentane] 1e Compound 1d (2 g, 4.43 mmol) was dissolved in toluene (40 mL), and tri-n-butyltin hydride (1.54 g, 5.32 mmol) and azobisisobutyronitrile (728 mg, 4.43 mmol) were added. The reaction mixture was reacted at 115 °C for 16 h. The reaction solution was cooled to room temperature, and 20% potassium fluoride solution was added and stirred for 3 h. The organic phase was separated, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to give the title compound 1e (1.4 g, yield: 97.1%).

[0324] MS m / z (ESI): 324.9 [M+1].

[0325] Step 4 6-Bromo-2 H -spiro[benzofuran-3,1'-cyclohexane]-4'-one 1f Compound 1e (1.4 g, 4.30 mmol) was dissolved in tetrahydrofuran (10 mL) and water (5 mL), and concentrated hydrochloric acid (5 mL) was added. The reaction was carried out at 40°C for 3 hours. After the reaction solution was cooled to room temperature, it was concentrated under reduced pressure to obtain the crude title compound 1f (1 g), which was used directly in the next step of the reaction without purification.

[0326] MS m / z (ESI): 279.2 [M-1].

[0327] Step 5 4-(bromomethyl)-3,6-dihydropyridine-1(2) H )-tert-butyl carboxylate 1h 4-(hydroxymethyl)-3,6-dihydropyridine-1(2 H1 g of tert-butyl carboxylate (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 the title compound 1h (64 g, yield: 98.8%).

[0328] MS m / z (ESI): 220.0 [M-55].

[0329] Step 6 6-Bromo-3-iodo-5-methoxy-1 H -Indazole1j The compound 6-bromo-5-methoxy-1 H -Indazole 1i (25 g, 110.10 mmol, Shanghai Bide) dissolved in N , N In dimethylformamide (400 mL), 1-iodopyrrolidine-2,5-dione (27.50 g, 122.23 mmol, Shanghai Bide) was added, and 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 1j (35 g). The product was used directly in the next reaction without purification.

[0330] MS m / z (ESI): 353.1 [M+1].

[0331] Step 7 6-Bromo-3-iodo-5-methoxy-1-methyl-1 H -Indazole 1k Compound 1j (35 g, 99.16 mmol) was dissolved in... N , N Dimethylformamide (500 mL) was added to methyl iodide (16.90 g, 119.06 mmol) and cesium carbonate (70 g, 214.84 mmol), and the mixture was stirred for 3 hours. Ethyl acetate (200 mL) was added to the reaction mixture, and the mixture was filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system D to give the title compound 1k (16 g, yield: 43.9%).

[0332] MS m / z (ESI): 367.2 [M+1].

[0333] Step 8 6-Bromo-3-iodo-1-methyl-1 H -Indazole-5-phenol 1l Compound 1k (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 1l (24.4 g) was obtained. The product was used directly in the next reaction without purification.

[0334] MS m / z (ESI): 353.1 [M+1].

[0335] Step 9 4-(((6-bromo-3-iodo-1-methyl-1- H -Indazol-5-yl)oxy)methyl)-3,6-dihydropyridine-1(2 H 1m-tert-butyl carboxylate Compound 1l (12.80 g, 36.26 mmol) and compound 1h (11.80 g, 42.73 mmol) were dissolved in... N , N Dimethylformamide (200 mL) was added to potassium carbonate (9.84 g, 71.20 mmol), and the mixture was stirred for 0.5 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to give the title compound 1m (19 g, yield: 97.33%).

[0336] MS m / z (ESI): 492.3 [M-55].

[0337] Step 10 4-(((3-(2,6-bis(benzyloxy)pyridin-3-yl)-6-bromo-1-methyl-1 H -Indazol-5-yl)oxy)methyl)-3,6-dihydropyridine-1(2 H 1n-tert-butyl carboxylate Compound 1m (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 1n (16.4 g, yield: 92.2%).

[0338] MS m / z (ESI): 711.5 [M+1].

[0339] Step 11 3-(2,6-bis(benzyloxy)pyridin-3-yl)-1-methyl-2',3'-dihydro-1 H ,1' H 6 H -spiro[furano[2,3-] f Indazole-7,4'-pyridine]-1'-carboxylic acid tert-butyl ester 1o Compound 1n (16.40 g, 23.04 mmol) was dissolved in... N , N 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 to dimethylformamide (150 mL), and the 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 1o (9.1 g, yield: 62.6%).

[0340] MS m / z (ESI): 631.8 [M+1].

[0341] Step Twelve 3-(2,6-dioxopiperidin-3-yl)-1-methyl-1 H 6 H Spiro[furano[2,3-] f Indazole-7,4'-piperidine]-1'-carboxylic acid tert-butyl ester 1p Compound 1o (1.50 g, 2.38 mmol) 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 give the crude title compound 1p (870 mg, yield: 24.2%). The product was used directly in the next reaction without purification.

[0342] MS m / z (ESI): 455.6 [M+1].

[0343] Step Thirteen 3-(1-methyl-1-yl) H 6 H -spiro[furano[2,3-] f [Indazole-7,4'-piperidine]-3-yl)piperidine-2,6-dione hydrochloride 1q Compound 1p (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 1q (750 mg). The product was used directly in the next reaction without purification.

[0344] MS m / z (ESI): 355.1 [M+1].

[0345] Step Fourteen 3-(1'-(6-bromo-2) H -spiro[benzofuran-3,1'-cyclohexane]-4'-yl)-1-methyl-1 H 6 H -spiro[furano[2,3-] f [Indazole-7,4'-piperidine]-3-yl)piperidine-2,6-dione 1r Compound 1f (50 mg, 178 μmol) and crude compound 1q (70 mg, 179 μmol) were dissolved in... N , NDimethylformamide (1 mL) and tetrahydrofuran (5 mL) were added, followed by the addition of triethylamine (36 mg, 256 μmol) under ice bath conditions. The mixture was stirred at room temperature for 0.5 h, followed by the addition of acetic acid (32 mg, 533 μmol) and sodium triacetoxyborohydride (113 mg, 533 μmol) under ice bath conditions. The mixture was stirred at room temperature for 16 h, and water was added to the reaction mixture. The mixture was extracted with ethyl acetate (5 mL × 3), and the organic phases were combined and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system B to give the title compound 1r (50 mg, yield: 45.3%).

[0346] MS m / z (ESI): 619.3 [M+1].

[0347] Step Fourteen 6-(1-(3-(1 H -pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-4-(4'-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1 H 6 H -spiro[furano[2,3-] f [Indazole-7,4'-piperidine]-1'-yl)-2 H -spiro[benzofuran-3,1'-cyclohexane]-6-yl)-7-fluoro- N , N -Dimethyl-1 H -Indole-2-formamide 1 Compound 1r (50 mg, 81 μmol), 6-(1-(3-(1) H -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)-1 H-Indole-2-carboxamide 1s (43 mg, 80 μmol, prepared by the method disclosed in Intermediate AR on page 1145 of patent application "WO2025049820") was dissolved in 1,4-dioxane (5 mL) and water (1 mL), and 1,1'-bis(diphenylphosphine)ferrocene palladium(II) dichloride (6 mg, 8.1 μmol) and potassium phosphate (35 mg, 167 μmol) were added. The mixture was then purged with nitrogen and reacted at 80°C for 2 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 (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 30%-60%, flow rate: 30 mL / min) to give title compound 1 (20 mg, yield: 26.4%).

[0348] MS m / z (ESI): 948.6 [M+1].

[0349] Example 2 6-(1-(3-(1 H -pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-4-(4'-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1 H 7 H -spiro[furano[3,2-] g [Indazole-6,4'-piperidine]-1'-yl)-2 H -spiro[benzofuran-3,1'-cyclohexane]-6-yl)-7-fluoro- N , N -Dimethyl-1 H -Indole-2-formamide 2 6-(1-(3-(1 H -pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-4-((3 s ,4' s )-4'-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1 H 7 H -spiro[furano[3,2-] g [Indazole-6,4'-piperidine]-1'-yl)-2 H -spiro[benzofuran-3,1'-cyclohexane]-6-yl)-7-fluoro- N , N -Dimethyl-1H -Indole-2-carboxamide 2-p1 6-(1-(3-(1 H -pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-4-((3 r ,4' r )-4'-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1 H 7 H -spiro[furano[3,2-] g [Indazole-6,4'-piperidine]-1'-yl)-2 H -spiro[benzofuran-3,1'-cyclohexane]-6-yl)-7-fluoro- N , N -Dimethyl-1 H -Indole-2-carboxamide 2-p2 first step 6-Bromo-7-methoxy-1 H -Indazole 2b 4-Bromo-2-fluoro-3-methoxybenzaldehyde 2a (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 2b (950 mg, yield: 10.8%).

[0350] MS m / z (ESI): 227.1 [M+1].

[0351] Step 2 6-Bromo-3-iodo-7-methoxy-1 H -Indazole 2c Compound 2b (1.10 g, 4.84 mmol) was dissolved in... N , N Add to dimethylformamide (15 mL) N - Iodosuccinimide (1.42 g, 6.30 mmol, Shanghai Titan) was stirred for 3 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to give the title compound 2c (1.41 g, yield: 82.4%).

[0352] MS m / z (ESI): 353.0 [M+1].

[0353] Step 3 6-Bromo-3-iodo-7-methoxy-1-methyl-1 H -Indazole 2d Compound 2c (1.41 g, 4.0 mmol) was dissolved in... N , N In 15 mL of dimethylformamide, potassium carbonate (1.10 g, 8.0 mmol, Sinopharm) and methyl iodide (1.13 g, 8.0 mmol, Shanghai Titan) were added, and the reaction was carried out 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 2d (900 mg, yield: 61.3%).

[0354] MS m / z (ESI): 367.1 [M+1].

[0355] Step 4 6-Bromo-3-iodo-1-methyl-1 H -Indazole-7-phenol 2e Compound 2d (900 mg, 2.45 mmol) was dissolved in... N , N Sodium ethanethiol (2.06 g, 24.52 mmol, Shanghai Titan) was added to 10 mL of dimethylformamide and 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 1M 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 with eluent system B to give the title compound 2e (800 mg, yield: 92.4%).

[0356] MS m / z (ESI): 353.0 [M+1].

[0357] Step 5 4-(bromomethyl)-3,6-dihydropyridine-1(2) H 2g of tert-butyl carboxylate 4-(hydroxymethyl)-3,6-dihydropyridine-1(2 H2f of tert-butyl carboxylate (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 2 g (64 g, yield: 98.8%) of the title compound.

[0358] MS m / z (ESI): 220.0 [M-55].

[0359] Step 6 4-(((6-bromo-3-iodo-1-methyl-1- H -Indazol-7-yl)oxy)methyl)-3,6-dihydropyridine-1(2 H )-tert-butyl carboxylate 2h Compound 2e (20 g, 56.66 mmol) and compound 8 g (16.43 g, 59.49 mmol) were dissolved in... N , N Dimethylformamide (200 mL) was added to potassium carbonate (15.66 g, 113.31 mmol), and 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 2h (26.8 g, yield: 86.2%).

[0360] MS m / z (ESI): 492.1 [M-55].

[0361] Step 7 4-(((3-(2,6-bis(benzyloxy)pyridin-3-yl)-6-bromo-1-methyl-1 H -Indazol-7-yl)oxy)methyl)-3,6-dihydropyridine-1(2 H 2i-tert-butyl carboxylate Compound 2h (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 hours. 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 2i (7 g, yield: 83.9%).

[0362] MS m / z (ESI): 711.6 [M+1].

[0363] Step 8 3-(2,6-bis(benzyloxy)pyridin-3-yl)-1-methyl-2',3'-dihydro-1 H ,1' H 7 H -spiro[furano[3,2-] g Indazole-6,4'-pyridine]-1'-carboxylic acid tert-butyl ester 2j Compound 2i (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 2j (5.5 g, yield: 62.05%).

[0364] MS m / z (ESI): 631.6 [M+1].

[0365] Step 9 3-(2,6-dioxopiperidin-3-yl)-1-methyl-1 H 7 H -spiro[furano[3,2-] g Indazole-6,4'-piperidine]-1'-carboxylic acid tert-butyl ester 2k Compound 2j (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 of 30 atm. After the reaction solution was cooled to room temperature, it was filtered, and the filtrate was concentrated under reduced pressure to give the crude title compound 2k (3.5 g). The product was used directly in the next reaction without purification.

[0366] MS m / z (ESI): 455.6 [M+1].

[0367] Step 10 3-(1-methyl-1-yl) H 7 H -spiro[furano[3,2-] g [Indazole-6,4'-piperidine]-3-yl)piperidine-2,6-dione hydrochloride 2l The crude compound 2k (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 2l (4.46 g). The product was used directly in the next reaction without purification.

[0368] MS m / z (ESI): 355.1 [M+1].

[0369] Step 11 3-(1'-(6-bromo-2) H -spiro[benzofuran-3,1'-cyclohexane]-4'-yl)-1-methyl-1 H 7 H -spiro[furano[3,2-] g [Indazole-6,4'-piperidine]-3-yl)piperidine-2,6-dione 2m Compound 1f (100 mg, 356 μmol) and crude compound 2l (139 mg, 356 μmol) were dissolved in 1,2-dichloroethane (10 mL) and dimethyl sulfoxide (2 mL). Sodium acetate (88 mg, 1.07 mmol) was added, and the mixture was stirred for 1 hour. Then, sodium triacetoxyborohydride (226 mg, 1.07 mmol) 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 using eluent system A to give title compound 2m (200 mg, yield: 90.7%).

[0370] MS m / z (ESI): 619.4 [M+1].

[0371] Step Twelve 6-(1-(3-(1 H -pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-4-(4'-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1 H 7 H -spiro[furano[3,2-] g [Indazole-6,4'-piperidine]-1'-yl)-2 H -spiro[benzofuran-3,1'-cyclohexane]-6-yl)-7-fluoro- N , N -Dimethyl-1 H -Indole-2-formamide 2 6-(1-(3-(1 H -pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-4-((3 s ,4' s )-4'-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1 H 7 H -spiro[furano[3,2-] g [Indazole-6,4'-piperidine]-1'-yl)-2 H -spiro[benzofuran-3,1'-cyclohexane]-6-yl)-7-fluoro- N , N -Dimethyl-1 H -Indole-2-carboxamide 2-p1 6-(1-(3-(1 H -pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-4-((3 r ,4' r )-4'-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1 H 7 H -spiro[furano[3,2-] g [Indazole-6,4'-piperidine]-1'-yl)-2 H -spiro[benzofuran-3,1'-cyclohexane]-6-yl)-7-fluoro- N , N -Dimethyl-1 H -Indole-2-carboxamide 2-p2 Compound 2m (200 mg, 323 μmol) and compound 1s (173 mg, 323 μmol) were dissolved in 1,4-dioxane (15 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) (41 mg, 48.4 μmol) and potassium phosphate (205 mg, 966 μmol) were added. The mixture was purged with nitrogen and reacted at 80°C for 2 hours. The reaction solution was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure to obtain crude title compound 1 (306 mg). Purification was performed by preparative high-performance liquid chromatography (Waters-2545, column: Welch Xtimate C18, 30*150 mm, 5 μm; mobile phase: aqueous phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 30%-60%, flow rate: 30 mL / min) to obtain title compound (20 mg, yield: 6.5%) and (6 mg, yield: 2%). Compounds with shorter retention times: (20 mg, yield: 6.5%).

[0372] MS m / z (ESI): 948.6 [M+1].

[0373] HPLC analysis: retention time 1.38 min, purity: 99% (column: Xtimate, C18, 1.8 μm, 2.1*50 mm; mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%), acetonitrile, gradient ratio: acetonitrile 10%-95%).

[0374] Compounds with longer retention time: (6 mg, yield: 2%).

[0375] MS m / z (ESI): 948.6 [M+1].

[0376] HPLC analysis: retention time 1.48 min, purity: 99% (column: Xtimate, C18, 1.8 μm, 2.1*50 mm; mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%), acetonitrile, gradient ratio: acetonitrile 10%-95%).

[0377] Example 3 6-(1-(3-(1 H -pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-4-(4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1 H 7H -spiro[furano[3,2-] g [Indazole-6,4'-piperidine]-1'-yl)-3' H -spiro[cyclohexane-1,1'-isobenzofuran]-5'-yl)-7-fluoro- N , N -Dimethyl-1 H -Indole-2-formamide 3 first step 3-(1-methyl-1-yl) H 7 H -spiro[furano[3,2-] g [Indazole-6,4'-piperidine]-3-yl)piperidine-2,6-dione 2,2,2-trifluoroacetate 3a The crude compound 2k (2 g, 4.40 mmol) was dissolved in dichloromethane (30 mL), and trifluoroacetic acid (10 mL) was added. The mixture was stirred for 16 hours, and the reaction solution was concentrated under reduced pressure to obtain the crude title compound 3a (2 g). The product was used directly in the next reaction without purification.

[0378] MS m / z (ESI): 355.1 [M+1].

[0379] Step 2 3-(1'-(5'-chloro-3') H -spiro[cyclohexane-1,1'-isobenzofuran]-4-yl)-1-methyl-1 H 7 H -spiro[furano[3,2-] g [Indazole-6,4'-piperidine]-3-yl)piperidine-2,6-dione 3c Compound 3a (139 mg, 296 μmol), 5'-chloro-3' H -spiro[cyclohexane-1,1'-isobenzofuran]-4-one 3b (139 mg, 356 μmol, prepared by the method disclosed in Intermediate 16 on page 77 of patent application "WO2022013408") was dissolved in 1,2-dichloroethane (10 mL) and dimethyl sulfoxide (2 mL), tetraethyl titanate (202 mg, 887 μmol) was added, and sodium cyanoborohydride (30 mg, 502 μmol) was added in portions. The mixture was stirred for 16 hours, saturated sodium bicarbonate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system A to give title compound 3c (65 mg, yield: 38.2%).

