Preparation of STAT6 protein degradation agent and use thereof in medicine

Abstract

The present invention relates to a compound capable of modulating signal transducer and activator of transcription 6 (STAT6) by means of ubiquitination and / or degradation, or a pharmaceutically acceptable salt thereof. The present invention further provides a composition comprising the compound of the present invention and a method for treating related diseases by using the composition.

Description

Preparation of STAT6 protein degrader and its use in medicine

[0001] This application claims priority to the Chinese patent application No. 2025102787645, filed on March 10, 2025, and entitled “Preparation of STAT6 protein degrader and its use in medicine”, the content of which is incorporated herein by reference in its entirety.

[0002] This application claims priority to the Chinese patent application No. 2025103050636, filed on March 14, 2025, and entitled “Preparation of STAT6 protein degrader and its use in medicine”, the content of which is incorporated herein by reference in its entirety.

[0003] This application claims priority to the Chinese patent application No. 2025103890431, filed on March 31, 2025, and entitled “Preparation of STAT6 protein degrader and its use in medicine”, the content of which is incorporated herein by reference in its entirety.

[0004] This application claims priority to the Chinese patent application No. 2025105670578, filed on April 30, 2025, and entitled “Preparation of STAT6 protein degrader and its use in medicine”, the content of which is incorporated herein by reference in its entirety.

[0005] This application claims priority to the Chinese patent application No. 2025107914539, filed on June 13, 2025, and entitled “Preparation of STAT6 protein degrader and its

[0006] This application claims priority to the Chinese patent application No. 2025108771918, filed on June 27, 2025, and entitled “Preparation of STAT6 protein degrader and its us

[0007] This application claims priority to the Chinese patent application No. 2025110603056, filed on July 30, 2025, and entitled “Preparation of STAT6 protein degrader

[0008] This application claims priority to the Chinese patent application No. 2025112243500, filed on August 29, 2025, and entitled “Preparation of STAT6 protein degrader and its use in medicine”, the entire contents of which are incorporated herein by reference.

[0009] This application claims priority to the Chinese patent application No. 2025113050721, filed on September 12, 2025, and entitled “Preparation of STAT6 protein degrader and its use in medicine”, the entire contents of which are incorporated herein by reference.

[0010] This application claims priority to the Chinese patent application No. 2025113997168, filed on September 28, 2025, and entitled “Preparation of STAT6 protein degrader and its use in medicine”, the entire contents of which are incorporated herein by reference.

[0011] This application claims priority to the Chinese patent application No. 2025117375366, filed on November 25, 2025, and entitled “Preparation of STAT6 protein degrader and its use in medicine”, the entire contents of which are incorporated herein by reference.

[0012] This application claims priority to the Chinese patent application No. 2025118584918, filed on December 10, 2025, and entitled “Preparation of STAT6 protein degrader and its use in medicine”, the entire contents of which are incorporated herein by reference.

[0013] This application claims priority to the Chinese patent application No. 2026102109209, filed on February 13, 2026, and entitled “Preparation of STAT6 protein degrader and its use in medicine”, the entire contents of which are incorporated herein by reference. TECHNICAL FIELD

[0014] The present application relates to the technical field of medicine, in particular to a compound or a pharmaceutically acceptable salt thereof capable of regulating signal transduction and transcriptional activator 6 (STAT6) through ubiquitination and / or degradation, and the use thereof in preventing or treating diseases or disorders mediated by signal transduction and transcriptional activator 6 (STAT6). BACKGROUND

[0015] The concept of the protein degradation targeting chimera (PROTACs, Proteolysis Targeting Chimeras) technology was proposed in 2001 (Proc. Natl. Acad. Sci. USA, 2001, 98, 8584). PROTACs molecules are bifunctional molecules, one end contains a ligand that binds E3 ubiquitin ligase, the other end contains a ligand that binds target proteins, and the two parts are connected by a linker unit. By pulling closer, the E3 ligase and the target protein are very close, which in turn causes the polyubiquitination of the target protein and the degradation of the proteasome. PROTACs use a completely different mechanism of action and mechanism from small molecule inhibitors. First, the E3 ubiquitin ligase ligand recruits the E3 ubiquitin ligase to the vicinity of the target protein, and by pulling the distance closer to the target protein, the target protein is ubiquitinated. The labeled target protein is degraded by the proteasome system in the body, thereby achieving the effect of inhibiting the corresponding protein pathway (Cell Biochem Funct. 2019, 37, 21-30). Compared with traditional small molecule drugs, due to the change in the binding mechanism, PROTACs only need to be transiently combined with the target protein to complete the ubiquitin transfer process to achieve irreversible degradation of the target protein. Therefore, PROTACs have the following advantages: 1) stronger degradation effect and more persistent drug efficacy; 2) higher selectivity for target proteins; 3) can overcome the drug resistance of traditional small molecule inhibitors due to target protein variation (Cell Chem. Biol. 2018, 25, 67-77).

[0016] The signal transducers and activators of tranion (STAT) family has six members, which can bind to specific peptide segments containing phosphorylated tyrosine. STAT6 (Signal Transducer and Activator of Transcription 6) is a core member of the STAT protein family, which plays a dual function in cell signal transduction and gene transcription regulation. STAT6 is composed of about 840 amino acids (molecular weight about 94 kDa), containing a highly conserved SH2 domain (Src homology 2 domain), which is responsible for recognizing phosphorylated tyrosine residues and mediating dimerization and nuclear translocation. Its gene is located on human chromosome 12q13.3, and there are various isoforms (such as STAT6α, STAT6β), among which STAT6α is the main functional form. It is mainly involved in immune regulation, inflammatory response, cell proliferation and differentiation and other physiological and pathological processes by mediating the downstream signaling pathway of cytokines such as IL-4 and IL-13. In the activation mechanism, after IL-4 or IL-13 binds to the cell membrane receptor, it induces the phosphorylation of STAT6 tyrosine residues (such as Y641 site) through JAK kinase (such as JAK1 / JAK3). Phosphorylated STAT6 forms a homodimer, which is transferred to the cell nucleus, binds to the STAT6 response element (such as the GAS sequence) in the target gene promoter region, and regulates key processes including Th2 cell differentiation, B cell class switching (such as IgE production), and inflammatory factor release.

[0017] In recent years, STAT6 has become a hot spot in drug research and development due to its core role in various diseases and potential for targeted therapy. Abnormal activation or expression disorder of STAT6 is closely related to immune diseases. STAT6 is a core regulator of Th2-type immune response, and its excessive activation drives the pathological process of Th2-type inflammatory diseases such as asthma, atopic dermatitis, and chronic obstructive pulmonary disease (COPD). In rheumatic diseases (such as rheumatoid arthritis), STAT6 promotes autoimmune response and inflammatory cell infiltration by enhancing IL-4 / IL-13 signaling pathway. Although the pathological mechanism of STAT6 is clear, the development of drugs targeting this target still faces multiple challenges. SUMMARY

[0018] In view of the core position of STAT6 in diseases and the limitations of existing therapies, the present application focuses on the development of specific PROTAC, aiming to provide more efficient and safe STAT6 targeted therapy by optimizing SH2 binding affinity and reducing off-target risk, and to fill the gap in current drug development.

[0019] The first aspect of the present application provides a compound, which has the structure shown in formula (I):

[0020] or an isomer, isotopic derivative, polymorph, prodrug, or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0021] CLM is an E3 ubiquitin ligase binding moiety, preferably the CLM is a human cereblon (CRBN) E3 ubiquitin ligase binding moiety; preferably the CLM is as defined in any embodiment of the present application;

[0022] PTM is a binding moiety targeting signal transducer and activator of transcription 6 (STAT6); preferably the PTM is as defined in any embodiment of the present application; and

[0023] L is a chemical linking moiety linking the CLM and the PTM; preferably the L is as defined in any embodiment of the present application.

[0024] In some embodiments, the present application provides a compound of formula (I), wherein the CLM is selected from the following structures:

[0025] W1and W2are each independently selected for each occurrence from CR b R c and C(O), and at least one of W1and W2is selected from C(O);

[0026] W3is independently selected for each occurrence from C(R b )2and C(O);

[0027] In formula 2-1-9, formula 2-1-10, formula 2-1-11, and formula 2-1-12, the between W4, W5, and W6is a single bond or a double bond; W4, W5, and W6are each independently selected for each occurrence from C, C(O), O, N, NR b , CR b , and CR b R c ; and when W4and W5are a double bond, W5and W6are a single bond, W4is selected from C, W5is selected from N and CR b , and W6is selected from NR b , O, and CR b R c ; when W4and W5are a single bond, W5and W6are a double bond, W4, W5, and W6are each independently selected from N and CR b ; when W4, W5, and W6are all single bonds, W4is selected from N and CR b, W5 and W6 are each independently selected from the group consisting of C(O), NR b , O and CR b ; c ;

[0028] R q is independently at each occurrence selected from the group consisting of a single bond and NR b ;

[0029] A1, A2, A3, A4, A5 and A6 are each independently at each occurrence selected from the group consisting of O, S, C(O), NR d and C(R d )2;

[0030] B1, B2, X and Z are each independently at each occurrence selected from the group consisting of N and CR d ;

[0031] E is independently at each occurrence selected from the group consisting of O, C(O)NR b and NR b ;

[0032] m1 and m2 are each independently at each occurrence selected from the group consisting of 0, 1, 2, 3, 4, 5 and 6, and 1≤m1+m2≤6;

[0033] m3 and m4 are each independently at each occurrence selected from the group consisting of 0, 1, 1, 3, 4, 5, 6 and 7, and 1≤m3+m4≤7;

[0034] m5 and m7 are each independently at each occurrence selected from the group consisting of 0, 1, 3, 4, 5, 6 and 7, m6 and m8 are each independently at each occurrence selected from the group consisting of 1, 2, 3, 4, 5, 6, 7 and 8, and 1≤m5+m6≤8, 1≤m7+m8≤8;

[0035] m9, m10 and m11 are each independently at each occurrence selected from the group consisting of 0, 1, 4 and 3, and m9+m10+m11≤3;

[0036] R1 and R2 are each independently at each occurrence selected from the group consisting of H, a deuterium atom, a halogen, a hydroxyl group, a C 1-6 alkyl group, a C 1-6 haloalkyl group, a C 1-6 alkoxy group, a C 1-6 hydroxyalkyl group and a C 3-6 cycloalkyl group;

[0037] R b and R c are each independently at each occurrence selected from the group consisting of H, a C 1-6 alkyl group, a C 1-6 alkoxy group and a C 3-6 cycloalkyl group;

[0038] R3, R4, R5 and Rd each occurrence is selected from the group consisting of H, halogen, hydroxyl, cyano, amino, nitro, C 1-6 alkyl, C 1-6 heteroalkyl, C 2- alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, halogenated C 1-6 alkyl, C 1-6 halogenated alkoxy, C 1-6 hydroxyalkyl, -NH(C 1-6 alkyl), -N(C 1-6 alkyl)2, C 1-6 alkyl-C(O)-, C 1-6 alkyl-O-C(O)-, C 1-6 alkyl-NH-C(O)-, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-8 aryl and 5-8 membered heteroaryl;

[0039] n and n5 are independently at each occurrence selected from the group consisting of 0, 1, 2, and 3; and

[0040] represents a point of attachment.

[0041] In some embodiments,

[0042] W1and W2are each independently at each occurrence selected from the group consisting of CH2and C(O), and at least one of W1and W2is selected from C(O); and / or

[0043] W3is selected from C(O); and / or

[0044] In Formula 2-1-9, Formula 2-1-10, Formula 2-1-11, and Formula 2-1-12, the represents a single or double bond; W4, W5, and W6are each independently at each occurrence selected from the group consisting of C, C(O), O, N, NH, N(C 1-3 alkyl), CH, C(C 1-3 alkyl), CH2, CH(C 1-3 alkyl), and C(C 1-3 alkyl)2;

[0045] and when W4and W5are a double bond, W5and W6are a single bond, W4is selected from C, W5is selected from N, CH, and C(C 1-3 alkyl), W6is selected from NH, N(C 1-3 alkyl), O, CH2, CH(C 1-3 alkyl), and C(C 1-3alkyl); when W4, W5and W6are each single bonds, W4is selected from the group consisting of N, CH and C(C 1-3 alkyl); when W4, W5and W6are each single bonds, W4is selected from the group consisting of N, CH and C(C 1-3 alkyl), W5and W6are each independently selected from the group consisting of C(O), NH, N(C 1-3 alkyl), O, CH2, CH(C 1-3 alkyl) and C(C 1-3 alkyl)2; and / or

[0046] R q is independently at each occurrence selected from the group consisting of a single bond and NH; and / or

[0047] A1, A2, A3, A4, A5and A6are each independently at each occurrence selected from the group consisting of O, C(O), NR d and C(R d )2; preferably, A1, A2, A3, A4, A5and A6are each independently at each occurrence selected from the group consisting of O, C(O), NH and CH2; and / or

[0048] B1and B2are each independently at each occurrence selected from the group consisting of N and CH; preferably, at least one of B1and B2is N;

[0049] X and Z are each independently at each occurrence selected from the group consisting of N and CH; preferably, X is N; and / or, Z is CH or N; and / or

[0050] E is independently at each occurrence selected from the group consisting of O, C(O)NH, C(O)N(C 1-3 alkyl), NH and N(C 1-3 alkyl); preferably, E is independently at each occurrence selected from the group consisting of O, C(O)NH, C(0)N(CH3), NH and N(CH3); and / or

[0051] m1and m2are each independently at each occurrence selected from the group consisting of 0, 1, 2, 3 and 4, and 1 < m1+ m2< 4; preferably, m1+ m2= 1 or m1+ m2= 2; and / or

[0052] m3and m4are each independently at each occurrence selected from the group consisting of 0, 1, 3 and 4, and 1 < m3+ m4< 4; preferably, m3and m4are each independently at each occurrence selected from the group consisting of 0,1, 2 and 3, and m3+ m4= 2 or m3+ m4= 3; and / or

[0053] m5and m7are each independently selected at each occurrence from 0, 1, 2, 3, and 4, m6and m8are each independently selected at each occurrence from 1, 2, 3, 4, and 5, and 1 < m5+ m6< 5, 1 < m7+ m8< 5; preferably, m5and m7are each independently selected at each occurrence from 0, 1, 2, and 3, m6and m8are each independently selected at each occurrence from 1, 2, 3, and 4, and m5+ m6= 2, m5+ m6= 3, or m5+ m6= 4; m7+ m8= 2, m7+ m8= 3, or m7+ m8= 4; and / or

[0054] R1and R2are each independently selected at each occurrence from H, a deuterium atom, a halogen, a hydroxyl group, a C 1-3 alkyl group, a C 1-3 haloalkyl group, a C 1-3 alkoxy group, a C 1-3 hydroxyalkyl group, and a C 3-6 cycloalkyl group; preferably, R1and R2are each independently selected at each occurrence from H, F, Cl, Br, a hydroxyl group, a methyl group, an ethyl group, a methoxy group, an ethoxy group, and a cyclopropyl group; preferably, R1is H at each occurrence; and / or, R2is each independently selected at each occurrence from a methyl group and -CH2CH2F; and / or

[0055] R b and R c are each independently selected at each occurrence from H, a C 1-3 alkyl group, a C 1-3 alkoxy group, and a C 3-6 cycloalkyl group; and / or

[0056] R3, R4, R5, and R d are each independently selected at each occurrence from H, F, Cl, Br, I, -OH, -CN, -NH2, -NO2, a C 1-3 alkyl group, a C 1-3 haloalkyl group, a C 1-3 alkoxy group, a C 1-3 haloalkoxy group, and a C 1-3 hydroxyalkyl group; preferably, R3, R4, R5, and R d are each independently selected at each occurrence from H, F, Cl, Br, I, a hydroxyl group, a CN group, a NH2 group, a NO2 group, a methyl group, an ethyl group, an isopropyl group, a methoxy group, and an ethoxy group; and / or

[0057] n is independently selected at each occurrence from 0, 1, and 2.

[0058] In some embodiments, the CLM is selected from a structure represented by the following formula:

[0059] wherein:

[0060] ​X and Z are each independently at each occurrence selected from N and CH;

[0061] E is independently at each occurrence selected from O, C(O)NH, C(O)N(C 1-3 alkyl), NH, and N(C 1-3 alkyl);

[0062] W1and W2are each independently at each occurrence selected from CH2and C(O), and at least one of W1and W2is selected from C(O);

[0063] when W4and W5are double-bonded, W5and W6are single-bonded, W4is selected from C, W5is selected from N, CH, and C(C 1-3 alkyl), W6is selected from NH, N(C 1-3 alkyl), O, CH2, CH(C 1-3 alkyl), and C(C 1-3 alkyl)2; when W4and W5are single-bonded, W5and W6are double-bonded, W4, W5, and W6are each independently selected from N, CH, and C(C 1-3 alkyl); when W4, W5, and W6are each single-bonded, W4is selected from N, CH, and C(C 1-3 alkyl), W5and W6are each independently selected from C(O), NH, N(C 1-3 alkyl), O, CH2, CH(C 1-3 alkyl), and C(C 1-3 alkyl)2;

[0064] R 2a is independently at each occurrence selected from H, F, Cl, Br, C 1-3 alkyl, and C 1-3 haloalkyl;

[0065] R 3a , R 4a , R 3b , R 4b , R 3c , R 4c , R 5c , R 3d , R 4d , R 5d , R 3e , and R 4e are each independently at each occurrence selected from H, halogen, hydroxyl, cyano, amino, nitro, C 1-6 alkyl, C 1-6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, and C1-6 Hydroxyalkyl; A a A b A c A d A e A f and A h Each occurrence is independently selected from O, S, C(O), NR. d and C(R) d )2, R d Each occurrence is independently selected from H, F, Cl, Br, -OH, -CN, -NH2, -NO2, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups and C 1-6 Hydroxyalkyl;

[0066] B 1a and B 2a Each occurrence is independently selected from N, CH, and C(C) 1-3 alkyl);

[0067] Each time m11, m21 and m31 appear, they are independently 0, 1, 2, 3 or 4, and 1≤m11+m21+m31≤5;

[0068] Each occurrence of m41 and m51 is independently 0, 1, 2, 3, or 4, and 1 ≤ m41 + m51 ≤ 5; and

[0069] Each time m61 and m71 appear, they are independently 0, 1, 2, 3 or 4, and 1≤m61+m71≤5;

[0070] Preferably:

[0071] X is selected independently from N each time it appears; and / or

[0072] W1 is C (=O), W2 is CH2; W1 is CH2, W2 is C (=O); or W1 is (=O), W2 is C (=O); and / or

[0073] W4is selected from C, W5is selected from N, CH and C(CH3), and W6is selected from NH, N(CH3), O, CH2, CH(CH3) and C(CH3)2; when W4and W5are single bonds and W5and W6are double bonds, W4, W5and W6are each independently selected from N, CH and C(CH3); when W4, W5and W6are single bonds, W4is selected from N, CH and C(CH3), and W5and W6are each independently selected from C(O), NH, N(CH3), O, CH2, CH(CH3) and C(CH3)2; and / or

[0074] A a , A b , A c , A d , A e , A f , A h each occurrence is independently selected from CH2, C(C 1-3 alkyl)2, CH(C 1-3 alkyl), NH, N(C 1-3 alkyl), C(O) and -O-; preferably, each occurrence of A a , A b , A c , A d , A e , A f , A h each occurrence is independently selected from CH2, C(CH3)2, CH(CH3), NH, N(CH3) and C(O); preferably, each occurrence of A a , A b , A c , A d , A e , A f , A h each occurrence is independently selected as CH2; and / or

[0075] m11, m21and m31are each independently 0, 1, 2, or 3, and 1 < m11+m21+m31< 4, preferably, m11+m21+m31= 1, m11+m21+m31= 2, m11+m21+m31= 3 or m11+m21+m31= 4; preferably, each occurrence of m11is independently 0 or 1, each occurrence of m21is independently 1, and each occurrence of m31is independently 0 or 1; preferably, each occurrence of m11is independently 0, each occurrence of m21is independently 1, and each occurrence of m31is independently O; and / or

[0076] m41and m51are each independently 0, 1, 2, or 3 at each occurrence, and 1 < m41+ m51< 4; preferably, m41+ m51= 2, m41+ m51= 3 or m41+ m51= 4; preferably, m41and m51are each independently 2 at each occurrence; and / or

[0077] m61and m71are each independently 0, 1, 2, or 3 at each occurrence, and 1 < m61+ m71< 4; preferably, m61+ m71= 2, m61+ m71= 3 or m61+ m71= 4; and / or

[0078] R 2a is independently selected from the group consisting of H, F, Cl, Br, and C 1-3 alkyl; preferably, R 2a is independently -CH3or -CH2CH2F at each occurrence; and / or

[0079] B 1a and B 2a is each independently selected from the group consisting of N, CH, and C(CH3) at each occurrence; preferably, B 1a and B 2a is each independently selected from the group consisting of N and CH at each occurrence; and / or

[0080] R 3a , R 4a , R 3b , R 4b , R 3c , R 4c , R 5c , R 3d , R 4d , R 5d , R 3e and R 4e is each independently selected from the group consisting of H, F, Cl, Br, cyano, hydroxyl, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 haloalkyl, C 1-3 haloalkoxy, and C 1-3 hydroxyalkyl; preferably, R 3a , R 4a , R 3b , R 4b , R 3c , R 4c , R 5c , R 3d , R 4d , R 5d , R 3e and R 4eeach occurrence is independently selected from the group consisting of H, F, CI, Br, -CN, -OH, -CH3, -CH2CH3, -CH(CH3)2, -C(CH3)3, -OCH3, -OCH2CH3, and -OCH(CH3)2; preferably, R 3a , R 4a , R 3b , R 4b , R 3c , R 4c , R 5c , R 3d , R 4d , R 5d , R 3e and R 4e each occurrence is independently selected from the group consisting of H, F, CI, Br, - CN, -OH, -CH3, and -OCH3.

[0081] In some embodiments, the CLM is selected from the following structures:

[0082] Preferably, the CLM is selected from the following structures:

[0083] In some embodiments, L is -(B L ) q -;

[0084] B​​L each occurrence is independently selected from a single bond, CR L5 R L6 , C(R L5 )2, O, S, S(O), S(O)2, NR L5 , C(O)NR L5 , C(O), -CºC-, cycloalkylene, heterocyclylene, bridged cyclylene, spiro cyclylene, arylene, and heteroarylene, wherein the cycloalkylene, heterocyclylene, bridged cyclylene, spiro cyclylene, arylene, and heteroarylene are optionally substituted with 1, 2, 3, 4, 5, or 6 R L5 and / or R L6 groups; preferably, B L each occurrence is independently selected from a single bond, CR L5 R L6 , C(R L5 )2, O, S, S(O), S(O)2, NR L5 , C(O)NR L5 , C(O), -CºC-, 3-15 membered cycloalkylene, 3-15 membered heterocyclylene containing 1, 2, 3, 4, or 5 heteroatoms independently selected from N, O, and S, 5-15 membered bridged cyclylene containing 0, 1, 2, 3, 4, or 5 heteroatoms independently L5 and / or R L6 groups;

[0085] R L5 and R L6 each occurrence is independently selected from H, halogen, -OH, -NH2, -SH, -C(O)2H, -CN, -CF3, -CHF2, -CH2F, -NO2, -S(O)2, -SF5, -CºCH, C 1-8 alkyl, C 1-8 alkoxy, -S-C 1-8 alkyl, -NH-C 1-8 alkyl, -N(C 1-8 alkyl)2, C 3-11 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, 3-11 membered heterocyclyl, -O-C 3-8cycloalkyl, -0-3-11 membered heterocyclyl, -0-C 6-10 aryl, -0-5-10 membered heteroaryl, -S-C 3-8 cycloalkyl, -NH-C 3-8 cycloalkyl, -N(C 3-8 cycloalkyl)2, -N(C 3-8 cycloalkyl)(C 1-8 alkyl), -NH-3-11 membered heterocyclyl, -N(3-11 membered heterocyclyl)2, -N(3-11 membered heterocyclyl)(C 1-8 alkyl), -NH-C 6-10 aryl, -N(C 6-10 aryl)(C 1-8 alkyl), -NH-5-10 membered heteroaryl, -N(5-10 membered heteroaryl)(C 1-8 alkyl), -S(O)2P(O)(O-C 1-8 alkyl)(C 1-8 alkyl), -P(O)(O-C 1-8 alkyl)2, -C≡C-C 1-8 alkyl, -CH=CH-(C 1-8 alkyl), -C(C 1-8 alkyl)=CH-(C 1-8 alkyl), -C(C 1-8 alkyl)=C(C 1-8 alkyl)2, -Si(OH)3, -Si(C 1-8 alkyl)3, -Si(OH)(C 1-8 alkyl)2, -C(O)-C 1-8 alkyl, -C(O)-O-C 1-8 alkyl, -S(O)2NH-C 1-8 alkyl, -S(O)2N(C 1-8 alkyl)2, -S(O)NH-C 1-8 alkyl, -S(O)N(C 1-8 alkyl)2, -C(O)NH-C 1-8 alkyl, -C(O)N(C 1-8 alkyl)2, -N(C 1-8 alkyl)C(O)NH(C 1-8 alkyl), -N(C 1-8 alkyl)C(O)N(C 1-8 alkyl)2, -NHC(O)NH(C 1-8 alkyl), -NHC(O)N(C 1-8 alkyl)2, -NHC(O)NH2, -N(C 1-8 alkyl)S(O)2NH(C 1-8 alkyl), -N(C1-8 alkyl)S(O)2N(C 1-8 alkyl)2, -NHS(O)2NH(C 1-8 alkyl), -NHS(O)2N(C 1-8 alkyl)2, and -NHS(O)2NH2, said C 1-8 alkyl, C 1-8 alkoxy, C 3-11 cycloalkyl, 3-11 membered heterocyclyl, C 6-10 aryl, and 5-10 membered heteroaryl are each independently optionally substituted with one or more substituents selected from halogen, hydroxyl, cyano, amino, nitro, C 1-6 alkyl, C 1-6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, 3-8 membered cycloalkyl, 3-8 membered heterocyclyl, 3-8 membered halocycloalkyl, C 1-6 alkylamino, C 6-10 aryl, 5-10 membered heteroaryl, C 6-10 haloaryl, and 5-10 membered haloheteroaryl; and

[0086] q is an integer greater than or equal to 1 and less than or equal to 15;

[0087] Preferably:

[0088] B L are each independently selected for each occurrence from a single bond, CR L5 R L6 , C(R L5 )2, O, S, S(O), S(O)2, NR L5 , C(O)NR L5 , C(O), -CºC-, 3-12 membered cycloalkylene, 3-12 membered heterocyclylene containing 1, 2, 3, 4, or 5 heteroatoms independently selected from N, O, and S, 5-12 membered bridged cycloalkylene containing 0, 1, 2, 3, 4, or 5 heteroatoms independently L5 and / or R L6 groups; and / or

[0089] R L5 and R L6 each occurrence is independently selected from H, halogen, -C(O)2H, -CN, -CF3, -CHF2, -CH2F, -NO2, -S(O)2, C 1-6 alkyl, -O-C 1-6 alkyl, -C(O)-C 1-6 alkyl, C 3-6 cycloalkyl, and 3-6 membered heterocyclyl, wherein the C 1-6 alkyl, C 3-6 cycloalkyl, and 3-6 membered heterocyclyl are each independently optionally substituted with one or more substituents selected from halogen, hydroxyl, cyano, nitro, C 1-3 alkyl, C 1-3 heteroalkyl, C 2-3 alkenyl, C 2-3 alkynyl, C 1-3 alkoxy, C 1-3 haloalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 3-6 halocycloalkyl, 3-6 membered heteroalkyl, C 6-8 aryl, 5-8 membered heteroaryl, C 6-8 haloaryl, and 5-8 membered haloheteroaryl; and / or L5 and R L6 each occurrence is independently selected from H, halogen, C 1-6 alkyl, C 1-6 alkoxy, -C(O)-C 1-6 alkyl, -C(O)2H, -CN, -CF3, -CHF2, 3-6 cycloalkyl, and 3-6 membered heterocyclyl wherein the C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, and 3-6 membered heterocyclyl each independently optionally substituted with one or more substituents selected from halogen, hydroxyl, 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 hydroxyalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, 6-8 aryl, 5-8 membered heteroaryl, 3-6 membered halocycloalkyl, C 6-8 haloaryl, and 5-8 membered haloheteroaryl; and / or

[0090] q is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or 13; preferably, q is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; preferably, q is selected from 1, 2, 3, 4, 5, 6, 7 and 8;

[0091] Preferably:

[0092] B L Selected from one or more of the following structures: single bond, -O-, -S-, -S(O)-, -S(O)2-, -C≡C-, -CH2-, -C(O)-, -NH-, -N(CH3)-, -N(CH2CH3)-, -C(O)-NH-, -C(O)-N(CH3)-, and

[0093] Indicates the connection site.

[0094] In some implementations, the L is selected from the following structures:

[0095] Covalent bond, -C(O)-, -C 2-6 -, -C ethynyl 2-6 Ethyne-C 1-6 Alkylene -, -(CH2) j -、-OC 1-6 Alkylene, -O-(CH2) j -、-C(O)-NC 1-6 Alkyl group -, -C(O)-(CH2) j -、-NH-C 1-6 Alkylene-, -NH-(CH2) j -、-(CH2) j -NH-, -NH-(CH2) j -NH-、-NC 1-6 Alkyl-(CH2) j -C(O)-NC 1-6 Alkyl-(CH2) j -、-NH-(CH2) j -C(O)-NH-(CH2) j -、

[0096]

[0097] and

[0098] j, p, and y are 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;

[0099] Preferably, the L is selected from single bonds, -C(O)-, and -C. 2-6 -, -C ethynyl 2-6 Ethyne-C 1-6 Alkylene-, -CH2-, -(CH2)2-, -(CH2)3-, -(CH2)4-, -(CH2)5-, -(CH2)6-, -(CH2)7-, -(CH2)8-, -O -CH2-, -O-(CH2)3-, -O-(CH2)4-, -O-(CH2)5-, -O-(CH2)6-, -O-(CH2)7-, -O-(CH2)8-, -NH-C 1-6 Alkylene-, -NH-CH2-, -NH-(CH2)2-, -NH-(CH2)3-, -NH-(CH2)4-, -NH-(CH2)5-, -NH-(CH2)6-, -NH-(CH2)4-C(O), -NH-(CH2)7-, -NH-(CH2)8-, -NH-C 1-6 Alkylene-OC 1-6 Alkylene, -NC 1-6 Alkyl-(CH2) 0-6 -C(O)-NC 1-6 Alkyl-(CH2) 0- 6-、-NH-(CH2) 0-7 -O-(CH2) 0-7 -、-NC 1-6 Alkyl-(CH2) 0-6 -C(O)-NC 1-6 Alkyl-(CH2) 0-6 -, -C(O)-CH2-, -C(O)-(CH2)3-, -C(O)-(CH2)4-, -C(O)-(CH2)5-, -C(O)-(CH2)6-, -NH-C 1-6 Alkylene-, -NH-C 1-6 Alkylene-OC 1-6 Alkylene, -NC 1-4 Alkyl-(CH2) 0-4 -C(O)-NC 1-4 Alkyl-(CH2) 0-4-CH2-CH2-CH2-CH2-CH2-CH2-CH2-,-CH2-CH2-CH2-CH2-CH2-CH2-,- CH2-CH2-CH2-CH2-CH2-, -CH2-CH2-CH2-CH2-,-CH2-CH2- CH2-,-CH2-CH2-,-C(O)-,-C(S)-,-NH-C(O)-,-C(O)-NH-, -NH-C(S)-, -C(S)-NH-, -SO2-NH-, -NH-SO2-, -SO2-, -CH2-O-, -O-CH2-, -O-, -CH2-NH-, -NH-CH2-, -CH2-S-, -S-CH2-, -CH2-CH2-S-, -S-CH2-CH2-, -CH2-C(O)-, -C(O)-CH2-, -CH2-S(O)-, -S(O)-CH2-, -CH2-S(O)2-, -S(O)2-CH2-, -CH2-NH-C(O)-, -C(O)-NH-CH2-, -CH2-N(C(O)-NH)-, -N(C(O)-NH)-CH2-, -CH2-NH-S(O)-, -S(O)-NH-CH2-, -CH2-NH-S(O)2-, -S(O)2-NH-CH2-, -CH2-NH-C(O)-NH-, -NH-C(O)-NH-CH2-, -CH2-NH-C(O)-S(O)-, -S(O)-C(O)-NH-CH2-, -CH2-NH-C(O)-S(O)2-, -S(O)2-C(O)-NH-CH2-, -CH2-NH-S(O)-C(O)-, -C(O)-S(O)-NH-CH2-, -CH2-NH-S(O)-C(O)-NH-, -NH-C(O)-S(O)-NH-CH2-, -CH2-NH-S(O)-C(S)-, -C(S)-S(O)-NH-CH2-, -CH2-NH-S(O)-C(S)2-, -C(S)2-S(O)-NH-CH2-, -CH2-NH-S(O)-C(O)-S(O)-, -S(O)-C(O)-S(O)-NH-CH2-, -CH2-NH-S(O)-, -S(O)-NH-, -CH2-NH-S(O)2-, -S(O)2-NH-, -CH2-NH-C(O)-, -C(O)-NH-, -CH2-NH-C(O)-NH-, -NH-C(O)-NH-CH-, -CH2-NH-C(O)-S(O)-, -S(O)-C(O)-C(O)-NH-(CH2-CH2-O)3-CH2-CH2-NH-, -CH2-CH2-(O-CH2-CH2)-, -CH2-CH2-(O-CH2-CH2)2-, -CH2-CH2-(O-CH2-CH2)3-, -NH-CH2-CH2-(O-CH2-CH2)-, -NH-CH2-CH2-(O-CH2-CH2)2-, -NH-CH2-CH2-(O-CH2-CH2)3-, -C(O)-NH-CH2-CH2-(O-CH2-CH2)-, -C(O)-NH-CH2-CH2-(O-CH2-CH2)2-, -C(O)-NH-CH2-CH2-(O-CH2-CH2)3-, -CH2-CH2-(O-CH2-CH2)-NH-, -CH2-CH2-(O-CH2-CH2)2-NH-, -CH2-CH2-(O-CH2-CH2)3-NH-, -NH-CH2-CH2-(O-CH2-CH2)-NH-, -NH-CH2-CH2-(O-CH2-CH2)2-NH-, -NH-CH2-CH2-(O-CH2-CH2)3-NH-, -C(O)-NH-CH2-CH2-(O-CH2-CH2)-NH-, -C(O)-NH-CH2-CH2-(O-CH2-CH2)2-NH-, -C(O)-NH-CH2-CH2-(O-CH2-CH2)3-NH-,

[0100]

[0101]

[0102]

[0103]

[0103]

[0104]

[0104]

[0105]

[0105]

[0106]

[0106]

[0107]

[0107] Preferably, said L is selected from a covalent bond, -C(O)-, -CH2-, -(CH2)2-, -(CH2)3-, -(CH2)4-, -(CH2)5-, -(CH2)6-, -(CH2)7-, -O-C 1-6alkylene, -0-CH2-, -0-(CH2)3-, -0-(CH2)4-, -0-(CH2)5-, -0-(CH2)6-, -NH-(CH2) 0-7 -C(O)-, -NH-(CH2) 0-7 -O-(CH2) 0-7 -, -NC 1-4 alkyl-(CH2) 0-4 -C(O)-NC 1-4 alkyl-(CH2) 0-4 -, C 2-6 alkylene, -0-CH2-, -0-(CH2)3-, -0-(CH2)4-, -0-(CH2)5-, -0-(CH2)6-, -NH-(CH2) 1-6 alkylene, -0-CH2-, -0-(CH2)3-, -0-(CH2)4-, -0-(CH2)5-, -0-(CH2)6-, -NH-(CH2) 1-6 alkylene, -0-CH2-, -0-(CH2)3-, -0-(CH2)4-, -0-(CH2)5-, -0-(CH2)6-, -NH-(CH2) 1-6 alkylene, -0-CH2-, -0-(CH2)3-, -O-(CH2)4-, -0-(CH2)5-, -0-(CH2) 1-4 alkylene, -0-CH2-, -0-(CH2)3-, -NH-(CH2) 0-4 -C(O)-NC 1-4 alkyl-(CH2) 0-4 -, -NH-CH2-, -NH-(CH2)2-, -NH-(CH2)3-, -NH-(CH2)4-, -NH-(CH2)5-, -NH-(CH2)6-, -NH-(CH2)7-, -NH-(CH2)8-, -C(O)-NH-CH2-, -C(O)-NH-(CH2)2-, -C(O)-NH-(CH2)3-, -C(O)-NH-(CH2)4-, -C(O)-NH-(CH2)5-, -C(O)-NH-(CH2)6-, -C(O)-NH-(CH2)7-, -C(O)-NH-(CH2)8-, -CH2-NH-, -(CH2)2-NH-, -(CH2)3-NH-, -(CH2)4-NH-, -(CH2)5-NH-,

[0108] Preferably, said L is selected from a single bond, C 1-8 alkylene, C 1-8 alkylene, C 1-8 alkylene, C 1-8 alkylene, C

[0109] In some embodiments, the present application provides a compound of formula (I), said PTM is a binding moiety targeting signal transducer and activator of transcription 6 (STAT6);​​

[0110] In some embodiments, the PTM has the structure of Formula (I-1):

[0111] R L1 , R L2 , and R L4 are each independently a covalent bond or C 1-6 divalent straight chain or branched chain saturated or unsaturated hydrocarbon radical, 1, 2, or 3 methylene units of which are independently optionally replaced with -Cyx-, -O-, -C(O)-, -C(S)-, -C(R)2-, -CR(OR)-, -NR-, -S-, -S(O)-, -S(O)2-, or -CR=CR-; or -CR=CR-;

[0112] R L3 is a covalent bond or C 1-6 divalent straight chain or branched chain saturated or unsaturated hydrocarbon radical, 1, 2, or 3 methylene units of which are independently optionally replaced with -Cyx-, -O-, -C(O)-, -C(S)-, -C(R)2-, - L3 is absent;

[0113] Cyx is selected from phenylene, saturated or partially unsaturated 3-7 membered cycloalkylene, saturated or partially unsaturated 3-7 membered heterocyclylene containing 1, 2, 3, or 4 heteroatoms each independently selected from nitrogen, oxygen, and sulfur, and 5-8 membered monocyclic or bicyclic heteroarylene containing 1, 2, 3, or 4 heteroatoms each independently 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkyl, and C 1-6 haloalkoxy;

[0114] Cy1 is selected from 6-10 membered arylene, saturated or partially unsaturated 5-11 membered monocyclic or bicyclic cycloalkylene, saturated or partially unsaturated 5-11 membered monocyclic or bicyclic heterocyclylene containing 1, 2, 3, or 4 heteroa toms each independently selected from nitrogen, oxygen, and sulfur, and 5-14 membered monocyclic, bicyclic, or tricyclic heteroarylene containing 1, 2, 3, or 4

[0115] Cy2 is selected from saturated or partially unsaturated 3-8 membered cyclic hydrocarbon groups, saturated or partially unsaturated 3-8 membered heterocyclic hydrocarbon groups, 6-10 membered aryl hydrocarbon groups, and 5-8 membered heterocyclic hydrocarbon groups.

[0116] Cy3 is absent or selected from 6-10 aryl groups, 3-11 saturated or partially unsaturated monocyclic, fused, or spirocyclic bicyclic hydrocarbon groups, saturated or partially unsaturated 3-11 heterocyclic groups containing 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5-10 aryl or bicyclic monocyclic groups containing 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Cy4 is selected from covalently bonded, saturated or partially unsaturated 3-8 aryl or bicyclic subcyclic hydrocarbon groups, saturated or partially unsaturated 3-8 aryl or bicyclic subcyclic groups containing 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 6-10 aryl groups, and 5-10 aryl groups containing 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

[0117] R P1 R P2 R P3 and R X Each time it appears, it is independently selected from hydrogen, deuterium, halogen, -CN, -NO2, oxo group (=O), C. 1-6 Alkyl, C 1-6 Alkoxy, -N(R)2, -S(O)2R, -C(O)R, -C(O)-N(R)2, saturated or partially unsaturated 3-8 membered cyclic hydrocarbon groups, saturated or partially unsaturated 3-8 membered heterocyclic groups containing 1, 2, 3 or 4 heteroatoms each independently selected from nitrogen, oxygen and sulfur, 6-10 membered aryl groups, and 5-10 membered heteroaryl groups containing 1, 2, 3 or 4 heteroatoms each independently selected from nitrogen, oxygen and sulfur, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, 3-8 membered cyclic hydrocarbon, 3-8 membered heterocyclic, 6-10 membered aryl, and 5-10 membered heteroaryl are optionally selected from F, Cl, Br, I, hydroxyl, carboxyl, -CN, -NO2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 The substituted group is replaced by one or more substituents of a haloalkoxy group, a 3-8 membered cyclic hydrocarbon group, and a 3-8 membered heterocyclic group; preferably, R P1 R P2 R P3 and R X Each time it appears, it is independently selected from deuterium, halogen, -CN, -NO2, oxo group (=O), C. 1-6 Alkyl, C 1-6Alkoxy, -N(R)2, -S(O)2R, -C(O)R, -C(O)-N(R)2, saturated or partially unsaturated 3-8 membered cyclic hydrocarbon groups, saturated or partially unsaturated 3-8 membered heterocyclic groups containing 1, 2, 3 or 4 heteroatoms each independently selected from nitrogen, oxygen and sulfur, 6-10 membered aryl groups, and 5-10 membered heteroaryl groups containing 1, 2, 3 or 4 heteroatoms each independently selected from nitrogen, oxygen and sulfur, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, 3-8 membered cyclic hydrocarbon, 3-8 membered heterocyclic, 6-10 membered aryl, and 5-10 membered heteroaryl are optionally selected from F, Cl, Br, I, hydroxyl, carboxyl, -CN, -NO2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 It is substituted by one or more substituents of haloalkoxy, 3-8 membered cyclic hydrocarbon and 3-8 membered heterocyclic groups;

[0118] R A Selected from hydrogen, -CN, -NO2, -N(R)2, -OH, halogens, C 1-6 Alkyl, C 1-6 Alkoxy, -CyB1-CyB2, 6-10 aryl, saturated or partially unsaturated 3-8 membered cyclic hydrocarbon, saturated or partially unsaturated 3-10 membered monocyclic or bicyclic heterocyclic groups containing 1, 2, 3, or 4 heteroatoms each independently selected from nitrogen, oxygen, and sulfur, and 5-10 membered monocyclic or bicyclic heteroaryl groups containing 1, 2, 3, or 4 heteroatoms each independently selected from nitrogen, oxygen, and sulfur, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, aryl, cyclic, heterocyclic, and heteroaryl groups are optionally selected from oxo (=O), F, Cl, Br, I, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl and C 1-6 The alkoxy group is substituted by one or more substituents of the haloalkoxy group;

[0119] CyB1 is selected from 3-10 saturated or partially unsaturated monocyclic or bicyclic alkylene groups, 3-10 saturated or partially unsaturated monocyclic or bicyclic heterocyclic alkylene groups containing 1, 2, 3, or 4 heteroatoms each independently selected from nitrogen, oxygen, and sulfur, 5-8 cyclic arylene groups, 9-10 cyclic arylene groups, and 5-8 cyclic heterocyclic arylene groups and 9-10 cyclic heterocyclic arylene groups containing 1, 2, 3, or 4 heteroatoms each independently selected from nitrogen, oxygen, and sulfur, wherein the alkylene group, heterocyclic group, arylene group, and heterocyclic arylene group are optionally selected from F, Cl, Br, I, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C1-6 haloalkyl and C 1-6 haloalkyl and C

[0120] CyB2is selected from 3-10 membered saturated or partially unsaturated monocyclic or bicyclic cycloalkyl, 3-10 membered saturated or partially unsaturated monocyclic or bicyclic heterocyclyl containing 1, 2, 3, or 4 heteroatoms each independently selected from nitrogen, oxygen, and sulfur, 6-10 membered monocyclic or bicyclic aryl, 5-10 membered heteroaryl containing 1, 2, 3, or 4 heteroatoms each independently selected 1-6 haloalkyl and C 1-6 haloalkyl and C 1-6 haloalkyl and C 1-6 haloalkyl and C

[0121] R each occurrence is independently hydrogen, halogen, hydroxyl, C 1-6 haloalkyl and C 2-6 haloalkyl and C 2-6 haloalkyl and C 1-6 haloalkyl and C 1-6 haloalkyl and C 2-6 haloalkyl and C 2-6 haloalkyl and C 1-6 haloalkyl and C 1-6 haloalkyl and C 1-6 haloalkyl and C 1-6 haloalkyl and C 1-6 haloalkyl and C 1-6 haloalkyl and C

[0122] n1, n2, n3, and n4 each occurrence is independently 0, 1, 2, 3, 4, 5, or 6;

[0123] In some embodiments,

[0124] R L1 , R L2 , and R L4 are each independently a covalent bond or C 1-6 bivalent straight or branched chain saturated or unsaturated hydrocarbon group (preferably C 1-6alkylene), 1, 2, or 3 methylene units of the hydrocarbyl group are independently optionally replaced with -0-, -C(O)-, -C(S)-, -C(R)2-, -NR-, or -S(0)2-NR-; preferably, R L1 L2 L4 each independently is a covalent bond, -C(R)2-, -0-, -NR-, -C(O)-C(R)2-, -0-C(R)2-, -0-C(O)-, -S(0)2-NR-, -C(O)-, -C(S)-NR-,

[0125] preferably, R L1 is a covalent bond or -C(R)2-; preferably, R L1 is a single bond;

[0126] preferably, R L2 is a covalent bond, -C(R)2-, -0-, -NR-, -C(O)-C(R)2-, -0-C(R)2-, or -0-C(O)-; preferably, R L2 is a single bond, -CH2-, -0-, -NH-, -N(CH3)-, -C(O)-CH2-, -C(O)-CH(CH3)-, -C(O)-C(CH3)2-, -0-CH2-, -0-CH(CH3)-, -0-C(CH3)2-, or -0-C(O)-; preferably, R L2 is a single bond;

[0127] preferably, R L4 is a covalent bond, -C(R)2-, -NR-, -S(0)2N(R)-, -C(S)-NR-, -C(O)-, or -C(O)-NR-; preferably, R L4 is a covalent bond, -C(R)2-, -NR-, -S(O)2N(R)-, -C(S)-NR-, -C(O)-NR-; preferably, R L4 is a single bond, -CH2-, -NH-, -N(CH3)-, -S(O)2NH-, -S(O)2N(CH3)-, -C(S)-NH-, -C(S)-N(CH3)-, -C(O)-, -C(O)NH-, or -C(O)N(CH3)-;

[0128] preferably, R L4 ​​​is a single bond, -CH2-, -NH-, -N(CH3)-, -S(O)2NH-, -S(O)2N(CH3)-, -C(S)-NH-, -C(S)-N(CH3)-, -C(O)NH-, or -C(O)N(CH3)-;

[0129] and / or

[0130] R L3 is a covalent bond or C 1-6 bivalent straight-chain or branched saturated or unsaturated hydrocarbyl (preferably C 1-6 alkylene) having 1, 2 or 3 methylene units independently optionally replaced by -Cyx-, -O-, -C(O)-, -C(S)-, -C(R)2-, -NR- or -S(O)2-, or absent; preferably R L3 is a covalent bond, -C(R)2-, -C(O)-, -C(O)-C(R)2-, -S(O)2-C(R)2-, -C(O)-NR-C(R)2-, -NR-C(O)-C(R)2-, or absent; preferably R L3 is selected from a single bond, -CH2-, -C(O)-, -C(O)CH2-, -C(O)(CH2)2-, -C(O)(CH2)3-, -C(O)CH(CH3)-, -C(O)CH(CH3)CH2-, -C(O)C(CH3)2CH2-, -C(O)CH2C(O)-, -C(O)NHCH2-, -C(O)NH(CH2)2-, -NHC(O)CH2-, -NHC(O)(CH2)2-, -S(O)2CH(CH3)-, or absent; preferably R L3 is -C(O)(CH2)2-; and / or

[0131] Cyx is selected from phenylene, saturated or partially unsaturated 3-6 membered cyclohydrocarbylene, saturated or partially unsaturated 3-6 membered heterocyclylene containing 1, 2, or 3 heteroatoms each independently selected from nitrogen, oxygen, and sulfur, and 5-8 membered monocyclic or bicyclic heteroarylene containing 1, 2, or 3 heteroatoms each independently selected from nitrogen, 1-3 alkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy, C 1-3 haloalkyl, and C 1-3 haloalkoxy; preferably Cyx is saturated or partially unsaturated 3-5 membered cyclohydrocarbylene optionally substituted with one or more substituents selected from F, Cl, Br, I, cyano, C 1-3 alkyl, C 1-3Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkyl and C 1-3 One or more substituents of the haloalkoxy group are substituted; and / or

[0132] Cy1 is selected from 6-10 membered monocyclic, fused, or spirocyclic bicyclic aryl groups; saturated or partially unsaturated 5-11 membered monocyclic, fused, or spirocyclic bicyclic cyclic hydrocarbon groups; saturated or partially unsaturated monocyclic, fused, or spirocyclic bicyclic 5-11 membered heterocyclic groups containing 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and 5-14 membered heteroaryl groups containing 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. Preferably, Cy1 is selected from... Bicyclic aryl groups with 6-10 member monocyclic or fused rings; bicyclic cyclic hydrocarbon groups with 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, either saturated or partially unsaturated; bicyclic 6-10 member heterocyclic groups with 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, either saturated or partially unsaturated; and monocyclic, bicyclic, or tricyclic heteroatoms with 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. The 5-10 membered heteroaryl group; preferably, Cy1 is phenyl, naphthyl, a 5-10 membered heteroaryl group containing 1, 2, 3 or 4 heteroatoms each independently selected from nitrogen, oxygen and sulfur, or a saturated or partially unsaturated 6-10 membered heterocyclic group containing 1, 2, 3 or 4 heteroatoms each independently selected from nitrogen, oxygen and sulfur, wherein the 5-10 membered heteroaryl group or the 6-10 membered heterocyclic group is a monocyclic, fused, or spirocyclic bicyclic group; preferably, Cy1 is selected from groups containing 1, 2, 3 or 4 heteroatoms each independently selected from nitrogen, oxygen and sulfur. The 8-10 membered bicyclic heteroaryl group selected from heteroatoms of nitrogen, oxygen, and sulfur, and the 5-11 membered monocyclic, fused, or spirocyclic bicyclic group containing 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, either saturated or partially unsaturated; preferably, Cy1 is selected from 9 membered bicyclic heteroaryl groups containing 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and the 9 membered fused or spirocyclic bicyclic group containing 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and / or

[0133] Cy2 is selected from phenylene, saturated or partially unsaturated 3-8 membered heterocyclic hydrocarbon groups, saturated or partially unsaturated 3-8 membered heterocyclic hydrocarbon groups containing 1, 2, 3 or 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, and 5-6 membered heteroaryl groups containing 1, 2, 3 or 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; preferably, Cy2 is selected from phenylene, saturated or partially unsaturated 5-7 membered heterocyclic hydrocarbon groups, saturated or partially unsaturated 3-8 membered heterocyclic hydrocarbon groups containing 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur. And / or partially unsaturated 5-7 membered heterocyclic groups, and 5-6 membered heterocyclic groups containing 1, 2, 3 or 4 heteroatoms each independently selected from nitrogen, oxygen and sulfur; preferably, Cy2 is selected from phenylene, saturated or partially unsaturated 6 membered heterocyclic groups, or saturated or partially unsaturated 6 membered heterocyclic groups containing 1, 2 or 3 heteroatoms each independently selected from nitrogen, oxygen and sulfur, and 5 or 6 membered heterocyclic groups containing 1, 2, 3 or 4 heteroatoms each independently selected from nitrogen, oxygen and sulfur; and / or

[0134] Cy3 is absent or selected from 6-10 aryl groups, saturated or partially unsaturated monocyclic or bicyclic (fused or spirocyclic) 3-8 membered cyclic hydrocarbon groups, saturated or partially unsaturated 3-10 membered heterocyclic groups containing 1, 2, 3 or 4 heteroatoms each independently selected from N, O and S, and 5-8 membered monocyclic or 9-10 membered bicyclic heteroaryl groups containing 1, 2, 3 or 4 heteroatoms each independently selected from N, O and S; preferably, Cy3 is absent or selected from phenyl or naphthalene. 3-6 membered ring hydrocarbon groups of monocyclic or bicyclic (fused or spirocyclic) nature, saturated or partially unsaturated 4-6 membered monocyclic heterocyclic groups containing 1, 2, 3 or 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, 8-10 membered bicyclic heterocyclic groups containing 1, 2, 3 or 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, and 5-6 membered monocyclic or 9 membered ring hydrocarbon groups containing 1, 2, 3 or 4 heteroatoms independently selected from nitrogen, oxygen and sulfur. -10-membered bicyclic heteroaryl; preferably, Cy3 is absent or selected from saturated or partially unsaturated 3-6-membered cyclic hydrocarbon groups, saturated or partially unsaturated 4-6-membered monocyclic or 8-9-membered bicyclic heterocyclic groups containing 1, 2, 3 or 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, and 5-6-membered monocyclic or 9-10-membered bicyclic heteroaryl groups containing 1, 2, 3 or 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; preferably, Cy3 is absent or selected from 3-membered, 4-membered, and 5-membered... Or a 6-membered cycloalkyl group, a 4-, 5-, or 6-membered monocyclic heterocyclic group containing 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a partially unsaturated 8- or 9-membered bicyclic heterocyclic group containing 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5- or 6-membered monocyclic heteroaryl group containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 9-membered bicyclic heteroaryl group containing 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and / or

[0135] Cy4 is selected from covalent bonds,

[0136] Q1 is selected independently from CR each time it appears. x And N; preferably, Q1 is independently selected from CH and N each time it appears;

[0137] Q2 is selected independently from C(R) each time it appears. x )2 and NR x Preferably, Q2 is independently selected from CH2 and NH each time it appears; and / or

[0138] n1, n2, n3, and n4 are each independently 1, 2, 3, or 4; and / or

[0139] R P1 R P2 R P3 and R X Each time it appears, it is independently selected from hydrogen, deuterium, halogen, -CN, -NO2, oxo group (=O), C. 1-3 Alkyl, C 1-3 Alkoxy, -N(R)2, -S(O)2R, -C(O)R, -C(O)-N(R)2, saturated or partially unsaturated 3-6 membered cyclic hydrocarbon groups, saturated or partially unsaturated 3-6 membered heterocyclic groups containing 1, 2, 3 or 4 heteroatoms each independently selected from nitrogen, oxygen and sulfur, 6-8 membered aryl and 5-8 membered heteroaryl, wherein the C 1-3 Alkyl, C 1-3 Alkoxy, 3-6 membered cyclic hydrocarbon, 3-6 membered heterocyclic, 6-8 membered aryl, or 5-8 membered heteroaryl are optionally selected from F, Cl, Br, I, hydroxyl, carboxyl, -CN, -NO2, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 The substituted group is replaced by one or more substituents of a haloalkoxy group, a 3-6 membered cyclic hydrocarbon group, and a 3-6 membered heterocyclic group; preferably, R P1 R P2 R P3 and R X Each time it appears, it is independently selected from H, F, Cl, Br, I, -CN, oxo group (=O), -C(O)H, C 1-3 Alkyl, C 1-3 Alkoxy group, -C(O)-C 1-3 Alkyl groups and -S(O)2-C 1-3 Alkyl, the C 1-3 Alkyl and C 1-3The alkoxy group is optionally substituted by one or more substituents selected from F, Cl, Br, I, hydroxyl, carboxyl, -CN, -NO2 and 3-6 membered cyclic hydrocarbon groups;

[0140] Preferably, R P1 Each time it appears, it is independently selected from H, F, Cl, Br, I, oxo group (=O), C. 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, -C 1-3 Alkylene-3-6-membered cycloalkylene and phenylene-NH-C 1-3 Alkyl; preferably, R P1 Each time it appears, it is independently selected from F, Cl, Br, I, oxo group (=O), C. 1-3 Alkyl and -C 1-3 alkylene-3-6-membered cycloalkyl; and / or

[0141] R P2 Each time it appears, it is independently selected from H, F, Cl, Br, I, oxo group (=O), C. 1-3 Alkyl, -S(O)2-C 1-3 Alkyl groups and -C(O)-C 1-3 Alkyl, the C 1-3 Alkyl groups are optionally surrounded by F, Cl, Br, I, hydroxyl, carboxyl, oxo (=O) and C. 1-3 One or more alkyl groups are substituted; preferably, R P2 Each time it appears, it is independently selected from F, Cl, Br, I, oxo group (=O), C. 1-3 Alkyl, -S(O)2-C 1-3 Alkyl, -C(O)-C 1-3 Alkyl, -C(O)-C 1-3 Hydroxyalkyl and -C(O)-C 1-3 alkylene-carboxyl group; preferably, R P2 Each occurrence is independently CH3; and / or

[0142] R P3 Each occurrence is independently selected from H, F, Cl, Br, I, -CN, -C(O)H, C 1-3 Alkyl and C 1-3 Alkoxy; preferably, R P3 Each occurrence is independently selected from F, Cl, Br, I, -CN, -C(O)H, C 1-3 Alkyl and C 1-3 Alkoxy; preferably, R P3 Each occurrence is independently selected from F and CF3; and / or

[0143] R XEach occurrence is independently selected from H, F, Cl, Br, I, -CN, C. 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkyl and C 1-3 Halogenated alkoxy groups; preferably, R X Each occurrence is independently selected from H, F, Cl, Br, I, C. 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkyl and C 1-3 Haloalkoxy; or, R X Each occurrence is independently selected from F, Cl, -CN, -CH3, -OCH3, and -OCF3; and / or

[0144] R A Selected from hydrogen, -CN, -NO2, -NH2, -N(C) 1-3 Alkyl)2, -N(C 1-3 Alkyl groups (H, -OH), halogens, C 1-3 Alkyl, C 1-3 Alkoxy, -CyB1-CyB2, 6-8 aryl, saturated or partially unsaturated 3-6 membered cyclic hydrocarbon, saturated or partially unsaturated 3-6 membered monocyclic or 8-10 membered bicyclic heterocyclic groups containing 1, 2, 3, or 4 heteroatoms each independently selected from nitrogen, oxygen, and sulfur, and 5-6 membered monocyclic or 8-10 membered bicyclic heteroaryl groups containing 1, 2, 3, or 4 heteroatoms each independently selected from nitrogen, oxygen, and sulfur, wherein the C 1-3 Alkyl, C 1-3 Alkoxy, aryl, cyclic, heterocyclic, and heteroaryl groups are optionally selected from oxo (=O), F, Cl, Br, I, and C. 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkyl and C 1-3 The alkoxy group is substituted with one or more substituents of the haloalkoxy group; preferably, R A Selected from hydrogen, -CN, -NO2, -NH2, -N(CH3)2, -N(CH3)H, -OH, halogens, C 1-3 Alkyl, C 1-3Alkoxy, -CyB1-CyB2, phenylene, saturated or partially unsaturated 3, 4, 5, or 6-membered monocyclic cycloalkyl group, saturated or partially unsaturated 3, 4, 5, or 6-membered monocyclic heterocyclic group containing 1, 2, or 3 heteroatoms each independently selected from nitrogen, oxygen, and sulfur, saturated or partially unsaturated 8, 9, or 10-membered bicyclic heterocyclic group containing 1, 2, or 3 heteroatoms each independently selected from nitrogen, oxygen, and sulfur, 5 or 6-membered monocyclic heteroaryl group containing 1, 2, or 3 heteroatoms each independently selected from nitrogen, oxygen, and sulfur, and 8, 9, or 10-membered bicyclic heteroaryl group containing 1, 2, or 3 heteroatoms each independently selected from nitrogen, oxygen, and sulfur, wherein C 1- 3-alkyl, C 1-3 Alkoxy, aryl, cyclic, heterocyclic, and heteroaryl groups are optionally selected from oxo (=O), F, Cl, Br, I, and C. 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkyl and C 1-3 The alkoxy group is substituted by one or more substituents of the haloalkoxy group;

[0145] CyB1 is selected from 3-8 membered saturated or partially unsaturated monocyclic heterocyclic groups containing 1, 2, 3, or 4 heteroatoms each independently selected from nitrogen, oxygen, and sulfur, wherein the heterocyclic group is optionally selected from F, Cl, Br, I, cyano, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkyl and C 1-3 One or more substituents of the haloalkoxy group are substituted;

[0146] CyB2 is selected from 3-8 membered saturated or partially unsaturated monocyclic cyclic hydrocarbon groups and 5-8 membered monocyclic heteroaryl groups containing 1, 2, 3, or 4 heteroatoms each independently selected from nitrogen, oxygen, and sulfur, wherein the cyclic hydrocarbon group and heteroaryl group are optionally selected from F, Cl, Br, I, cyano, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkyl and C 1-3 One or more substituents of the haloalkoxy group are substituted; and / or

[0147] Each time R appears, it is independently hydrogen, halogen, hydroxyl, or C. 1-3 Alkyl, C 1-3 Alkoxy, saturated or partially unsaturated 3-8 membered cyclic hydrocarbon group, saturated or partially unsaturated 3-8 membered heterocyclic group, 6-8 membered aryl or 5-8 membered heteroaryl, wherein C 1-3 Alkyl, C 1-3 Alkoxy, cyclic hydrocarbon, heterocyclic, aryl, or heteroaryl groups are optionally selected from F, Cl, Br, I, cyano, hydroxyl, oxo (=O), C 1-3 Alkyl, C1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 1-3 Halogenated alkyl and C 1-3 One or more substituents of the haloalkoxy group are substituted; preferably, R is independently hydrogen, F, Cl, Br, I, hydroxyl, C each time it appears. 1-3 Alkyl, C 1-3 Alkoxy, saturated or partially unsaturated 3-6 membered cyclic hydrocarbon group, saturated or partially unsaturated 3-6 membered heterocyclic group, phenyl or 5-6 membered heteroaryl group, wherein C 1-3 Alkyl, C 1-3 Alkoxy, cyclic hydrocarbon, heterocyclic, phenyl, or heteroaryl groups are optionally selected from F, Cl, Br, I, cyano, hydroxyl, oxo (=O), C 1-3 Alkyl, C 1-3 Alkoxy and C 1-3 One or more substituents of the hydroxyalkyl group are substituted; preferably, R is hydrogen each time it appears.

