Polyheterocyclic VAV1 degradation molecule derivative and use thereof

Abstract

The present disclosure relates to a VAV1 degradation molecule, a preparation method therefor, a pharmaceutical composition comprising the degradation molecule, and pharmaceutical use thereof. Provided in the present disclosure are a compound derivative represented by general formula (I) or a stereoisomer thereof, or a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof, a preparation method therefor, and use thereof as the VAV1 degradation molecule.

Description

Polycyclic VAV1 degradation molecular derivatives and their uses

[0001] Cross-references

[0002] This application claims priority to Chinese application 202510120064.3, filed January 25, 2025; Chinese application 202510656780.3, filed May 21, 2025; Chinese application 202510996807.3, filed July 18, 2025; and Chinese application 202511205079.6, filed August 27, 2025. The contents of the earlier applications are considered part of this disclosure and are incorporated herein by reference in their entirety. Technical Field

[0003] This disclosure relates to a polycyclic VAV1 degradation molecule derivative, a method for preparing the derivative, a pharmaceutical composition containing the derivative, and its use as a therapeutic agent, particularly as a VAV1 degradation molecule. Background Technology

[0004] The VAV family, comprising guanine nucleotide exchange factors (GEFs) of the Rho family of small GTPases, includes three members: VAV1, VAV2, and VAV3. In cell signal transduction, VAV proteins act as phosphorylation-dependent molecular switches, flexibly switching between inactive (unphosphorylated) and active (tyrosine-phosphorylated) conformations. VAV1 primarily encodes and expresses GEFs in human hematopoietic stem cells, including T cells, B cells, monocytes, natural killer (NK) cells, granulocytes, and dendritic cells, while family members VAV2 and VAV3 are more widely expressed. However, the multi-domain structure of VAV1 is crucial for its activation and function; different domains regulate both GEF-dependent and GEF-independent VAV1 activity and subsequent downstream signal transduction.

[0005] VAV1 has attracted significant attention in the field of autoimmune diseases. Given its crucial role in the activation of immune cells, abnormal regulation of the VAV1 signaling pathway can lead to overactivation of immune cells, causing them to mistakenly attack their own tissues and organs, ultimately resulting in autoimmune diseases such as rheumatoid arthritis and systemic lupus erythematosus. Similarly, VAV1 exhibits aberrant expression or altered activity in various tumors. Overactivation of VAV1 can significantly enhance the proliferation, migration, and invasion of tumor cells, making VAV1 an important target in tumor research. In summary, VAV1 offers new therapeutic opportunities for autoimmune diseases, chronic and acute inflammatory diseases, specific tumors, and neurological disorders. This disclosure aims to develop novel VAV1 degrading agents to provide new therapeutic strategies for autoimmune diseases, chronic and acute inflammatory diseases, specific tumors, and neurological disorders. Summary of the Invention

[0006] This disclosure provides compounds having the structure shown in general formula (I) that exhibit good VAV1 degradation activity, providing new therapeutic opportunities for the treatment of autoimmune diseases, chronic and acute inflammatory diseases, certain tumors, and neurological diseases.

[0007] In a first aspect, this disclosure provides a compound of general formula (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof:

[0008] in:

[0009] Cy1 is selected from C6-C 10 Aryl, 5-12 heteroaryl, C3-C 12 Cycloalkyl, 4-12 membered heterocyclic groups, or 7-14 membered fused cyclic groups;

[0010] Cy2 is selected from non-existent C6-C 10 Aryl, 5-10 heteroaryl, C3-C 12 Cycloalkyl or 4-12 membered heterocyclic groups;

[0011] X1 is selected from CR6 and N;

[0012] X2 is selected from CR7 and N;

[0013] X3 is selected from CR8 and N;

[0014] X4 is selected from CR9 and N;

[0015] R1 is selected from H, halogen, cyano, nitro, amino, hydroxyl, C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, or C3-C6 cycloalkyl;

[0016] R2 and R3 are each independently selected from H, halogen, cyano, nitro, amino, hydroxyl, carboxyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C1-C6 alkylamino, halogenated C1-C6 alkylamino, oxo, C6-C 10 Aryl, 5-10 heteroaryl, C3-C 12 Cycloalkyl, 3-12 membered heterocyclic groups, -OR g -SR g -OC(O)R g -C(O)R g -C(O)OR g -C(O)N(R) x )R y -NR x R y -N(CH3)R g -N(R) x )C(O)R y -N(R) x )C(O)NR x R y -N(R) x )C(O)OR g -C1-C8 alkylene-R g -N(R) x )S(O)NR x R y -N(R) x )S(O)2NR x R y -N(R) x )S(O)2R g -S(O)R g -S(O)2R g -S(O)2NR x R y -S(O)NR x R y or -P(O)R x R y The alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocyclic groups are optionally selected from one or more of R. r Substituents;

[0017] R4 is selected from -O-C3~C8 cycloalkyl, -O-3~8-membered heterocyclic, -O-C1-C2 alkylene-3~8-membered heterocyclic, -NR5-C3~C8 cycloalkyl, -NR5-3~8-membered heterocyclic, wherein the cycloalkyl or heterocyclic group may optionally be further selected from one or more groups selected from R.r Substituents;

[0018] R5 is selected from H, C1-C6 alkyl, halo-C1-C6 alkyl, C3-C8 cycloalkyl or 3-12 membered heterocyclic groups;