[0380] MS m / z (ESI): 575.3 [M+1].

[0381] Step 3 6-(1-(3-(1 H -pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-4-(4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1 H 7 H -spiro[furano[3,2-] g [Indazole-6,4'-piperidine]-1'-yl)-3' H -spiro[cyclohexane-1,1'-isobenzofuran]-5'-yl)-7-fluoro- N , N -Dimethyl-1 H -Indole-2-formamide 3 Compound 3c (65 mg, 113 μmol) and compound 1s (66 mg, 124 μmol) were dissolved in 1,4-dioxane (10 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) (14.3 mg, 17 μmol) and potassium phosphate (48 mg, 226 μmol) were added. The mixture was purged with nitrogen and reacted at 80°C for 2 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*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 3 (5 mg, yield: 4.6%).

[0382] MS m / z (ESI): 948.8 [M+1].

[0383] 1H NMR (500 MHz, DMSO-d6): δ 12.23 (s, 1H), 10.90 (s, 1H), 8.35 (s,1H), 7.80 – 7.33 (m, 5H), 7.27 – 6.83 (m, 4H), 6.20 (d, 2H), 5.34 (s, 1H),5.06 (s, 2H), 4.63 (s, 2H), 4.47 – 4.28 (m, 3H), 4.09 (s, 2H), 3.63 (d, 4H), 3.04 (d, 7H), 2.63 (d, 3H), 2.38 – 1.37 (m, 19H).

[0384] Example 4 6-(1-(3-(1 H -pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-4-((3 s ,4' s )-4'-((3-(2,6-dioxopiperidin-3-yl)-1-methyl-1 H 7 H -spiro[furano[3,2-] g [Indazole-6,4'-piperidine]-1'-yl)methyl)-2 H -spiro[benzofuran-3,1'-cyclohexane]-6-yl)-7-fluoro- N , N -Dimethyl-1 H -Indole-2-carboxamide 4-p1 6-(1-(3-(1 H -pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-4-((3 r ,4' r )-4'-((3-(2,6-dioxopiperidin-3-yl)-1-methyl-1 H 7 H -spiro[furano[3,2-] g [Indazole-6,4'-piperidine]-1'-yl)methyl)-2 H -spiro[benzofuran-3,1'-cyclohexane]-6-yl)-7-fluoro- N , N -Dimethyl-1 H -Indole-2-formamide 4-p2 first step 6-Bromo-4'-(methoxymethylene)-2 H -spiro[benzofuran-3,1'-cyclohexane] 4a Methoxymethyltriphenylphosphine chloride (1.10 g, 3.21 mmol) was dissolved in tetrahydrofuran (10 mL). A 1 M potassium tert-butoxide solution in tetrahydrofuran (3.73 mL) was added dropwise under ice bath conditions. The mixture was stirred for 1 hour while maintaining the temperature. Then, a tetrahydrofuran solution of compound 1f (500 mg, 1.78 mmol) (10 mL) was added dropwise. The mixture was stirred for 0.5 hours while maintaining the temperature, and then allowed to react at room temperature for 16 hours. Water was added to the reaction mixture, 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 B to give title compound 4a (280 mg, yield: 50.9%).

[0385] Step 2 6-Bromo-2 H -spiro[benzofuran-3,1'-cyclohexane]-4'-formaldehyde 4b Compound 4a (150 mg, 485 μmol) was dissolved in tetrahydrofuran (10 mL), 6M hydrochloric acid (5 mL) was added, and the mixture was stirred for 1 hour. The reaction solution was neutralized with saturated sodium bicarbonate solution, 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 to obtain crude title compound 4b (143 mg), which was used directly in the next reaction without purification.

[0386] MS m / z (ESI): 296.3 [M+1].

[0387] Step 3 6-(1-(3-(1 H -pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-4-((3 s ,4' s )-4'-((3-(2,6-dioxopiperidin-3-yl)-1-methyl-1 H 7 H -spiro[furano[3,2-] g [Indazole-6,4'-piperidine]-1'-yl)methyl)-2 H -spiro[benzofuran-3,1'-cyclohexane]-6-yl)-7-fluoro- N , N -Dimethyl-1 H -Indole-2-carboxamide 4-p1 6-(1-(3-(1 H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-4-((3 r ,4' r )-4'-((3-(2,6-dioxopiperidin-3-yl)-1-methyl-1 H 7 H -spiro[furano[3,2-] g [Indazole-6,4'-piperidine]-1'-yl)methyl)-2 H -spiro[benzofuran-3,1'-cyclohexane]-6-yl)-7-fluoro- N , N -Dimethyl-1 H -Indole-2-formamide 4-p2 Using steps eleven and twelve of the synthetic route in Example 2, the title compound (28 mg, yield: 16.7%) and (6 mg, yield: 3.6%) were prepared by replacing the starting compound 1f in step eleven with compound 4b.

[0388] Compounds with shorter retention times: (28 mg, yield: 16.7%).

[0389] MS m / z (ESI): 962.6 [M+1].

[0390] HPLC analysis: retention time 1.65 min, purity: 99% (column: Xtimate, C18, 1.8 μm, 2.1*50 mm; mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%), acetonitrile, gradient ratio: acetonitrile 10%-95%).

[0391] Compounds with longer retention time: (6 mg, yield: 3.6%).

[0392] MS m / z (ESI): 962.6 [M+1].

[0393] HPLC analysis: retention time 1.68 min, purity: 99% (column: Xtimate, C18, 1.8 μm, 2.1*50 mm; mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%), acetonitrile, gradient ratio: acetonitrile 10%-95%).

[0394] Example 4-1 6-(1-(3-(1 H -pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-4-((3 R ,4' s )-4'-((3-((S )-2,6-dioxopiperidin-3-yl)-1-methyl-1 H 7 H -spiro[furano[3,2-] g [Indazole-6,4'-piperidine]-1'-yl)methyl)-2 H -spiro[benzofuran-3,1'-cyclohexane]-6-yl)-7-fluoro- N , N -Dimethyl-1 H -Indole-2-carboxamide 4-p1-1 6-(1-(3-(1 H -pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-4-((3 S ,4' s )-4'-((3-(( R )-2,6-dioxopiperidin-3-yl)-1-methyl-1 H 7 H -spiro[furano[3,2-] g [Indazole-6,4'-piperidine]-1'-yl)methyl)-2 H -spiro[benzofuran-3,1'-cyclohexane]-6-yl)-7-fluoro- N , N -Dimethyl-1 H -Indole-2-carboxamide 4-p1-2 6-(1-(3-(1 H -pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-4-((3 S ,4' r )-4'-((3-(( S )-2,6-dioxopiperidin-3-yl)-1-methyl-1 H 7 H -spiro[furano[3,2-] g [Indazole-6,4'-piperidine]-1'-yl)methyl)-2 H -spiro[benzofuran-3,1'-cyclohexane]-6-yl)-7-fluoro- N , N -Dimethyl-1 H -Indole-2-carboxamide 4-p2-1 6-(1-(3-(1 H -pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-4-((3 R ,4' r )-4'-((3-(( R)-2,6-dioxopiperidin-3-yl)-1-methyl-1 H 7 H -spiro[furano[3,2-] g [Indazole-6,4'-piperidine]-1'-yl)methyl)-2 H -spiro[benzofuran-3,1'-cyclohexane]-6-yl)-7-fluoro- N , N -Dimethyl-1 H -Indole-2-carboxamide 4-p2-2 The compounds with shorter retention times (200 mg) of 4-p1 and 4-p2 were resolved by chiral column chromatography (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 obtain two compounds 4-p1-1 and 4-p1-2 or two compounds 4-p2-1 and 4-p2-2 (80 mg, yield: 40%) and (80 mg, yield: 40%).

[0395] Single configuration compound (shorter retention time): 4-p1-2 or 4-p2-2 (80 mg, yield: 40%).

[0396] MS m / z (ESI): 962.9 [M+1].

[0397] Chiral HPLC analysis: retention time 6.458 min, purity: 99.2% (column: ReGIS (S,S)-Whelk-O1, 4.6×150 mm, 5 μm; mobile phase A: ethanol containing (0.1% diethylamine), mobile phase B: acetonitrile, gradient ratio: A:B = 80:20, flow rate: 1.0 mL / min).

[0398] 1 H NMR (500 MHz, DMSO- d6): δ 12.17 (s, 1H), 10.88 (s, 1H), 7.71 (dd,1H), 7.40 (dd, 1H), 7.26 (d, 1H), 7.22–7.11 (m, 2H), 7.06–6.95 (m, 3H), 6.84(d, 1H), 6.23–6.10 (m, 2H), 4.58 (s, 2H), 4.45–4.26 (m, 7H), 4.07 (s, 3H), 3.60 (dt, 2H), 3.28–2.94 (m, 9H), 2.85 (d, 2H), 2.71–2.53 (m, 2H), 2.39–2.22(m, 3H), 2.21-2.10 (m, 3H), 2.06-1.96 (m, 5H), 1.88–1.59 (m, 9H).

[0399] Single configuration compound (longer retention time): 4-p1-1 or 4-p2-1 (80 mg, yield: 40%).

[0400] MS m / z (ESI): 962.9 [M+1].

[0401] Chiral HPLC analysis: retention time 9.916 min, purity: 98.2% (column: ReGIS (S,S)-Whelk-O1, 4.6×150 mm, 5 μm; mobile phase A: ethanol containing (0.1% diethylamine), mobile phase B: acetonitrile, gradient ratio: A:B = 80:20, flow rate: 1.0 mL / min).

[0402] 1 H NMR (500 MHz, DMSO- d6): δ 12.17 (s, 1H), 10.88 (s, 1H), 7.71 (dd,1H), 7.40 (dd, 1H), 7.26 (d, 1H), 7.22–7.11 (m, 2H), 7.06–6.95 (m, 3H), 6.84(d, 1H), 6.23–6.10 (m, 2H), 4.58 (s, 2H), 4.45–4.26 (m, 7H), 4.07 (s, 3H), 3.60 (dt, 2H), 3.28–2.94 (m, 9H), 2.85 (d, 2H), 2.71–2.53 (m, 2H), 2.39–2.22(m, 3H), 2.21-2.10 (m, 3H), 2.06-1.96 (m, 5H), 1.88–1.59 (m, 9H).

[0403] Example 5 6-(1-(3-(1 H -1,2,3-triazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-4-(4'-((3-(2,6-dioxopiperidin-3-yl)-1-methyl-1 H 7 H -spiro[furano[3,2-] g [Indazole-6,4'-piperidine]-1'-yl)methyl)-2 H -spiro[benzofuran-3,1'-cyclohexane]-6-yl)-7-fluoro- N , N -Dimethyl-1 H -Indole-2-formamide 5 6-(1-(3-(1 H -1,2,3-triazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-4-((3 s ,4' s )-4'-((3-(2,6-dioxopiperidin-3-yl)-1-methyl-1 H 7 H -spiro[furano[3,2-] g [Indazole-6,4'-piperidine]-1'-yl)methyl)-2 H -spiro[benzofuran-3,1'-cyclohexane]-6-yl)-7-fluoro- N , N -Dimethyl-1 H -Indole-2-carboxamide 5-p1 6-(1-(3-(1 H-1,2,3-triazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-4-((3 r ,4' r )-4'-((3-(2,6-dioxopiperidin-3-yl)-1-methyl-1 H 7 H -spiro[furano[3,2-] g [Indazole-6,4'-piperidine]-1'-yl)methyl)-2 H -spiro[benzofuran-3,1'-cyclohexane]-6-yl)-7-fluoro- N , N -Dimethyl-1 H -Indole-2-formamide 5-p2 Using steps eleven and twelve of the synthetic route in Example 2, the starting compound 1f in step eleven was replaced with compound 4b, and compound 1s in step twelf was replaced with 6-(1-(3-(1 H -1,2,3-triazol-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)-1 H -Indole-2-carboxamide (prepared using the method disclosed in Intermediate AK on page 1138 of patent application "WO2025049820") yielded crude title compound 5, which was then purified by high performance liquid chromatography (Waters-2545, column: Welch Xtimate C18, 30*150 mm, 5 μm; mobile phase: aqueous phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 30%-60%, flow rate: 30 mL / min) to obtain title compounds 5-p1 and 5-p2.

[0404] MS m / z (ESI): 963.6 [M+1].

[0405] Example 6 6-(1-(3-(1 H -1,2,3-triazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-4-(4'-((3-(2,6-dioxopiridin-3-yl)-1-methyl-2-oxo-2,3-dihydro-1 H 7 H -spiro[benzofurano[6,7-]d [Imidazol-6,4'-piperidin]-1'-yl)methyl)-2 H -spiro[benzofuran-3,1'-cyclohexane]-6-yl)-7-fluoro- N , N -Dimethyl-1 H -Indole-2-formamide 6 6-(1-(3-(1 H -1,2,3-triazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-4-((3 s ,4' s )-4'-((3-(2,6-dioxopiperidin-3-yl)-1-methyl-2-oxo-2,3-dihydro-1 H 7 H -spiro[benzofurano[6,7-] d [Imidazol-6,4'-piperidin]-1'-yl)methyl)-2 H -spiro[benzofuran-3,1'-cyclohexane]-6-yl)-7-fluoro- N , N -Dimethyl-1 H -Indole-2-carboxamide 6-p1 6-(1-(3-(1 H -1,2,3-triazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-4-((3 r ,4' r )-4'-((3-(2,6-dioxopiperidin-3-yl)-1-methyl-2-oxo-2,3-dihydro-1 H 7 H -spiro[benzofurano[6,7-] d [Imidazol-6,4'-piperidin]-1'-yl)methyl)-2 H -spiro[benzofuran-3,1'-cyclohexane]-6-yl)-7-fluoro- N , N -Dimethyl-1 H -Indole-2-formamide 6-p2 first step 6-Bromo-2-fluoro-3-nitrophenol 6b 2-Fluoro-3-nitrophenol 6a (5 g, 31.83 mmol, Shanghai Shaoyuan) was dissolved in dichloromethane (100 mL), and then added... N- Bromosuccinimide (5.67 g, 31.86 mmol) was stirred for 4 hours. Water was added to the reaction solution, the organic phase was separated, washed with saturated sodium chloride solution, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to give title compound 6b (5 g, yield: 66.5%).

[0406] MS m / z (ESI): 234.0 [M-1].

[0407] Step 2 4-((6-bromo-2-fluoro-3-nitrophenoxy)methyl)-3,6-dihydropyridine-1(2 H 6c-tert-butyl carboxylate Compound 2f (7.77 g, 36.43 mmol) and compound 6b (8.6 g, 36.44 mmol) were dissolved in tetrahydrofuran (100 mL). Triphenylphosphine (14.34 g, 54.67 mmol) and diisopropyl azodicarbonate (11.05 g, 54.65 mmol) were added under ice bath conditions, 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 B to give the title compound 6c (5 g, yield: 31.8%).

[0408] Step 3 7-Fluoro-6-nitro-2 H 6d Spiro[benzofuran-3,4'-piperidine]-1'-carboxylic acid tert-butyl ester Compound 6c (115 mg, 267 μmol) was dissolved in toluene (10 mL), and tri-n-butyltin hydride (93 mg, 320 μmol) and azobisisobutyronitrile (53 mg, 320 μmol) were added. The mixture was reacted at 115 °C for 16 hours. The reaction solution was cooled to room temperature, and 20% potassium fluoride solution was added and stirred for 3 hours. The organic phase was separated, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to give the title compound 6d (80 mg, yield: 85%).

[0409] MS m / z (ESI): 353.2 [M+1].

[0410] Step 4 7-(methylamino)-6-nitro-2 H 6e-spiro[benzofuran-3,4'-piperidine]-1'-carboxylic acid tert-butyl ester Compound 6d (200 mg, 568 μmol) was dissolved in tetrahydrofuran (5 mL), and a 2M methylamine tetrahydrofuran solution (3 mL) was added. The reaction mixture was stirred at 60 °C for 12 hours. The reaction solution was cooled to room temperature, and a saturated sodium bicarbonate solution was added. The mixture was extracted with ethyl acetate (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 to obtain the crude title compound 6e (200 mg). The product was used directly in the next reaction without purification.

[0411] MS m / z (ESI): 364.2 [M+1].

[0412] Step 5 6-Amino-7-(methylamino)-2 H 6f-spiro[benzofuran-3,4'-piperidine]-1'-carboxylic acid tert-butyl ester The crude compound 6e (200 mg, 551 μmol) was dissolved in ethyl acetate (5 mL) and water (0.5 mL), acetic acid (1.5 mL) was added, and the mixture was heated to 50 °C. Iron powder (123 mg, 2.20 mmol) was added, and the mixture was heated to 80 °C and reacted for 4 hours. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate (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 to obtain the crude title compound 6f (150 mg). The product was used directly in the next reaction without purification.

[0413] MS m / z (ESI): 334.2 [M+1].

[0414] Step 6 1-Methyl-2-oxo-2,3-dihydro-1 H 7 H -spiro[benzofurano[6,7-] d Imidazole-6,4'-piperidine]-1'-carboxylic acid tert-butyl ester 6g The crude compound 6f (150 mg, 450 μmol) was dissolved in acetonitrile (5 mL), and then added... N , N '-Carbonyldiimidazole (146 mg, 900 μmol) was reacted under nitrogen purging at 85 °C with stirring for 12 hours. The reaction solution was cooled to room temperature, water was added, and a solid was precipitated. The solid was filtered, and the filter cake was washed with water and dried to obtain 6 g (150 mg) of crude title compound. The product was used directly in the next reaction without purification.