[0148] In some implementations, Cy1 is selected from optional alternatives. Provided that it is chemically permissible, each occurrence of M1 and M2 can be independently selected from C, N, and NR. X O, S, CR X and C(R) X )2; Preferably, Cy1 is selected from optionally substituted... Preferably, Cy1 is selected from optionally substituted... in Indicates with R L1 The connection site, Indicates with R L4 The connection sites, and Indicates with R L2 Connection sites; and / or

[0149] n1 is 0, 1, 2, 3, or 4; and / or

[0150] Cy2 is selected from the optional substitutions. and / or

[0151] n2 is 0, 1, 2, 3, or 4;

[0152] and / or

[0153] Cy3 is absent or is selected from optional substitutions. and / or

[0154] n3 is 0, 1, 2, 3, or 4; and / or

[0155] Cy4 is selected from covalently bonded, optionally substituted and / or

[0156] n4 is 0, 1, 2, 3, or 4; and / or

[0157] R A Selected from hydrogen, -CN, C 1-3 Alkyl, -NH2, -N(CH3)2, -N(CH3)H, C 1-3 Alkoxy, C 1-3 Halogenated alkyl, Preferably, R A Selected from H, -N(CH3)2, and -CH3.

[0158] In some embodiments, the compound is selected from compounds represented by the following formula:

[0159] Among them, L, CLM, R L1 R L2 R L3 R L4 Cy2, Cy3, Cy4, R A R X R P1 R P2 R P3 The definitions of n1, n2, n3, and n4 are the same as those defined above;

[0160] M1 and M2 are each independently selected from N and NR respectively. X O, S, CR X and C(R) X )2, provided that it is chemically permissible; preferably, M1 and M2 are each independently selected from N, NH, O, S, CH, and CH2 each time they appear, provided that it is chemically permissible.

[0161] In some embodiments, the compound is selected from compounds represented by the following formula:

[0162] Among them, L, CLM, R L1 R L2 R L3 R L4Cy2, Cy3, Cy4, R A R X R P1 R P2 R P3 The definitions of n1, n2, n3 and n4 are the same as those defined above.

[0163] In some embodiments, the compound is selected from compounds represented by the following formula:

[0164] Among them, L, CLM, R L1 R L2 R L3 R L4 Cy3, Cy4, R A R X R P1 R P2 R P3 The definitions of n1, n2, n3, and n4 are the same as those defined above;

[0165] Preferably, R A Selected from H, F, Cl, Br, I, C 1-3 Alkyl, C 1-3 Alkoxy, -CN, -NH2, -N(C) 1-3 alkyl)2、-NH(C 1-3 Alkyl), -NO2, 3-6 membered monocyclic cycloalkyl group, 3-6 membered monocyclic heterocyclic group, 5-6 membered monocyclic heteroaryl group, 8-10 membered bicyclic heterocyclic group, 8-10 membered bicyclic heteroaryl group, 3-6 membered monocyclic heterocyclic group-3-6 membered monocyclic cycloalkyl group and 3-6 membered monocyclic heterocyclic group-5-6 membered monocyclic heteroaryl group, wherein the C 1-3 Alkyl, C 1-3 Alkoxy, 3-6 membered monocyclic cycloalkyl group, 3-6 membered monocyclic heterocyclic group, 5-6 membered monocyclic heteroaryl group, 8-10 membered bicyclic heterocyclic group, and 8-10 membered bicyclic heteroaryl group are optionally selected from F, Cl, Br, I, cyano, hydroxyl, oxo (=O), C 1-3 Alkyl and C 1-3 The alkoxy group is substituted by one or more substituents;

[0166] Preferably, R A Selected from H, -CN, C 1-3 Alkyl, -NH2, -N(CH3)2, -N(CH3)H, C 1-3 Alkoxy, C 1-3 Halogenated alkyl,

[0167] Preferably, -R L4 -R A Selected from hydrogen, methyl, -C(O)NHCH3, -C(O)N(CH3)CH2CH2CH3, -C(O)N(CH3)2, -C(O)N(CH3)-CH2CF3, -C(O)N(CH3)-cyclopropyl, -C(O)N(CH3)-cyclobutyl,

[0168] In some implementations, the PTM is selected from the following structures:

[0169] In some embodiments, the compound has the structure shown in formula (I-AA):

[0170] Or its isomers, isotopic derivatives, polymorphs, prodrugs, or pharmaceutically acceptable salts or solvates thereof, wherein:

[0171] R L1 It is a single bond or -C(R)2-;

[0172] R L2 For single bonds, -C(R)2-, -O-, -NR-, -C(O)-C(R)2-, -OC(R)2- or -OC(O)-;

[0173] R L3 For single bonds, -C(R)2-, -C(O)-, -C(O)-[C(R)2]n RL3 -、-C(O)-[C(R)2]n RL3 -C(O)-、-S(O)2-[C(R)2]n RL3 -、-C(O)-NR-[C(R)2]n RL3 -or-NR-C(O)-[C(R)2]n RL3 - or does not exist;

[0174] n RL3 It can be 0, 1, 2, 3, or 4;

[0175] R L4 It can be a single bond, -C(R)2-, -NR-, -S(O)2-NR-, -C(S)-NR-, -C(O)-, or -C(O)-NR-;

[0176] R P1 Each occurrence is independently selected from H, F, Cl, Br, I, C. 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups and C 1-3 Alkylene-3-6 membered cycloalkyl;

[0177] R P2 Each time it appears, it is independently selected from H, F, Cl, Br, I, oxo group (=O), C. 1-3 Alkyl, -S(O)2-C 1-3 Alkyl groups and -C(O)-C 1-3 Alkyl, the C 1-3 Alkyl groups are optionally selected from F, Cl, Br, I, hydroxyl, carboxyl, oxo (=O) and C. 1-3 Alkyl groups are substituted with one or more substituents; preferably R P2 Each time it appears, it is independently selected from F, Cl, Br, I, oxo group (=O), C. 1-3 Alkyl, -S(O)2-C 1-3 Alkyl groups and -C(O)-C 1-3 Alkyl, the C 1-3 Alkyl groups are optionally selected from F, Cl, Br, I, hydroxyl, carboxyl, oxo (=O) and C. 1-3 The alkyl group is substituted by one or more substituents;

[0178] R P3 Each occurrence is independently selected from H, F, Cl, Br, I, -CN, -C(O)H, C 1-3 Alkyl and C 1-3 Alkyl group; preferably R P3 Each occurrence is independently selected from F, Cl, Br, I, -CN, -C(O)H, C 1-3 Alkyl and C 1-3 Alkoxy;

[0179] R X Each time it appears, it is independently selected from H, F, Cl, Br, I, cyano, C. 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkyl and C1-3 Halogenated alkoxy groups; preferably R X Each time it appears, it is independently selected from F, Cl, Br, I, cyano, and C. 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkyl and C 1-3 Halogenated alkoxy groups;

[0180] R A Selected from H, F, Cl, Br, I, C 1-3 Alkyl, C 1-3 Alkoxy, -CN, -NO2, -NH2, -N(CH3)2, -NH(CH3), 3-6 membered monocyclic cycloalkyl group, 3-6 membered monocyclic heterocyclic group, 5-6 membered monocyclic heteroaryl group, 8-10 membered bicyclic heterocyclic group, 8-10 membered bicyclic heteroaryl group, 3-6 membered monocyclic heterocyclic group-3-6 membered monocyclic cycloalkyl group and 3-6 membered monocyclic heterocyclic group-5-6 membered monocyclic heteroaryl group, wherein the C 1-3 Alkyl, C 1-3 Alkoxy, -NH2, 3-6 membered monocyclic cycloalkyl group, 3-6 membered monocyclic heterocyclic group, 5-6 membered monocyclic heteroaryl group, 8-10 membered bicyclic heterocyclic group, and 8-10 membered bicyclic heteroaryl group are optionally selected from F, Cl, Br, I, cyano, hydroxyl, oxo (=O), C 1-3 Alkyl and C 1-3 The alkoxy group is substituted by one or more substituents;

[0181] Each time R appears, it is independently H, F, Cl, Br, I, hydroxyl group, or C. 1-3 Alkyl, C 1-3 Alkoxy, saturated or partially unsaturated 3-6 membered cyclic hydrocarbon group, saturated or partially unsaturated 3-6 membered heterocyclic group, phenyl or 5-6 membered heteroaryl group, wherein C 1-3 Alkyl, C 1-3 Alkoxy, cyclic hydrocarbon, heterocyclic, phenyl, or heteroaryl groups are optionally selected from F, Cl, Br, I, cyano, hydroxyl, oxo (=O), C 1-3 Alkyl, C 1-3 Alkoxy and C 1-3 One or more substituents of the hydroxyalkyl group are used for substitution;

[0182] n2, n3, and n4 are each independently 0, 1, 2, or 3;

[0183] Cy3 does not exist or is selected from R by choice. P3 Replacement

[0184] Cy4 is selected from single bonds, arbitrarily assigned to R X Replacement

[0185] In formula (Ι-AA), Indicates a single or double bond; L is the chemical linker; preferably, L is -(B L ) q -;

[0186] B L Each occurrence is independently selected from covalent bonds and CR L5 R L6 C(R) L5 )2, O, S, S(O), S(O)2, NR L5 C(O)NR L5 C(O), 3-12 membered cycloalkylene groups, 3-12 membered heterocyclic groups containing 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S, 5-12 membered bridged heterocyclic groups, 5-12 membered bridged heterocyclic groups containing 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S, 5-12 membered spirocyclic groups, 5-12 membered spirocyclic groups containing 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S, 6- A 12-membered arylene and a 5-12-membered heteroarylene containing 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S, wherein the 3-12-membered cycloalkylene, 3-12-membered heterocyclic, 5-12-membered bridged cycloalkyl, 5-12-membered bridged heterocyclic, 5-12-membered spirocyclic, 5-12-membered spirocyclic, 6-12-membered arylene, and 5-12-membered heteroarylene are optionally represented by 1, 2, 3, or 4 heteroatoms independently selected from R. L5 and R L6 Group substitution; preferably, B L Each occurrence is independently selected from covalent bonds, C(R) bonds. L5 )2, O, S, S(O), S(O)2, NR L5 C(O)NR L5 C(O), 3-12 membered cycloalkylene groups, 3-12 membered heterocyclic groups containing 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S, 5-12 membered bridged heterocyclic groups, 5-12 membered bridged heterocyclic groups containing 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S, 5-12 membered spirocyclic groups, 5-12 membered spirocyclic groups containing 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S, The 6-12-membered arylene and the 5-12-membered heteroarylene containing 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S, wherein the 3-12-membered cycloalkylene, 3-12-membered heterocyclic, 5-12-membered bridged cycloalkylene, 5-12-membered bridged heterocyclic, 5-12-membered spirocyclic, 5-12-membered spirocyclic, 6-12-membered arylene, and 5-12-membered heteroarylene are optionally surrounded by 1, 2, 3, or 4 R atoms. L6replace;

[0187] R L5 and R L6 Each time it appears, it is independently selected from H, halogen, hydroxyl, cyano, amino, nitro, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -C(O)-C 1-6 Alkyl, C 3-6 cycloalkyl and 3-6 membered heterocyclic groups, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-6 The cycloalkyl group and the 3-6 membered heterocyclic group are each independently and optionally selected from C. 1-3 Alkyl, C 1-3 Heteroalkyl, C 1-3 Alkoxy, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 3-6 Halogenated cycloalkyl, 3-6-membered halogenated heteroalkyl, C 6-8 Aryl, 5-8 quinone heteroaryl, C 6-8 The aryl group is substituted by one or more substituents in the 5-8 membered haloaryl group;

[0188] q is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;

[0189] The CLM is selected from the structure shown in the following formula:

[0190] in,

[0191] Each time X appears, it is independently selected from N and CR. d Preferably, X is independently selected from N and CH each time it appears;

[0192] Each time E appears, it is independently selected from O, C(O)NH, C(O)N(C) 1-3 Alkyl), NH and N(C) 1-3 alkyl);

[0193] When W1 and W2 appear, they are each independently selected from CH2 and C(O), and at least one of W1 and W2 is C(O);

[0194] R 2a Each occurrence is independently selected from H, F, Cl, Br, C. 1-3 Alkyl and C 1-3 Halogenated alkyl groups;

[0195] R 3a R 4a R 3b R 4b R 3c R 4c R 5c R 3d R 4d and R 5d Each time it appears, it is independently selected from H, halogen, hydroxyl, cyano, amino, nitro, C. 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups and C 1-6 Hydroxyalkyl;

[0196] A a A b A c A d and A e Each occurrence is independently selected from O, S, C(O), NR. d and C(R) d )2;

[0197] R d Each occurrence is independently selected from H, F, Cl, Br, -OH, -CN, -NH2, -NO2, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups and C 1-6 Hydroxyalkyl;

[0198] B 1a and B 2a Each occurrence is independently selected from N, CH, and C(C) 1-3 alkyl);

[0199] Each time m11, m21 and m31 appear, they are independently 0, 1, 2, 3 or 4, and 1≤m11+m21+m31≤5;

[0200] Each occurrence of m41 and m51 is independently 0, 1, 2, 3, or 4, and 1 ≤ m41 + m51 ≤ 5; and

[0201] Indicates the connection site.

[0202] In some implementation schemes,

[0203] R L1 It is a single bond or -CH2-; preferably, R L1 For single bonds; and / or

[0204] R L2 It is a single bond, -CH2-, -O-, -NH-, -N(CH3)-, -C(O)-CH2-, -O-CH2-, or -OC(O)-; preferably, R L2 For single bonds; and / or

[0205] R L3 It is a single bond, -CH2-, -C(O)-, -C(O)CH2-, -C(O)(CH2)2-, -C(O)(CH2)3-, -C(O)CH(CH3)-, -C(O)CH(CH3)CH2-, -C(O)C(CH3)2CH2-, -C(O)CH2C(O)-, -C(O)NHCH2-, -C(O)NH(CH2)2-, -NHC(O)CH2-, -NHC(O)(CH2)2- or -S(O)2CH(CH3)-, or absent; preferably, R L3 It is -C(O)(CH2)2-, or does not exist; preferably, R L3 -C(O)(CH2)2-; and / or

[0206] R L4 It is a single bond, -CH2-, -NH-, -C(O)-, -N(CH3)-, -S(O)2NH-, -S(O)2N(CH3)-, -C(S)-NH-, -C(S)-N(CH3)-, -C(O)NH-, or -C(O)N(CH3)-; preferably, R L4 It is a single bond, -CH2-, -C(O)-, -NH-, -N(CH3)-, -C(O)NH-, or -C(O)N(CH3)-; preferably, R L4 -C(O)-, -C(O)NH-, or -C(O)N(CH3)-; and / or

[0207] R P1 Each occurrence is independently selected from H, F, Cl, Br, I, C. 1-3 Alkyl, C 1-3 Alkoxy and C 1-3 Halogenated alkoxy groups; preferably, R P1 Each occurrence is independently selected from H, F, Cl, Br, -CH3, -CH2CH3, -CH(CH3)2, -C(CH3)3, -OCH3, -OCH2CH3, -OCH(CH3)2, and -OC(CH3)3; preferably, R P1Each occurrence is independently selected from F, Cl, Br, -CH3, -CH2CH3, -CH(CH3)2, -C(CH3)3, -OCH3, -OCH2CH3, -OCH(CH3)2, and -OC(CH3)3; and / or

[0208] R P2 Each time it appears, it is independently selected from H, F, Cl, Br, I, oxo group (=O), C. 1-3 Alkyl, -S(O)2-C 1-3 Alkyl, -C(O)-C 1-3 Alkyl, -C(O)-C 1-3 Hydroxyalkyl and -C(O)-C 1-3 alkylene-carboxyl group; preferably, R P2 Each occurrence is independently selected from H, F, Cl, Br, -CH3, -CH2CH3, -CH(CH3)2, -C(CH3)3, -C(O)-CH3, -C(O)-CH2CH3, -C(O)-CH2CH2CH3, and -C(O)-CH(CH3)2; preferably, R P2 Each occurrence is independently selected from F, Cl, Br, -CH3, -CH2CH3, -CH(CH3)2, -C(CH3)3, -C(O)-CH3, -C(O)-CH2CH3, -C(O)-CH2CH2CH3 and -C(O)-CH(CH3)2; and / or

[0209] R P3 Each occurrence is independently selected from H, F, Cl, Br, -CN, -CH3, -CH2CH3, and -CH(CH3)2; preferably, R P3 Each occurrence is independently selected from F, Cl, Br, -CN, -CH3, -CH2CH3, and -CH(CH3)2; and / or

[0210] R X Each occurrence is independently selected from H, F, Cl, Br, -CN, -CH3, -CH2CH3, -CH(CH3)2, -C(CH3)3, -OCH3, -OCH2CH3, -OCH(CH3)2, -OC(CH3)3, and -OCF3; preferably, R X Each occurrence is independently selected from F, Cl, Br, -CN, -CH3, -CH2CH3, -CH(CH3)2, -C(CH3)3, -OCH3, -OCH2CH3, -OCH(CH3)2, -OC(CH3)3, and -OCF3; and / or

[0211] n2, n3, and n4 are each independently selected from 0, 1, and 2; and / or

[0212] Each time R appears, it is independently selected from H, F, Cl, Br, hydroxyl group, -CH3, -CH2CH3, -CH(CH3)2, -C(CH3)3, -OCH3, -OCH2CH3, -OCH(CH3)2, and -OC(CH3)3; each time R appears, it is independently selected from H, F, Cl, Br, hydroxyl group, -CH3, -CH2CH3, -OCH3, and -OCH2CH3; and / or

[0213] R A Selected from H, -CN, C 1-3 Alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, -N(CH3)2, Preferably, R A Selected from H, -CN, C 1-3 Alkyl group, -N(CH3)2, C 1- 3-hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkyl, Preferably, R A Selected from H, -N(CH3)2, -CN, -CH3, -CH2CH3, -CH(CH3)2, -OCH3, -OCH2CH3, and -OCH(CH3)2; and / or

[0214] Cy3 does not exist or is selected from R by choice. P3 Replacement Preferably, Cy3 is absent or selected from any of the R... P3 Replacement and / or

[0215] Cy4 is selected from single bonds, arbitrarily assigned to R X Replacement Preferably, Cy4 is selected from single bonds, optionally R X Replacement and / or

[0216] B L Each occurrence is independently selected from single bonds, -O-, -S-, -S(O)-, -S(O)2-, -C≡C-, -CH2-, -C(O)-, -NH-, -N(CH3)-, -N(CH2CH3)-, -C(O)-NH-, -C(O)-N(CH3)-, and / or

[0217] R L5 and R L6 Each time it appears, it is independently selected from H, halogen, hydroxyl, cyano, amino, nitro, C. 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, -C(O)-C 1-3 Alkyl, C 3-6 cycloalkyl and 3-6 membered heterocyclic groups, wherein the C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 3-6 The cycloalkyl group and the 3-6 membered heterocyclic group are each independently and optionally selected from C. 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-8 The aryl group is substituted with one or more substituents from the 5-8 membered heteroaryl group; preferably, R L5 and R L6 Each time it appears, it is independently selected from H, F, Cl, Br, hydroxyl, cyano, nitro, amino, C. 1-3 Alkyl, C 1-3 Alkoxy, -CF3, -CHF2, -CH2F, C 3-6 cycloalkyl and 3-6 membered heterocyclic groups; and / or

[0218] q is selected from 1, 2, 3, 4, 5, 6, 7, and 8; preferably, q is selected from 1, 2, 3, 4, 5, and 6; and / or

[0219] X is independently N each time it appears; and / or

[0220] W1 is C (=O), and W2 is CH2; W1 is CH2, and W2 is C (=O); or W1 is C (=O), and W2 is C (=O); and / or

[0221] R 2a Each occurrence is independently selected from H, F, Cl, Br, -CH3, and -CH2CH2F; and / or

[0222] R 3a R 4a R 3b R 4b R 3c R 4c R 5c R 3d R 4d and R5d Each occurrence is independently selected from H, F, Cl, Br, -CN, -NO2, -CH3, -CH2CH3, -CH(CH3)2, -OCH3, -OCH2CH3, and -OCH(CH3)2; preferably, R 3a R 4a R 3b R 4b R 3c R 4c R 5c R 3d R 4d and R 5d Each occurrence is independently selected from H, F, Cl, Br, -CN, -NO2, -CH3, and -OCH3; and / or

[0223] A a A b A c A d and A e Each occurrence is independently CH2; and / or

[0224] B 1a and B 2a Each occurrence is independently selected from N and CH; and / or

[0225] Each occurrence of m11, m21, and m31 is independently 0, 1, 2, or 3, and 1 ≤ m11 + m21 + m31 ≤ 4; preferably, m11 + m21 + m31 = 1, m11 + m21 + m31 = 2, m11 + m21 + m31 = 3, or m11 + m21 + m31 = 4; preferably, each occurrence of m11 is independently 0 or 1, each occurrence of m21 is independently 1, and each occurrence of m31 is independently 0 or 1; preferably, each occurrence of m11 is independently 0, each occurrence of m21 is independently 1, and each occurrence of m31 is independently 0; and / or

[0226] Each time m41 and m51 appear, they are independently 0, 1, 2, or 3, and 1 ≤ m41 + m51 ≤ 4; preferably, m41 + m51 = 2, m41 + m51 = 3, or m41 + m51 = 4; more preferably, each time m41 and m51 appear, they are independently 2.

[0227] In some embodiments, the compound is selected from compounds of formula (I-AA-1), (I-AA-2), (I-AA-3), and (I-AA-4):

[0228] Among them, X, W1, W2, R L1 R L2 R L3 R L4 R P1 R P2 R P3 R X R A Cy3, Cy4, R 2a R 3a R 4a R 3b R 4b A a A b A c A d A e m11, m21, m31, m41, m51, n2, n3, n4 and L are as defined above;

[0229] Preferably:

[0230] X is independently N each time it appears; and / or

[0231] W1 is C (=O), and W2 is CH2; W1 is CH2, and W2 is C (=O); or W1 is C (=O), and W2 is C (=O); and / or

[0232] R L1 For single bonds; and / or

[0233] R L2 For single bonds; and / or

[0234] R L3 Each occurrence is independently -C(O)CH2-, -C(O)(CH2)2-, -C(O)(CH2)3-, or -C(O)CH(CH3)-; preferably, R L3 Each occurrence is independently -C(O)(CH2)2-; and / or

[0235] R L4 Each occurrence is independently a single bond, -CH2-, -NH-, -N(CH3)-, -C(O), -C(O)NH-, or -C(O)N(CH3)-; preferably, R L4 Each occurrence is independently -C(O)NH-, -C(O) or -C(O)N(CH3)-; and / or

[0236] R P1Each occurrence is independently selected from H, F, Cl, Br, -CH3, -CH2CH3, -CH(CH3)2, -C(CH3)3, -OCH3, -OCH2CH3, and -OCH(CH3)2; preferably, R P1 Each occurrence is independently selected from F, Cl, Br, -CH3, -CH2CH3, -CH(CH3)2, -C(CH3)3, -OCH3, -OCH2CH3, and -OCH(CH3)2; preferably, R P1 Each occurrence is independently selected from F, Cl, and Br; and / or

[0237] R P2 Each occurrence is independently selected from H, F, Cl, Br, -CH3, -CH2CH3, -CH(CH3)2, -C(CH3)3, -C(O)-CH3, -C(O)-CH2CH3, -C(O)-CH2CH2CH3, and -C(O)-CH(CH3)2; preferably, R P2 Each occurrence is independently selected from F, Cl, Br, -CH3, -CH2CH3, -CH(CH3)2, -C(CH3)3, -C(O)-CH3, -C(O)-CH2CH3, -C(O)-CH2CH2CH3, and -C(O)-CH(CH3)2; preferably, R P2 Each occurrence is independently selected from F, Cl, Br, and -CH3; and / or

[0238] R P3 Each occurrence is independently selected from H, F, Cl, Br, -CN, -CH3, -CH2CH3, and -CH(CH3)2; preferably, R P3 Each occurrence is independently selected from F, Cl, Br, -CN, -CH3, -CH2CH3, and -CH(CH3)2; preferably, R P3 Each occurrence is independently selected from F, Cl, and Br; and / or

[0239] R X Each occurrence is independently selected from H, F, Cl, Br, -CN, -CH3, -CH2CH3, -CH(CH3)2, -OCH3, -OCH2CH3, and -OCF3; preferably, R X Each occurrence is independently selected from F, Cl, Br, -CN, -CH3, -CH2CH3, -CH(CH3)2, -OCH3, -OCH2CH3, and -OCF3; R X Each occurrence is independently selected from F, Cl, Br, -CN, -CH3, -OCH3, and -OCF3; and / or

[0240] n2, n3, and n4 are each independently selected from 0, 1, and 2; preferably, n2, n3, and n4 are each independently selected from 0 and 1; and / or

[0241] R A Selected from H, CN, -CH3, -CH2CH3, -CH(CH3)2, -N(CH3)2, Preferably, R A Selected from H, -N(CH3)2, and -CH3; preferably, R A Selected from H and -CH3; and / or

[0242] Cy3 is selected from R (random selection). P3 Replacement Preferably, Cy3 is selected from the optional R P3 Replacement and / or

[0243] Cy4 is selected from single bonds, arbitrarily assigned to R X Replacement Preferably, Cy4 is selected from single bonds and optionally R X Replacement and / or

[0244] R 2a -CH3; and / or

[0245] R 3a R 4a R 3b and R 4b Each occurrence is independently selected from H, F, Cl, Br, -CN, -NO2, -OH, -CH3, and -OCH3; and / or

[0246] A a A b A c A d and A e Each occurrence is independently CH2; and / or

[0247] Each occurrence of m11, m21, and m31 is independently 0, 1, 2, or 3, and m11+m21+m31 = 1, m11+m21+m31 = 2, or m11+m21+m31 = 3; preferably, each occurrence of m11, m21, and m31 is independently 0, 1, or 2, and m11+m21+m31 = 1; preferably, each occurrence of m11 is independently 0 or 1, each occurrence of m21 is independently 1, and each occurrence of m31 is independently 0 or 1; preferably, each occurrence of m11 is independently 0, each occurrence of m21 is independently 1, and each occurrence of m31 is independently 0; and / or

[0248] Each time m41 and m51 appear, they are each independently 0, 1, 2, or 3, and m41+m51=3 or m41+m51=4; preferably, each time m41 and m51 appear, they are each independently 0, 1, or 2, and m41+m51=4; more preferably, each time m41 and m51 appear, they are each independently 2.

[0249] In some embodiments, the compound is selected from the compounds of claim 19.

[0250] In some embodiments, the compound is selected from the compounds in Table A.

[0251] A second aspect of the present invention provides a compound having the structures shown in formula (III-A), formula (III-B), and formula (III-C):

[0252] Among them, Cy3, R A R E R L3 R L4 R P1 R P2 R P3 n2 and n3 are defined as described above;

[0253] R E The group is selected from H, F, Cl, Br, I, hydroxyl, nitro, cyano, amino, aldehyde, carboxyl, alkyl, alkoxy, hydroxyalkyl, -C(O)-alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, and -arylene-heterocyclic, wherein the alkyl, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, and arylene are optionally substituted by one or more substituents selected from H, F, Cl, Br, I, hydroxyl, nitro, cyano, amino, alkyl, alkoxy, haloalkyl, and haloalkoxy; preferably, R E Selected from H, or C with optional substitution 1-3 Alkyl, phenyl, cyclohexyl, 5-6 membered heteroaryl containing 1 or 2 nitrogen atoms; preferably, R E Selected from H, or optionally substituted methyl groups 、 Phenyl, cyclohexyl, and 6-membered heteroaryl groups containing one nitrogen atom;

[0254] Q1 is selected from NH, O and S; preferably, Q1 is NH;

[0255] Cy5 is selected from optionally substituted phenyl groups and 5-6-membered heteroaryl groups containing 1, 2, or 3 heteroatoms each independently selected from nitrogen, oxygen, and sulfur; preferably, Cy5 is selected from optionally substituted phenyl groups.

[0256] Cy6 is selected from 8- or 9-membered heteroaryl groups containing 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 8-, 9-, or 10-membered heterocyclic groups containing 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; preferably, Cy6 is selected from optionally substituted groups.

[0257] Cy7 is selected from optional substitutions. and

[0258] R L5 Selected from O, -C(O)-, -OC(O)-, -NH-, -CH2- and -CH2-C(O)-.

[0259] In some embodiments, the compound is selected from the compounds of claim 21.

[0260] In some embodiments, the compound is selected from the compounds in Table B.

[0261] A third aspect of the present invention provides a pharmaceutical composition comprising an effective amount of a compound or a pharmaceutically acceptable salt thereof as described in the first or second aspect of the present invention, and a pharmaceutically acceptable carrier.

[0262] The fourth aspect of the present invention provides the use of a compound or a pharmaceutically acceptable salt thereof as described in the first or second aspect of the present invention, or a pharmaceutical composition as described in the third aspect of the present invention, in the preparation of a medicament for treating or preventing diseases or conditions mediated by signal transduction and transcription activator 6 (STAT6) protein levels; preferably, the disease or condition is an autoimmune disease, cancer, inflammatory disease, genetic disease, metabolic disease, cardiovascular disease, or central nervous system disease; preferably, the disease or condition is asthma, atopic dermatitis, chronic obstructive pulmonary disease, leukemia, non-small cell lung cancer (NSCLC), or hyperthyroidism (Graves' disease).

[0263] The fifth aspect of the present invention provides a compound or a pharmaceutically usable salt thereof as described in the first or second aspect of the present invention, or a pharmaceutical composition as described in the third aspect of the present invention, for the treatment or prevention of a disease or condition mediated by the level of signal transduction and activating transcription factor 6 (STAT6) protein; preferably, the disease or condition is an autoimmune disease, cancer, inflammatory disease, genetic disease, metabolic disease, cardiovascular disease, or central nervous system disease; preferably, the disease or condition is an autoimmune disease, hematologic malignancy, lung cancer, or autoimmune thyroid disease; preferably, the disease or condition is asthma, atopic dermatitis, chronic obstructive pulmonary disease, leukemia, non-small cell lung cancer (NSCLC), or hyperthyroidism (Graves' disease).

[0264] The sixth aspect of the present invention provides a method for treating or preventing a disease or condition mediated by signal transduction and transcription activator 6 (STAT6) levels, comprising administering to a subject in need an effective amount of a compound or a pharmaceutically acceptable salt thereof as described in the first or second aspect, or a pharmaceutical composition as described in the third aspect; preferably, the disease or condition is an autoimmune disease, cancer, inflammatory disease, genetic disease, metabolic disease, cardiovascular disease, or central nervous system disease; preferably, the disease or condition is an autoimmune disease, a hematologic malignancy, lung cancer, or an autoimmune thyroid disease; preferably, the disease or condition is asthma, atopic dermatitis, chronic obstructive pulmonary disease, leukemia, non-small cell lung cancer (NSCLC), or hyperthyroidism (Graves' disease).

[0265] A seventh aspect of the present invention provides a method for degrading or inhibiting STAT6 in a patient or biological sample, the method comprising administering to the patient a compound according to a first aspect of the present invention or a pharmaceutical composition according to a third aspect of the present invention, or contacting the biological sample with a compound according to any one of the first aspects of the present invention or a pharmaceutical composition according to a third aspect of the present invention; or

[0266] STAT6 is brought into contact with the compound described in the second aspect of the invention or a pharmaceutically acceptable salt thereof; preferably, the contact is made in a patient or biological sample. Attached Figure Description

[0267] Figure 1 shows the proteomics results of compounds B-1 and D-21 [P-value < 0.05; |Log2 FC| > 1 (FC > 2)].

[0268] Figure 2 shows the effect of compounds A-10, A-71 and B-1 on reducing ear thickness in a mouse model of MC-903-induced atopic dermatitis (AD).

[0269] Figure 3 illustrates the degradation effects of compounds A-10, A-71, and B-1 on STAT6 protein in the spleen of a mouse model of MC-903-induced atopic dermatitis (AD).

[0270] Figure 4 shows the inhibitory effects of compounds A-10, A-71, and B-1 on serum IgE levels in a mouse model of MC-903-induced atopic dermatitis (AD). Detailed Implementation

[0271] The following detailed description of specific implementation schemes illustrates the content of this disclosure, but does not imply any adverse limitation thereof. Various specific implementation schemes of this disclosure have been described in detail herein, and it will be apparent to those skilled in the art that various changes and modifications can be made to these specific implementation schemes without departing from the spirit and scope of this disclosure.

[0272] I. Terms and Definitions

[0273] In this invention, unless otherwise stated, the scientific and technical terms used herein have the meanings commonly understood by those skilled in the art. Furthermore, the related terms and laboratory procedures used herein are all widely used terms and routine procedures in the respective fields. To better understand this invention, definitions and explanations of related terms are provided below.

[0274] In the description herein, references to “some embodiments,” “some implementations,” or “some implementation schemes” describe a subset of all possible embodiments. However, it is understood that “some embodiments” may be the same subset or different subsets of all possible embodiments and may be combined with each other without conflict.

[0275] In this specification and claims, the phrase “and / or” is interpreted as meaning “any one or both” of the elements, that is, the elements may exist together in some cases or the elements may exist separately in other cases.

[0276] As used herein and unless otherwise stated, the terms “comprising,” “including,” “having,” and “containing” include their grammatical equivalents and should generally be understood as open-ended and non-restrictive, e.g., not excluding other unlisted elements or steps.

[0277] When listing a range of values, it is assumed that each value and the subranges within that range are included. For example, "C 1-6 Alkyl groups include C1, C2, C3, C4, C5, C6, and C6. 1-6 C 1-5 C 1-4 C 1-3 C 1-2 C 2-6 C 2-5 C 2-4 C 2-3 C 3-6 C 3-4 C 3-5 C 4-6 C 4-5 and C 5-6 Alkyl; for example, "1-5 heteroatoms" includes 1, 2, 3, 4 and 5 heteroatoms.

[0278] The term "heteroatom" is selected from nitrogen, oxygen, and sulfur. Nitrogen atoms may optionally be substituted; sulfur atoms may also optionally be substituted, for example, by oxidizing (=O), thus forming S(O). t3 (where t3 is an integer from 0 to 2).

[0279] The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight-chain or branched group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) carbon atoms, and more preferably an alkyl group containing 1 to 6 carbon atoms. 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. More preferably, lower alkyl groups containing 1 to 6 carbon atoms are used. 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, etc. The alkyl group may be substituted or unsubstituted. When substituted, the substituent may be substituted at any usable connection point. The substituent is preferably selected independently from one or more substituents chosen from H atom, D atom, halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl and heteroaryl.

[0280] The term "heteroalkyl" refers to an alkyl group in which one or more -CH2- atoms are replaced by heteroatoms selected from NH, O, and S, or where one or more -CH- atoms are replaced by N atoms; wherein the alkyl group is as defined above; the heteroalkyl group may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any usable connection point, wherein the substituent is preferably independently selected independently from one or more substituents selected from H atoms, D atoms, halogens, alkyl groups, alkoxy groups, haloalkyl groups, hydroxy groups, hydroxyalkyl groups, cyano groups, amino groups, nitro groups, cycloalkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups.

[0281] The term "cyclic hydrocarbon group" refers to a group with a cyclic structure consisting of carbon atoms. Cyclic hydrocarbon groups can be monocyclic or polycyclic. In polycyclic compounds, multiple carbon rings can be linked by sharing a carbon atom or a carbon chain. For example, two carbon rings sharing a single carbon atom are called spirocyclic hydrocarbons, and those sharing two or more carbon atoms are called bridged cyclic hydrocarbons. Cyclic hydrocarbon groups can be substituted or unsubstituted. When substituted, the substituent can be replaced at any usable connection point, preferably independently selected independently from one or more substituents chosen from H atoms, D atoms, halogens, alkyl groups, alkoxy groups, haloalkyl groups, hydroxyl groups, hydroxyalkyl groups, cyano groups, amino groups, nitro groups, cycloalkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups. The terms "cyclic hydrocarbon group" and "cyclic hydrocarbon ring" are used interchangeably.

[0282] The term "alkoxy" refers to -O- (alkyl) and -O- (unsubstituted cycloalkyl), wherein alkyl or cycloalkyl is defined as described herein. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, and cyclohexyloxy. Alkoxy groups may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more substituents independently selected from H atom, D atom, halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0283] The term "alkenyl" refers to an alkyl compound containing a carbon-carbon double bond in its molecule, wherein the definition of alkyl is as described above. Alkenyl groups can be substituted or unsubstituted, and when substituted, the substituent is preferably one or more substituents selected independently from one or more of the following groups: hydrogen atom, alkyl, alkoxy, halogen, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0284] The term "alkynyl" refers to an alkyl compound containing a carbon-carbon triple bond in its molecule, wherein the definition of alkyl is as described above. The alkynyl group can be substituted or unsubstituted, and when substituted, the substituent is preferably one or more substituents selected independently from one or more of the following groups: hydrogen atom, alkyl, alkoxy, halogen, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0285] The term "cycloalkyl" refers to a cyclic hydrocarbon substituent of a saturated or partially unsaturated monocyclic, bicyclic, or more rings, including, for example, fused, bridged, or spirocyclic groups. The cycloalkyl ring may contain 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, more preferably 3 to 8 (e.g., 3, 4, 5, 6, 7, or 8) carbon atoms, and even more preferably 4 to 7 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclohepttrienyl, and cyclooctyl. The cycloalkyl group may be substituted or unsubstituted. When substituted, the substituent may be substituted at any usable connection point, and the substituent is preferably independently selected independently from one or more substituents chosen from hydrogen, halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0286] The term "heterocyclic group" refers to a substituent in a saturated or partially unsaturated monocyclic hydrocarbon containing 3 to 20 ring atoms, one or more of which are selected from nitrogen, oxygen, or S(O). m The ring contains 3 to 12 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12) ring atoms, of which 1 to 4 (e.g., 1, 2, 3, and 4) are heteroatoms; more preferably, it contains 3 to 8 ring atoms, of which 1 to 3 are heteroatoms; even more preferably, it contains 3 to 6 ring atoms, of which 1 to 3 are heteroatoms; and most preferably, it contains 5 or 6 ring atoms, of which 1 to 3 are heteroatoms. Non-limiting examples of monocyclic heterocyclic groups include pyrrolidinyl, tetrahydropyranyl, 1,2,3,6-tetrahydropyridyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, and homopiperazinyl, etc. The terms "heterocyclic group" and "heterocyclic ring" are used interchangeably. The heterocyclic group can be substituted or unsubstituted. When substituted, the substituent can be substituted at any usable connection point. The substituent is preferably selected independently and optionally from one or more substituents selected from hydrogen, halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0287] The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (fused polycyclic) group having a conjugated π-electron system, preferably 6- to 10-membered, such as phenyl and naphthyl. The aryl ring comprises an aryl ring fused to a heteroaryl, heterocyclic, or cycloalkyl ring as described above, wherein the ring attached to the parent structure is an aryl ring. The aryl group can be substituted or unsubstituted; when substituted, the substituent can be substituted at any usable connection point, preferably independently selected independently from one or more substituents chosen from hydrogen, halogen, alkyl, alkoxy, haloalkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl. The terms "aryl" and "aromatic ring" are used interchangeably. The term "6-10-membered aryl" refers to a C10-100 aryl group. 6-10 Aryl.

[0288] The term "heteroaryl" refers to a heteroaryl system comprising 1 to 4 (e.g., 1, 2, 3, and 4) heteroatoms and 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen. The heteroaryl group is preferably 5 to 10-membered (e.g., 5, 6, 7, 8, 9, or 10-membered), more preferably 5- or 6-membered, such as indolyl, furanyl, thiophene, pyridyl, pyrroleyl, N-alkylpyrroleyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, etc. The heteroaryl ring comprises a heteroaryl group fused to an aryl, heterocyclic, or cycloalkyl ring as described above, wherein the ring connected to the parent structure is a heteroaryl ring. The heteroaryl group can be substituted or unsubstituted. When substituted, the substituent can be replaced at any usable connection point. The substituent is preferably independently selected independently from one or more substituents chosen from hydrogen, halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl. The terms "heteroaryl" and "heteroaryl ring" are used interchangeably.

[0289] The term "bridged ring" refers to a polycyclic hydrocarbon containing 0-5 heteroatoms, either saturated or partially unsaturated, consisting of two or more rings connected by sharing two or more non-adjacent carbon atoms (bridgehead carbon atoms), wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen. Unless otherwise specified, it generally refers to a bicyclic structure consisting of 5-15 ring atoms, either saturated or partially unsaturated, connected by sharing two or more non-adjacent carbon atoms (bridgehead carbon atoms).

[0290] The term "spirocyclic" refers to a polycyclic hydrocarbon formed by two or more saturated or partially unsaturated rings containing 0-5 heteroatoms connected by sharing a single carbon atom (spiro atom), wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen. Unless otherwise specified, it generally refers to a bicyclic, tricyclic, or tetracyclic structure formed by two, three, or four saturated or partially unsaturated rings containing 5-15 ring atoms connected by sharing a single carbon atom (spiro atom).

[0291] The term "fused ring" or "fused ring" refers to a polycyclic hydrocarbon formed by two or more saturated or partially unsaturated rings containing 0-5 heteroatoms, connected by sharing two or more adjacent carbon atoms (forming a shared edge), wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen. Unless otherwise specified, it generally refers to a bicyclic, tricyclic, or tetracyclic structure formed by two, three, or four saturated or partially unsaturated rings containing 0-5 heteroatoms, connected by sharing two or more adjacent carbon atoms (forming a shared edge).

[0292] The term "subunit" refers to a group obtained by removing a hydrogen atom from a carbon atom containing free valence electrons, and has two connection sites for attaching to the rest of the molecule. For example, the term "arylene" refers to a divalent aryl group formed by further substituting one hydrogen atom of an aryl group, as defined above.

[0293] 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. The definitions of other halogenated substituents are the same.

[0294] The term "deuterated alkyl" refers to an alkyl group that has been substituted with one or more deuterium atoms, wherein the alkyl group is as defined above. The definitions of other deuterated substituents are the same.

[0295] The term "hydroxyalkyl" refers to an alkyl group that is substituted with one or more hydroxyl groups, wherein the alkyl group is as defined above.

[0296] The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0297] The term "amino" refers to -NH2.

[0298] The term "cyano" refers to -CN.

[0299] The term "nitro" refers to -NO2.

[0300] "Optional" or "optionally" means that the event or situation described below may, but does not have to, occur, and the description includes the circumstances in which the event or situation occurs or does not occur. For example, "optionally substituted cyclopropyl" means that cyclopropyl can be substituted but is not required to be present, and the description includes the cases in which cyclopropyl is substituted and the cases in which cyclopropyl is not substituted.

[0301] "Substituted" refers to one or more hydrogen atoms in a group, preferably up to five, more preferably one to three hydrogen atoms, which are independently substituted by the corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art can determine possible or impossible substitutions without much effort (through experiment or theory).

[0302] As used in this article, "replaced by one or more substituents" means that, where substitution is possible, one or more hydrogen atoms in the group are independently replaced by the corresponding number of substituents, and "one or more" is preferably 1 to 5 (1, 2, 3, 4 or 5).

[0303] The term "covalent bond" refers to a chemical bond formed by two or more atoms sharing electron pairs. Generally, one pair of electrons between two atoms represents a covalent single bond, two pairs of electrons represent a double bond, and three pairs of electrons represent a triple bond.

[0304] The term "ubiquitin ligase" refers to a family of proteins that facilitate the transfer of ubiquitin to specific substrate proteins, targeting those proteins for degradation. For example, cerebellar proteins are E3 ubiquitin ligase proteins, alone or in combination with E2 ubiquitin-binding enzymes, that cause ubiquitin to attach to a lysine residue on a target protein and subsequently target a specific protein substrate for degradation via the proteasome. Therefore, E3 ubiquitin ligases, alone or in combination with E2 ubiquitin-binding enzymes, are the cause of ubiquitin transfer to the target protein. Generally, ubiquitin ligases participate in polyubiquitination, where a second ubiquitin is attached to a first ubiquitin, a third ubiquitin to a second ubiquitin, and so on. Polyubiquitinated proteins are used for degradation via the proteasome. However, there are some ubiquitination events limited to monoubiquitination, where only a single ubiquitin is added to the substrate molecule via a ubiquitin ligase. Monoubiquitinated proteins are not targeted to the proteasome for degradation but may instead be altered in their cellular location or function, for example, by binding to other proteins with domains capable of binding ubiquitin. Complicating matters further, different lysine residues on ubiquitin can be targeted by E3 to prepare chains. The most common lysine is Lys48 on the ubiquitin chain. This is the lysine used to prepare polyubiquitin, and it is recognized by the proteasome.

[0305] The term "target protein" refers to proteins and peptides that have any biological function or activity (including structural, regulatory, hormonal, enzymatic, genetic, immune, contractile, storage, transport, and signal transduction). In some implementations, target proteins include structural proteins, receptors, enzymes, cell surface proteins, and proteins involved in integrated cellular functions, including proteins involved in: catalytic activity, aromatase activity, motility activity, helicase activity, metabolic processes (anabolism and catabolism), antioxidant activity, proteolysis, biosynthesis, proteins with kinase activity, oxidoreductase activity, transferase activity, hydrolase activity, lyase activity, isomerase activity, ligase activity, enzyme regulator activity, signal transduction factor activity, structural molecule activity, binding activity (proteins, lipids, carbohydrates), receptor activity, cell motility, membrane fusion, cell communication, regulation of biological processes, development, cell differentiation, stimulus response, behavioral proteins, cell adhesion proteins, proteins involved in cell death, proteins involved in transport (including protein transport activity, nuclear transport, ion transport activity, channel transport activity, carrier activity), permease activity, secretory activity, electron transport activity, pathogens, associated protein regulator activity, nucleic acid binding activity, transcription regulator activity, extracellular structure and biological origin activity, and translation regulator activity. The proteins include proteins derived from eukaryotes and prokaryotes, which include microorganisms, viruses, fungi, and parasites, as well as numerous others, including humans, microorganisms, viruses, fungi, and parasites that are targets for drug therapy, other animals including domestic animals, microorganisms and other antimicrobial drugs used to determine the targets of antibiotics, plants, and even viruses, as well as numerous others.

[0306] The term "compound of this invention or disclosure" refers to compounds of formula (I), (I4), (I3), (I2), (I0), (I-AA), or (II) and their sub-formulas, as well as isomers such as stereoisomers (including diastereomers, enantiomers, and racemates), geometric isomers, conformational isomers (including rotational isomers and throttling isomers), tautomers, isotopically labeled compounds (including deuterium-substituted compounds), and intrinsically formed moieties (e.g., polymorphs, solvates, and / or hydrates). Salts are also included when a salt-forming moiety is present, particularly pharmaceutically acceptable salts.

[0307] The term "isomer" refers to a compound that has the same molecular formula as the compound of this invention but differs in atomic arrangement or spatial configuration. It generally includes structural isomers, stereoisomers, enantiomers, mirror-symmetric chiral molecules, diastereomers, and non-mirror-symmetric stereoisomers. Those skilled in the art will recognize that the compounds disclosed herein may contain chiral centers and therefore may exist in different isomeric forms.

[0308] An enantiomer is a pair of stereoisomers that are non-overlapping mirror images of each other. A 1:1 mixture of a pair of enantiomers is a racemic mixture. This term is used to denote suitable racemic mixtures. When specifying the stereochemistry of the compounds of this disclosure, a single stereoisomer with known relative and absolute configurations of two chiral centers (e.g., (1S,2S)) is specified using the conventional RS system; a single stereoisomer with known relative configurations but unknown absolute configurations is indicated by an asterisk (e.g., (1R*,2R*)); and racemates with two letters (e.g., (1RS,2RS) as a racemic mixture of (1R,2R) and (1S,2S); (1RS,2SR) as a racemic mixture of (1R,2S) and (1S,2R)). A diastereomer is a stereoisomer having at least two asymmetric atoms that are not mirror images of each other. Absolute stereochemistry is specified according to the Cahn-Ingold-Prelog RS system. When the compound is a pure enantiomer, the stereochemistry at each chiral carbon atom can be specified by R or S. Dissociated compounds whose absolute conformation is unknown can be specified (+) or (-) according to the direction (dextrorotatory or levorotatory) in which they rotate plane-polarized light at the wavelength of the sodium D line. Alternatively, the resolved compound can be defined by chiral HPLC using the corresponding retention times of the enantiomers / diastereomers.

[0309] Some of the compounds described herein contain one or more asymmetric centers or axes, and thus can produce enantiomers, diastereomers, and other stereoisomers that can be determined in absolute stereochemistry, such as (R)- or (S)-.

[0310] Geometric isomers occur when a compound contains a double bond or other features that provide a certain degree of structural rigidity to the molecule. If the compound contains a double bond, its substituents can be E or Z configurations. If the compound contains a disubstituted cycloalkyl group, the cycloalkyl substituents can have cis- or trans-configurations.

[0311] Conformational isomers are isomers that differ by rotation of one or more bonds. Rotational isomers are conformational isomers that differ by rotation of only one bond.

[0312] The term "restricted rotation isomer" refers to structural isomers based on axial or planar chirality, which are generated by restricted rotation in the molecule.

[0313] Unless otherwise stated, the compounds disclosed herein are intended to include all such possible isomers, including racemic mixtures, optionally pure forms, and intermediate mixtures. Optically active (R)- and (S)- isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques (e.g., separation on chiral SFC or HPLC columns, such as those available from Daicel Corp. and other equivalent columns, using suitable solvents or mixed solvents to achieve good separation).

[0314] The compounds of this disclosure can be separated in optically active or racemic form. The optically active form can be prepared by resolving the racemic form or by synthesizing optically active starting materials. All methods used to prepare the compounds of this disclosure and the intermediates prepared therein are considered part of this disclosure. When preparing enantiomers or diastereomers, they can be separated by conventional methods, such as chromatography or fractional crystallization.

[0315] Depending on the process conditions, the final products of this disclosure are obtained in free (neutral) or salt form. Both the free form and the salt of these final products are within the scope of this disclosure. If desired, one form of the compound can be converted to another. Free bases or acids can be converted to salts; salts can be converted to free compounds or another salt; mixtures of isomers of this disclosure can be separated into individual isomers.

[0316] Pharmaceutically acceptable salts are preferred. However, other salts may be useful, for example, in the separation or purification steps that may be used in the preparation process, and are therefore contemplated within the scope of this disclosure.

[0317] The term "pharmaceutically acceptable salt" refers to a salt of the compounds of this invention that possesses the desired biological activity, meets pharmaceutical standards, and is safe and effective when used in mammals. "Pharmaceutically acceptable salt" refers to a derivative of the disclosed compound, wherein the parent compound is modified by preparing its acid or base salt. For example, pharmaceutically acceptable salts include, but are not limited to, acetates, aspartates, benzoates, benzenesulfonates, bicarbonates / carbonates, bisulfates / sulfates, camphorsulfonates, decanoates, chlorides / hydrochlorides, chlorourea acetates, citrates, ethanediosulfates, fumarates, gluconates, glucurons, glucuronides, glutamates, glutarate, glycolates, hippurates, hydroiodates / iodides, hydroxyethylsulfonates, lactates, lactobionates, dodecyl sulfates, and malates. Maleate, malonate / hydroxymalonate, mandelate, methyl sulfate, mucilage, naphthate, naphthalene sulfonate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, dihydroxynaphthalate, phenylacetate, phosphate / hydrogen phosphate / dihydrogen phosphate, polygalacturonate, propionate, salicylate, stearate, succinate, aminosulfonate, sulfosalicylate, tartrate, toluenesulfonate, trifluoroacetate, and xinafoate.

[0318] Pharmaceutically acceptable acid addition salts can be formed from inorganic and organic acids. Inorganic acids from which salts can be obtained include, for example, hydrochloric acid, sulfuric acid, nitric acid, and phosphoric acid. Organic acids from which salts can be obtained include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, ethanesulfonic acid, toluenesulfonic acid, and sulfosalicylic acid.

[0319] Pharmaceutically acceptable base addition salts can be formed from inorganic and organic bases. Inorganic bases from which salts can be obtained include, for example, ammonium salts and metals from columns I through XII of the periodic table. In some embodiments, salts are obtained from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper; particularly suitable salts include ammonium, potassium, sodium, calcium, and magnesium salts. Organic bases from which salts can be obtained include, for example, primary, secondary, and tertiary amines, substituted amines (including naturally occurring substituted amines), cyclic amines, basic ion exchange resins, etc. Certain organic amines include isopropylamine, benzylamine, choline, diethanolamine, diethylamine, lysine, meglumine, piperazine, and tromethamine.

[0320] The pharmaceutically acceptable salts disclosed herein can be synthesized by conventional chemical methods from parent compounds containing a basic or acidic moiety. Typically, such salts are prepared by reacting the free acidic or basic form of these compounds with a stoichiometric amount of a suitable base or acid in water, in an organic solvent, or in a mixture of both; typically, non-aqueous media such as diethyl ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred.

[0321] The term "polymorph" refers to the different crystal structures formed by the compounds of this invention due to different molecular packing arrangements.

[0322] Compounds of this disclosure containing groups capable of acting as hydrogen bond donors and / or acceptors can form cocrystals with suitable cocrystal formers. These cocrystals can be prepared from the compounds of this disclosure using known cocrystal formation methods. Such methods include grinding, heating, co-sublimation, co-melting the compounds of this disclosure with a cocrystal former under crystallization conditions, or contacting the compounds of formula (I) with a cocrystal former in solution and separating the resulting cocrystal. Therefore, this disclosure also provides cocrystals comprising the compounds of this disclosure.

[0323] The term "isotope derivative" refers to a derivative of a compound of the present invention in which one or more atoms are substituted with their isotopes. Any formula given herein is also intended to represent both the unlabeled and isotopically labeled forms of the compound. Isotopically labeled compounds have a structure represented by the formulas given herein, except that one or more atoms are substituted with atoms having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into the compounds of this disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, respectively, for example... 2 H, 3 H, 11 C 13 C 14 C 15 N、 18 F, 31 P, 32 P, 35 S, 36 Cl、 125 I. This disclosure includes various isotopically labeled compounds as described herein, for example, those such as 3 H and 14 Those radioactive isotopes of C, or those containing, etc. 2 H and 13 Those are non-radioactive isotopes of carbon. Compounds labeled with these isotopes can be used in metabolic studies (using...). 14 C) Reaction kinetic studies (using, for example) 2 H or 3 H), including in the tissue distribution testing of drugs or substrates using detection or imaging techniques (such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT)), or in the treatment of patients with radiation. Specifically, this may be particularly necessary. 18 F-labeled compounds are used in PET or SPECT studies.

[0324] In addition, heavier isotopes, especially deuterium (i.e., 2H or D substitution can provide certain therapeutic advantages due to increased metabolic stability, such as prolonged in vivo half-life, reduced dose requirements, or improved therapeutic parameters. It should be understood that deuterium as described herein is considered a substituent for the compounds disclosed herein. The concentration of such heavier isotopes (specifically deuterium) can be defined by an isotope enrichment factor. As used herein, the term "isotope enrichment factor" refers to the ratio between the isotopic abundance and the native abundance of a particular isotope. If the substituent in the compounds disclosed herein is deuterium, then such compounds have an isotopic enrichment factor for each specified deuterium atom of at least 3500 (52.5% deuterium doping for each specified deuterium atom), at least 4000 (60% deuterium doping), at least 4500 (67.5% deuterium doping), at least 5000 (75% deuterium doping), at least 5500 (82.5% deuterium doping), at least 6000 (90% deuterium doping), at least 6333.3 (95% deuterium doping), at least 6466.7 (97% deuterium doping), at least 6600 (99% deuterium doping), or at least 6633.3 (99.5% deuterium doping).

[0325] The isotopically labeled compounds disclosed herein can generally be prepared using conventional techniques known to those skilled in the art or by the methods disclosed in the schemes or examples and the preparation methods described below (or processes similar to those described herein): by replacing any other non-isotopically labeled reagents with a suitable or readily available isotopically labeled reagent. Such compounds have a variety of potential uses, for example, as standards and reagents for determining the ability of potential pharmaceutical compounds to bind to target proteins or receptors, or for imaging substances binding to the disclosed biological receptors in vivo or in vitro.

[0326] The term "solvent" refers to the physical combination of the disclosed compound with one or more solvent molecules, whether organic or inorganic. This physical combination includes hydrogen bonds. In some cases, the solvate will be separable, such as when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. Solvent molecules in a solvate may be present in a regular and / or disordered arrangement. A solvate may contain stoichiometric or non-stoichiometric amounts of solvent molecules. "Solvent" includes both a solution phase and a separable solvate. Exemplary solvates include, but are not limited to, hydrates, ethanolates, methanolates, and isopropanolates. Methods of solvation are generally known in the art.

[0327] The compounds of the present invention may also be in prodrug form. The term "prodrug" refers to a compound that produces an active compound when metabolized (e.g., in vivo or in vitro). In some embodiments, a prodrug may be inactive or have lower activity than the free drug, but may provide advantageous processing, administration, or metabolic properties.

[0328] The term "pharmaceuticalally acceptable carrier" refers to an inactive ingredient or medium used in pharmaceuticals that is formulated with the active ingredient without significantly reducing its therapeutic effect and without causing toxic side effects to the human body.

[0329] Example II

[0330] The following examples pertain to the intermediate compounds and final products identified in the specification and synthetic regimens. The preparation of the compounds of the present invention is described in detail using the following examples, but the described chemical reactions are disclosed in accordance with their general applicability to the preparation of the compounds of the present invention. Sometimes, the reactions may not be applicable to every compound as described in the scope of the present invention. Compounds in which this may occur are readily identifiable to those skilled in the art. In these cases, the reactions can be successfully carried out with conventional modifications known to those skilled in the art. In all preparation methods, all starting materials are known or can be readily prepared using known starting materials.

[0331] The starting materials, chemical reagents, and solvents used in this disclosure are all commercially available and were purchased from companies such as Anaiji Chemical, Shanghai Bide Pharmaceutical, Beijing Innocare, Jiangsu Aikon, Sinopharm Group, Beijing Bailingwei, and Yunnan Xinlanjing.

[0332] The structures of the compounds synthesized in this disclosure were determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS).

[0333] Nuclear magnetic resonance (NMR) measurements were performed using a Bruke AVANCE-400 / 600 NMR spectrometer. The deuterated solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD), with tetramethylsilane (TMS) as the internal standard.

[0334] Mass spectrometry (MS) measurements were performed using Waters Acquity Plus device implementation.

[0335] High-performance liquid chromatography (HPLC) preparation was carried out using a Waters 2489 system.

[0336] The medium-pressure rapid preparative chromatograph is a COMBIFLASH NEXTGEN 300+.

[0337] The thin-layer chromatography silica gel plates used are Silica gel 60 thin-layer chromatography silica gel plates (aluminum plates, containing fluorescence).

[0338] The silica gel (100-200 mesh, 200-300 mesh) used in silica gel thin-layer chromatography was purchased from Inokai.

[0339] The reaction process in the examples was detected using thin-layer chromatography (TLC). The systems used to monitor the developing solvent and the eluent used to purify the compounds by column chromatography included: petroleum ether / ethyl acetate system and dichloromethane / methanol system.

[0340] The PTM portion of the disclosed compounds can be prepared by the synthetic methods described in patent applications WO2025049820A1 and WO2025049821A1; the CLM portion of the disclosed compounds can be prepared by the synthetic methods described in patent applications CN118632848A and WO2024240268A1; the disclosed compounds can be prepared by the synthetic formulas and examples shown below. The meanings or definitions of the numbers or variables represented by letters in the following synthetic formulas are independent of their respective definitions in the corresponding synthetic formula.