[0019] R6, R7, R8, and R9 are each independently selected from H, halogen, cyano, nitro, amino, hydroxyl, carboxyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamino, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, halo-C1-C6 alkylamino, C3-C8 cycloalkyl, or 3-12 membered heterocyclic groups; wherein the alkyl, cycloalkyl, or heterocyclic group is optionally further selected by one or more groups selected from R r Substituents;

[0020] Alternatively, R7 and R8 or R8 and R9, together with the atoms they are attached to, form a 4- to 8-membered ring, wherein the 4- to 8-membered ring contains 0, 1, or 2 heteroatoms selected from N, O, S, and P, and the 4- to 8-membered ring is optionally further surrounded by one or more atoms selected from halogens, C1-C8 alkyl groups, C1-C8 haloalkyl groups, C3-C4 alkyl groups, and C5-C6 alkyl groups. 12 Substituted with cycloalkyl, 3-12 membered heterocyclic, C1-C8 alkoxy, C1-C8 alkylamino, halogen, amino, hydroxyl, oxo, nitro or cyano substituents;

[0021] L1 is selected from: -Y1-Y2-Y3-Y4-Y5-Y6-, Ra;

[0022] Y1, Y2, Y3, Y4, Y5, and Y6 are each independently selected from chemical bonds, -CR 01 R 02 -、-C(R 01 )=C(R 02 )-、-C≡C-、-NR 03 -, -O-, -CO, -S-, -S(O)-, -SO2-, -POR 04 - 3-6 membered heterocyclic groups, C3-C6 cycloalkyl groups, phenyl groups, 5-12 membered heteroaryl groups;

[0023] Ra is selected from -NR 05 -SO2-R 06 -SO2-NR 07 R 08 -NR 05 -C(O)-R 09 -NR 05 -C(O)-NR 010 ;

[0024] R 01 R 02Each is independently selected from H, halogen, hydroxyl, amino, cyano, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, C3-C 12 Cycloalkyl, phenyl, 5-12-membered heteroaryl or 3-12-membered heterocyclic;

[0025] R 03 R 04 R 05 Each group is independently selected from H, halogen, hydroxyl, amino, cyano, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamino, C3-C 12 Cycloalkyl, phenyl, 5-12-membered heteroaryl, or 3-12-membered heterocyclic group, wherein the alkyl, cycloalkyl, phenyl, heteroaryl, or heterocyclic group may optionally be further selected from one or more groups selected from R. r Substituents;

[0026] R 06 Selected from H, C1-C6 alkyl, halo-C1-C6 alkyl, -C1-C6 alkylene-R b ;

[0027] R 07 R 08 Each group is independently selected from H, halogen, hydroxyl, amino, cyano, C1-C6 alkyl, halo-C1-C6 alkyl, C3-C8 cycloalkyl, and 3-12 membered heterocyclic groups;

[0028] R 09 Selected from halogenated C1-C4 alkyl groups, C3-C6 cycloalkyl groups, and 3-12 membered heterocyclic groups;

[0029] R 010 Selected from H, C1-C6 alkyl, halo-C1-C6 alkyl, C3-C8 cycloalkyl, and 3-12 membered heterocyclic groups;

[0030] R b Selected from H, halogen, hydroxyl, amino, cyano, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamino, C3-C 12 Cycloalkyl, phenyl, 5-12-membered heteroaryl, or 3-12-membered heterocyclic group, wherein the alkyl, cycloalkyl, phenyl, heteroaryl, or heterocyclic group is optionally selected from one or more of R. r Substituents;

[0031] Or R 01 and R 02 Together with the carbon atoms they are connected to, they form 3-12 membered rings, which contain 0, 1 or 2 heteroatoms selected from N, O, S and P;

[0032] R r Rg R x R y Each group is independently selected from H, halogen, cyano, nitro, amino, hydroxyl, carboxyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkoxy, halogenated C1-C6 alkoxy, C1-C6 alkylamino, halogenated C1-C6 alkylamino, oxo, C6-C 10 Aryl, 5-10 heteroaryl, C3-C 12 Cycloalkyl, 3-12 membered heterocyclic groups, -OR s -SR s -C1-C8 alkylene-R s -OC(O)R s -C(O)R s -C(O)OR s -C(O)N(R) s )R t -NR s R t -N(CH3)R s -N(R) s )C(O)R t -N(R) s )C(O)NR s R t -N(R) s )C(O)OR t -N(R) s )S(O)NR s R t -N(R) s )S(O)2NR s R t -N(R) s )S(O)2R t -S(O)R s -S(O)2R s -S(O)2NR s R t or -P(O)R s R t The alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocyclic groups are optionally selected from one or more of R. w Substituents;

[0033] R w R s R tEach is independently selected from H, deuterium, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, halogen, cyano, amino, nitro, hydroxyl, oxo, C1-C8 alkoxy, C1-C8 haloalkyl, hydroxyC1-C8 alkyl, aminoC1-C8 alkyl, C1-C8 alkylamino, C1-C8 alkylcarbonyl, C1-C8 alkoxycarbonyl, haloC1-C8 hydroxyalkyl, C1-C8 haloalkylamino, C3-C 12 Cycloalkyl, 3-12 membered heterocyclic groups, carboxyl groups, amides, C6-C 10 Aryl or 5-12 heteroaryl groups;

[0034] o can be selected from 0, 1, 2, 3, or 4;

[0035] p is selected from 0, 1, 2, 3 or 4;