[0415] MS m / z (ESI): 360.2 [M+1].

[0416] Step 7 3-(1-(4-methoxybenzyl)-2,6-dioxopiperidin-3-yl)-1-methyl-2-oxo-2,3-dihydro-1 H 7 H -spiro[benzofurano[6,7-] d Imidazole-6,4'-piperidine]-1'-carboxylic acid tert-butyl ester 6h 6 g (150 mg, 418 μmol) of the crude compound was dissolved in acetonitrile (5 mL). Potassium tert-butoxide (536 mg, 502 μmol) was added under ice bath conditions. The mixture was stirred for 0.5 hours while maintaining the temperature. Then, a tetrahydrofuran solution (1.5 mL) of 1-(4-methoxybenzyl)-2,6-dioxopiperidin-3-yltrifluoromethanesulfonate (153 mg, 418 μmol, prepared by the method disclosed in Intermediate G on page 1104 of patent application "WO2025049820") was added dropwise. The mixture was stirred at room temperature for 2 hours. The reaction solution was quenched with saturated ammonium chloride solution. The mixture was extracted with ethyl acetate (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 B to give the title compound 6h (136 mg, yield: 55%).

[0417] MS m / z (ESI): 591.2 [M+1].

[0418] Step 8 3-(1-methyl-2-oxo-1,2-dihydro-3-) H 7 H -spiro[benzofurano[6,7-] d [Imidazol-6,4'-piperidin]-3-yl)piperidin-2,6-dione 6i Compound 6h (136 mg, 230 μmol) was dissolved in toluene (5 mL) and methanesulfonic acid (3 mL), purged with nitrogen, and reacted at 120 °C with stirring for 2 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. Saturated sodium bicarbonate solution was added to the residue, and the mixture was extracted with ethyl acetate (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 to obtain the crude title compound 6i (70 mg). The product was used directly in the next reaction without purification.

[0419] MS m / z (ESI): 360.2 [M+1].

[0420] Step 9 6-(1-(3-(1H -1,2,3-triazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-4-(4'-((3-(2,6-dioxopiridin-3-yl)-1-methyl-2-oxo-2,3-dihydro-1 H 7 H -spiro[benzofurano[6,7-] d [Imidazol-6,4'-piperidin]-1'-yl)methyl)-2 H -spiro[benzofuran-3,1'-cyclohexane]-6-yl)-7-fluoro- N , N -Dimethyl-1 H -Indole-2-formamide 6 6-(1-(3-(1 H -1,2,3-triazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-4-((3 s ,4' s )-4'-((3-(2,6-dioxopiperidin-3-yl)-1-methyl-2-oxo-2,3-dihydro-1 H 7 H -spiro[benzofurano[6,7-] d [Imidazol-6,4'-piperidin]-1'-yl)methyl)-2 H -spiro[benzofuran-3,1'-cyclohexane]-6-yl)-7-fluoro- N , N -Dimethyl-1 H -Indole-2-carboxamide 6-p1 6-(1-(3-(1 H -1,2,3-triazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-4-((3 r ,4' r )-4'-((3-(2,6-dioxopiperidin-3-yl)-1-methyl-2-oxo-2,3-dihydro-1 H 7 H -spiro[benzofurano[6,7-] d [Imidazol-6,4'-piperidin]-1'-yl)methyl)-2 H -spiro[benzofuran-3,1'-cyclohexane]-6-yl)-7-fluoro- N , N -Dimethyl-1 H -Indole-2-formamide 6-p2 Using steps eleven and twelve of the synthetic route in Example 2, in step eleven, starting compound 1f is replaced with compound 4b, compound 2l is replaced with compound 6i, and in step twelf, compound 1s is replaced with 6-(1-(3-(1)). H -1,2,3-triazol-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)-1 H The crude title compound 6 was prepared by indole-2-carboxamide and purified by preparative high-performance liquid chromatography (Waters-2545, column: Welch Xtimate C18, 30×150 mm, 5 μm; mobile phase: aqueous phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 30%-60%, flow rate: 30 mL / min) to obtain title compounds 6-p1 and 6-p2.

[0421] MS m / z (ESI): 979.6 [M+1].

[0422] The compounds in the following examples can be obtained by referring to the methods in Examples 1-6 above: Example 7: MS m / z (ESI): 978.8 [M+1].

[0423] Example 8: MS m / z (ESI): 980.5 [M+1].

[0424] The one with the shorter retention time among 8-p1 and 8-p2: HPLC analysis: retention time 3.19 min, purity: 99% (column: Xtimate, C18, 1.8 μm, 2.1×50 mm; mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%).

[0425] 1 H NMR (DMSO- d6): δ 12.22 (s, 1H), 10.88 (s, 1H), 7.71 (d, 1H), 7.40(d, 1H), 7.18 (d, 1H), 7.10–6.78 (m, 5H), 6.17 (t, 2H), 4.57 (s, 2H), 4.47(s, 2H), 4.33 (d, 5H), 4.07 (s, 3H), 3.60 (d, 2H), 3.24–2.91 (m, 9H), 2.91–2.77 (m, 2H), 2.65 (dd, 2H), 2.39–2.07 (m, 7H), 2.05–1.77 (m, 10H), 1.73–1.54 (m, 3H).

[0426] The one with the longer retention time among 8-p1 and 8-p2: HPLC analysis: retention time 3.24 min, purity: 99% (column: Xtimate, C18, 1.8 μm, 2.1×50 mm; mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%), acetonitrile, gradient ratio: acetonitrile 10%-95%).

[0427] 1 H NMR (DMSO- d 6): δ 12.21 (s, 1H), 10.88 (s, 1H), 7.71 (d, 1H), 7.40(d, 1H), 7.18 (d, 1H), 7.09–6.83 (m, 5H), 6.24–6.11 (m, 2H), 4.58 (s, 2H),4.46 (d, 2H), 4.34 (dt, 5H), 4.07 (s, 3H), 3.61 (dd, 2H), 3.28–2.92 (m, 9H),2.86 (d, 2H), 2.61 (ddt, 2H), 2.41–2.21 (m, 5H), 2.15 (p, 2H), 2.09–1.86 (m,7H), 1.64 (q, 6H).

[0428] Example 9: MS m / z (ESI): 981.7 [M+1].

[0429] Example 10: MS m / z (ESI): 996.6 [M+1].

[0430] Example 11: MS m / z (ESI): 997.6 [M+1].

[0431] Example 12: MS m / z (ESI): 980.6 [M+1].

[0432] Example 13: MS m / z (ESI): 981.6 [M+1].

[0433] Example 14: MS m / z (ESI): 996.6 [M+1].

[0434] Example 15: MS m / z (ESI): 997.6 [M+1].

[0435] Example 16: MS m / z (ESI): 974.6 [M+1].

[0436] Example 17: MS m / z (ESI): 974.6 [M+1].

[0437] Example 18: MS m / z (ESI): 990.6 [M+1].

[0438] Example 19: MS m / z (ESI): 991.5 [M+1].

[0439] Example 20 6-(1-(3-(1 H -pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-4-((6 aR 8 S )-8-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1 H 7 H -spiro[furano[3,2-] g [Indazole-6,4'-piperidine]-1'-yl)-1-fluoro-6,6 a ,7,8,9,10-hexahydrobenzo[ b ]pyrido[1,2- d [1,4]oxazine-3-yl)-7-fluoro- N , N -Dimethyl-1 H -Indole-2-carboxamide 20-1 6-(1-(3-(1 H -pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-4-((6 aR 8 R )-8-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1 H 7 H -spiro[furano[3,2-] g [Indazole-6,4'-piperidine]-1'-yl)-1-fluoro-6,6 a ,7,8,9,10-hexahydrobenzo[ b ]pyrido[1,2- d [1,4]oxazine-3-yl)-7-fluoro- N, N -Dimethyl-1 H -Indole-2-formamide 20-2 first step ( R )-(8-(2,6-difluoro-4-nitrophenyl)-1,4-dioxa-8-azaspiro[4.5]dec-7-yl)methanol20c Will( R )-(1,4-dioxa-8-azaspiro[4.5]dec-7-yl)methanol 2,2,2-trifluoroacetate 20a (4.40 g, 15.32 mmol, prepared by the method disclosed in Example 26 on page 124 of patent application "WO2023137225") and 3,4,5-trifluoronitrobenzene 20b (2.76 g, 15.58 mmol, Shanghai Shaoyuan) dissolved in N , N -Dimethylformamide (50 mL), added N , N -Diisopropylethylamine (19.79 g, 153.12 mmol), 4-dimethylaminopyridine (DMAP) (189 mg, 1.53 mmol), were stirred at 100°C for 96 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 20c (1 g, yield: 19.7%).

[0440] MS m / z (ESI): 331.4 [M+1].

[0441] Step 2 ( R )-1-Fluoro-3-nitro-6 a ,7,9,10-tetrahydro-6 H -spiro[benzo[ b ]pyrido[1,2- d [1,4]oxazine-8,2'-[1,3]dioxapentane] 20d Compound 20c (1 g, 3.03 mmol) was dissolved in... N , NDimethylformamide (20 mL) was added in portions to sodium hydride (182 mg, 4.55 mmol, 60% purity) in an ice bath. The mixture was allowed to return to room temperature and stirred for 3 hours. The reaction mixture was then quenched with 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 20d (700 mg, yield: 74.5%).

[0442] MS m / z (ESI): 311.3[M+1].

[0443] Step 3 ( R )-1-Fluoro-6 a ,7,9,10-tetrahydro-6 H -spiro[benzo[ b ]pyrido[1,2- d [1,4]oxazine-8,2'-[1,3]dioxapentane]-3-amine20e Compound 20d (800 mg, 2.58 mmol) was dissolved in methanol (20 mL), and 10% palladium on carbon hydrogenation catalyst (200 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 20e (720 mg). The product was used directly in the next step of the reaction without purification.

[0444] MS m / z (ESI): 281.3 [M+1].

[0445] Step 4 ( R )-1-Fluoro-3-iodine-6 a ,7,9,10-tetrahydro-6 H -spiro[benzo[ b ]pyrido[1,2- d [1,4]oxazine-8,2'-[1,3]dioxapentane] 20f The crude compound 20e (720 mg, 2.57 mmol) and tert-butyl nitrite (530 mg, 5.14 mmol) were dissolved in acetonitrile (20 mL), stirred for 1 hour, and then cooled to 0°C. Sodium iodide (770 mg, 5.14 mmol) was added, and the mixture was reacted at 80°C for 16 hours. After the reaction solution was cooled to room temperature, it was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to give the title compound 20f (600 mg, yield: 59.7%).

[0446] MS m / z (ESI): 392.2 [M+1].

[0447] Step 5 ( R )-1-Fluoro-3-iodine-6 a ,7,9,10-Tetrahydrobenzo[ b ]pyrido[1,2- d [1,4]Oxazine-8(6 H )-ketone 20g Compound 20f (700 mg, 1.79 mmol) was dissolved in tetrahydrofuran (30 mL), and 2M sulfuric acid solution (9 mL) was added. The mixture was stirred at 75°C for 16 hours. The reaction mixture was cooled to room temperature, and the pH was adjusted to neutral with saturated sodium bicarbonate solution under ice bath conditions. The mixture was extracted with ethyl acetate (15 mL × 3), and the organic phases were combined and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to give the title compound 20 g (470 mg, yield: 75.6%).

[0448] MS m / z (ESI): 348.3 [M+1].

[0449] Step 6 3-(1'-((6 aR )-1-Fluoro-3-iodine-6,6 a ,7,8,9,10-hexahydrobenzo[ b ]pyrido[1,2- d [1,4]oxazine-8-yl)-1-methyl-1 H 7 H -spiro[furano[3,2-] g [Indazole-6,4'-piperidine]-3-yl)piperidine-2,6-dione 20h Compound 20 g (80 mg, 230 μmol) and crude compound 2 l (82 mg, 210 μmol) were dissolved in 1,2-dichloroethane (10 mL) and dimethyl sulfoxide (1 mL), and sodium triacetoxyborohydride (146 mg, 691 μmol) were added. The mixture was stirred for 16 hours. Saturated sodium bicarbonate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system A to give the title compound 20 h (50 mg, yield: 31.6%).

[0450] MS m / z (ESI): 686.7 [M+1].

[0451] Step 7 6-(1-(3-(1 H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-4-((6 aR 8 S )-8-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1 H 7 H -spiro[furano[3,2-] g [Indazole-6,4'-piperidine]-1'-yl)-1-fluoro-6,6 a ,7,8,9,10-hexahydrobenzo[ b ]pyrido[1,2- d [1,4]oxazine-3-yl)-7-fluoro- N , N -Dimethyl-1 H -Indole-2-carboxamide 20-1 6-(1-(3-(1 H -pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-4-((6 aR 8 R )-8-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1 H 7 H -spiro[furano[3,2-] g [Indazole-6,4'-piperidine]-1'-yl)-1-fluoro-6,6 a ,7,8,9,10-hexahydrobenzo[ b ]pyrido[1,2- d [1,4]oxazine-3-yl)-7-fluoro- N , N -Dimethyl-1 H -Indole-2-formamide 20-2 Compound 20h (50 mg, 73 μmol) and compound 1s (66 mg, 145 μmol) were dissolved in 1,4-dioxane (10 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) (12.3 mg, 14.6 μmol) and potassium phosphate (46 mg, 219 μmol) were added. The mixture was purged with nitrogen and reacted at 70°C for 1 hour. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by high performance liquid chromatography (Waters-2545, column: Welch Xtimate C18, 30 × 150 mm, 5 μm; mobile phase: aqueous phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 30%-60%, flow rate: 30 mL / min) to give the title compound (16 mg, yield: 22.7%) and (3 mg, yield: 4.2%).

[0452] Compounds with shorter retention times: (3 mg, yield: 4.2%).

[0453] MS m / z (ESI): 967.9 [M+1].

[0454] HPLC analysis: retention time 1.44 min, purity: 95% (column: Xtimate, C18, 1.8 μm, 2.1*50 mm; mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%), acetonitrile, gradient ratio: acetonitrile 10%-95%).

[0455] 1 H NMR (500 MHz, DMSO- d6): δ 12.18 (s, 1H), 10.88 (s, 1H), 7.71 (d,1H), 7.40 (d, 1H), 7.18 (d, 1H), 6.99 (t, 3H), 6.88 (dd, 2H), 6.22 – 6.10 (m,2H), 4.58 (s, 2H), 4.41 – 4.19 (m, 6H), 4.07 (s, 3H), 3.95 (t, 1H), 3.60 (d,3H), 3.24 – 3.14 (m, 3H), 3.05 (s, 2H), 3.01 – 2.87 (m, 4H), 2.80 (t,2H),2.64 (t, 3H), 2.39 – 2.22 (m, 5H), 2.19 – 2.12 (m, 1H), 1.99 (d,2H), 1.90 (d,3H), 1.69 (d, 2H), 1.60 (d, 1H), 1.46 (d, 1H).

[0456] Compounds with longer retention time: (3 mg, yield: 4.2%).

[0457] MS m / z (ESI): 967.9 [M+1].

[0458] HPLC analysis: retention time 1.48 min, purity: 93% (column: Xtimate, C18, 1.8 μm, 2.1*50 mm; mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%), acetonitrile, gradient ratio: acetonitrile 10%-95%).

[0459] 1 H NMR (500 MHz, DMSO- d6): δ 12.20 (s, 1H), 10.88 (s, 1H), 7.71 (d,1H), 7.40 (d, 2H), 7.19 (d, 1H), 7.05 – 6.93 (m, 2H), 6.84 (s, 1H), 6.62 (d,1H), 6.23 – 6.10 (m, 2H), 5.32 (t, 1H), 4.60 (s, 1H), 4.42 – 4.27 (m, 3H), 4.21 (d, 2H), 4.07 (s, 3H), 3.61 (d, 3H), 3.53 – 3.44 (m, 6H), 3.12 – 2.92(m, 5H), 2.63 (s, 6H), 2.34 (d, 2H), 2.29 – 2.11 (m, 3H), 2.05 – 1.81 (m,5H), 1.73 (t, 2H), 1.45 (t, 2H).

[0460] Example 21 6-(1-(3-(1 H -pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-4-((6 aS )-8-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1 H 7 H -spiro[furano[3,2-] g [Indazole-6,4'-piperidine]-1'-yl)-1-fluoro-6,6 a ,7,8,9,10-hexahydrobenzo[ b ]pyrido[1,2- d [1,4]oxazine-3-yl)-7-fluoro- N , N -Dimethyl-1 H -Indole-2-formamide 21 Using the synthetic route in Example 20, the first-step starting compound 20a was replaced with compound ( S The title compound (9 mg, yield: 15.9%) was prepared by using 2,2,2-trifluoroacetate of 1,4-dioxa-8-azaspiro[4.5]dec-7-yl)methanol (prepared by the method disclosed in Example 24 on page 118 of the specification of patent application "WO2023137225").

[0461] MS m / z (ESI): 967.9 [M+1].