[0341] PROTAC Synthetic Formula 1

[0342] PROTAC Synthesis Formula 2

[0343] PROTAC Synthesis Formula 3

[0344] PROTAC Synthesis Formula 4

[0345] PROTAC Synthesis Formula 5

[0346] PROTAC Synthesis Formula 6

[0347] PROTAC Synthetic Formula 7

[0348] PROTAC Synthetic Formula 8

[0349] PROTAC Synthetic Formula 9

[0350] PROTAC Synthesis Formula 10

[0351] PROTAC Synthesis Formula 11

[0352] PROTAC Synthesis Formula 12

[0353] PROTAC Synthesis Formula 13

[0354] PROTAC Synthesis Formula 14

[0355] PROTAC Synthesis Formula 15

[0356] PROTAC Synthesis Formula 16

[0357] PROTAC Synthesis Formula 17

[0358] PROTAC Synthesis Formula 18

[0359] PROTAC Synthesis Formula 19

[0360] PROTAC Synthesis Formula 20

[0361] PROTAC Synthesis Formula 21

[0362] PROTAC Synthesis Formula 22

[0363] PROTAC Synthesis Formula 23

[0364] PROTAC Synthesis Formula 24

[0365] PROTAC Synthesis Formula 25

[0366] PROTAC Synthesis Formula 26

[0367] Example 1: Synthesis of compound a-1

[0368] 6-Bromo-4-chloro-7-fluoro-N,N-dimethyl-1H-indole-2-carboxamide (compound a-1)

[0369] Synthesis scheme

[0370] Step 1: Methyl acrylate (Z)-2-azido-3-(4-bromo-2-chloro-5-fluorophenyl)methyl acrylate (compound a-1a)

[0371] 4-Bromo-2-chloro-5-fluorobenzaldehyde (6.0 g, 25.3 mmol) and methyl azide acetate (13.1 g, 113.7 mmol) were dissolved in methanol (60 mL). The reaction mixture was cooled to -10 °C under a nitrogen atmosphere, and sodium methoxide (5.5 g, 101.1 mmol) was slowly added to the reaction system. The reaction was allowed to proceed at room temperature for 8 hours. The reaction was quenched at 0 °C with a supersaturated aqueous solution of ammonium chloride. After filtration, a filter cake was obtained. The crude product was purified by column chromatography to give a white solid compound a-1a (5.0 g, 59%).

[0372] 1 H NMR (600MHz, Chloroform-d) δ8.12(d,J=10.1Hz,1H),7.63(dd,J=6.5,1.1Hz,1H),7.16(s,1H),3.97(d,J=1.2Hz,3H).

[0373] Step 2: Methyl 6-bromo-4-chloro-7-fluoro-1H-indole-2-carboxylic acid (compound a-1b)

[0374] Compound a-1a (3.8 g, 11.4 mmol) was dissolved in xylene (38 mL). The reaction system was reacted at 150 °C for 3 hours. The reaction system was filtered to give a white solid compound a-1b (2.2 g, 63%).

[0375] 1 H NMR (600MHz, DMSO-d6) δ13.12(s,1H),7.46(d,J=4.9Hz,1H),7.17(d,J=2.7Hz,1H),3.91(s,3H).

[0376] Step 3: 6-Bromo-4-chloro-7-fluoro-1H-indole-2-carboxylic acid (compound a-1c)

[0377] Compound a-1b (0.7 g, 2.3 mmol) and lithium hydroxide monohydrate (0.29 g, 6.9 mmol) were dissolved in methanol (14 mL), tetrahydrofuran (3.5 mL), and water (3.5 mL). This reaction system was reacted at 45 °C for 12 hours. The reaction system was then added to water, filtered, and the filter cake was washed three times with water. After drying the filter cake, a white solid compound a-1c (0.5 g, 74%) was obtained.

[0378] 1 H NMR (400MHz, DMSO-d6) δ13.62(s,1H),12.87(s,1H),7.40(d,J=4.9Hz,1H),7.08(d,J=2.9Hz,1H).

[0379] Step 4: 6-Bromo-4-chloro-7-fluoro-N,N-dimethyl-1H-indole-2-carboxamide (compound a-1)

[0380] Compound a-1c (1.2 g, 4.1 mmol), dimethylamine hydrochloride (0.5 g, 6.2 mmol), N,N-diisopropylethylamine (2.7 g, 20.5 mmol), and N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea (1.87 g, 4.9 mmol) were dissolved in N,N-dimethylformamide (20 mL). The reaction mixture was reacted at room temperature for 2 hours. The reaction mixture was then added to water, filtered, and the filter cake was washed three times with water. After drying, a brown solid compound a-1 (1.0 g, 76%) was obtained.

[0381] 1 H NMR (400MHz, DMSO-d6) δ12.69(s,1H),7.40(d,J=5.0Hz,1H),6.88(d,J=3.0Hz,1H),3.05(s,3H).

[0382] LC-MS(ESI):[M+H] + =319.18

[0383] Example 2 Synthesis of compound a-2

[0384] 4-Bromo-6-chloro-7-fluoro-N,N-dimethyl-1H-indole-2-carboxamide (compound a-2)

[0385] Synthesis scheme

[0386] Step 1: 2-Bromo-4-chloro-5-fluoroaniline (compound a-2a)

[0387] 4-Chloro-3-fluoroaniline (35 g, 1.0 eq) was dissolved in acetonitrile (525 mL), and N-bromosuccinimide (42.8 g, 1.0 eq) was added with stirring at 0 °C. The mixture was then stirred at 25 °C for 12 hours. After completion, the solvent was concentrated. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 10 / 1) to give a yellow solid compound a-2a (50 g, 92.64%).

[0388] 1 H NMR (400MHz, DMSO-d6) δ7.53 (d, J = 7.8Hz, 1H), 6.73 (d, J = 11.7Hz, 1H), 5.77 (s, 2H).

[0389] LC-MS(ESI): [M+H] = 226.16.

[0390] Step 2: 1-Bromo-5-chloro-4-fluoro-2-iodobenzene (compounds a-2b)

[0391] Compound a-2b (50 g, 1.0 eq) was added to water (1600 mL), and sulfuric acid (415.08 g, 19.0 eq) was added dropwise with stirring at 0 °C. Next, an aqueous solution of sodium nitrite (16.91 g, 1.1 eq) (75 mL) was added dropwise at 0 °C. After the addition was complete, the mixture was stirred at 0 °C for 1 hour. Then, an aqueous solution of potassium iodide (48.07 g, 1.3 eq) (250 mL) was added dropwise at 0 °C. After the addition was complete, the reaction mixture was stirred at 25 °C for 12 hours. After completion, ethyl acetate was added, and the phase was separated. The aqueous phase was extracted with ethyl acetate (150 mL x 2). The combined organic phases were washed with 1N sodium hydroxide aqueous solution (125 mL), 1N sodium thiosulfate (125 mL), 1N hydrochloric acid aqueous solution (75 mL), saturated sodium bicarbonate aqueous solution (125 mL), and saturated sodium chloride aqueous solution (125 mL), then dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 1:0) to give a yellow solid compound a-2b (35 g, 46.85%).

[0392] 1 H NMR (600MHz, DMSO-d6) δ8.05 (d, J = 8.8 Hz, 1H), 8.02 (d, J = 7.1 Hz, 1H).

[0393] Step 3: 2-Bromo-4-chloro-5-fluorobenzaldehyde (compound a-2c)

[0394] Compound a-2b (5 g, 14.9 mmol) was dissolved in toluene (50 mL). The reaction was cooled to -30 °C, and isopropyl magnesium chloride (2.3 g, 22.37 mmol) was slowly added over half an hour. The reaction system was then reacted at -30 °C for 1 hour. N,N-dimethylformamide (4.36 g, 59.6 mmol) was added to the reaction system, and the reaction system was then reacted at 25 °C for 16 hours. The reaction system was quenched at 0 °C with a supersaturated aqueous solution of ammonium chloride. The mixture was extracted with ethyl acetate, and the organic phase was washed with saturated sodium bicarbonate and dried over anhydrous sodium sulfate. The crude product obtained by rotary evaporation was a white solid compound a-2c (3 g, 84.73%).

[0395] 1 H NMR (400MHz, Chloroform-d) δ10.25(d,J=3.0Hz,1H),7.76(d,J=6.3Hz,1H),7.70(d,J=8.7Hz,1H).

[0396] Step 4: Methyl acrylate (Z)-2-azido-3-(2-bromo-4-chloro-5-fluorophenyl)methyl acrylate (compound a-2d)

[0397] Compound a-2c (1.0 g, 4.21 mmol) and methyl azidoacetate (1.94 g, 16.85 mmol) were dissolved in methanol (20 mL). The reaction was cooled to -60 °C under a nitrogen atmosphere, and sodium methoxide (0.91 g, 16.85 mmol) was slowly added to the reaction system. The reaction was allowed to proceed at room temperature for 8 hours. The reaction was quenched at 0 °C with a supersaturated aqueous solution of ammonium chloride. After filtration, a filter cake was obtained. The crude product was purified by column chromatography to give a white solid compound a-2d (0.5 g, 35.49%).

[0398] 1 H NMR (400MHz, DMSO-d6) δ8.18(d,J=11.0Hz,1H),8.06(d,J=7.3Hz,1H),6.95(d,J=1.1Hz,1H),3.88(s,3H).

[0399] Step 5: Methyl 4-bromo-6-chloro-7-fluoro-1H-indole-2-carboxylic acid (compounds a-2e)

[0400] Compound a-2d (70 g, 209.25 mmol) was dissolved in xylene (700 mL). The reaction system was reacted at 160 °C for 3 hours. The reaction system was cooled to 0 °C and filtered to give a white solid compound a-2e (26 g, 40.5%).

[0401] 1 H NMR (400MHz, DMSO-d6) δ13.16(s,1H),7.52(d,J=5.6Hz,1H),7.10(d,J=2.9Hz,1H),3.91(s,3H).

[0402] LC-MS(ESI):[MH] - =305.98

[0403] Step 6: 4-Bromo-6-chloro-7-fluoro-1H-indole-2-carboxylic acid (compound a-2f)

[0404] Compound a-2e (0.7 g, 2.3 mmol) and lithium hydroxide monohydrate (0.29 g, 6.9 mmol) were dissolved in methanol (14 mL), tetrahydrofuran (3.5 mL), and water (3.5 mL). The reaction mixture was reacted at 45 °C for 12 hours. After the reaction was complete, the reaction mixture was diluted with water (2 mL). The mixture was then extracted with dichloromethane (6 mL × 3). The combined aqueous phases were treated with hydrochloric acid to adjust the pH to 3–4. The mixture was then extracted with dichloromethane (4 mL × 3). The combined organic phases were concentrated under reduced pressure to give a white solid compound a-2f (0.5 g, 74%).

[0405] 1 H NMR (400MHz, DMSO-d6) δ13.43 (s, 1H), 12.99 (s, 1H), 7.50 (d, J = 5.5Hz, 1H), 7.04 (d, J = 2.0Hz, 1H).

[0406] LC-MS(ESI):[MH] - =291.55.

[0407] Step 7: 4-Bromo-6-chloro-7-fluoro-N,N-dimethyl-1H-indole-2-carboxamide (compound a-2)

[0408] Compound a-2e (1.2 g, 4.1 mmol), dimethylamine hydrochloride (0.5 g, 6.2 mmol), N,N-diisopropylethylamine (2.7 g, 20.5 mmol), and N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea (1.87 g, 4.9 mmol) were dissolved in N,N-dimethylformamide (20 mL). The reaction mixture was reacted at room temperature for 2 hours. The reaction mixture was then added to water, filtered, and the filter cake was washed three times with water. After drying, a white solid compound a-2 (1.0 g, 76%) was obtained.

[0409] 1 H NMR (400MHz, DMSO-d6) δ12.72(s,1H),7.48–7.39(m,1H),6.79(d,J=3.0Hz,1H),3.34(d,J=7.1Hz,10H).

[0410] LC-MS(ESI):[M+H] + =319.18

[0411] Example 3 Synthesis of compound a-3

[0412] 1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)-3,6-dihydropyridin-1(2H)-yl)-3-(1H-1,2,3-triazol-1-yl)prop-1-one (compound a-3)

[0413] Synthesis scheme

[0414] Step 1: 5-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)-1,2,3,6-tetrahydropyridine hydrochloride (compounds a-3b)

[0415] Compound a-3a (5 g, 16.17 mmol) was dissolved in dichloromethane (25 mL), and hydrochloric acid in 1,4-dioxane (4 M, 25 mL) was added to the reaction system. The reaction solution was reacted at room temperature for 1 hour. The mixture was then concentrated directly under reduced pressure to give a yellow-brown solid compound a-3b (3.3 g, 97%).

[0416] LC-MS(ESI):[M+H] + =210.30.

[0417] Step 2: Methyl 3-(1H-1,2,3-triazol-1-yl)propionate (compound a-3d)

[0418] Compound a-3c (6 g, 86.87 mmol) was dissolved in ethyl acrylate (9.45 mL), and pyridine (687 mg, 8.69 mmol) was added to the reaction system. The reaction was heated to 90 °C and reacted for 4 hours. After completion, the mixture was concentrated under vacuum to give a crude product. The crude product was purified by reverse-phase column chromatography (C18, 40 g; conditions: water / acetonitrile = 1 / 0 to 0 / 1, 0.1% trifluoroacetic acid) and lyophilized to give a pale yellow oily compound a-3d (12.30 g, 84%).

[0419] 1 H NMR (600MHz, Chloroform-d) δ7.70(dd,J=8.3,1.1Hz,2H),4.70(t,J=6.4Hz,2H),4.16(q,J=7.2Hz,2H),2.98(t,J=6.4Hz,2H),1.25(t,J=7.2Hz,3H).

[0420] LC-MS(ESI):[M+H] + =170.25.

[0421] Step 3: 3-(1H-1,2,3-triazol-1-yl)propionic acid (compound a-3e)

[0422] Compound a-3d (5 g, 29.55 mmol) was dissolved in tetrahydrofuran (12.5 mL) and water (12.5 mL). Lithium hydroxide hydrate (2.48 g, 59.11 mmol) was added to the reaction system, and the reaction mixture was allowed to react overnight at room temperature. After completion, the pH of the mixture was adjusted to 5 with hydrochloric acid (1 M) and lyophilized to give a white solid compound a-3e (4.1 g, 98%).

[0423] 1 H NMR (400MHz, DMSO-d6) δ8.08 (s, 1H), 7.65 (s, 1H), 4.49 (t, J = 7.2Hz, 2H), 2.52-2.48 (m, 2H).

[0424] LC-MS(ESI):[M+H] + =142.25.

[0425] Step 4: 1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)-3,6-dihydropyridin-1(2H)-yl)-3-(1H-1,2,3-triazol-1-yl)prop-1-one (compound a-3)

[0426] Compounds a-3e (1 g, 7.09 mmol) and a-3b (1.48 g, 7.09 mmol) were dissolved in pyridine (10 mL). 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.49 g, 7.79 mmol) was added to the reaction mixture, and the reaction was carried out at room temperature for 2 hours. After completion, the reaction mixture was concentrated under reduced pressure, and the crude product was purified by column chromatography to give a white solid compound a-3 (900 mg, 38%).

[0427] 1 H NMR(400MHz,Chloroform-d)δ7.86(d,J=7.5Hz,1H),7.62(d,J=7.5Hz,1H),5.80(t,J=6.1Hz,1H),4.34(t,J=5.8Hz,2 H),4.01(t,J=4.9Hz,2H),3.30(s,1H),3.30(d,J=2.1Hz,1H),2.66(t,J=4.9Hz,2H),2.34–2.26(m,2H),1.38(s,12H).

[0428] LC-MS(ESI):[M+H] + =333.35.

[0429] Example 4 Synthesis of compound a-4

[0430] 4-(dimethoxymethyl)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxabor-2-yl)phenyl)piperidine (compound a-4)

[0431] Synthesis scheme

[0432] Step 1: 1-(4-bromophenyl)-4-(dimethoxymethyl)piperidine (compounds a-4b)

[0433] 1-Bromo-4-iodobenzene (5.0 g, 17.7 mmol), compound a-4a (2.8 g, 17.6 mmol), tris(dibenzylacetone)dipalladium (810 mg, 0.9 mmol), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (1.03 g, 18 mmol), and sodium tert-butoxide (3.40 g, 35.37 mmol) were added to toluene (50 mL). The reaction was carried out at 80 °C for 1 hour under a nitrogen atmosphere. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated. The crude product was purified by column chromatography to give a yellow solid compound a-4b (4.2 g, 75%).

[0434] 1 H NMR (400MHz, DMSO-d6) δ7.34–7.28(m,2H),6.91–6.84(m,2H),4.07(d,J=6.7Hz,1H),3. 75–3.63(m,2H),3.26(s,6H),2.67–2.55(m,2H),1.78–1.64(m,3H),1.35–1.21(m,2H).

[0435] LC-MS(ESI)[M+H] + =316.25.

[0436] Step 2: 4-(dimethoxymethyl)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxabor-2-yl)phenyl)piperidine (compound a-4)

[0437] Compound a-4b (4 g, 12.7 mmol), pinacol diborate (4.85 g, 19.1 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium(I) dichloride (931 mg, 1.3 mmol), and potassium acetate (2.5 g, 25.5 mmol) were added to 1,4-dioxane (40 mL). The reaction was carried out overnight at 80 °C under a nitrogen atmosphere. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated. The crude product was purified by column chromatography to give a yellow solid compound a-4 (4 g, 97%).

[0438] 1H NMR (400MHz, DMSO-d6) δ7.51–7.46(m,2H),6.91–6.84(m,2H),3.81(d,J=12.8 Hz, 2H), 3.26 (s, 6H), 2.73–2.63 (m, 2H), 1.68 (d, J = 13.1Hz, 2H), 1.26 (s, 14H).

[0439] LC-MS(ESI)[M+H] + =362.29.

[0440] Example 5: Synthesis of compound a-5

[0441] 6-(6-((2-(1H-1,2,3-triazol-1-yl)ethyl)carbamoyl)pyridin-2-yl)-7-fluoro-N,N-dimethyl-4-(4-(4-methylpiperazin-1-yl)phenyl)-1H-indole-2-carboxamide (compound a-5)

[0442] Synthesis scheme

[0443] Step 1: 4-Chloro-7-fluoro-N,N-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-indole-2-carboxamide (compound a-5a)

[0444] Compound a-1a (500 mg, 1.00 eq) was dissolved in dioxane (10 mL), and pinacol diborate (160 mg, 2.70 eq), 1,1-bis(diphenylphosphine)diberberine palladium dichloride (130 mg, 0.10 eq), and potassium acetate (461 mg, 3.00 eq) were added. The reaction was carried out overnight at 100 °C under nitrogen protection. After the reaction was completed, water (5 mL) and ethyl acetate (10 mL) were added to the reaction system, and the mixture was extracted three times. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was collected. The filtrate was concentrated under vacuum, and the crude product was purified by column chromatography (0-35% EA / PE) to give a yellow solid compound a-5a (240 mg).

[0445] LC-MS(ESI):[M+H] + =367.30

[0446] Step 2: 6-(6-((2-(1H-1,2,3-triazol-1-yl)ethyl)carbamoyl)pyridin-2-yl)-4-chloro-7-fluoro-N,N-dimethyl-1H-indole-2-carboxamide (compound a-5c)

[0447] Compound a-5a (110 mg, 1.00 eq) was dissolved in dioxane (5 mL) and water (1 mL). Compound a-5c (89 mg, 1.00 eq), 1,1-bis(diphenylphosphine)dimerferropalladium dichloride (22 mg, 0.10 eq), and potassium carbonate (124 mg, 3.00 eq) were added. The reaction was carried out at 100 °C for 4 hours under nitrogen protection. After the reaction was completed, water (5 mL) and ethyl acetate (10 mL) were added to the reaction system for extraction three times. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was collected. The filtrate was concentrated under vacuum, and the crude product was purified by column chromatography (0-5% MeOH / DCM) to give a yellow solid compound a-5c (80 mg).

[0448] 1 H NMR (400MHz, DMSO-d6) δ12.71(d,J=2.1Hz,1H),9.03(t,J=6.0Hz,1H),8.13–8.08(m,2H),8.00(dd,J=5.8,2.9Hz,1H),7. 95(d,J=5.5Hz,1H),7.82(s,2H),6.92(dd,J=3.0,2.1Hz,1H),4.68(t,J=6.3Hz,2H),3.17(d,J=5.3Hz,2H),1.07(s,6H).

[0449] LC-MS(ESI):[M+H] + =456.30.

[0450] Step 3: 6-(6-((2-(1H-1,2,3-triazol-1-yl)ethyl)carbamoyl)pyridin-2-yl)-7-fluoro-N,N-dimethyl-4-(4-(4-methylpiperazin-1-yl)phenyl)-1H-indole-2-carboxamide (compound a-5)

[0451] Compound a-5c (50 mg, 1.00 eq) was dissolved in dioxane:water = 5:1 (6 mL), and compound a-5d (133 mg, 4.00 eq), methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (9 mg, 0.10 eq), and potassium phosphate (70 mg, 3.00 eq) were added. The reaction was carried out at 100 °C for 4 hours under nitrogen protection. After the reaction was completed, water (5 mL) and ethyl acetate (10 mL) were added to the reaction system for extraction three times. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was collected. The filtrate was concentrated under vacuum, and the crude product was purified by HPLC to obtain a white solid compound a-1 (6 mg).

[0452] 1H NMR (400MHz, DMSO-d6) δ12.41(d,J=2.1Hz,1H),8.90(t,J=6.0Hz,1H),8.14–7.98(m,3H),7.74–7.58(m,5H),7.18(d,J=8.5Hz,2H),6.91(t, J=2.7Hz,1H),4.65(t,J=6.2Hz,2H),3.96(d,J=13.3Hz,2H),3.82(q,J=6.2Hz,2H),3.57(d,J=12.0Hz,2H),3.29–2.96(m,10H),2.90(s,3H).

[0453] LC-MS(ESI):[M+H] + =596.48.

[0454] Example 6 Synthesis of compound a-6

[0455] 1-(5-(7-fluoro-2-(5-methyl-1,3,4-oxazol-2-yl)-4-(4-(4-methylpiperazin-1-yl)phenyl)-1H-indol-6-yl)-3,6-dihydropyridin-1(2H)-yl)-3-(1H-1,2,3-triazol-1-yl)prop-1-one (compound a-6)

[0456] Synthesis scheme

[0457] Step 1: N'-acetyl-4-bromo-6-chloro-7-fluoro-1H-indole-2-carbazide (compound a-6a)

[0458] Compound a-2f (500 mg, 1.71 mmol) was dissolved in N,N-dimethylformamide (10 mL), and N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea (845 mg, 2.22 mmol), triethylamine (518 mg, 5.13 mmol), and acetylhydrazine (151 mg, 2.05 mmol) were added. The mixture was stirred at room temperature for 2 hours. After the reaction was complete, water was added to precipitate the product, which was then filtered and dried under reduced pressure to obtain the crude compound a-6a, which could be used directly in the next step.

[0459] 1 H NMR (400MHz, DMSO-d6) δ12.80(s,1H),10.52(s,1H),10.01(s,1H),7.43(d,J=4.9Hz,1H),7.37(d,J=2.9Hz,1H),1.95(s,3H).

[0460] LC-MS(ESI):[M+H]+ =348.19

[0461] Step 2: 2-(4-bromo-6-chloro-7-fluoro-1H-indol-2-yl)-5-methyl-1,3,4-oxadiazole (compounds a-6b)

[0462] Compound a-6a (50 mg, 0.14 mmol) was dissolved in phosphorus oxychloride (1 mL) and reacted at 105 °C for 2 hours. After the reaction was completed, the precipitated solid was quenched in water, filtered, and then slurried with methanol (1 mL). The filtered cake was dried under reduced pressure to obtain crude brown solid compound a-6b (40 mg).

[0463] 1 H NMR (400MHz, DMSO-d6) δ13.39(d,J=2.3Hz,1H),7.42(d,J=5.0Hz,1H),7.13(t,J=2.5Hz,1H),2.62(s,3H).

[0464] LC-MS(ESI):[M+H] + =330.18

[0465] Step 3: 2-(6-chloro-7-fluoro-4-(4-(4-methylpiperazin-1-yl)phenyl)-1H-indol-2-yl)-5-methyl-1,3,4-oxadiazole (compound a-6c)

[0466] Compound a-6b (30 mg, 0.09 mmol), compound a-5d (38 mg, 0.12 mmol), potassium carbonate (12 mg, 0.09 mmol), and 1,1-bis(diphenylphosphine)diferropalladium dichloride (7 mg, 0.01 mmol) were dissolved in 1,4-dioxane (2 mL) and water (0.4 mL). The reaction system was reacted at 100 °C for 2 hours under a nitrogen atmosphere. The reaction system was concentrated, and the crude product was purified by column chromatography to give a yellow oily compound a-6c (10 mg, 25%).

[0467] LC-MS(ESI):[M+H] + =426.30

[0468] Step 4: 1-(5-(7-fluoro-2-(5-methyl-1,3,4-oxazol-2-yl)-4-(4-(4-methylpiperazin-1-yl)phenyl)-1H-indol-6-yl)-3,6-dihydropyridin-1(2H)-yl)-3-(1H-1,2,3-triazol-1-yl)prop-1-one (compound a-6)

[0469] Compound a-6c (100 mg, 0.22 mmol), compound a-3 (66 mg, 0.22 mmol), potassium phosphate (46 mg, 0.22 mmol), and methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (18 mg, 0.02 mmol) were dissolved in 1,4-dioxane (2 mL) and water (0.4 mL). The reaction system was carried out at 100 °C for 2 hours under a nitrogen atmosphere. The reaction system was concentrated, and the crude product was purified by high performance liquid chromatography to obtain a white solid compound a-6 (66 mg, 62%).

[0470] 1 H NMR (400MHz, DMSO-d6) δ12.96–12.92(m,1H),8.12(d,J=16.9Hz,1H),7.71(s,1H),7.61(dd,J=8.5,3.9Hz,2H),7.21 –7.15(m,3H),7.02(d,J=5.9Hz,1H),6.22–6.17(m,1H),4.63(dt,J=11.4,6.9Hz,2H),4.40(s,1H),4.35(s,1H),3.96 (d,J=13.3Hz,2H),3.67(t,J=5.9Hz,1H),3.62(t,J=5.8Hz,1H),3.56(d,J=12.1Hz,2H),3.20(t,J=13.0Hz,2H),3.1 1(dt,J=15.1,6.9Hz,2H),3.04(t,J=12.8Hz,2H),2.90(d,J=3.6Hz,3H),2.61(s,3H),2.39–2.36(m,1H),2.29(s,1H)

[0471] LC-MS(ESI):[M+H] + =596.50

[0472] Example 7 Synthesis of compound a-7

[0473] 1-(5-(7-fluoro-4-(4-(4-methylpiperazin-1-yl)phenyl)-1H-indol-6-yl)-3,6-dihydropyridin-1(2H)-yl)-3-(1H-1,2,3-triazol-1-yl)prop-1-one (compound a-7)

[0474] Synthesis scheme

[0475] Step 1: 5-Bromo-1-chloro-2-fluoro-3-nitrobenzene (compound a-7a)

[0476] 3-Chloro-2-fluoronitrobenzene (5 g, 56.97 mmol) was dissolved in concentrated sulfuric acid (25 mL) at room temperature, and N-bromosuccinimide (5.58 g, 62.66 mmol) was added. The reaction mixture was stirred at 70 °C for 3 hours under nitrogen protection. After the reaction was complete, the reaction solution was cooled to room temperature, and the mixture was placed in a beaker containing ice water (100 mL) and extracted with ethyl acetate. The combined organic layers were washed successively with water (60 mL), saturated sodium bicarbonate aqueous solution (60 mL), and brine (60 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography (0-10% ethyl acetate / petroleum ether) to give a pale yellow solid compound a-7a (7.2 g, 99.35%).

[0477] 1 H NMR (400MHz, DMSO-d6) δ8.37 (ddd, J=19.2, 6.0, 2.5Hz, 2H).

[0478] Step 2: 4-Bromo-6-chloro-7-fluoro-1H-indole (compounds a-7b)

[0479] Compound a-7a (2 g, 3.93 mmol) was dissolved in ultradry tetrahydrofuran (5 mL) at room temperature, and the mixture was cooled to -78 °C and then vinyl magnesium bromide (18.08 mL, 1 M) was added. The reaction mixture was stirred at this temperature for half an hour under nitrogen protection. After the reaction was completed, the reaction was quenched at -78 °C with MeOH (1 mL), then acidified with 1 M hydrochloric acid aqueous solution (10 mL), the mixture was extracted with ethyl acetate, the combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography (0-10% ethyl acetate / petroleum ether) to give compound a-7b (190 mg, 19.46%) as a pale yellow solid.

[0480] 1 H NMR (400MHz, DMSO-d6) δ12.26(s,1H),7.60(t,J=2.8Hz,1H),7.38(d,J=5.7Hz,1H),6.49(td,J=3.2,2.0Hz,1H).

[0481] LC-MS(ESI):[MH] - =247.85

[0482] Step 3: 6-Chloro-7-fluoro-4-(4-(4-methylpiperazin-1-yl)phenyl)-1H-indole (compound a-7c)

[0483] Compound a-7b (50 mg, 201.22 μmol), compound a-5d (109.05 mg, 301.84 μmol), potassium carbonate (83.43 mg, 603.67 μmol), and 1,1-bis(diphenylphosphine)dipyridylferric palladium dichloride (21.90 mg, 30.18 μmol) were dissolved in 1,4-dioxane (1 mL) and water (0.2 mL). The reaction system was carried out at 100 °C for 2 hours under a nitrogen atmosphere. The reaction system was concentrated, and the crude product was purified by column chromatography to give a yellow solid compound a-7c (50 mg, 61.67%).

[0484] 1 H NMR(400MHz,DMSO-d6)δ11.94(s,1H),7.53–7.48(m,3H),7.09–7.02(m,3H),6 .61(td,J=3.3,1.9Hz,1H),3.33–3.30(m,4H),3.25–3.19(m,4H),2.26(s,3H).

[0485] LC-MS(ESI):[M+H] + =344.30

[0486] Step 4: 1-(5-(7-fluoro-4-(4-(4-methylpiperazin-1-yl)phenyl)-1H-indol-6-yl)-3,6-dihydropyridin-1(2H)-yl)-3-(1H-1,2,3-triazol-1-yl)prop-1-one (compound a-7)

[0487] Compound a-7c (50 mg, 124.10 μmol), compound a-3 (61.84 mg, 186.15 μmol), potassium phosphate (79.03 mg, 372.31 μmol), and methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (10.50 mg, 12.41 μmol) were dissolved in 1,4-dioxane (1 mL) and water (0.2 mL). The reaction system was carried out at 100 °C for 2 hours under a nitrogen atmosphere. The reaction system was concentrated, and the crude product was purified by column chromatography to give a yellow solid compound a-7 (70 mg, 98.49%).

[0488] 1H NMR (600MHz, DMSO-d6) δ11.75(d,J=6.1Hz,1H),8.12(d,J=15.2Hz,1H),7.70(d,J=17.6Hz,1H),7.57(dd,J=8.4,5.4Hz,2H) ,7.47(q,J=2.8Hz,1H),7.13(d,J=8.3Hz,2H),6.90(d,J=6.1Hz,1H),6.57(q,J=2.8Hz,1H),6.16–6.10(m,1H),4.67–4.59(m ,2H),4.38(s,1H),4.33(s,1H),3.93(d,J=13.3Hz,2H),3.67(t,J=5.9Hz,1H),3.61(t,J=5.8Hz,1H),3.55(d,J=12.2Hz,2H) ,3.20(q,J=11.1Hz,2H),3.10(dt,J=14.5,6.9Hz,2H),3.02(t,J=12.9Hz,2H),2.89(s,3H),2.38–2.34(m,1H),2.28(s,1H).

[0489] LC-MS(ESI):[M+H] + =514.45

[0490] Example 8 Synthesis of compound a-8

[0491] 1-(5-(7-fluoro-4-(4-(4-methylpiperazin-1-yl)phenyl)-2-(1,3,4-oxadiazol-2-yl)-1H-indol-6-yl)-3,6-dihydropyridin-1(2H)-yl)-3-(1H-1,2,3-triazol-1-yl)prop-1-one (compound a-8)

[0492] Synthesis scheme

[0493] Step 1: 4-Bromo-6-chloro-7-fluoro-1H-indole-2-carbazide (compound a-8a)

[0494] At room temperature, compound a-2e (100 mg, 326.25 μmol) was dissolved in methanol (1 mL), and hydrazine hydrate (33 mg, 652.50 μmol) was added. The reaction mixture was stirred at 70 °C for 6 hours. After the reaction was completed, the reaction solution was cooled to room temperature, and the mixture was allowed to stand until a solid precipitated. The solid was filtered, and the filter cake was washed with ethanol to give a white solid compound a-8a (100 mg, 100%).

[0495] 1H NMR (600MHz, DMSO-d6) δ12.78(s,1H),9.99(s,1H),7.46(d,J=5.3Hz,1H),7.20(d,J=2.7Hz,1H),4.58(s,2H).

[0496] LC-MS(ESI):[M+H] + =306.05

[0497] Step 2: 4-Bromo-6-chloro-7-fluoro-N'-formyl-1H-indole-2-carbazide (compounds a-8b)

[0498] Compound a-8a (80 mg, 260.99 μmol) was dissolved in formic acid (7 mL) at room temperature. The reaction mixture was stirred at 100 °C for 6 hours under nitrogen protection. After the reaction was completed, excess formic acid was removed under reduced pressure. The resulting solid was washed with cold ethanol, filtered, and dried to give compound A-2b (80 mg, 91.63%) as a white solid.

[0499] 1 H NMR (600MHz, DMSO-d6) δ12.94(s,1H),10.69(s,1H),10.18(s,1H),8.17(s,1H),7.50(d,J=5.5Hz,1H),7.36(d,J=2.6Hz,1H).

[0500] LC-MS(ESI):[M+H] + =334.10

[0501] Step 3: 2-(4-bromo-6-chloro-7-fluoro-1H-indol-2-yl)-1,3,4-oxadiazole (compound a-8c)

[0502] Compound a-8b (70 mg, 209.25 μmol) was dissolved in phosphorus oxychloride (7 mL) at room temperature. The reaction mixture was stirred at 110 °C for 2 hours under nitrogen protection. After the reaction was complete, the resulting reaction mixture was cooled to room temperature and poured into crushed ice. A saturated sodium bicarbonate solution was slowly added while stirring until the solution was weakly alkaline (pH = 8). The solid product was filtered, washed with cold ethanol, and dried. Recrystallization of the product from ethanol gave a white solid compound a-8c (34 mg, 51.34%).

[0503] 1 H NMR (600MHz, DMSO-d6) δ13.57(s,1H),9.47(s,1H),7.57(d,J=5.4Hz,1H),7.20(t,J=2.4Hz,1H).

[0504] LC-MS(ESI):[M+H] + =316.10

[0505] Step 4: 2-(6-chloro-7-fluoro-4-(4-(4-methylpiperazin-1-yl)phenyl)-1H-indol-2-yl)-1,3,4-oxadiazole (compounds a-8d)

[0506] Compound a-8c (50 mg, 201.22 μmol), compound a-5d (109.05 mg, 301.84 μmol), potassium carbonate (83.43 mg, 603.67 μmol), and 1,1-bis(diphenylphosphine)dipyridylferric palladium dichloride (21.90 mg, 30.18 μmol) were dissolved in 1,4-dioxane (1 mL) and water (0.2 mL). The reaction system was carried out at 100 °C for 2 hours under a nitrogen atmosphere. The reaction system was concentrated, and the crude product was purified by column chromatography to give a yellow solid compound a-8d (50 mg, 61.67%).

[0507] 1 H NMR (600MHz, DMSO-d6) δ13.22(s,1H),9.42(s,1H),7.56(d,J=8.3Hz,2H),7.31(d,J=2.6Hz,1 H),7.20(d,J=6.0Hz,1H),7.10(d,J=8.3Hz,2H),3.26(s,4H),2.30(s,4H),2.04–1.89(m,3H)

[0508] LC-MS(ESI):[M+H] + =412.39

[0509] Step 5: 1-(5-(7-fluoro-4-(4-(4-methylpiperazin-1-yl)phenyl)-2-(1,3,4-oxadiazol-2-yl)-1H-indol-6-yl)-3,6-dihydropyridin-1(2H)-yl)-3-(1H-1,2,3-triazol-1-yl)prop-1-one (compound a-8)

[0510] Compound a-8d (40 mg, 97.12 μmol), compound a-3 (48.40 mg, 145.68 μmol), potassium phosphate (61.84 mg, 291.36 μmol), and methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (8.22 mg, 9.71 μmol) were dissolved in 1,4-dioxane (1 mL) and water (0.2 mL). The reaction system was carried out at 100 °C for 2 hours under a nitrogen atmosphere. The reaction system was concentrated, and the crude product was purified by reverse-phase chromatography to give a yellow solid compound a-8 (35 mg, 61.96%).

[0511] 1 H NMR(400MHz,DMSO-d6)δ13.01(s,1H),9.41(d,J=1.3Hz,1H),8.18–8.08(m,1 H),7.74–7.58(m,3H),7.30–7.13(m,3H),7.06(dd,J=24.1,6.0Hz,1H),6.20( s,1H),4.63(q,J=7.0Hz,2H),4.37(d,J=19.7Hz,2H),3.96(d,J=13.1Hz,2H), 3.69–3.52(m,4H),3.22–3.00(m,6H),2.89(s,3H),2.37(s,1H),2.29(s,1H).

[0512] LC-MS(ESI):[M+H] + =582.50

[0513] Example 9: Synthesis of Compound b-1

[0514] 7-Fluoro-N,N-Dimethyl-4-(4-(4-methylpiperazin-1-yl)phenyl)-6-(1-(3-(2-oxopyridin-1(2H)-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-1H-indole-2-carboxamide (compound b-1)

[0515] Synthesis scheme

[0516] Step 1: 6-Chloro-7-fluoro-N,N-dimethyl-4-(4-(4-methylpiperazin-1-yl)phenyl)-1H-indole-2-carboxamide (compound b-1a)

[0517] Compound a-5d (150 mg, 1.00 eq), compound a-2 (174.5 mg, 1.10 eq), 1,1-bis(diphenylphosphine)dimerferropalladium dichloride (81 mg, 0.20 eq), potassium carbonate (206 mg, 3.00 eq), and 1,4-dioxane:water = 5:1 (1 mL) were added to a 25 mL round-bottom flask and placed under an inert atmosphere (N2). The flask was stirred at 100 °C for 1 hour. The reaction solution was concentrated to obtain a crude product. The crude product was purified by column chromatography (0-20% DCM / MeOH) to obtain a brown solid compound b-1a (100 mg, 51%).

[0518] 1 H NMR (400MHz, DMSO-d6) δ12.38(d,J=2.1Hz,1H),7.58–7.46(m,2H),7.11(d,J=6.1Hz,1H),7.06(d,J=8.8 Hz,2H),6.89(t,J=2.6Hz,1H),3.23(t,J=5.1Hz,6H),3.09(d,J=27.3Hz,4H),2.50(s,4H),2.26(s,3H).

[0519] LC-MS(ESI):[M+H] + =415.25.

[0520] Step 2: Ethyl 3-(2-oxopyridin-1(2H)-yl)propionate (compound b-1c)

[0521] Compound b-1b (1 g, 1.00 eq), ethyl acrylate (0.53 g, 0.50 eq), and ultra-dry acetonitrile (5 mL) were added to a 50 mL round-bottom flask. The flask was placed under an inert atmosphere (N2). Bismuth tribromide (0.17 g, 0.04 eq) and triethylamine (1.46 mL, 1.00 eq) were added through a delivery tube. The flask was heated to 80 °C and stirred overnight. The reaction mixture was concentrated to obtain a crude product. The crude product was purified by column chromatography (0-70% EA / PE) to obtain a pale yellow liquid compound b-1c (542 mg, 26%).

[0522] LC-MS(ESI):[M+H] + =196.25.

[0523] Step 3: 3-(2-oxopyridin-1(2H)-yl)propionic acid (compound b-1d)

[0524] Compound b-1c (542 mg, 1.00 eq), lithium hydroxide monohydrate (665 mg, 10.00 eq), tetrahydrofuran (5 mL), and methanol (5 mL) were added to a 50 mL round-bottom flask. The flask was heated to 40 °C and stirred for 2 hours. The reaction solution was concentrated to obtain crude compound b-1d (310 mg). The crude product was used directly in the next reaction step.

[0525] LC-MS(ESI):[M+H] + =168.20.

[0526] Step 4: 1-(3-oxo-3-(5-(4,4,5,5-tetramethyl-1,3,2-dioxoboran-2-yl)-3,6-dihydropyridin-1(2H)-yl)propyl)pyridin-2(1H)-one (compound b-1e)

[0527] Compound a-3b (430 mg, 1.10 eq), compound b-1d (430 mg, 1.20 eq), and pyridine (5 mL) were added to a 50 mL round-bottom flask and placed under an inert atmosphere (N2). The flask was stirred at room temperature for 5 hours. The reaction solution was concentrated to obtain a crude product. The crude product was purified by column chromatography (0-20% DCM / MeOH) to obtain a pale yellow liquid compound b-1e (380 mg, 18%).

[0528] 1 H NMR(400MHz, DMSO-d6)δ7.76–7.60(m,1H),7.40(dddd,J=8.8,6.3,4.0,2.1Hz, 1H),6.53(ddt,J=17.8,4.0,1.9Hz,1H),6.40–6.29(m,1H),6.19(tdd,J=6.7,3. 6,1.3Hz,1H),4.05(q,J=6.9Hz,2H),3.99–3.80(m,2H),3.47(dt,J=23.6,5.8H z,2H),2.70(dt,J=38.2,7.0Hz,2H),2.27–2.02(m,2H),1.21(d,J=1.9Hz,12H).

[0529] LC-MS(ESI):[M+H] + =359.30.

[0530] Step 5: 7-Fluoro-N,N-Dimethyl-4-(4-(4-methylpiperazin-1-yl)phenyl)-6-(1-(3-(2-oxopyridin-1(2H)-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-1H-indole-2-carboxamide (compound b-1)

[0531] Compound b-1a (18 mg, 1.00 eq), compound b-1e (18.65 mg, 1.20 eq), methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (7.3 mg, 0.20 eq), potassium phosphate (27.63 mg, 3.00 eq), and 1,4-dioxane:water = 5:1 (1 mL) were added to a 25 mL round-bottom flask and placed under an inert atmosphere (N2). The flask was stirred at 80 °C for 2 hours. The reaction solution was purified by high pressure to obtain compound b-1 (6 mg, 22%) as a white solid.

[0532] 1 H NMR (400MHz, DMSO-d6) δ12.22–12.10(m,1H),7.72(ddd,J=11.1,6.7,2.1Hz,1H),7.59(dd,J=8.5,4.4H z,2H),7.40(dddd,J=14.9,8.9,6.6,2.1Hz,1H),7.13(d,J=8.6Hz,2H),7.03–6.92(m,1H),6.84(q,J=2. 7Hz,1H),6.41–6.30(m,1H),6.24–6.11(m,2H),4.40–4.28(m,2H),4.09(q,J=6.8Hz,1H),3.93(d,J=13. 2Hz,2H),3.69–3.46(m,5H),3.27–2.97(m,10H),2.88(s,4H),2.41–2.24(m,2H),2.08(d,J=7.9Hz,1H).

[0533] LC-MS(ESI):[M+H] + =611.50.

[0534] Example 10 Synthesis of compound b-2

[0535] 6-(1-(2-(1H-1,2,3-triazol-1-yl)acetyl)-1,2,5,6-tetrahydropyridin-3-yl)-7-fluoro-N,N-dimethyl-4-(4-(4-methylpiperazin-1-yl)phenyl)-1H-indole-2-carboxamide (compound b-2)

[0536] Synthesis scheme

[0537] Step 1: 1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)-3,6-dihydropyridin-1(2H)-yl)-2-(1H-1,2,3-triazol-1-yl)acet-1-one (compound b-2b)

[0538] Compound b-2a (100 mg, 0.79 mmol) and compound a-3b (181 mg, 0.87 mmol) were dissolved in pyridine (2 mL). 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (181 mg, 0.94 mmol) was slowly added to the reaction system, and the reaction was carried out at room temperature for 2 hours. The reaction system was concentrated, and the crude product was purified by column chromatography to give a white solid compound b-2b (39 mg, 16%).

[0539] LC-MS(ESI):[M+H] + =319.30

[0540] Step 2: 6-(1-(2-(1H-1,2,3-triazol-1-yl)acetyl)-1,2,5,6-tetrahydropyridin-3-yl)-7-fluoro-N,N-dimethyl-4-(4-(4-methylpiperazin-1-yl)phenyl)-1H-indole-2-carboxamide (compound b-2)

[0541] Compound b-2b (30 mg, 0.09 mmol), compound b-1b (39 mg, 0.09 mmol), potassium phosphate (60 mg, 0.28 mmol), and methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (16 mg, 0.02 mmol) were dissolved in 1,4-dioxane (1 mL) and water (0.2 mL). The reaction system was carried out at 100 °C for 12 hours under a nitrogen atmosphere. The reaction system was concentrated and purified by high pressure to obtain a white solid compound b-2 (4 mg, 7%).

[0542] 1H NMR(400MHz,DMSO-d6)δ12.20(dd,J=7.7,2.2Hz,1H),8.08–8.01(m,1H),7.78–7.71(m,1H),7. 60(dd,J=14.4,8.5Hz,2H),7.18–7.08(m,2H),6.96(d,J=6.0Hz,1H),6.85(dt,J=7.2,2.6Hz,1 H),6.26–6.17(m,1H),5.60(d,J=6.5Hz,2H),4.49–4.38(m,2H),3.94(d,J=13.2Hz,2H),3.74( d,J=5.7Hz,3H),3.55(d,J=12.2Hz,3H),3.26–2.98(m,9H),2.89(d,J=3.0Hz,3H),2.34(s,1H).

[0543] LC-MS(ESI):[M+H] + =601.60

[0544] Example 11 Synthesis of compound b-3

[0545] 7-Fluoro-N,N-Dimethyl-4-(4-(4-methylpiperazin-1-yl)phenyl)-6-(1-(3-(2-oxopyrrolidone-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-1H-indole-2-carboxamide (compound b-3)

[0546] Synthesis scheme

[0547] Step 1: 1-(3-oxo-3-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-3,6-dihydropyridin-1(2H)-yl)propyl)pyrrolidone-2-one (compound b-3b)

[0548] Compound b-3a (100 mg, 0.64 mmol) and compound a-3b (146 mg, 0.70 mmol) were dissolved in pyridine (2 mL). 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (146 mg, 0.76 mmol) was slowly added to the reaction system, and the reaction was carried out at room temperature for 2 hours. The reaction system was concentrated, and the crude product was purified by column chromatography to give a white solid compound b-3b (100 mg, 43%).

[0549] LC-MS(ESI):[M+H] + =349.35

[0550] Step 2: 7-Fluoro-N,N-Dimethyl-4-(4-(4-methylpiperazin-1-yl)phenyl)-6-(1-(3-(2-oxopyrrolidone-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-1H-indole-2-carboxamide (compound b-3)

[0551] Compound b-3b (30 mg, 0.09 mmol), compound b-1b (36 mg, 0.09 mmol), potassium phosphate (55 mg, 0.26 mmol), and methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (15 mg, 0.02 mmol) were dissolved in 1,4-dioxane (1 mL) and water (0.2 mL). The reaction system was carried out at 100 °C for 12 hours under a nitrogen atmosphere. The reaction system was concentrated and purified by high pressure to obtain a white solid compound b-3 (10 mg, 19%).

[0552] 1 H NMR (400MHz, DMSO-d6) δ12.18(t,J=2.1Hz,1H),7.59(dd,J=8.5,5.6Hz,2H),7.14(d,J=8.8Hz,2H),6.98(dd,J=23 .5,6.1Hz,1H),6.84(t,J=2.5Hz,1H),6.16(qd,J=4.3,2.8,2.2Hz,1H),4.40–4.32(m,2H),3.94(d,J=13.3Hz,2H), 3.66–3.62(m,2H),3.55(d,J=12.0Hz,3H),3.44–3.33(m,4H),3.10(dt,J=65.9,11.4Hz,9H),2.89(d,J=3.9Hz,3H) ,2.62(dt,J=14.3,7.4Hz,2H),2.33(d,J=40.4Hz,2H),2.17(dt,J=20.6,8.1Hz,2H),1.88(dt,J=18.3,7.6Hz,2H).

[0553] LC-MS(ESI):[M+H] + =571.50

[0554] Example 12 Synthesis of compound b-4

[0555] 6-(1-(3-(1H-1,2,3-triazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-7-fluoro-N,N-dimethyl-4-(4-(4-methylpiperazin-1-yl)phenyl)benzothiophene-2-carboxamide (compound b-4)

[0556] Synthesis scheme

[0557] Step 1: 6-Bromo-4-chloro-2,3-difluorobenzaldehyde (compound b-4b)

[0558] Compound b-4a (1 g, 4.39 mmol) was dissolved in ultradry tetrahydrofuran (10 mL) at room temperature, and then cooled to -78 °C with lithium diisopropylamino (2.64 mL, 2 M). The reaction mixture was stirred at this temperature for 2 h under nitrogen protection, followed by the addition of N,N-dimethylformamide (0.64 g, 8.79 mmol), and stirring was continued at -78 °C for another 2 h. After the reaction was complete, it was quenched at -78 °C with saturated ammonium chloride aqueous solution (10 mL), and the mixture was extracted with dichloromethane. The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography (0-10% ethyl acetate / petroleum ether) to give solid compound b-4b (0.97 g, 86.36%).

[0559] 1 H NMR (400MHz, DMSO-d6) δ10.10 (d, J = 1.6 Hz, 1H), 8.07 (d, J = 4.4 Hz, 1H).

[0560] Step 2: Ethyl 4-bromo-6-chloro-7-fluorobenzothiophene-2-carboxylate (compound b-4c)

[0561] Compound b-4b (200 mg, 0.78 mmol) was dissolved in N,N-dimethylformamide (4 mL). Ethyl 2-mercaptoacetate (113 mg, 0.94 mmol) and potassium carbonate (216 mg, 1.57 mmol) were slowly added to the reaction system. After the reaction was complete, pure water (10 mL) was added to the reaction system, and a solid precipitated out. The precipitate was filtered and washed with pure water to obtain a white solid compound b-4c (270 mg, 100%).

[0562] Step 3: 4-Bromo-6-chloro-7-fluorobenzothiophene-2-carboxylic acid (compound b-4d)

[0563] Compound b-4c (270 mg, 0.80 mmol) and lithium hydroxide monohydrate (336 mg, 8.00 mmol) were added to a mixed solution of tetrahydrofuran (4 mL) and methanol (1 mL), and the mixture was stirred at 25 °C for 2 hours. After the reaction was complete, 2 M hydrochloric acid was added dropwise to adjust the pH to approximately 5, and the mixture was extracted three times with ethyl acetate (5 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum to give a white solid compound b-4d (250 mg, 100%).

[0564] LC-MS(ESI):[MH] - =308.75

[0565] Step 4: 4-Bromo-6-chloro-7-fluoro-N,N-dimethylbenzothiophene-2-carboxamide (compound b-4e)

[0566] Compound b-4d (250 mg, 0.81 mmol) was dissolved in N,N-dimethylformamide (5 mL). Dimethylamine (29 mg, 0.65 mmol), N,N,N,N-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea (460 mg, 1.21 mmol), and N,N-diisopropylethylamine (522 mg, 4.04 mmol) were added to the reaction system, and the mixture was stirred at 25 °C for 2 hours. After the reaction was completed, pure water (10 mL) was added to the reaction system, and a solid precipitated out. The solid was filtered and the filter cake was washed with pure water to obtain solid compound b-4e (280 mg, 100%).

[0567] 1 H NMR (400MHz, DMSO-d6) δ8.00(d,J=6.2Hz,1H),7.74(d,J=3.6Hz,1H),3.26(s,3H),3.05(d,J=12.4Hz,3H).

[0568] LC-MS(ESI):[M+H] + =338.05

[0569] Step 5: 6-Chloro-7-fluoro-N,N-dimethyl-4-(4-(4-methylpiperazin-1-yl)phenyl)benzothiophene-2-carboxamide (compound b-4f)

[0570] Compound b-4e (140 mg, 0.42 mmol), compound a-5d (138 mg, 0.46 mmol), potassium carbonate (172 mg, 1.25 mmol), and 1,1-bis(diphenylphosphine)dimerferropalladium dichloride (61.40 mg, 0.08 mmol) were dissolved in 1,4-dioxane (3 mL) and water (0.6 mL). The reaction system was reacted at 100 °C for 2 hours under a nitrogen atmosphere. The reaction system was concentrated, and the crude product was purified by column chromatography to give a yellow solid compound b-4f (85 mg, 47.31%).

[0571] LC-MS(ESI):[M+H] + =432.30

[0572] Step 6: 6-(1-(3-(1H-1,2,3-triazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-7-fluoro-N,N-dimethyl-4-(4-(4-methylpiperazin-1-yl)phenyl)benzothiophene-2-carboxamide (compound b-4)

[0573] Compound b-4f (85 mg, 0.20 mmol) and compound a-3 (65 mg, 0.20 mmol) were dissolved in dioxane:water = 5:1 (2 mL). Methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (33 mg, 0.04 mmol) and potassium phosphate (125 mg, 0.60 mmol) were added. The reaction was carried out at 100 °C for 12 hours under nitrogen protection. After the reaction was complete, the mixture was concentrated under vacuum, and the reaction solution was prepared by reverse reaction to give a white solid compound b-4 (10 mg, 8.44%).

[0574] 1 H NMR(400MHz, DMSO-d6)δ9.80(s,1H),8.11(dd,J=11.7,1.0Hz,1H),7.67(d,J=4.1Hz,1H),7. 54(d,J=8.7Hz,2H),7.35(dd,J=29.0,6.7Hz,1H),7.16(d,J=8.8Hz,2H),6.28(td,J=4.2,2. 2Hz,1H),4.62(q,J=7.0Hz,2H),4.37(dd,J=14.4,2.7Hz,2H),3.97(d,J=13.3Hz,2H),3.65– 3.53(m,5H),3.12(ddt,J=37.5,24.5,7.4Hz,11H),2.89(d,J=3.2Hz,3H),2.40–2.26(m,2H).

[0575] LCMS:[M+H] + =602.50

[0576] Example 13 Synthesis of compound b-5

[0577] 6-(1-(3-(1H-1,2,3-triazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-7-fluoro-N,N-dimethyl-4-(4-(4-methylpiperazin-1-yl)phenyl)benzofuran-2-carboxamide (compound b-5)

[0578] Synthesis scheme

[0579] Step 1: 5-Bromo-3-chloro-2-fluorophenol (compound b-5b)

[0580] Compound b-5a (3.9 g, 17.3 mmol) and trifluoroacetic acid (12 mL) were added to a 250 mL round-bottom flask and placed under an inert atmosphere (N2) to cool the mixture to 0 °C. Then, hexamethylenetetramine (2.9 g, 20.7 mmol) was slowly added to the mixture. The mixture was then stirred at 80 °C for 12 hours. After this, water (20 mL) was added to the mixture at 0 °C, followed by 50% sulfuric acid (20 mL). The mixture was then stirred for 1 hour and filtered, and the filter cake was dried under reduced pressure to obtain a yellow solid compound b-5b (300 mg). The crude product was used directly in the next reaction.

[0581] 1 H NMR (400MHz, DMSO-d6) δ11.85 (s, 1H), 10.17 (s, 1H), 7.57 (d, J = 5.9Hz, 1H).

[0582] LC-MS(ESI): [M+H]-=252.55.

[0583] Step 2: Ethyl 2-(3-bromo-5-chloro-6-fluoro-2-formylphenoxy)acetate (compound b-5c)

[0584] Compound b-5b (350 mg, 1.38 mmol), potassium carbonate (381 mg, 2.76 mmol), potassium iodide (45 mg, 0.27 mmol), and N,N-dimethylformamide (4 mL) were added to a 250 mL round-bottom flask and placed under an inert atmosphere (N2). Ethyl 1-bromoacetic acid (276 mg, 1.65 mmol) was then slowly added to the mixture. The mixture was then stirred at 40 °C for 1 hour. After stirring, the mixture was quenched with 2 M hydrochloric acid, extracted with ethyl acetate (3 x 10 mL), and the organic layer was washed with brine (2 x 10 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated. The crude product was purified by column chromatography (0-40% EA / PE) to give a pale yellow liquid compound b-5c (390 mg, 83.17%).

[0585] 1 H NMR (400MHz, DMSO-d6) δ10.27(s,1H),7.87(d,J=6.1Hz,1H),4.95(d,J=1.3Hz,2H),4.16(q,J=7.1Hz,2H),1.20(t,J=7.1Hz,3H).

[0586] LC-MS(ESI): [M+2H] + =341.10.

[0587] Step 3: Ethyl 4-bromo-6-chloro-7-fluorobenzofuran-2-carboxylate (compounds b-5d)

[0588] Compound b-5c (370 mg, 1.08 mmol), anhydrous magnesium sulfate (196 mg, 1.63 mmol), and toluene (5 mL) were added to a 250 mL round-bottom flask and placed under an inert atmosphere (N2). Then, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (365 mg, 2.39 mmol) was slowly added to the mixture. The mixture was then stirred at 120 °C for 2 hours. After stirring, the mixture was quenched with 1 M hydrochloric acid, extracted with ethyl acetate (3 x 50 mL), the organic layer was washed with brine (2 x 50 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by column chromatography (0-30% EA / PE) to give a pale yellow liquid compound b-5d (220 mg, 62.78%).

[0589] 1 H NMR (400MHz, DMSO-d6) δ7.91(d,J=5.6Hz,1H),7.71(d,J=2.7Hz,1H),4.40(q,J=7.1Hz,2H),1.36(t,J=7.1Hz,3H).

[0590] Step 4: 4-Bromo-6-chloro-7-fluorobenzofuran-2-carboxylic acid (compounds b-5e)

[0591] Compound b-5d (220 mg, 0.68 mmol) and lithium hydroxide monohydrate (287 mg, 6.84 mmol) were added to a mixed solution of tetrahydrofuran (4 mL) and methanol (1 mL), and the mixture was stirred at 25 °C for 2 hours. After the reaction was complete, 2 M hydrochloric acid was added dropwise to adjust the pH to approximately 5, and the mixture was extracted three times with ethyl acetate (5 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum to give a white solid compound b-5e (262 mg, 100%).

[0592] LC-MS(ESI):[M+H] + =292.80

[0593] Step 5: 4-Bromo-6-chloro-7-fluoro-N,N-dimethylbenzofuran-2-carboxamide (compound b-5f)

[0594] Compound b-5e (262 mg, 0.89 mmol) was dissolved in N,N-dimethylformamide (5 mL). Dimethylamine (32 mg, 0.71 mmol), N,N,N,N-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea (506 mg, 1.33 mmol), and N,N-diisopropylethylamine (573 mg, 4.33 mmol) were added to the reaction system, and the mixture was stirred at 25 °C for 2 hours. After the reaction was completed, pure water (10 mL) was added to the reaction system, and a solid precipitated out. The solid was filtered and the filter cake was washed with pure water to obtain solid compound b-5f (250 mg, 100%).

[0595] 1 H NMR (400MHz, DMSO-d6) δ7.85 (d, J = 5.6 Hz, 1H), 7.41 (d, J = 2.8 Hz, 1H), 3.24 (s, 3H), 3.04 (s, 3H).

[0596] LC-MS(ESI):[M+H] + =322.05

[0597] Step 6: 6-Chloro-7-fluoro-N,N-dimethyl-4-(4-(4-methylpiperazin-1-yl)phenyl)benzofuran-2-carboxamide (compound b-5g)

[0598] Compound b-5f (100 mg, 0.31 mmol), compound a-5d (94 mg, 0.31 mmol), potassium carbonate (129 mg, 0.94 mmol), and 1,1-bis(diphenylphosphine)dimerferropalladium dichloride (45.32 mg, 0.06 mmol) were dissolved in 1,4-dioxane (2 mL) and water (0.4 mL). The reaction system was reacted at 100 °C for 2 hours under a nitrogen atmosphere. The reaction system was concentrated, and the crude product was purified by column chromatography to give a yellow solid compound b-5g (150 mg, 29.22%).

[0599] LCMS:[M+H] + =416.30

[0600] Step 7: 6-(1-(3-(1H-1,2,3-triazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-7-fluoro-N,N-dimethyl-4-(4-(4-methylpiperazin-1-yl)phenyl)benzofuran-2-carboxamide (compound b-5)

[0601] Compound b-5 g (80 mg, 0.19 mmol) and compound a-3 (64 mg, 0.19 mmol) were dissolved in dioxane:water = 5:1 (2 mL). Methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (33 mg, 0.04 mmol) and potassium phosphate (122 mg, 0.58 mmol) were added. The reaction was carried out at 100 °C for 12 hours under nitrogen protection. After the reaction was complete, the mixture was concentrated under vacuum, and the reaction solution was prepared by reverse reaction to give a white solid compound b-5 (5 mg, 4.43%).

[0602] 1 H NMR (400MHz, DMSO-d6) δ8.11(d,J=12.2Hz,1H),7.69(d,J=12.7Hz,1H),7.60(dd,J=8.8 ,2.7Hz,2H),7.44(s,1H),7.31(dd,J=28.5,5.8Hz,1H),7.16(d,J=8.6Hz,2H),6.25(td, J=4.3,2.2Hz,1H),4.63(q,J=6.8Hz,2H),4.41–4.32(m,2H),3.97(d,J=13.3Hz,2H),3.6 5(dd,J=18.8,5.8Hz,3H),3.30–2.98(m,13H),2.89(d,J=3.4Hz,3H),2.40–2.27(m,2H).

[0603] LC-MS(ESI):[M+H] + =586.60.