[0036] m is selected from 0, 1, 2, 3 or 4;

[0037] n is selected from 0, 1, or 2;

[0038] When X1 is selected from CR6, X2 is selected from CR7, X3 is selected from CR8, and X4 is selected from CR9, Cy1 is selected from 5-membered heteroaryl, 7-8-membered heteroaryl, 11-12-membered heteroaryl, and C3-C 12 Cycloalkyl, 4-12 membered heterocyclic groups, *6-membered fused-to-7-membered fused-to-cyclic groups, *6-membered fused-to-8-membered fused-to-cyclic groups, *5-membered fused-to-6-membered fused-to-cyclic groups, *5-membered fused-to-7-membered fused-to-cyclic groups; the * indicates a combination with... connect;

[0039] Alternatively, when X1 is selected from CR6, X2 is selected from CR7, X3 is selected from CR8, and X4 is selected from CR9, Cy2 is selected when it exists, and p is selected from 1 and 2;

[0040] Alternatively, when X1 is selected from CR6, X2 is selected from CR7, X3 is selected from CR8, X4 is selected from CR9, Cy2 is selected when it does not exist, and L1 is selected from Ra.

[0041] In a second aspect, this disclosure provides a pharmaceutical composition comprising an effective dose of a compound of the first aspect of this disclosure or a stereoisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient, or combination thereof.

[0042] Thirdly, this disclosure provides the use of the compounds of the first aspect of this disclosure or the pharmaceutical compositions of the second aspect of this disclosure in the preparation of medicaments for treating diseases mediated by VAV1.

[0043] Fourthly, this disclosure provides the use of the compounds of the first aspect of this disclosure or the pharmaceutical compositions of the second aspect of this disclosure in the preparation of medicaments for treating autoimmune diseases, malignant tumors, chronic and acute inflammation, nervous system diseases, and transplant-related diseases.

[0044] The above description is only an overview of the technical solution of this application. In order to better understand the technical means of this application and to implement it in accordance with the contents of the specification, and to make the above and other objects, features and advantages of this application more obvious and understandable, the following are specific embodiments of this application. Detailed Implementation

[0045] The following embodiments are only used to illustrate the technical solutions of this application more clearly, and are therefore only examples and should not be used to limit the scope of protection of this application.

[0046] compound

[0047] In a first aspect, this disclosure provides a compound of general formula (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof:

[0048] in:

[0049] Cy1 is selected from C6-C 10 Aryl, 5-12 heteroaryl, C3-C 12 Cycloalkyl, 4-12 membered heterocyclic groups, or 7-14 membered fused cyclic groups;

[0050] Cy2 is selected from non-existent C6-C 10 Aryl, 5-10 heteroaryl, C3-C 12 Cycloalkyl or 4-12 membered heterocyclic groups;

[0051] X1 is selected from CR6 and N;

[0052] X2 is selected from CR7 and N;

[0053] X3 is selected from CR8 and N;

[0054] X4 is selected from CR9 and N;

[0055] R1 is selected from H, halogen, cyano, nitro, amino, hydroxyl, C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, or C3-C6 cycloalkyl;

[0056] R2 and R3 are each independently selected from H, halogen, cyano, nitro, amino, hydroxyl, carboxyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C1-C6 alkylamino, halogenated C1-C6 alkylamino, oxo, C6-C 10 Aryl, 5-10 heteroaryl, C3-C 12 Cycloalkyl, 3-12 membered heterocyclic groups, -OR g -SR g -OC(O)R g -C(O)R g -C(O)OR g -C(O)N(R) x )R y -NR x R y -N(CH3)R g -N(R) x )C(O)R y -N(R) x )C(O)NR x R y -N(R) x )C(O)OR g -C1-C8 alkylene-R g -N(R) x )S(O)NR x R y -N(R) x )S(O)2NR x R y -N(R) x )S(O)2R g -S(O)R g -S(O)2R g -S(O)2NR x R y -S(O)NR x R y or -P(O)R x R y The alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocyclic groups are optionally selected from one or more of R. r Substituents;

[0057] R4 is selected from -O-C3~C8 cycloalkyl, -O-3~8-membered heterocyclic, -O-C1-C2 alkylene-3~8-membered heterocyclic, -NR5-C3~C8 cycloalkyl, -NR5-3~8-membered heterocyclic, wherein the cycloalkyl or heterocyclic group may optionally be further selected from one or more groups selected from R. r Substituents;

[0058] R5 is selected from H, C1-C6 alkyl, halo-C1-C6 alkyl, C3-C8 cycloalkyl or 3-12 membered heterocyclic groups;

[0059] R6, R7, R8, and R9 are each independently selected from H, halogen, cyano, nitro, amino, hydroxyl, carboxyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamino, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, halo-C1-C6 alkylamino, C3-C8 cycloalkyl, or 3-12 membered heterocyclic groups; wherein the alkyl, cycloalkyl, or heterocyclic group is optionally further selected by one or more groups selected from R r Substituents;

[0060] Alternatively, R7 and R8 or R8 and R9, together with the atoms they are attached to, form a 4- to 8-membered ring, wherein the 4- to 8-membered ring contains 0, 1, or 2 heteroatoms selected from N, O, S, and P, and the 4- to 8-membered ring is optionally further surrounded by one or more atoms selected from halogens, C1-C8 alkyl groups, C1-C8 haloalkyl groups, C3-C4 alkyl groups, and C5-C6 alkyl groups. 12 Substituted with cycloalkyl, 3-12 membered heterocyclic, C1-C8 alkoxy, C1-C8 alkylamino, halogen, amino, hydroxyl, oxo, nitro or cyano substituents;