[0462] 1 H NMR (500 MHz, DMSO- d 6): δ 12.18 (s, 1H), 10.88 (d, 1H), 7.71 (d,1H), 7.46–7.35 (m, 1H), 7.23–7.15 (m, 1H), 7.06–6.80 (m, 5H), 6.16 (dd, 2H),4.62–4.53 (m, 2H), 4.42–4.18 (m, 7H), 4.11–4.03 (m, 3H), 3.96 (d, 1H), 3.67–3.55 (m, 2H), 3.25–2.75 (m, 9H), 2.70–2.57 (m, 2H), 2.22 (dd, 8H), 2.05–1.81(m, 7H), 1.75–1.53 (m, 3H).

[0463] Example 22 6-(1-(3-(1 H -pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-4-((1 r 4 r )-4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1 H 7 H -spiro[furano[3,2-] g [Indazole-6,4'-piperidine]-1'-yl)-2' H -spiro[cyclohexane-1,3'-furano[3,2-] b ]pyridine]-6'-yl)-7-fluoro- N , N -Dimethyl-1 H -Indole-2-carboxamide 22-1 6-(1-(3-(1 H -pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-4-((1 s 4 s )-4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1 H 7 H -spiro[furano[3,2-] g [Indazole-6,4'-piperidine]-1'-yl)-2' H -spiro[cyclohexane-1,3'-furano[3,2-] b ]pyridine]-6'-yl)-7-fluoro- N , N-Dimethyl-1 H -Indole-2-carboxamide 22-2 Using the synthetic route in Example 1, the starting material 1a in the first step was replaced with compound 5-bromo-2-iodopyridine-3-phenol (Shanghai Bide), and compound 1r in the fifteenth step was replaced with compound 2m to obtain the title compound (8 mg, yield: 10.5%) and (6 mg, yield: 7.8%).

[0464] Compounds with shorter retention times: (8 mg, yield: 10.5%).

[0465] MS m / z (ESI): 950.0 [M+1].

[0466] HPLC analysis: retention time 1.33 min, purity: 96% (column: Xtimate, C18, 1.8 μm, 2.1*50 mm; mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%), acetonitrile, gradient ratio: acetonitrile 10%-95%).

[0467] 1 H NMR (500 MHz, DMSO- d 6): δ 12.26 (s, 1H), 10.88 (s, 1H), 8.30 (s,1H), 7.71 (d, 1H), 7.43 (s, 1H), 7.20 (d, 1H), 7.14 – 6.92 (m, 3H), 6.85 (s,1H), 6.19 (d, 2H), 4.59 (d, 3H), 4.42 – 4.25 (m, 4H), 4.07 (s, 3H), 2.98 (t,7H), 2.41 – 2.07 (m, 7H), 2.07 – 1.77 (m, 8H), 1.71 (s, 1H), 1.45 (s, 2H), 1.24 (d, 10H).

[0468] Compounds with longer retention time: (6 mg, yield: 7.8%).

[0469] MS m / z (ESI): 950.0 [M+1].

[0470] HPLC analysis: retention time 1.52 min, purity: 93% (column: Xtimate, C18, 1.8 μm, 2.1*50 mm; mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%), acetonitrile, gradient ratio: acetonitrile 10%-95%).

[0471] 1 H NMR (500 MHz, DMSO- d 6): δ 12.25 (s, 1H), 10.88 (s, 1H), 8.32 (d,1H), 7.71 (d, 1H), 7.43 (d, 1H), 7.20 (d, 1H), 7.15 – 6.94 (m, 3H), 6.87 (s,1H), 6.19 (dd, 2H), 4.61 (s, 2H), 4.45 – 4.27 (m, 6H), 4.07 (s, 3H), 3.61(dt, 6H), 3.11 – 2.93 (m, 6H), 2.42 – 2.19 (m, 6H), 2.19 – 2.10 (m, 1H), 2.10– 1.91 (m, 5H), 1.78 – 1.56 (m, 5H), 1.46 (d, 1H), 1.23 (s, 4H).

[0472] Example 23 6-(1-(3-(1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-4-((6 aS )-8-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1 H 7 H -spiro[furano[3,2-] g [Indazole-6,4'-piperidine]-1'-yl)-4-fluoro-6,6 a ,7,8,9,10-hexahydrobenzo[ b ]pyrido[1,2- d [1,4]oxazine-2-yl)-7-fluoro- N , N -Dimethyl-1 H -Indole-2-formamide 23 first step ( S)-(8-(2,6-difluoro-4-nitrophenyl)-1,4-dioxa-8-azaspiro[4.5]dec-7-yl)methanol23b (S)-4-Fluoro-2-nitro-6 a ,7,9,10-tetrahydro-6 H -spiro[benzo[b]pyrido[1,2-] d [1,4]oxazine-8,2'-[1,3]dioxapentane] 23c Will( S )-(1,4-dioxa-8-azaspiro[4.5]dec-7-yl)methanol 2,2,2-trifluoroacetate 23a (38.6 g, 134.39 mmol, prepared by the method disclosed in Example 24 on page 118 of patent application "WO2023137225") and 3,4,5-trifluoronitrobenzene 20b (14 g, 79.06 mmol, Shanghai Shaoyuan) dissolved in N , N -Dimethylformamide (200 mL), added N , N -Diisopropylethylamine (51.09 g, 395.30 mmol), 4-dimethylaminopyridine (DMAP) (1.95 g, 15.83 mmol), were reacted at 110°C with stirring for 96 hours. After the reaction solution cooled to room temperature, it was filtered. Water was added to the filtrate, 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 title compound 23b (1.2 g, yield: 4.6%) and compound 23c (3 g, yield: 12.2%).

[0473] Compound 23b: MS m / z (ESI): 331.0 [M+1].

[0474] Compound 23c: MS m / z (ESI): 311.0 [M+1].

[0475] Step 2 6-(1-(3-(1 H -pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-4-((6 aS )-8-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1 H 7 H -spiro[furano[3,2-] g [Indazole-6,4'-piperidine]-1'-yl)-4-fluoro-6,6 a,7,8,9,10-hexahydrobenzo[ b ]pyrido[1,2- d [1,4]oxazine-2-yl)-7-fluoro- N , N -Dimethyl-1 H -Indole-2-formamide 23 Using the synthetic route in Example 20, the title compound 23 (55 mg, yield: 26%) was obtained by replacing the starting compound 20d in the third step with compound 23c.

[0476] MS m / z (ESI): 967.9 [M+1].

[0477] 1 H NMR (500 MHz, DMSO- d 6): δ 12.17 (d, 1H), 10.88 (s, 1H), 7.71 (d,1H), 7.40 (d, 1H), 7.18 (d, 1H), 7.04–6.92 (m, 3H), 6.86 (d, 2H), 6.22–6.11(m, 2H), 4.57 (s, 2H), 4.41–4.27 (m, 6H), 4.04 (d, 5H), 3.61 (dt, 2H), 3.28–2.82 (m, 12H), 2.74–2.54 (m, 4H), 2.38–2.20 (m, 5H), 2.20–2.11 (m, 1H), 2.03–1.85 (m, 5H), 1.68 (d, 2H).

[0478] Example 24 6-(1-(3-(1 H -pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-4-(4'-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1 H 7 H -spiro[furano[3,2-] g [Indazole-6,4'-piperidine]-1'-yl)-4-fluoro-2 H -spiro[benzofuran-3,1'-cyclohexane]-6-yl)-7-fluoro- N , N -Dimethyl-1 H -Indole-2-formamide 24 6-(1-(3-(1 H -pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-4-((3s ,4' s )-4'-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1 H 7 H -spiro[furano[3,2-] g [Indazole-6,4'-piperidine]-1'-yl)-4-fluoro-2 H -spiro[benzofuran-3,1'-cyclohexane]-6-yl)-7-fluoro- N , N -Dimethyl-1 H -Indole-2-carboxamide 24-1 6-(1-(3-(1 H -pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-4-((3 r, 4' r )-4'-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1 H 7 H -spiro[furano[3,2-] g [Indazole-6,4'-piperidine]-1'-yl)-4-fluoro-2 H -spiro[benzofuran-3,1'-cyclohexane]-6-yl)-7-fluoro- N , N -Dimethyl-1 H -Indole-2-formamide 24-2 6-(1-(3-(1 H -pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-4-((3 R ,4' s )-4'-(3-(( S )-2,6-dioxopiperidin-3-yl)-1-methyl-1 H 7 H -spiro[furano[3,2-] g [Indazole-6,4'-piperidine]-1'-yl)-4-fluoro-2 H -spiro[benzofuran-3,1'-cyclohexane]-6-yl)-7-fluoro- N , N -Dimethyl-1 H -Indole-2-carboxamide 24-1-1 6-(1-(3-(1 H -pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-4-((3 S ,4' s )-4'-(3-(( R)-2,6-dioxopiperidin-3-yl)-1-methyl-1 H 7 H -spiro[furano[3,2-] g [Indazole-6,4'-piperidine]-1'-yl)-4-fluoro-2 H -spiro[benzofuran-3,1'-cyclohexane]-6-yl)-7-fluoro- N , N -Dimethyl-1 H -Indole-2-carboxamide 24-1-2 6-(1-(3-(1 H -pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-4-((3 S 4 'r )-4'-(3-(( S )-2,6-dioxopiperidin-3-yl)-1-methyl-1 H 7 H -spiro[furano[3,2-] g [Indazole-6,4'-piperidine]-1'-yl)-4-fluoro-2 H -spiro[benzofuran-3,1'-cyclohexane]-6-yl)-7-fluoro- N , N -Dimethyl-1 H -Indole-2-carboxamide 24-2-1 6-(1-(3-(1 H -pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-4-((3 R ,4' r )-4'-(3-(( R )-2,6-dioxopiperidin-3-yl)-1-methyl-1 H 7 H -spiro[furano[3,2-] g [Indazole-6,4'-piperidine]-1'-yl)-4-fluoro-2 H -spiro[benzofuran-3,1'-cyclohexane]-6-yl)-7-fluoro- N , N -Dimethyl-1 H -Indole-2-formamide 24-2-2 Using the synthetic route in Example 1, the starting material 1a in the first step was replaced with compound 2-bromo-5-chloro-3-fluorophenol 24a (Shanghai Bide), and compound 1r in the fifteenth step was replaced with compound 2m to obtain crude title compound 24 (586 mg). It was purified by high performance liquid chromatography (Waters-2545, column: Welch Xtimate C18, 30*150 mm, 5 μm; mobile phase: aqueous phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 30%-60%, flow rate: 30 mL / min) to obtain two compounds, 24-1 and 24-2 (23 mg, yield: 3.9%) and (108 mg, yield: 18.4%).

[0479] Compounds with shorter retention times: (23 mg, yield: 3.9%).

[0480] MS m / z (ESI): 966.8 [M+1].

[0481] HPLC analysis: retention time 1.50 min, purity: 99% (column: Xtimate, C18, 1.8 μm, 2.1*50 mm; mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%), acetonitrile, gradient ratio: acetonitrile 10%-95%).

[0482] 1 H NMR (500 MHz, DMSO- d 6): δ 12.31–12.12 (m, 1H), 10.88 (s, 1H), 7.75–7.68 (m, 1H), 7.40 (d, 1H), 7.19 (d, 1H), 7.04 (dd, 1H), 6.99 (d, 1H), 6.95–6.89 (m, 2H), 6.85 (d, 1H), 6.22–6.12 (m, 2H), 4.58 (s, 2H), 4.50 (s, 2H), 4.33 (dt, 5H), 4.07 (s, 3H), 3.60 (dt, 2H), 3.27–2.83 (m, 11H), 2.72–2.53 (m, 3H), 2.31 (dq, 5H), 2.15 (dt, 1H), 1.93 (ddt, 9H), 1.68 (d, 2H).

[0483] Compounds with longer retention time: (108 mg, yield: 18.4%).

[0484] MS m / z (ESI): 966.8 [M+1].

[0485] HPLC analysis: retention time 1.64 min, purity: 99% (column: Xtimate, C18, 1.8 μm, 2.1*50 mm; mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%), acetonitrile, gradient ratio: acetonitrile 10%-95%).

[0486] 1 H NMR (500 MHz, DMSO- d 6): δ 12.23 (d, 1H), 10.88 (s, 1H), 7.71 (d,1H), 7.40 (d, 1H), 7.21 (d, 1H), 7.06 (dd, 1H), 6.96 (dd, 2H), 6.94–6.84 (m,2H), 6.24–6.12 (m, 2H), 4.59 (s, 2H), 4.43 (s, 2H), 4.40–4.25 (m, 5H), 4.07(s, 3H), 3.60 (dt, 2H), 3.27–2.92 (m, 10H), 2.72–2.54 (m, 2H), 2.41–2.20 (m,6H), 2.19–1.89 (m, 8H), 1.73 (d, 2H), 1.57 (t, 3H).

[0487] Compounds with longer retention times in 24-1 and 24-2 (15 mg) were separated 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 obtain two compounds 24-1-1 and 24-1-2 or two compounds 24-2-1 and 24-2-2 (5 mg, yield: 33.3%) and (5 mg, yield: 33.3%).

[0488] Single configuration compound (shorter retention time): 24-1-2 or 24-2-2 (5 mg, yield: 33.3%).

[0489] MS m / z (ESI): 966.8 [M+1].

[0490] Chiral HPLC analysis: retention time 6.492 min, purity: 98.2% (column: ReGIS (S,S)-Whelk-O1, 4.6×150 mm, 5 μm; mobile phase A: ethanol containing (0.1% diethylamine), mobile phase B: acetonitrile, gradient ratio: A:B = 80:20, flow rate: 1.0 mL / min).

[0491] 1 H NMR (500 MHz, DMSO- d 6): δ 12.23 (d, 1H), 10.88 (s, 1H), 7.71 (d,1H), 7.40 (d, 1H), 7.21 (d, 1H), 7.06 (dd, 1H), 6.96 (dd, 2H), 6.94–6.84 (m,2H), 6.24–6.12 (m, 2H), 4.59 (s, 2H), 4.43 (s, 2H), 4.40–4.25 (m, 5H), 4.07(s, 3H), 3.60 (dt, 2H), 3.27–2.92 (m, 10H), 2.72–2.54 (m, 2H), 2.41–2.20 (m,6H), 2.19–1.89 (m, 8H), 1.73 (d, 2H), 1.57 (t, 3H).

[0492] Single configuration compound (longer retention time): 24-1-1 or 24-2-1 (5 mg, yield: 33.3%).

[0493] MS m / z (ESI): 966.8 [M+1].

[0494] Chiral HPLC analysis: retention time 9.883 min, purity: 97.5% (column: ReGIS (S,S)-Whelk-O1, 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).

[0495] 1 H NMR (500 MHz, DMSO- d6): δ12.23 (d, 1H), 10.88 (s, 1H), 7.71 (d,1H), 7.40 (d, 1H), 7.21 (d, 1H), 7.06 (dd, 1H), 6.96 (dd, 2H), 6.94–6.84 (m,2H), 6.24–6.12 (m, 2H), 4.59 (s, 2H), 4.43 (s, 2H), 4.40–4.25 (m, 5H), 4.07(s, 3H), 3.60 (dt, 2H), 3.27–2.92 (m, 10H), 2.72–2.54 (m, 2H), 2.41–2.20 (m,6H), 2.19–1.89 (m, 8H), 1.73 (d, 2H), 1.57 (t, 3H).

[0496] Example 25 6-(1-(3-(1 H -pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-4-(1'-((1 s 4 s )-3'-(2,6-dioxopiperidin-3-yl)-1'-methyl-1' H ,7' H -spiro[cyclohexane-1,6'-furano[3,2-] g [Indazole]-4-yl)-4-fluoro-2 H -spiro[benzofuran-3,4'-piperidin]-6-yl)-7-fluoro- N , N -Dimethyl-1 H -Indole-2-carboxamide 25-1 6-(1-(3-(1 H -pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-4-(1'-((1 r 4 r )-3'-(2,6-dioxopiperidin-3-yl)-1'-methyl-1' H ,7' H -spiro[cyclohexane-1,6'-furano[3,2-] g [Indazole]-4-yl)-4-fluoro-2 H -spiro[benzofuran-3,4'-piperidin]-6-yl)-7-fluoro- N , N -Dimethyl-1 H -Indole-2-formamide 25-2 first step 2,6-Di(benzyloxy)nicotinic acid 25b Potassium tert-butoxide (146.10 g, 1.30 mol) was added under a nitrogen atmosphere and ice bath. N , N Add benzyl alcohol (84.50 g, 781.41 mmol) and 2,6-dichloronicotinic acid 25a (50 g, 260.4 mmol) dropwise to dimethylformamide (300 mL). N , N Dimethylformamide (200 mL) was stirred at 55°C for 1 hour. After the reaction solution cooled to room temperature, water, ethyl acetate, and n-hexane (500 mL) were added (V:V = 1:1). The mixture was stirred thoroughly and separated. The pH of the aqueous phase was adjusted to ≈6-7 with acetic acid, and a solid precipitated. The solid was filtered, and the filter cake was washed with water and dried to obtain the crude title compound 25b (80 g). The product was used directly in the next reaction without purification.

[0497] MS m / z (ESI): 336.2 [M+1].

[0498] Step 2 2,6-bis(benzyloxy)- N -Methoxy- N -Methylnicotinamide 25c Dimethylhydroxylamine hydrochloride (1.92 g, 19.68 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC HCl) (4.12 g, 21.49 mmol), and 1-hydroxybenzotriazole (HOBT) (726 mg, 5.37 mmol) were mixed in acetonitrile (20 mL), followed by the addition of triethylamine (3.62 g, 35.77 mmol) and compound 25b (50 g, 260.4 mmol). N , N - Dimethylformamide (200 mL), stirred for 16 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 25c (6.5 g, yield: 96%).

[0499] MS m / z (ESI): 379.2 [M+1].