[0604] Example 14 Synthesis of compound b-6

[0605] 5-(1-(3-(1H-1,2,3-triazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-4-fluoro-N,N-dimethyl-7-(4-(4-methylpiperazin-1-yl)phenyl)benzofuran-2-carboxamide (compound b-6)

[0606] Synthesis scheme

[0607] Step 1: 2-Bromo-4-chloro-5-fluorophenol (compound b-6b)

[0608] Compound b-6a (15 g, 1.00 eq) and carbon disulfide (150 mL) were added to a 500 mL round-bottom flask and placed under an inert atmosphere (N2) to cool the mixture to 0 °C. Bromine (16.36 g, 5.24 mL, 1.00 eq) was then slowly added to the mixture. The mixture was then stirred at 25 °C for 12 hours. After completion, the mixture was concentrated under reduced pressure and then quenched with sodium hypochlorite solution. The residue was diluted in ethyl acetate (200 mL), and the organic layer was washed with brine (2 x 200 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated. The crude product was purified by column chromatography (0-40% EA / PE) to give a pale yellow liquid compound b-6b (20.7 g, 89.70%).

[0609] LC-MS(ESI):[MH] - =224.85.

[0610] Step 2: 3-Bromo-5-chloro-6-fluoro-2-hydroxybenzaldehyde (compound b-6c)

[0611] Compound b-6c (20.7 g, 1.00 eq) and trifluoroacetic acid (105 mL) were added to a 250 mL round-bottom flask and placed under an inert atmosphere (N2) to cool the mixture to 0 °C. Then, hexamethylenetetramine (15.67 g, 1.20 eq) was slowly added to the mixture. The mixture was then stirred at 80 °C for 12 hours. After this, water (50 mL) was added to the mixture at 0 °C, followed by 50% sulfuric acid (50 mL). The mixture was then stirred for 1 hour and filtered, and the filter cake was dried under reduced pressure to obtain a yellow solid, compound b-6c (18.8 g). The crude product was used directly in the next reaction.

[0612] Step 3: Ethyl 2-(6-bromo-4-chloro-3-fluoro-2-carboxylphenoxy) (compound b-6d)

[0613] Compound b-6c (18.8 g, 1.00 eq), potassium carbonate (20.5 g, 2.00 eq), potassium iodide (2.46 g, 0.20 eq), and N,N-dimethylformamide (95 mL) were added to a 250 mL round-bottom flask and placed under an inert atmosphere (N2). Ethyl 1-bromoacetic acid (14.87 g, 9.87 mL, 1.20 eq) was then slowly added to the mixture. The mixture was then stirred at 40 °C for 1 hour. After stirring, the mixture was quenched with 2 M hydrochloric acid, extracted with ethyl acetate (3 x 100 mL), and the organic layer was washed with brine (2 x 100 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated. The crude product was purified by column chromatography (0-40% EA / PE) to give a pale yellow liquid compound b-6d (4.84 g, 19.22%).

[0614] 1 H NMR (400MHz, DMSO-d6) δ10.28(d,J=1.1Hz,1H),8.34(d,J=7.7Hz,1H),4.85(s,2H),4.18(q,J=7.1Hz,2H),1.30(s,3H).

[0615] LC-MS(ESI): [M+2H] + =341.10.

[0616] Step 4: Ethyl 7-bromo-5-chloro-4-fluorobenzofuran-2-carboxylate (compound b-6e)

[0617] Compound b-6d (4.84 g, 1.00 eq), anhydrous magnesium sulfate (2.66 g, 1.50 eq), and toluene (50 mL) were added to a 250 mL round-bottom flask and placed under an inert atmosphere (N2). Then, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (4.93 g, 4.68 mL, 2.20 eq) was slowly added to the mixture. The mixture was then stirred at 120 °C for 2 hours. After stirring, the mixture was quenched with 1 M hydrochloric acid, extracted with ethyl acetate (3 x 50 mL), the organic layer was washed with brine (2 x 50 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by column chromatography (0-30% EA / PE) to give a pale yellow liquid compound b-6e (1.02 g, 21.54%).

[0618] 1H NMR (400MHz, DMSO-d6) δ8.15–8.00(m,2H),4.41(q,J=7.1Hz,2H),1.35(t,J=7.1Hz,3H).

[0619] Step 5: 7-Bromo-5-chloro-4-fluorobenzofuran-2-carboxylic acid (compound b-6f)

[0620] Compound b-6e (1.02 g, 1.00 eq) and tetrahydrofuran:methanol = 4:1 (10 mL) were added to a 250 mL round-bottom flask. Then, an aqueous solution of lithium hydroxide monohydrate (0.40 g, 2 mL, 3.00 eq) was slowly added to the mixture. The mixture was then stirred at 40 °C for 12 hours. After this, the reaction mixture was diluted with water (2 mL). Extraction was then performed with dichloromethane (6 mL x 3). The aqueous phase was treated with HCl to adjust the pH to 3–4, and then the mixture was extracted with dichloromethane (4 mL x 3). The organic phases were combined and concentrated under reduced pressure to give a white solid compound b-6f (0.775 g), which was used directly in the next reaction.

[0621] LC-MS(ESI):[MH] - =292.50.

[0622] Step 6: 7-Bromo-5-chloro-4-fluoro-N,N-dimethylbenzofuran-2-carboxamide (compound b-6g)

[0623] Compound b-6f (0.775 g, 1.00 eq), dimethylamine hydrochloride (0.323 g, 1.50 eq), N,N-diisopropylethylamine (3.41 g, 4.60 mL, 10.0 eq), N,N,N,N-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea (1.20 g, 1.20 eq), and N,N-dimethylformamide (10 mL) were added to a 250 mL round-bottom flask. The mixture was then stirred at 0 °C for 2 hours. After stirring, the mixture was poured into water (10 mL) to precipitate a solid. The solid was filtered and dried to obtain compound b-6f (1.1 g), which was used directly in the next reaction.

[0624] LC-MS(ESI): [M+2H] + =322.05.

[0625] Step 7: 5-Chloro-4-fluoro-N,N-dimethyl-7-(4-(4-methylpiperazin-1-yl)phenyl)benzofuran-2-carboxamide (compound b-6h)

[0626] Compound b-6g (70 mg, 1.10 eq), compound a-5d (60 mg, 1.00 eq), potassium carbonate (82.9 mg, 3.00 eq), DPPF palladium dichloride (29.0 mg, 0.20 eq), and dioxane:water = 5:1 (1 mL) were added to a 25 mL round-bottom flask and placed under an inert atmosphere (N2). The mixture was then stirred at 100 °C for 12 hours. After completion, the reaction solution was concentrated. The crude product was purified by column chromatography (0-20% MeOH / DCM) to give compound b-6h (50 mg, 55.05%).

[0627] LC-MS(ESI):[M+H] + =416.30.

[0628] Step 8: 5-(1-(3-(1H-1,2,3-triazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-4-fluoro-N,N-dimethyl-7-(4-(4-methylpiperazin-1-yl)phenyl)benzofuran-2-carboxamide (compound b-6)

[0629] Compound b-6h (20 mg, 1.00 eq), compound a-3 (19.2 mg, 1.20 eq), potassium phosphate (30.7 mg, 3.00 eq), methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (8.20 mg, 0.20 eq), and dioxane:water = 5:1 (1 mL) were added to a 25 mL round-bottom flask and placed under an inert atmosphere (N2). The mixture was then stirred at 80 °C for 2 hours. After completion, the reaction solution was concentrated. The crude product was purified by preparative liquid chromatography (10-40% ACN / H2O) to give compound b-6 (3 mg, 8.86%).

[0630] 1H NMR (400MHz, DMSO-d6) δ8.11(d,J=11.1Hz,1H),7.80(dd,J=8.8,4.1Hz,2H),7.69(d,J=11.5Hz,1H),7 .57(s,1H),7.48(d,J=7.1Hz,1H),7.17(d,J=8.6Hz,2H),6.20–6.16(m,1H),4.63(q,J=6.6Hz,2H),4. 36–4.31(m,2H),3.98(d,J=13.3Hz,2H),3.64(dt,J=20.6,5.8Hz,4H),3.28(s,3H),3.15–2.98(m,6H) ,2.89(d,J=3.7Hz,4H),2.35(ddd,J=12.3,4.8,2.4Hz,2H),2.32–2.24(m,1H),2.00(q,J=7.1Hz,1H).

[0631] LC-MS(ESI):[M+H] + =586.50.

[0632] Example 15 Synthesis of compound g-1

[0633] 7-Fluoro-N,N-Dimethyl-4-(4-(4-methylpiperazin-1-yl)phenyl)-6-(1-(3-(thiazolyl-2-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-1H-indole-2-carboxamide (compound g-1)

[0634] Synthesis scheme

[0635] Step 1: 1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxoboron-2-yl)-3,6-dihydropyridin-1(2H)-yl)-3-(thiazolyl-2-yl)prop-1-one (compound g-1a)

[0636] 3-(thiazol-2-yl)propionic acid (233 mg, 1.42 mmol) was dissolved in N,N-dimethylformamide (4 mL), and N,N-diisopropylethylamine (611 mg, 4.73 mmol) and N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea (900 mg, 2.36 mmol) were added. The mixture was reacted at room temperature for 10 minutes, followed by the addition of compound a-3b (330 mg, 1.57 mmol). The reaction mixture was stirred at 25 °C for 4 hours. After the reaction was complete, the mixture was poured into a saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The crude product was purified by column chromatography to give a yellow oil compound g-1a (480.00 mg, 87%).

[0637] 1 H NMR (400MHz, DMSO-d6) δ7.66(d,J=3.3Hz,1H),7.54(d,J=3.3Hz,1H),6.62–6.44(m,1H),3.98–3.95(m ,2H),3.55–3.44(m,2H),3.23–3.18(m,2H),2.86–2.79(m,2H),2.25–2.08(m,2H),1.22–1.20(m,12H).

[0638] LC-MS(ESI):[M+H] + =349.35

[0639] Step 2: 7-Fluoro-N,N-Dimethyl-4-(4-(4-methylpiperazin-1-yl)phenyl)-6-(1-(3-(thiazolyl-2-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-1H-indole-2-carboxamide (compound g-1)

[0640] Compound g-1a (50 mg, 0.14 mmol), compound b-1b (53 mg, 0.13 mmol), methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (10 mg, 0.014 mmol), potassium phosphate (91 mg, 0.43 mmol), and 1,4-dioxane:water = 5:1 (6 mL) were added to a 50 mL dry round-bottom flask. The system was purged with nitrogen three times and stirred at 100 °C for 2 hours. After the reaction was completed, the system was concentrated under vacuum and then purified by column chromatography to obtain a yellow solid compound g-1 (5 mg, 5.8%).

[0641] 1H NMR (400MHz, DMSO-d6) δ12.19–12.14(m,1H),7.72–7.62(m,1H),7.61–7.51(m,3H),7.13(d,J=8.8Hz,2H),7.04–6.92(m,1H),6.86–6.81(m, 1H),6.19–6.12(m,1H),4.39–4.35(m,2H),3.97–3.90(m,2H),3.69–3 .62(m,2H),3.58–3.51(m,2H),3.29–2.86(m,17H),2.42–2.25(m,2H).

[0642] LC-MS(ESI):[M+H] + =601.45

[0643] Example 16 Synthesis of compound g-2

[0644] 6-(1-(3-(1H-imidazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-7-fluoro-N,N-dimethyl-4-(4-(4-methylpiperazin-1-yl)phenyl)-1H-indole-2-carboxamide (compound g-2)

[0645] Synthesis scheme

[0646] Step 1: 3-(1H-imidazol-1-yl)-1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxoboron-2-yl)-3,6-dihydropyridin-1(2H)-yl)prop-1-one (compound g-2a)

[0647] 3-(1H-imidazol-1-yl)propionic acid (100 mg, 713.56 μmol) and compound a-3b (179.04 mg, 856.27 μmol) were dissolved in N,N-dimethylformamide (2.5 mL), followed by the addition of N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea (325.59 mg, 856.27 μmol) and N,N-diisopropylethylamine (276.68 mg, 2.14 μmol). The mixture was stirred at 25 °C for 1 hour. After the reaction was complete, the mixture was quenched with water, and the aqueous phase was extracted three times with dichloromethane:methanol = 10:1. The combined organic phases were washed once with saturated sodium chloride aqueous solution. The residue was purified by normal chromatography to give a pale yellow oil compound g-2a (26 mg, 11%).

[0648] 1H NMR (400MHz, DMSO-d6) δ7.83(d,J=12.9Hz,1H),7.26(d,J=9.0Hz,1H),6.96(d,J=3.6Hz,1H),6.59–6.48(m,1H),4. 21(t,J=6.8Hz,2H),4.00–3.88(m,2H),3.52–3.45(m,2H),2.87(t,J=6.9Hz,2H),2.23–2.08(m,2H),1.21(s,12H).

[0649] LC-MS(ESI):[M+H] + =332.35.

[0650] Step 2: 6-(1-(3-(1H-imidazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-7-fluoro-N,N-dimethyl-4-(4-(4-methylpiperazin-1-yl)phenyl)-1H-indole-2-carboxamide (compound g-2)

[0651] Compound g-2a (27 mg, 65.07 μmol) was dissolved in 1,4-dioxane / water (1 mL / 0.2 mL), followed by compound b-1b (26 mg, 78.09 μmol), methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (11.02 mg, 13.01 μmol), and potassium phosphate (41.44 mg, 195.22 mmol). The mixture was purged with nitrogen and heated to 80 °C with stirring for 1 hour. After the reaction was complete, the mixture was concentrated under reduced pressure, and the residue was purified by reverse HPLC to give a white solid compound g-2 (3.51 mg, 9%).

[0652] 1 H NMR (400MHz, DMSO-d6) δ12.18(s,1H),9.17–9.05(m,1H),7.83–7.72(m,1H),7.69–7. 60(m,1H),7.61–7.52(m,2H),7.13(d,J=8.7Hz,2H),7.03–6.91(m,1H),6.88–6.81(m, 1H),6.25–6.12(m,1H),4.47–4.40(m,2H),4.40–4.31(m,2H),4.02–3.85(m,2H),3.68 –3.60(m,2H),3.57–3.47(m,2H),3.25–2.94(m,12H),2.89(s,3H),2.43–2.24(m,2H).

[0653] LC-MS(ESI): [M+H]+=584.58.

[0654] Example 17 Synthesis of compound g-3

[0655] 6-(1-(3-(1H-pyrrolo-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-7-fluoro-N,N-dimethyl-4-(4-(4-methylpiperazin-1-yl)phenyl)-1H-indole-2-carboxamide (compound g-3)

[0656] Synthesis scheme

[0657] Step 1: 3-(1H-pyrrolo-1-yl)-1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxoboran-2-yl)-3,6-dihydropyridin-1(2H)-yl)propane-1-one (compound g-3a)

[0658] The synthesis method is the same as that of compound g-2a.

[0659] 1 H NMR(400MHz,DMSO-d6)δ6.77–6.73(m,2H),6.62–6.45(m,1H),5.96–5.91(m,2H),4.13–4.06(m,2H),3.97–3.93(m,1H),3 .89–3.85(m,1H),3.50(t,J=5.7Hz,1H),3.40(t,J=5.7Hz,1H),2.83–2.74(m,2H),2.20–2.08(m,2H),1.23–1.17(m,12H).

[0660] LC-MS(ESI):[M+H] + =331.30.

[0661] Step 2: 6-(1-(3-(1H-pyrrolo-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-7-fluoro-N,N-dimethyl-4-(4-(4-methylpiperazin-1-yl)phenyl)-1H-indole-2-carboxamide (compound g-3)

[0662] The synthesis method is the same as that of compound g-2

[0663] 1H NMR (600MHz, DMSO-d6) δ12.21–12.13(m,1H),9.71(s,1H),7.58(d,J=8.7Hz,2H),7. 13(d,J=8.6Hz,2H),6.99–6.93(m,1H),6.86–6.82(m,1H),6.79–6.74(m,2H),6.18– 6.11(m,1H),5.97–5.91(m,2H),4.39–4.24(m,2H),4.17–4.10(m,2H),3.97–3.90(m ,2H),3.69–3.50(m,4H),3.26–2.95(m,10H),2.91–2.84(m,5H),2.34–2.25(m,2H).

[0664] LC-MS(ESI):[M+H] + =583.58.

[0665] Example 18 Synthesis of compound g-4

[0666] 7-Fluoro-N,N-Dimethyl-4-(4-(4-methylpiperazin-1-yl)phenyl)-6-(1-(3-oxazol-2-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-1H-indole-2-carboxamide (compound g-4)

[0667] Synthesis scheme

[0668] Step 1: Methyl acrylate (E)-3-(oxazol-2-yl)acrylate (compound g-4a)

[0669] Sodium hydride (412.02 mg, 10.3 mmol) was dissolved in DME (25 mL). Methyl 2-(dimethoxyphosphono)acetate (1.88 g, 10.3 mmol) was added at 0 °C under nitrogen protection. The mixture was stirred for 1 hour, cooled to 0 °C, and then oxazole-2-carboxaldehyde (1 g, 10.3 mmol) was added. The mixture was stirred at 25 °C for 15 minutes. After the reaction was complete, the reaction mixture was concentrated under vacuum, and the residue was purified by column chromatography to give the corresponding white solid compound g-4a (1.2 g, 76%).

[0670] 1 H NMR (400MHz, DMSO-d6) δ8.30–8.27(m,1H),7.49–7.45(m,1H),7.37(d,J=16.0Hz,1H),6.71(d,J=16.0Hz,1H),3.76(s,3H).

[0671] LC-MS(ESI):[M+H] + =154.22.

[0672] Step 2: Methyl propionate 3-(oxazol-2-yl)propionate (compound g-4b)

[0673] Compound g-4a (1.2 g, 7.84 mmol) was dissolved in methanol (30 mL), purged with nitrogen, and palladium on carbon (240 mg) was added, followed by purging with hydrogen. The mixture was stirred at 25 °C for 16 hours. After the reaction was complete, the mixture was filtered, and the filtrate was concentrated under reduced pressure and used directly in the next reaction step.

[0674] 1 H NMR (400MHz, CDCl3-d6) δ7.58–7.54(m,1H),7.03–6.99(m,1H),3.70(s,3H),3.10(t,J=7.4Hz,2H),2.83(t,J=7.4Hz,2H).

[0675] LC-MS(ESI):[M+H] + =156.25.

[0676] Step 3: 3-(oxazol-2-yl)propionic acid (compound g-4c)

[0677] Compound g-4b (1.2 g, 7.73 mmol) was dissolved in tetrahydrofuran / water (21 mL / 7 mL). Lithium hydroxide monohydrate (1.62 g, 38.67 mmol) was added, and the mixture was stirred at 25 °C for 1 hour. After the reaction was complete, the pH was adjusted to 1–2 by slowly adding 2 M hydrochloric acid aqueous solution. The mixture was extracted three times with ethyl acetate, and the organic phases were combined. The organic phase was washed twice with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a pale yellow oil g-4c (212 mg, 19%).

[0678] 1 H NMR (400MHz, DMSO-d6) δ7.98–7.96(m,1H),7.10–7.07(m,1H),2.94(t,J=7.1Hz,2H),2.68(t,J=7.0Hz,2H).

[0679] LC-MS(ESI):[M+H] + =142.25.

[0680] Step 4: 3-(oxazol-2-yl)-1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxoboran-2-yl)-3,6-dihydropyridin-1(2H)-yl)propane-1-one (compound g-4d)

[0681] The synthesis method is the same as that of compound g-2a.

[0682] 1 H NMR(400MHz,DMSO-d6)δ7.99–7.93(m,1H),7.10–7.05(m,1H),6.61–6.48(m,1H),4.01–3.92(m,2H),3 .50(t,J=5.6Hz,2H),2.94(t,J=6.9Hz,2H),2.84–2.76(m,2H),2.27–2.08(m,2H),1.26–1.16(m,12H).

[0683] LC-MS(ESI):[M+H] + =333.30.

[0684] Step 5: 7-Fluoro-N,N-Dimethyl-4-(4-(4-methylpiperazin-1-yl)phenyl)-6-(1-(3-oxazol-2-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-1H-indole-2-carboxamide (compound g-4)

[0685] The synthesis method is the same as that of compound g-2

[0686] 1 H NMR (600MHz, DMSO-d6) δ12.19–12.16(m,1H),9.72(s,1H),7.99–7.93(m,1H),7.62–7. 55(m,2H),7.17–7.11(m,2H),7.10–7.05(m,1H),7.03–6.93(m,1H),6.86–6.82(m,1H) ,6.19–6.14(m,1H),4.41–4.34(m,2H),3.97–3.89(m,2H),3.68–3.63(m,2H),3.57–3. 53(m,2H),3.25–3.14(m,5H),3.10–2.96(m,7H),2.93–2.84(m,5H),2.41–2.24(m,2H).

[0687] LC-MS(ESI): [M+H]+=585.58.

[0688] Example 19 Synthesis of compound g-5

[0689] 7-Fluoro-N,N-Dimethyl-4-(4-(4-methylpiperazin-1-yl)phenyl)-6-(1-(3-(pyrimidin-2-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-1H-indole-2-carboxamide (compound g-5)

[0690] Synthesis scheme

[0691] Step 1: 3-(pyrimidin-2-yl)-1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-3,6-dihydropyridin-1(2H)-yl)prop-1-one (compound g-5a)

[0692] The synthesis method is the same as that for compound g-2a.

[0693] 1 H NMR(400MHz, CDCl3)δ8.65(d,J=4.9Hz,2H),7.11(t,J=4.9Hz,1H),6.75–6.57(m,1H),4.20–4.05(m,2H), 3.68–3.53(m,2H),3.35(t,J=7.3Hz,2H),2.98–2.90(m,2H),2.29–2.17(m,2H),1.26(s,6H),1.23(s,6H).

[0694] LC-MS(ESI):[M+H] + =344.49

[0695] Step 2: 7-Fluoro-N,N-Dimethyl-4-(4-(4-methylpiperazin-1-yl)phenyl)-6-(1-(3-(pyrimidin-2-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-1H-indole-2-carboxamide (compound g-5)

[0696] The synthesis method is the same as that for compound g-2.

[0697] 1 H NMR(600MHz,DMSO-d6)δ12.19–12.15(m,1H),9.69–9.55(m,1H),8.74–8.65(m ,2H),7.62–7.55(m,2H),7.35–7.27(m,1H),7.16–7.10(m,2H),7.03–6.93(m,1 H),6.86–6.81(m,1H),6.19–6.14(m,1H),4.44–4.32(m,2H),3.96–3.91(m,2H) ,3.71–3.62(m,2H),3.57–3.52(m,2H),3.24–2.86(m,17H),2.44–2.22(m,2H).

[0698] LC-MS(ESI):[M+H] + =596.58

[0699] Example 20 Synthesis of compound g-6

[0700] 7-Fluoro-6-(1-(3-(isoxazo-5-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-N,N-dimethyl-4-(4-(4-methylpiperazin-1-yl)phenyl)-1H-indole-2-carboxamide (compound g-6)

[0701] Synthesis scheme

[0702] Step 1: Isoxazol-5-ylmethanol (compound g-6b)

[0703] Compound g-6a (1.50 g, 11.81 mmol) was added to a 50 mL three-necked flask, followed by 20 mL of ultra-dry dichloromethane solvent. The reaction mixture was degassed three times with nitrogen, and then cooled to -78 °C. Diisobutylaluminum hydride (14.16 mL, 14.16 mmol) was then added dropwise, and the reaction was stirred at -78 °C for 1 hour. After the reaction was complete, the mixture was concentrated under vacuum and then purified by column chromatography to obtain a clear, oily liquid compound g-6b (0.98 g, 84%).

[0704] 1 H NMR (400MHz, Chloroform-d) δ8.20 (d, J = 1.7Hz, 1H), 6.25 (d, J = 1.7Hz, 1H), 4.79 (s, 2H).

[0705] LC-MS(ESI):[M+H] + =100.15

[0706] Step 2: Isoxazole-5-carboxaldehyde (compound g-6c)

[0707] Compound g-6b (1.20 g, 12.11 mmol) was dissolved in acetonitrile (20 mL), and 2-iodobenzoic acid (6.78 g, 24.22 mmol) was added to the system. The system was reacted at 70 °C for 2 hours. After the reaction was completed, the system was filtered and concentrated under vacuum to obtain a yellow oily liquid compound g-6c (1.18 g, 99%), which was used directly in the next step.

[0708] LC-MS(ESI):[M+H] + =156.20

[0709] Step 3: (E)-3-(isoxazo-5-yl)methyl acrylate (compound g-6d)

[0710] Ethylene glycol dimethyl ether (20 mL) was added to a 100 mL dry three-necked flask. The system was degassed three times with nitrogen. Sodium hydride (0.12 g, 4.94 mmol) and trimethylphosphonoacetate (1.18 g, 6.48 mmol) were added at 0 °C, and the system was stirred at room temperature for 1 hour. Subsequently, compound g-6c (0.48 g, 4.94 mmol) was dissolved in ethylene glycol dimethyl ether (5 mL) and slowly added to the reaction system. The system was stirred at room temperature for 15 minutes. After the reaction was completed, the system was concentrated under vacuum and then purified by column chromatography to obtain compound g-6d (0.63 g, 83%).

[0711] 1 H NMR (600MHz, Chloroform-d) δ8.28(d,J=1.8Hz,1H),7.52(d,J=16.0Hz,1H),6.65(d,J=16.0Hz,1H),6.47(d,J=1.8Hz,1H),3.83(s,3H).

[0712] LC-MS(ESI):[M+H] + =154.10

[0713] Step 4: Methyl 3-(isoxazo-5-yl)propionate (compound g-6e)

[0714] Palladium / carbon (5 mg, 5% wt) was added to a 5 mL solution of compound g-6d (50.00 mg, 0.33 mmol) in ethyl acetate, followed by hydrogen purging. The mixture was stirred at 25 °C for 3 hours. After the reaction was complete, the mixture was filtered. The filtrate was concentrated under reduced pressure and purified by column chromatography to give a white solid compound g-6e (48.00 mg, 95%).

[0715] 1 H NMR (600MHz, Chloroform-d) δ8.15(d,J=1.7Hz,1H),6.03(d,J=1.7Hz,1H),3.70(s,3H),3.12(t,J=7.5Hz,2H),2.74(t,J=7.5Hz,2H).

[0716] LC-MS(ESI):[M+H] + =156.52

[0717] Step 5: 3-(isoxazo-5-yl)propionic acid (compound g-6f)

[0718] Compound g-6e (48.00 mg, 0.31 mmol) was dissolved in a tetrahydrofuran / water (4 / 1) solution, and lithium hydroxide monohydrate (37.12 mg, 1.55 mmol) was added to the system. The mixture was stirred at 25 °C for 2 hours. After the reaction was complete, 2 M hydrochloric acid was added dropwise to adjust the pH to 1-2, followed by extraction three times with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure to give a white solid compound g-6f (40.00 mg, 92%).

[0719] 1 H NMR (600MHz, DMSO-d6) δ8.43 (d, J = 1.7Hz, 1H), 6.26 (d, J = 1.7Hz, 1H), 2.99 (t, J = 7.3Hz, 2H), 2.65 (t, J = 7.4Hz, 2H).

[0720] LC-MS(ESI):[M+H] + =142.06

[0721] Step 6: 6-Chloro-7-fluoro-N,N-dimethyl-4-(4-(4-methylpiperazin-1-yl)phenyl)-1H-indole-2-carboxamide (compound g-6g)

[0722] Compound b-1b (520 g, 1.25 mmol), compound a-3a (580 mg, 1.87 mmol), methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (106 mg, 0.125 mmol), potassium phosphate (798 mg, 3.75 mmol), and 1,4-dioxane / water = 5:1 (20 mL) were added to a 100 mL dry round-bottom flask. The system was purged with nitrogen three times and stirred at 100 °C for 2 hours. After the reaction was completed, the system was concentrated under vacuum and then purified by column chromatography to obtain a yellow solid compound g-6 g (610 mg, 86%).

[0723] LC-MS(ESI): [M+H]+=562.48

[0724] Step 7: 7-Fluoro-N,N-Dimethyl-4-(4-(4-methylpiperazin-1-yl)phenyl)-6-(1,2,5,6-tetrahydropyridin-3-yl)-1H-indole-2-carboxamide (compound g-6h)

[0725] Compound g-6 g (610 mg, 1.08 mmol) was dissolved in dichloromethane (6 mL), and dioxane hydrochloride solution (6 mL) was added. The mixture was stirred at room temperature for 2 hours. After the reaction was complete, the mixture was concentrated under vacuum to obtain a yellow solid compound g-6 h (501 mg, 100%). The product was used directly in the next step without purification.

[0726] LC-MS(ESI): [M+H]+=462.25

[0727] Step 8: 7-Fluoro-6-(1-(3-(isoxazo-5-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-N,N-dimethyl-4-(4-(4-methylpiperazin-1-yl)phenyl)-1H-indole-2-carboxamide (compound g-6)

[0728] Compounds g-6f (13.76 mg, 0.10 mmol) and g-6h (30.00 mg, 0.06 mmol) were dissolved in a solution of N,N-dimethylformamide (3 mL). Then, N,N-diisopropylethylamine (25.20 mg, 0.19 mmol) and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (29.65 mg, 0.08 mmol) were added to the system, and the mixture was stirred at 25 °C for 1 hour. After the reaction was complete, the system was purified by preparative chromatography to give a white solid compound g-6 (3.00 mg, 8%).

[0729] 1 H NMR (600MHz, DMSO-d6) δ8.42–8.34(m,1H),7.61–7.53(m,2H),7.12(d,J=8.4Hz,2H),7.02–6.92(m,1H),6.83(d,J=3.0Hz,1H),6.29–6.21(m ,1H),6.17–6.11(m,1H),4.38–4.30(m,2H),3.94–3.80(m,2H),3.56–3 .37(m,2H),3.27–2.94(m,12H),2.89–2.75(m,5H),2.41–2.33(m,2H).

[0730] LC-MS(ESI):[M+H] + =585.38.

[0731] Example 21 Synthesis of compound g-7

[0732] 7-Fluoro-6-(1-(3-(isoxazo-3-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-N,N-dimethyl-4-(4-(4-methylpiperazin-1-yl)phenyl)-1H-indole-2-carboxamide (compound g-7)

[0733] Synthesis scheme

[0734] Step 1: Isoxazol-3-carboxaldehyde (compound g-7b)

[0735] Compound g-7a (3 g, 30.27 mmol) was dissolved in dichloromethane (60 mL), and Desmartin oxidant (12.84 g, 30.27 mmol) was added at 0 °C. The reaction mixture was stirred at 25 °C for 4 hours. After the reaction was complete, the mixture was filtered through diatomaceous earth, and the filtrate was concentrated to give colorless oil compound g-7b (2.94 g, 100%). The crude product was used directly in the next step without purification (2.94 g, 100%).

[0736] Step 2: Methyl acrylate (E)-3-(isoxazole-3-yl)acrylate (compound g-7c)

[0737] Sodium hydride (1.21 g, 30.28 mmol, 60% wt) was dissolved in ethylene glycol dimethyl ether (40 ml). Methyl 2-(dimethoxyphosphono)acetate (5.51 g, 30.28 mmol) was added under nitrogen protection, and the reaction mixture was stirred at 0 °C for 1 hour. Then, compound g-7b (2.94 g, 30.28 mmol) was added, and the reaction mixture was stirred at 25 °C for 15 minutes. After the reaction was complete, water was added to quench the reaction, and the system was concentrated under vacuum and then purified by column chromatography to give a white solid compound g-7c (2.1 g, 45%).

[0738] 1 H NMR (400MHz, DMSO-d6) δ9.02–8.98(m,1H),7.55(d,J=16.1Hz,1H),7.16(d,J=1.7Hz,1H),6.88(d,J=16.1Hz,1H),3.76(s,3H).

[0739] LC-MS(ESI):[M+H] + =154.22

[0740] Step 3: Methyl 3-(isoxazo-3-yl)propionate (compound g-7d)

[0741] Compound g-7c (1 g, 6.53 mmol) was placed in a 100 mL round-bottom flask, dissolved completely in methanol (10 mL), purged with nitrogen, and then purged with hydrogen after adding 5% palladium / carbon (0.5 g). The reaction was carried out at 50 °C for 4 hours. After the reaction was completed, the reaction mixture was filtered under reduced pressure, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to give a white solid compound g-7d (0.65 g, 64%).

[0742] 1 H NMR (600MHz, Chloroform-d) δ8.31 (d, J = 1.7Hz, 1H), 6.22 (d, J = 1.7Hz, 1H), 3.68 (s, 3H), 3.02 (t, J = 7.5Hz, 2H), 2.74 (t, J = 7.5Hz, 2H).

[0743] LC-MS(ESI):[M+H] + =156.20.

[0744] Step 4: 3-Isoxazol-5-ylpropionic acid (compound g-7e)

[0745] Compound g-7d (0.65 g, 4.19 mmol) was placed in a 100 mL round-bottom flask and dissolved thoroughly in a 3 / 1 (v / v) tetrahydrofuran / water mixture (8 mL). Lithium hydroxide monohydrate (0.88 g, 21 mmol) was added, and the reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the pH of the reaction mixture was adjusted to 1-2 with 2 M hydrochloric acid aqueous solution. The mixture was extracted three times with ethyl acetate, and the organic phase was washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain a white-gray solid compound g-7e (0.46 g, 77%).

[0746] 1 H NMR (400MHz, Chloroform-d) δ8.39–8.27(m,1H),6.32–6.19(m,1H),3.05(t,J=7.4Hz,2H),2.82(t,J=7.4Hz,2H).

[0747] LC-MS(ESI):[M+H] + =142.10.

[0748] Step 5: 7-Fluoro-6-(1-(3-(isoxazol-3-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-N,N-dimethyl-4-(4-(4-methylpiperazin-1-yl)phenyl)-1H-indole-2-carboxamide (compound g-7)

[0749] Compound g-7e (0.46 g, 3.26 mmol) was placed in a 100 mL round-bottom flask and dissolved thoroughly in N,N-dimethylformamide (15 mL). Compound g-6h (0.75 g, 1.62 mmol), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (0.74 g, 1.95 mmol), and N,N-diisopropylethylamine (0.85 mL, 4.87 mmol) were added. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was completed, the reaction mixture was purified by preparative chromatography to give a white solid compound g-7 (0.42 g, 44%).

[0750] 1 H NMR (600MHz, DMSO-d6) δ12.18–12.14(m,1H),8.79–8.73(m,1H),7.61–7.56(m,2H),7. 13(d,J=8.5Hz,2H),7.02–6.94(m,1H),6.84(t,J=2.7Hz,1H),6.54–6.48(m,1H),6.17 –6.14(m,1H),4.39–4.35(m,2H),3.93(d,J=13.3Hz,2H),3.69–3.62(m,2H),3.57–3.5 2(m,2H),3.23–2.98(m,10H),2.94–2.87(m,5H),2.86–2.77(m,2H),2.40–2.25(m,2H).

[0751] LC-MS(ESI):[M+H] + =585.48

[0752] Example 22 Synthesis of compound a-11

[0753] 6-[1-[3-(1H-1,2,3-triazol-1-yl)propionyl]-1,2,5,6-tetrahydropyridin-3-yl]-4-(4-bromophenyl)-7-fluoro-N,N-dimethyl-1H-indole-2-carboxamide (compound a-11)

[0754] Synthesis scheme

[0755] Step 1: 6-[1-[3-(1H-1,2,3-triazol-1-yl)propionyl]-1,2,5,6-tetrahydropyridin-3-yl]-7-fluoro-N,N-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborone-2-yl)-1H-indole-2-carboxamide (compound a-11a)

[0756] Compound A-1a (28 mg, 1.00 eq) was dissolved in dioxane (5 mL), and pinacol diborate (23 mg, 1.5 eq), 1,1-bis(diphenylphosphine)diberberine palladium dichloride (5.3 mg, 0.10 eq), and potassium acetate (18 mg, 3.00 eq) were added. The reaction was carried out overnight at 100 °C under nitrogen protection. After the reaction was completed, water (5 mL) and ethyl acetate (10 mL) were added to the reaction system, and the mixture was extracted three times. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was collected. The filtrate was concentrated under vacuum, and the crude product was purified by column chromatography (0-10% DCM / MeOH) to give a yellow solid compound a-11a (25 mg, 74%).

[0757] 1 H NMR (400MHz, CDCl3) δ7.82–7.74(m,1H),7.71–7.65(m,1H),7.55–7.45(m,1H) ,7.35–7.28(m,1H),6.19–6.07(m,1H),4.81(q,J=6.5Hz,2H),4.49–4.43(m,1H ),4.29–4.23(m,1H),3.81–3.74(m,1H),3.62–3.53(m,1H),3.49(s,3H),3.22 (s,3H),3.11–3.01(m,2H),2.40–2.31(m,2H),1.41–1.37(m,9H),1.28(s,3H).

[0758] LC-MS(ESI):[M+H] + =537.68

[0759] Step 2: 6-(1-(3-(1H-1,2,3-triazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-4-(4-bromophenyl)-7-fluoro-N,N-dimethyl-1H-indole-2-carboxamide (compound a-11)

[0760] Compounds a-11a (50 mg, 1.00 eq) and a-11b (39 mg, 1.2 eq) were dissolved in a mixed solvent of dioxane (3 mL) and water (1 mL). Potassium carbonate (25 mg, 2.00 eq) and dichloro[1,1'-bis(diphenylphosphine)ferrocene]palladium (6.5 mg, 0.1 eq) were added sequentially, and the mixture was stirred at 25 °C. The reaction mixture was then heated to 80 °C and stirred for 12 hours. After the reaction was complete, the mixture was concentrated under reduced pressure, and the crude product was purified by high-pressure pretreatment to obtain a white solid product, compound a-11 (10 mg, 18.97%).

[0761] 1H NMR (400MHz, DMSO-d6) δ12.27(dd,J=6.8,2.1Hz,1H),8.11(d,J=12.1Hz,1H),7.80–7.49(m,5H),7.06(dd,J=24.6,6.0Hz,1H),6.86(m,1H ),6.25–6.08(m,1H),4.62(m,2H),4.35(dd,J=21.2,2.7Hz,2H),3.63(m,3H),3.21–3.01(m,6H),2.39–2.23(m,2H),1.24(d,J=3.1Hz,1H).

[0762] LC-MS(ESI):[M+H] + =565.38

[0763] Example 23 Synthesis of compound a-12

[0764] 6-(1-(3-(1H-1,2,3-triazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-7-fluoro-N,N-dimethyl-4-(4-(piperazin-1-yl)phenyl)-1H-indole-2-carboxamide (compound a-12)

[0765] Synthesis scheme

[0766] Step 1: 4-(4-bromophenyl)piperazine-1-carboxylic acid tert-butyl ester (compound a-12c)

[0767] Compound a-12a (2 g, 1 eq), compound a-12b (2.63 g, 2 eq), potassium carbonate (2.93 g, 3 eq), L-proline (160 mg, 0.2 eq), and cuprous iodide (260 mg, 0.2 eq) were dissolved in dimethyl sulfoxide (20 mL). The reaction mixture was then heated to 80 °C and stirred for 3 hours. After the reaction was complete, the mixture was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to give a yellow solid compound a-12c (2.1 g, 67%).

[0768] 1 H NMR (400MHz, Chloroform-d) δ7.41–7.35(m,2H),6.86–6.79(m,2H),3.61–3.57(m,4H),3.11(t,J=5.1Hz,4H),1.50(s,9H).

[0769] LC-MS(ESI):[M+H] + =341.25

[0770] Step 2: 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl]piperazine-1-carboxylic acid tert-butyl ester (compound a-12d)

[0771] Compound a-12c (1.8 g, 1.00 eq) was dissolved in dioxane (20 mL), and pinacol diborate (4 g, 3 eq), 1,1-bis(diphenylphosphine)diberberine palladium dichloride (771 mg, 0.20 eq), and potassium acetate (1.5 g, 3.00 eq) were added. The reaction was carried out overnight at 100 °C under nitrogen protection. After the reaction was completed, water (5 mL) and ethyl acetate (10 mL) were added to the reaction system, and the mixture was extracted three times. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was collected. The filtrate was concentrated under vacuum, and the crude product was purified by column chromatography (0-20% EA / PE) to give a yellow solid compound a-12d (1.3 g, 63%).

[0772] 1 H NMR (400MHz, DMSO-d6) δ7.54–7.50(m,2H),6.94–6.88(m,2H),3.44(t,J=5.2Hz,4H),3.18(dd,J=6.5,4.0Hz,4H),1.42(s,9H),1.26(s,12H).

[0773] LC-MS(ESI):[M+H] + =389.45.

[0774] Step 3: 4-(4-(6-chloro-2-(dimethylcarbamoyl)-7-fluoro-1H-indol-4-yl)phenyl)piperazine-1-carboxylic acid tert-butyl ester (compound a-12e)

[0775] Compound a-2 (500 mg, 1.56 mmol) and compound a-12d (607 mg, 1.56 mmol) were dissolved in a mixed solvent of dioxane (12 mL) and water (4 mL). Potassium carbonate (648 mg, 4.69 mmol) and dichloro[1,1'-bis(diphenylphosphine)ferrocene]palladium (114 mg, 0.156 mmol) were added sequentially, and the mixture was stirred at 25 °C. The reaction mixture was then heated to 80 °C and stirred for 4 hours. After the reaction was complete, the mixture was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to give a yellow solid compound a-12e (100 mg, 12.76%).

[0776] 1H NMR(400MHz,DMSO-d6)δ12.40(s,1H),7.58–7.47(m,2H),7.14–7.03(m,3H),6.88(d,J=3.0Hz, 1H),3.47(dd,J=7.0,3.7Hz,4H),3.19(d,J=5.2Hz,4H),3.04(s,3H),2.68(s,3H),1.42(s,9H).

[0777] LC-MS(ESI):[M+H] + =501.45

[0778] Step 4: 6-(1-(3-(1H-1,2,3-triazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-7-fluoro-N,N-dimethyl-4-(4-(piperazin-1-yl)phenyl)-1H-indole-2-carboxamide (compound a-12)

[0779] Compound a-12e (100 mg, 0.19 mmol) and compound a-3 (66 mg, 0.19 mmol) were dissolved in a mixed solvent of dioxane (12 mL) and water (4 mL). Potassium phosphate (127 mg, 0.59 mmol) and methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tris-isopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium (16 mg, 0.0019 mmol) were added sequentially and stirred at 25 °C. The reaction mixture was then heated to 80 °C and stirred for 2 hours. The mixture was concentrated under reduced pressure, and the crude product was dissolved in a mixed solvent of dichloromethane (3 mL) and trifluoroacetic acid (3 mL) and reacted at 25 °C for one hour. The reaction mixture was purified by high pressure to give a white solid product, compound a-12 (30 mg, 26.34%).

[0780] 1 H NMR (400MHz, DMSO-d6) δ12.18(dd,J=7.2,2.1Hz,1H),8.11(d,J=11.5Hz,1H),7.69 (d,J=12.2Hz,1H),7.58(dd,J=8.9,2.7Hz,2H),7.12(d,J=8.5Hz,2H),6.97(dd,J= 23.1,6.1Hz,1H),6.84(m,1H),6.23–6.10(m,1H),4.62(m,2H),4.34(dd,J=20.7,2 .6Hz,2H),3.81–3.54(m,4H),3.31–2.86(m,12H),2.41–1.92(m,3H),1.24(m,1H).

[0781] LC-MS(ESI):[M+H] + =571.50

[0782] Example 24 Synthesis of compound a-13

[0783] 6-[1-[3-(1H-1,2,3-triazol-1-yl)propionyl]-1,2,5,6-tetrahydropyridin-3-yl]-7-fluoro-N,N-dimethyl-4-[4-(4-methylpiperazin-1-yl)phenyl]-1H-indole-2-carboxamide (compound a-13)

[0784] Synthesis scheme

[0785] Step 1: 6-[1-[3-(1H-1,2,3-triazol-1-yl)propionyl]-1,2,5,6-tetrahydropyridin-3-yl]-7-fluoro-N,N-dimethyl-4-[4-(4-methylpiperazin-1-yl)phenyl]-1H-indole-2-carboxamide (compound a-13)

[0786] Compound a-12 (30 mg, 0.05 mmol), formaldehyde (1.58 mg, 0.05 mmol), sodium triacetoxyborohydride (36 mg, 0.15 mmol), and acetic acid (0.1 mL) were dissolved in dimethyl sulfoxide (4 mL), and the reaction system was reacted at room temperature for 1 hour. The reaction system was purified by high pressure to give a white solid product a-13 (20 mg, 65%).

[0787] 1 H NMR (600MHz, DMSO-d6) δ12.19(d,J=10.6Hz,1H),8.12(d,J=17.1Hz,1H),7.70(d,J=19.0Hz,1 H),7.62–7.47(m,2H),7.36–7.10(m,2H),7.09–6.92(m,1H),6.75(d,J=1.7Hz,1H),6.19–6.0 9(m,1H),5.66(s,2H),4.63(m,2H),4.41–4.25(m,2H),3.93(d,J=13.3Hz,2H),3.70–3.60(m, 2H),3.24–2.97(m,10H),2.89(d,J=3.4Hz,2H),2.41–2.25(m,2H),2.00(m,1H),1.24(m,2H).

[0788] LC-MS(ESI):[M+H] + =585.50

[0789] Example 25 Synthesis of compound a-14

[0790] 6-(1-Acetyl-1,2,5,6-tetrahydropyridin-3-yl)-7-fluoro-N,N-di-4-(4-(4-methylpiperazin-1-yl)phenyl)-1H-indole-2-carboxamide (compound a-14)

[0791] Synthesis scheme

[0792] Step 1: 6-Chloro-7-fluoro-N,N-dimethyl-4-(4-(4-methylpiperazin-1-yl)phenyl)-1H-indole-2-carboxamide (compounds a-14b)

[0793] Compound a-2 (300 mg, 940 μmol) and compound a-14a (312 mg, 1.03 mmol) were dissolved in 1,4-dioxane:water = 5:1 (6 mL). Dichloro[1,1'-bis(diphenylphosphine)ferrocene]palladium (68 mg, 94 μmol) and potassium carbonate (390 mg, 2.8 mmol) were added. The mixture was stirred at 100 °C for 2 hours under nitrogen protection. After the reaction was complete, the mixture was concentrated under reduced pressure. The crude product was purified by normal phase chromatography to obtain the yellow solid product compound a-14b (250 mg, 64.2%).

[0794] 1 H NMR(400MHz,Chloroform-d)δ9.56(s,1H),7.56–7.48(m,2H),7.14–7.03(m,3H),6.97(dd,J =3.2,2.2Hz,1H),3.44–3.30(m,7H),3.24–3.21(m,3H),2.66(t,J=5.0Hz,4H),2.42(s,3H).

[0795] LC-MS(ESI):[M+H] + =415.30

[0796] Step 2: Tert-butyl 5-(2-(dimethylcarbonyl)-7-fluoro-4-(4-(4-methylpiperazin-1-yl))-1H-indol-6-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid ester (compound a-14d)

[0797] Compounds a-14b (250 mg, 602 μmol) and a-14c (196 mg, 602 μmol) were dissolved in 1,4-dioxane:water = 5:1 (6 mL). Methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tris-isopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium (51 mg, 60 μmol) and potassium phosphate (384 mg, 1.8 mmol) were added. The mixture was stirred at 100 °C for 2 hours under nitrogen protection. After the reaction was complete, the mixture was concentrated under reduced pressure. The crude product was purified by normal-phase chromatography to obtain a yellow solid product a-14d (210 mg, 62.1%).

[0798] 1 H NMR(400MHz,Chloroform-d)δ9.72(s,1H),7.58(d,J=8.2Hz,2H),7.04(dd,J=22.2,7.2Hz,3H),6.94(t,J=2.7Hz,1H),6.16(s,1H),4.33(s,2H) ,3.77(d,J=11.9Hz,4H),3.62(t,J=5.8Hz,2H),3.48–3.35(m,5H),3.23 (s,3H),3.13–3.07(m,2H),2.94(s,3H),2.41–2.33(m,2H),1.51(s,9H).

[0799] LC-MS(ESI):[M+H] + =562.55

[0800] Step 3: 7-Fluoro-N,N-Dimethyl-4-(4-(4-methylpiperazin-1-yl)phenyl)-6-(1,2,,6-tetrahydropyridin-3-yl)-1H-indole-2-carboxamide (compound a-14e)

[0801] Compound a-14d (250 mg, 445 μmol) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (3 mL) was added. The mixture was stirred at room temperature for 1 hour. After the reaction was complete, the solution was concentrated under reduced pressure to give a crude brown oily compound a-14e (240 mg).

[0802] LC-MS(ESI):[M+H] + =462.58

[0803] Step 4: 6-(1-acetyl-1,2,5,6-tetrahydropyridin-3-yl)-7-fluoro-N,N-dimethyl-4-(4-(4-methylpiperazin-1-yl)phenyl)-1H-indole-2-carboxamide (compound a-14)

[0804] Compound a-14e (30 mg, 65 μmol) was dissolved in dichloromethane (2 mL) at 0 °C, and triethylamine (20 mg, 195 μmol) and acetic anhydride (6.6 mg, 65 μmol) were added. The mixture was stirred at 0 °C for 1 hour. After the reaction was complete, the mixture was concentrated under reduced pressure, and the crude product was purified by reversed-phase chromatography to give a white solid product, compound a-14 (10.8 mg, 33%).

[0805] 1 H NMR (600MHz, DMSO-d6) δ12.18(s,1H),7.59(t,J=8.1Hz,2H),7.14(d,J=8.3Hz,2H) ,6.98(dd,J=36.7,6.0Hz,1H),6.85–6.84(m,1H),6.17–6.15(m,1H),4.37–4.32(m, 2H),3.94(d,J=13.3Hz,2H),3.66–3.59(m,2H),3.55(d,J=12.0Hz,2H),3.21–3.17 (m,5H),3.07–2.98(m,5H),2.89(s,3H),2.40–2.25(m,2H),2.09(d,J=11.9Hz,3H).

[0806] LC-MS(ESI):[M+H] + =504.45

[0807] Example 26 Synthesis of compound a-15

[0808] 7-Fluoro-N,N-Dimethyl-4-(4-(4-methylpiperazin-1-yl)phenyl)-6-(1-propionyl-1,2,5,6-tetrahydropyridin-3-yl)-1H-indole-2-carboxamide (compound a-15)

[0809] Synthesis scheme

[0810] Step 1: 7-Fluoro-N,N-Dimethyl-4-[4-(4-methylpiperazin-1-yl)phenyl]-6-(1-propionyl-1,2,5,6-tetrahydropyridin-3-yl)-1H-indole-2-carboxamide (Compound a-15)

[0811] At 0°C, α-14e (30 mg, 65 μmol) was dissolved in dichloromethane (2 mL), and triethylamine (20 mg, 195 μmol) and acryloyl chloride (6 mg, 65 μmol) were added. The mixture was stirred at 0°C for 1 hour. After the reaction was complete, the solution was concentrated under reduced pressure, and the crude product was purified by reversed-phase chromatography to give a white solid product, compound α-15 (14.9 mg, 44.3%).

[0812] 1 H NMR (600MHz, DMSO-d6) δ12.20–12.12(m,1H),7.60–7.57(m,2H),7.14(d,J=8.4Hz,2H ),6.98(dd,J=30.4,6.0Hz,1H),6.85–6.84(m,1H),6.18–6.11(m,1H),4.40–4.30(m,2 H),3.93(d,J=13.2Hz,2H),3.66–3.60(m,2H),3.54(d,J=12.0Hz,2H),3.21–3.16(m, 5H), 3.05 (t, J = 12.3Hz, 5H), 2.88–2.86 (m, 3H), 2.45–2.25 (m, 4H), 1.11–0.91 (m, 3H).

[0813] LC-MS(ESI):[M+H] + =518.45

[0814] Example 27 Synthesis of compound a-16

[0815] 6-(1-(3-acetylaminopropionyl)-1,2,5,6-tetrahydropyridin-3-yl)-7-fluoro-N,N-dimethyl-4-(4-(4-methylpiperazin-1-yl)phenyl)-1H-indole-2-carboxamide (compound a-16)

[0816] Synthesis scheme

[0817] Step 1: Tert-butyl (3-(5-(2-(dimethylcarbamoyl)-7-fluoro-4-(4-(4-methylpiperazin-1-yl)phenyl)-1H-indol-6-yl)-1,2,3,6-tetrahydropyridin-1-yl)-3-oxopropyl)carbamate (compound a-16b)

[0818] Compound a-14e (180 mg, 390 μmol) was dissolved in N,N-dimethylformamide (3 mL), and compound a-16a (74 mg, 390 μmol), HATU (148 mg, 390 μmol), and DIEA (151 mg, 1.17 mol) were added. The mixture was stirred at room temperature for 1 hour. After the reaction was complete, the mixture was concentrated under reduced pressure, and the crude product was purified by normal phase chromatography to obtain a yellow oily compound a-16b (200 mg, 81%).

[0819] LC-MS(ESI):[M+H] + =633.65

[0820] Step 2: 6-(1-(3-aminopropionyl)-1,2,5,6-tetrahydropyridin-3-yl)-7-fluoro-N,N-dimethyl-4-(4-(4-methylpiperazin-1-yl)phenyl)-1H-indole-2-carboxamide (compound a-16c)

[0821] Compound a-16b (200 mg, 316 μmol) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (3 mL) was added. The mixture was stirred at room temperature for 1 hour. After the reaction was complete, the solution was concentrated under reduced pressure to give a crude yellow oily compound a-16c (180 mg).

[0822] LC-MS(ESI):[MH] - =531.30

[0823] Step 3: 6-(1-(3-acetamidopropionyl)-1,2,5,6-tetrahydropyridin-3-yl)-7-fluoro-N,N-dimethyl-4-(4-(4-methylpiperazin-1-yl)phenyl)-1H-indole-2-carboxamide (compound a-16)

[0824] At 0 °C, 30 mg (56 μmol) of a-16c was dissolved in 2 mL of dichloromethane, and triethylamine (17 mg, 169 μmol) and acetic anhydride (6 mg, 56 μmol) were added. The mixture was stirred at 0 °C for 1 hour. After the reaction was complete, the solution was concentrated under reduced pressure, and the crude product was purified by reversed-phase chromatography to obtain a white solid product, compound a-16 (9 mg, 27.8%).

[0825] 1 H NMR (400MHz, DMSO-d6) δ12.18(s,1H),7.90–7.84(m,1H),7.61–7.56(m,2H),7.19–7. 10(m,2H),6.98(dd,J=24.4,6.1Hz,1H),6.84(t,J=2.6Hz,1H),6.17–6.15(m,1H),4.3 7–4.33(m,2H),3.94(d,J=13.2Hz,2H),3.69–3.50(m,4H),3.30–3.11(m,7H),3.05-2. 99(m,5H),2.89(s,3H),2.59–2.52(m,2H),2.37–2.29(m,2H),1.77(d,J=17.1Hz,3H).

[0826] LC-MS(ESI):[M+H] + =575.90

[0827] Example 28 Synthesis of compound a-17

[0828] 4-(4-bromophenyl)-6-(1-(3-(5,6-dihydrocyclopentano[c]pyrazol-1(4H)-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-7-fluoro-N,N-dimethyl-1H-indole-2-carboxamide (compound a-17)

[0829] Step 1: Ethyl 3-(5,6-dihydrocyclopentano[c]pyrazole-1(4H)-yl)propionate (compound a-17a)

[0830] 1,4,5,6-Tetrahydrocyclopentano[c]pyrazole (1.8 g, 16.7 mmol) was dissolved in ethyl acrylate (5 mL), and pyridine (132 mg, 1.7 mmol) was added to the reaction system. The reaction was heated to 90 °C and reacted for 4 hours. After completion, the mixture was concentrated under vacuum to give a crude product. The crude product was purified by reverse-phase column chromatography (C18, 40 g; conditions: water / acetonitrile = 100% / 0% to 0% / 100%, 0.1% trifluoroacetic acid) and lyophilized to give a pale yellow oily compound a-17a (1 g, 28.9%).

[0831] 1 H NMR(600MHz,DMSO-d6)δ7.14(s,1H),4.19(t,J=6.6Hz,2H),4.08–4.01(m,2H),2.81(t,J=6.6H z,2H),2.69(t,J=7.3Hz,2H),2.52(d,J=6.4Hz,2H),2.48–2.42(m,2H),1.15(t,J=7.1Hz,3H).

[0832] LC-MS(ESI):[M+H] + =209.25.

[0833] Step 2: 3-(5,6-dihydrocyclopentan[c]pyrazole-1(4H)-yl)propionic acid (compound a-17b)

[0834] Compound a-17a (800 mg, 3.8 mmol) and lithium hydroxide monohydrate (322.4 mg, 7.7 mmol) were added to a mixed solution of tetrahydrofuran (4 mL) and water (4 mL), and the mixture was stirred at 25 °C for 2 hours. After the reaction was complete, 1 M hydrochloric acid was added dropwise to adjust the pH to approximately 5, and the mixture was then lyophilized to obtain a crude white solid compound a-17b (1 g).

[0835] 1H NMR (600MHz, DMSO-d6) δ7.04(s,1H),4.10(t,J=6.8Hz,2H),2.65(dt,J=10.0,6.9Hz,4H),2.48(d,J=6.9Hz,2H),2.43(q,J=6.8Hz,2H).

[0836] LC-MS(ESI):[M+H] + =181.25.

[0837] Step 3: 3-(5,6-dihydrocyclopentano[c]pyrazol-1(4H)-yl)-1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxoboronocyclopentan-2-yl)-3,6-dihydropyridin-1(2H)-yl)prop-1-one (compound a-17c)

[0838] Compound a-17b (800 mg, 4.4 mmol) and compound a-3b (1.0 g, 4.9 mmol) were dissolved in pyridine (8 mL). 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.0 g, 5.3 mmol) was added to the reaction system, and the reaction mixture was reacted at room temperature for 2 hours. After completion, the reaction mixture was concentrated under reduced pressure, and the crude product was purified by column chromatography to give a white solid compound a-17c (520 mg, 31.6%).

[0839] 1 H NMR (600MHz, DMSO-d6) δ7.05(d,J=7.4Hz,1H),6.57–6.48(m,1H),4.16–4.13(m,2H),3.83(d,J=2.8Hz,1H),3.49–3.47(m,1H),3.40(t,J=5 .8Hz,1H),3.35(s,1H),2.85–2.80(m,2H),2.70–2.64(m,2H),2.49–2 .48(m,2H),2.46–2.41(m,2H),2.16–2.09(m,2H),1.22–1.20(m,12H).

[0840] LC-MS(ESI):[M+H] + =372.40.

[0841] Step 4: 4-Chloro-6-(1-(3-(5,6-dihydrocyclopentano[c]pyrazol-1(4H)-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-7-fluoro-N,N-dimethyl-1H-indole-2-carboxamide (compound a-17d)

[0842] Compounds a-17c (200 mg, 0.5 mmol) and a-1 (172 mg, 0.5 mmol) were dissolved in a mixed solvent of dioxane (2 mL) and water (0.4 mL). Potassium carbonate (223 mg, 1.6 mmol) and dichloro[1,1'-bis(diphenylphosphine)ferrocene]palladium (59 mg, 0.1 mmol) were added sequentially, and the mixture was stirred at 25 °C. The reaction mixture was then heated to 80 °C and stirred for 2 hours. After the reaction was complete, the mixture was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography to finally obtain a yellow solid compound a-17d (150 mg, 57.5%).

[0843] 1 H NMR(400MHz, DMSO-d6)δ12.48(s,1H),7.14–6.99(m,2H),6.83(dt,J=3.6,1.8Hz,1H),6.17–6.07(m,1H),4.35–4.12(m,4H),3.62 –2.52(m,2H),3.24–3.05(m,6H),2.94–2.88(m,2H),2.72–2.64(m,2H),2.48–2.41(m,2H),2.32–2.21(m,2H),1.36–1.21(m,2H).

[0844] LC-MS(ESI):[M+H] + =484.40.

[0845] Step 5: 6-(1-(3-(5,6-dihydrocyclopentano[c]pyrazol-1(4H)-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-7-fluoro-N,N-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboronecyclo-2-yl)-1H-indole-2-carboxamide (compound a-17e)

[0846] Compound a-17d (70 mg, 0.1 mmol), pinacol diboronate (73 mg, 0.2 mmol), methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tris-isopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (25 mg, 0.02 mmol), and potassium acetate (43 mg, 0.3 mmol) were added to 1,4-dioxane (3.5 mL). The reaction was carried out overnight at 80 °C under a nitrogen atmosphere. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated. The crude product was purified by column chromatography to give a yellow solid compound a-17e (43 mg, 51.7%).

[0847] 1H NMR (400MHz, DMSO-d6) δ12.13–11.90(m,1H),7.41–7.30(m,1H),7.05(d,J=25.1Hz,2H),6.55(s,1H),4.51–4.13(m,4H),3.59(d,J=29.2Hz, 2H),3.12(d,J=45.8Hz,6H),2.94–2.84(m,2H),2.67(d,J=7.1Hz,2H),2.45(s,2H),2.27(s,2H),2.06–1.83(m,2H),1.28(d,J=38.8Hz,12H).

[0848] LC-MS(ESI):[M+H] + =576.55.

[0849] Step 6: 4-(4-bromophenyl)-6-(1-(3-(5,6-dihydrocyclopentano[c]pyrazol-1(4H)-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-7-fluoro-N,N-dimethyl-1H-indole-2-carboxamide (compound a-17)

[0850] Compound a-17e (30 mg, 0.05 mmol), 1-bromo-4-iodobenzene (15 mg, 0.05 mmol), palladium dichloride bis(triphenylphosphine) (4 mg, 0.01 mmol), and potassium carbonate (22 mg, 0.15 mmol) were dissolved in 1,4-dioxane (0.5 mL) and water (0.1 mL). The reaction system was reacted at 80 °C for 4 hours under a nitrogen atmosphere. The reaction system was concentrated, and the crude product was purified by high performance liquid chromatography to give a white solid compound a-17 (3 mg, 9.5%).