[0061] L1 is selected from: -Y1-Y2-Y3-Y4-Y5-Y6-, Ra;

[0062] Y1, Y2, Y3, Y4, Y5, and Y6 are each independently selected from chemical bonds, -CR 01 R 02 -、-C(R 01 )=C(R 02 )-、-C≡C-、-NR 03 -, -O-, -CO, -S-, -S(O)-, -SO2-, -POR 04 - 3-6 membered heterocyclic groups, C3-C6 cycloalkyl groups, phenyl groups, 5-12 membered heteroaryl groups;

[0063] Ra is selected from -NR 05 -SO2-R 06 -SO2-NR 07 R 08 -NR 05 -C(O)-R 09 -NR 05 -C(O)-NR 010 ;

[0064] R 01 R 02Each is independently selected from H, halogen, hydroxyl, amino, cyano, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, C3-C 12 Cycloalkyl, phenyl, 5-12-membered heteroaryl or 3-12-membered heterocyclic;

[0065] R 03 R 04 R 05 Each group is independently selected from H, halogen, hydroxyl, amino, cyano, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamino, C3-C 12 Cycloalkyl, phenyl, 5-12-membered heteroaryl, or 3-12-membered heterocyclic group, wherein the alkyl, cycloalkyl, phenyl, heteroaryl, or heterocyclic group may optionally be further selected from one or more groups selected from R. r Substituents;

[0066] R 06 Selected from H, C1-C6 alkyl, halo-C1-C6 alkyl, -C1-C6 alkylene-R b ;

[0067] R 07 R 08 Each group is independently selected from H, halogen, hydroxyl, amino, cyano, C1-C6 alkyl, halo-C1-C6 alkyl, C3-C8 cycloalkyl, and 3-12 membered heterocyclic groups;

[0068] R 09 Selected from halogenated C1-C4 alkyl groups, C3-C6 cycloalkyl groups, and 3-12 membered heterocyclic groups;

[0069] R 010 Selected from H, C1-C6 alkyl, halo-C1-C6 alkyl, C3-C8 cycloalkyl, and 3-12 membered heterocyclic groups;

[0070] R b Selected from H, halogen, hydroxyl, amino, cyano, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamino, C3-C 12 Cycloalkyl, phenyl, 5-12-membered heteroaryl, or 3-12-membered heterocyclic group, wherein the alkyl, cycloalkyl, phenyl, heteroaryl, or heterocyclic group is optionally selected from one or more of R. r Substituents;

[0071] Or R 01 and R 02 Together with the carbon atoms they are connected to, they form 3-12 membered rings, which contain 0, 1 or 2 heteroatoms selected from N, O, S and P;

[0072] R r Rg R x R y Each group is independently selected from H, halogen, cyano, nitro, amino, hydroxyl, carboxyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkoxy, halogenated C1-C6 alkoxy, C1-C6 alkylamino, halogenated C1-C6 alkylamino, oxo, C6-C 10 Aryl, 5-10 heteroaryl, C3-C 12 Cycloalkyl, 3-12 membered heterocyclic groups, -OR s -SR s -C1-C8 alkylene-R s -OC(O)R s -C(O)R s -C(O)OR s -C(O)N(R) s )R t -NR s R t -N(CH3)R s -N(R) s )C(O)R t -N(R) s )C(O)NR s R t -N(R) s )C(O)OR t -N(R) s )S(O)NR s R t -N(R) s )S(O)2NR s R t -N(R) s )S(O)2R t -S(O)R s -S(O)2R s -S(O)2NR s R t or -P(O)R s R t The alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocyclic groups are optionally selected from one or more of R. w Substituents;

[0073] R w R s R tEach is independently selected from H, deuterium, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, halogen, cyano, amino, nitro, hydroxyl, oxo, C1-C8 alkoxy, C1-C8 haloalkyl, hydroxyC1-C8 alkyl, aminoC1-C8 alkyl, C1-C8 alkylamino, C1-C8 alkylcarbonyl, C1-C8 alkoxycarbonyl, haloC1-C8 hydroxyalkyl, C1-C8 haloalkylamino, C3-C 12 Cycloalkyl, 3-12 membered heterocyclic groups, carboxyl groups, amides, C6-C 10 Aryl or 5-12 heteroaryl groups;

[0074] o can be selected from 0, 1, 2, 3, or 4;

[0075] p is selected from 0, 1, 2, 3 or 4;

[0076] m is selected from 0, 1, 2, 3 or 4;

[0077] n is selected from 0, 1, or 2;

[0078] When X1 is selected from CR6, X2 is selected from CR7, X3 is selected from CR8, and X4 is selected from CR9, Cy1 is selected from 5-membered heteroaryl, 7-8-membered heteroaryl, 11-12-membered heteroaryl, and C3-C 12 Cycloalkyl, 4-12 membered heterocyclic groups, *6-membered fused-to-7-membered fused-to-cyclic groups, *6-membered fused-to-8-membered fused-to-cyclic groups, *5-membered fused-to-6-membered fused-to-cyclic groups, *5-membered fused-to-7-membered fused-to-cyclic groups; the * indicates a combination with... connect;

[0079] Alternatively, when X1 is selected from CR6, X2 is selected from CR7, X3 is selected from CR8, and X4 is selected from CR9, Cy2 is selected when it exists, and p is selected from 1 and 2;

[0080] Alternatively, when X1 is selected from CR6, X2 is selected from CR7, X3 is selected from CR8, X4 is selected from CR9, Cy2 is selected when it does not exist, and L1 is selected from Ra.