[0500] Step 3 8-((2-bromo-6-fluorophenoxy)methyl)-1,4-dioxaspiro[4.5]dec-7-ene 25f 2-Bromo-6-fluorophenol 25d (1.4 g, 7.33 mmol, Shanghai Titan), (1,4-dioxaspiro[4.5]dec-7-en-8-yl)methanol 25e (1.31 g, 7.70 mmol, prepared by the method disclosed in Example 14 on page 64 of patent application "WO2019074824") was dissolved in tetrahydrofuran (30 mL). Triphenylphosphine (2.88 g, 10.98 mmol) and diisopropyl azodicarbonate (2.22 g, 10.98 mmol) were added under ice bath. The mixture was allowed to return to room temperature and stirred for 0.5 h. Calcium bromide dihydrate (4.40 g, 22.01 mmol) was added under ice bath. The mixture was allowed to return to room temperature and stirred for 16 h. The reaction mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 25f (2.35 g, 7.70 mmol). g, yield: 93.4%).

[0501] MS m / z (ESI): 343.2 [M+1].

[0502] Step 4 7-Fluoro-2 H -Dispiro[benzofuran-3,1'-cyclohexane-4',2''-[1,3]dioxapentane] 25g Compound 25f (2.35 g, 6.85 mmol) was dissolved in toluene (60 mL), and tri-n-butyltin hydride (3.18 g, 10.96 mmol) and azobisisobutyronitrile (225 mg, 1.37 mmol) were added. The mixture was purged with nitrogen and reacted at 115 °C for 16 h. The reaction solution was cooled to room temperature, and 20% potassium fluoride solution was added and stirred for 3 h. The organic phase was separated, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to give the title compound 25 g (1.78 g, yield: 98.3%).

[0503] MS m / z (ESI): 265.5 [M+1].

[0504] Step 5 (2,6-bis(benzyloxy)pyridin-3-yl)(7-fluoro-2-yl) H -Dispiro[benzofuran-3,1'-cyclohexane-4',2''-[1,3]dioxacyclopentane]-6-yl)methyl ketone 25h Compound 25 g (1.78 g, 6.73 mmol) and pentamethyldiethylenetriamine (1.63 g, 9.40 mmol) were dissolved in tetrahydrofuran (30 mL). Under a nitrogen atmosphere, a 2.5 M n-butyllithium solution in n-hexane (3.8 mL) was added dropwise at -78°C, and the mixture was stirred at a constant temperature for 2 hours. Compound 25c (2.68 g, 7.08 mmol) in tetrahydrofuran (15 mL) was added dropwise at -78°C. The mixture was stirred at a constant temperature for 1 hour, and then the reaction was allowed to proceed to room temperature for 16 hours. The reaction mixture was quenched with saturated ammonium chloride solution and extracted with ethyl acetate (30 mL × 3). The organic phases were combined, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system B to give the title compound 25h (2.2 g, yield: 56.2%).

[0505] MS m / z (ESI): 582.6 [M+1].

[0506] Step 6 3-(2,6-bis(benzyloxy)pyridin-3-yl)-1 H 7 H -Dispiro[furano[3,2-g]indazole-6,1'-cyclohexane-4',2''-[1,3]dioxapentane] 25i Compound 25h (2.2 g, 3.78 mmol) was dissolved in pyridine (20 mL), and 4-dimethylaminopyridine (DMAP) (466 mg, 3.78 mmol) and 85% hydrazine hydrate (1.11 g, 18.84 mmol) were added. The reaction mixture was reacted at 120 °C for 16 h. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to give the title compound 25i (1.75 g, yield: 80.4%).

[0507] MS m / z (ESI): 576.5 [M+1].

[0508] Step 7 3-(2,6-bis(benzyloxy)pyridin-3-yl)-1-methyl-1 H 7 H -Dispiro[furano[3,2-g]indazole-6,1'-cyclohexane-4',2''-[1,3]dioxapentane] 25j Compound 25i (1.75 g, 3.04 mmol) was dissolved in... N , NIn dimethylformamide (30 mL), sodium tert-butoxide (438 mg, 4.56 mmol) was added in portions under ice bath conditions. The mixture was stirred and kept at the same temperature for 0.5 hours. Then, methyl iodoform (647 mg, 4.56 mmol) was added, and the mixture was allowed to return to room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate, washed with water, and the organic phase was separated. The organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system B to give the title compound 25j (1.2 g, yield: 66.9%).

[0509] MS m / z (ESI): 590.6 [M+1].

[0510] Step 8 3-(1-methyl-1-yl) H 7 H -Dispiro[furano[3,2-] g [Indazole-6,1'-cyclohexane-4',2''-[1,3]dioxapentane]-3-yl)piperidine-2,6-dione 25k Compound 25j (280 mg, 475 μmol) was dissolved in tetrahydrofuran (5 mL) and methanol (5 mL), and 10% palladium on carbon (250 mg) was added. The reaction was carried out at 60°C for 16 hours under a hydrogen atmosphere. After the reaction solution was cooled to room temperature, it was filtered, and the filtrate was concentrated under reduced pressure to obtain crude title compound 25j (195 mg). The product was used directly in the next reaction without purification.

[0511] MS m / z (ESI): 412.4 [M+1].

[0512] Step 9 3-(1'-methyl-4-oxo-1') H ,7' H -spiro[cyclohexane-1,6'-furano[3,2-] g [Indazole]-3'-yl)piperidine-2,6-dione 25l Compound 25k (120 mg, 292 μmol) was dissolved in tetrahydrofuran (8 mL), and 2M sulfuric acid solution (1.2 mL) was added. The mixture was stirred at 75°C for 2 hours. The reaction solution was cooled to room temperature, and the pH was adjusted to neutral with saturated sodium bicarbonate solution under ice bath conditions. The mixture was extracted with ethyl acetate (10 mL × 3), and the organic phases were combined and concentrated under reduced pressure to obtain the crude title compound 25l (120 mg). The product was used directly in the next reaction without purification.

[0513] MS m / z (ESI): 368.4 [M+1].

[0514] Step 10 4-((2-bromo-5-chloro-3-fluorophenoxy)methyl)-3,6-dihydropyridine-1(2 H 25m-tert-butyl carboxylate 2-Bromo-5-chloro-3-fluorophenol 24a (3 g, 13.30 mmol) and compound 1h (4 g, 14.64 mmol) were dissolved in... N , N Dimethylformamide (100 mL) was added to potassium carbonate (3.68 g, 26.61 mmol), and the mixture was stirred for 2 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 25m (5 g, yield: 89.3%).

[0515] MS m / z (ESI): 364.1 [M-55].

[0516] Step 11 6-Chloro-4-Fluoro-2 H 25n spiro[benzofuran-3,4'-piperidine]-1'-carboxylic acid tert-butyl ester Compound 25m (5 g, 11.88 mmol) was dissolved in toluene (100 mL), and tri-n-butyltin hydride (1.2 g, 4.15 mmol) and azobisisobutyronitrile (1.95 g, 11.88 mmol) were added. The mixture was purged with nitrogen and reacted at 115 °C for 18 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in diethyl ether, and 20% potassium fluoride solution was added and stirred for 3 hours. The organic phase was separated, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to give the title compound 25n (2.88 g, yield: 70.9%).

[0517] MS m / z (ESI): 286.0 [M-55].

[0518] Step Twelve 6-Chloro-4-Fluoro-2 H -spiro[benzofuran-3,4'-piperidine] 25o Compound 25n (1.88 g, 5.50 mmol) was dissolved in dichloromethane (10 mL), and a 1,4-dioxane solution of 4M hydrogen chloride (3 mL) was added. The mixture was stirred for 1 hour, and the reaction solution was concentrated under reduced pressure. The residue was dissolved in a dichloromethane / methanol mixed solvent (V:V = 1:1, 10 mL), and potassium carbonate was added. The mixture was stirred for 0.5 hours, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude title compound 25o (1.1 g). The product was used directly in the next reaction without purification.

[0519] MS m / z (ESI): 242.1 [M+1].

[0520] Step Thirteen 3-(4-(6-chloro-4-fluoro-2-) H -spiro[benzofuran-3,4'-piperidin]-1'-yl)-1'-methyl-1' H ,7' H -spiro[cyclohexane-1,6'-furano[3,2-] g [Indazole]-3'-yl)piperidine-2,6-dione 25p Compound 25o (80 mg, 331 μmol) and crude compound 25l (122 mg, 332 μmol) were dissolved in 1,2-dichloroethane (10 mL) and dimethyl sulfoxide (1 mL). Sodium acetate (81 mg, 987 μmol) was added, and the mixture was stirred for 1 hour. Then, sodium triacetoxyborohydride (210 mg, 991 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 using eluent system A to give the title compound 25p (196 mg, yield: 99%).

[0521] MS m / z (ESI): 592.2 [M+1].

[0522] Step Fourteen 6-(1-(3-(1 H -pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-4-(1'-((1 s 4 s )-3'-(2,6-dioxopiperidin-3-yl)-1'-methyl-1' H ,7' H -spiro[cyclohexane-1,6'-furano[3,2-] g [Indazole]-4-yl)-4-fluoro-2 H -spiro[benzofuran-3,4'-piperidin]-6-yl)-7-fluoro- N , N -Dimethyl-1 H -Indole-2-carboxamide 25-1 6-(1-(3-(1 H -pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-4-(1'-((1 r 4 r )-3'-(2,6-dioxopiperidin-3-yl)-1'-methyl-1' H ,7' H-spiro[cyclohexane-1,6'-furano[3,2-] g [Indazole]-4-yl)-4-fluoro-2 H -spiro[benzofuran-3,4'-piperidin]-6-yl)-7-fluoro- N , N -Dimethyl-1 H -Indole-2-formamide 25-2 Compound 25p (100 mg, 169 μmol) and compound 1s (99 mg, 185 μmol) were dissolved in 1,4-dioxane (10 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) (21 mg, 25 μmol) and potassium phosphate (107 mg, 504 μmol) were added. The mixture was purged with nitrogen and reacted at 100°C for 2 hours. The reaction solution was cooled to room temperature and filtered. The filtrate 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 the title compound (6 mg, yield: 3.7%). Compounds with shorter retention times: (6 mg, yield: 3.7%).

[0523] MS m / z (ESI): 967.2 [M+1].

[0524] HPLC analysis: retention time 1.50 min, purity: 98% (column: Xtimate, C18, 1.8 μm, 2.1*50 mm; mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%), acetonitrile, gradient ratio: acetonitrile 10%-95%).

[0525] 1H NMR (500 MHz, DMSO-d6): δ 12.18 (s, 1H), 10.88 (s, 1H), 7.71 (d,1H), 7.40 (d, 1H), 7.18 (d, 1H), 7.05 (dd, 1H), 6.98–6.89 (m, 3H), 6.85 (d,1H), 6.24–6.10 (m, 2H), 4.57 (s, 2H), 4.51 (s, 2H), 4.34 (dt, 5H), 4.07 (s,3H), 3.60 (dt, 2H), 3.26–2.84 (m, 11H), 2.62 (tdd, 3H), 2.39–2.08 (m, 8H), 1.99 (dt, 1H), 1.80 (dd, 8H).

[0526] Compounds with longer retention time: (6 mg, yield: 3.7%).

[0527] MS m / z (ESI): 967.2 [M+1].

[0528] HPLC analysis: retention time 1.64 min, purity: 96% (column: Xtimate, C18, 1.8 μm, 2.1*50 mm; mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%), acetonitrile, gradient ratio: acetonitrile 10%-95%).

[0529] 1 H NMR (500 MHz, DMSO- d 6): δ 12.22 (s, 1H), 10.89 (s, 1H), 7.71 (d,1H), 7.40 (d, 1H), 7.21 (d, 1H), 7.13 (d, 1H), 7.05 (dd, 1H), 7.00–6.90 (m,2H), 6.86 (s, 1H), 6.26–6.12 (m, 2H), 4.52 (s, 2H), 4.46 (s, 2H), 4.34 (dt,5H), 4.08 (s, 3H), 3.61 (dt, 2H), 3.26–2.94 (m, 8H), 2.72–2.53 (m, 3H), 2.46–2.10 (m, 9H), 2.07–1.78 (m, 7H), 1.72–1.52 (m, 4H).

[0530] The compounds in the following examples can be obtained by referring to the methods in Examples 1-25 above: Example 26: MS m / z (ESI): 985.7 [M+1].

[0531] Example 27: MS m / z (ESI): 980.8 [M+1].

[0532] Example 28: MS m / z (ESI): 998.7 [M+1].

[0533] Example 29: MS m / z (ESI): 1006.9 [M+1].

[0534] Example 30: MS m / z (ESI): 992.7 [M+1].

[0535] Example 31: MS m / z (ESI): 981.7 [M+1].

[0536] Example 32: MS m / z (ESI): 1011.9 [M+1].

[0537] Example 33: MS m / z (ESI): 1011.9 [M+1].

[0538] Example 34: MS m / z (ESI): 997.7 [M+1].

[0539] Example 35: MS m / z (ESI): 997.7 [M+1].

[0540] Example 36: MS m / z (ESI): 986.7 [M+1].

[0541] Example 37: MS m / z (ESI): 986.7 [M+1].

[0542] Example 38: MS m / z (ESI): 985.7 [M+1].

[0543] Example 38-1 4-((6 aR 8 S )-8-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1 H 7 H -spiro[furano[3,2-] g [Indazole-6,4'-piperidine]-1'-yl)-1-fluoro-6,6 a ,7,8,9,10-hexahydrobenzo[ b ]pyrido[1,2- d[1,4]Oxazine-3-yl)-7-fluoro-6-(1-(3-(3-fluoro-1) H -pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)- N , N -Dimethyl-1 H -Indole-2-carboxamide 38-1 4-((6 aR 8 R )-8-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1 H 7 H -spiro[furano[3,2-] g [Indazole-6,4'-piperidine]-1'-yl)-1-fluoro-6,6 a ,7,8,9,10-hexahydrobenzo[ b ]pyrido[1,2- d [1,4]Oxazine-3-yl)-7-fluoro-6-(1-(3-(3-fluoro-1) H -pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)- N , N -Dimethyl-1 H -Indole-2-formamide 38-2 4-((6 aR 8 S )-8-(3-(( S )-2,6-dioxopiperidin-3-yl)-1-methyl-1 H 7 H -spiro[furano[3,2-] g [Indazole-6,4'-piperidine]-1'-yl)-1-fluoro-6,6 a ,7,8,9,10-hexahydrobenzo[ b ]pyrido[1,2- d [1,4]Oxazine-3-yl)-7-fluoro-6-(1-(3-(3-fluoro-1) H -pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)- N , N -Dimethyl-1 H -Indole-2-carboxamide 38-1-1 4-((6 aR 8 S )-8-(3-(( R )-2,6-dioxopiperidin-3-yl)-1-methyl-1 H 7 H -spiro[furano[3,2-] g[Indazole-6,4'-piperidine]-1'-yl)-1-fluoro-6,6 a ,7,8,9,10-hexahydrobenzo[ b ]pyrido[1,2- d [1,4]Oxazine-3-yl)-7-fluoro-6-(1-(3-(3-fluoro-1) H -pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)- N , N -Dimethyl-1 H -Indole-2-carboxamide 38-1-2 4-((6 aR 8 R )-8-(3-(( S )-2,6-dioxopiperidin-3-yl)-1-methyl-1 H 7 H -spiro[furano[3,2-] g [Indazole-6,4'-piperidine]-1'-yl)-1-fluoro-6,6 a ,7,8,9,10-hexahydrobenzo[ b ]pyrido[1,2- d [1,4]Oxazine-3-yl)-7-fluoro-6-(1-(3-(3-fluoro-1) H -pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)- N , N -Dimethyl-1 H -Indole-2-carboxamide 38-2-1 4-((6 aR 8 R )-8-(3-(( R )-2,6-dioxopiperidin-3-yl)-1-methyl-1 H 7 H -spiro[furano[3,2-] g [Indazole-6,4'-piperidine]-1'-yl)-1-fluoro-6,6 a ,7,8,9,10-hexahydrobenzo[ b ]pyrido[1,2- d [1,4]Oxazine-3-yl)-7-fluoro-6-(1-(3-(3-fluoro-1) H -pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)- N , N -Dimethyl-1 H -Indole-2-formamide 38-2-2 first step 3-(3-Fluoro-1) H 38b pyrazole-1-yl)methyl propionate 3-fluoro-1 H -Pyrazole 38a (3.5 g, 40.66 mmol, Shanghai Bide) dissolved in N , N Dimethylformamide (40 mL) was added to potassium carbonate (11.22 g, 81.33 mmol) and methyl 3-bromopropionate (10.19 g, 61 mmol). The mixture was stirred for 16 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (50 mL × 2). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to give the title compound 38b (6.1 g, yield: 87.1%).

[0544] MS m / z (ESI): 173.0 [M+1].

[0545] Step 2 3-(3-Fluoro-1) H 38c-pyrazole-1-yl)propionic acid Compound 38b (6 g, 34.85 mmol) was dissolved in tetrahydrofuran (10 mL) and water (10 mL), and lithium hydroxide monohydrate (2.92 g, 69.70 mmol) was added. The mixture was stirred for 1 hour, diluted with water, and the pH was adjusted to approximately 5 with 1M hydrochloric acid solution. The mixture was filtered, and the filter cake was washed with water and dried to obtain the crude title compound 38c (5.5 g). The product was used directly in the next step of the reaction without purification.

[0546] MS m / z (ESI): 159.0 [M+1].