[0851] 1 H NMR (400MHz, DMSO-d6) δ12.27(s,1H),7.73–7.60(m,3H),7.12–6.98(m,2H),6.89–6.83(m,1H),6.67(s,1H),6.16(d,J=10.5Hz,1H),4.39–4. 15(m,4H),3.12(d,J=59.2Hz,6H),2.93(d,J=6.9Hz,2H),2.69(s,2H), 2.37–2.24(m,2H),2.05–1.86(m,2H),1.55–1.40(m,2H),1.24(s,2H).

[0852] LC-MS(ESI):[M+H] + =604.40.

[0853] Example 29 Synthesis of compound b-8

[0854] 6-(1-(3-(1H-1,2,3-triazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-N-cyclopropyl-7-fluoro-N-methyl-4-(4-(4-methylpiperazin-1-yl)phenyl)-1H-indole-2-carboxamide (compound b-8)

[0855] Synthesis scheme

[0856] Step 1: 6-Bromo-4-chloro-7-fluoro-1H-indole-2-carboxylic acid (compound b-8a)

[0857] Methyl 6-bromo-4-chloro-7-fluoro-1H-indole-2-carboxylate (400 mg, 1.30 mmol) and lithium hydroxide monohydrate (164 mg, 3.91 mmol) were added to a mixed solution of tetrahydrofuran (8 mL) and methanol (2 mL), and the mixture was stirred at 25 °C for 2 hours. After the reaction was complete, 2 M hydrochloric acid was added dropwise to adjust the pH to approximately 5, and the mixture was extracted three times with dichloromethane (10 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum to give a white solid compound b-8a (450 mg, 100%).

[0858] LC-MS(ESI):[MH] - =291.90

[0859] Step 2: 6-Bromo-4-chloro-N-cyclopropyl-7-fluoro-N-methyl-1H-indole-2-carboxamide (compound b-8b)

[0860] Compound b-8a (140 mg, 0.48 mmol) was dissolved in N,N-dimethylformamide (3 mL). N-methylcyclopropylamine hydrochloride (77 mg, 0.72 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate (218 mg, 0.57 mmol), and N,N-diisopropylethylamine (619 mg, 4.79 mmol) were added to the reaction system, and the mixture was stirred at 25 °C for 2 hours. After the reaction was complete, pure water (6 mL) was added to the reaction system, and a solid precipitated out. The precipitate was filtered and washed with pure water to obtain solid compound b-8b (290 mg, 100%).

[0861] LC-MS(ESI):[M+H] + =347.15

[0862] Step 3: 6-(1-(3-(1H-1,2,3-triazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-4-chloro-N-cyclopropyl-7-fluoro-N-methyl-1H-indole-2-carboxamide (compound b-8c)

[0863] Compound b-8b (140 mg, 0.41 mmol), compound a-3 (148 mg, 0.45 mmol), potassium carbonate (168 mg, 1.21 mmol), and 1,1-bis(diphenylphosphine)diferropalladium dichloride (63 mg, 0.08 mmol) were dissolved in 1,4-dioxane (3 mL) and water (0.6 mL). The reaction system was reacted at 100 °C for 12 hours under a nitrogen atmosphere. The reaction system was concentrated, and the crude product was purified by column chromatography to give a yellow solid compound b-8c (180 mg, 94.38%).

[0864] LC-MS(ESI):[M+H] + =471.35

[0865] Step 4: 4-(4-(6-(1-(3-(1H-1,2,3-triazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-2-(cyclopropyl(methyl)carbamoyl)-7-fluoro-1H-indol-4-yl)phenyl)piperazine-1-carboxylic acid tert-butyl ester (compound b-8d)

[0866] Compound b-8c (120 mg, 0.25 mmol), tert-butyl piperazine-1-carboxylate (99 mg, 0.25 mmol), potassium phosphate (162 mg, 0.76 mmol), and methanesulfonic acid (2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (43 mg, 0.05 mmol) were dissolved in 1,4-dioxane (2 mL) and water (0.4 mL). The reaction system was carried out at 60 °C for 2 hours under a nitrogen atmosphere. The reaction system was concentrated, and the crude product was purified by column chromatography to give a yellow solid compound b-8d (110 mg, 61.95%).

[0867] LC-MS(ESI):[M+H] + =697.60

[0868] Step 5: 6-(1-(3-(1H-1,2,3-triazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-N-cyclopropyl-7-fluoro-N-methyl-4-(4-(piperazin-1-yl)phenyl)-1H-indole-2-carboxamide (compound b-8e)

[0869] Compound b-8d (50 mg, 0.07 mmol) was dissolved in dichloromethane (1 mL), and 1 mL of 1,4-dioxane hydrochloric acid solution (4N) was slowly added dropwise. The mixture was stirred at 25 °C for 1 hour. The reaction mixture was then concentrated under reduced pressure to obtain crude compound b-8e (50 mg, 100%).

[0870] LC-MS(ESI):[M+H] + =597.55

[0871] Step 6: 6-(1-(3-(1H-1,2,3-triazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-N-cyclopropyl-7-fluoro-N-methyl-4-(4-(4-methylpiperazin-1-yl)phenyl)-1H-indole-2-carboxamide (compound b-8)

[0872] Compound b-8e (50 mg, 0.08 mmol), paraformaldehyde (11 mg, 0.12 mmol), sodium triacetoxyborohydride (36 mg, 0.17 mmol), and acetic acid (0.1 mL) were dissolved in dimethyl sulfoxide (1 mL), and the reaction mixture was reacted at room temperature for 12 hours. The reaction mixture was purified by high pressure to give compound b-8 (2 mg, 4%) as a white solid product.

[0873] 1 H NMR(400MHz,DMSO-d6)δ9.63(s,1H),8.15–8.07(m,1H),7.72–7.65(m,1H),7.58(dd,J=8.9,2.6Hz ,1H),7.38(t,J=9.7Hz,1H),7.17–6.85(m,4H),6.16(d,J=12.8Hz,1H),4.63(dd,J=8.7,5.8Hz,2H ),4.35(d,J=20.1Hz,2H),3.92(s,2H),3.70–3.56(m,3H),3.45(s,2H),3.20–2.97(m,8H),2.87(s ,3H),2.32(d,J=31.6Hz,3H),1.46(s,1H),1.38–1.29(m,1H),0.75(d,J=6.2Hz,1H),0.62(s,1H).

[0874] LC-MS(ESI):[M+H] + =611.50

[0875] Example 30 Synthesis of compound b-9

[0876] 6-(1-(3-(1H-1,2,3-triazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-7-fluoro-N-methyl-4-(4-(4-methylpiperazin-1-yl)phenyl)-1H-indole-2-carboxamide (compound b-9)

[0877] Synthesis scheme

[0878] The synthesis steps are the same as those for compound b-10.

[0879] White solid product compound b-9 (2 mg, 17.35%).

[0880] 1 H NMR(400MHz,DMSO-d6)δ12.15(s,1H),8.53–8.47(m,1H),8.14–8.09(m,1H),7.72–7.66(m,1 H),7.62–7.54(m,2H),7.29–7.24(m,1H),7.19–7.12(m,2H),7.02–6.91(m,1H),6.18–6.11( m,1H),4.67–4.58(m,2H),4.34(d,J=20.1Hz,2H),4.00–3.88(m,2H),3.69–3.52(m,4H),3.2 6–3.15(m,3H),3.13–2.97(m,4H),2.91–2.88(m,2H),2.82–2.79(m,2H),2.39–2.23(m,3H).

[0881] LC-MS(ESI):[M+H] + =571.50

[0882] Example 31 Synthesis of compound b-10

[0883] 1-(5-(2-(azacyclobutane-1-carbonyl)-7-fluoro-4-(4-(4-methylpiperazin-1-yl)phenyl)-1H-indol-6-yl)-3,6-dihydropyridin-1(2H)-yl)-3-(1H-1,2,3-triazol-1-yl)prop-1-one (compound b-10)

[0884] Synthesis scheme

[0885] Step 1: Methyl 4-(4-(4-tert-butoxycarbonylpiperazin-1-yl)phenyl)-6-chloro-7-fluoro-1H-indole-2-carboxylate (compound b-10a)

[0886] Methyl 6-bromo-4-chloro-7-fluoro-1H-indole-2-carboxylate (215 mg, 0.70 mmol), tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborin-2-yl)phenyl)piperazine-1-carboxylate (300 mg, 0.77 mmol), potassium carbonate (291 mg, 1.20 mmol), and 1,1-bis(diphenylphosphine)diberberine palladium dichloride (107 mg, 0.14 mmol) were dissolved in 1,4-dioxane (5 mL) and water (1 mL). The reaction system was carried out at 100 °C for 2 hours under a nitrogen atmosphere. The reaction system was concentrated, and the crude product was purified by column chromatography to give a yellow solid compound b-10a (100 mg, 29.22%).

[0887] LC-MS(ESI):[M+H] + =488.35

[0888] Step 2: Methyl 6-(1-(3-(1H-1,2,3-triazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-4-(4-(4-(4-(tert-butoxycarbonyl)piperazin-1-yl)phenyl)-7-fluoro-1H-indole-2-carboxylate (compound b-10b)

[0889] Compound b-10a (100 mg, 0.20 mmol), compound a-3 (68 mg, 0.20 mmol), potassium phosphate (131 mg, 0.61 mmol), and methanesulfonic acid (2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (35 mg, 0.04 mmol) were dissolved in 1,4-dioxane (2 mL) and water (0.4 mL). The reaction system was carried out at 60 °C for 2 hours under a nitrogen atmosphere. The reaction system was concentrated, and the crude product was purified by column chromatography to give a yellow solid compound b-10b (150 mg, 54.07%).

[0890] 1H NMR (400MHz, DMSO-d6) δ12.60(s,1H),8.11(d,J=17.5Hz,1H),7.69(d,J=17.9Hz,1H),7.56– 7.51(m,2H),7.21(s,1H),7.04(dd,J=63.3,7.0Hz,3H),6.18(s,1H),4.63(dt,J=13.8,6.9Hz ,2H),4.36(d,J=29.6Hz,2H),3.95(s,3H),3.63(dt,J=33.4,5.7Hz,2H),3.49(t,J=5.2Hz,4 H), 3.19 (t, J = 5.2Hz, 4H), 3.10 (dt, J = 14.1, 6.9Hz, 2H), 2.32 (d, J = 46.5Hz, 2H), 1.44 (s, 9H).

[0891] LC-MS(ESI):[M+H] + =658.45

[0892] Step 3: 6-(1-(3-(1H-1,2,3-triazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-4-(4-(4-(4-(tert-butoxycarbonyl)piperazin-1-yl)phenyl)-7-fluoro-1H-indole-2-carboxylic acid (compound b-10c)

[0893] Compound b-10b (150 mg, 0.23 mmol) and lithium hydroxide monohydrate (96 mg, 2.28 mmol) were added to a mixed solution of tetrahydrofuran (4 mL) and methanol (1 mL), and the mixture was stirred at 40 °C for 2 hours. After the reaction was complete, 2 M hydrochloric acid was added dropwise to adjust the pH to approximately 5, and the mixture was extracted three times with dichloromethane (5 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum to give a white solid compound b-10c (160 mg, 100%).

[0894] LC-MS(ESI):[M+H] + =644.50

[0895] Step 4: 4-(4-(6-(1-(3-(1H-1,2,3-triazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-2-(azacyclobutane-1-carbonyl)-7-fluoro-1H-indole-4-yl)phenyl)piperazine-1-carboxylic acid tert-butyl ester (compound b-10d)

[0896] Compound b-10c (80 mg, 0.12 mmol) was dissolved in N,N-dimethylformamide (2 mL). Azacyclobutane hydrochloride (12 mg, 0.12 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate (47 mg, 0.12 mmol), and N,N-diisopropylethylamine (80 mg, 0.62 mmol) were added to the reaction mixture, and the mixture was stirred at 25 °C for 2 hours. The reaction mixture was purified by high pressure to obtain a white solid product, compound b-10d (14 mg, 16.5%).

[0897] LC-MS(ESI):[M+H] + =683.55

[0898] Step 5: 1-(5-(2-(azacyclobutane-1-carbonyl)-7-fluoro-4-(4-(piperazin-1-yl)phenyl)-1H-indol-6-yl)-3,6-dihydropyridin-1(2H)-yl)-3-(1H-1,2,3-triazol-1-yl)prop-1-one (compound b-10e)

[0899] Compound b-10d (14 mg, 0.02 mmol) was dissolved in dichloromethane (1 mL), and 1 mL of trifluoroacetic acid was slowly added dropwise. The mixture was stirred at 25 °C for 1 hour. The reaction mixture was then concentrated under reduced pressure to obtain crude compound b-10e (10 mg, 83.70%).

[0900] LC-MS(ESI):[M+H] + =583.55

[0901] Step 6: 1-(5-(2-(azacyclobutane-1-carbonyl)-7-fluoro-4-(4-(4-methylpiperazin-1-yl)phenyl)-1H-indol-6-yl)-3,6-dihydropyridin-1(2H)-yl)-3-(1H-1,2,3-triazol-1-yl)prop-1-one (compound b-10)

[0902] Compound b-10e (10 mg, 0.02 mmol), paraformaldehyde (2 mg, 0.03 mmol), sodium triacetoxyborohydride (7 mg, 0.03 mmol), and acetic acid (0.1 mL) were dissolved in dimethyl sulfoxide (1 mL), and the reaction system was reacted at room temperature for 1 hour. The reaction system was purified by high pressure to give compound b-10 (2 mg, 19.53%) as a white solid product.

[0903] 1H NMR (400MHz, DMSO-d6) δ12.26–12.20(m,1H),8.15–8.08(m,1H),7.73–7.66(m,1H),7.59(dd ,J=8.8,2.8Hz,2H),7.20–7.11(m,2H),6.98(dd,J=23.2,6.0Hz,1H),6.83(t,J=2.6Hz,1H), 6.15(s,1H),4.62(q,J=7.2Hz,2H),4.42(d,J=42.5Hz,4H),4.10(s,2H),3.94(d,J=13.3Hz, 2H), 3.60 (ddd, J=26.6, 18.5, 8.9Hz, 5H), 3.20–2.98 (m, 5H), 2.88 (s, 2H), 2.40–2.21 (m, 5H).

[0904] LC-MS(ESI):[M+H] + =597.50

[0905] Example 32 Synthesis of compound b-11

[0906] 1-(5-(2-(4-cyclopropylpiperazin-1-carbonyl)-7-fluoro-4-(4-(4-methylpiperazin-1-yl)phenyl)-1H-indol-6-yl)-3,6-dihydropyridin-1(2H)-yl)-3-(1H-1,2,3-triazol-1-yl)propane-1-one (compound b-11)

[0907] Synthesis scheme

[0908] Step 1: Methyl 6-chloro-7-fluoro-4-(4-(4-methylpiperazin-1-yl)phenyl)-1H-indole-2-carboxylic acid ester (compound b-11a)

[0909] Compound a-2e (100 mg, 0.33 mmol), compound a-5d (111 mg, 0.36 mmol), potassium carbonate (138 mg, 0.99 mmol), and 1,1-bis(diphenylphosphine)diferropalladium dichloride (48 mg, 0.06 mmol) were dissolved in 1,4-dioxane (2 mL) and water (0.2 mL). The reaction system was reacted at 100 °C for 2 hours under a nitrogen atmosphere. The reaction system was concentrated, and the crude product was purified by column chromatography to give a yellow solid compound b-11a (80 mg, 61.55%).

[0910] LC-MS(ESI):[M+H] + =402.30

[0911] Step 2: Methyl 6-(1-(3-(1H-1,2,3-triazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-7-fluoro-4-(4-(4-methylpiperazin-1-yl)phenyl)-1H-indole-2-carboxylic acid ester (compound b-11b)

[0912] Compound b-11a (170 mg, 0.42 mmol), 1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentan-2-yl)-3,6-dihydropyridin-1(2H)-yl)-3-(1H-1,2,3-triazol-1-yl)propane-1-one (140 mg, 0.42 mmol), potassium phosphate (127 mg, 1.26 mmol), and methanesulfonic acid (2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (71 mg, 0.07 mmol) were dissolved in 1,4-dioxane (2 mL) and water (0.4 mL). The reaction system was carried out at 80 °C for 2 hours under a nitrogen atmosphere. The reaction system was concentrated, and the crude product was purified by column chromatography to obtain a yellow solid compound b-11b (187 mg, 77.33%).

[0913] LC-MS(ESI):[M+H] + =572.45

[0914] Step 3: 6-(1-(3-(1H-1,2,3-triazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-7-fluoro-4-(4-(4-methylpiperazin-1-yl)phenyl)-1H-indole-2-carboxylic acid (compound b-11c)

[0915] Compound b-11b (200 mg, 0.34 mmol) and lithium hydroxide monohydrate (143 mg, 3.49 mmol) were added to a mixed solution of tetrahydrofuran (4 mL) and methanol (1 mL), and the mixture was stirred at 40 °C for 2 hours. After the reaction was complete, 2 M hydrochloric acid was added dropwise to adjust the pH to approximately 5, and the mixture was extracted three times with dichloromethane (5 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum to give a white solid compound b-11c (158 mg, 80.98%).

[0916] LC-MS(ESI):[M+H] + =556.20

[0917] Step 4: 1-(5-(2-(4-cyclopropylpiperazin-1-carbonyl)-7-fluoro-4-(4-(4-methylpiperazin-1-yl)phenyl)-1H-indol-6-yl)-3,6-dihydropyridin-1(2H)-yl)-3-(1H-1,2,3-triazol-1-yl)propane-1-one (compound b-11)

[0918] Compound b-11c (80 mg, 0.14 mmol) was dissolved in N,N-dimethylformamide (2 mL). 1-Cyclopropylpiperazine hydrochloride (25 mg, 0.15 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate (74 mg, 0.19 mmol), and N,N-diisopropylethylamine (50 mg, 0.39 mmol) were added to the reaction mixture, and the mixture was stirred at 25 °C for 2 hours. The reaction mixture was purified by high pressure to obtain a white solid product b-11 (16 mg, 16.82%).

[0919] 1 H NMR(400MHz,DMSO-d6)δ12.31(s,1H),8.15–8.09(m,1H),7.73–7.67(m,1H),7.59( dd,J=8.8,2.7Hz,2H),7.13(d,J=8.7Hz,2H),7.05–6.95(m,1H),6.89–6.81(m,1H), 6.21–6.12(m,1H),4.68–4.59(m,2H),4.42–4.29(m,2H),3.99–3.89(m,2H),3.70– 3.52(m,8H),3.26–2.97(m,9H),2.89(s,3H),2.41–2.25(m,2H),0.94–0.60(m,4H).

[0920] LC-MS(ESI):[M+H] + =666.60

[0921] Example 33 Synthesis of compound b-12

[0922] 6-(1-(3-(1H-1,2,3-triazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-4-(9-((dimethylamino)methyl)-3-azaspiro[5.5]undecane-3-yl)-7-fluoro-N,N-dimethyl-1H-indole-2-carboxamide (compound b-12)

[0923] Synthesis scheme

[0924] Step 1: 6-Chloro-4-(9-(dimethoxymethyl)-3-azaspiro[5.5]undecane-3-yl)-7-fluoro-N,N-dimethyl-1H-indole-2-carboxamide (compound b-12)

[0925] Compound B-1d (15 mg, 0.025 mmol), dimethylamine (2.29 mg, 0.050 mmol), sodium triacetoxyborohydride (10 mg, 0.050 mmol), and acetic acid (0.1 mL) were dissolved in dimethyl sulfoxide (1 mL), and the reaction mixture was reacted at room temperature for 2 hours. The reaction mixture was purified by high pressure to give compound b-12 (7 mg, 46.67%) as a white solid product.

[0926] 1 H NMR(400MHz,DMSO-d6)δ12.00(s,1H),8.15–8.07(m,1H),7.74–7.66(m,1H),6. 79–6.71(m,1H),6.42(s,1H),6.07(s,1H),4.67–4.59(m,2H),4.36–4.24(m,2H) ,3.69–3.56(m,3H),3.37–2.92(m,16H),2.78(d,J=4.8Hz,4H),2.56–2.52(m,3 H),2.29–2.23(m,1H),1.83–1.65(m,4H),1.63–1.51(m,3H),1.28–1.11(m,3H).

[0927] LC-MS(ESI):[M+H] + =619.15

[0928] Example 34 Synthesis of compound b-13

[0929] 6-(1-(3-(1H-1,2,3-triazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-4-(2-((dimethylamino)methyl)-8-azaspiro[4.5]decane-8-yl)-7-fluoro-N,N-dimethyl-1H-indole-2-carboxamide (compound b-13)

[0930] Synthesis scheme

[0931] The synthesis steps are the same as those for compound b-14.

[0932] White solid product compound b-13 (5 mg, 15.86%).

[0933] 1H NMR(600MHz,DMSO-d6)δ12.17(s,1H),8.15–8.10(m,1H),7.73–7.67(m,1H),6.87–6.82 (m,1H),6.68–6.57(m,1H),6.13–6.08(m,1H),4.66–4.60(m,5H),3.68–3.57(m,2H),3.2 4(s,6H),3.13–3.05(m,6H),2.79(s,6H),2.43–2.32(m,3H),2.29–2.22(m,1H),1.93–1 .85(m,2H),1.81–1.70(m,4H),1.65–1.55(m,2H),1.41–1.34(m,1H),1.19–1.13(m,1H).

[0934] LC-MS(ESI):[M+H] + =605.60

[0935] Example 35 Synthesis of compound b-14

[0936] 6-(1-(3-(1H-1,2,3-triazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-4-(2-((dimethylamino)methyl)-7-azaspiro[3,5]heptane-7-yl)-7-fluoro-N,N-dimethyl-1H-indole-2-carboxamide (compound b-14)

[0937] Synthesis scheme

[0938] Step 1: 6-Chloro-4-(2-(dimethoxymethyl)-7-azaspiro[3.5]heptane-7-yl)-7-fluoro-N,N-dimethyl-1H-indole-2-carboxamide (compound b-14b)

[0939] Compound a-2 (200 mg, 0.62 mmol), compound b-14a (137 mg, 0.68 mmol), 2-dicyclohexylphosphine-2',6'-diisopropoxy-1,1'-biphenyl (29 mg, 0.06 mmol), [2'-(amino)[1,1'-biphenyl]-2-yl][[2',6'-di(1-methylethoxy)[1,1'-biphenyl]-2-yl]dicyclohexylphosphine]palladium chloride (24 mg, 0.03 mmol), and bis(trimethylsilylamino)lithium (628 mg, 3.75 mmol) were dissolved in 1,4-dioxane (4 mL) and water (0.8 mL). The reaction system was reacted at 100 °C for 2 hours under a nitrogen atmosphere. The reaction system was concentrated, and the crude product was purified by column chromatography to obtain compound b-14b (250 mg, 91.21%).

[0940] 1 H NMR (400MHz, DMSO-d6) δ12.17(s,1H),6.74(dd,J=3.0,2.2Hz,1H),6.44(d,J=5.3Hz ,1H),3.22–2.88(m,15H),2.60–2.53(m,1H),1.90–1.73(m,5H),1.71–1.57(m,5H).

[0941] LC-MS(ESI):[M+H] + =438.35

[0942] Step 2: 6-(1-(3-(1H-1,2,3-triazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-4-(2-(dimethoxymethyl)-7-azaspiro[3.5]nonane-7-yl)-7-fluoro-N,N-dimethyl-1H-indole-2-carboxamide (compound b-14c)

[0943] Compound b-14b (250 mg, 0.57 mmol), compound a-3 (227 mg, 0.68 mmol), potassium phosphate (363 mg, 1.71 mmol), and methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (96 mg, 0.11 mmol) were dissolved in 1,4-dioxane (4 mL) and water (1 mL). The reaction system was carried out at 100 °C for 12 hours under a nitrogen atmosphere. The reaction system was concentrated, and the crude product was purified by column chromatography to obtain compound b-14c (80 mg, 23.05%).

[0944] LC-MS(ESI):[M+H] + =608.59

[0945] Step 3: 6-(1-(3-(1H-1,2,3-triazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-7-fluoro-4-(2-formyl-7-azaspiro[3.5]non-7-yl)-N,N-dimethyl-1H-indole-2-carboxamide (compound b-14d)

[0946] Compound B-1c (80 mg, 0.13 mmol) was dissolved in formic acid (1 mL), and the reaction system was reacted at room temperature for 1 hour. The reaction system was concentrated to give the crude product compound b-14d (70 mg, 87.5%).

[0947] LC-MS(ESI):[M+H] +=562.55

[0948] Step 4: 6-(1-(3-(1H-1,2,3-triazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-4-(2-((dimethylamino)methyl)-7-azaspiro[3.5]heptane-7-yl)-7-fluoro-N,N-dimethyl-1H-indole-2-carboxamide (compound b-14)

[0949] The synthesis steps were the same as those for compound b-12, resulting in a white solid product, compound b-14 (7 mg, 44.57%).

[0950] 1 H NMR (400MHz, DMSO-d6) δ11.98(s,1H),8.12(d,J=8.5Hz,1H),7.70(d,J=9.3Hz,1H),6.75–6. 69(m,1H),6.39–6.29(m,1H),6.10–6.02(m,1H),4.67–4.59(m,2H),4.34–4.25(m,2H),3.63– 3.56(m,3H),3.30–2.91(m,13H),2.76–2.72(m,4H),2.71–2.61(m,2H),2.37–2.29(m,2H),2. 29–2.22(m,1H),2.10–2.02(m,2H),1.86–1.79(m,2H),1.75–1.68(m,2H),1.65–1.56(m,2H).

[0951] LC-MS(ESI):[M+H] + =591.55

[0952] Example 36 Synthesis of compounds b-15-1 and b-15-2

[0953] 6-(1-(3-(1H-1,2,3-triazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-4-(8-((dimethylamino)methyl)-2-azaspiro[4.5]dec-2-yl)-7-fluoro-N,N-dimethyl-1H-indole-2-carboxamide (compound b-15)

[0954] Synthesis scheme

[0955] The synthetic steps are the same as those for compound b-14; a pair of isomers are obtained, which are arbitrarily numbered as b-15-1 and b-15-2.

[0956] White solid product compound b-15-1 (5 mg, 33.33%).

[0957] 1 H NMR (400MHz, DMSO-d6) δ11.75–11.62(m,1H),8.11(d,J=8.3Hz,1H),7.69(d,J=9.5H z,1H),7.00–6.94(m,1H),6.04(dd,J=4.1,2.2Hz,1H),5.80–5.71(m,1H),4.67–4.58 (m,2H),4.30(d,J=2.6Hz,2H),3.66–3.56(m,4H),3.26–2.95(m,15H),2.78(d,J=4.7 Hz,6H),2.36–2.28(m,2H),1.87–1.81(m,2H),1.71–1.63(m,4H),1.49–1.41(m,2H).

[0958] LC-MS(ESI):[M+H] + =605.60

[0959] White solid product compound b-15-2 (6 mg, 40.0%).

[0960] 1 H NMR (400MHz, DMSO-d6) δ11.76–11.71(m,1H),8.12(d,J=8.8Hz,1H),7.70(d,J=9. 1Hz,1H),6.06–6.01(m,1H),5.83–5.77(m,1H),4.66–4.60(m,2H),4.32–4.23(m, 2H),3.67–3.55(m,4H),3.35–3.28(m,2H),3.24–2.94(m,10H),2.78(d,J=4.6Hz, 6H),2.35–2.23(m,2H),1.83–1.60(m,7H),1.46–1.35(m,2H),1.21–1.05(m,2H).

[0961] LC-MS(ESI):[M+H] + =605.60

[0962] Example 37 Synthesis of compound b-16

[0963] 6-(1-(3-(1H-1,2,3-triazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-4-(7-((dimethylamino)methyl)-2-azaspiro[3,5]heptane-2-yl)-7-fluoro-N,N-dimethyl-1H-indole-2-carboxamide (compound b-16)

[0964] Synthesis scheme

[0965] The synthesis steps are the same as those for compound b-14.

[0966] White solid product compound b-16 (8 mg, 25.35%).

[0967] 1 H NMR(400MHz,DMSO-d6)δ11.80(s,1H),8.14–8.09(m,1H),7.73–7.67(m,1H),6.79–6.73(m, 1H),6.07–6.01(m,1H),5.74–5.65(m,1H),4.65–4.60(m,2H),4.31–4.25(m,2H),3.78–3.7 1(m,4H),3.65–3.56(m,2H),3.23–3.03(m,7H),2.97–2.90(m,2H),2.83–2.73(m,6H),2.36 –2.20(m,3H),2.00–1.91(m,2H),1.80–1.65(m,3H),1.58–1.47(m,2H),1.14–1.01(m,2H).

[0968] LC-MS(ESI):[M+H] + =591.55

[0969] Example 38 Synthesis of compound b-17

[0970] 7-Fluoro-N,N-Dimethyl-4-(4-(4-methylpiperazin-1-yl)phenyl)-6-(1-(3-(2-oxopiperidin-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-1H-indole-2-carboxamide (compound b-17)

[0971] The synthesis steps were the same as for compound b-1, and the white solid product was compound b-17 (7 mg, 35.0%).

[0972] 1H NMR (400MHz, DMSO-d6) δ12.20–12.15(m,1H),7.63–7.55(m,2H),7.17–7.10(m,2H),7.0 5–6.93(m,1H),6.87–6.81(m,1H),6.16(dd,J=8.7,6.1Hz,1H),4.36(d,J=2.8Hz,2H),3 .99–3.90(m,2H),3.69–3.61(m,2H),3.59–3.41(m,4H),3.34–2.97(m,11H),2.89(d,J= 3.4Hz,3H),2.70–2.57(m,2H),2.42–2.24(m,2H),2.23–2.10(m,2H),1.77–1.59(m,4H).

[0973] LC-MS(ESI):[M+H] + =615.55

[0974] Example 39 Synthesis of compound b-18

[0975] 7-Fluoro-N,N-Dimethyl-4-(4-(4-methylpiperazin-1-yl)phenyl)-6-(1-(3-phenylpropionyl)-1,2,5,6-tetrahydropyridin-3-yl)-1H-indole-2-carboxamide (compound b-18)

[0976] The synthesis steps were the same as for compound b-2, and the white solid product was compound b-18 (5 mg, 35.0%).

[0977] 1 H NMR(400MHz, DMSO-d6)δ12.17(dd,J=12.2,2.1Hz,1H),7.58(dd,J=8.8,2.7Hz,2H),7.37–7 .04(m,7H),6.96(t,J=6.2Hz,1H),6.84(q,J=3.1Hz,1H),6.21–6.08(m,1H),4.35(d,J=21. 2Hz,2H),3.94(d,J=13.2Hz,2H),3.66(t,J=5.8Hz,1H),3.61(t,J=5.8Hz,1H),3.55(d,J=1 2.0Hz,2H),3.27–2.95(m,9H),2.92–2.64(m,7H),2.54(d,J=8.0Hz,1H),2.37–2.21(m,2H).

[0978] LC-MS(ESI):[M+H] + =594.50

[0979] Example 40 Synthesis of compound b-19

[0980] 7-Fluoro-N,N-Dimethyl-4-(4-(4-methylpiperazin-1-yl)phenyl)-6-(1-(((4,5,6,7-tetrahydro-[1,2,3]triazolo[1,5-a]pyridin-3-yl)methyl)carbamoyl)-1,2,5,6-tetrahydropyridin-3-yl (compound b-19)

[0981] Synthesis scheme

[0982] Step 1: [1,2,3]triazolo[1,5-a]pyridine-3-carboxylic acid methyl ester (compound b-19b)

[0983] Methyl (pyridin-2-yl)acetate (1.0 g, 6.62 mmol) was dissolved in acetonitrile (15 mL). 4-acetamidobenzenesulfonyl azide (1.59 g, 6.62 mmol) was added under nitrogen protection at 0 °C, followed by 1,8-diazabicyclo[5.4.0]undec-7-ene; 1,8-diazabicyclo[5.4.0]undec-7-ene (1.01 g, 6.62 mmol). The mixture was stirred for 10 minutes, then brought to room temperature and stirred for 3 hours. After the reaction was complete, water and ethyl acetate were added for extraction. The organic phase was concentrated and purified by column chromatography to obtain compound b-19b (920 mg, 78.50%).

[0984] 1 H NMR(400MHz,Chloroform-d)δ8.86(dt,J=7.0,1.0Hz,1H),8.31(dt,J=8.9,1.2Hz ,1H),7.58(ddd,J=8.9,6.7,1.0Hz,1H),7.19(td,J=6.9,1.3Hz,1H),4.07(s,3H).

[0985] LC-MS(ESI):[M+H] + =178.16

[0986] Step 2: Methyl 4,5,6,7-tetrahydro-[1,2,3]triazolo[1,5-a]pyridine-3-carboxylate (compound b-19c)

[0987] Compound b-19b (500 mg, 2.82 mmol) was dissolved in ethanol (10 mL), and palladium / carbon (0.3 g) was added. The mixture was stirred at room temperature under hydrogen pressure for 12 hours. After the reaction was complete, the mixture was filtered through diatomaceous earth, and the filtrate was concentrated to obtain crude compound b-19c, which could be used directly in the next step without purification.

[0988] 1 H NMR (400MHz, Chloroform-d) δ4.42(t,J=6.1Hz,2H),3.95(s,3H),3.11(t,J=6.4Hz,2H),2.16–2.06(m,2H),2.00–1.91(m,2H).

[0989] LC-MS(ESI):[M+H] + =182.25

[0990] Step 3: [1,2,3]triazolo[1,5-a]pyridin-3-ylmethanol (compound b-19d)

[0991] Compound b-19c (500 mg, 2.76 mmol) was dissolved in tetrahydrofuran (10 mL), and a 1 M lithium aluminum hydride tetrahydrofuran solution (5.52 mL, 5.52 mmol) was added dropwise at 0°C. After the addition was complete, the mixture was stirred at room temperature for 1 hour. After the reaction was complete, sodium sulfate decahydrate was added at 0°C and stirred for 2 minutes. The mixture was filtered, and the filtrate was concentrated to obtain the crude compound b-19d, which could be used directly for the next step without further purification.

[0992] 1 H NMR (400MHz, Methanol-d4) δ4.65(s,2H),4.37(t,J=6.1Hz,2H),2.90(t,J=6.4Hz,2H),2.10(tdd,J=7.5,4.9,2.3Hz,2H),1.99–1.92(m,2H).

[0993] LC-MS(ESI):[M+H] + =154.25

[0994] Step 4: 3-(azidomethyl)-[1,2,3]triazolo[1,5-a]pyridine (compound b-19e)

[0995] Compound b-19d (400 mg, 2.61 mmol), diphenyl azidophosphate (862 mg, 3.13 mmol), 1,8-diazabicyclo[5.4.0]undec-7-ene, and 1,8-diazabicyclo[5.4.0]undec-7-ene (516 mg, 3.39 mmol) were sequentially added to toluene (15 mL). The mixture was stirred at room temperature for 12 hours under nitrogen protection. After the reaction was complete, 2N hydrochloric acid aqueous solution and ethyl acetate were added. The organic phase was collected, concentrated, and purified by column chromatography to obtain compound b-19e (200 mg, 42.98%).

[0996] 1H NMR (400MHz, DMSO-d6) δ4.32(t,J=6.1Hz,2H),2.78(t,J=6.4Hz,2H),1.98(dtd,J=12.0,5.9,2.6Hz,2H),1.86–1.77(m,2H).

[0997] LC-MS(ESI):[M+H] + =179.30

[0998] Step 5: (4,5,6,7-Tetrahydro-[1,2,3]triazolo[1,5-a]pyridin-3-yl)methylamine (compound b-19f)

[0999] Compound b-19e (200 mg, 1.12 mmol), triphenylphosphine (588 mg, 2.24 mmol), and ammonium hydroxide (25%, 0.5 mL) were dissolved in tetrahydrofuran (2 mL) and stirred at 70 °C for 3 hours. After the reaction was complete, the system was concentrated, and 4 N dioxane hydrochloride solution (4 mL) was added. The mixture was stirred at room temperature for 1 hour, and then ethyl acetate was added. A solid precipitated out. The filter cake was collected to give compound b-19f (130 mg).

[1000] LC-MS(ESI):[M+H] + =153.20

[1001] Step 6: N-((4,5,6,7-tetrahydro-[1,2,3]triazolo[1,5-a]pyridin-3-yl)methyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-3,6-dihydropyridine-1(2H)-formamide (compound b-19g)

[1002] At room temperature, triphosgene (204 mg, 0.68 mmol) was added to dichloromethane (1 mL), followed by dropwise addition of a dichloromethane solution (1 mL) containing compound b-19 g (130 mg, 0.68 mmol). After the addition was complete, the reaction system was cooled to 0 °C, and triethylamine (348 mg, 3.45 mmol) was added dropwise, followed by stirring for 2 hours. Then, 5-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (144 mg, 0.68 mmol) was added, and the mixture was stirred at room temperature for 1 hour. After the reaction was complete, the system was concentrated, and compound b-19 g (150 mg, 56.21%) was purified by column chromatography.

[1003] 1H NMR (400MHz, DMSO-d6) δ6.92(t,J=5.5Hz,1H),6.53(dp,J=4.0,2.1Hz,1H),4.25(t,J=6.1Hz,2H),4.19(d,J=5.4Hz,2H),3.80(q,J= 2.6Hz,2H),2.75(t,J=6.4Hz,2H),2.10(dq,J=5.9,2.9Hz,2H),1.98–1.88(m,3H),1.77(ddd,J=9.3,7.5,4.6Hz,3H),1.21(s,12H).

[1004] LC-MS(ESI):[M+H] + =388.40

[1005] Step 7: 4-Chloro-7-fluoro-N,N-dimethyl-6-(1-(((4,5,6,7-tetrahydro-[1,2,3]triazolo[1,5-a]pyridin-3-yl)methyl)carbamoyl)-1,2,5,6-tetrahydropyridin-3-yl (compound b-19h)

[1006] The synthesis method is the same as step three of compound b-8.

[1007] 1 H NMR(400MHz, DMSO-d6)δ12.46(s,1H),7.61–7.45(m,4H),7.12–7.03(m,2H),6.82(t,J=2.5Hz,1H),6.12(s,1H),4.29–4.20(m,4H),4.18–4.12 (m,2H),3.52–3.45(m,2H),3.29–3.18(m,3H),3.11–3.00(m,3H),2.80 –2.73(m,2H),2.28–2.20(m,2H),1.97–1.89(m,2H),1.81–1.73(m,2H).

[1008] LC-MS(ESI):[M+H] + =500.45

[1009] Step 8: 4-(4-(2-(dimethylcarbamoyl)-7-fluoro-6-(1-(((4,5,6,7-tetrahydro-[1,2,3]triazolo[1,5-a]pyridin-3-yl)methyl)carbamoyl)-1,2,5,6-tetrahydropyridin-3-yl, 1H-indol-4-yl)phenyl)piperazine-1-carboxylic acid tert-butyl ester (compound b-19i)

[1010] The synthesis method is the same as step four of compound b-8.

[1011] LC-MS(ESI):[M+H] + =726.70

[1012] Step 9: 7-Fluoro-N,N-Dimethyl-4-(4-(piperazin-1-yl)phenyl)-6-(1-(((4,5,6,7-tetrahydro-[1,2,3]triazolo[1,5-a]pyridin-3-yl)methyl)carbamoyl)-1,2,5,6-tetrahydropyridin-3-yl (compound b-19j)

[1013] The synthesis method is the same as step 5 of compound b-8.

[1014] LC-MS(ESI):[M+H] + =626.60

[1015] Step 10: 7-Fluoro-N,N-Dimethyl-4-(4-(4-methylpiperazin-1-yl)phenyl)-6-(1-(((4,5,6,7-tetrahydro-[1,2,3]triazolo[1,5-a]pyridin-3-yl)methyl)carbamoyl)-1,2,5,6-tetrahydropyridin-3-yl (Compound b-19)

[1016] The synthesis method is the same as step six of compound b-8.

[1017] 1 H NMR(400MHz,DMSO-d6)δ12.21–12.10(m,1H),7.58(d,J=8.7Hz,2H),7.18–7.10(m,2H), 7.05(t,J=5.5Hz,1H),6.96(d,J=6.1Hz,1H),6.83(t,J=2.6Hz,1H),6.16–6.10(m,1H), 4.29–4.17(m,6H),3.99–3.89(m,3H),3.61–3.47(m,4H),3.28–2.97(m,9H),2.89(d,J= 3.9Hz,3H),2.81–2.73(m,2H),2.31–2.21(m,2H),1.98–1.87(m,2H),1.82–1.72(m,2H).

[1018] LC-MS(ESI):[M+H] + =640.60

[1019] Example 41 Synthesis of compound d-1

[1020] 6-(1-(3-(1H-1,2,3-triazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-7-fluoro-N,N-dimethyl-4-(9-methyl-3,9-diazaspiro[5.5]undecane-3-yl)-1H-indole-2-carboxamide (compound d-1)

[1021] Synthesis scheme

[1022] Step 1: 6-(1-(3-(1H-1,2,3-triazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-7-fluoro-N,N-dimethyl-4-(9-methyl-3,9-diazaspiro[5.5]undecane-3-yl)-1H-indole-2-carboxamide (compound d-1)

[1023] Compound d-1a (10 mg, 17.77 μmol) and 38% formaldehyde (2 mg) were dissolved in methanol (2 mL) solution and stirred at 25 °C for 30 minutes. Then, sodium triacetoxyborohydride (7 mg, 53.31 μmol) was added and stirred for 1 hour. After the reaction was complete, the product compound d-1 (6.5 mg, 63.4%) was directly prepared by pre-HPLC.

[1024] 1 H NMR(600MHz, Methanol-d4)δ8.03(d,J=13.9Hz,1H),7.72(d,J=12.8Hz,1H),7.14–6.68(m,2H),6.14(d,J=25.3Hz,1H),4.85-4.77(m,3H),4.51–4.3 0(m,2H),3.82-3.65(m,2H),3.58–3.39(m,6H),3.27-3.15(m,9H),2.93(s ,3H),2.49–2.32(m,2H),2.11(q,J=34.9,27.5Hz,4H),1.95–1.65(m,4H).

[1025] LC-MS(ESI):[M+H] + =577.58

[1026] Example 42 Synthesis of compound d-2

[1027] 6-(1-(3-(1H-1,2,3-triazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-4-(4-(((dimethylamino)methyl)piperidin-1-yl)phenyl)-7-fluoro-N,N-dimethyl-1H-indole-2-carboxamide (compound d-2)

[1028] Step 1: 6-(1-(3-(1H-1,2,3-triazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-4-(4-(((dimethylamino)methyl)piperidin-1-yl)phenyl)-7-fluoro-N,N-dimethyl-1H-indole-2-carboxamide (compound d-2)

[1029] The synthesis method is the same as the first step of compound b-12, resulting in white solid compound d-2 (7 mg, 36.0%).

[1030] 1 H NMR(600MHz, Methanol-d4)δ8.03(dd,J=11.5,1.0Hz,1H),7.76–7.66(m,3H),7.41(dd,J=8.7,3.1Hz,2H ),7.04(dd,J=7.9,6.0Hz,1H),6.95(t,J=2.9Hz,1H),6.20-6.17(m,1H),4.81-4.77(m,2H),4.44(dt,J=4 5.5,2.4Hz,2H),3.86(d,J=12.2Hz,2H),3.74(dt,J=50.2,5.8Hz,2H),3.29–3.09(m,10H),2.98(s,6H), 2.46–2.34(m,2H),2.26–2.19(m,1H),2.05(d,J=13.2Hz,2H),1.68(q,J=12.7Hz,2H),1.41–1.26(m,2H).

[1031] LC-MS(ESI):[M+H] + =627.55

[1032] Example 43 Synthesis of compound d-3

[1033] 6-(1-(3-(1H-1,2,3-triazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-4-(4-((dimethylamino)methyl)piperidin-1-yl)-2-methoxyphenyl)-7-fluoro-N,N-dimethyl-1H-indole-2-carboxamide (compound d-3)

[1034] Step 1: 6-(1-(3-(1H-1,2,3-triazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-7-fluoro-4-(4-(4-formylpiperidin-1-yl)-2-methoxyphenyl)-N,N-dimethyl-1H-indole-2-carboxamide (compound d-3b)

[1035] SM1 (20 mg, 29.7 μmol) was dissolved in dichloromethane (1 mL), and formic acid (1 mL) was added. The mixture was stirred at 25 °C for 4 hours. After the reaction was complete, the mixture was concentrated under reduced pressure to give the crude product compound d-3a (18.6 mg, 99.9%). The unpurified product was directly used in the next step.

[1036] LC-MS(ESI):[M+H] + =628.48

[1037] Step 2: 6-(1-(3-(1H-1,2,3-triazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-4-(4-((dimethylamino)methyl)piperidin-1-yl)-2-methoxyphenyl)-7-fluoro-N,N-dimethyl-1H-indole-2-carboxamide (compound d-3)

[1038] The synthesis method is the same as the first step of compound b-12, yielding white solid compound d-3 (8.5 mg, 41.0%).

[1039] 1 H NMR (600MHz, Methanol-d4) δ8.03(dd,J=9.4,1.0Hz,1H),7.72(dd,J=15.2,1.0Hz,1H),7.40(dd,J=8.2,2.9Hz,1H) ,7.05(dd,J=6.7,2.2Hz,1H),7.03–6.92(m,2H),6.60(t,J=3.0Hz,1H),6.20–6.12(m,1H),4.81-4.77(m,2H),4.47- 4.38(m,2H),3.88(d,J=12.2Hz,2H),3.81(d,J=3.7Hz,3H),3.78(t,J=5.9Hz,1H),3.69(t,J=5.8Hz,1H),3.30(s,3H ),3.23–3.15(m,6H),2.99(s,6H),2.44–2.33(m,2H),2.25–2.05(m,4H),1.71(q,J=12.7Hz,2H),1.39–1.30(m,2H).

[1040] LC-MS(ESI):[M+H] + =657.55

[1041] Example 44 Synthesis of compound d-4

[1042] 6-(1-(3-(1H-1,2,3-triazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-4-(4-((dimethylamino)methyl)piperidin-1-yl)-2-methylphenyl)-7-fluoro-N,N-dimethyl-1H-indole-2-carboxamide (compound d-4)

[1043] The synthesis method is the same as that of compound d-3, and the white solid product is compound d-4 (5 mg, 23.9%).

[1044] 1 H NMR(600MHz, Methanol-d4)δ8.03(d,J=9.7Hz,1H),7.71(d,J=14.7Hz,1H),7.33–7.21(m,2H),7.16(d,J =8.4Hz,1H),6.84(dd,J=13.9,6.0Hz,1H),6.48(t,J=2.8Hz,1H),6.17-6.13(m,1H),4.78(dt,J=11.1,6. 5Hz,2H),4.42(dd,J=41.9,2.6Hz,2H),3.88–3.74(m,3H),3.68(t,J=5.8Hz,1H),3.25–3.10(m,11H),2. 98(s,6H),2.42-2.34(m,2H),2.19(s,4H),2.04(d,J=13.2Hz,2H),1.73–1.59(m,2H),1.43–1.26(m,1H).

[1045] LC-MS(ESI):[M+H] + =641.55

[1046] Example 45 Synthesis of compound d-5

[1047] 6-(1-(3-(1H-1,2,3-triazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-4-(2-cyano-4-(4-(dimethylamino)methyl)piperidin-1-yl)phenyl)-7-fluoro-N,N-dimethyl-1H-indole-2-carboxamide (compound d-5)

[1048] The synthesis method is the same as that of compound d-3, and the white solid product is compound d-5 (7 mg 33.4%).

[1049] 1H NMR (600MHz, Methanol-d4) δ8.03(d,J=8.1Hz,1H),7.71(d,J=15.8Hz,1H),7.56(dd,J=17.6,8.6Hz,1H),7. 44–7.36(m,2H),7.08(dd,J=25.2,6.0Hz,1H),6.73(dd,J=11.8,3.1Hz,1H),6.27–6.18(m,1H),4.79(dt,J=1 1.4,6.5Hz,2H),4.45(dt,J=48.3,2.4Hz,2H),3.93(dd,J=12.8,3.3Hz,2H),3.82-3.69(m,2H),3.25–3.09(m ,8H),2.96(s,9H),2.72(s,1H),2.45–2.34(m,2H),2.17-2.09(m,1H),1.96–1.88(m,2H),1.52-1.45(m,2H).

[1050] LC-MS(ESI):[M+H] + =652.55

[1051] Example 46 Synthesis of compound d-6

[1052] 6-(1-(3-(1H-1,2,3-triazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-4-(4-(4-((dimethylamino)methyl)piperidin-1-yl)-2-fluorophenyl)-7-fluoro-N,N-dimethyl-1H-indole-2-carboxamide (compound d-6)

[1053] 7. The synthesis method is the same as that of compound d-3. The white solid product is compound d-6 (6 mg, 57.1%).

[1054] 1H NMR (600MHz, Methanol-d4) δ8.03(d,J=10.0Hz,1H),7.71(d,J=15.1Hz,1H),7.39(td,J=8.7,4.8Hz,1H),6.98(dd,J =8.8,6.0Hz,1H),6.90(dt,J=8.6,2.1Hz,1H),6.84(dd,J=13.7,2.5Hz,1H),6.73(t,J=2.7Hz,1H),6.19-6.14(m,1H ),4.79(dt,J=12.1,6.5Hz,2H),4.45-4.38(m,2H),3.93–3.83(m,2H),3.74(dt,J=52.4,5.8Hz,2H),3.30-3.11(m,7 H),2.98(d,J=7.2Hz,2H),2.92–2.78(m,8H),2.72(s,1H),2.46–2.34(m,2H),2.10–1.85(m,3H),1.50-1.43(m,2H).

[1055] LC-MS(ESI):[M+H] + =645.50

[1056] Example 47 Synthesis of compound d-7

[1057] 7-Fluoro-N,N-Dimethyl-4-(4-(4-methylpiperazin-1-yl)phenyl)-6-(1-(3-(pyridin-2-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-1H-indole-2-carboxamide (compound d-7)

[1058] Step 1: 5-(2-(dimethylcarbamoyl)-7-fluoro-4-(4-(4-methylpiperazin-1-yl)phenyl)-1H-indol-6-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (compound d-7a)

[1059] Compound b-1b (100 mg, 241.4 μmol), compound a-3a (89.5 mg, 289.6 μmol), potassium phosphate (1.5 g, 724.2 μmol), and XPons Pd G3 (19.6 mg, 24.1 μmol) were dissolved in 1,4-dioxane (2 mL) and water (0.4 mL). The reaction system was reacted at 100 °C for 2 hours under a nitrogen atmosphere. The reaction system was concentrated, and the crude product was purified by column chromatography to give a yellow solid compound d-7a (90 mg, 66.6%).

[1060] 1H NMR (400MHz, Methanol-d4) δ7.59–7.53(m,2H),7.15–7.09(m,2H),6.97(dd,J=7.3,4.6Hz,2H),6.15(s,1H),4.40–4.27(m,2H),3.62(d,J= 6.6Hz,2H),3.18(s,2H),2.82(t,J=5.0Hz,4H),2.51(s,3H),2.37(d,J=5.5Hz,2H),2.01(d,J=20.8Hz,2H),1.51(s,9H),1.42–1.18(m,6H).

[1061] LC-MS(ESI):[M+H] + =562.55

[1062] Step 2: 7-Fluoro-N,N-Dimethyl-4-(4-(4-methylpiperazin-1-yl)phenyl)-6-(1,2,5,6-tetrahydropyridin-3-yl)-1H-indole-2-carboxamide (compound d-7b)

[1063] Compound d-7b (80 mg, 0.14 mmol) was dissolved in dichloromethane (2 mL), and 4 M dioxane hydrochloride solution (2 mL) was added. The reaction system was reacted at room temperature for 0.5 hours. The reaction system was concentrated to give a white solid product, compound d-7b (65 mg, 99%).

[1064] LC-MS(ESI):[M+H] + =460.25

[1065] Step 3: 7-Fluoro-N,N-Dimethyl-4-(4-(4-methylpiperazin-1-yl)phenyl)-6-(1-(3-(pyridin-2-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-1H-indole-2-carboxamide (compound d-7)

[1066] Compound d-7b (15 mg, 32.4 μmol), compound d-7c (9.8 mg, 64.9 μmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (12.4 mg, 64.9 μmol), 1-hydroxybenzotriazole (8.7 mg, 64.9 μmol), and N,N-diisopropylethylamine (20.9 mg, 162.4 μmol) were dissolved in dimethylformamide (1 mL), and the reaction system was reacted at room temperature for 2 hours. The reaction system was purified by high pressure to give compound d-7 (4.2 mg, 21.7%) as a white solid product.

[1067] 1H NMR(400MHz, Methanol-d4)δ8.78–8.60(m,2H),8.06–7.92(m,2H),7.65–7.54(m,2H),7.18(dd,J=8.9,2.7Hz,2H),7.06–6 .87(m,2H),6.22-6.19(m,1H),4.48-4.46(m,2H),3.96(s,2H),3.82–3.57(m,4H),3.34-3.25(m,9H),3.22–2.95(m,10H).

[1068] LC-MS(ESI):[M+H] + =595.58

[1069] Example 48 Synthesis of compound d-8

[1070] 7-Fluoro-N,N-Dimethyl-4-(4-(4-methylpiperazin-1-yl)phenyl)-6-(1-(3-(pyridin-3-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-1H-indole-2-carboxamide (compound d-8)

[1071] The synthesis method is the same as that of compound d-7, and the white solid product is compound d-8 (5 mg, 21.9%).

[1072] 1 H NMR(400MHz, Methanol-d4)δ8.78(d,J=15.8Hz,1H),8.66(s,1H),8.46(dd,J=20.3,8 .1Hz,1H),7.99–7.84(m,1H),7.66–7.55(m,2H),7.22–7.11(m,2H),7.05–6.89(m,2H) ,6.18(td,J=4.5,2.3Hz,1H),4.45(dd,J=8.4,2.7Hz,2H),3.95(s,2H),3.81–3.54(m ,4H),3.26(s,4H),3.20(dt,J=9.1,6.9Hz,7H),3.05–2.92(m,5H),2.49–2.30(m,2H).

[1073] LC-MS(ESI): [M+H]+=595.58

[1074] Example 49 Synthesis of compound d-9

[1075] 7-Fluoro-N,N-Dimethyl-4-(4-(4-methylpiperazin-1-yl)phenyl)-6-(1-(3-(pyridin-4-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-1H-indole-2-carboxamide (compound d-9)

[1076] The synthesis method is the same as that of compound d-7, and the white solid product is compound d-9 (4 mg, 20.7%).

[1077] 1 H NMR(600MHz,Methanol-d4)δ8.71–8.60(m,1H),8.39–8.26(m,1H),7.93–7.70(m, 2H),7.65–7.57(m,2H),7.23–7.14(m,2H),7.07–6.92(m,2H),6.37–6.15(m,1H), 4.51–4.13(m,2H),3.96(s,2H),3.79-3.61(m,4H),3.46(t,J=6.2Hz,1H),3.32-3 .25(m,3H),3.22–3.07(m,6H),3.02(s,3H),2.70–2.33(m,2H),1.43–1.30(m,4H).

[1078] LC-MS(ESI): [M+H]+=595.58

[1079] Example 50 Synthesis of compound e-1

[1080] 6-(1-(3-(1H-1,2,3-triazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-7-fluoro-N,N-dimethyl-4-(2-methyl-2,8-diazaspiro[4.5]dec-8-yl)-1H-indole-2-carboxamide (compound e-1)

[1081] Synthesis scheme

[1082] Step 1: 5-(4,4,5,5-tetramethyl-1,3,2-dioxoborhecyclopentan-2-yl)-1,2,3,6-tetrahydropyridine (compound e-1b)

[1083] Compound a-2 (230 mg, 1.14 mmol), 2-methyl-2,8-diazaspiro[4.5]decane (167 mg, 557 μmol), methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (48 mg, 59 μmol), 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (51 mg, 117 μmol), and toluene (10 mL) were added to a 100 mL dry round-bottom flask. The system was purged with nitrogen three times. Bistrimethylsilylaminolithium (2.93 mL, 1 N) was then added to the system, and the mixture was stirred at 100 °C for 1 hour. After the reaction was complete, the system was concentrated under vacuum and then purified by column chromatography to obtain compound e-1b (135 mg, 51%).

[1084] LC-MS(ESI):[M+H] + =393.49.

[1085] Step 2: 6-(1-(3-(1H-1,2,3-triazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-7-fluoro-N,N-dimethyl-4-(2-methyl-2,8-diazaspiro[4.5]dec-8-yl)-1H-indole-2-carboxamide (compound e-1)

[1086] Compound e-1b (30.00 mg, 0.06 mmol), compound a-3 (25.31 mg, 0.07 mmol), methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (5.4 mg, 0.006 mmol), potassium phosphate (40.34 mg, 0.19 mmol), and 1,4-dioxane / water = 5:1 (40 mL) were added to a 100 mL dry round-bottom flask. The system was purged with nitrogen three times and stirred at 100 °C for 2 hours. After the reaction was completed, the system was concentrated under vacuum and then purified by column chromatography to obtain a yellow solid compound e-1 (14.00 mg, 67%).

[1087] 1H NMR(400MHz, Methanol-d4)δ8.03(dd,J=7.6,1.0Hz,1H),7.76–7.69(m,1H),6.93–6.76(m,1H),6.60 (dd,J=5.3,3.2Hz,1H),6.15–6.07(m,1H),5.75(s,1H),4.79(q,J=6.7Hz,2H),4.45–4.31(m,2H),3.7 3(dt,J=32.6,5.7Hz,4H),3.29(s,3H),3.24–3.14(m,6H),3.05(d,J=8.8Hz,1H),3.01(d,J=2.7Hz,3 H),2.46–2.31(m,2H),2.21(t,J=7.5Hz,1H),2.14–2.00(m,4H),1.95(d,J=15.2Hz,2H),1.32(s,2H).

[1088] LC-MS(ESI):[M+H] + =563.69.

[1089] Example 51 Synthesis of compound e-2

[1090] 6-(1-(3-(1H-1,2,3-triazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-4-(4-(4-((dimethylamino)methyl)piperidin-1-yl)-2-(trifluoromethoxy)phenyl)-7-fluoro-N,N-dimethyl-1H-indole-2-carboxamide (compound e-2)

[1091] Synthesis scheme

[1092] Step 1: 1-(4-bromo-3-(trifluoromethoxy)phenyl)-4,4-dimethoxypiperidine (compound e-2b)

[1093] 3-Trifluoromethoxy-1-bromo-4-iodobenzene (5.0 g, 17.7 mmol), compound e-2a (2.8 g, 17.6 mmol), tris(dibenzylacetone)dipalladium (810 mg, 0.9 mmol), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (1.03 g, 18 mmol), and sodium tert-butoxide (3.40 g, 35.37 mmol) were added to toluene (50 mL). The reaction was carried out at 80 °C for 1 hour under a nitrogen atmosphere. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated. The crude product was purified by column chromatography to give a yellow solid compound e-2b (4.2 g, 75%).

[1094] LCMS(ESI)[M+H] +=384.25.

[1095] Step 2: 4,4-Dimethoxy-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-3-(trifluoromethoxy)phenyl)piperidine (compound e-2c)

[1096] Compound e-2b (4 g, 12.7 mmol), pinacol diborate (4.85 g, 19.1 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium(I) dichloride (931 mg, 1.3 mmol), and potassium acetate (2.5 g, 25.5 mmol) were added to 1,4-dioxane (40 mL). The reaction was carried out overnight at 80 °C under a nitrogen atmosphere. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated. The crude product was purified by column chromatography to give a yellow solid compound e-2c (4 g, 97%).

[1097] LCMS(ESI)[M+H] + =431.26.

[1098] Step 3: 6-Chloro-4-(4-(4,4-dimethoxypiperidin-1-yl)-2-(trifluoromethoxy)phenyl)-7-fluoro-N,N-dimethyl-1H-indole-2-carboxamide (compound e-2d)

[1099] Compound e-2c (300 mg, 0.6 mmol) and compound a-2 (375 mg, 0.9 mmol) were dissolved in a mixed solvent of dioxane (2 mL) and water (0.4 mL). Potassium phosphate (197.3 mg, 1.0 mmol) and methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tris-isopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium (26 mg, 0.03 mmol) were added sequentially, and the mixture was stirred at 25 °C. The reaction mixture was then heated to 80 °C and stirred for 2 hours. After the reaction was complete, the mixture was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to give a yellow solid compound e-2d (90 mg, 42.5%).

[1100] LC-MS(ESI):[M+H] + =543.94

[1101] Step 4: 6-(1-(3-(1H-1,2,3-triazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-4-(4-(4,4-dimethoxypiperidin-1-yl)-2-(trifluoromethoxy)phenyl)-7-fluoro-N,N-dimethyl-1H-indole-2-carboxamide (compound e-2e)

[1102] Compound e-2d (1.08 g, 2.31 mmol), compound a-3 (0.92 g, 2.78 mmol), potassium phosphate (1.48 g, 6.95 mmol), and methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (0.39 mg, 0.46 mmol) were dissolved in 1,4-dioxane (20 mL) and water (4 mL). The reaction system was carried out at 100 °C for 12 hours under a nitrogen atmosphere. The reaction system was concentrated, and the crude product was purified by column chromatography to give compound e-1e (890 mg, 60.40%).