[0081] In some embodiments, it is a compound of general formula (II) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof:

[0082] in:

[0083] Cy1 is selected from phenyl, 5-12 heteroaryl, C3-C 12 Cycloalkyl, 4-12 membered heterocyclic groups, or 9-14 membered fused cyclic groups;

[0084] Cy2 is selected from non-existent C6-C 10 Aryl, 5-10 heteroaryl, C3-C 12 Cycloalkyl or 4-12 membered heterocyclic groups;

[0085] X1 is selected from CR6 and N;

[0086] X2 is selected from CR7 and N;

[0087] X3 is selected from CR8 and N;

[0088] X4 is selected from CR9 and N;

[0089] R2 and R3 are each independently selected from H, halogen, cyano, nitro, amino, hydroxyl, carboxyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C1-C6 alkylamino, halogenated C1-C6 alkylamino, oxo, C6-C 10 Aryl, 5-10 heteroaryl, C3-C 12 Cycloalkyl, 3-12 membered heterocyclic groups, -OR g -SR g -OC(O)R g -C(O)R g -C(O)OR g -C(O)N(R) x )R y -NR x R y -N(CH3)R g -N(R) x )C(O)R y -N(R) x )C(O)NR x R y -N(R) x )C(O)OR g -C1-C8 alkylene-R g -N(R) x )S(O)NR x R y -N(R) x )S(O)2NR x R y -N(R) x )S(O)2R g -S(O)R g -S(O)2R g -S(O)2NR x R y -S(O)NR x R y or -P(O)R x R yThe alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocyclic groups may optionally be substituted by one or more substituents selected from Rr.

[0090] R4 is selected from -O-C3~C8 cycloalkyl, -O-3~8-membered heterocyclic, -O-C1-C2 alkylene-3~8-membered heterocyclic, -NR5-C3~C8 cycloalkyl, -NR5-3~8-membered heterocyclic, wherein the cycloalkyl or heterocyclic group may optionally be further selected from one or more groups selected from R. r Substituents;

[0091] R5 is selected from H, C1-C6 alkyl, halo-C1-C6 alkyl, C3-C8 cycloalkyl or 3-12 membered heterocyclic groups;

[0092] R6, R7, R8, and R9 are each independently selected from H, halogen, cyano, nitro, amino, hydroxyl, carboxyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamino, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, halo-C1-C6 alkylamino, C3-C8 cycloalkyl, or 3-12 membered heterocyclic groups; wherein the alkyl, cycloalkyl, or heterocyclic group is optionally selected by one or more groups from R r Substituents;

[0093] Alternatively, R7 and R8 or R8 and R9, together with the atoms they are attached to, form a 4- to 8-membered ring, wherein the 4- to 8-membered ring contains 0, 1, or 2 heteroatoms selected from N, O, S, and P, and the 4- to 8-membered ring is optionally further surrounded by one or more atoms selected from halogens, C1-C8 alkyl groups, C1-C8 haloalkyl groups, C3-C4 alkyl groups, and C5-C6 alkyl groups. 12 Substituted with cycloalkyl, 3-12 membered heterocyclic, C1-C8 alkoxy, C1-C8 alkylamino, halogen, amino, hydroxyl, oxo, nitro or cyano substituents;

[0094] L1 is selected from: -Y1-Y2-Y3-Y4-Y5-Y6-, Ra;

[0095] Y1, Y2, Y3, Y4, Y5, and Y6 are each independently selected from chemical bonds, -CR 01 R 02 -、-C(R 01 )=C(R 02 )-、-c≡c-、-NR 03 -, -O-, -CO, -S-, -S(O)-, -SO2-, -POR 04 - 3-6 membered heterocyclic groups, C3-C6 cycloalkyl groups, phenyl groups, 5-12 membered heteroaryl groups;

[0096] Ra is selected from -NR 05 -SO2-R 06 -SO2-NR07 R 08 -NR 05 -C(O)-R 09 -NR 05 -C(O)-NR 010 ;

[0097] R 01 R 02 Each is independently selected from H, halogen, hydroxyl, amino, cyano, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, C3-C 12 Cycloalkyl, phenyl, 5-12-membered heteroaryl or 3-12-membered heterocyclic;

[0098] R 03 R 04 R 05 Each group is independently selected from H, halogen, hydroxyl, amino, cyano, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamino, C3-C 12 Cycloalkyl, phenyl, 5-12-membered heteroaryl, or 3-12-membered heterocyclic group, wherein the alkyl, cycloalkyl, phenyl, heteroaryl, or heterocyclic group may optionally be further selected from one or more groups selected from R. r Substituents;

[0099] R 06 Selected from H, C1-C6 alkyl, halo-C1-C6 alkyl, -C1-C6 alkylene-R b ;

[0100] R 07 R 08 Each group is independently selected from H, halogen, hydroxyl, amino, cyano, C1-C6 alkyl, halo-C1-C6 alkyl, C3-C8 cycloalkyl, and 3-12 membered heterocyclic groups;