[0547] Step 3 3-(3-Fluoro-1) H -pyrazol-1-yl)-1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxoborhexacyclopentan-2-yl)-3,6-dihydropyridine-1(2 H )-propyl-1-one 38d Compound 38c (5.5 g, 34.78 mmol) was dissolved in dry pyridine (50 mL), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (7.84 g, 45.17 mmol) and compound 117b (8.54 g, 7.65 mmol) were added. The mixture was stirred for 2 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 38d (8 g, yield: 65.8%). MS m / z (ESI): 350.2 [M+1].

[0548] Step 4 4-Chloro-7-Fluoro-6-(1-(3-(3-Fluoro-1) H -pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)- N , N -Dimethyl-1 H -Indole-2-formamide 38e Compound 38d (1.42 g, 4.07 mmol), 6-bromo-4-chloro-7-fluoro- N , N -Dimethyl-1 H -Indole-2-carboxamide (1 g, 3.13 mmol, prepared by the method disclosed in Intermediate Z on page 1128 of patent application "WO2025049820"), 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (229 mg, 313 μmol) and anhydrous potassium carbonate (865 mg, 6.26 mmol) were dissolved in 1,4-dioxane (20 mL) and water (5 mL), purged with nitrogen, stirred at 85 °C for 10 h, the reaction mixture was cooled to room temperature and diluted with water, extracted with ethyl acetate (30 mL × 3), the organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system A to give title compound 38e (1.4 g, yield: 96.8%).

[0549] MS m / z (ESI): 462.5 [M+1].

[0550] Step 5 7-Fluoro-6-(1-(3-(3-Fluoro-1) H -pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)- N , N -Dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxoborhexacyclopentan-2-yl)-1H -Indole-2-formamide 38f Compound 38e (1.4 g, 3.03 mmol), pinacol diborate (3.07 g, 12.09 mmol), potassium acetate (1.48 g, 15.08 mmol), and bis(tricyclohexylphosphine)palladium(II) dichloride (1.11 g, 1.50 mmol) were mixed in 1,4-dioxane (60 mL), purged with nitrogen, and stirred at 110°C for 16 hours. After the reaction mixture 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 38f (1 g, yield: 59.6%).

[0551] MS m / z (ESI): 554.5 [M+1].

[0552] Step 6 4-((6 aR 8 S )-8-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1 H 7 H -spiro[furano[3,2-] g [Indazole-6,4'-piperidine]-1'-yl)-1-fluoro-6,6 a ,7,8,9,10-hexahydrobenzo[ b ]pyrido[1,2- d [1,4]Oxazine-3-yl)-7-fluoro-6-(1-(3-(3-fluoro-1) H -pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)- N , N -Dimethyl-1 H -Indole-2-carboxamide 38-1 4-((6 aR 8 R )-8-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1 H 7 H -spiro[furano[3,2-] g [Indazole-6,4'-piperidine]-1'-yl)-1-fluoro-6,6 a ,7,8,9,10-hexahydrobenzo[ b ]pyrido[1,2- d [1,4]Oxazine-3-yl)-7-fluoro-6-(1-(3-(3-fluoro-1) H -pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)- N , N -Dimethyl-1H -Indole-2-formamide 38-2 4-((6 aR 8 S )-8-(3-(( S )-2,6-dioxopiperidin-3-yl)-1-methyl-1 H 7 H -spiro[furano[3,2-] g [Indazole-6,4'-piperidine]-1'-yl)-1-fluoro-6,6 a ,7,8,9,10-hexahydrobenzo[ b ]pyrido[1,2- d [1,4]Oxazine-3-yl)-7-fluoro-6-(1-(3-(3-fluoro-1) H -pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)- N , N -Dimethyl-1 H -Indole-2-carboxamide 38-1-1 4-((6 aR 8 S )-8-(3-(( R )-2,6-dioxopiperidin-3-yl)-1-methyl-1 H 7 H -spiro[furano[3,2-] g [Indazole-6,4'-piperidine]-1'-yl)-1-fluoro-6,6 a ,7,8,9,10-hexahydrobenzo[ b ]pyrido[1,2- d [1,4]Oxazine-3-yl)-7-fluoro-6-(1-(3-(3-fluoro-1) H -pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)- N , N -Dimethyl-1 H -Indole-2-carboxamide 38-1-2 4-((6 aR 8 R )-8-(3-(( S )-2,6-dioxopiperidin-3-yl)-1-methyl-1 H 7 H -spiro[furano[3,2-] g [Indazole-6,4'-piperidine]-1'-yl)-1-fluoro-6,6 a ,7,8,9,10-hexahydrobenzo[ b ]pyrido[1,2- d[1,4]Oxazine-3-yl)-7-fluoro-6-(1-(3-(3-fluoro-1) H -pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)- N , N -Dimethyl-1 H -Indole-2-carboxamide 38-2-1 4-((6 aR 8 R )-8-(3-(( R )-2,6-dioxopiperidin-3-yl)-1-methyl-1 H 7 H -spiro[furano[3,2-] g [Indazole-6,4'-piperidine]-1'-yl)-1-fluoro-6,6 a ,7,8,9,10-hexahydrobenzo[ b ]pyrido[1,2- d [1,4]Oxazine-3-yl)-7-fluoro-6-(1-(3-(3-fluoro-1) H -pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)- N , N -Dimethyl-1 H -Indole-2-formamide 38-2-2 Compound 20h (50 mg, 73 μmol) and compound 38f (48 mg, 87 μmol) were dissolved in 1,4-dioxane (10 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) (12.3 mg, 14.6 μmol) and potassium phosphate (25 mg, 182 μmol) were added. The mixture was purged with nitrogen and reacted at 70°C for 1 hour. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by high performance liquid chromatography (Waters-2545, column: Welch Xtimate C18, 30*150 mm, 5 μm; mobile phase: aqueous phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 30%-60%, flow rate: 30 mL / min) to give the title compound 38-1 or 38-2 (13 mg, yield: 18%).

[0553] MS m / z (ESI): 985.7 [M+1].

[0554] 38-1 or 38-2: 1 H NMR (500 MHz, DMSO-d 6): δ 12.18 (s, 1H), 10.88 (s, 1H),7.67 – 7.64 (m, 1H), 7.19 (d, 1H), 7.03-6.95 (m, 3H), 6.91 (d, 1H), 6.85 (d,1H), 6.16 (s, 1H), 5.89-5.87(m, 1H), 4.59 (s, 2H), 4.36-4.20 (m, 7H), 4.07(s, 3H), 3.97 (d, 1H), 3.65-3.58 (m, 2H), 3.18-2.97 (m, 7H), 2.95-2.91 (m,4H), 2.83-2.80 (m, 1H), 2.67-2.51 (m, 3H), 2.49 (d, 5H), 2.34-2.26 (m, 1H), 2.17-2.14 (m, 4H), 1.91-1.62 (m, 4H).

[0555] Compounds 38-1 or 38-2 (40 mg) were resolved by a chiral column (column: (S,S)-Whelk-O1, 50*250 mm, 10 μm; mobile phase A: acetonitrile, mobile phase B: ethanol, gradient ratio: A:B = 30:70, flow rate: 80 mL / min) to give the title compounds 38-1-1, 38-1-2 or 38-2-1, 38-2-2 (15 mg, yield: 37.5%), (11 mg, yield: 27.5%).

[0556] Single configuration compound (shorter retention time): 38-1-2 or 38-2-2 (15 mg, yield: 37.5%).

[0557] MS m / z (ESI): 985.7 [M+1].

[0558] Chiral HPLC analysis: retention time 7.022 min, purity: 99.9% (column: ReGIS (S,S)-Whelk-O1, 4.6×150 mm, 5 μm; mobile phase A: ethanol (containing 0.1% diethylamine), mobile phase B: acetonitrile, gradient ratio: A:B = 80:20, flow rate: 1.0 mL / min).

[0559] 1 H NMR (500 MHz, DMSO- d6): δ 12.18 (d, 1H), 10.88 (s, 1H), 7.65 (dt,1H), 7.19 (d, 1H), 7.06 – 6.94 (m, 2H), 6.91 (d, 1H), 6.89 – 6.83 (m, 1H), 6.64 (s, 1H), 6.16 (s, 1H), 5.87 (ddd, 1H), 4.59 (s, 2H), 4.39 – 4.17 (m,6H), 4.07 (s, 3H), 3.99 – 3.91 (m, 1H), 3.61 (dt, 2H), 3.12 (d, 6H), 2.99 –2.87 (m, 3H), 2.80 (t, 1H), 2.72 – 2.58 (m, 3H), 2.38 – 2.22 (m, 4H), 2.21 –2.11 (m, 2H), 1.94 (d, 3H), 1.64 (dd, 3H), 1.35 (s, 5H).

[0560] Single configuration compound (longer retention time): 38-1-1 or 38-2-1 (11 mg, yield: 27.5%).

[0561] MS m / z (ESI): 985.7 [M+1].

[0562] Chiral HPLC analysis: retention time 11.194 min, purity: 98.9% (column: ReGIS (S,S)-Whelk-O1®AD, 4.6×150 mm, 5 μm; mobile phase A: ethanol (containing 0.1% diethylamine), mobile phase B: acetonitrile, gradient ratio: A:B = 80:20, flow rate: 1.0 mL / min).

[0563] 1 H NMR (500 MHz, DMSO- d6): δ 12.18 (d,1H), 10.88 (s, 1H), 7.65 (dt,1H), 7.19 (d, 1H), 7.05 – 6.97 (m, 2H), 6.96 (d, 1H), 6.91 (d, 1H), 6.88 –6.83 (m, 1H), 6.16 (s, 1H), 5.87 (ddd, 1H), 4.59 (s, 2H), 4.41 – 4.18 (m,6H), 4.07 (s, 3H), 3.96 (dd, 1H), 3.61 (dt, 2H), 3.12 (d, 6H), 2.97 – 2.87(m, 3H), 2.80 (t, 1H), 2.70 – 2.56 (m, 3H), 2.40 – 2.22 (m, 4H), 2.21 – 2.09(m, 2H), 2.02 – 1.85 (m, 4H), 1.64 (dd, 4H), 1.35 (s, 3H).

[0564] The compounds in the following examples can be obtained by referring to the methods in Examples 1-25 above: Example 39: MS m / z (ESI): 974.4 [M+1].

[0565] Example 40: MS m / z (ESI): 992.8 [M+1].

[0566] Example 41: MS m / z (ESI): 1002.7 [M+1].

[0567] Example 42: MS m / z (ESI): 1000.9 [M+1].

[0568] Example 43: MS m / z (ESI): 997.8 [M+1].

[0569] Example 44: MS m / z (ESI): 997.8 [M+1].

[0570] Example 45: MS m / z (ESI): 997.7 [M+1].

[0571] Example 46: MS m / z (ESI): 990.7 [M+1].

[0572] Example 47: MS m / z (ESI): 1005.7 [M+1].

[0573] Example 48 4-(4'-((3-(2,6-dioxopiperidin-3-yl)-1-methyl-1 H 7 H -spiro[furano[3,2-] g [Indazole-6,4'-piperidine]-1'-yl)methyl)-2 H -spiro[benzofuran-3,1'-cyclohexane]-6-yl)-7-fluoro- N , N -Dimethyl-6-(1-(2-(pyridin-2-yl)cyclopropane-1-carbonyl)-1,2,5,6-tetrahydropyridin-3-yl)-1 H -Indole-2-formamide 48 Title compound 48 can be prepared by referring to this patent and known technical methods.

[0574] MS m / z (ESI): 985.7 [M+1].

[0575] The compounds in the following examples can be obtained by referring to the methods in Examples 1-38 above: Example 49: MS m / z (ESI): 1014.7 [M+1].

[0576] Example 50: MS m / z (ESI): 1026.7 [M+1].

[0577] Example 51: MS m / z (ESI): 1022.7 [M+1].

[0578] Example 52: MS m / z (ESI): 1001.7 [M+1].

[0579] Example 53: MS m / z (ESI): 1013.7 [M+1].

[0580] Example 54: MS m / z (ESI): 1013.7 [M+1].

[0581] Example 55: MS m / z (ESI): 968.7 [M+1].

[0582] Example 56: MS m / z (ESI): 984.7 [M+1].

[0583] Example 57: MS m / z (ESI): 1002.7 [M+1].

[0584] Example 58: MS m / z (ESI): 997.7 [M+1].

[0585] Example 58-1 3-(1'-((6 aR 8 S )-1-Fluoro-3-(8-Fluoro-7-(1-(3-(3-Fluoro-1) H -pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-2-methyl-1-oxo-2,3,4,9-tetrahydro-1 H -pyrido[3,4- b Indole-5-yl)-6,6 a ,7,8,9,10-hexahydrobenzo[ b ]pyrido[1,2- d [1,4]oxazine-8-yl)-1-methyl-1 H 7 H -spiro[furano[3,2-] g [Indazole-6,4'-piperidine]-3-yl)piperidine-2,6-dione 58-1 3-(1'-((6 aR 8 R )-1-Fluoro-3-(8-Fluoro-7-(1-(3-(3-Fluoro-1) H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-2-methyl-1-oxo-2,3,4,9-tetrahydro-1 H -pyrido[3,4- b Indole-5-yl)-6,6 a ,7,8,9,10-hexahydrobenzo[ b ]pyrido[1,2- d [1,4]oxazine-8-yl)-1-methyl-1 H 7 H -spiro[furano[3,2-] g [Indazole-6,4'-piperidine]-3-yl)piperidine-2,6-dione 58-2 ( S )-3-(1'-((6 aR 8 S )-1-Fluoro-3-(8-Fluoro-7-(1-(3-(3-Fluoro-1) H -pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-2-methyl-1-oxo-2,3,4,9-tetrahydro-1 H -pyrido[3,4- b Indole-5-yl)-6,6 a ,7,8,9,10-hexahydrobenzo[ b ]pyrido[1,2- d [1,4]oxazine-8-yl)-1-methyl-1 H 7 H -spiro[furano[3,2-] g [Indazole-6,4'-piperidine]-3-yl)piperidine-2,6-dione 58-1-1 ( R )-3-(1'-((6 aR 8 S )-1-Fluoro-3-(8-Fluoro-7-(1-(3-(3-Fluoro-1) H -pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-2-methyl-1-oxo-2,3,4,9-tetrahydro-1 H -pyrido[3,4- b Indole-5-yl)-6,6 a ,7,8,9,10-hexahydrobenzo[ b ]pyrido[1,2- d [1,4]oxazine-8-yl)-1-methyl-1 H 7 H -spiro[furano[3,2-] g[Indazole-6,4'-piperidine]-3-yl)piperidine-2,6-dione 58-1-2 ( S )-3-(1'-((6 aR 8 R )-1-Fluoro-3-(8-Fluoro-7-(1-(3-(3-Fluoro-1) H -pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-2-methyl-1-oxo-2,3,4,9-tetrahydro-1 H -pyrido[3,4- b Indole-5-yl)-6,6 a ,7,8,9,10-hexahydrobenzo[ b ]pyrido[1,2- d [1,4]oxazine-8-yl)-1-methyl-1 H 7 H -spiro[furano[3,2-] g [Indazole-6,4'-piperidine]-3-yl)piperidine-2,6-dione 58-2-1 ( R )-3-(1'-((6 aR 8 R )-1-Fluoro-3-(8-Fluoro-7-(1-(3-(3-Fluoro-1) H -pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-2-methyl-1-oxo-2,3,4,9-tetrahydro-1 H -pyrido[3,4- b Indole-5-yl)-6,6 a ,7,8,9,10-hexahydrobenzo[ b ]pyrido[1,2- d [1,4]oxazine-8-yl)-1-methyl-1 H 7 H -spiro[furano[3,2-] g [Indazole-6,4'-piperidine]-3-yl)piperidine-2,6-dione 58-2-2 first step 2-Azide-3-(4-bromo-2-chloro-5-fluorophenyl)methyl acrylate 58b Sodium methoxide (907 mg, 16.8 mmol) was dissolved in methanol (20 mL). A methanol solution of 4-bromo-2-chloro-5-fluorobenzaldehyde 58a (2 g, 8.42 mmol, Shanghai Biotech) and ethyl 2-azidoacetate (4.34 g, 33.7 mmol) was added dropwise at -10°C. The mixture was allowed to return to room temperature naturally with stirring 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 58b (1.5 g). This product was used directly in the next reaction without purification.

[0586] MS m / z (ESI): 333.9 [M+1].

[0587] Step 2 6-Bromo-4-chloro-7-fluoro-1 H Methyl indole-2-carboxylate 58c The crude compound 58b (1.5 g, 4.89 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 title compound 58c (1.0 g). The product was used directly in the next step of the reaction without purification.

[0588] MS m / z (ESI): 305.9 [M+1].

[0589] Step 3 6-Bromo-4-chloro-7-fluoro-3-iodine-1 H Methyl indole-2-carboxylate 58d Compound 58c (1.5 g, 4.89 mmol) was dissolved in... N,N -Dimethylformamide (10 mL), added N - Bromosuccinimide (1 g, 4.44 mmol) was stirred for half an hour. The reaction solution was quenched with saturated sodium sulfite solution, extracted with dichloromethane (30 mL × 3), the organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, 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 58d (2.1 g, 99.9%).

[0590] MS m / z (ESI): 431.8 [M+1].

[0591] Step 4 ( E )-6-bromo-4-chloro-3-(2-ethoxyvinyl)-7-fluoro-1 H Methyl indole-2-carboxylate 58e Compound 58d (0.50 g, 1.16 mmol), 2-[( E [-2-ethoxyvinyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborane (0.34 g, 1.73 mmol, Shaoyuan Technology (Shanghai) Co., Ltd.), 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (84 mg, 0.11 mmol) and potassium carbonate (0.24 g, 1.72 mmol) were dissolved in a mixed solvent of 1,4-dioxane (20 mL) and water (4 mL). The reaction was carried out under nitrogen atmosphere and stirred at 100 °C for 5 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 58e (0.30 g, 68.9%).