[1103] LC-MS(ESI):[M+H] + =713.73

[1104] Step 5: 6-(1-(3-(1H-1,2,3-triazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-7-fluoro-4-(4-(4-formaldehydepiperidin-1-yl)-2-(trifluoromethoxy)phenyl)-N,N-dimethyl-1H-indole-2-carboxamide (compound e-2f)

[1105] Compound e-1d (240 mg, 0.38 mmol) was dissolved in formic acid (5 mL), and the reaction system was reacted at room temperature for 1 hour. The reaction system was concentrated to give the crude product compound e-2f (220 mg, 99%).

[1106] LC-MS(ESI):[M+H] + =681.69

[1107] Step 6: 6-(1-(3-(1H-1,2,3-triazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-4-(4-(4-((dimethylamino)methyl)piperidin-1-yl)-2-(trifluoromethoxy)phenyl)-7-fluoro-N,N-dimethyl-1H-indole-2-carboxamide (compound e-2)

[1108] Compound e-2f (220 mg, 0.37 mmol), dimethylamine (35 mg, 0.45 mmol), sodium triacetoxyborohydride (158 mg, 0.75 mmol), and acetic acid (0.5 mL) were dissolved in dimethyl sulfoxide (5 mL), and the reaction mixture was reacted at room temperature for 2 hours. The reaction mixture was purified by high pressure to give compound e-2 (58 mg, 44.57%) as a white solid product.

[1109] 1H NMR (600MHz, Methanol-d4) δ8.03(dd,J=8.3,1.0Hz,1H),7.71(dd,J=14.2,1.1Hz,1H),7.44(dd,J=8.5,7.1Hz,1H),7.10 (dd,J=8.7,2.6Hz,1H),6.99–6.92(m,2H),6.67–6.63(m,1H),6.18–6.13(m,1H),4.79(dt,J=10.1,6.5Hz,2H),4.43(dd,J =44.5,2.7Hz,2H),3.89(d,J=12.4Hz,2H),3.78(t,J=5.9Hz,1H),3.70(t,J=5.8Hz,1H),3.23–3.11(m,7H),2.96(s,6H),2 .95–2.88(m,2H),2.45–2.35(m,2H),2.14–1.99(m,2H),1.91(d,J=12.9Hz,2H),1.55–1.45(m,2H),1.35(d,J=4.3Hz,2H).

[1110] LC-MS(ESI):[M+H] + =710.78

[1111] Example 52 Synthesis of compound e-4

[1112] 6-(1-(3-(1H-1,2,3-triazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-4-(2-chloro-4-(4-((dimethylamino)methyl)piperidin-1-yl)-5-fluorophenyl)-7-fluoro-N,N-dimethyl-1H-indole-2-carboxamide (compound e-4)

[1113] Synthesis scheme

[1114] Step 1: 6-(1-(3-(1H-1,2,3-triazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-7-fluoro-N,N-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-1H-indole-2-carboxamide (compound e-4a)

[1115] Compound A-1a (300 mg, 0.674 mmol), pinacol diboronate (257 mg, 1.01 mmol), methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (931 mg, 1.3 mmol), and potassium acetate (198 mg, 2.02 mmol) were added to 1,4-dioxane (40 mL). The reaction was carried out overnight at 80 °C under a nitrogen atmosphere. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated. The crude product was purified by column chromatography to give a yellow solid compound e-4a (350 mg, 97%).

[1116] LC-MS(ESI):[M+H] + =537.49.

[1117] Step 2: 1-(5-chloro-2-fluorophenyl)-4-(dimethoxymethyl)piperidine (compound e-4b)

[1118] In a 250 mL round-bottom flask, 3-bromo-4-fluorochlorobenzene (10 g, 47.75 mmol), 4-(dimethoxymethyl)-piperidine (8.36 g, 52.52 mmol), tris(dibenzylacetone)dipalladium (138 mg, 0.238 mmol), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (874 mg, 0.954 mmol), and sodium tert-butoxide (1.38 g, 14.32 mmol) were added, followed by toluene (50 mL). The reaction was carried out at 80 °C for 1 hour under a nitrogen atmosphere. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated. The crude product was purified by column chromatography to give a yellow solid compound e-4b (10 g, 73%).

[1119] LC-MS(ESI):[M+H] + =288.38.

[1120] Step 3: 1-(4-bromo-5-chloro-2-fluorophenyl)-4-(dimethoxymethyl)piperidine (compound e-4c)

[1121] N-bromosuccinimide (124 mg, 0.695 mmol) was added to a 5 mL solution of dichloromethane containing compound e-4b (200 mg, 0.695 mmol) at 0 °C, and the mixture was placed under an inert atmosphere (N2). The mixture was then stirred at 25 °C for 2 hours. The reaction solution was filtered, the filtrate was concentrated, and the crude product was purified by column chromatography to give a yellow solid compound e-4c (140 mg, 54.94%).

[1122] LC-MS(ESI):[M+H] + =367.39

[1123] Step 4: 6-(1-(3-(1H-1,2,3-triazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-4-(2-chloro-4-(4-(dimethoxymethyl)piperidin-1-yl)-5-fluorophenyl)-7-fluoro-N,N-dimethyl-1H-indole-2-carboxamide (compound e-4d)

[1124] Compound e-4c (110 mg, 0.272 mmol) was dissolved in dioxane (5 mL) and water (1 mL). Compound e-4a (160 mg, 0.3 mmol), 1,1-bis(diphenylphosphine)dimerferropalladium dichloride (20 mg, 0.027 eq), and potassium carbonate (113 mg, 0.818 mmol) were added. The reaction was carried out at 100 °C for 4 hours under nitrogen protection. After the reaction was completed, water (5 mL) and ethyl acetate (10 mL) were added to the reaction system for extraction three times. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was collected. The filtrate was concentrated under vacuum, and the crude product was purified by column chromatography (0-5% MeOH / DCM) to give a yellow solid compound e-4d (80 mg).

[1125] LC-MS(ESI):[M+H] + =696.57

[1126] Step 5: 6-(1-(3-(1H-1,2,3-triazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-4-(2-chloro-5-fluoro-4-(4-formylpiperidin-1-yl)phenyl)-7-fluoro-N,N-dimethyl-1H-indole-2-carboxamide (compound e-4e)

[1127] Compound e-4d (100 mg, 0.143 mmol) was dissolved in formic acid (1 mL), and the reaction system was reacted at room temperature for 3 hours. The reaction system was concentrated to give a yellow solid crude product, compound e-4e (90 mg, 96%).

[1128] LC-MS(ESI):[M+H] + =650.50

[1129] Step 6: 6-(1-(3-(1H-1,2,3-triazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-4-(2-chloro-4-(4-((dimethylamino)methyl)piperidin-1-yl)-5-fluorophenyl)-7-fluoro-N,N-dimethyl-1H-indole-2-carboxamide (compound e-4)

[1130] Compound e-4e (10 mg, 0.015 mmol), dimethylamine (2 mg, 0.03 mmol), sodium triacetoxyborohydride (10 mg, 0.046 mmol), and acetic acid (0.1 mL) were dissolved in dimethyl sulfoxide (1 mL), and the reaction mixture was reacted at room temperature for 1 hour. The reaction mixture was purified by high pressure to give compound e-4 (2 mg, 19%) as a white solid product.

[1131] 1 H NMR (400MHz, DMSO-d6) δ12.22(dd,J=7.5,2.2Hz,1H),8.11(d,J=10.1Hz,1H),7.69(d,J=11.7Hz,1H),7.30(d d,J=13.1,6.4Hz,1H),7.17(d,J=8.1Hz,1H),6.94(dd,J=28.6,6.0Hz,1H),6.48(q,J=2.8Hz,1H),6.19–6.11 (m,1H),4.62(q,J=7.0Hz,2H),4.34(dd,J=21.8,2.7Hz,2H),3.62(dt,J=21.2,5.8Hz,3H),3.25–2.95(m,11H ),2.85–2.75(m,8H),2.38–2.25(m,2H),1.99–1.93(m,1H),1.84(dd,J=13.2,3.7Hz,2H),1.44–1.35(m,2H).

[1132] LC-MS(ESI):[M+H] + =679.47.

[1133] Example 53 Synthesis of compound e-5

[1134] 6-(1-(3-(1H-1,2,3-triazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-7-fluoro-N,N-dimethyl-4-(2-methyl-2,7-diazaspiro[3.5]nonan-7-yl)-1H-indole-2-carboxamide (compound e-5)

[1135] Synthesis scheme

[1136] Step 1: tert-butyl 7-(6-chloro-2-(dimethylcarbamoyl)-7-fluoro-1H-indol-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid ester (compound e-5b)

[1137] Compound a-2 (180 mg, 0.56 mmol), compound e-5a (127 mg, 0.56 mmol), 2-dicyclohexylphosphine-2',6'-diisopropoxy-1,1'-biphenyl (47 mg, 0.1 mmol), [2'-(amino)[1,1'-biphenyl]-2-yl][[2',6'-di(1-methylethoxy)[1,1'-biphenyl]-2-yl]dicyclohexylphosphine]palladium chloride (43 mg, 0.05 mmol), and bis(trimethylsilylamino)lithium (471 mg, 2.82 mmol) were dissolved in 1,4-dioxane (4 mL) and water (0.8 mL). The reaction system was reacted at 100 °C for 2 hours under a nitrogen atmosphere. The reaction system was concentrated, and the crude product was purified by column chromatography to obtain compound e-5b (45 mg, 17.18%).

[1138] LC-MS(ESI):[M+H] + =466.26

[1139] Step 2: 6-(1-(3-(1H-1,2,3-triazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-4-(9-(dimethoxymethyl)-3-azaspiro[5.5]undecane-3-yl)-7-fluoro-N,N-dimethyl-1H-indole-2-carboxamide tert-butyl 7-(6-(1-(3-(1H-1,2,3-triazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-2-(dimethylcarbamoyl)-7-fluoro-1H-indole-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid ester (compound e-5c)

[1140] Compound e-5b (1.08 g, 2.31 mmol), compound a-3 (0.92 g, 2.78 mmol), potassium phosphate (1.48 g, 6.95 mmol), and methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (0.39 mg, 0.46 mmol) were dissolved in 1,4-dioxane (20 mL) and water (4 mL). The reaction system was carried out at 100 °C for 12 hours under a nitrogen atmosphere. The reaction system was concentrated, and the crude product was purified by column chromatography to obtain compound e-5c (750 mg, 50.80%).

[1141] LC-MS(ESI):[M+H] + =635.60

[1142] Step 3: 6-(1-(3-(1H-1,2,3-triazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-7-fluoro-N,N-dimethyl-4-(2,7-diazaspiro[3.5]non-7-yl)-1H-indole-2-carboxamide (compound e-5d)

[1143] Compound e-5c (240 mg, 0.38 mmol) was dissolved in dichloromethane (5 mL), and a solution of dioxane (5 mL) of hydrogen chloride was added to the reaction system. The reaction was carried out at room temperature for 1 hour. The reaction system was concentrated to obtain the crude product compound e-5d (200 mg, 98%).

[1144] LC-MS(ESI):[M+H] + =535.64

[1145] Step 4: 6-(1-(3-(1H-1,2,3-triazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-7-fluoro-N,N-dimethyl-4-(2-methyl-2,7-diazaspiro[3.5]non-7-yl)-1H-indole-2-carboxamide (compound e-5)

[1146] Compound e-5d (220 mg, 0.37 mmol), formaldehyde (15 mg, 0.45 mmol), sodium triacetoxyborohydride (158 mg, 0.75 mmol), and acetic acid (0.5 mL) were dissolved in dimethyl sulfoxide (5 mL), and the reaction mixture was reacted at room temperature for 2 hours. The reaction mixture was purified by high pressure to give compound e-5 (115 mg, 50.57%) as a white solid product.

[1147] 1 H NMR (400MHz, DMSO-d6) δ11.98(d,J=6.7Hz,1H),8.12(d,J=8.8Hz,1H),7.70(d,J=8.5Hz,1H),6.73(d,J=2 .4Hz,1H),6.33(dd,J=11.3,5.2Hz,1H),6.05(d,J=1.9Hz,1H),4.63(t,J=5.7Hz,2H),4.28(d,J=21.0Hz,2 H),4.05–3.99(m,2H),3.82(dd,J=10.8,6.6Hz,4H),3.59(t,J=5.8Hz,3H),3.13–3.05(m,5H),2.96(d,J=5 .7Hz,2H),2.88(d,J=5.0Hz,2H),2.33(d,J=8.1Hz,2H),2.00(q,J=6.6,5.0Hz,4H),1.24(d,J=3.3Hz,3H).

[1148] LC-MS(ESI):[M+H] + =549.48

[1149] Example 54 Synthesis of compound e-6

[1150] 6-(1-(3-(1H-1,2,3-triazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-4-(4-(4-((dimethylamino)methyl)piperidin-1-yl)-2,5-difluorophenyl)-7-fluoro-N,N-dimethyl-1H-indole-2-carboxamide (compound e-6)

[1151] Synthesis scheme

[1152] Step 1: 1-(4-bromo-2,5-difluorophenyl)-4-(dimethoxymethyl)piperidine (compound e-6b)

[1153] Piperidine carbaldehyde (5.0 g, 17.7 mmol), compound e-6a (10 g, 17.6 mmol), tris(dibenzylacetone)dipalladium (810 mg, 0.9 mmol), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (1.03 g, 18 mmol), and sodium tert-butoxide (3.40 g, 35.37 mmol) were added to toluene (50 mL). The reaction was carried out at 80 °C for 1 hour under a nitrogen atmosphere. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated. The crude product was purified by column chromatography to give a yellow solid compound e-6b (4.2 g, 75%).

[1154] LCMS(ESI)[M+H] + =350.05.

[1155] Step 2: 1-(2,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)-4-(dimethoxymethyl)piperidine (compound e-6c)

[1156] Compound e-6b (4 g, 12.7 mmol), pinacol diborate (4.85 g, 19.1 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium(I) dichloride (931 mg, 1.3 mmol), and potassium acetate (2.5 g, 25.5 mmol) were added to 1,4-dioxane (40 mL). The reaction was carried out overnight at 80 °C under a nitrogen atmosphere. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated. The crude product was purified by column chromatography to give a yellow solid compound e-6c (3.8 g, 85%).

[1157] LCMS(ESI)[M+H]+ =398.22.

[1158] Step 3: 6-Chloro-4-(4-(4-(dimethoxymethyl)piperidin-1-yl)-2,5-difluorophenyl)-7-fluoro-N,N-dimethyl-1H-indole-2-carboxamide (compound e-6d)

[1159] Compound e-6c (110 mg, 1.00 eq) was dissolved in dioxane (5 mL) and water (1 mL), and compound a-2 (89 mg, 1.00 eq), 1,1-bis(diphenylphosphine)dimerferropalladium dichloride (22 mg, 0.10 eq), and potassium carbonate (124 mg, 3.00 eq) were added. The reaction was carried out at 100 °C for 4 hours under nitrogen protection. After the reaction was completed, water (5 mL) and ethyl acetate (10 mL) were added to the reaction system for extraction three times. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was collected. The filtrate was concentrated under vacuum, and the crude product was purified by column chromatography (0-5% MeOH / DCM) to give a yellow solid compound e-6d (100 mg, 70.25%).

[1160] LC-MS(ESI):[M+H] + =510.16.

[1161] Step 4: 6-(1-(3-(1H-1,2,3-triazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-4-(4-(4-(4-(dimethoxymethyl)piperidin-1-yl)-2,5-difluorophenyl)-7-fluoro-N,N-dimethyl-1H-indole-2-carboxamide (compound e-6e)

[1162] Compound e-6d (1.08 g, 2.31 mmol), compound a-3 (0.92 g, 2.78 mmol), potassium phosphate (1.48 g, 6.95 mmol), and methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (0.39 mg, 0.46 mmol) were dissolved in 1,4-dioxane (20 mL) and water (4 mL). The reaction system was carried out at 100 °C for 12 hours under a nitrogen atmosphere. The reaction system was concentrated, and the crude product was purified by column chromatography to obtain compound e-6e (730 mg, 50.80%).

[1163] LC-MS(ESI):[M+H] + =680.30

[1164] Step 5: 6-(1-(3-(1H-1,2,3-triazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-4-(2,5-difluoro-4-(4-formaldehydepiperidin-1-yl)phenyl)-7-fluoro-N,N-dimethyl-1H-indole-2-carboxamide (e-6f)

[1165] Compound e-6e (264.00 mg, 0.35 mmol) and formic acid (4 mL) were added to a 25 mL dry round-bottom flask, and the mixture was stirred at room temperature for 2 hours. After the reaction was complete, the mixture was poured into a saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The crude product was purified by column chromatography to give a yellow solid compound e-6f (210.00 mg, 93%).

[1166] LC-MS(ESI):[M+H] + =634.26.

[1167] Step 6: 6-(1-(3-(1H-1,2,3-triazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-4-(4-(4-((dimethylamino)methyl)piperidin-1-yl)-2,5-difluorophenyl)-7-fluoro-N,N-dimethyl-1H-indole-2-carboxamide (compound e-6)

[1168] Compound e-6f (240 mg, 0.37 mmol), dimethylamine (17 mg, 0.37 mmol), sodium triacetoxyborohydride (158 mg, 0.75 mmol), and acetic acid (0.5 mL) were dissolved in dimethyl sulfoxide (5 mL), and the reaction mixture was reacted at room temperature for 2 hours. The reaction mixture was purified by high pressure to give compound e-6 (110 mg, 47.57%) as a white solid.

[1169] 1H NMR (600MHz, DMSO-d6) δ12.28–12.13(m,1H),8.11(d,J=16.9Hz,1H),7.69(d,J=19.1Hz,1H),7.37(dt,J=13.5 ,6.8Hz,1H),7.05–6.89(m,2H),6.62(dq,J=8.2,2.7Hz,1H),6.20–6.09(m,1H),4.63(dt,J=11.6,6.9Hz,2H), 4.41–4.27(m,2H),3.63(dt,J=32.3,5.8Hz,3H),3.51(s,3H),3.25–2.98(m,9H),2.83(d,J=4.7Hz,4H),2.77( t,J=11.9Hz,2H),2.38–2.26(m,2H),1.93–1.79(m,2H),1.39(qd,J=12.3,3.9Hz,2H),1.24(d,J=5.4Hz,2H)..

[1170] LC-MS(ESI):[M+H] + =663.47

[1171] Example 55 Synthesis of compound e-7

[1172] 6-(1-(3-(1H-1,2,3-triazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-4-(2-chloro-4-(4-((dimethylamino)methyl)piperidin-1-yl)phenyl)-7-fluoro-N,N-dimethyl-1H-indole-2-carboxamide (compound e-7)

[1173] Synthesis scheme

[1174] Step 1: 1-(4-bromo-3-chlorophenyl)-4-(dimethoxymethyl)piperidine (compound e-7a)

[1175] 1-Bromo-2-chloro-4-iodobenzene (500 mg, 1.00 eq) was dissolved in dimethyl sulfoxide (5 mL), and 4-(dimethoxymethyl)piperidine (300 mg, 1.20 eq), cuprous iodide (60 mg, 0.2 eq), L-hydroxyproline (83 mg, 0.4 eq), and potassium carbonate (653 mg, 3.00 eq) were added. The reaction was carried out overnight at 100 °C under nitrogen protection. After the reaction was completed, water (5 mL) was added to the reaction system, and the mixture was extracted three times with ethyl acetate (10 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was collected. The filtrate was concentrated under vacuum, and the crude product was purified by column chromatography (0-60% EA / PE) to give a yellow solid compound e-7a (240 mg).

[1176] LC-MS(ESI):[M+H] + =348.67

[1177] Step 2: 1-(3-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)-4-(dimethoxymethyl)piperidine (compound e-7b)

[1178] Compound e-7a (240 mg, 1.00 eq) was dissolved in dioxane (2 mL), and pinacol diborate (350 mg, 2.00 eq), 1,1-bis(diphenylphosphine)diberberine palladium dichloride (51 mg, 0.10 eq), and potassium acetate (203 mg, 3.00 eq) were added. The reaction was carried out overnight at 100 °C under nitrogen protection. After the reaction was completed, water (5 mL) and ethyl acetate (10 mL) were added to the reaction system, and the mixture was extracted three times. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was collected. The filtrate was concentrated under vacuum, and the crude product was purified by column chromatography (0-45% EA / PE) to give a yellow solid compound e-7b (220 mg).

[1179] LC-MS(ESI):[M+H] + =395.73

[1180] Step 3: 6-(1-(3-(1H-1,2,3-triazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-4-(2-chloro-4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-7-fluoro-N,N-dimethyl-1H-indole-2-carboxamide (compound e-7c)

[1181] Compound e-7b (220 mg, 1.00 eq) was dissolved in dioxane:water = 5:1 (6 mL), and compound a-5c (297 mg, 1.20 eq), methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (47 mg, 0.10 eq), and potassium phosphate (354 mg, 3.00 eq) were added. The reaction was carried out at 100 °C for 4 hours under nitrogen protection. After the reaction was completed, water (5 mL) and ethyl acetate (10 mL) were added to the reaction system for extraction three times. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was collected. The filtrate was concentrated under vacuum, and the crude product was purified by HPLC to obtain a white solid compound e-7c (180 mg).

[1182] LC-MS(ESI):[M+H] + =678.21

[1183] Step 4: 6-(1-(3-(1H-1,2,3-triazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-4-(2-chloro-4-(4-formylpiperidin-1-yl)phenyl)-7-fluoro-N,N-dimethyl-1H-indole-2-carboxamide (compound e-7d)

[1184] Compound e-7c (180 mg, 1 eq) was dissolved in a mixed solution of 1 M sulfuric acid (1.8 mL) and tetrahydrofuran (1.8 mL), and the reaction system was reacted at room temperature for 3 hours. After the reaction was completed, the mixture was extracted three times with dichloromethane, washed once with saturated brine, dried over anhydrous sodium sulfate, and the organic phase was concentrated to give a yellow solid crude product, compound e-7d (150 mg).

[1185] LC-MS(ESI):[M+H] + =632.14

[1186] Step 5: 6-(1-(3-(1H-1,2,3-triazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-4-(2-chloro-4-(4-((dimethylamino)methyl)piperidin-1-yl)phenyl)-7-fluoro-N,N-dimethyl-1H-indole-2-carboxamide (compound e-7)

[1187] Compound e-7d (150 mg, 1 eq), dimethylamine (22 mg, 2 eq), sodium triacetoxyborohydride (151 mg, 3 eq), and acetic acid (0.1 mL) were dissolved in dimethyl sulfoxide (1 mL), and the reaction system was reacted at room temperature for 1 hour. The reaction system was purified by high pressure to obtain a white solid product, compound e-7 (100 mg).

[1188] 1H NMR (600MHz, DMSO-d6) δ12.15(d,J=12.8Hz,1H),8.11(d,J=14.7Hz,1H),7.69(d,J=18.0Hz,1H),7.31(dd,J=8.5,4.5Hz, 1H),7.11(s,1H),7.02(d,J=8.7Hz,1H),6.89(dd,J=40.1,6.0Hz,1H),6.45(s,1H),6.14(d,J=15.4Hz,1H),5.35–5.24(m ,1H),4.68–4.58(m,1H),4.34(d,J=29.7Hz,1H),3.85(d,J=11.0Hz,1H),3.70–3.49(m,6H),3.34–2.97(m,9H),2.82(d,J =4.8Hz,2H),2.51(s,6H),2.46–2.23(m,2H),2.03–1.93(m,1H),1.80(d,J=11.9Hz,1H),1.46(s,1H),1.35–1.27(m,1H).

[1189] LC-MS(ESI):[M+H] + =661.22

[1190] Example 56 Synthesis of compound g-10

[1191] 6-(1-(3-(1H-1,2,3-triazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-4-(9-(dimethylamino)-3-azaspiro[5.5]undecane-3-yl)-7-fluoro-N,N-dimethyl-1H-indole-2-carboxamide (compound g-10)

[1192] Synthesis scheme

[1193] Step 1: 9-oxo-3-azanoyl[5.5]undecane-3-carboxylate (compound g-10b)

[1194] 9-oxo-3-azaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester (6 g, 22.4 mmol) was dissolved in dichloromethane, and a 4N hydrochloric acid / 1,4-dioxane solution was added. The mixture was reacted at room temperature for 1 hour, evaporated to dryness, and then dissolved in tetrahydrofuran solution. Triethylamine (7.3 g, 72.16 mmol) was added, and the reaction mixture was stirred at 25 °C for 10 minutes. Then, benzyl chloroformate (8.21 g, 48.11 mmol) was added at 0 °C. The reaction mixture was stirred at 25 °C for 16 hours. After the reaction was complete, the reaction mixture was concentrated under vacuum, and the residue was separated by column chromatography to give a pale yellow oil compound g-10b (7.16 g, 99%).

[1195] 1 H NMR (400MHz, DMSO-d6) δ7.40–7.29(m,5H),5.07(s,2H),3.50–3.37(m,4H),2.25(t,J=6.8Hz,4H),1.68(t,J=6.8Hz,4H),1.53–1.45(m,4H).

[1196] LCMS(ESI):[M+H] + =302.25

[1197] Step 2: Benzyl 1,4-dioxa-11-azaspiro[4.2.5] 8 .2 5 Pentadecane-11-carboxylate (compound g-10c)

[1198] To a toluene (70 mL) solution of compound g-10b (7.16 g, 23.76 mmol), 4-methylbenzenesulfonic acid (409.09 mg, 2.38 mmol) and ethylene glycol (14.75 g, 237.57 mmol) were added. The mixture was stirred at 110 °C for 4 hours. After the reaction was complete, the reaction mixture was concentrated under vacuum, and the residue was separated by column chromatography to give a pale yellow oil compound g-10c (5.0 g, 61%).

[1199] 1 H NMR (400MHz, DMSO-d6) δ7.39–7.28(m,5H),5.05(s,2H),3.83(s,4H),3.35–3.34(m,4H),1.54–1.48(m,4H),1.47–1.41(m,4H),1.38–1.31(m,4H).

[1200] LCMS(ESI):[M+H] + =346.35

[1201] Step 3: 1,4-Dioxa-11-azaspiro[4.2.5] 8 .2 5 Pentadecane (compound g-10d)

[1202] Palladium on carbon (500 mg) was added to a methanol (100 mL) solution of compound g-10c (5 g, 14.47 mmol), and the mixture was purged with hydrogen. The mixture was stirred at 25 °C for 16 hours. After the reaction was complete, the mixture was filtered. The filtrate was concentrated under reduced pressure to give a pale yellow oil compound g-10d (3.4 g, >99%).

[1203] 1 H NMR (400MHz, DMSO-d6) δ3.82(s,4H),2.68–2.61(m,4H),1.52–1.46(m,4H),1.45–1.36(m,4H),1.33–1.27(m,4H).

[1204] LCMS(ESI):[M+H] + =212.35

[1205] Step 4: 6-Chloro-4-(1,4-dioxo-11-azabispirol) [4.2.5] 8 .2 5 Pentadecane-11-yl)-7-fluoro-N,N-dimethyl-1H-indole-2-carboxamide (compound g-10e)

[1206] Compound g-10d (248 mg, 1.17 mmol), a-2 (188 mg, 587 μmol), methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (49 mg, 59 μmol), 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (55 mg, 117 μmol), and toluene (10 mL) were added to a 100 mL dry round-bottom flask. The system was purged with nitrogen three times. Bistrimethylsilylaminolithium (2.93 mL, 1 N) was then added, and the system was stirred at 100 °C for 1 hour. After the reaction was complete, the system was concentrated under vacuum and then purified by column chromatography to obtain compound g-10e (135 mg, 51%).

[1207] 1 H NMR (400MHz, DMSO-d6) δ6.73–6.70(m,1H),6.46(d,J=5.3Hz,1H),3.85(s,4H),3.28–2.97(m,10H),1.67–1.48(m,12H).

[1208] LC-MS(ESI):[M+H] + =405.39.

[1209] Step 5: 6-(1-(3-(1H-1,2,3-triazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-4-(1,4-dioxo-11-azabispirol[4.2.5] 8 .2 5 Pentadecane-11-yl)-7-fluoro-N,N-dimethyl-1H-indole-2-carboxamide (compound g-10f)

[1210] Compound g-10e (285.00 mg, 0.63 mmol), a-3 (252.51 mg, 0.76 mmol), methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (53.61 mg, 0.06 mmol), potassium phosphate (403.35 mg, 1.90 mmol), and 1,4-dioxane / water = 5:1 (20 mL) were added to a 100 mL dry round-bottom flask. The system was purged with nitrogen three times and stirred at 100 °C for 2 hours. After the reaction was completed, the system was concentrated under vacuum and then purified by column chromatography to obtain a yellow solid compound g-10f (264.00 mg, 67%).

[1211] 1 H NMR(400MHz,Chloroform-d)δ9.43–9.32(m,1H),7.80–7.73(m,1H),7.70–7.64( m,1H),6.86–6.74(m,1H),6.43–6.30(m,1H),6.13–6.02(m,1H),4.85–4.74(m,2 H),4.47–4.39(m,1H),4.28–4.23(m,1H),3.96(s,4H),3.76(t,J=5.8Hz,1H),3. 56(t,J=5.8Hz,1H),3.51–3.00(m,12H),2.40–2.30(m,2H),1.77–1.61(m,12H).

[1212] LC-MS(ESI):[M+H] + =620.58.

[1213] Step 6: 6-(1-(3-(1H-1,2,3-triazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-7-fluoro-N,N-dimethyl-4-(9-oxo-3-azaspiro[5.5]undecane-3-yl)-1H-indole-2-carboxamide (compound g-10g)

[1214] Compound g-10f (264.00 mg, 0.42 mmol) and formic acid (4 mL) were added to a 25 mL dry round-bottom flask, and the mixture was stirred at room temperature for 2 hours. After the reaction was complete, the mixture was poured into a saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The crude product was purified by column chromatography to give a yellow solid compound g-10g (240.00 mg, 99%).

[1215] 1 H NMR(400MHz,Chloroform-d)δ9.59–9.44(m,1H),7.81–7.71(m,1H),7.70–7.61(m ,1H),6.82–6.77(m,1H),6.43–6.33(m,1H),6.12–6.04(m,1H),4.85–4.73(m,2H) ,4.47–4.40(m,1H),4.27–4.22(m,1H),3.76(t,J=5.9Hz,1H),3.57(t,J=5.8Hz,1 H),3.40–3.12(m,10H),3.10–2.99(m,2H),2.45–2.30(m,6H),1.90–1.80(m,8H).

[1216] LC-MS(ESI):[M+H] + =576.58.

[1217] Step 7: 6-(1-(3-(1H-1,2,3-triazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-4-(9-(dimethylamino)-3-azaspiro[5.5]undecane-3-yl)-7-fluoro-N,N-dimethyl-1H-indole-2-carboxamide (compound g-10)

[1218] Compound g-10 g (40.00 mg, 0.07 mmol), dimethylamine (3.76 mg, 0.08 mmol), and tetraisopropyl titanate (59.24 mg, 0.21 mmol) were added to a 10 mL vial. The mixture was dissolved in dimethyl sulfoxide (2 mL) and stirred overnight at 60 °C. Sodium triacetoxyborohydride (44.18 mg, 0.21 mmol) was then added to the mixture, and stirring was continued at 60 °C for 5 hours. After the reaction was complete, the mixture was purified by preparative chromatography to give a white solid compound g-10 (2.00 mg, 5%).

[1219] 1 H NMR(400MHz, Methanol-d4)δ8.05–7.97(m,1H),7.75–7.67(m,1H),7.04–6.93(m,2H),6.21–6.13(m,1H),4.82–4.73(m,2H),4.45–4.31(m,2H),3 .80–3.66(m,2H),3.57–3.50(m,4H),3.24–3.10(m,6H),2.89(s,6H),2.4 6–2.30(m,2H),2.12–1.94(m,6H),1.87–1.58(m,4H),1.48–1.35(m,2H).

[1220] LC-MS(ESI):[M+H] + =605.58.

[1221] Example 57 Synthesis of compound g-11

[1222] 6-(1-(3-(1H-1,2,3-triazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-4-(2-(dimethylamino)-8-aza[4,5]dec-8-yl)-7-fluoro-N,N-dimethyl-1H-indole-2-carboxamide (compound g-11)

[1223] Synthesis scheme

[1224] Step 1: 6-Chloro-4-(1,4-dioxa-10-azaspiro[4.1.5]) 7 .2 5 Tetradecane-10-yl)-7-fluoro-N,N-dimethyl-1H-indole-2-carboxamide (compound g-11b)

[1225] The synthesis method is the same as that of compound g-10e.

[1226] 1H NMR(400MHz, DMSO-d6)δ6.88–6.70(m,1H),6.47–6.36(m,1H),3.83–3.79(m,4H),3.31–2. 85(m,10H),1.82(t,J=7.6Hz,2H),1.74(s,2H),1.72–1.64(m,4H),1.59(t,J=7.6Hz,2H).

[1227] LCMS(ESI):[M+H] + =436.39.

[1228] Step 2: 6-(1-(3-(1H-1,2,3-triazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-4-(1,4-dioxa-10-azaspiro[4.1.5]) 7 .2 5 Tetradec-10-yl)-7-fluoro-N,N-dimethyl-1H-indole-2-carboxamide (compound g-11c)

[1229] The synthesis method is the same as that of compound g-10f

[1230] 1 H NMR (400MHz, DMSO-d6) δ11.96–11.88(m,1H),8.11(d,J=9.2Hz,1H),7.69(d,J=9.9Hz,1H) ,6.72–6.67(m,1H),6.36–6.28(m,1H),6.09–6.02(m,1H),4.68–4.57(m,2H),4.36–4.22(m ,2H),3.84–3.78(m,4H),3.67–3.53(m,2H),3.27–3.00(m,10H),2.99–2.89(m,2H),2.36– 2.21(m,2H),1.82(t,J=7.6Hz,2H),1.74(s,2H),1.72–1.65(m,4H),1.59(t,J=7.6Hz,2H).

[1231] LCMS(ESI):[M+H] + =606.58.

[1232] Step 3: 6-(1-(3-(1H-1,2,3-triazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-7-fluoro-N,N-dimethyl-4-(2-oxo-8-aza[4.5]dec-8-yl)-1H-indole-2-carboxamide (compound g-11d)

[1233] The synthesis method is the same as that of compound g-10g

[1234] 1 H NMR (400MHz, DMSO-d6) δ11.93(s,1H),8.11(d,J=9.2Hz,1H),7.69(d,J=9.6Hz ,1H),6.76–6.70(m,1H),6.39–6.31(m,1H),6.10–6.04(m,1H),4.66–4.59(m, 2H),4.35–4.23(m,2H),3.66–3.55(m,2H),3.28–3.00(m,10H),2.99–2.91(m, 2H),2.37–2.21(m,4H),2.18(s,2H),1.87(t,J=7.8Hz,2H),1.80–1.66(m,4H).

[1235] LCMS(ESI):[M+H]+=562.45.

[1236] Step 4: 6-(1-(3-(1H-1,2,3-triazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-4-(2-(dimethylamino)-8-aza[4.5]dec-8-yl)-7-fluoro-N,N-dimethyl-1H-indole-2-carboxamide (compound g-11)

[1237] The synthesis method is the same as that of compound g-10.

[1238] 1 H NMR(400MHz,DMSO-d6)δ12.12–11.94(m,1H),9.49(s,1H),8.11(d,J=8.7H z,1H),7.69(d,J=9.4Hz,1H),6.79–6.71(m,1H),6.48–6.34(m,1H),6.11– 6.03(m,1H),4.68–4.59(m,2H),4.33–4.25(m,2H),3.30–2.93(m,15H),2. 82–2.76(m,6H),2.39–2.21(m,2H),2.17–2.02(m,2H),1.85–1.44(m,8H).

[1239] LCMS(ESI):[M+H] + =591.68.

[1240] Example 58 Synthesis of compounds g-12-P1 and g-12-P2

[1241] Synthesis of 6-(1-(3-(1H-1,2,3-triazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-4-(8-(dimethylamino)-2-azaspiro[4.5]dec-2-yl)-7-fluoro-N,N-dimethyl-1H-indole-2-carboxamide (compounds g-12-P1 and g-12-P2)

[1242] Synthesis scheme:

[1243] Step 1: 1,4-Dioxa-10-azabispirol [4.2.4] 8 .2 5 Tetradecane-10-carboxylic acid benzyl ester (compound g-12b)

[1244] Compound g-12a (100 mg, 0.35 mmol, 1.0 equivalent) was dissolved in 3.0 mL of DCM, and ethylene glycol (3...

Claims

1. A compound having the structure shown in formula (I): Or its isomers, isotopic derivatives, polymorphs, prodrugs, or pharmaceutically acceptable salts or solvates thereof, wherein: The PTM has the structure shown in equation (I-1): R L1 R L2 and R L4 Each is independently a covalent bond or C 1-6 Divalent straight-chain or branched saturated or unsaturated hydrocarbon groups, wherein one, two, or three methylene units of the hydrocarbon group are independently and optionally surrounded by -Cyx-, -O-, -C(O)-, -C(S)-, -C(R)2-, -CR(OR)-, -NR-, -S-, -S(O)-, -S(O)2-, Or -CR = CR- substitution; R L3 For covalent bonds or C 1-6 A divalent straight-chain or branched saturated or unsaturated hydrocarbon group, wherein one, two, or three methylene units of the hydrocarbon group are independently and optionally replaced by -Cyx-, -O-, -C(O)-, -C(S)-, -C(R)2-, -CR(OR)-, -NR-, -C(NR-), -S-, -S(O-), -S(O)2-, or -CR=CR-, or R L3 It does not exist; Cyx is selected from phenylene, saturated or partially unsaturated 3-7 membered heterocyclic hydrocarbon groups, saturated or partially unsaturated 3-7 membered heterocyclic hydrocarbon groups containing 1, 2, 3, or 4 heteroatoms each independently selected from nitrogen, oxygen, and sulfur, and 5-8 membered monocyclic or bicyclic heteroaryl groups containing 1, 2, 3, or 4 heteroatoms each independently selected from nitrogen, oxygen, and sulfur, wherein the phenylene, heterocyclic hydrocarbon group, heterocyclic hydrocarbon group, and heteroaryl group are optionally selected from F, Cl, Br, I, cyano, C 1-6 Alkyl, C 1- 6-hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl groups and C 1-6 One or more substituents of the haloalkoxy group are substituted; Cy1 is selected from 6-10 arylene groups, saturated or partially unsaturated 5-11 cyclic or bicyclic alkyl groups, saturated or partially unsaturated 5-11 cyclic or bicyclic heterocyclic groups containing 1, 2, 3 or 4 heteroatoms each independently selected from nitrogen, oxygen and sulfur, and 5-14 cyclic, bicyclic or tricyclic arylene groups containing 1, 2, 3 or 4 heteroatoms each independently selected from nitrogen, oxygen and sulfur. Cy2 is selected from saturated or partially unsaturated 3-8 membered cyclic hydrocarbon groups, saturated or partially unsaturated 3-8 membered heterocyclic hydrocarbon groups, 6-10 membered aryl hydrocarbon groups, and 5-8 membered heterocyclic hydrocarbon groups. Cy3 is absent or selected from 6-10 aryl groups, 3-11 saturated or partially unsaturated monocyclic, fused, or spirocyclic bicyclic hydrocarbon groups, saturated or partially unsaturated 3-11 heterocyclic groups containing 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5-10 aryl or bicyclic monocyclic groups containing 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Cy4 is selected from covalently bonded, saturated or partially unsaturated 3-8 aryl or bicyclic subcyclic hydrocarbon groups, saturated or partially unsaturated 3-8 aryl or bicyclic subcyclic groups containing 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 6-10 aryl groups, and 5-10 aryl groups containing 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R P1 R P2 R P3 and R X Each time it appears, it is independently selected from hydrogen, deuterium, halogen, -CN, -NO2, oxo group (=O), C. 1-6 Alkyl, C 1-6 Alkoxy, -N(R)2, -S(O)2R, -C(O)R, -C(O)-N(R)2, saturated or partially unsaturated 3-8 membered cyclic hydrocarbon groups, saturated or partially unsaturated 3-8 membered heterocyclic groups containing 1, 2, 3 or 4 heteroatoms each independently selected from nitrogen, oxygen and sulfur, 6-10 membered aryl groups, and 5-10 membered heteroaryl groups containing 1, 2, 3 or 4 heteroatoms each independently selected from nitrogen, oxygen and sulfur, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, 3-8 membered cyclic hydrocarbon, 3-8 membered heterocyclic, 6-10 membered aryl, and 5-10 membered heteroaryl are optionally selected from F, Cl, Br, I, hydroxyl, carboxyl, -CN, -NO2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 The substituted group is replaced by one or more substituents of a haloalkoxy group, a 3-8 membered cyclic hydrocarbon group, and a 3-8 membered heterocyclic group; preferably, R P1 R P2 R P3 and R X Each time it appears, it is independently selected from deuterium, halogen, -CN, -NO2, oxo group (=O), C. 1-6 Alkyl, C 1-6 Alkoxy, -N(R)2, -S(O)2R, -C(O)R, -C(O)-N(R)2, saturated or partially unsaturated 3-8 membered cyclic hydrocarbon groups, saturated or partially unsaturated 3-8 membered heterocyclic groups containing 1, 2, 3 or 4 heteroatoms each independently selected from nitrogen, oxygen and sulfur, 6-10 membered aryl groups, and 5-10 membered heteroaryl groups containing 1, 2, 3 or 4 heteroatoms each independently selected from nitrogen, oxygen and sulfur, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, 3-8 membered cyclic hydrocarbon, 3-8 membered heterocyclic, 6-10 membered aryl, and 5-10 membered heteroaryl are optionally selected from F, Cl, Br, I, hydroxyl, carboxyl, -CN, -NO2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 It is substituted by one or more substituents of haloalkoxy, 3-8 membered cyclic hydrocarbon and 3-8 membered heterocyclic groups; R A Selected from hydrogen, -CN, -NO2, -N(R)2, -OH, halogens, C 1-6 Alkyl, C 1-6 Alkoxy, -CyB1-CyB2, 6-10 aryl, saturated or partially unsaturated 3-8 membered cyclic hydrocarbon, saturated or partially unsaturated 3-10 membered monocyclic or bicyclic heterocyclic groups containing 1, 2, 3, or 4 heteroatoms each independently selected from nitrogen, oxygen, and sulfur, and 5-10 membered monocyclic or bicyclic heteroaryl groups containing 1, 2, 3, or 4 heteroatoms each independently selected from nitrogen, oxygen, and sulfur, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, aryl, cyclic, heterocyclic, and heteroaryl groups are optionally selected from oxo (=O), F, Cl, Br, I, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl groups and C 1-6 The alkoxy group is substituted by one or more substituents of the haloalkoxy group; CyB1 is selected from 3-10 saturated or partially unsaturated monocyclic or bicyclic alkylene groups, 3-10 saturated or partially unsaturated monocyclic or bicyclic heterocyclic alkylene groups containing 1, 2, 3, or 4 heteroatoms each independently selected from nitrogen, oxygen, and sulfur, 5-8 cyclic arylene groups, 9-10 cyclic arylene groups, and 5-8 cyclic heterocyclic arylene groups and 9-10 cyclic heterocyclic arylene groups containing 1, 2, 3, or 4 heteroatoms each independently selected from nitrogen, oxygen, and sulfur, wherein the alkylene group, heterocyclic group, arylene group, and heterocyclic arylene group are optionally selected from F, Cl, Br, I, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl groups and C 1-6 One or more substituents of the haloalkoxy group are substituted; CyB2 is selected from 3-10 member saturated or partially unsaturated monocyclic or bicyclic cyclic hydrocarbon groups, 3-10 member saturated or partially unsaturated monocyclic or bicyclic heterocyclic groups containing 1, 2, 3, or 4 heteroatoms each independently selected from nitrogen, oxygen, and sulfur, 6-10 member monocyclic or bicyclic aryl groups, and 5-10 member heteroaryl groups containing 1, 2, 3, or 4 heteroatoms each independently selected from nitrogen, oxygen, and sulfur. The cyclic hydrocarbon group, heterocyclic group, aryl group, and heteroaryl group are optionally selected from F, Cl, Br, I, cyano, C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl groups and C 1-6 One or more substituents of the haloalkoxy group are substituted; Each time R appears, it is independently hydrogen, halogen, hydroxyl, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, saturated or partially unsaturated 3-10 membered cyclic hydrocarbon group, saturated or partially unsaturated 3-10 membered heterocyclic group, 6-10 membered aryl or 5-10 membered heteroaryl, wherein C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, cyclic hydrocarbon, heterocyclic, aryl, or heteroaryl groups are optionally selected from F, Cl, Br, I, cyano, hydroxyl, oxo (=O), C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Halogenated alkyl groups and C 1-6 One or more substituents of the haloalkoxy group are substituted; Each occurrence of n1, n2, n3, and n4 is independently 0, 1, 2, 3, 4, 5, or 6; L is the chemical linker connecting the CLM and the PTM; The CLM is selected from the following structures: W1 and W2 are each selected independently from CR each time they appear. b R c And C(O), and at least one of W1 and W2 is selected from C(O); W3 is selected independently from C(R) each time it appears. b )2 and C(O); In equations 2-1-9, 2-1-10, 2-1-11, and 2-1-12, the relationships between W4, W5, and W6... Indicates a single or double bond; W4, W5, and W6 are each independently selected from C, C(O), O, N, and NR, respectively. b CR b and CR b R c Furthermore, when there is a double bond between W4 and W5, and a single bond between W5 and W6, W4 is selected from C, and W5 is selected from N and CR. b W6 is selected from NR b O and CR b R c When there is a single bond between W4 and W5, and a double bond between W5 and W6, W4, W5, and W6 are each independently selected from N and CR. b When all bonds between W4, W5, and W6 are single bonds, W4 is selected from N and CR. b W5 and W6 are each independently selected from C(O) and NR. b O and CR b R c ; R q Each occurrence is independently selected from single bonds and NR. b ; A1, A2, A3, A4, A5, and A6 are each independently selected from O, S, C(O), and NR when they appear. d and C(R) d )2; B1, B2, X, and Z are each independently selected from N and CR each time they appear. d ; E is selected independently from O, C(O)NR each time it appears. b and NR b ; Each time m1 and m2 appear, they are independently selected from 0, 1, 2, 3, 4, 5 and 6, and 1≤m1+m2≤6; Each time m3 and m4 appear, they are independently selected from 0, 1, 2, 3, 4, 5, 6 and 7, and 1≤m3+m4≤7; Each time m5 and m7 appear, they are each independently selected from 0, 1, 2, 3, 4, 5, 6 and 7. Each time m6 and m8 appear, they are each independently selected from 1, 2, 3, 4, 5, 6, 7 and 8. And 1≤m5+m6≤8, 1≤m7+m8≤8. Each time m9, m10, and m11 appear, they are each independently selected from 0, 1, 2, and 3, and m9 + m10 + m11 ≤ 3; R1 and R2 are each independently selected from H, deuterium, halogen, hydroxyl, and C atoms each time they appear. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl and C 3-6 cycloalkyl; R b and R c Each time it appears, it is independently selected from H and C. 1-6 Alkyl, C 1-6 Alkoxy and C 3-6 cycloalkyl; R3, R4, R5 and R d Each time it appears, it is independently selected from H, halogen, hydroxyl, cyano, amino, nitro, C. 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, -NH(C 1-6 alkyl), -N(C) 1-6 Alkyl)2, C 1-6 Alkyl-C(O)-, C 1-6 Alkyl-OC(O)-, C 1-6 Alkyl-NH-C(O)-, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-8 Aryl and 5-8 quinone heteroaryl groups; n and n5 are each selected independently from 0, 1, 2 and 3 each time they appear; and Indicates the connection site.

2. A compound having the structure shown in formula (Ι4): Or its isomers, isotopic derivatives, polymorphs, prodrugs, or pharmaceutically acceptable salts or solvates thereof, wherein: PTM is the binding site that targets signal transduction and transcriptional activator 6 (STAT6), and it has the structure shown in formula (I-14): R L1 R L2 and R L4 Each is independently a covalent bond or C 1-6 Divalent straight-chain or branched saturated or unsaturated hydrocarbon groups, wherein one, two or three methylene units of the hydrocarbon group are independently and optionally replaced by -Cyx-, -O-, -C(O)-, -C(S)-, -C(R)2-, -CF2-, -CRF-, -CR(OR)-, -NR-, -C(NR)-, -S-, -S(O)-, -S(O)2-, -S(O)(NR)- or -CR=CR-; R L3 For covalent bonds or C 1-6 Divalent straight-chain or branched saturated or unsaturated hydrocarbon groups, wherein one, two or three methylene units of the hydrocarbon group are independently and optionally replaced by -Cyx-, -O-, -C(O)-, -C(S)-, -C(R)2-, -CF2-, -CRF-, -CR(OR)-, -NR-, -C(NR)-, -S-, -S(O)-, -S(O)2-, -S(O)(NR)- or -CR=CR-, or are absent; -Cyx- is selected from phenylene, 3 to 7 saturated or partially unsaturated heterocyclic hydrocarbon groups or heterocyclic groups containing 1, 2, 3 or 4 heteroatoms each independently selected from nitrogen, oxygen and sulfur, and 5 to 8 cyclic monocyclic or bicyclic heteroaryl groups containing 1, 2, 3 or 4 heteroatoms each independently selected from nitrogen, oxygen and sulfur. Cy1 is selected from 6-10 arylene groups, saturated or partially unsaturated 5-11 cyclic or bicyclic alkyl groups, or heterocyclic groups containing 1, 2, 3, or 4 heteroatoms each independently selected from nitrogen, oxygen, and sulfur, and 5-14 cyclic, bicyclic, or tricyclic arylene groups containing 1, 2, 3, or 4 heteroatoms each independently selected from nitrogen, oxygen, and sulfur, wherein the arylene group, alkyl group, or heterocyclic group is optionally surrounded by n1 R P1 Replaced; Cy2 is selected from saturated or partially unsaturated 3-8 membered cyclic hydrocarbon groups, saturated or partially unsaturated 3-8 membered heterocyclic hydrocarbon groups, 6-10 membered aryl hydrocarbon groups, and 5-8 membered heterocyclic hydrocarbon groups, wherein the cyclic hydrocarbon group, heterocyclic hydrocarbon group, aryl hydrocarbon group, or heterocyclic hydrocarbon group is optionally surrounded by n2 R groups. P2 Replaced; Cy3 is absent or selected from 6-10 aryl groups, 3-11 saturated or partially unsaturated monocyclic or bicyclic cyclic hydrocarbon groups containing 1, 2, 3 or 4 heteroatoms each independently selected from nitrogen, oxygen and sulfur, and 5-10 cyclic monocyclic or bicyclic heteroaryl groups containing 1, 2, 3 or 4 heteroatoms each independently selected from nitrogen, oxygen and sulfur, wherein the aryl, cyclic hydrocarbon, heterocyclic and heteroaryl groups are optionally separated by n3 R groups. P3 Replaced; Cy4 is absent or selected from covalently bonded, saturated or partially unsaturated 3-8 membered monocyclic or bicyclic alkyl groups, saturated or partially unsaturated 3-8 membered monocyclic or bicyclic heterocyclic groups containing 1-4 heteroatoms each independently selected from N, O, and S, 6-10 membered arylene groups, and 5-10 membered heteroarylene groups containing 1, 2, 3, or 4 heteroatoms each independently selected from N, O, and S, wherein the alkyl group, heterocyclic group, arylene group, or heteroarylene group is optionally surrounded by n4 R groups. x Replaced; R A Each time it appears, it is independently selected from hydrogen and R. B R C Halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, -CN, -NO2, -OR, -SR, -N(R)2, -SiR3, -S(O)R, -S(O)2R, -S(O)(NR)R, -S(O)2N(R)2, -S(O)R, -C(O)R, -C(S)R, -C(O)OR, -C(O)N(R)2, - C(O)NROR, -OC(O)R, -OC(O)N(R)2, -P(O)(R)2, -P(O)(OR)2, -OP(O)(R)2, -OP(O)(OR)2, -NRC(O)OR, -NRC(O)R, -NRC(O)N(R)2, and -NRS(O)2R; R P1 R P2 R P3 and R x Each time it appears, it is independently selected from hydrogen and R. B , Deuterium atom, halogen, oxo group (=O), -CN, -NO2, -OR, -SR, -N(R)2, -Si(R)3, -S(O)R, -S(O)2R, -S(O)(NR)R, -S(O)2N(R)2, -S(O)R, -C(O)R, -C(S)R, -C(O)OR, -C(O)N (R)2, -C(O)NROR, -OC(O)R, -OC(O)N(R)2, -P(O)(R)2, -P(O)(OR)2, -OP(O)(R)2, -OP(O)(OR)2, -NRC(O)OR, -NRC(O)R, -NRC(O)N(R)2 and -NRS(O)2R; R B Selected from C 1-6 Aliphatic, 6-10 aryl, 3-8 saturated or partially unsaturated cyclic hydrocarbon groups, 3-8 heterocyclic groups containing 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5-10 monocyclic or bicyclic heteroaryl groups containing 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein C 1-6 Aliphatic, phenyl, saturated or partially unsaturated cyclic hydrocarbon or heterocyclic groups, and monocyclic or bicyclic heteroaryl groups may be substituted; R C Independently for -L B -CyB1-H or -L B -CyB1-CyB2; L B For covalent bonds or C 1-3 Divalent straight-chain or branched saturated or unsaturated hydrocarbon groups, wherein one or two methylene units of the hydrocarbon group are independently and optionally replaced by -O-, -C(O)-, -C(S)-, -C(R)2-, -CF2-, -CRF-, -CR(OR)-, -NR-, -S-, -S(O)-, -S(O)2-, -S(O)(NR)- or -CR=CR-; CyB1 is independently selected from phenylene, 3-10 member saturated or partially unsaturated monocyclic or bicyclic cyclic hydrocarbon groups or heterocyclic groups containing 1, 2, 3, or 4 heteroatoms each independently selected from nitrogen, oxygen, and sulfur, and 5-8 member or 10 member monocyclic or bicyclic arylene groups or heteroarylene groups containing 1, 2, 3, or 4 heteroatoms each independently selected from nitrogen, oxygen, and sulfur; CyB2 is independently selected from phenyl, 3-10 member saturated or partially unsaturated monocyclic or bicyclic cyclic hydrocarbon groups or heterocyclic groups containing 1, 2, 3 or 4 heteroatoms each independently selected from nitrogen, oxygen and sulfur, 6-10 member monocyclic or bicyclic aryl groups and 5-8 member or 10 member heteroaryl groups containing 1, 2, 3 or 4 heteroatoms each independently selected from nitrogen, oxygen and sulfur; Each time R appears, it independently represents hydrogen or C. 1-6 Aliphatic, 3-7 member saturated or partially unsaturated cyclic hydrocarbon groups, 3-7 member saturated or partially unsaturated heterocyclic groups containing 1-4 heteroatoms each independently selected from nitrogen, oxygen, and sulfur, or 5-8 or 10 member heteroaryl groups having 1-4 heteroatoms each independently selected from nitrogen, oxygen, and sulfur; or: two R groups located on the same or adjacent atoms, together with the atoms between them, forming optionally substituted 3-11 member saturated or partially unsaturated heterocyclic groups or 3-11 member saturated or partially unsaturated cyclic hydrocarbon groups containing 1-4 heteroatoms each independently selected from nitrogen, oxygen, and sulfur, wherein the heterocyclic group or cyclic hydrocarbon group is a monocyclic, bridged, or spirocyclic ring; wherein the aryl, cyclic hydrocarbon, heterocyclic, and heteroaryl groups are optionally selected from F, Cl, Br, I, C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Substituents of haloalkoxy groups; n1, n2, n3 and n4 are each independently 0, 1, 2, 3, 4, 5 or 6; preferably, n1, n2, n3 and n4 are each independently 0, 1, 2, 3 or 4; L is a bond or chemical linker connecting the CLM and the PTM; preferably, L is a covalent bond or a -(B) bond. L ) q -; B L Each time it appears, it is selected independently from CR. L5 R L6 O, S, S(O), S(O)2, NR L5 C(O)NR L5 C(O), cycloalkylene, heterocyclic, bridged cycloalkyl, spirocyclic, aryl, and heteroaryl, wherein the cycloalkylene, heterocyclic, bridged cycloalkyl, spirocyclic, aryl, and heteroaryl groups are optionally represented by 0, 1, 2, 3, 4, 5, or 6 R groups. L5 and / or R L6 Group substitution; preferably, B L Each time it appears, it is selected independently from CR. L5 R L6 O, S, S(O), S(O)2, NR L5 C(O)NR L5 C(O), -C≡C-, 3-15 membered cycloalkylene groups, 3-15 membered heterocyclic groups containing 1, 2, 3, 4 or 5 heteroatoms independently selected from N, O and S, 5-15 membered bridged cycloalkyl groups containing 0, 1, 2, 3, 4 or 5 heteroatoms independently selected from N, O and S, 5-15 membered spirocyclic groups containing 0, 1, 2, 3, 4 or 5 heteroatoms independently selected from N, O and S The 3-15-membered cycloalkyl group, 6-15-membered heteroalkylene group, and 5-15-membered heteroalkylene group containing 1, 2, 3, 4, or 5 heteroatoms independently selected from N, O, and S, wherein the 3-15-membered cycloalkylene group, 3-15-membered heteroalkylene group, 5-15-membered bridged cycloalkylene group, 5-15-membered spirocycloalkylene group, 6-15-membered arylene group, and 5-15-membered heteroalkylene group are optionally surrounded by 0, 1, 2, 3, 4, 5, or 6 R atoms. L5 and / or R L6 Group substitution; R L5 and R L6 Each occurrence is independently selected from H, halogens, -OH, -NH2, -SH, -C(O)2H, -CN, -CF3, -CHF2, -CH2F, -NO2, -S(O)2, -SF5, -C≡CH, C 1-8 Alkyl, -OC 1-8 Alkyl, -SC 1-8 Alkyl, -NH-C 1-8 Alkyl, N(C) 1-8 Alkyl)2, C 3-11 cycloalkyl, C 6-10 Aryl, C 5-10 heteroaryl, C 3-11 Heterocyclic groups, -OC 3-8 cycloalkyl, -OC 3-11 Heterocyclic groups, -OC 6-10 Aryl, -OC 5-10 heteroaryl, -SC 3-8 cycloalkyl, -NH-C 3- 8-cycloalkyl, -N(C) 3-8 cycloalkyl)2, -N(C 3-8 cycloalkyl)(C 1-8 alkyl), -NH-C 3-8 Heterocyclic groups, -N(C) 3-8 Heterocyclic group)2, -N(C 3-8 Heterocyclic group)(C 1-8 alkyl), -NH-C 6-10 Aryl, -N(C 6-10 Aryl)(C 1-8 alkyl), -NH-C 5-10 heteroaryl, -N(C 5-10 (C) 1-8 Alkyl), S(O)2P(O)(OC 1-8 Alkyl)(C 1-8 Alkyl), -P(O)(OC 1-8 Alkyl)2、-C≡CC 1-8 Alkyl group, -CH=CH-(C 1-8 alkyl), -C(C 1-8 Alkyl)=CH-(C 1-8 alkyl), -C(C 1-8 Alkyl) = C(C 1- 8-alkyl)2, -Si(OH)3, -Si(C 1-8 Alkyl)3、-Si(OH)(C 1-8 Alkyl)2、-C(O)-C 1-8 Alkyl group, -S(O)2NH-C 1-8 Alkyl group, -S(O)2N(C) 1-8 Alkyl)2、-S(O)NH-C 1-8 Alkyl, -S(O)N(C) 1-8 Alkyl)2、-C(O)NH-C 1-8 Alkyl, -C(O)N(C) 1-8 Alkyl)2, -N(C 1-8 alkyl)C(O)NH(C 1-8 alkyl), -N(C) 1- 8alkyl)C(O)N(C 1-8 alkyl)2、-NHC(O)NH(C 1-8 Alkyl), -NHC(O)N(C 1-8 Alkyl)2, -NHC(O)NH2, -N(C 1-8 alkyl)S(O)2NH(C 1-8 alkyl), -N(C) 1-8 alkyl)S(O)2N(C 1-8 alkyl)2、-NHS(O)2NH(C 1-8 Alkyl), -NHS(O)2N(C 1-8 alkyl)2 and -NHS(O)2NH2, the C 1-8 Alkyl, C 3-11 cycloalkyl, C 3-11 Heterocyclic group, C 6-10 Aryl and C 5-10 Each heteroaryl group is independently and optionally selected from halogen, hydroxyl, cyano, amino, nitro, C 1-6 Alkyl, C 2-6 Heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, hydroxy, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, 3-8 membered cycloalkyl, 3-8 membered heterocyclic, 3-8 membered halocycloalkyl, 3-8 membered haloheteroalkyl, C 1-6 Alkylamino, C 6-10 Aryl, C 5-10 heteroaryl, halogenated C 6-10 Aryl and halogenated C 5-10 One or more substituents in the heteroaryl group are substituted; q is an integer greater than or equal to 1 and less than or equal to 15; preferably, q is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15; more preferably, q is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; The CLM is the human cerebellar protein (CRBN) E3 ubiquitin ligase-binding moiety, which is selected from the following structures: W1 and W2 are each selected independently from CR each time they appear. b R c And C(O), and at least one of W1 and W2 is selected from C(O); W3 is selected independently from C(R) each time it appears. b )2 and C(O); W4, W5, and W6 are each selected independently from C, C(O), O, N, and NR, respectively. b CR b and CR b R c The area between W4, W5 and W6 Indicates a single bond or a double bond; In equations 2-1-9, 2-1-10, 2-1-11, and 2-1-12, when there is a double bond between W4 and W5 and a single bond between W5 and W6, W4 is selected from C, and W5 is selected from N and CR. b W6 is selected from NR b O and CR b R c When there is a single bond between W4 and W5, and a double bond between W5 and W6, W4, W5, and W6 are each independently selected from N and CR. b When all bonds between W4, W5, and W6 are single bonds, W4 is selected from N and CR. b W5 and W6 are each independently selected from C(O) and NR. b O and CR b R c ; A1, A2, A3, A4, A5, and A6 are each independently selected from O, S, C(O), and NR when they appear. d and C(R) d )2; B1, B2, X, and Z are each independently selected from N and CR each time they appear. d ; E is selected independently from O, C(O)NR each time it appears. b and NR b ; Each time m1 and m2 appear, they are independently selected from 0, 1, 2, 3, 4, 5 and 6, and 1≤m1+m2≤6; Each time m3 and m4 appear, they are independently selected from 0, 1, 2, 3, 4, 5, 6 and 7, and 1≤m3+m4≤7; Each time m5 and m7 appear, they are each independently selected from 0, 1, 2, 3, 4, 5, 6 and 7. Each time m6 and m8 appear, they are each independently selected from 1, 2, 3, 4, 5, 6, 7 and 8. And 1≤m5+m6≤8 or 1≤m7+m8≤8. Each time m9, m10, and m11 appear, they are each independently selected from 0, 1, 2, and 3, and m9 + m10 + m11 ≤ 3; R1 and R2 are each independently selected from H, deuterium, halogen, hydroxyl, and C atoms each time they appear. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl and C 3-6 cycloalkyl; R b and R c Each time it appears, it is independently selected from H and C. 1-6 Alkyl, C 1-6 Alkoxy and C 3-6 cycloalkyl; R3, R4, R5 and R d Each time it appears, it is independently selected from H, halogen, hydroxyl, cyano, amino, nitro, C. 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, C 1-6 Alkyl acyl, C 1-6 alkyl-O-acyl, C 1-6 alkyl-N-acyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 5-8 Aryl and 5-8 quinone heteroaryl groups; Each time n appears, it is independently selected from 0, 1, 2, and 3; and Indicates the connection site.