[0101] R 09 Selected from halogenated C1-C4 alkyl groups, C3-C6 cycloalkyl groups, and 3-12 membered heterocyclic groups;

[0102] R 010 Selected from H, C1-C6 alkyl, halo-C1-C6 alkyl, C3-C8 cycloalkyl, and 3-12 membered heterocyclic groups;

[0103] R b Selected from H, halogen, hydroxyl, amino, cyano, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamino, C3-C 12 Cycloalkyl, phenyl, 5-12-membered heteroaryl, or 3-12-membered heterocyclic group, wherein the alkyl, cycloalkyl, phenyl, heteroaryl, or 3-12-membered heterocyclic group is optionally selected from one or more groups selected from R. rSubstituents;

[0104] Or R 01 and R 02 Together with the carbon atoms they are connected to, they form 3-12 membered rings, which contain 0, 1 or 2 heteroatoms selected from N, O, S and P;

[0105] R r R g R x R y Each group is independently selected from H, halogen, cyano, nitro, amino, hydroxyl, carboxyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkoxy, halogenated C1-C6 alkoxy, C1-C6 alkylamino, halogenated C1-C6 alkylamino, oxo, C6-C 10 Aryl, 5-10 heteroaryl, C3-C 12 Cycloalkyl, 3-12 membered heterocyclic groups, -OR s -SR s -C1-C8 alkylene-R s -OC(O)R s -C(O)R s -C(O)OR s -C(O)N(R) s )R t -NR s R t -N(CH3)R s -N(R) s )C(O)R t -N(R) s )C(O)NR s R t -N(R) s )C(O)OR t -N(R) s )S(O)NR s R t -N(R) s )S(O)2NR s R t -N(R) s )S(O)2R t -S(O)R s -S(O)2R s -S(O)2NR s R t or -P(O)R s R t The alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocyclic groups are optionally selected from one or more of R. wSubstituents;

[0106] R w R s R t Each is independently selected from H, deuterium, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, halogen, cyano, amino, nitro, hydroxyl, oxo, C1-C8 alkoxy, C1-C8 haloalkyl, hydroxyC1-C8 alkyl, aminoC1-C8 alkyl, C1-C8 alkylamino, C1-C8 alkylcarbonyl, C1-C8 alkoxycarbonyl, haloC1-C8 hydroxyalkyl, C1-C8 haloalkylamino, C3-C 12 Cycloalkyl, 3-12 membered heterocyclic groups, carboxyl groups, amides, C6-C 10 Aryl or 5-12 heteroaryl groups;

[0107] o can be selected from 0, 1, 2, 3, or 4;

[0108] p is selected from 0, 1, 2, 3 or 4;

[0109] m is selected from 0, 1, 2, 3 or 4;

[0110] When X1 is selected from CR6, X2 is selected from CR7, X3 is selected from CR8, and X4 is selected from CR9, Cy1 is selected from a 5-membered heteroaryl group, *6-membered 7-membered fused cycloyl group, *6-membered 8-membered fused cycloyl group, *5-membered 6-membered fused cycloyl group, or *5-membered 7-membered fused cycloyl group; the * indicates a combination with... connect;

[0111] Alternatively, when X1 is selected from CR6, X2 is selected from CR7, X3 is selected from CR8, and X4 is selected from CR9, Cy2 is selected when it exists, and p is selected from 1 and 2;

[0112] Alternatively, when X1 is selected from CR6, X2 is selected from CR7, X3 is selected from CR8, X4 is selected from CR9, Cy2 is selected when it does not exist, and L1 is selected from Ra.

[0113] In some embodiments, it is a compound of general formula (VIIa-VIIb) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof:

[0114] Ra is selected from -NR 05 -SO2-R 06 -SO2-NR 07 R 08 -NR 05 -C(O)-R 09 -NR 05 -C(O)-NR 010 ;

[0115] R05 Selected from H, halogen, hydroxyl, amino, cyano, C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkoxy, and C1-C6 alkylamino;

[0116] R 06 Selected from C1-C4 alkyl and halo-C1-C4 alkyl;

[0117] R 07 Selected from H, C1-C4 alkyl, and C3-C6 cycloalkyl;

[0118] R 08 Selected from H, C1-C4 alkyl, and C3-C6 cycloalkyl;

[0119] R 09 Selected from halogenated C1-C4 alkyl groups, C3-C6 cycloalkyl groups, and 3-12 membered heterocyclic groups;

[0120] R 010 Selected from H, C1-C4 alkyl groups;

[0121] L1 is selected from chemical bonds, methylene, -O-, -NH-,

[0122] Cy2 is selected from a 6-membered heteroaryl group;

[0123] R3 is selected from H, halogen, cyano, amino, oxo, C1-C4 alkyl, C1-C4 alkoxy, halogenated C1-C4 alkyl, C3-C6 cycloalkyl, 4-6 membered heterocyclic, or -C1-C3 alkylene-R. 3a C2-C4 alkenyl, C2-C4 alkynyl; the alkyl, cycloalkyl, heterocyclic, alkenyl, and alkynyl groups may be further substituted by one or more substituents selected from C1-C4 alkyl, halo-C1-C4 alkyl, halogen, cyano, C3-C6 cycloalkyl, and 4-6 membered heterocyclic groups;