[0592] MS m / z (ESI): 376.0 [M+1].

[0593] Step 5 6-Bromo-4-chloro-7-fluoro-3-(2-oxoethyl)-1 H Methyl indole-2-carboxylate 58f Compound 58e (0.52 g, 1.38 mmol) was dissolved in tetrahydrofuran (15 mL), and 6M dilute hydrochloric acid (689 μL) was added. The mixture was stirred at 60 °C for 1 hour. After the reaction solution was cooled to room temperature, it was concentrated under reduced pressure to obtain crude title compound 58f (0.48 g). The product was used directly in the next step of the reaction without purification.

[0594] MS m / z (ESI): 348.0 [M+1].

[0595] Step 6 6-Bromo-4-chloro-7-fluoro-3-(2-(methylamino)ethyl)-1 H 58g of methyl indole-2-carboxylate The crude compound 58f (0.16 g, 0.47 mmol) was dissolved in dichloromethane (10 mL), and an ethanolic solution of methylamine (0.67 mL, 4.7 mmol), sodium borohydride acetate (299 mg, 1.41 mmol), and acetic acid (300 mg, 3.57 mmol) were added. The mixture was stirred for 0.1 h, and water was added to the reaction solution. The mixture was 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 to obtain the crude title compound 58f (0.217 g). The product was used directly in the next reaction without purification.

[0596] MS m / z (ESI): 365.0 [M+1].

[0597] Step 7 7-Bromo-5-chloro-8-fluoro-2-methyl-2,3,4,9-tetrahydro-1 H -pyrido[3,4- b Indole-1-one 58h 58 g (0.17 g, 0.47 mmol) of the crude compound was dissolved in a mixed solvent of tetrahydrofuran (10 mL) and water (1 mL), and lithium hydroxide monohydrate (39 mg, 0.92 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 obtain the title compound 58h (0.15 g, 85.0%).

[0598] MS m / z (ESI): 333.1 [M+1].

[0599] Step 8 3-(1'-((6 aR 8 S )-1-Fluoro-3-(8-Fluoro-7-(1-(3-(3-Fluoro-1) H -pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-2-methyl-1-oxo-2,3,4,9-tetrahydro-1 H -pyrido[3,4- b Indole-5-yl)-6,6 a ,7,8,9,10-hexahydrobenzo[ b ]pyrido[1,2- d [1,4]oxazine-8-yl)-1-methyl-1 H 7 H -spiro[furano[3,2-] g [Indazole-6,4'-piperidine]-3-yl)piperidine-2,6-dione 58-1 3-(1'-((6 aR 8 R )-1-Fluoro-3-(8-Fluoro-7-(1-(3-(3-Fluoro-1) H -pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-2-methyl-1-oxo-2,3,4,9-tetrahydro-1 H -pyrido[3,4- b Indole-5-yl)-6,6 a ,7,8,9,10-hexahydrobenzo[ b ]pyrido[1,2- d [1,4]oxazine-8-yl)-1-methyl-1 H 7 H-spiro[furano[3,2-] g [Indazole-6,4'-piperidine]-3-yl)piperidine-2,6-dione 58-2 ( S )-3-(1'-((6 aR 8 S )-1-Fluoro-3-(8-Fluoro-7-(1-(3-(3-Fluoro-1) H -pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-2-methyl-1-oxo-2,3,4,9-tetrahydro-1 H -pyrido[3,4- b Indole-5-yl)-6,6 a ,7,8,9,10-hexahydrobenzo[ b ]pyrido[1,2- d [1,4]oxazine-8-yl)-1-methyl-1 H 7 H -spiro[furano[3,2-] g [Indazole-6,4'-piperidine]-3-yl)piperidine-2,6-dione 58-1-1 ( R )-3-(1'-((6 aR 8 S )-1-Fluoro-3-(8-Fluoro-7-(1-(3-(3-Fluoro-1) H -pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-2-methyl-1-oxo-2,3,4,9-tetrahydro-1 H -pyrido[3,4- b Indole-5-yl)-6,6 a ,7,8,9,10-hexahydrobenzo[ b ]pyrido[1,2- d [1,4]oxazine-8-yl)-1-methyl-1 H 7 H -spiro[furano[3,2-] g [Indazole-6,4'-piperidine]-3-yl)piperidine-2,6-dione 58-1-2 ( S )-3-(1'-((6 aR 8 R )-1-Fluoro-3-(8-Fluoro-7-(1-(3-(3-Fluoro-1) H -pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-2-methyl-1-oxo-2,3,4,9-tetrahydro-1 H -pyrido[3,4- bIndole-5-yl)-6,6 a ,7,8,9,10-hexahydrobenzo[ b ]pyrido[1,2- d [1,4]oxazine-8-yl)-1-methyl-1 H 7 H -spiro[furano[3,2-] g [Indazole-6,4'-piperidine]-3-yl)piperidine-2,6-dione 58-2-1 ( R )-3-(1'-((6 aR 8 R )-1-Fluoro-3-(8-Fluoro-7-(1-(3-(3-Fluoro-1) H -pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-2-methyl-1-oxo-2,3,4,9-tetrahydro-1 H -pyrido[3,4- b Indole-5-yl)-6,6 a ,7,8,9,10-hexahydrobenzo[ b ]pyrido[1,2- d [1,4]oxazine-8-yl)-1-methyl-1 H 7 H -spiro[furano[3,2-] g [Indazole-6,4'-piperidine]-3-yl)piperidine-2,6-dione 58-2-2 Using steps four to six of the synthetic route in Example 38, the starting compound 6-bromo-4-chloro-7-fluoro- N , N -Dimethyl-1 H -Indole-2-carboxamide was replaced with compound 58h to obtain title compound 58-1 or 58-2 (15 mg, yield: 12.9%), which was then chirally resolved to obtain title compounds 58-1-1, 58-1-2 or 58-2-1, 58-2-2.

[0600] MS m / z (ESI): 997.7 [M+1].

[0601] 58-1 or 58-2: 1 H NMR (500 MHz, DMSO- d 6): δ12.29 (s, 1H), 10.88 (s, 1H),7.65 (dt, 1H), 7.19 (d, 1H), 6.99 (d, 1H), 6.90 – 6.77 (m, 2H), 6.70 (d, 1H),6.18 – 6.12 (m, 1H), 5.86 (ddd, 1H), 4.59 (s, 2H), 4.38 – 4.16 (m, 7H), 4.07(s, 3H), 3.94 (dd, 1H), 3.60 (dt, 2H), 3.51 (t, 2H), 3.18 (d, 1H), 2.99 (s,3H), 2.95-2.91 ( (m, 4H), 2.79(m,1H), 2.69-2.63 – 2.55 (m, 5H), 2.36 – 2.20(m, 5H), 2.15 (dt, 1H), 2.02 – 1.83 (m, 4H), 1.65 (dd, 4H).

[0602] The compounds in the following examples can be obtained by referring to the methods in Examples 1-58 above: Example 59: MS m / z (ESI): 1031.7 [M+1].

[0603] Example 60: MS m / z (ESI): 1014.7 [M+1].

[0604] Example 61: MS m / z (ESI): 1013.7 [M+1].

[0605] Example 62: MS m / z (ESI): 996.7 [M+1].

[0606] Biological evaluation The following test examples further describe and explain this disclosure, but these test examples are not intended to limit the scope of this disclosure.

[0607] Test Example 1-1: Degradation Activity Test of the Compounds Disclosed on Total STAT6 Protein in THP-1 Cells I. Experimental Objective The purpose of this experiment was to test the degradation activity of the compound on total STAT6 protein in THP-1 cells, based on absolute DC. 50 The Dmax value is used to evaluate the in vitro activity of the compound.

[0608] II. Experimental Principle This experiment uses KeyTec. ® The TR-FRET STAT6 Total Protein Kit detects the level of intracellular STAT6 total protein after THP-1 cell lysis. This kit uses two specific antibodies, one of which is conjugated to KeyTec. ® TR-FRET Solar Eu, as a fluorescence resonance energy transfer (FRET) donor; another antibody conjugated with KeyTec ® TR-FRET LA acts as a fluorescence resonance energy transfer (FRET) receptor. When two antibodies bind to different epitopes of the STAT6 protein, the TR-FRET donor and receptor approach each other close enough that laser excitation (615 nm or 620 nm) triggers FRET energy transfer to the receptor, causing it to fluoresce at a specific wavelength (665 nm). The intensity of this specific signal is proportional to the total STAT6 protein level in the cell. The degradation activity of the compound can be determined by measuring the signal value in the presence of the compound.

[0609] III. Experimental Materials 1. Instruments 2. Reagents and consumables IV. Experimental Methods On day 1, THP-1 cells were centrifuged and resuspended in RPMI 1640 complete medium containing 10% fetal bovine serum and 0.05 mM 2-mercaptoethanol. After counting, cells were seeded at 30,000 cells / 16 μL / well in 384-well cell culture microplates. The test compounds (final concentration range: 10,000-0.5 nM, 3-fold serial dilution, DMSO final concentration 0.25%) were added using a TECAND 300e micro-volume dispensing system and the cells were incubated at 37°C in a 5% CO2 cell culture incubator for 48 hours.

[0610] On the third day, first prepare 5× lysis buffer, then remove the incubated 384-well plate. Add 4 μL of 5× lysis buffer to each well and vortex at room temperature for 60 minutes to lyse. Prepare 1× detection buffer, then prepare the premixed detection antibody pair according to the kit instructions, protecting it from light. Add 5 μL of antibody to each well of the 384-well cell culture microplate, vortex at room temperature for 2 minutes to mix, centrifuge, and incubate overnight at 25°C in the dark.

[0611] On the third day, the luminescence values ​​at 620nm and 665nm were read using an Envision microplate reader.

[0612] V. Data Analysis Calculate the ratio of acceptor to donor emission signals per well: Ratio = (665nm fluorescence signal value / 620nm fluorescence signal value) × 10000. Perform curve fitting using XLfit based on the logarithmic concentration and degradation rate of the compounds, and calculate the absolute DC. 50 Value, Degradation rate (%) = 100 × (ratio) 化合物 -ratio 空白对照 ) / (ratio 溶媒对照 -ratio 空白对照 ).

[0613] Table 1-1 Degradation activity of the disclosed compounds on total STAT6 protein in THP-1 cells Among them, for DC 50 DC 50 <1 nM is A; DC 50 B is defined as B in the range of 1 nM to 100 nM; DC 50 >100 nM is C; For Dmax, Dmax > 90% is A; Dmax between 70% and 90% is B; Dmax between 50% and 70% is C.

[0614] Conclusion: The compound disclosed herein exhibits good degradation activity against total STAT6 protein in THP-1 cells.

[0615] Test Examples 1-2: Degradation Activity Tests of the Disclosed Compounds on Total STAT6 Protein in THP-1 Cells I. Experimental Objective The purpose of this experiment was to test the degradation activity of the compound on total STAT6 protein in THP-1 cells, based on absolute DC. 50 The Dmax value is used to evaluate the in vitro activity of the compound.

[0616] II. Experimental Principle This experiment uses KeyTec. ®The TR-FRET STAT6 Total Protein Kit detects the level of intracellular STAT6 total protein after THP-1 cell lysis. This kit uses two specific antibodies, one of which is conjugated to KeyTec. ® TR-FRET Solar Eu, as a fluorescence resonance energy transfer (FRET) donor; another antibody conjugated with KeyTec ® TR-FRET LA acts as a fluorescence resonance energy transfer (FRET) receptor. When two antibodies bind to different epitopes of the STAT6 protein, the TR-FRET donor and receptor approach each other close enough that excitation of the fluorescent donor with a xenon lamp (320 or 340 nm) or a laser (337 nm) triggers a resonance energy transfer (FRET) between the donor and receptor molecules, which emit a TRFRET signal at 665 nm. The signal intensity at 665 nm is proportional to the concentration of the target protein in the cell lysate. The residual energy of the Solar Eu chelate allows for signal intensity detection at 615 nm or 620 nm, which can serve as an internal standard for homogenizing the signal intensity at 665 nm. The total protein level can be determined by detecting the signal intensity at a specific wavelength and calculating the 665 nm / 615 nm ratio. The degradation activity of the compound can be determined by measuring the signal value in the presence of the compound.

[0617] III. Experimental Materials 1. Instruments 2. Reagents and consumables IV. Experimental Methods On day 1, THP-1 cells were centrifuged and resuspended in RPMI 1640 complete medium containing 10% fetal bovine serum and 0.05 mM 2-mercaptoethanol. After counting, the cells were seeded at 30,000 cells / 16 μL / well in columns 3-24 of a 384-well cell culture microplate. Columns 1 and 2 were filled with the same volume of medium as control wells. The test compounds (final concentration range: 30 nM-0.001524 nM or 1-0.000051 nM, 3-fold serial dilution, DMSO final concentration 0.25%) were added using a TECAN D300e microfluidic analyzer and incubated at 37°C in a 5% CO2 cell culture incubator for 24 hours.

[0618] On the second day, first prepare 5× lysis buffer, then remove the incubated 384-well plate. Add 4 μL of 5× lysis buffer to each well and vortex at room temperature for 60 minutes. Prepare 1× detection buffer, then prepare the premixed detection antibody pair according to the kit instructions. Add 5 μL of antibody to each well of the 384-well cell culture microplate, vortex at room temperature for 2 minutes, centrifuge, and incubate overnight at 25°C in the dark.

[0619] On the third day, the total protein level can be determined by reading the luminescence values ​​at 620 nm and 665 nm using an Envision microplate reader and calculating the signal intensity of the 665 nm / 620 nm ratio.

[0620] V. Data Analysis Calculate the ratio of acceptor to donor emission signals per well: Ratio = (665nm fluorescence signal value / 620nm fluorescence signal value) × 10000. Perform curve fitting using XLfit based on the logarithmic concentration and degradation rate of the compounds, and calculate the absolute DC. 50 Value, Degradation rate (%) = 100 × (ratio) 化合物 ratio 空白对照 ) / (ratio 溶媒对照 -ratio 空白对照 ).

[0621] Reference compound 1: (Compound I-757 in WO2025049820A1) Table 1-2 Degradation activity of the disclosed compounds against total STAT6 protein in THP-1 cells Test Example 2: Inhibitory activity test of the disclosed compound on STAT6 phosphorylation level in PBMC cells. I. Experimental Objective The purpose of this experiment was to test the inhibitory effect of the compound on STAT6 phosphorylation levels in PBMC cells, based on IC50. 50 Size is used to evaluate the in vitro activity of compounds.

[0622] II. Experimental Principle The KeyTec® TR-FRET Phosphorylated Protein Kit is based on the principle of traditional sandwich immunoassay. First, cells are pretreated by lysis. Then, a pair of specific antibodies conjugated to either a TR-FRET Solar Eu fluorescent resonance energy transfer donor or a TR-FRET LA fluorescent resonance energy transfer receptor are added to the sample. When these two antibodies bind to different epitopes of the phosphorylated protein, the donor and receptor approach each other close enough that excitation of the fluorescent donor with a xenon lamp or laser triggers resonance energy transfer (FRET) between the donor and receptor molecules, which emits a TR-FRET signal at 665 nm. The signal intensity at 665 nm is proportional to the concentration of the target protein in the cell lysate. The residual energy of the Solar Eu chelate can be detected at 615 nm or 620 nm, which serves as an internal standard for homogenizing the signal intensity at 665 nm. The level of total phosphorylated protein can be determined by detecting the signal intensity at a specific wavelength and calculating the 665 nm / 615 nm ratio.

[0623] III. Experimental Materials 1. Instruments 2. Reagents and consumables IV. Experimental Methods On day 1, frozen PBMC cells were resuspended in IMDM medium containing 10% inactivated fetal bovine serum and seeded at 50,000 cells / 14 μL / well in 384-well plates. The test compound was added to each well using an ultra-micro pipette to achieve 10 concentration points with a 3-fold serial dilution starting from 10 μM (final concentration range: 10,000-0.5 nM or 30 nM-0.001524 nM or 1-0.000051 nM, depending on the properties of different series of compounds). The well plates were incubated at 37°C in a 5% CO2 cell culture incubator for 48 hours.

[0624] On the third day, after 48 hours of incubation, 2 μL of IL-4 (final concentration 3 ng / mL) was added to each well of the cell culture plate, and the plate was placed in an incubator for 10 minutes of stimulation. After incubation, 4 μL of 5× lysis buffer from the KeyTec® TR-FRET Phospho STAT6 (Y641) Kit was added to each well, and the plate was lysed at room temperature (400 rpm) for 30 minutes. Then, following the recommended procedure of the KeyTec® TR-FRET Phospho STAT6 (Y641) Kit, 4× premixed detection antibody pairs (detection buffer + Ab1-Solar Eu + Ab2-LA) were prepared, and 5 μL of antibody was added to each well of a 384-well cell culture microplate. The plates were mixed by shaking at room temperature for 2 minutes, centrifuged, and then incubated overnight at 25°C in the dark.

[0625] On the fourth day, the level of phosphorylated protein can be determined by reading the 665nm and 620nm wavelengths using an Envision microplate reader and calculating the signal intensity of the 665nm / 620nm ratio.

[0626] V. Data Analysis The IC50 of the compound's inhibitory activity was calculated using Xlfit software. 50 value.