3. A compound having the structure shown in formula (Ι3): Or its isomers, isotopic derivatives, polymorphs, prodrugs, or pharmaceutically acceptable salts or solvates thereof, wherein: PTM is the binding site that targets signal transduction and transcriptional activator 6 (STAT6), and it has the structure shown in formula (I-13): R L1 R L2 and R L4 Each is independently a covalent bond or C 1-6 Divalent straight-chain or branched saturated or unsaturated hydrocarbon groups, wherein one, two or three methylene units of the hydrocarbon group are independently and optionally replaced by -Cyx-, -O-, -C(O)-, -C(S)-, -C(R)2-, -CF2-, -CRF-, -CR(OR)-, -NR-, -C(NR)-, -S-, -S(O)-, -S(O)2-, -S(O)(NR)- or -CR=CR-; R L3 For covalent bonds or C 1-6 Divalent straight-chain or branched saturated or unsaturated hydrocarbon groups, wherein one, two or three methylene units of the hydrocarbon group are independently and optionally replaced by -Cyx-, -O-, -C(O)-, -C(S)-, -C(R)2-, -CF2-, -CRF-, -CR(OR)-, -NR-, -C(NR)-, -S-, -S(O)-, -S(O)2-, -S(O)(NR)- or -CR=CR-, or are absent; -Cyx- is selected from phenylene, 3 to 7 saturated or partially unsaturated heterocyclic hydrocarbon groups or heterocyclic groups containing 1, 2, 3 or 4 heteroatoms each independently selected from nitrogen, oxygen and sulfur, and 5 to 8 cyclic monocyclic or bicyclic heteroaryl groups containing 1, 2, 3 or 4 heteroatoms each independently selected from nitrogen, oxygen and sulfur. Cy1 is selected from 6-10 arylene groups, saturated or partially unsaturated 5-11 cyclic or bicyclic alkyl groups, or heterocyclic groups containing 1, 2, 3, or 4 heteroatoms each independently selected from nitrogen, oxygen, and sulfur, and 5-14 cyclic, bicyclic, or tricyclic arylene groups containing 1, 2, 3, or 4 heteroatoms each independently selected from nitrogen, oxygen, and sulfur, wherein the arylene group, alkyl group, or heterocyclic group is optionally surrounded by n1 R P1 Replaced; Cy2 is selected from saturated or partially unsaturated 3-8 membered cyclic hydrocarbon groups, saturated or partially unsaturated 3-8 membered heterocyclic hydrocarbon groups, 6-10 membered aryl hydrocarbon groups, and 5-8 membered heterocyclic hydrocarbon groups, wherein the cyclic hydrocarbon group, heterocyclic hydrocarbon group, aryl hydrocarbon group, or heterocyclic hydrocarbon group is optionally surrounded by n2 R groups. P2 Replaced; Cy3 is absent or selected from 6-10 aryl groups, 3-11 saturated or partially unsaturated monocyclic or bicyclic cyclic hydrocarbon groups containing 1, 2, 3 or 4 heteroatoms each independently selected from nitrogen, oxygen and sulfur, and 5-10 cyclic monocyclic or bicyclic heteroaryl groups containing 1, 2, 3 or 4 heteroatoms each independently selected from nitrogen, oxygen and sulfur, wherein the aryl, cyclic hydrocarbon, heterocyclic and heteroaryl groups are optionally separated by n3 R groups. P3 Replaced; Cy4 is absent or selected from covalently bonded, saturated or partially unsaturated 3-8 membered monocyclic or bicyclic alkyl groups, saturated or partially unsaturated 3-8 membered monocyclic or bicyclic heterocyclic groups containing 1-4 heteroatoms each independently selected from N, O, and S, 6-10 membered arylene groups, and 5-10 membered heteroarylene groups containing 1, 2, 3, or 4 heteroatoms each independently selected from N, O, and S, wherein the alkyl group, heterocyclic group, arylene group, or heteroarylene group is optionally surrounded by n4 R groups. x Replaced; R A Each time it appears, it is independently selected from hydrogen and R. B R C Halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, -CN, -NO2, -OR, -SR, -N(R)2, -Si(R)3, -S(O)R, -S(O)2R, -S(O)(NR)R, -S(O)2N(R)2, -S(O)R, -C(O)R, -C(S)R, -C(O)OR, -C(O)N(R)2, -C(O)NROR, -OC(O)R, -OC(O)N(R)2, -P(O)(R)2, -P(O)(OR)2, -OP(O)(R)2, -OP(O)(OR)2, -NRC(O)OR, -NRC(O)R, -NRC(O)N(R)2, and -NRS(O)2R; R P1 R P2 R P3 and R x Each time it appears, it is independently selected from hydrogen and R. B , Deuterium atom, halogen, oxo group (=O), -CN, -NO2, -OR, -SR, -N(R)2, -Si(R)3, -S(O)R, -S(O)2R, -S(O)(NR)R, -S(O)2N(R)2, -S(O)R, -C(O)R, -C(S)R, -C(O)OR, -C(O)N (R)2, -C(O)NROR, -OC(O)R, -OC(O)N(R)2, -P(O)(R)2, -P(O)(OR)2, -OP(O)(R)2, -OP(O)(OR)2, -NRC(O)OR, -NRC(O)R, -NRC(O)N(R)2 and -NRS(O)2R; R B Selected from C 1-6 Aliphatic, 6-10 aryl, 3-8 saturated or partially unsaturated cyclic hydrocarbon groups, 3-8 heterocyclic groups containing 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5-10 monocyclic or bicyclic heteroaryl groups containing 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein C 1-6 Aliphatic, phenyl, saturated or partially unsaturated cyclic hydrocarbon or heterocyclic groups, and monocyclic or bicyclic heteroaryl groups may be substituted; R C Independently for -L B -CyB1-H or -L B -CyB1-CyB2; L B For covalent bonds or C 1-3 Divalent straight-chain or branched saturated or unsaturated hydrocarbon groups, wherein one or two methylene units of the hydrocarbon group are independently and optionally replaced by -O-, -C(O)-, -C(S)-, -C(R)2-, -CF2-, -CRF-, -CR(OR)-, -NR-, -S-, -S(O)-, -S(O)2-, -S(O)(NR)- or -CR=CR-; CyB1 is independently selected from phenylene, 3-10 member saturated or partially unsaturated monocyclic or bicyclic cyclic hydrocarbon groups or heterocyclic groups containing 1, 2, 3, or 4 heteroatoms each independently selected from nitrogen, oxygen, and sulfur, and 5-8 member or 10 member monocyclic or bicyclic arylene groups or heteroarylene groups containing 1, 2, 3, or 4 heteroatoms each independently selected from nitrogen, oxygen, and sulfur; CyB2 is independently selected from phenyl, 3-10 member saturated or partially unsaturated monocyclic or bicyclic cyclic hydrocarbon groups or heterocyclic groups containing 1, 2, 3 or 4 heteroatoms each independently selected from nitrogen, oxygen and sulfur, 6-10 member monocyclic or bicyclic aryl groups and 5-8 member or 10 member heteroaryl groups containing 1, 2, 3 or 4 heteroatoms each independently selected from nitrogen, oxygen and sulfur; Each time R appears, it independently represents hydrogen or C. 1-6 Aliphatic, 3-7 member saturated or partially unsaturated cyclic hydrocarbon groups, 3-7 member saturated or partially unsaturated heterocyclic groups containing 1-4 heteroatoms each independently selected from nitrogen, oxygen, and sulfur, or 5-8 or 10 member heteroaryl groups having 1-4 heteroatoms each independently selected from nitrogen, oxygen, and sulfur; or: two R groups located on the same or adjacent atoms, together with the atoms between them, forming optionally substituted 3-11 member saturated or partially unsaturated heterocyclic groups or 3-11 member saturated or partially unsaturated cyclic hydrocarbon groups containing 1-4 heteroatoms each independently selected from nitrogen, oxygen, and sulfur, wherein the heterocyclic group or cyclic hydrocarbon group is a monocyclic, bridged, or spirocyclic ring; wherein the aryl, cyclic hydrocarbon, heterocyclic, and heteroaryl groups are optionally selected from F, Cl, Br, I, C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Substituents of haloalkoxy groups; n1, n2, n3 and n4 are each independently 0, 1, 2, 3, 4, 5 or 6; preferably, n1, n2, n3 and n4 are each independently 0, 1, 2, 3 or 4; L is the bond or chemical linker connecting the CLM and the PTM; The CLM is the human cerebellar protein (CRBN) E3 ubiquitin ligase binding moiety; It is selected from the following structure: W1 and W2 are each selected independently from CR each time they appear. b R c And C(O), and at least one of W1 and W2 is selected from C(O); W3 is selected independently from C(R) each time it appears. b )2 and C(O); W4, W5, and W6 are each selected independently from C(O), O, N, and NR. b CR b and CR b R c ; Indicates a single or double bond; in Equation 2-25, there is at most one double bond; when a double bond exists between W4 and W5 or between W5 and W6, W4 and W5 are independently selected from N and CR. b W6 is selected from NR b O and CR b R c When both W4 and W5, or both W5 and W6, are single bonds, W4 is selected from N, W5 from C(O), and W6 from NR. b O and CR b R c ; G1 and G2 are each independently selected from O, S, and Se each time they appear; A1, A2, A3, A4, A5, and A6 are each independently selected from O, S, C(O), and NR when they appear. d and C(R) d )2; B1, B2, X, and Z are each independently selected from N and CR each time they appear. d ; E is selected independently from C(O)NR each time it appears. b and NR b ; Each time m1 and m2 appear, they are independently selected from 0, 1, 2, 3, 4, 5 and 6, and 1≤m1+m2≤6; Each time m3 and m4 appear, they are independently selected from 0, 1, 2, 3, 4, 5, 6 and 7, and 1≤m3+m4≤7; Each time m5 and m7 appear, they are each independently selected from 0, 1, 2, 3, 4, 5, 6 and 7. Each time m6 and m8 appear, they are each independently selected from 1, 2, 3, 4, 5, 6, 7 and 8. And 1≤m5+m6≤8 or 1≤m7+m8≤8. Each time m9, m10, and m11 appear, they are each independently selected from 0, 1, 2, and 3, and m9 + m10 + m11 ≤ 3; R1 and R6 are each independently selected from H, deuterium, halogen, hydroxyl, and C atoms each time they appear. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl and C 3-6 cycloalkyl; R2, R b and R c Each time it appears, it is independently selected from H and C. 1-6 Alkyl, C 1-6 Alkoxy and C 3-6 cycloalkyl; R3, R4, R5 and R d Each time it appears, it is independently selected from H, halogen, hydroxyl, cyano, amino, nitro, C. 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, C 1-6 Alkyl acyl, C 1-6 alkyl-O-acyl, C 1-6 alkyl-N-acyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 5-8 Aryl and 5-8 quinone heteroaryl groups; Each time n appears, it is independently selected from 0, 1, 2, and 3; and Indicates the connection site.

4. A compound having the structure shown in formula (Ι2): Or its isomers, isotopic derivatives, polymorphs, prodrugs, or pharmaceutically acceptable salts or solvates thereof, wherein: PTM is the binding site that targets signal transduction and transcriptional activator 6 (STAT6), and it has the structure shown in formula (I-12): R L1 R L2 and R L4 Each is independently a covalent bond or C 1-6 Divalent straight-chain or branched saturated or unsaturated hydrocarbon groups, wherein one, two or three methylene units of the hydrocarbon group are independently and optionally replaced by -Cyx-, -O-, -C(O)-, -C(S)-, -C(R)2-, -CF2-, -CRF-, -CR(OR)-, -NR-, -C(NR)-, -S-, -S(O)-, -S(O)2-, -S(O)(NR)- or -CR=CR-; R L3 For covalent bonds or C 1-6 Divalent straight-chain or branched saturated or unsaturated hydrocarbon groups, wherein one, two or three methylene units of the hydrocarbon group are independently and optionally replaced by -Cyx-, -O-, -C(O)-, -C(S)-, -C(R)2-, -CF2-, -CRF-, -CR(OR)-, -NR-, -C(NR)-, -S-, -S(O)-, -S(O)2-, -S(O)(NR)- or -CR=CR-, or are absent; -Cyx- is selected from phenylene, 3 to 7 saturated or partially unsaturated heterocyclic hydrocarbon groups or heterocyclic groups containing 1, 2, 3 or 4 heteroatoms each independently selected from nitrogen, oxygen and sulfur, and 5 to 8 cyclic monocyclic or bicyclic heteroaryl groups containing 1, 2, 3 or 4 heteroatoms each independently selected from nitrogen, oxygen and sulfur. Cy1 is selected from 6-10 arylene groups, saturated or partially unsaturated 5-11 cyclic or bicyclic alkyl groups, or heterocyclic groups containing 1, 2, 3 or 4 heteroatoms each independently selected from nitrogen, oxygen and sulfur, and 5-14 cyclic, bicyclic or tricyclic arylene groups containing 1, 2, 3 or 4 heteroatoms each independently selected from nitrogen, oxygen and sulfur; Cy2 is selected from saturated or partially unsaturated 3-8 membered cyclic hydrocarbon groups, saturated or partially unsaturated 3-8 membered heterocyclic hydrocarbon groups, 6-10 membered aryl hydrocarbon groups, and 5-8 membered heterocyclic hydrocarbon groups. Cy3 is selected from 6-10 aryl groups, 3-11 saturated or partially unsaturated monocyclic or bicyclic groups containing 1, 2, 3 or 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, and 5-10 cyclic or bicyclic heteroaryl groups containing 1, 2, 3 or 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or is absent; Cy4 is selected from covalently bonded, saturated or partially unsaturated 3-8 membered monocyclic or bicyclic alkyl groups, saturated or partially unsaturated 3-8 membered monocyclic or bicyclic heterocyclic groups containing 1-4 heteroatoms each independently selected from N, O, and S, 6-10 membered arylene groups, and 5-10 membered heteroarylene groups containing 1, 2, 3, or 4 heteroatoms each independently selected from N, O, and S, wherein the alkyl group, heterocyclic group, arylene group, or heteroarylene group is optionally bounded by 1, 2, 3, or 4 R atoms. x replace; R A Each time it appears, it is independently selected from hydrogen and R. B R C Halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, -CN, -NO2, -OR, -SR, -N(R)2, -Si(R)3, -S(O)R, -S(O)2R, -S(O)(NR)R, -S(O)2N(R)2, -S(O)R, -C(O)R, -C(S)R, -C(O)OR, -C(O)N(R)2, -C(O)NROR, -OC(O)R, -OC(O)N(R)2, -P(O)(R)2, -P(O)(OR)2, -OP(O)(R)2, -OP(O)(OR)2, -NRC(O)OR, -NRC(O)R, -NRC(O)N(R)2, and -NRS(O)2R; R P1 R P2 R P3 and R x Each time it appears, it is independently selected from hydrogen and R. B , Deuterium atom, halogen, oxo group (=O), -CN, -NO2, -OR, -SR, -N(R)2, -Si(R)3, -S(O)R, -S(O)2R, -S(O)(NR)R, -S(O)2N(R)2, -S(O)R, -C(O)R, -C(S)R, -C(O)OR, -C(O)N (R)2, -C(O)NROR, -OC(O)R, -OC(O)N(R)2, -P(O)(R)2, -P(O)(OR)2, -OP(O)(R)2, -OP(O)(OR)2, -NRC(O)OR, -NRC(O)R, -NRC(O)N(R)2 and -NRS(O)2R; R B Selected from C 1-6 Aliphatic, 6-10 aryl, 3-8 saturated or partially unsaturated cyclic hydrocarbon groups, 3-8 heterocyclic groups containing 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5-10 monocyclic or bicyclic heteroaryl groups containing 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein C 1-6 Aliphatic, phenyl, saturated or partially unsaturated cyclic hydrocarbon or heterocyclic groups, and monocyclic or bicyclic heteroaryl groups may be substituted; R C Independently for -L B -CyB1-H or -L B -CyB1-CyB2; L B For covalent bonds or C 1-3 Divalent straight-chain or branched saturated or unsaturated hydrocarbon groups, wherein one or two methylene units of the hydrocarbon group are independently and optionally substituted with -O-, -C(O)-, -C(S)-, -C(R)2-, -CF2-, -CRF-, -CR(OR)-, -NR-, -S-, -S(O)-, -S(O)2-, -S(O)(NR)- or -CR=CR-; each CyB1 is independently selected from phenylene, 3-10 member saturated or partially unsaturated monocyclic or bicyclic hydrocarbon groups or heterocyclic groups containing 1, 2, 3, or 4 heteroatoms each independently selected from nitrogen, oxygen, and sulfur, and 5-8 member or 10 member monocyclic or bicyclic arylene groups or heteroarylene groups containing 1, 2, 3, or 4 heteroatoms each independently selected from nitrogen, oxygen, and sulfur; CyB2 is independently selected from phenyl, 3-10 member saturated or partially unsaturated monocyclic or bicyclic cyclic hydrocarbon groups or heterocyclic groups containing 1, 2, 3 or 4 heteroatoms each independently selected from nitrogen, oxygen and sulfur, 6-10 member monocyclic or bicyclic aryl groups and 5-8 member or 10 member heteroaryl groups containing 1, 2, 3 or 4 heteroatoms each independently selected from nitrogen, oxygen and sulfur; Each time R appears, it independently represents hydrogen or C. 1-6 Aliphatic, 3-7 member saturated or partially unsaturated cyclic hydrocarbon groups, 3-7 member saturated or partially unsaturated heterocyclic groups containing 1-4 heteroatoms each independently selected from nitrogen, oxygen, and sulfur, or 5-8 or 10 member heteroaryl groups having 1-4 heteroatoms each independently selected from nitrogen, oxygen, and sulfur; or: two R groups located on the same or adjacent atoms, together with the atoms between them, forming optionally substituted 3-11 member saturated or partially unsaturated heterocyclic groups or 3-11 member saturated or partially unsaturated cyclic hydrocarbon groups containing 1-4 heteroatoms each independently selected from nitrogen, oxygen, and sulfur, wherein the heterocyclic group or cyclic hydrocarbon group is a monocyclic, bridged, or spirocyclic ring; wherein the aryl, cyclic hydrocarbon, heterocyclic, and heteroaryl groups are optionally selected from F, Cl, Br, I, C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Substituents of haloalkoxy groups; n1, n2, and n3 are each independently 0, 1, 2, 3, 4, 5, or 6; preferably, n1, n2, and n3 are each independently 0, 1, 2, 3, or 4. L is the bond or chemical linker connecting the CLM and the PTM; The CLM is the human cerebellar protein (CRBN) E3 ubiquitin ligase binding moiety; It is selected from the following structure: W1 and W2 are each selected independently from CR each time they appear. b R c And C(O), and at least one of W1 and W2 is selected from C(O); W3 is selected from C(R) b )2 and C(O); G1 and G2 are each independently selected from O, S, and Se each time they appear; A1, A2, A3, A4, A5, and A6 are each independently selected from O, S, C(O), and NR when they appear. d and C(R) d )2; B1, B2, X, and Z are each independently selected from N and CR each time they appear. d ; E is selected independently from C(O)NR each time it appears. b and NR b ; Each time m1 and m2 appear, they are independently selected from 0, 1, 2, 3, 4, 5 and 6, and m1 + m2 ≤ 6; Each time m3 and m4 appear, they are independently selected from 0, 1, 2, 3, 4, 5, 6 and 7, and m3 + m4 ≤ 7; Each time m5 and m7 appear, they are each independently selected from 0, 1, 2, 3, 4, 5, 6 and 7. Each time m6 and m8 appear, they are each independently selected from 1, 2, 3, 4, 5, 6, 7 and 8. Furthermore, m5+m6≤8 or m7+m8≤8. Each time m9, m10, and m11 appear, they are each independently selected from 0, 1, 2, and 3, and m9 + m10 + m11 ≤ 3; R1 and R6 are each independently selected from H, deuterium, halogen, hydroxyl, and C atoms each time they appear. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl and C 3-6 cycloalkyl; R2, R b and R c Each time it appears, it is independently selected from H and C. 1-6 Alkyl, C 1-6 Alkoxy and C 3-6 cycloalkyl; R3, R4, R5 and R d Each time it appears, it is independently selected from H, halogen, hydroxyl, cyano, amino, nitro, C. 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, C 1-6 Alkyl acyl, C 1-6 alkyl-O-acyl, C 1-6 alkyl-N-acyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 5-8 Aryl and 5-8 quinone heteroaryl groups; Each time n appears, it is independently selected from 0, 1, 2, and 3; and Indicates the connection site.

5. A compound having the structure shown in formula (I0): Or its isomers, isotopic derivatives, polymorphs, prodrugs, or pharmaceutically acceptable salts or solvates thereof, wherein: PTM is the binding site that targets signal transduction and transcriptional activator 6 (STAT6), and it has the structure shown in formula (I-10): R L1 R L2 and R L4 Selected from single bond, C 1-6 Alkylene, C 2-6 Heteroalkyl, -C(O)-C 1-6 Alkylene, O, S, SO2, -NR-, -C(O)-, and -NRC(O)-; R L3 Selected from single bond, C 1-6 Alkylene, C 2-6 Heteroalkyl, -C(O)-C 1-6 Alkylene, O, S, SO2, NR, C(O), and NRCO, or none at all; Cy1 is selected from 6-10 arylene or 5-10 heteroarylene, wherein the 6-10 arylene or 5-10 heteroarylene is selected from monocyclic, fused, fused, or spirocyclic bicyclic structures; preferably, Cy1 is selected from 8-10 bicyclic heteroarylene containing 1-4 heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur; Cy2 is selected from saturated or unsaturated 3-8 membered cyclic hydrocarbon groups, saturated or unsaturated 3-8 membered heterocyclic hydrocarbon groups, 6-10 membered aryl hydrocarbon groups, and 5-8 membered heterocyclic hydrocarbon groups; preferably, Cy2 is selected from saturated or unsaturated 5-7 membered cyclic hydrocarbon groups and saturated or unsaturated 5-7 membered heterocyclic hydrocarbon groups containing 1-3 heteroatoms each independently selected from nitrogen, oxygen, and sulfur; Cy3 is selected from 3-8-membered cycloalkyl groups, 3-8-membered heterocyclic groups containing 1-3 heteroatoms each independently selected from N, O and S, 6-10-membered aryl groups, and 5-8-membered heteroaryl groups containing 1-3 heteroatoms each independently selected from N, O and S, or is absent; Cy4 is selected from saturated or unsaturated 3-8 membered monocyclic or bicyclic alkylene groups, saturated or unsaturated 3-8 membered monocyclic or bicyclic heterocyclic groups containing 1-4 heteroatoms each independently selected from N, O, and S, 6-10 membered arylene groups, and 5-10 membered heteroarylene groups containing 1-4 heteroatoms each independently selected from N, O, and S, wherein the alkylene group, heterocyclic group, arylene group, or heteroarylene group is optionally surrounded by 1-4 R atoms. x Replacement; preferably, Cy4 is selected from Q1 is selected independently from CR each time it appears. x and N; Q2 is selected independently from C(R) each time it appears. x )2 and NR x ; R A Selected from hydrogen, F, Cl, Br, I, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, -CN, -NO2, -OR, -SR, -N(R)2, -Si(R)3, -S(O)R, -S(O)2R, -S(O)(NR)R, -S(O)2N(R)2, -S(O)R, -C(O)R, -C(O)OR, -C(O)N(R)2, -C( O)NROR, -OC(O)R, -OC(O)N(R)2, -P(O)(R)2, -P(O)(OR)2, -OP(O)(R)2, -OP(O)(OR)2, -NRC(O)OR, -NRC(O)R, -NRC(O)N(R)2, -NRS(O)2RC 1-6 Alkyl, 6-10 aryl, 3-7 saturated or partially unsaturated cyclic hydrocarbon groups or heterocyclic groups containing 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, and monocyclic or bicyclic 5-10 heteroaryl groups containing 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein the aryl, cyclic hydrocarbon, heterocyclic or heteroaryl group is optionally selected from O, F, Cl, Br, I, C 1-3 Alkyl, C 1-3 Alkoxy group, -C(O)C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and C 1-6 Substituents of haloalkoxy groups; preferably, R A Selected from hydrogen, F, Cl, Br, I, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 The aryl group may contain halogenated alkoxy groups, -CN, -NO2, -C(O)R, 6-10 aryl groups, 3-7 saturated or partially unsaturated cyclic hydrocarbon groups, or heterocyclic alkyl groups containing 1-4 heterocyclic atoms independently selected from nitrogen, oxygen, and sulfur heteroatoms, and monocyclic or bicyclic 5-10 heteroaryl groups containing 1-4 heterocyclic atoms independently selected from nitrogen, oxygen, and sulfur heteroatoms, wherein the aryl, cycloalkyl, heterocyclic alkyl, or heteroaryl group is optionally selected from O, F, Cl, Br, I, C. 1-3 Alkyl, C 1-3 Alkoxy group, -C(O)C 1-3 Alkyl, C 1-3 Halogenated alkyl groups and C 1-3 The alkyl halooxy group is substituted with 1, 2, 3, 4 or 5 substituents; Each time R appears, it independently represents hydrogen or C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 The following are possible interpretations of heterocyclic compounds: haloalkoxy groups, 6-10 aryl groups, 3-7 saturated or partially unsaturated cyclic hydrocarbon groups, 3-7 saturated or partially unsaturated heterocyclic compounds containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or 5-6 aryl groups having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or two R groups located on the same or adjacent atoms, together with the atoms between them, forming optionally substituted 3-11 saturated or partially unsaturated heterocyclic compounds containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or 3-11 saturated or partially unsaturated cyclic hydrocarbon groups, wherein the heterocyclic compound or cyclic hydrocarbon group is a monocyclic, bridged, or spirocyclic ring; the aryl, cyclic hydrocarbon, heterocyclic, and heteroaryl groups are optionally selected from F, Cl, Br, I, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Substituents of haloalkoxy groups; preferably, R is independently hydrogen or C each time it appears. 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 The following are possible interpretations of heterocyclic compounds: haloalkoxy, 6-10 aryl, 3-7 saturated or partially unsaturated cycloalkyl groups, 3-7 saturated or partially unsaturated heterocyclic groups containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or 5-6 aryl groups having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or two R groups located on the same or adjacent atoms, together with the atoms between them, forming optionally substituted 3-11 saturated or partially unsaturated heterocyclic groups or 3-11 saturated or partially unsaturated cycloalkyl groups containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the heterocyclic alkyl or cycloalkyl group is a monocyclic, bridged, or spirocyclic ring; the aryl, cycloalkyl, cycloalkyl, heterocyclic, and heteroaryl groups are optionally selected from F, Cl, Br, I, and C. 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 Substituents of haloalkoxy groups; R P1 R P2 R P3 and R x Each time it appears, it is independently selected from H, deuterium, halogen, and C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 2-6 Heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy, hydroxyl, C 1-6 Hydroxyalkyl, nitro, cyano, amino, C 1-6 Alkylamino, C 1-6 Alkyl acyl, C 1-6 Alkyloxyacyl, C 1-6 Alkylaminoacyl, 3-8 membered cycloalkyl, 3-8 membered heterocyclic, 6-10 membered aryl, and 5-10 membered heteroaryl, wherein the alkyl, heteroalkyl, alkenyl, alkoxy, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each independently selected from halogens, C 1-6 Alkyl, C 2-6 Heteroalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, hydroxyl, C 1-6 Hydroxyalkyl, cyano, amino, nitro, 3-8 membered cycloalkyl, 3-8 membered heterocyclic, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkylamino, C 1-6 Alkyl acyl, C 1-6 Alkyloxyacyl, C 1-6 The substituent is selected from one or more substituents of alkylaminoacyl, 6-10 aryl, and 5-10 heteroaryl; preferably, R P1 R P2 R P3 and R X Each time it appears, it is independently selected from H, deuterium, F, Cl, Br, I, and C. 1- 3-alkyl, C 1-3 Deuterated alkyl, C 2-3 Heteroalkyl, C 2-3 alkenyl, C 2-3 alkynyl group, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 Halogenated alkoxy, hydroxyl, C 1-3 Hydroxyalkyl, nitro, cyano, amino, C 1-3 Alkyl acyl, 3-8 membered cycloalkyl, 3-8 membered heterocyclic, 6-10 membered aryl, and 5-10 membered heteroaryl, wherein the alkyl, heteroalkyl, alkenyl, alkoxy, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each independently selected from halogens, C 1-3 Alkyl, C 2-3 Heteroalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkyl, hydroxyl, C 1-3 Hydroxyalkyl, cyano, amino, nitro, 3-8 membered cycloalkyl, 3-8 membered heterocyclic, C 2-3 alkenyl, C 2- The substituent is one or more of the following: 3-alkynyl, 6-10 aryl and 5-10 heteroaryl; Preferably, R P1 R P2 R P3 and R X Each time it appears, it is independently selected from H, deuterium, F, Cl, Br, I, and C. 1-3 Alkyl, C 1-3 Alkoxy, C 1- 3-Hydroalkyl, C 1-3 Halogenated alkoxy groups, C 1-3 Alkylene-3-6 membered cycloalkyl, -C(O)-C 1-3 Alkyl groups and -CN; Preferably, R P1 Each time it appears, it is independently selected from F, Cl, Br, I, and C. 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups and C 1-3 Alkylene-3-6 membered cycloalkyl; Preferably, R P2 Each occurrence is independently selected from -C(O)-C. 1-3 Alkyl; preferably, R P3 Each time it appears, it is independently selected from C. 1-3 Alkyl groups and -CN; Preferably, R x Each time it appears, it is independently selected from H, F, Cl, Br, I, C. 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkyl groups and C 1-3 Halogenated alkoxy groups; n1, n2, and n3 are each independently selected from 1, 2, 3, 4, 5, and 6; L is the bond or chemical link connecting the ULM and the PTM; The ULM is the human cerebellar protein (CRBN) E3 ubiquitin ligase binding moiety; It is selected from the following structure: W1 and W2 are each selected independently from CR each time they appear. b R c And C(O), and at least one of W1 and W2 is selected from C(O); W3 is selected from C(R) b )2 and C(O); G1 and G2 are each independently selected from O, S, and Se each time they appear; A1, A2, A3, A4, A5, and A6 are each independently selected from O, S, C(O), and NR when they appear. d and C(R) d )2; B1, B2, X, and Z are each independently selected from N and CR each time they appear. d ; E is selected independently from C(O)NR each time it appears. b and NR b ; Each time m1 and m2 appear, they are independently selected from 0, 1, 2, 3, 4, 5 and 6, and m1 + m2 ≤ 6; Each time m3 and m4 appear, they are independently selected from 0, 1, 2, 3, 4, 5, 6 and 7, and m3 + m4 ≤ 7; Each time m5 and m7 appear, they are each independently selected from 0, 1, 2, 3, 4, 5, 6 and 7. Each time m6 and m8 appear, they are each independently selected from 1, 2, 3, 4, 5, 6, 7 and 8. Furthermore, m5+m6≤8 or m7+m8≤8. Each time m9, m10, and m11 appear, they are each independently selected from 0, 1, 2, and 3, and m9 + m10 + m11 ≤ 3; R1 and R6 are each independently selected from H, deuterium, halogen, hydroxyl, and C atoms each time they appear. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl and C 3-6 cycloalkyl; R2, R b and R c Each time it appears, it is independently selected from H and C. 1-6 Alkyl, C 1-6 Alkoxy and C 3-6 cycloalkyl; R3, R4, R5 and R d Each time it appears, it is independently selected from H, halogen, hydroxyl, cyano, amino, nitro, C. 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, C 1-6 Alkyl acyl, C 1-6 alkyl-O-acyl, C 1-6 alkyl-N-acyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 5-8 Aryl and 5-8 quinone heteroaryl groups; Each time n and n1 appear, they are independently selected from 0, 1, 2, and 3; and Indicates the connection site.

6. The compound according to any one of claims 2-5, wherein, R L1 R L2 and R L4 Each is independently a covalent bond or C 1-6 A divalent straight-chain or branched saturated or unsaturated hydrocarbon group, wherein one or two methylene units of the hydrocarbon group are independently and optionally replaced by -O-, -C(O)-, -C(S)-, -C(R)2-, -NR-, -S-, -S(O-)-, or -S(O)2-; preferably, R L1 R L2 and R L4 Each is independently selected from covalent bonds, C 1-6 Alkylene, C 2-6 Heteroalkyl, -C(O)-C 1-6 Alkylene, -O-, -S-, -S(O)2-, -NR-, -C(O)-, and -NRC(O)-; and / or R L3 For covalent bonds or C 1-5 A divalent straight-chain or branched saturated or unsaturated hydrocarbon group, wherein one or two methylene units of the hydrocarbon group are independently and optionally replaced by -O-, -C-, -C(S)-, -C(R)2-, -NR-, -S-, -S(O-)- or -S(O)2-; preferably, R L3 Selected from covalent bonds, C 1-6 Alkylene, C 2-6 Heteroalkyl, -C(O)-C 1-6 Alkylene, -O-, -S-, -S(O)2-, -NR-, -C(O)-, and -NRC(O)-, or absent; and / or Cy1 is selected from 6-10 arylene groups, saturated or partially unsaturated 5-11 cyclic monocyclic groups, or bicyclic groups that are fused, fused, or spirocyclic, or heterocyclic groups containing 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5-14 arylene groups that are monocyclic, bicyclic, or tricyclic, containing 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; preferably, Cy1 is a 6-10 arylene group, a saturated or partially unsaturated 6-10 cyclic monocyclic group containing 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5-10 arylene group containing 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the 6-10 arylene group or the 6-10 cyclic monocyclic group... The 5-10 member heteroaryl group is selected from monocyclic, fused-ring, fused-ring, or spirocyclic bicyclic structures; preferably, Cy1 is phenylene, naphthylene, 5-10 member heteroaryl, or 6-10 member cyclic hydrocarbon group, wherein the 5-10 member heteroaryl or 6-10 member cyclic hydrocarbon group is a monocyclic, fused-ring, fused-ring, or spirocyclic bicyclic structure; preferably, Cy1 is selected from 8-10 member bicyclic heteroaryl or bicyclic cyclic hydrocarbon group containing 1, 2, 3, or 4 heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur; preferably, Cy1 is selected from 9 member bicyclic heteroaryl containing 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or 9 member bicyclic cyclic hydrocarbon group containing 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and / or Cy2 is selected from phenylene, 3-8 membered saturated or partially unsaturated hemicyclic hydrocarbon groups, or hemicyclic hydrocarbon groups containing 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5-6 membered heteroaryl groups containing 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; preferably, Cy2 is selected from saturated or partially unsaturated 5-7 membered hemicyclic hydrocarbon groups, saturated or unsaturated 5-7 membered hemicyclic hydrocarbon groups containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or 5-6 membered hemicyclic hydrocarbon groups containing 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; preferably, Cy2 is a saturated or partially unsaturated 6 membered hemicyclic hydrocarbon group, a hemicyclic hydrocarbon group containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5- or 6 membered hemicyclic hydrocarbon group containing 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and / or Cy3 is selected from 3-8 membered cycloalkyl groups, 3-10 membered heterocyclic groups containing 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S, 6-10 membered aryl groups, and 5-8 membered monocyclic or 9-10 membered bicyclic heteroaryl groups containing 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S, or is absent; preferably, Cy3 is phenyl, naphthyl, 3-6 membered saturated or partially unsaturated cycloalkyl groups, 4-6 membered monocyclic saturated or partially unsaturated heterocyclic groups containing 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 8-10 membered groups containing 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S, or is absent. The heterocyclic saturated or partially unsaturated heterocyclic group selected from nitrogen, oxygen, or sulfur heteroatoms, or a 9-10 member bicyclic heteroaryl group containing 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or none thereof; preferably, Cy3 is a 3-6 member saturated or partially unsaturated cyclic hydrocarbon group, or a 4-6 member monocyclic or 8-9 member bicyclic heterocyclic group containing 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 4-6 member monocyclic or 9-10 member bicyclic heteroaryl group containing 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; and / or Cy4 is selected from covalent bonds, Preferably, Cy4 is selected from Q1 is selected independently from CR each time it appears. x and N; Q2 is selected independently from C(R) each time it appears. x )2 and NR x ; and / or R B Selected from C 1-6 Aliphatic, phenyl, naphthyl, 3-8 membered saturated or partially unsaturated cyclic hydrocarbon groups or heterocyclic groups, and 5-10 membered monocyclic or bicyclic heterocyclic groups containing 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and 7-11 membered bicyclic heterocycles containing 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and / or R C Independently for -L B -CyB1-H or -L B -CyB1-CyB2; L B For covalent bonds or C 1-3 Divalent straight-chain or branched saturated or unsaturated hydrocarbon groups, wherein one or two methylene units of the hydrocarbon group are independently and optionally substituted with -O-, -C(O)-, -C(S)-, -C(R)2-, -CF2-, -CRF-, -CR(OR)-, -NR-, -S-, -S(O)-, -S(O)2-, -S(O)(NR)-, or -CR=CR-; each CyB1 is independently selected from phenylene, 3-10 membered saturated or partially unsaturated monocyclic or bicyclic hydrocarbon groups or heterocyclic groups containing 1, 2, 3, or 4 heteroatoms each independently selected from nitrogen, oxygen, and sulfur, and 5-8 membered or 10 membered monocyclic or bicyclic aryl groups or heteroaryl groups containing 1, 2, 3, or 4 heteroatoms each independently selected from nitrogen, oxygen, and sulfur; and / or R P1 R P2 R P3 and R x Each occurrence is independently selected from hydrogen, deuterium, halogen, oxo group (=O), -CN, -NO2, -OR, -SR, -N(R)2, -Si(R)3, -S(O)R, -S(O)2R, -S(O)(NR)R, -S(O)2N(R)2, -S(O)R, -C(O)R, -C(O)OR, -C(O)N(R)2, -C(O)NROR, -OC(O)R, -OC(O)N(R)2, -P(O)(R)2, -P(O)(OR)2, -OP(O)(R)2, -OP(O)(OR)2, -NRC(O)OR, -NRC(O)R, -NRC(O)N(R)2, -NRS(O)2R, C 1-6 Aliphatic, 6-10 aryl, 3-8 saturated or partially unsaturated cyclic hydrocarbon groups, 3-8 heterocyclic groups, and 5-10 cyclic monocyclic or bicyclic heteroaryl groups containing 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein C 1-6 Aliphatic, phenyl, saturated or partially unsaturated cyclic hydrocarbon groups or heterocyclic groups, and monocyclic or bicyclic heteroaryl groups are optionally substituted; preferably, R P1 R P2 R P3 and R x Each time it appears, it is independently selected from H, deuterium, halogen, oxo group (=O), C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 2-6 Heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy, hydroxyl, C 1-6 Hydroxyalkyl, nitro, cyano, amino, C 1-6 Alkylamino, C 1-6 Alkyl acyl, C 1-6 Alkyloxyacyl, C 1-6 Alkylaminoacyl, 3-8 membered saturated or partially unsaturated cyclic hydrocarbon group, 3-8 membered heterocyclic group, 6-10 membered aryl group, and 5-10 membered monocyclic or bicyclic heteroaryl group containing 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the alkyl, heteroalkyl, alkenyl, alkoxy, cyclic hydrocarbon group, heterocyclic group, aryl group, and heteroaryl group are each independently selected independently of halogen, C 1-6 Alkyl, C 2-6 Heteroalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, hydroxyl, C 1-6 Hydroxyalkyl, cyano, amino, nitro, 3-8 membered cycloalkyl, 3-8 membered heterocyclic, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkylamino, C 1-6 Alkyl acyl, C 1-6 Alkyloxyacyl, C 1-6 The substituent is selected from one or more substituents of alkylaminoacyl, 6-10 aryl, and 5-10 heteroaryl; preferably, R P1 R P2 R P3 and R X Each time it appears, it is independently selected from H, deuterium, F, Cl, Br, I, oxo group (=O), C. 1-3 Alkyl, C 1-3 Deuterated alkyl, C 2-3 Heteroalkyl, C 2-3 alkenyl, C 2-3 alkynyl group, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 Halogenated alkoxy, hydroxyl, C 1-3 Hydroxyalkyl, nitro, cyano, amino, C 1-3 Alkyl acyl, 3-8 membered saturated or partially unsaturated cyclic hydrocarbons, 3-8 membered heterocyclic groups containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 6-10 membered aryl groups, and 5-10 membered monocyclic or bicyclic heteroaryl groups containing 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the alkyl, heteroalkyl, alkenyl, alkoxy, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each independently optionally selected from halogens, C 1-3 Alkyl, C 2-3 Heteroalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkyl, hydroxyl, C 1-3 Hydroxyalkyl, cyano, amino, nitro, 3-8 membered cycloalkyl, 3-8 membered heterocyclic, C 2-3 alkenyl, C 2-3 The substituent is selected from one or more substituents of alkynyl, 6-10 aryl, and 5-10 heteroaryl; preferably, R P1 R P2 R P3 and R X Each time it appears, it is independently selected from H, deuterium, F, Cl, Br, I, oxo group (=O), C. 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 Halogenated alkoxy groups, C 1-3 Alkylene-3-6 membered cycloalkyl, -C(O)-C 1-3 Alkyl groups and -CN; and / or R P1 Each time it appears, it is independently selected from F, Cl, Br, I, oxo group (=O), C. 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups and C 1-3 alkylene-3-6-membered cycloalkyl; and / or R P2 Each time it appears, it is independently selected from oxo groups (=O) and -C(O)-C. 1-3 Alkyl groups; and / or R P3 Each time it appears, it is independently selected from C. 1-3 Alkyl groups and -CN; and / or R x Each time it appears, it is independently selected from H, F, Cl, Br, I, C. 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkyl groups and C 1-3 Halogenated alkoxy groups; and / or R L5 and R L6 Each time it appears, it is independently selected from H, halogen, and C. 1-6 Alkyl, -OC 1-6 Alkyl, -C(O)-C 1-6 Alkyl, -C(O)2H, -CN, -CF3, -CHF2, -CH2F, -NO2, -S(O)2, C 3-6 cycloalkyl and C 3-6 Heterocyclic groups, optionally, the C 1-6 Alkyl, C 3-6 cycloalkyl and C 3-6 Each heterocyclic group is independently selected from halogens, C 1-6 Alkyl, C 2-6 Heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, hydroxy, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, cyano, amino, nitro, 3-8 membered cycloalkyl, 3-8 membered heterocyclic, 3-8 membered halocycloalkyl, C 1-6 Halogenated heteroalkyl, C 1-6 Alkylamino, C 6-10 Aryl, C 5-10 heteroaryl, C 6-10 Halogenated aryl and C 5-10 One or more substituents in the haloaryl group are substituted; and / or R A Selected from hydrogen, F, Cl, Br, I, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, -CN, -NO2, -OR, -SR, -N(R)2, -Si(R)3, -S(O)R, -S(O)2R, -S(O)(NR)R, -S(O)2N(R)2, -S(O)R, -C(O)R, -C(S)R, -C(O)OR, -C(O)N(R)2, -C(O)NROR, -OC(O)R, -OC(O)N(R)2, -P(O)(R)2, -P(O)(OR)2, -OP(O)(R)2, -OP(O)(OR)2, -NRC(O)OR, -NRC(O)R, -NRC(O)N(R)2, -NRS(O)2R,C 1-6 Alkyl, 6-10 aryl, 3-7 saturated or partially unsaturated cycloalkyl, or heterocyclic group containing 1, 2, 3 or 4 heteroatoms each independently selected from nitrogen, oxygen and sulfur, and 5-10 cyclic or bicyclic heteroaryl containing 1, 2, 3 or 4 heteroatoms each independently selected from nitrogen, oxygen and sulfur; wherein the aryl, cycloalkyl, heterocyclic or heteroaryl group is optionally selected from O, F, Cl, Br, I, C 1-6 Alkyl, C 1-6 Alkoxy group, -C(O)C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and C 1-6 Substituents of haloalkoxy groups; preferably, R A Selected from hydrogen, F, Cl, Br, I, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 The aryl group may be a halogenated alkoxy group, a -CN group, a -NO2 group, a -C(O)R group, a 6-10 aryl group, a 3-7 saturated or partially unsaturated cycloalkyl group, or a heterocyclic alkyl group containing 1, 2, 3, or 4 heteroatoms each independently selected from nitrogen, oxygen, and sulfur, or a 5-10 aryl group of a monocyclic or bicyclic structure containing 1, 2, 3, or 4 heteroatoms each independently selected from nitrogen, oxygen, and sulfur, wherein the aryl group, cycloalkyl group, heterocyclic alkyl group, or heteroaryl group is optionally selected from O, F, Cl, Br, I, C. 1-3 Alkyl, C 1-3 Alkoxy group, -C(O)C 1-3 Alkyl, C 1-3 Halogenated alkyl groups and C 1-3 The alkyl halogen is substituted with 1, 2, 3, 4 or 5 substituents; and / or Each time R appears, it independently represents hydrogen or C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 The following are possible interpretations of heterocyclic compounds: haloalkoxy groups, 6-10 aryl groups, 3-7 saturated or partially unsaturated cyclic hydrocarbon groups, 3-7 saturated or partially unsaturated heterocyclic compounds containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or 5-6 aryl groups having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or two R groups located on the same or adjacent atoms, together with the atoms between them, forming optionally substituted 3-11 saturated or partially unsaturated heterocyclic compounds containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or 3-11 saturated or partially unsaturated cyclic hydrocarbon groups, wherein the heterocyclic compound or cyclic hydrocarbon group is a monocyclic, bridged, or spirocyclic ring; the aryl, cyclic hydrocarbon, heterocyclic, and heteroaryl groups are optionally selected from F, Cl, Br, I, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Substituents of haloalkoxy groups; preferably, R is independently hydrogen or C each time it appears. 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 The following are possible interpretations of heterocyclic compounds: haloalkoxy, 6-10 aryl, 3-7 saturated or partially unsaturated cycloalkyl groups, 3-7 saturated or partially unsaturated heterocyclic groups containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or 5-6 aryl groups having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or two R groups located on the same or adjacent atoms, together with the atoms between them, forming optionally substituted 3-11 saturated or partially unsaturated heterocyclic groups or 3-11 saturated or partially unsaturated cycloalkyl groups containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the heterocyclic alkyl or cycloalkyl group is a monocyclic, bridged, or spirocyclic ring; the aryl, cycloalkyl, cycloalkyl, heterocyclic, and heteroaryl groups are optionally selected from F, Cl, Br, I, and C. 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 Substituents of haloalkoxy groups.

7. The compound according to any one of claims 1-5, wherein, R L1 R L2 and R L4 Each is independently a covalent bond or C 1-6 Divalent straight-chain or branched saturated or unsaturated hydrocarbon group (preferably C) 1-6 Alkylene), wherein one, two, or three methylene units of the hydrocarbon group are independently and optionally replaced by -O-, -C(O)-, -C(S)-, -C(R)2-, -NR-, or -S(O)2-NR-; preferably, R L1 R L2 and R L4 Each is independently a covalent bond, -C(R)2-, -O-, -NR-, -C(O)-C(R)2-, -OC(R)2-, -OC(O-), -S(O)2-NR-, -C(O-), -C(S)-NR-, Or -C(O)-NR-; Preferably, R L1 It is a covalent bond or -C(R)2-; preferably, R L1 It is a single bond; Preferably, R L2 It is a covalent bond, -C(R)2-, -O-, -NR-, -C(O)-C(R)2-, -OC(R)2-, or -OC(O-); preferably, R L2 It is a single bond, -CH2-, -O-, -NH-, -N(CH3)-, -C(O)-CH2-, -C(O)-CH(CH3)-, -C(O)-C(CH3)2-, -O-CH2-, -O-CH(CH3)-, -OC(CH3)2-, or -OC(O)-; preferably, R L2 It is a single bond; Preferably, R L4 For covalent bonds, -C(R)2-, -NR-, -S(O)2N(R)-, -C(S)-NR-, -C(O)- or -C(O)-NR-; preferably, R L4 For covalent bonds, -C(R)2-, -NR-, -S(O)2N(R)-, -C(S)-NR-, Or -C(O)-NR-; preferably, R L4 It can be a single bond, -CH2-, -NH-, -N(CH3)-, -S(O)2NH-, -S(O)2N(CH3)-, -C(S)-NH-, -C(S)-N(CH3)-, -C(O)-, -C(O)NH-, or -C(O)N(CH3)-; Preferably, R L4 It can be a single bond, -CH2-, -NH-, -N(CH3)-, -S(O)2NH-, -S(O)2N(CH3)-, -C(S)-NH-, -C(S)-N(CH3)-, -C(O)NH-, or -C(O)N(CH3)-; and / or R L3 For covalent bonds or C 1-6 Divalent straight-chain or branched saturated or unsaturated hydrocarbon group (preferably C) 1-6 Alkylene), wherein one, two, or three methylene units of the hydrocarbon group are independently and optionally replaced by -Cyx-, -O-, -C(O)-, -C(S)-, -C(R)2-, -NR-, or -S(O)2-, or are absent; preferably, R L3 It is a covalent bond, -C(R)2-, -C(O)-, -C(O)-C(R)2-, -S(O)2-C(R)2-, -C(O)-NR-C(R)2-, -NR-C(O)-C(R)2-, or does not exist; preferably, R L3 Selected from single bonds, -CH2-, -C(O)-, -C(O)CH2-, -C(O)(CH2)2-, -C(O)(CH2)3-, -C(O)CH(CH3)-, -C(O)CH(CH3)CH2-, -C(O)C(CH3)2CH2-, -C(O)CH2C(O)-, -C(O)NHCH2-, -C(O)NH(CH2)2-, -NHC(O)CH2-, -NHC(O)(CH2)2-, -S(O)2CH(CH3)-, or absent; preferably, R L3 -C(O)(CH2)2-; and / or Cyx is selected from phenylene, saturated or partially unsaturated 3-6 membered heterocyclic hydrocarbon groups, saturated or partially unsaturated 3-6 membered heterocyclic hydrocarbon groups containing 1, 2, or 3 heteroatoms each independently selected from nitrogen, oxygen, and sulfur, and 5-8 membered monocyclic or bicyclic heteroaryl groups containing 1, 2, or 3 heteroatoms each independently selected from nitrogen, oxygen, and sulfur, wherein the phenylene, heterocyclic hydrocarbon group, heterocyclic hydrocarbon group, and heteroaryl group are optionally selected from F, Cl, Br, I, cyano, C 1-3 Alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkyl groups and C 1-3 One or more substituents of the haloalkoxy group are substituted; preferably, Cyx is a saturated or partially unsaturated 3-5 membered cyclic hydrocarbon group, said cyclic hydrocarbon group optionally selected from F, Cl, Br, I, cyano, C 1-3 Alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkyl groups and C 1-3 One or more substituents of the haloalkoxy group are substituted; and / or Cy1 is selected from 6-10 membered monocyclic, fused, or spirocyclic bicyclic aryl groups; saturated or partially unsaturated 5-11 membered monocyclic, fused, or spirocyclic bicyclic cyclic hydrocarbon groups; saturated or partially unsaturated monocyclic, fused, or spirocyclic bicyclic 5-11 membered heterocyclic groups containing 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and 5-14 membered heteroaryl groups containing 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. Preferably, Cy1 is selected from... Bicyclic aryl groups with 6-10 member monocyclic or fused rings; bicyclic cyclic hydrocarbon groups with 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, either saturated or partially unsaturated; bicyclic 6-10 member heterocyclic groups with 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, either saturated or partially unsaturated; and monocyclic, bicyclic, or tricyclic heteroatoms with 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. The 5-10 membered heteroaryl group; preferably, Cy1 is phenyl, naphthyl, a 5-10 membered heteroaryl group containing 1, 2, 3 or 4 heteroatoms each independently selected from nitrogen, oxygen and sulfur, or a saturated or partially unsaturated 6-10 membered heterocyclic group containing 1, 2, 3 or 4 heteroatoms each independently selected from nitrogen, oxygen and sulfur, wherein the 5-10 membered heteroaryl group or the 6-10 membered heterocyclic group is a monocyclic, fused, or spirocyclic bicyclic group; preferably, Cy1 is selected from groups containing 1, 2, 3 or 4 heteroatoms each independently selected from nitrogen, oxygen and sulfur. The 8-10 membered bicyclic heteroaryl group selected from heteroatoms of nitrogen, oxygen, and sulfur, and the 5-11 membered monocyclic, fused, or spirocyclic bicyclic group containing 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, either saturated or partially unsaturated; preferably, Cy1 is selected from 9 membered bicyclic heteroaryl groups containing 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and the 9 membered fused or spirocyclic bicyclic group containing 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and / or Cy2 is selected from phenylene, saturated or partially unsaturated 3-8 membered heterocyclic hydrocarbon groups, saturated or partially unsaturated 3-8 membered heterocyclic hydrocarbon groups containing 1, 2, 3 or 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, and 5-6 membered heteroaryl groups containing 1, 2, 3 or 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; preferably, Cy2 is selected from phenylene, saturated or partially unsaturated 5-7 membered heterocyclic hydrocarbon groups, saturated or partially unsaturated 3-8 membered heterocyclic hydrocarbon groups containing 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur. And / or partially unsaturated 5-7 membered heterocyclic groups, and 5-6 membered heterocyclic groups containing 1, 2, 3 or 4 heteroatoms each independently selected from nitrogen, oxygen and sulfur; preferably, Cy2 is selected from phenylene, saturated or partially unsaturated 6 membered heterocyclic groups, or saturated or partially unsaturated 6 membered heterocyclic groups containing 1, 2 or 3 heteroatoms each independently selected from nitrogen, oxygen and sulfur, and 5 or 6 membered heterocyclic groups containing 1, 2, 3 or 4 heteroatoms each independently selected from nitrogen, oxygen and sulfur; and / or Cy3 is absent or selected from 6-10 aryl groups, saturated or partially unsaturated monocyclic or bicyclic (fused or spirocyclic) 3-8 membered cyclic hydrocarbon groups, saturated or partially unsaturated 3-10 membered heterocyclic groups containing 1, 2, 3 or 4 heteroatoms each independently selected from N, O and S, and 5-8 membered monocyclic or 9-10 membered bicyclic heteroaryl groups containing 1, 2, 3 or 4 heteroatoms each independently selected from N, O and S; preferably, Cy3 is absent or selected from phenyl or naphthalene. 3-6 membered ring hydrocarbon groups of monocyclic or bicyclic (fused or spirocyclic) nature, saturated or partially unsaturated 4-6 membered monocyclic heterocyclic groups containing 1, 2, 3 or 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, 8-10 membered bicyclic heterocyclic groups containing 1, 2, 3 or 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, and 5-6 membered monocyclic or 9 membered ring hydrocarbon groups containing 1, 2, 3 or 4 heteroatoms independently selected from nitrogen, oxygen and sulfur. -10-membered bicyclic heteroaryl; preferably, Cy3 is absent or selected from saturated or partially unsaturated 3-6-membered cyclic hydrocarbon groups, saturated or partially unsaturated 4-6-membered monocyclic or 8-9-membered bicyclic heterocyclic groups containing 1, 2, 3 or 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, and 5-6-membered monocyclic or 9-10-membered bicyclic heteroaryl groups containing 1, 2, 3 or 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; preferably, Cy3 is absent or selected from 3-membered, 4-membered, and 5-membered... Or a 6-membered cycloalkyl group, a 4-, 5-, or 6-membered monocyclic heterocyclic group containing 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a partially unsaturated 8- or 9-membered bicyclic heterocyclic group containing 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5- or 6-membered monocyclic heteroaryl group containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 9-membered bicyclic heteroaryl group containing 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and / or Cy4 is selected from covalent bonds, Q1 is selected independently from CR each time it appears. x And N; preferably, Q1 is independently selected from CH and N each time it appears; Q2 is selected independently from C(R) each time it appears. x )2 and NR x Preferably, Q2 is independently selected from CH2 and NH each time it appears; and / or n1, n2, n3, and n4 are each independently 1, 2, 3, or 4; and / or R P1 R P2 R P3 and R X Each time it appears, it is independently selected from hydrogen, deuterium, halogen, -CN, -NO2, oxo group (=O), C. 1-3 Alkyl, C 1-3 Alkoxy, -N(R)2, -S(O)2R, -C(O)R, -C(O)-N(R)2, saturated or partially unsaturated 3-6 membered cyclic hydrocarbon groups, saturated or partially unsaturated 3-6 membered heterocyclic groups containing 1, 2, 3 or 4 heteroatoms each independently selected from nitrogen, oxygen and sulfur, 6-8 membered aryl and 5-8 membered heteroaryl, wherein the C 1-3 Alkyl, C 1-3 Alkoxy, 3-6 membered cyclic hydrocarbon, 3-6 membered heterocyclic, 6-8 membered aryl, or 5-8 membered heteroaryl are optionally selected from F, Cl, Br, I, hydroxyl, carboxyl, -CN, -NO2, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 The substituted group is replaced by one or more substituents of a haloalkoxy group, a 3-6 membered cyclic hydrocarbon group, and a 3-6 membered heterocyclic group; preferably, R P1 R P2 R P3 and R X Each time it appears, it is independently selected from H, F, Cl, Br, I, -CN, oxo group (=O), -C(O)H, C 1-3 Alkyl, C 1-3 Alkoxy group, -C(O)-C 1-3 Alkyl groups and -S(O)2-C 1-3 Alkyl, the C 1-3 Alkyl and C 1-3 The alkoxy group is optionally substituted by one or more substituents selected from F, Cl, Br, I, hydroxyl, carboxyl, -CN, -NO2 and 3-6 membered cyclic hydrocarbon groups; Preferably, R P1 Each time it appears, it is independently selected from H, F, Cl, Br, I, oxo group (=O), C. 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, -C 1-3 Alkylene-3-6-membered cycloalkylene and phenylene-NH-C 1-3 Alkyl; preferably, R P1 Each time it appears, it is independently selected from F, Cl, Br, I, oxo group (=O), C. 1- 3 alkyl groups and -C 1-3 alkylene-3-6-membered cycloalkyl; and / or R P2 Each time it appears, it is independently selected from H, F, Cl, Br, I, oxo group (=O), C. 1-3 Alkyl, -S(O)2-C 1-3 Alkyl groups and -C(O)-C 1-3 Alkyl, the C 1-3 Alkyl groups are optionally surrounded by F, Cl, Br, I, hydroxyl, carboxyl, oxo (=O) and C. 1-3 One or more alkyl groups are substituted; preferably, R P2 Each time it appears, it is independently selected from F, Cl, Br, I, oxo group (=O), C. 1-3 Alkyl, -S(O)2-C 1-3 Alkyl, -C(O)-C 1-3 Alkyl, -C(O)-C 1-3 Hydroxyalkyl and -C(O)-C 1-3 alkylene-carboxyl group; preferably, R P2 Each occurrence is independently CH3; and / or R P3 Each occurrence is independently selected from H, F, Cl, Br, I, -CN, -C(O)H, C 1-3 Alkyl and C 1-3 Alkoxy; preferably, R P3 Each occurrence is independently selected from F, Cl, Br, I, -CN, -C(O)H, C 1-3 Alkyl and C 1-3 Alkoxy; preferably, R P3 Each occurrence is independently selected from F and CF3; and / or R X Each occurrence is independently selected from H, F, Cl, Br, I, -CN, C. 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkyl groups and C 1-3 Halogenated alkoxy groups; preferably, R X Each occurrence is independently selected from H, F, Cl, Br, I, C. 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkyl groups and C 1-3 Haloalkoxy; or, R X Each occurrence is independently selected from F, Cl, -CN, -CH3, -OCH3, and -OCF3; and / or R A Selected from hydrogen, -CN, -NO2, -NH2, -N(C) 1-3 Alkyl)2, -N(C 1-3 Alkyl groups (H, -OH), halogens, C 1-3 Alkyl, C 1-3 Alkoxy, -CyB1-CyB2, 6-8 aryl, saturated or partially unsaturated 3-6 membered cyclic hydrocarbon, saturated or partially unsaturated 3-6 membered monocyclic or 8-10 membered bicyclic heterocyclic groups containing 1, 2, 3, or 4 heteroatoms each independently selected from nitrogen, oxygen, and sulfur, and 5-6 membered monocyclic or 8-10 membered bicyclic heteroaryl groups containing 1, 2, 3, or 4 heteroatoms each independently selected from nitrogen, oxygen, and sulfur, wherein the C 1-3 Alkyl, C 1-3 Alkoxy, aryl, cyclic, heterocyclic, and heteroaryl groups are optionally selected from oxo (=O), F, Cl, Br, I, and C. 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkyl groups and C 1-3 The alkoxy group is substituted with one or more substituents of the haloalkoxy group; preferably, R A Selected from hydrogen, -CN, -NO2, -NH2, -N(CH3)2, -N(CH3)H, -OH, halogens, C 1-3 Alkyl, C 1-3 Alkoxy, -CyB1-CyB2, phenylene, saturated or partially unsaturated 3, 4, 5, or 6-membered monocyclic cycloalkyl group, saturated or partially unsaturated 3, 4, 5, or 6-membered monocyclic heterocyclic group containing 1, 2, or 3 heteroatoms each independently selected from nitrogen, oxygen, and sulfur, saturated or partially unsaturated 8, 9, or 10-membered bicyclic heterocyclic group containing 1, 2, or 3 heteroatoms each independently selected from nitrogen, oxygen, and sulfur, 5 or 6-membered monocyclic heteroaryl group containing 1, 2, or 3 heteroatoms each independently selected from nitrogen, oxygen, and sulfur, and 8, 9, or 10-membered bicyclic heteroaryl group containing 1, 2, or 3 heteroatoms each independently selected from nitrogen, oxygen, and sulfur, wherein C 1-3 Alkyl, C 1-3 Alkoxy, aryl, cyclic, heterocyclic, and heteroaryl groups are optionally selected from oxo (=O), F, Cl, Br, I, and C. 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkyl groups and C 1-3 The alkoxy group is substituted by one or more substituents of the haloalkoxy group; CyB1 is selected from 3-8 membered saturated or partially unsaturated monocyclic heterocyclic groups containing 1, 2, 3, or 4 heteroatoms each independently selected from nitrogen, oxygen, and sulfur, wherein the heterocyclic group is optionally selected from F, Cl, Br, I, cyano, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkyl groups and C 1-3 One or more substituents of the haloalkoxy group are substituted; CyB2 is selected from 3-8 membered saturated or partially unsaturated monocyclic cyclic hydrocarbon groups and 5-8 membered monocyclic heteroaryl groups containing 1, 2, 3, or 4 heteroatoms each independently selected from nitrogen, oxygen, and sulfur, wherein the cyclic hydrocarbon group and heteroaryl group are optionally selected from F, Cl, Br, I, cyano, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkyl groups and C 1-3 One or more substituents of the haloalkoxy group are substituted; and / or Each time R appears, it is independently hydrogen, halogen, hydroxyl, or C. 1-3 Alkyl, C 1-3 Alkoxy, saturated or partially unsaturated 3-8 membered cyclic hydrocarbon group, saturated or partially unsaturated 3-8 membered heterocyclic group, 6-8 membered aryl or 5-8 membered heteroaryl, wherein C 1-3 Alkyl, C 1-3 Alkoxy, cyclic hydrocarbon, heterocyclic, aryl, or heteroaryl groups are optionally selected from F, Cl, Br, I, cyano, hydroxyl, oxo (=O), C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 1-3 Halogenated alkyl groups and C 1-3 One or more substituents of the haloalkoxy group are substituted; preferably, R is independently hydrogen, F, Cl, Br, I, hydroxyl, C each time it appears. 1-3 Alkyl, C 1-3 Alkoxy, saturated or partially unsaturated 3-6 membered cyclic hydrocarbon group, saturated or partially unsaturated 3-6 membered heterocyclic group, phenyl or 5-6 membered heteroaryl group, wherein C 1-3 Alkyl, C 1-3 Alkoxy, cyclic hydrocarbon, heterocyclic, phenyl, or heteroaryl groups are optionally selected from F, Cl, Br, I, cyano, hydroxyl, oxo (=O), C 1-3 Alkyl, C 1-3 Alkoxy and C 1-3 One or more substituents of the hydroxyalkyl group are substituted; preferably, R is hydrogen each time it appears; and / or When W1 and W2 appear, they are each independently selected from CH2 and C(O), and at least one of W1 and W2 is selected from C(O); and / or W3 is selected from C(O); and / or In Equations 2-1-9, 2-1-10, 2-1-11, and 2-1-12, the terms W4, W5, and W6 are... Indicates a single or double bond; W4, W5, and W6 are each independently selected from C, C(O), O, N, NH, N(C) each time they appear. 1-3 Alkyl), CH, C(C) 1-3 Alkyl), CH2, CH(C) 1-3 alkyl) and C(C) 1-3 Alkyl)2; Furthermore, when there is a double bond between W4 and W5, and a single bond between W5 and W6, W4 is selected from C, and W5 is selected from N, CH, and C(C) 1-3 Alkyl), W6 is selected from NH, N(C) 1-3 Alkyl), O, CH2, CH(C) 1-3 alkyl) and C(C) 1-3 Alkyl)2; when there is a single bond between W4 and W5 and a double bond between W5 and W6, W4, W5, and W6 are each independently selected from N, CH, and C (C 1-3 Alkyl); when there are single bonds between W4, W5, and W6, W4 is selected from N, CH, and C (C 1-3 Alkyl groups, W5 and W6 are each independently selected from C(O), NH, N(C) 1-3 Alkyl), O, CH2, CH(C) 1-3 alkyl) and C(C) 1-3 Alkyl)2; and / or R q Each occurrence is independently selected from single bonds and NH; and / or A1, A2, A3, A4, A5, and A6 are each independently selected from O, C(O), and NR when they appear. d and C(R) d )2; Preferably, A1, A2, A3, A4, A5 and A6 are each independently selected from O, C(O), NH and CH2 each time they appear; and / or When B1 and B2 appear, they are each independently selected from N and CH; preferably, at least one of B1 and B2 is N; Each time X and Z appear, they are independently selected from N and CH; preferably, X is N; and / or, Z is CH or N; and / or Each time E appears, it is independently selected from O, C(O)NH, C(O)N(C) 1-3 Alkyl), NH and N(C) 1-3 Alkyl); preferably, E is independently selected from O, C(O)NH, C(O)N(CH3), NH and N(CH3) each time it appears; and / or Each time m1 and m2 appear, they are independently selected from 0, 1, 2, 3, and 4, and 1 ≤ m1 + m2 ≤ 4; preferably, m1 + m2 = 1 or m1 + m2 = 2; and / or Each time m3 and m4 appear, they are independently selected from 0, 1, 2, 3, and 4, and 1 ≤ m3 + m4 ≤ 4; preferably, each time m3 and m4 appear, they are independently selected from 0, 1, 2, and 3, and m3 + m4 = 2 or m3 + m4 = 3; and / or Each time m5 and m7 appear, they are independently selected from 0, 1, 2, 3, and 4; each time m6 and m8 appear, they are independently selected from 1, 2, 3, 4, and 5, and 1 ≤ m5 + m6 ≤ 5, 1 ≤ m7 + m8 ≤ 5; preferably, each time m5 and m7 appear, they are independently selected from 0, 1, 2, and 3; each time m6 and m8 appear, they are independently selected from 1, 2, 3, and 4, and m5 + m6 = 2, m5 + m6 = 3, or m5 + m6 = 4; m7 + m8 = 2, m7 + m8 = 3, or m7 + m8 = 4; and / or R1 and R2 are each independently selected from H, deuterium, halogen, hydroxyl, and C atoms each time they appear. 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Hydroxyalkyl and C 3-6 Cycloalkyl; preferably, R1 and R2 are each independently selected from H, F, Cl, Br, hydroxyl, methyl, ethyl, methoxy, ethoxy, and cyclopropyl each time they appear; preferably, R1 is always H each time it appears; and / or, R2 is each independently selected from methyl and -CH2CH2F each time it appears; and / or R b and R c Each time it appears, it is independently selected from H and C. 1-3 Alkyl, C 1-3 Alkoxy and C 3-6 cycloalkyl; and / or R3, R4, R5 and R d Each occurrence is independently selected from H, F, Cl, Br, I, -OH, -CN, -NH2, -NO2, C. 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups and C 1-3 Hydroxyalkyl; preferably, R3, R4, R5 and R d Each occurrence is independently selected from H, F, Cl, Br, I, -OH, -CN, -NH2, -NO2, methyl, ethyl, isopropyl, methoxy, and ethoxy; and / or Each time n appears, it is independently selected from 0, 1, and 2.