[0124] R 3a The group is selected from H, halogen, cyano, amino, hydroxyl, oxo, C1-C4 alkyl, C1-C4 alkoxy, halo-C1-C4 alkyl, C3-C6 cycloalkyl, or 4-6 membered heterocyclic group; wherein the alkyl, cycloalkyl, or heterocyclic group is optionally further substituted by one or more substituents selected from C1-C4 alkyl, halo-C1-C4 alkyl, halogen, cyano, C3-C6 cycloalkyl, or 4-6 membered heterocyclic group;

[0125] R4 is selected from -O-C3-C6 cycloalkyl, -O-4-6 heterocyclic, -O-C1-C2 alkylene-4-6 heterocyclic, -NH-C3-C6 cycloalkyl, -NH-4-6 heterocyclic; wherein the cycloalkyl or heterocyclic group is optionally further substituted by one or more substituents selected from C1-C4 alkyl, halogen, cyano, halogenated C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl or 4-6 heterocyclic.

[0126] In some implementations, Cy2 is selected from...

[0127] Connect to R4, Connected to L1.

[0128] In some implementations, Cy2 is selected from...

[0129] In some implementations, R4 is selected from...

[0130] In some implementations... Selected from

[0131] In some embodiments, it is a compound of general formula (VIII) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof:

[0132] CyB is selected from 7- to 8-membered heterocycles, wherein the heterocycle contains one or two heteroatoms selected from N or O;

[0133] Selected from

[0134] L1 is selected from chemical bonds, methylene, -O- or -NH-;

[0135] Selected from non-existent

[0136] W1, W2, W3, W4, and W5 are each independently selected from: CH, N, or CO;

[0137] j is selected from 1, 2, 3, or 4;

[0138] R3 is selected from H, oxo, halogen, cyano, C1-C4 alkyl or halo-C1-C4 alkyl;

[0139] R4 is selected from -O-C3 to C6 cycloalkyl, -O-4 to 6-membered heterocyclic, -NH-C3 to C6 cycloalkyl, or -NH-4 to 6-membered heterocyclic; the cycloalkyl or heterocyclic group may optionally be further substituted by one or more substituents selected from halogen, C1-C4 alkyl, C1-C4 alkoxy, or halogenated C1-C4 alkyl.

[0140] In some implementations... Selected from non-existent

[0141] In some implementations... Selected from

[0142] In some embodiments, it is a compound represented by general formulas (IXa-IXb) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof:

[0143] in:

[0144] T1 is selected from CR 10 N;

[0145] T2 is selected from CR 11 N;

[0146] T3 is selected from CR 12 N;

[0147] T4 is selected from CR 13 N;

[0148] R 10 R 11 R 12 R 13 Each group is independently selected from H, halogen, cyano, nitro, amino, hydroxyl, carboxyl, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylamino, halo-C1-C3 alkyl, halo-C1-C3 alkoxy, halo-C1-C3 alkylamino, C3-C6 cycloalkyl, 4-6 membered heterocyclic, C2-C4 alkenyl, C2-C4 alkynyl, halo-C2-C4 alkenyl, or halo-C2-C4 alkynyl.

[0149] R2 is selected from H, halogen, C1-C3 alkyl, or halo-C1-C3 alkyl;

[0150] R3 is selected from H, halogen, cyano, amino, oxo, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 alkoxy, halogenated C1-C4 alkyl, C3-C6 cycloalkyl, 4-6 membered heterocyclic, -C1-C3 alkylene-R 3aThe alkyl, cycloalkyl, heterocyclic, alkenyl, and alkynyl groups may be further substituted by one or more substituents selected from C1-C4 alkyl, halo-C1-C4 alkyl, halogen, cyano, C3-C6 cycloalkyl, and 4-6 membered heterocyclic groups;

[0151] R 3a The group is selected from H, halogen, cyano, amino, hydroxyl, oxo, C1-C4 alkyl, C1-C4 alkoxy, halo-C1-C4 alkyl, C3-C6 cycloalkyl, and 4-6 membered heterocyclic groups, wherein the alkyl, cycloalkyl, and heterocyclic groups are optionally further substituted by one or more substituents selected from C1-C4 alkyl, halo-C1-C4 alkyl, halogen, cyano, C3-C6 cycloalkyl, and 4-6 membered heterocyclic groups;

[0152] R 4a The alkyl group is selected from C3-C6 cycloalkyl, 4-6 membered heterocyclic group, -C1-C2 alkylene-4-6 membered heterocyclic group, and the cycloalkyl or heterocyclic group is optionally further substituted by one or more substituents selected from C1-C4 alkyl, halo-C1-C4 alkyl, halogen, cyano, C1-C4 alkoxy, C3-C6 cycloalkyl, 4-6 membered heterocyclic group;

[0153] m is selected from 0, 1, or 2;

[0154] o can be selected from 0, 1, or 2.

[0155] In some implementations, wherein Selected from

[0156] In some embodiments, it is a compound of general formula (X) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof:

[0157] in:

[0158] R2 is selected from H or halogen;

[0159] R3 is selected from H, halogen, cyano, C1-C4 alkyl, ethynyl, trifluoromethyl, difluoromethyl, cyclopropyl, or

[0160] T3 is selected from CH or N;

[0161] R 4a Selected from C3-C6 cycloalkyl or 4-6 membered heterocyclic groups.