[0627] Conclusion: The compound disclosed herein exhibits good inhibitory activity against STAT6 phosphorylation levels in PBMC cells.

[0628] Test Example 3: Pharmacokinetic Evaluation I. SD Rat Experiment 1. Abstract Using SD rats as test animals, the plasma drug concentration of the disclosed compound at different time points after gavage (ig) administration to SD rats was determined by LC / MS / MS. The pharmacokinetic behavior of the disclosed compound in SD rats was investigated to evaluate its pharmacokinetic characteristics.

[0629] 2. Test Plan 2.1 Test Drugs This compound is disclosed.

[0630] 2.2 Experimental Animals SD rats were provided by Viton Lever Laboratories. After fasting overnight, the drugs were administered via gavage.

[0631] 2.3 Drug Preparation Weigh out a certain amount of the test compound, add 5% DMSO + 5% Tween 80 + 90% physiological saline, and prepare a colorless and clear solution of 0.2 mg / mL.

[0632] 2.4 Administration The dosage is 2.0 mg / kg, and the administration volume is 10.0 mL / kg.

[0633] 3. Operation Blood samples of 0.1 mL were collected from the orbital cavity before administration and at 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 11.0, and 24.0 hours after administration. The samples were placed in EDTA-K2 anticoagulant tubes and centrifuged at 10,000 rpm for 1 minute (4°C). Plasma was separated within 1 hour and stored at -20°C for analysis. The entire process, from blood collection to centrifugation, was performed under ice bath conditions. Patients ate 2 hours after administration.

[0634] The levels of the target compound in the plasma of SD rats were determined after administration of different concentrations of the drug.

[0635] Conclusion: The compound disclosed herein has a high exposure level in SD rats and exhibits pharmacokinetic advantages.

[0636] II. C57 Mouse Experiment 1. Abstract Using C57 mice as test animals, the plasma drug concentrations of the disclosed compound at different time points after administration by gavage (ig) / intravenous injection (iv) in C57 mice were determined by LC / MS / MS. The pharmacokinetic behavior of the disclosed compound in C57 mice was investigated to evaluate its pharmacokinetic characteristics.

[0637] 2. Test Plan 2.1 Test Drugs This disclosed compound 2.2 Experimental Animals C57 mice were provided by Vital River Laboratory Animal Technology Co., Ltd. The drugs were administered via gavage and intravenous injection, respectively.

[0638] 2.3 Drug Preparation Weigh out a certain amount of the test compound, add 5% DMSO + 5% Tween 80 + 90% physiological saline, and prepare a colorless and clear solution of 0.1 mg / mL.

[0639] 2.4 Administration Gavage administration group: The dosage was 2.0 mg / kg, and the administration volume was 0.2 mL / 10g.

[0640] Intravenous administration group: The dosage was 1.0 mg / kg, and the administration volume was 0.1 mL / 10g.

[0641] 3. Operation In the gavage administration group: 0.1 mL of blood was collected from the orbital cavity before administration and at 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 11.0, and 24.0 hours after administration. The blood samples were placed in EDTA-K2 anticoagulant tubes, centrifuged at 10,000 rpm for 1 minute (4℃), and the plasma was separated within 1 hour and stored at -80℃ for analysis. The entire process from blood collection to centrifugation was performed under ice bath conditions.

[0642] Intravenous injection group: Blood samples were collected before administration and 5 minutes after administration, and at 0.25, 0.5, 1.0, 2.0, 4.0, 8.0, 11.0 and 24 hours after administration. The treatment was the same as that of the gavage group.

[0643] The levels of the target compound in the plasma of C57 mice were determined after administration of different concentrations of the drug.

[0644] Table 3. Pharmacokinetic parameters of the compounds disclosed herein in C57 mice. Conclusion: The compound disclosed herein exhibits high exposure levels in C57 mice and demonstrates pharmacokinetic advantages.

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 1x The replacement of the four rings; 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); L 2 is selected from the group consisting of a bond, O, C(O), S, S(O), S(O)₂, NR a , C(O)NR a , NR a C(O), (CR d R f ) h , (CR d R f ) h1 O(CR d R f ) h2 , (CR d R f ) h1 S(CR d R f ) h2 , (CR d R f ) h1 NR a (CR d R f ) h2 , (CR d R f ) h1 C(O)NR a (CR d R f ) h2 and (CR d R f ) h1 NR a C(O)(CR d R f ) h2 ; R a Selected from hydrogen atoms, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, and cycloalkylalkyl; h, h1, and h2 are each independently 0, 1, 2, 3, 4, or 5; X 2 For N or CH; Ring B is arbitrarily controlled by one or more R 2 The three rings that were replaced; Cycloyl X is selected from cycloalkyl, heterocyclic, aryl, and heteroaryl groups; G is selected from hydrogen atom, halogen and The ring Y is selected from cycloalkyl, heterocyclic, aryl, and heteroaryl groups. 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 and Y 2 Each is independently selected from O, S, N, NR. w3 CR w4 and CR w4 R w5 ; R w0 R w1 R w2 R w4 R w5 R d R f R x R y R 1x and R 2 The same or different, and each independently selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, cyano, nitro, hydroxyl, amino, alkoxy, haloalkyl, hydroxyalkyl, haloalkoxy, alkoxyalkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, -OR 3 -NR 4 R 5 -C(O)R 3 -C(O)OR 3 -C(O)NR 4 R 5 -C(O)NR 4 OR 3 -NR 6 C(O)R 3 -NR 6 C(O)OR 3 -NR 6 C(O)NR 4 R 5 -OC(O)R 3 -OC(O)NR 4 R 5 -S(O) v R 3 -S(O)(=NR) 7 )R 3 -S(O) v NR 4 R 5 -NR 6 S(O)2R 3 =O, =CR 8 R 9 、-Si(R 3 3. -P(O)(OR) 3 )2、-OP(O)(R 3 )2 and -OP(O)(OR 3 )2; the alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each independently and optionally composed of one or more R groups. 0 replace; R w3 The atom is selected from hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups is independently and optionally converted by one or more R atoms. 0 replace; Or, R w0 With R w3 Together with their respective attached atoms, they form a heterocyclic group or a heteroaryl group, each of which is independently and optionally influenced by one or more R atoms. C replace; Or, R w0 With R w4 Together with their respective attached atoms, they form cycloalkyl, heterocyclic, aryl, or heteroaryl groups, each of which is independently and optionally influenced by one or more R groups. C replace; Or, R w2 With R x Together with their respective attached atoms, they form cycloalkyl, heterocyclic, aryl, or heteroaryl groups, each of which is independently and optionally influenced by one or more R groups. D replace; R C and R D 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 3a -NR 4a R 5a -C(O)R 3a -C(O)OR 3a -C(O)NR 4a R 5a -C(O)NR 4a OR 3a -NR 6a C(O)R 3a -NR 6a C(O)OR 3a -NR 6a C(O)NR 4a R 5a -OC(O)R 3a -OC(O)NR 4a R 5a -S(O) v R 3a -S(O)(=NR) 7a )R 3a -S(O) v NR 4a R 5a -NR 6a S(O)2R 3a =O, =CR 8a R 9a 、-Si(R 3a 3. -P(O)(OR) 3a )2、-OP(O)(R 3a )2 and -OP(O)(OR 3a )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 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 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; Or, two Rs 2 Together with the attached atoms, they form a cycloalkyl or heterocyclic group, each of which is independently and optionally influenced by one or more R atoms. 0 replace; Or, two Rs C 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 D 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 and y 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; the alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl groups are each independently and optionally converted by one or more R 0 replace; R b Selected from hydrogen atoms, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, and cycloalkylalkyl; t1 is selected from integers from 0 to 10; t2 is selected from integers from 0 to 20; R 3 R 4 R 5 R 3a R 4a and R 5a 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; or R 4a and R 5a 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; or, R w3 and R 5 Together with their respective attached atoms, they form a heterocyclic group or a heteroaryl group, each of which is independently and optionally influenced by one or more R atoms. C Replace; or, R w4 and R 5 Together with their respective attached atoms, they form a heterocyclic group or a heteroaryl group, each of which is independently and optionally influenced by one or more R atoms. C replace; R 6 and R 6a They may be the same or different, and each is independently selected from hydrogen atoms, alkyl, haloalkyl, hydroxyalkyl and cycloalkyl; R 7 and R 7a They may be the same or different, and each is independently selected from hydrogen atoms, alkyl, haloalkyl, hydroxyalkyl, hydroxyl, alkoxy, haloalkoxy and cycloalkyl; R 8 R 9 R 8a and R 9a 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 a cycloalkyl or heterocyclic group; or, R 8a and R 9a Together with the attached carbon atom, they form cycloalkyl or heterocyclic groups; R 0 The same or different, and each independently selected from =O, halogen, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, aminoalkyl, hydroxy, alkenyl, alkynyl, cyano, nitro, amino, -NHalkyl, -N(alkyl)2, -C(O)Oalkyl, -C(O)OH, -C(O)NH2, -C(O)NH(alkyl), -C(O)N(alkyl)2, -C(O)halogen, -C(O)alkyl, -S(alkyl), cycloalkyl, cycloalkylalkyl, cycloalkyloxy, heterocyclic, heterocyclic alkyl, heterocyclic oxy, aryl, arylalkyl, aryloxy, heteroaryl, heteroarylalkyl, and heteroaryloxy; and v can be 0, 1, or 2.

2. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein it is the compound of formula (IV) or a pharmaceutically acceptable salt thereof. in, It can be a single bond or a double bond; Y 3 Selected from NR w3 O and S; Ring Y, R y y, L x R x , x, L 2 R w1 R w2 R w3 R w4 R 4 R 5 Rings B, L, A, and X 2 As defined in claim 1.

3. The compound of general formula (I) according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein ring B is selected from... , , and * Connect to L; B 1 B 2 and B 5 Whether they are the same or different, and each is independently N or CR 2 Z 1 Selected from N and CR z1 Z 2 For N or CR z2 ;R z1 and R z2 The same or different, and each independently selected from hydrogen atom, halogen, alkyl, cyano, hydroxyl, haloalkyl, hydroxyalkyl, alkoxy, cycloalkyl, and cycloalkylalkyl; J is selected from bond, (CR 2a R 2b ) q O, S, S(O), S(O)2, NR 2c C(O), C(O)NR 2c and NR 2c C(O); n1 is 0, 1, 2, 3 or 4; q, q1 and q2 are each independently 0, 1, 2, 3 or 4; R 2c Selected from hydrogen atoms, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, and cycloalkylalkyl; R 2a and R 2b The same or different, and each independently selected from hydrogen atom, halogen, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, aminoalkyl, alkenyl, alkynyl, cyano, hydroxyl, nitro, amino, -NHalkyl, -N(alkyl)2, -C(O)Oalkyl, -C(O)OH, -C(O)NH2, -C(O)NH(alkyl), -C(O)N(alkyl)2, -C(O)halogen, -C(O)alkyl, -S(alkyl), oxo, cycloalkyl, cycloalkylalkyl, cycloalkyloxy, heterocyclic, heterocyclic alkyl, heterocyclic oxy, aryl, arylalkyl, aryloxy, heteroaryl, heteroarylalkyl and heteroaryloxy; or, R 2a and R 2b Together with the attached carbon atom, they form a cycloalkyl or heterocyclic group; or, R 2a and R 2b Together form = O; R 2d For R 2 ;R 2 As defined in claim 1; Preferably, ring B is selected from , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ... , , , , , , , , , , , , , , , , 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 , , , , , , , , , , , , , and * The terminal is connected to L.

4. The compound of general formula (I) according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein ring A is selected from... , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and * The terminal is connected to L; Q is selected from O, S, and NR. q and CR q1 R q2 A1 is N or CR a1 A2 is N or CR a2 U is selected from bonds, 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); U 3 and U 4 Each is independently selected from O, S, S(O), S(O)2, and NR. J C(O), C(O)NR J NR J C(O), (CR) j1 R j2 ) k1 、(CR j1 R j2 ) k2 O(CR j1 R j2 ) k3 、(CR j1 R j2 ) k2 S(CR j1 R j2 ) k3 、(CR j1 R j2 ) k2 NR J (CR j1 R j2 ) k3 、(CR j1 R j2 ) k2 C(O)(CR j1 R j2 ) k3 、(CR j1 R j2 ) k2 C(O)NR J (CR j1 R j2 ) k3 and (CR) j1 R j2 ) k2 NR J C(O)(CR j1 R j2 ) k3 k1 is 1, 2, 3, or 4; k2 and k3 are each independently 0, 1, 2, or 3; p, p1, and p2 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 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 attached atoms, they form a cycloalkyl or heterocyclic group; a4 is 0, 1, or 2; R 1x As defined in claim 1; Preferably, ring A is selected from the following structures: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 , , , , , , , , , , , , , , , , , , , , , and More preferably, ring A is selected from , , , and * The terminal is connected to L.

5. The compound of general formula (I) according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein R w1 Selected from hydrogen atoms, halogens and C 1-6 Alkyl; preferably, R w1 It is F.

6. The compound of general formula (I) according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein R w2 Selected from hydrogen atoms, halogens and C 1-6 Alkyl; R x Selected from hydrogen atoms, halogens, C 1-6 Alkyl and oxo groups; or, R w2 With R x Together with their respective attached atoms, they form a 5- to 8-membered cycloalkyl group or a 5- to 8-membered heterocyclic group; preferably, R w2 For hydrogen atoms; R x For hydrogen atoms; or, R w2 With R x Together with their respective connected atoms, they form 6- or 7-membered heterocyclic groups; More preferably, R w2 It is a hydrogen atom; and / or R x It is a hydrogen atom.

7. The compound of general formula (I) according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R w4 Selected from hydrogen atoms, halogens and C 1-6 Alkyl; 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; or, R w4 and R 5 Together with their respective connected atoms, they form 5- to 8-membered heterocyclic groups; Preferably, R w4 It is a hydrogen atom; and / or R 4 and R 5 C 1-6 alkyl.

8. The compound of general 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 may be the same or different, and each is independently selected from O, NH, N(CH3), C(O), C 1-6 Alkylene, C 2-6 Alkyne group, 3- to 8-membered cycloalkyl group and 3- to 8-membered heterocyclic group; the C 1-6 Alkylene, 3- to 8-membered cycloalkyl, and 3- to 8-membered heterocyclic groups are each independently selected from hydroxyl, halogen, C 1-6 Alkyl, C 1-6 The alkyl halogroup and =O are substituted with one or more substituents; t2 is 0, 1, 2, 3, 4, 5 or 6; preferably, L is selected from bond, CH2 and C(O).

9. The compound of general formula (I) according to any one of claims 1 to 8, 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 CH2, CH2CH2, , , , , , , , , , , , , , , , , , and * The terminal is connected to G or ring Y; more preferably, L x for * The terminal is connected to G or ring Y.

10. The compound of general formula (I) according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein ring Y is a 5-membered heteroaryl group; R y Selected from hydrogen atoms, halogens and C 1-6 Alkyl; y is 0 or 1; preferably, for , , or .

11. The compound of general formula (I) according to any one of claims 2 to 10, or a pharmaceutically acceptable salt thereof, wherein Y 3 Selected from O, S and NH; preferably, Y 3 It is NH.

12. The compound of general formula (I) according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, selected from the group consisting of: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and .

13. A compound of general formula (IVB) or a salt thereof, in, R LP It is a leaving group; preferably, R LP It is a halogen; Rings B, L, A, and X 2 As defined in claim 2.

14. A compound or a salt thereof, selected from the following compounds or salts thereof: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ... , , , , , , , , , , and .

15. A method for preparing a compound of general formula (IV) or a pharmaceutically acceptable salt thereof, said method comprising the following steps: The compound represented by general formula (IVA) or its salt reacts with the compound represented by general formula (IVB) or its salt to give the compound represented by general formula (IV) or its pharmaceutically usable salt. in, It can be a single bond or a double bond; R T -B(OH)2 or ; R LP It is a leaving group; Ring Y, R y y, L x R x , x, L 2 Y 3 R w1 R w2 R w4 R 4 R 5 Rings B, L, A, and X 2 As defined in claim 2.

16. A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 12, and one or more pharmaceutically acceptable carriers, diluents or excipients.

17. Use of the compound of any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of claim 16 in the preparation of a medicament for inhibiting STAT6.

18. Use of the compound of any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of claim 16 in the preparation of a medicament for treating and / or preventing diseases or conditions mediated or dependent on STAT6.

19. The compound of any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 13, for the preparation of a 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, and diseases involving T cells. Use in medicaments for the treatment and / or prevention of asthma, atopic dermatitis (AD), chronic obstructive pulmonary disease (COPD), bronchitis, diabetes, atherosclerosis, gout, gouty arthritis, osteoarthritis, systemic lupus erythematosus, polychondritis, colitis, conjunctivitis, allergic rhinitis, rheumatoid arthritis, scleroderma, Wegener's granulomatosis, dermatomyositis, hepatitis, myasthenia gravis, Stevens-Johnson syndrome, ulcerative colitis, Crohn's disease, irritable bowel syndrome, celiac disease, and other conditions. Periodontitis, kidney disease, glomerular disease, alcoholic liver disease, multiple sclerosis, endocrine eye disease, Graves' disease, sarcoidosis, alveolitis, chronic allergic pneumonia, multiple 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, myasthenia gravis, thyroiditis. Uses in medications for appendicitis, allergies, cervicitis, cholangitis, cholecystitis, conjunctivitis, cystitis, dacryoadenitis, dermatitis, dermatomyositis, encephalitis, encephalomyelitis, endocarditis, endometritis, upper gastritis, gastroenteritis, allergic purpura, 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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