8. The compound according to any one of claims 1-7, wherein, Cy1 is selected from optional substitutions. Provided that it is chemically permissible, each occurrence of M1 and M2 can be independently selected from C, N, and NR. X O, S, CR X and C(R) X )2; Preferably, Cy1 is selected from optionally substituted... Preferably, Cy1 is selected from optionally substituted... in Indicates with R L1 The connection site, Indicates with R L4 The connection sites, and Indicates with R L2 Connection sites; and / or n1 is 0, 1, 2, 3, or 4; and / or Cy2 is selected from the optional substitutions. and / or n2 is 0, 1, 2, 3, or 4; and / or Cy3 is absent or is selected from optional substitutions. And / or n3 is 0, 1, 2, 3, or 4; and / or Cy4 is selected from covalently bonded, optionally substituted and / or n4 is 0, 1, 2, 3, or 4; and / or R A Selected from hydrogen, -CN, C 1-3 Alkyl, -NH2, -N(CH3)2, -N(CH3)H, C 1-3 Alkoxy, C 1-3 Halogenated alkyl, Preferably, R A Selected from H, -N(CH3)2, and -CH3.

9. The compound according to any one of claims 1-8, wherein the compound is selected from compounds represented by the following formula: in, L, CLM, R L1 R L2 R L3 R L4 Cy2, Cy3, Cy4, R A R X R P1 R P2 R P3 The definitions of n1, n2, n3, and n4 are the same as those defined in any one of claims 1-8; M1 and M2 are each independently selected from N and NR respectively. X O, S, CR X and C(R) X )2, provided that it is chemically permissible; preferably, M1 and M2 are each independently selected from N, NH, O, S, CH, and CH2 each time they appear, provided that it is chemically permissible; Preferably, the compound is selected from compounds shown in the following formula: Among them, L, CLM, R L1 R L2 R L3 R L4 Cy2, Cy3, Cy4, R A R X R P1 R P2 R P3 The definitions of n1, n2, n3 and n4 are as defined in any one of claims 1-8.

10. The compound according to any one of claims 1-9, wherein the compound is selected from compounds represented by the following formula: in, L, CLM, R L1 R L2 R L3 R L4 Cy3, Cy4, R A R X R P1 R P2 R P3 The definitions of n1, n2, n3 and n4 are the same as those defined in any one of claims 1-9; Preferably, R A Selected from H, F, Cl, Br, I, C 1-3 Alkyl, C 1-3 Alkoxy, -CN, -NH2, -N(C) 1-3 alkyl)2、-NH(C 1-3 Alkyl), -NO2, 3-6 membered monocyclic cycloalkyl group, 3-6 membered monocyclic heterocyclic group, 5-6 membered monocyclic heteroaryl group, 8-10 membered bicyclic heterocyclic group, 8-10 membered bicyclic heteroaryl group, 3-6 membered monocyclic heterocyclic group-3-6 membered monocyclic cycloalkyl group and 3-6 membered monocyclic heterocyclic group-5-6 membered monocyclic heteroaryl group, wherein the C 1-3 Alkyl, C 1-3 Alkoxy, 3-6 membered monocyclic cycloalkyl group, 3-6 membered monocyclic heterocyclic group, 5-6 membered monocyclic heteroaryl group, 8-10 membered bicyclic heterocyclic group, and 8-10 membered bicyclic heteroaryl group are optionally selected from F, Cl, Br, I, cyano, hydroxyl, oxo (=O), C 1-3 Alkyl and C 1-3 The alkoxy group is substituted by one or more substituents; Preferably, R A Selected from H, -CN, C 1-3 Alkyl, -NH2, -N(CH3)2, -N(CH3)H, C 1-3 Alkoxy, C 1-3 Halogenated alkyl, Preferably, -R L4 -R A Selected from hydrogen, methyl, -C(O)NHCH3, -C(O)N(CH3)CH2CH2CH3, -C(O)N(CH3)2, -C(O)N(CH3)-CH2CF3, -C(O)N(CH3)-cyclopropyl, -C(O)N(CH3)-cyclobutyl, 11. The compound according to any one of claims 1-10, wherein, The PTM is selected from the following structures:

12. The compound according to any one of claims 1-11, wherein, The CLM is selected from the structure shown in the following formula: in: Each time X and Z appear, they are independently selected from N and CH; Each time E appears, it is independently selected from O, C(O)NH, C(O)N(C) 1-3 Alkyl), NH and N(C) 1-3 alkyl); When W1 and W2 appear, they are each independently selected from CH2 and C(O), and at least one of W1 and W2 is selected from C(O); When there is a double bond between W4 and W5, and a single bond between W5 and W6, W4 is selected from C, and W5 is selected from N, CH, and C(C) 1-3 Alkyl), W6 is selected from NH, N(C) 1-3 Alkyl), O, CH2, CH(C) 1-3 alkyl) and C(C) 1-3 Alkyl)2; when there is a single bond between W4 and W5 and a double bond between W5 and W6, W4, W5, and W6 are each independently selected from N, CH, and C (C 1-3 Alkyl); when there are single bonds between W4, W5, and W6, W4 is selected from N, CH, and C (C 1-3 Alkyl groups, W5 and W6 are each independently selected from C(O), NH, N(C) 1-3 Alkyl), O, CH2, CH(C) 1-3 alkyl) and C(C) 1-3 Alkyl)2; R 2a Each occurrence is independently selected from H, F, Cl, Br, C. 1-3 Alkyl and C 1-3 Halogenated alkyl groups; R 3a R 4a R 3b R 4b R 3c R 4c R 5c R 3d R 4d R 5d R 3e and R 4e Each time it appears, it is independently selected from H, halogen, hydroxyl, cyano, amino, nitro, C. 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups and C 1-6 Hydroxyalkyl; A a A b A c A d A e A f and A h Each occurrence is independently selected from O, S, C(O), NR. d and C(R) d )2, R d Each occurrence is independently selected from H, F, Cl, Br, -OH, -CN, -NH2, -NO2, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups and C 1-6 Hydroxyalkyl; B 1a and B 2a Each occurrence is independently selected from N, CH, and C(C) 1-3 alkyl); Each time m11, m21 and m31 appear, they are independently 0, 1, 2, 3 or 4, and 1≤m11+m21+m31≤5; Each occurrence of m41 and m51 is independently 0, 1, 2, 3, or 4, and 1 ≤ m41 + m51 ≤ 5; and Each time m61 and m71 appear, they are independently 0, 1, 2, 3 or 4, and 1≤m61+m71≤5; Preferably: X is selected independently from N each time it appears; and / or W1 is C (=O), W2 is CH2; W1 is CH2, W2 is C (=O); or W1 is (=O), W2 is C (=O); and / or When W4 and W5 form a double bond and W5 and W6 form a single bond, W4 is selected from C, W5 is selected from N, CH, and C(CH3), and W6 is selected from NH, N(CH3), O, CH2, CH(CH3), and C(CH3)2; when W4 and W5 form a single bond and W5 and W6 form a double bond, W4, W5, and W6 are each independently selected from N, CH, and C(CH3); when W4, W5, and W6 are all single bonds, W4 is selected from N, CH, and C(CH3), and W5 and W6 are each independently selected from C(O), NH, N(CH3), O, CH2, CH(CH3), and C(CH3)2; and / or A a A b A c A d A e A f and A h Each time it appears, it is independently selected from CH2, C(C) 1-3 Alkyl)2, CH(C) 1-3 Alkyl), NH, N(C) 1-3 Alkyl), C(O) and -O-; preferably, A a A b A c A d A e A f and A h Each occurrence is independently selected from CH2, C(CH3)2, CH(CH3), NH, N(CH3), and C(O); preferably, A a A b A c A d A e A f and A h Each occurrence is independently selected as CH2; and / or Each occurrence of m11, m21, and m31 is independently 0, 1, 2, or 3, and 1 ≤ m11 + m21 + m31 ≤ 4. Preferably, m11 + m21 + m31 = 1, m11 + m21 + m31 = 2, m11 + m21 + m31 = 3, or m11 + m21 + m31 = 4. Preferably, each occurrence of m11 is independently 0 or 1, each occurrence of m21 is independently 1, and each occurrence of m31 is independently 0 or 1. Preferably, each occurrence of m11 is independently 0, each occurrence of m21 is independently 1, and each occurrence of m31 is independently 0. And / or Each time m41 and m51 appear, they are independently 0, 1, 2, or 3, and 1 ≤ m41 + m51 ≤ 4; preferably, m41 + m51 = 2, m41 + m51 = 3, or m41 + m51 = 4; preferably, each time m41 and m51 appear, they are independently 2; and / or Each occurrence of m61 and m71 is independently 0, 1, 2, or 3, and 1 ≤ m61 + m71 ≤ 4; preferably, m61 + m71 = 2, m61 + m71 = 3, or m61 + m71 = 4; and / or R 2a Each occurrence is independently selected from H, F, Cl, Br, and C. 1-3 Alkyl; preferably, R 2a Each occurrence is independently -CH3 or -CH2CH2F; and / or B 1a and B 2a Each occurrence is independently selected from N, CH, and C(CH3); preferably, B 1a and B 2a Each occurrence is independently selected from N and CH; and / or R 3a R 4a R 3b R 4b R 3c R 4c R 5c R 3d R 4d R 5d R 3e and R 4e Each time it appears, it is independently selected from H, F, Cl, Br, cyano, hydroxyl, C. 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 Halogenated alkoxy groups and C 1-3 Hydroxyalkyl; preferably, R 3a R 4a R 3b R 4b R 3c R 4c R 5c R 3d R 4d R 5d R 3e and R 4e Each occurrence is independently selected from H, F, Cl, Br, -CN, -OH, -CH3, -CH2CH3, -CH(CH3)2, -C(CH3)3, -OCH3, -OCH2CH3, and -OCH(CH3)2; preferably, R 3a R 4a R 3b R 4b R 3c R 4c R 5c R 3d R 4d R 5d R 3e and R 4e Each time it appears, it is independently selected from H, F, Cl, Br, -CN, -OH, -CH3 and -OCH3.

13. The compound according to any one of claims 1-12, wherein, The CLM is selected from the following structures: Indicates the connection site; Preferably, the CLM is selected from the following structures:

14. The compound according to any one of claims 1-13, wherein, The L is -(B) L ) q -; B L Each occurrence is independently selected from single-key and CR. L5 R L6 C(R) L5 )2, O, S, S(O), S(O)2, NR L5 C(O)NR L5 C(O), -C≡C-, cycloalkylene, heterocyclic, bridged cycloalkyl, spirocyclic, aryl, and heteroaryl, wherein the cycloalkylene, heterocyclic, bridged cycloalkyl, spirocyclic, aryl, and heteroaryl groups are optionally represented by 1, 2, 3, 4, 5, or 6 R groups. L5 and / or R L6 Group substitution; preferably, B L Each occurrence is independently selected from single-key and CR. L5 R L6 C(R) L5 )2, O, S, S(O), S(O)2, NR L5 C(O)NR L5 C(O), -C≡C-, 3-15-membered cycloalkylene, 3-15-membered heterocyclic group containing 1, 2, 3, 4 or 5 heteroatoms independently selected from N, O and S, 5-15-membered bridged cycloalkyl group containing 0, 1, 2, 3, 4 or 5 heteroatoms independently selected from N, O and S, 5-15-membered spirocyclic group containing 0, 1, 2, 3, 4 or 5 heteroatoms independently selected from N, O and S, 6-15-membered aryl group and 5-15-membered heteroaryl group containing 1, 2, 3, 4 or 5 heteroatoms independently selected from N, O and S, wherein the 3-15-membered cycloalkylene, 3-15-membered heterocyclic group, 5-15-membered bridged cycloalkyl group, 5-15-membered spirocyclic group, 6-15-membered aryl group and 5-15-membered heteroaryl group are optionally separated by 1, 2, 3, 4, 5 or 6 R L5 and / or R L6 Group substitution; R L5 and R L6 Each occurrence is independently selected from H, halogens, -OH, -NH2, -SH, -C(O)2H, -CN, -CF3, -CHF2, -CH2F, -NO2, -S(O)2, -SF5, -C≡CH, C 1-8 Alkyl, C 1-8 Alkoxy, -SC 1-8 Alkyl, -NH-C 1-8 Alkyl, -N(C) 1-8 Alkyl)2, C 3-11 cycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, 3-11 membered heterocyclic, -OC 3-8 Cycloalkyl, -O-3-11 membered heterocyclic groups, -OC 6-10 Aryl, -O-5-10 heteroaryl, -SC 3-8 cycloalkyl, -NH-C 3-8 cycloalkyl, -N(C) 3-8 cycloalkyl)2, -N(C 3-8 cycloalkyl)(C 1-8 Alkyl), -NH-3-11-membered heterocyclic group, -N(3-11-membered heterocyclic group)2, -N(3-11-membered heterocyclic group) (C 1-8 alkyl), -NH-C 6-10 Aryl, -N(C 6-10 Aryl)(C 1-8 alkyl), -NH-5-10 heteroaryl, -N(5-10 heteroaryl) (C 1-8 Alkyl), -S(O)2P(O)(OC 1-8 Alkyl)(C 1-8 Alkyl), -P(O)(OC 1-8 Alkyl)2、-C≡CC 1-8 Alkyl group, -CH=CH-(C 1-8 alkyl), -C(C 1-8 Alkyl)=CH-(C 1-8 alkyl), -C(C 1-8 Alkyl) = C(C 1-8 Alkyl group 2, -Si(OH)3, -Si(C) 1-8 Alkyl)3、-Si(OH)(C 1-8 Alkyl)2、-C(O)-C 1-8 Alkyl, -C(O)-OC 1-8 Alkyl group, -S(O)2NH-C 1-8 Alkyl group, -S(O)2N(C) 1-8 Alkyl)2、-S(O)NH-C 1-8 Alkyl, -S(O)N(C) 1-8 Alkyl)2、-C(O)NH-C 1-8 Alkyl, -C(O)N(C) 1-8 Alkyl)2, -N(C 1-8 alkyl)C(O)NH(C 1-8 alkyl), -N(C) 1-8 alkyl)C(O)N(C 1-8 alkyl)2、-NHC(O)NH(C 1-8 Alkyl), -NHC(O)N(C 1-8 Alkyl)2, -NHC(O)NH2, -N(C 1-8 alkyl)S(O)2NH(C 1-8 alkyl), -N(C) 1-8 alkyl)S(O)2N(C 1-8 alkyl)2、-NHS(O)2NH(C 1-8 Alkyl), -NHS(O)2N(C 1-8 alkyl)2 and -NHS(O)2NH2, the C 1-8 Alkyl, C 1-8 Alkoxy, C 3-11 Cycloalkyl, 3-11 membered heterocyclic groups, C 6-10 The aryl group and the 5-10 heteroaryl group are each independently and optionally selected from halogen, hydroxyl, cyano, amino, nitro, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, 3-8 membered cycloalkyl, 3-8 membered heterocyclic, 3-8 membered halocycloalkyl, C 1-6 Alkylamino, C 6-10 Aryl, 5-10 heteroaryl, C 6-10 The substituent is one or more of the haloaryl and 5-10 member haloheteroaryl groups; and q is an integer greater than or equal to 1 and less than or equal to 15; Preferably: B L Each occurrence is independently selected from single-key and CR. L5 R L6 C(R) L5 )2, O, S, S(O), S(O)2, NR L5 C(O)NR L5 C(O), -C≡C-, 3-12-membered cycloalkylene, 3-12-membered heterocyclic group containing 1, 2, 3, 4 or 5 heteroatoms independently selected from N, O and S, 5-12-membered bridged cycloalkylene, 5-12-membered spirocyclic group containing 0, 1, 2, 3, 4 or 5 heteroatoms independently selected from N, O and S, 6-12-membered aryl group and 5-12-membered heteroaryl group containing 1, 2, 3, 4 or 5 heteroatoms independently selected from N, O and S, wherein the 3-12-membered cycloalkylene, 3-12-membered heterocyclic group, 5-12-membered bridged cycloalkylene, 5-12-membered spirocyclic group, 6-12-membered aryl group and 5-12-membered heteroaryl group are optionally surrounded by 1, 2, 3, 4, 5 or 6 R L5 and / or R L6 Group substitution; and / or R L5 and R L6 Each occurrence is independently selected from H, halogens, -C(O)2H, -CN, -CF3, -CHF2, -CH2F, -NO2, -S(O)2, C 1-6 Alkyl, -OC 1-6 Alkyl, -C(O)-C 1-6 Alkyl, C 3-6 cycloalkyl and 3-6 membered heterocyclic groups, wherein the C 1-6 Alkyl, C 3-6 The cycloalkyl group and the 3-6 membered heterocyclic group are each independently selected from halogen, hydroxyl, cyano, amino, nitro, C 1-3 Alkyl, C 1-3 Heteroalkyl, C 2-3 alkenyl, C 2-3 alkynyl group, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 3-6 Halogenated cycloalkyl, 3-6-membered halogenated heteroalkyl, C 6-8 Aryl, 5-8 quinone heteroaryl, C 6-8 The substituted group is one or more substituents selected from haloaryl and 5-8 membered haloheteroaryl groups; preferably, R L5 and R L6 Each time it appears, it is independently selected from H, halogen, and C. 1-6 Alkyl, C 1-6 Alkoxy group, -C(O)-C 1-6 Alkyl, -C(O)2H, -CN, -CF3, -CHF2, -CH2F, -NO2, -S(O)2, C 3-6 cycloalkyl and 3-6 membered heterocyclic groups, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 The cycloalkyl group and the 3-6 membered heterocyclic group are each independently selected from halogen, hydroxyl, cyano, nitro, amino, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Hydroxyalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-8 Aryl, 5-8 membered heteroaryl, 3-6 membered halocycloalkyl, C 6-8 Substituted with one or more substituents of haloaryl and 5-8-membered haloheteroaryl; and / or q is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or 13; preferably, q is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; preferably, q is selected from 1, 2, 3, 4, 5, 6, 7 and 8; Preferably: B L Selected from one or more of the following structures: single bond, -O-, -S-, -S(O)-, -S(O)2-, -C≡C-, -CH2-, -C(O)-, -NH-, -N(CH3)-, -N(CH2CH3)-, -C(O)-NH-, -C(O)-N(CH3)-, and Indicates the connection site.

15. The compound according to any one of claims 1-14, wherein, The L is selected from the following structures: Covalent bond, -C(O)-, -C 2-6 -, -C ethynyl 2-6 Iso-ynyl-C 1-6 Alkylene -, -(CH2) j -、-OC 1-6 Alkylene, -O-(CH2) j -、-C(O)-NC 1-6 Alkyl group -, -C(O)-(CH2) j -、-NH-C 1-6 Alkylene-, -NH-(CH2) j -、-(CH2) j -NH-, -NH-(CH2) j -NH-、-NC 1-6 Alkyl-(CH2) j -C(O)-NC 1-6 Alkyl-(CH2) j -、-NH-(CH2) j -C(O)-NH-(CH2) j -、 and j, p, and y are 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; Preferably, the L is selected from single bonds, -C(O)-, and -C. 2-6 -, -C ethynyl 2-6 Iso-ynyl-C 1-6 Alkylene-, -CH2-, -(CH2)2-, -(CH2)3-, -(CH2)4-, -(CH2)5-, -(CH2)6-, -(CH2)7-, -(CH2)8-, -O -CH2-, -O-(CH2)3-, -O-(CH2)4-, -O-(CH2)5-, -O-(CH2)6-, -O-(CH2)7-, -O-(CH2)8-, -NH-C 1-6 Alkylene-, -NH-CH2-, -NH-(CH2)2-, -NH-(CH2)3-, -NH-(CH2)4-, -NH-(CH2)5-, -NH-(CH2)6-, -NH-(CH2)4-C(O), -NH-(CH2)7-, -NH-(CH2)8-, -NH-C 1-6 Alkylene-OC 1-6 Alkylene, -NC 1-6 Alkyl-(CH2) 0-6 -C(O)-NC 1-6 Alkyl-(CH2) 0-6 -、-NH-(CH2) 0- 7-O-(CH2) 0-7 -、-NC 1-6 Alkyl-(CH2) 0-6 -C(O)-NC 1-6 Alkyl-(CH2) 0-6 -, -C(O)-CH2-, -C(O)-(CH2)3-, -C(O)-(CH2)4-, -C(O)-(CH2)5-, -C(O)-(CH2)6-, -NH-C 1-6 Alkylene-, -NH-C 1-6 Alkylene-OC 1-6 Alkylene, -NC 1-4 Alkyl-(CH2) 0-4 -C(O)-NC 1-4 Alkyl-(CH2) 0-4 -C(O)-NH-CH2-,-C(O)-NH-(CH2)2-,-C(O)-NH-(CH2)3-,-C(O)-NH-(CH2)4-,-C(O)-NH-(CH2)5-,-C(O)-NH-(CH2)6-,-C(O)-NH-(CH2)7-,-C(O)-NH-(CH2)8-,-CH2-NH-(CH2)2-NH-,-(CH2)3-NH-,-(CH2)4-NH-,-(CH2)5-NH-,-(CH2)6-NH-,-(CH2)7-NH-,-(CH2)8-NH-,-NH-CH2-NH-,-N H-(CH2)2-NH-,-NH-(CH2)3-NH-,-NH-(CH2)4-NH-,-NH-(CH2)5-NH-,-NH-(CH2)6-NH-,-NH-(CH2)7-NH-,-NH-(CH2)8-NH-,-C(O)-NH-CH2-NH-,-C(O)-NH-(CH2)2-NH-,-C(O)-NH-(CH2)3-NH-,-C(O)-NH-(CH2)4-NH-,-C(O)-NH-(CH2)5-NH-,-C(O)-NH-(CH2)6-NH-,-C(O)-NH-(CH2)7-NH-,-C (O)-NH-(CH2)8-NH-,-(CH2-CH2-O)-CH2-CH2-,-(CH2-CH2-O)2-CH2-CH2-,-(CH2-CH2-O)3-CH2-CH2-,-NH-(CH2-CH2-O)-CH2-CH2-,-NH-(CH2-CH2-O)2-CH2-CH2-,-NH-(CH2-CH2-O)3-CH2-CH2-,-C(O)-NH-(CH2-CH2-O)-CH2-CH2-,-C(O)-NH-(CH2-CH2-O)2-CH2-CH2-,-C(O)-NH-(CH2-CH2- O)3-CH2-CH2-,-(CH2-CH2-O)-CH2-CH2-NH-,-(CH2-CH2-O)2-CH2-CH2-NH-,-(CH2-CH2-O)3-CH2-CH2-NH-,-NH-(CH2-CH2-O)-CH2-CH2-NH-,-NH-(CH2-CH2-O)2-CH2-CH2-NH-,-NH-(CH2-CH2-O)3-CH2-CH2-NH-,-C(O)-NH-(CH2-CH2-O)-CH2-CH2-NH-,-C(O)-NH-(CH2-CH2-O)2-CH2-CH2-NH-,-C(O)-NH-(CH2-CH2-O)3-CH2-CH2-NH-、-CH2-CH2-(O-CH2-CH2)-、-CH2-CH2-(O-CH2-CH2)2-、-CH2-CH2-(O-CH2-CH2)3-、-NH-CH2-CH2-(O-CH2-CH2)-、-NH-CH2-CH2-(O-CH2-CH2)2-、-NH-CH2-CH2-(O-CH2-CH2)3-、-C(O)-NH-CH2-CH2-(O-CH2-CH2)-、-C(O)-NH-CH2-CH2-(O-CH2-CH2)2-、-C(O)-NH-CH2-CH2-(O-CH2-CH2 )3-、-CH2-CH2-(O-CH2-CH2)-NH-、-CH2-CH2-(O-CH2-CH2)2-NH-、-CH2-CH2-(O-CH2-CH2)3-NH-、-NH-CH2-CH2-(O-CH2-CH2)-NH-、-NH-CH2-CH2-(O-CH2-CH2)2-NH-、-NH-CH2-CH2-(O-CH2-CH2)3-NH-、-C(O)-NH-CH2-CH2-(O-CH2-CH2)-NH-、-C(O)-NH-CH2-CH2-(O-CH2-CH2)2-NH-、-C(O)-NH-CH2-CH2-(O-CH2-CH2)3-NH-、 Preferably, L is selected from covalent bonds, -C(O)-, -CH2-, -(CH2)2-, -(CH2)3-, -(CH2)4-, -(CH2)5-, -(CH2)6-, -(CH2)7-, and -OC. 1-6 Alkylene, -O-CH2-, -O-(CH2)3-, -O-(CH2)4-, -O-(CH2)5-, -O-(CH2)6-, -NH-(CH2) 0-7 -C(O)-, -NH-(CH2) 0-7 -O-(CH2) 0-7 -、-NC 1- 4-alkyl-(CH2) 0-4 -C(O)-NC 1-4 Alkyl-(CH2) 0-4 -、C 2-6 -ethynyl, -C(O)-CH2-, -C(O)-(CH2)3-, -C(O)-(CH2)4-, -C(O)-(CH2)5-, -C(O)-(CH2)6-, -NH-C 1-6 Alkylene-, -NH-C 1-6 Alkylene-OC 1-6 Alkylene, -NC 1-4 Alkyl-(CH2) 0-4 -C(O)-NC 1-4 Alkyl-(CH2) 0-4 -, -NH-CH2-, -NH-(CH2)2-, -NH-(CH2)3-, -NH-(CH2)4-, -NH-(CH2)5-, -NH-(CH2)6-, -NH-(CH2)7-, -NH-(CH2)8-, -C(O)-NH-CH2-, -C(O)-NH-(CH2)2-, -C(O)-NH-(CH2)3- , -C(O)-NH-(CH2)4-, -C(O)-NH-(CH2)5-, -C(O)-NH-(CH2)6-, -C(O)-NH-(CH2)7-, -C (O)-NH-(CH2)8-, -CH2-NH-, -(CH2)2-NH-, -(CH2)3-NH-, -(CH2)4-NH-, -(CH2)5-NH-, Preferably, L is selected from single bonds, C 1-8 Alkylene, C 1-8 alkeneoxy, C 1-8 Halogenated alkyl, C 1-8 Iminoalkyl, 16. A compound having the structure shown in formula (I-AA): Or its isomers, isotopic derivatives, polymorphs, prodrugs, or pharmaceutically acceptable salts or solvates thereof, wherein: R L1 It is a single bond or -C(R)2-; R L2 For single bonds, -C(R)2-, -O-, -NR-, -C(O)-C(R)2-, -OC(R)2- or -OC(O)-; R L3 is a single bond, -C(R)2-, -C(O)-, -C(O)-[C(R)2]n RL3 -, -C(O)-[C(R)2]n RL3 -C(O)-, -S(O)2-[C(R)2]n RL3 -, -C(O)-NR- [C(R)2]n RL3 -or-NR-C(O)-[C(R)2]n RL3 - or does not exist; n RL3 It can be 0, 1, 2, 3, or 4; R L4 It can be a single bond, -C(R)2-, -NR-, -S(O)2-NR-, -C(S)-NR-, -C(O)-, or -C(O)-NR-; R P1 Each occurrence is independently selected from H, F, Cl, Br, I, C. 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups and C 1-3 Alkylene-3-6 membered cycloalkyl; R P2 Each time it appears, it is independently selected from H, F, Cl, Br, I, oxo group (=O), C. 1-3 Alkyl, -S(O)2-C 1-3 Alkyl groups and -C(O)-C 1-3 Alkyl, the C 1-3 Alkyl groups are optionally selected from F, Cl, Br, I, hydroxyl, carboxyl, oxo (=O) and C. 1-3 Alkyl groups are substituted with one or more substituents; preferably R P2 Each time it appears, it is independently selected from F, Cl, Br, I, oxo group (=O), C. 1-3 Alkyl, -S(O)2-C 1-3 Alkyl groups and -C(O)-C 1-3 Alkyl, the C 1-3 Alkyl groups are optionally selected from F, Cl, Br, I, hydroxyl, carboxyl, oxo (=O) and C. 1-3 The alkyl group is substituted by one or more substituents; R P3 Each occurrence is independently selected from H, F, Cl, Br, I, -CN, -C(O)H, C 1-3 Alkyl and C 1-3 Alkyl group; preferably R P3 Each occurrence is independently selected from F, Cl, Br, I, -CN, -C(O)H, C 1-3 Alkyl and C 1-3 Alkoxy; R X Each time it appears, it is independently selected from H, F, Cl, Br, I, cyano, C. 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkyl groups and C 1-3 Halogenated alkoxy groups; preferably R X Each time it appears, it is independently selected from F, Cl, Br, I, cyano, and C. 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkyl groups and C 1-3 Halogenated alkoxy groups; R A Selected from H, F, Cl, Br, I, C 1-3 Alkyl, C 1-3 Alkoxy, -CN, -NO2, -NH2, -N(CH3)2, -NH(CH3), 3-6 membered monocyclic cycloalkyl group, 3-6 membered monocyclic heterocyclic group, 5-6 membered monocyclic heteroaryl group, 8-10 membered bicyclic heterocyclic group, 8-10 membered bicyclic heteroaryl group, 3-6 membered monocyclic heterocyclic group-3-6 membered monocyclic cycloalkyl group and 3-6 membered monocyclic heterocyclic group-5-6 membered monocyclic heteroaryl group, wherein the C 1-3 Alkyl, C 1-3 Alkoxy, -NH2, 3-6 membered monocyclic cycloalkyl group, 3-6 membered monocyclic heterocyclic group, 5-6 membered monocyclic heteroaryl group, 8-10 membered bicyclic heterocyclic group, and 8-10 membered bicyclic heteroaryl group are optionally selected from F, Cl, Br, I, cyano, hydroxyl, oxo (=O), C 1-3 Alkyl and C 1-3 The alkoxy group is substituted by one or more substituents; Each time R appears, it is independently H, F, Cl, Br, I, hydroxyl group, or C. 1-3 Alkyl, C 1-3 Alkoxy, saturated or partially unsaturated 3-6 membered cyclic hydrocarbon group, saturated or partially unsaturated 3-6 membered heterocyclic group, phenyl or 5-6 membered heteroaryl group, wherein C 1-3 Alkyl, C 1-3 Alkoxy, cyclic hydrocarbon, heterocyclic, phenyl, or heteroaryl groups are optionally selected from F, Cl, Br, I, cyano, hydroxyl, oxo (=O), C 1-3 Alkyl, C 1-3 Alkoxy and C 1-3 One or more substituents of the hydroxyalkyl group are used for substitution; n2, n3, and n4 are each independently 0, 1, 2, or 3; Cy3 does not exist or is selected from R by choice. P3 Replacement Cy4 is selected from single bonds, arbitrarily assigned to R X Replacement In formula (Ι-AA), Indicates a single or double bond; L is the chemical linker; preferably, L is -(B L ) q -; B L Each occurrence is independently selected from covalent bonds, CR L5 R L6 C(R) L5 )2, O, S, S(O), S(O)2, NR L5 C(O)NR L5 C(O), 3-12 membered cycloalkylene groups, 3-12 membered heterocyclic groups containing 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S, 5-12 membered bridged heterocyclic groups, 5-12 membered bridged heterocyclic groups containing 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S, 5-12 membered spirocyclic groups, 5-12 membered spirocyclic groups containing 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S, 6- A 12-membered arylene and a 5-12-membered heteroarylene containing 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S, wherein the 3-12-membered cycloalkylene, 3-12-membered heterocyclic, 5-12-membered bridged cycloalkyl, 5-12-membered bridged heterocyclic, 5-12-membered spirocyclic, 5-12-membered spirocyclic, 6-12-membered arylene, and 5-12-membered heteroarylene are optionally represented by 1, 2, 3, or 4 heteroatoms independently selected from R. L5 and R L6 Group substitution; preferably, B L Each occurrence is independently selected from covalent bonds, C(R) bonds. L5 )2, O, S, S(O), S(O)2, NR L5 C(O)NR L5 C(O), 3-12 membered cycloalkylene groups, 3-12 membered heterocyclic groups containing 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S, 5-12 membered bridged heterocyclic groups, 5-12 membered bridged heterocyclic groups containing 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S, 5-12 membered spirocyclic groups, 5-12 membered spirocyclic groups containing 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S, The 6-12-membered arylene and the 5-12-membered heteroarylene containing 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S, wherein the 3-12-membered cycloalkylene, 3-12-membered heterocyclic, 5-12-membered bridged cycloalkylene, 5-12-membered bridged heterocyclic, 5-12-membered spirocyclic, 5-12-membered spirocyclic, 6-12-membered arylene, and 5-12-membered heteroarylene are optionally surrounded by 1, 2, 3, or 4 R atoms. L6 replace; R L5 and R L6 Each time it appears, it is independently selected from H, halogen, hydroxyl, cyano, amino, nitro, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -C(O)-C 1-6 Alkyl, C 3-6 cycloalkyl and 3-6 membered heterocyclic groups, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-6 The cycloalkyl group and the 3-6 membered heterocyclic group are each independently and optionally selected from C. 1-3 Alkyl, C 1-3 Heteroalkyl, C 1-3 Alkoxy, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 3-6 Halogenated cycloalkyl, 3-6-membered halogenated heteroalkyl, C 6-8 Aryl, 5-8 quinone heteroaryl, C 6-8 The aryl group is substituted by one or more substituents in the 5-8 membered haloaryl group; q is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; The CLM is selected from the structure shown in the following formula: in, Each time X appears, it is independently selected from N and CR. d Preferably, X is independently selected from N and CH each time it appears; Each time E appears, it is independently selected from O, C(O)NH, C(O)N(C) 1-3 Alkyl), NH and N(C) 1-3 alkyl); When W1 and W2 appear, they are each independently selected from CH2 and C(O), and at least one of W1 and W2 is C(O); R 2a Each occurrence is independently selected from H, F, Cl, Br, C. 1-3 Alkyl and C 1-3 Halogenated alkyl groups; R 3a R 4a R 3b R 4b R 3c R 4c R 5c R 3d R 4d and R 5d Each time it appears, it is independently selected from H, halogen, hydroxyl, cyano, amino, nitro, C. 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups and C 1-6 Hydroxyalkyl; A a A b A c A d and A e Each occurrence is independently selected from O, S, C(O), NR. d and C(R) d )2; R d Each occurrence is independently selected from H, F, Cl, Br, -OH, -CN, -NH2, -NO2, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups and C 1-6 Hydroxyalkyl; B 1a and B 2a Each occurrence is independently selected from N, CH, and C(C) 1-3 alkyl); Each time m11, m21 and m31 appear, they are independently 0, 1, 2, 3 or 4, and 1≤m11+m21+m31≤5; Each occurrence of m41 and m51 is independently 0, 1, 2, 3, or 4, and 1 ≤ m41 + m51 ≤ 5; and Indicates the connection site.

17. The compound of claim 16, wherein, R L1 It is a single bond or -CH2-; preferably, R L1 For single bonds; and / or R L2 It is a single bond, -CH2-, -O-, -NH-, -N(CH3)-, -C(O)-CH2-, -O-CH2-, or -OC(O)-; preferably, R L2 For single bonds; and / or R L3 It is a single bond, -CH2-, -C(O)-, -C(O)CH2-, -C(O)(CH2)2-, -C(O)(CH2)3-, -C(O)CH(CH3)-, -C(O)CH(CH3)CH2-, -C(O)C(CH3)2CH2-, -C(O)CH2C(O)-, -C(O)NHCH2-, -C(O)NH(CH2)2-, -NHC(O)CH2-, -NHC(O)(CH2)2- or -S(O)2CH(CH3)-, or absent; preferably, R L3 It is -C(O)(CH2)2-, or does not exist; preferably, R L3 -C(O)(CH2)2-; and / or R L4 It is a single bond, -CH2-, -NH-, -C(O)-, -N(CH3)-, -S(O)2NH-, -S(O)2N(CH3)-, -C(S)-NH-, -C(S)-N(CH3)-, -C(O)NH-, or -C(O)N(CH3)-; preferably, R L4 It is a single bond, -CH2-, -C(O)-, -NH-, -N(CH3)-, -C(O)NH-, or -C(O)N(CH3)-; preferably, R L4 -C(O)-, -C(O)NH-, or -C(O)N(CH3)-; and / or R P1 Each occurrence is independently selected from H, F, Cl, Br, I, C. 1-3 Alkyl, C 1-3 Alkoxy and C 1-3 Halogenated alkoxy groups; preferably, R P1 Each occurrence is independently selected from H, F, Cl, Br, -CH3, -CH2CH3, -CH(CH3)2, -C(CH3)3, -OCH3, -OCH2CH3, -OCH(CH3)2, and -OC(CH3)3; preferably, R P1 Each occurrence is independently selected from F, Cl, Br, -CH3, -CH2CH3, -CH(CH3)2, -C(CH3)3, -OCH3, -OCH2CH3, -OCH(CH3)2, and -OC(CH3)3; and / or R P2 Each time it appears, it is independently selected from H, F, Cl, Br, I, oxo group (=O), C. 1-3 Alkyl, -S(O)2-C 1-3 Alkyl, -C(O)-C 1-3 Alkyl, -C(O)-C 1-3 Hydroxyalkyl and -C(O)-C 1-3 alkylene-carboxyl group; preferably, R P2 Each occurrence is independently selected from H, F, Cl, Br, -CH3, -CH2CH3, -CH(CH3)2, -C(CH3)3, -C(O)-CH3, -C(O)-CH2CH3, -C(O)-CH2CH2CH3, and -C(O)-CH(CH3)2; preferably, R P2 Each occurrence is independently selected from F, Cl, Br, -CH3, -CH2CH3, -CH(CH3)2, -C(CH3)3, -C(O)-CH3, -C(O)-CH2CH3, -C(O)-CH2CH2CH3 and -C(O)-CH(CH3)2; and / or R P3 Each occurrence is independently selected from H, F, Cl, Br, -CN, -CH3, -CH2CH3, and -CH(CH3)2; preferably, R P3 Each occurrence is independently selected from F, Cl, Br, -CN, -CH3, -CH2CH3, and -CH(CH3)2; and / or R X Each occurrence is independently selected from H, F, Cl, Br, -CN, -CH3, -CH2CH3, -CH(CH3)2, -C(CH3)3, -OCH3, -OCH2CH3, -OCH(CH3)2, -OC(CH3)3, and -OCF3; preferably, R X Each occurrence is independently selected from F, Cl, Br, -CN, -CH3, -CH2CH3, -CH(CH3)2, -C(CH3)3, -OCH3, -OCH2CH3, -OCH(CH3)2, -OC(CH3)3, and -OCF3; and / or n2, n3, and n4 are each independently selected from 0, 1, and 2; and / or Each time R appears, it is independently selected from H, F, Cl, Br, hydroxyl group, -CH3, -CH2CH3, -CH(CH3)2, -C(CH3)3, -OCH3, -OCH2CH3, -OCH(CH3)2, and -OC(CH3)3; each time R appears, it is independently selected from H, F, Cl, Br, hydroxyl group, -CH3, -CH2CH3, -OCH3, and -OCH2CH3; and / or R A Selected from H, -CN, C 1-3 Alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, -N(CH3)2, Preferably, R A Selected from H, -CN, C 1-3 Alkyl group, -N(CH3)2, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkyl, Preferably, R A Selected from H, -N(CH3)2, -CN, -CH3, -CH2CH3, -CH(CH3)2, -OCH3, -OCH2CH3, and -OCH(CH3)2; and / or Cy3 does not exist or is selected from R by choice. P3 Replacement Preferably, Cy3 is absent or selected from any of the R... P3 Replacement and / or Cy4 is selected from single bonds, arbitrarily assigned to R X Replacement Preferably, Cy4 is selected from single bonds, optionally R X Replacement and / or B L Each occurrence is independently selected from single bonds, -O-, -S-, -S(O)-, -S(O)2-, -C≡C-, -CH2-, -C(O)-, -NH-, -N(CH3)-, -N(CH2CH3)-, -C(O)-NH-, -C(O)-N(CH3)-, and / or R L5 and R L6 Each time it appears, it is independently selected from H, halogen, hydroxyl, cyano, amino, nitro, C. 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, -C(O)-C 1-3 Alkyl, C 3-6 cycloalkyl and 3-6 membered heterocyclic groups, wherein the C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 3-6 The cycloalkyl group and the 3-6 membered heterocyclic group are each independently and optionally selected from C. 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-8 The aryl group is substituted with one or more substituents from the 5-8 membered heteroaryl group; preferably, R L5 and R L6 Each time it appears, it is independently selected from H, F, Cl, Br, hydroxyl, cyano, nitro, amino, C. 1-3 Alkyl, C 1-3 Alkoxy, -CF3, -CHF2, -CH2F, C 3-6 cycloalkyl and 3-6 membered heterocyclic groups; and / or q is selected from 1, 2, 3, 4, 5, 6, 7, and 8; preferably, q is selected from 1, 2, 3, 4, 5, and 6; and / or X is independently N each time it appears; and / or W1 is C (=O), and W2 is CH2; W1 is CH2, and W2 is C (=O); or W1 is C (=O), and W2 is C (=O); and / or R 2a Each occurrence is independently selected from H, F, Cl, Br, -CH3, and -CH2CH2F; and / or R 3a R 4a R 3b R 4b R 3c R 4c R 5c R 3d R 4d and R 5d Each occurrence is independently selected from H, F, Cl, Br, -CN, -NO2, -CH3, -CH2CH3, -CH(CH3)2, -OCH3, -OCH2CH3, and -OCH(CH3)2; preferably, R 3a R 4a R 3b R 4b R 3c R 4c R 5c R 3d R 4d and R 5d Each occurrence is independently selected from H, F, Cl, Br, -CN, -NO2, -CH3, and -OCH3; and / or A a A b A c A d and A e Each occurrence is independently CH2; and / or B 1a and B 2a Each occurrence is independently selected from N and CH; and / or Each occurrence of m11, m21, and m31 is independently 0, 1, 2, or 3, and 1 ≤ m11 + m21 + m31 ≤ 4; preferably, m11 + m21 + m31 = 1, m11 + m21 + m31 = 2, m11 + m21 + m31 = 3, or m11 + m21 + m31 = 4; preferably, each occurrence of m11 is independently 0 or 1, each occurrence of m21 is independently 1, and each occurrence of m31 is independently 0 or 1; preferably, each occurrence of m11 is independently 0, each occurrence of m21 is independently 1, and each occurrence of m31 is independently 0; and / or Each time m41 and m51 appear, they are independently 0, 1, 2, or 3, and 1 ≤ m41 + m51 ≤ 4; preferably, m41 + m51 = 2, m41 + m51 = 3, or m41 + m51 = 4; more preferably, each time m41 and m51 appear, they are independently 2.

18. The compound of claim 16 or 17, wherein the compound is selected from the compounds of formula (I-AA-1), formula (I-AA-2), formula (I-AA-3), and formula (I-AA-4): in, X, W1, W2, R L1 R L2 R L3 R L4 R P1 R P2 R P3 R X R A Cy3, Cy4, R 2a R 3a R 4a R 3b R 4b A a A b A c A d A e m11, m21, m31, m41, m51, n2, n3, n4 and L are as defined in claim 16 or 17; Preferably: X is independently N each time it appears; and / or W1 is C (=O), and W2 is CH2; W1 is CH2, and W2 is C (=O); or W1 is C (=O), and W2 is C (=O); and / or R L1 For single bonds; and / or R L2 For single bonds; and / or R L3 Each occurrence is independently -C(O)CH2-, -C(O)(CH2)2-, -C(O)(CH2)3-, or -C(O)CH(CH3)-; preferably, R L3 Each occurrence is independently -C(O)(CH2)2-; and / or R L4 Each occurrence is independently a single bond, -CH2-, -NH-, -N(CH3)-, -C(O), -C(O)NH-, or -C(O)N(CH3)-; preferably, R L4 Each occurrence is independently -C(O)NH-, -C(O) or -C(O)N(CH3)-; and / or R P1 Each occurrence is independently selected from H, F, Cl, Br, -CH3, -CH2CH3, -CH(CH3)2, -C(CH3)3, -OCH3, -OCH2CH3, and -OCH(CH3)2; preferably, R P1 Each occurrence is independently selected from F, Cl, Br, -CH3, -CH2CH3, -CH(CH3)2, -C(CH3)3, -OCH3, -OCH2CH3, and -OCH(CH3)2; preferably, R P1 Each occurrence is independently selected from F, Cl, and Br; and / or R P2 Each occurrence is independently selected from H, F, Cl, Br, -CH3, -CH2CH3, -CH(CH3)2, -C(CH3)3, -C(O)-CH3, -C(O)-CH2CH3, -C(O)-CH2CH2CH3, and -C(O)-CH(CH3)2; preferably, R P2 Each occurrence is independently selected from F, Cl, Br, -CH3, -CH2CH3, -CH(CH3)2, -C(CH3)3, -C(O)-CH3, -C(O)-CH2CH3, -C(O)-CH2CH2CH3, and -C(O)-CH(CH3)2; preferably, R P2 Each occurrence is independently selected from F, Cl, Br, and -CH3; and / or R P3 Each occurrence is independently selected from H, F, Cl, Br, -CN, -CH3, -CH2CH3, and -CH(CH3)2; preferably, R P3 Each occurrence is independently selected from F, Cl, Br, -CN, -CH3, -CH2CH3, and -CH(CH3)2; preferably, R P3 Each occurrence is independently selected from F, Cl, and Br; and / or R X Each occurrence is independently selected from H, F, Cl, Br, -CN, -CH3, -CH2CH3, -CH(CH3)2, -OCH3, -OCH2CH3, and -OCF3; preferably, R X Each occurrence is independently selected from F, Cl, Br, -CN, -CH3, -CH2CH3, -CH(CH3)2, -OCH3, -OCH2CH3, and -OCF3; R X Each occurrence is independently selected from F, Cl, Br, -CN, -CH3, -OCH3, and -OCF3; and / or n2, n3, and n4 are each independently selected from 0, 1, and 2; preferably, n2, n3, and n4 are each independently selected from 0 and 1; and / or R A Selected from H, CN, -CH3, -CH2CH3, -CH(CH3)2, -N(CH3)2, Preferably, R A Selected from H, -N(CH3)2, and -CH3; preferably, R A Selected from H and -CH3; and / or Cy3 is selected from R (random selection). P3 Replacement Preferably, Cy3 is selected from the optional R P3 Replacement and / or Cy4 is selected from single bonds, arbitrarily assigned to R X Replacement Preferably, Cy4 is selected from single bonds and optionally R X Replacement and / or R 2a -CH3; and / or R 3a R 4a R 3b and R 4b Each occurrence is independently selected from H, F, Cl, Br, -CN, -NO2, -OH, -CH3, and -OCH3; and / or A a A b A c A d and A e Each occurrence is independently CH2; and / or Each occurrence of m11, m21, and m31 is independently 0, 1, 2, or 3, and m11+m21+m31 = 1, m11+m21+m31 = 2, or m11+m21+m31 = 3; preferably, each occurrence of m11, m21, and m31 is independently 0, 1, or 2, and m11+m21+m31 = 1; preferably, each occurrence of m11 is independently 0 or 1, each occurrence of m21 is independently 1, and each occurrence of m31 is independently 0 or 1; preferably, each occurrence of m11 is independently 0, each occurrence of m21 is independently 1, and each occurrence of m31 is independently 0; and / or Each time m41 and m51 appear, they are each independently 0, 1, 2, or 3, and m41+m51=3 or m41+m51=4; preferably, each time m41 and m51 appear, they are each independently 0, 1, or 2, and m41+m51=4; more preferably, each time m41 and m51 appear, they are each independently 2.

19. The compound according to any one of claims 1-18, wherein the compound is selected from the group consisting of: Preferably, the compound is selected from the compounds in Table A.

20. A compound selected from the compounds shown in formula (III-A), (III-B) and (III-C): in, Cy3, R A R L3 R L4 R P1 R P2 R P3 n2 and n3 are as defined in any one of claims 1-13; R E The group is selected from H, F, Cl, Br, I, hydroxyl, nitro, cyano, amino, aldehyde, carboxyl, alkyl, alkoxy, hydroxyalkyl, -C(O)-alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, and -arylene-heterocyclic, wherein the alkyl, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, and arylene are optionally substituted by one or more substituents selected from H, F, Cl, Br, I, hydroxyl, nitro, cyano, amino, alkyl, alkoxy, haloalkyl, and haloalkoxy; preferably, R E Selected from H, or C with optional substitution 1-3 Alkyl, phenyl, cyclohexyl, 5-6 membered heteroaryl containing 1 or 2 nitrogen atoms; preferably, R E Selected from H, or optionally substituted methyl groups 、 Phenyl, cyclohexyl, and 6-membered heteroaryl groups containing one nitrogen atom; Q1 is selected from NH, O and S; preferably, Q1 is NH; Cy5 is selected from optionally substituted phenyl groups and 5-6-membered heteroaryl groups containing 1, 2, or 3 heteroatoms each independently selected from nitrogen, oxygen, and sulfur; preferably, Cy5 is selected from optionally substituted phenyl groups. Cy6 is selected from 8- or 9-membered heteroaryl groups containing 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 8-, 9-, or 10-membered heterocyclic groups containing 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; preferably, Cy6 is selected from optionally substituted groups. Cy7 is selected from optional replacements. and R L5 Selected from O, -C(O)-, -OC(O)-, -NH-, -CH2- and -CH2-C(O)-.

21. The compound of claim 20, wherein the compound is selected from the group consisting of: Preferably, the compound is selected from the compounds in Table B.

22. A pharmaceutical composition comprising an effective amount of the compound as claimed in any one of claims 1-21 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

23. Use of the compound of any one of claims 1-21 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 22, in the preparation of a medicament for treating or preventing diseases or conditions mediated by signal transduction and transcription activator 6 (STAT6) levels, or in the preparation of a STAT6 protein degrader, wherein the protein degrader is preferably a targeted protein degradation chimera; preferably, the disease or condition is an autoimmune disease, cancer, inflammatory disease, genetic disease, metabolic disease, cardiovascular disease, or central nervous system disease; preferably, the disease or condition is an autoimmune disease, hematologic malignancy, lung cancer, or autoimmune thyroid disease; preferably, the disease or condition is asthma, atopic dermatitis, chronic obstructive pulmonary disease, leukemia, non-small cell lung cancer (NSCLC), or hyperthyroidism (Graves' disease).

24. The compound of any one of claims 1-21 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 22, for the treatment or prevention of a disease or condition mediated by signal transduction and transcription activator 6 (STAT6) levels; preferably, the disease or condition is an autoimmune disease, cancer, inflammatory disease, genetic disease, metabolic disease, cardiovascular disease, or central nervous system disease; preferably, the disease or condition is an autoimmune disease, hematologic malignancy, lung cancer, or autoimmune thyroid disease; preferably, the disease or condition is asthma, atopic dermatitis, chronic obstructive pulmonary disease, leukemia, non-small cell lung cancer (NSCLC), or hyperthyroidism (Graves' disease).

25. A method for treating or preventing a disease or condition mediated by signal transduction and activating factor 6 (STAT6) levels, comprising administering to a subject in need an effective amount of the compound of any one of claims 1-21 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 22; preferably, the disease or condition is an autoimmune disease, cancer, inflammatory disease, genetic disease, metabolic disease, cardiovascular disease, or central nervous system disease; preferably, the disease or condition is an autoimmune disease, a hematologic malignancy, lung cancer, or an autoimmune thyroid disease; preferably, the disease or condition is asthma, atopic dermatitis, chronic obstructive pulmonary disease, leukemia (e.g., human myeloid monocytic leukemia cells), non-small cell lung cancer (NSCLC), or hyperthyroidism (Graves' disease).

26. A method for degrading or inhibiting STAT6 in a patient or biological sample, the method comprising administering to the patient a compound of any one of claims 1-19 or a pharmaceutical composition of claim 22, or contacting the biological sample with a compound of any one of claims 1-19 or a pharmaceutical composition of claim 23; or STAT6 is brought into contact with the compound of any one of claims 20-21 or a pharmaceutically acceptable salt thereof; preferably, the contact is made in a patient or biological sample.

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