[0162] In some embodiments, R2 is selected from H or fluorine;

[0163] R3 is selected from H, chlorine, fluorine, cyano, methyl, isopropyl, trifluoromethyl, difluoromethyl, cyclopropyl, or

[0164] R 4a Selected from C3-C6 cycloalkyl groups,

[0165] In some embodiments, the compound is selected from:

[0166] Or its stereoisomers, or mixtures thereof, or pharmaceutically acceptable salts thereof.

[0167] In this disclosure, if there is a difference between the drawn structure and the given name of the structure, the drawn structure will be given greater weight.

[0168] It should be noted that when specific compounds are mentioned in this disclosure, the corresponding number below the compound (such as 50 in the table above) corresponds to the corresponding compound; when the compound number is mentioned in other parts of this document, it refers to the compound, such as "compound 50" which refers to the compound structure corresponding to number 50.

[0169] In this disclosure, when substituents with the same letter appear at different positions within the same group, the substituents at these different positions are independent of each other and can be the same or different. For example, in "-N(Rx)S(O)NRxRy", the Rx on the two N atoms before and after can be the same or different. Another example is the use of "R" in the textual descriptions of different substituents. r "They are independent of each other; they can be the same or different. The above explanation also applies to other cases where they are the same."

[0170] Pharmaceutical Composition

[0171] In a second aspect, this disclosure provides a pharmaceutical composition comprising an effective dose of a compound of the first aspect of this disclosure or a stereoisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient, or combination thereof.

[0172] Uses and methods

[0173] Thirdly, this disclosure provides the use of the compounds of the first aspect of this disclosure or the pharmaceutical compositions of the second aspect of this disclosure in the preparation of medicaments for treating diseases mediated by VAV1.

[0174] In some implementations, the VAV1-mediated related diseases are autoimmune diseases, malignant tumors, chronic and acute inflammation, neurological diseases, and transplant-related diseases.

[0175] Fourthly, this disclosure provides the use of the compounds of the first aspect of this disclosure or the pharmaceutical compositions of the second aspect of this disclosure in the preparation of medicaments for treating autoimmune diseases, malignant tumors, chronic and acute inflammation, nervous system diseases, and transplant-related diseases.

[0176] This disclosure aims to develop novel VAV1 degradation molecules to provide new therapeutic strategies for the treatment of autoimmune diseases, chronic and acute inflammatory diseases, malignancies, and neurological diseases.

[0177] On the one hand, this disclosure is characterized by methods for treating conditions caused by or related to immunopathology in subjects in need, including administering to the subject a therapeutically effective amount of the compound described herein or a pharmaceutically acceptable salt thereof.

[0178] In some implementations, the condition is an autoimmune disease. In some implementations, the autoimmune disease is selected from multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus, Hashimoto's thyroiditis, myasthenia gravis, type I or type II diabetes and related diseases, vasculitis, pernicious anemia, Sjögren's syndrome, uveitis, psoriasis, Graves' ophthalmopathy, alopecia areata, allergic diseases (e.g., allergic asthma, atopic dermatitis, allergic rhinitis / conjunctivitis, allergic contact dermatitis), optional inflammatory diseases with potential adverse reactions (e.g., inflammatory bowel disease, Crohn's disease) or ulcerative colitis, endogenous asthma, inflammatory lung injury, inflammatory liver injury, inflammatory glomerular injury), atherosclerosis, osteoarthritis, irritant contact dermatitis and further eczematous dermatitis, seborrheic dermatitis, skin manifestations of immune-mediated diseases, inflammatory eye diseases, keratoconjunctivitis, myocarditis, or hepatitis.

[0179] In some embodiments, the disease is a hematologic malignancy, optionally wherein the disease is a T-cell or B-cell malignancy. In some embodiments, the disease is selected from the group consisting of: leukemia, lymphoma, T-cell prolymphocytic leukemia, T-cell granulocytic lymphocytic leukemia, aggressive NK-cell leukemia, hairy cell leukemia, nasal and nasal-type NK / T-cell lymphoma, mycosis fungoides and Cezari syndrome, angioimmunoblastic T-cell lymphoma, unspecified peripheral T-cell lymphoma, adult T-cell leukemia / lymphoma (HTLV1+), anaplastic large cell lymphoma. Primary cutaneous CD30-positive T-cell lymphoproliferative disorders, cutaneous T-cell lymphoma, subcutaneous panniculitis (e.g., T-cell lymphoma), intestinal T-cell lymphoma (+ enteropathy)), hepatosplenic γ / δ T-cell lymphoma, and non-Hodgkin lymphoma (e.g., B-cell non-Hodgkin lymphoma; e.g., Burkitt lymphoma, chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SLL), diffuse large B-cell lymphoma, follicular lymphoma, and mantle cell lymphoma). Transplantation-related diseases include graft-versus-host disease, chronic graft rejection, acute graft rejection, transplant vascular disease, graft vascular disease, graft atherosclerosis, and graft coronary artery disease.

[0180] On one hand, this disclosure is characterized by methods for treating conditions caused or associated with VAV1 polymorphism or immunopathology in subjects in need, including administering to the subject a therapeutically effective amount of the compound described herein or a pharmaceutically acceptable salt thereof. In some embodiments, the condition is T-cell mediated. In some embodiments, the condition is selected from type I or II diabetes, pernicious anemia, uveitis, psoriasis, alopecia areata, ulcerative colitis, Crohn's disease, atherosclerosis, myocarditis, pericarditis, pulmonary fibrosis, systemic sclerosis, scleroderma, Alzheimer's disease, acute graft-versus-host disease, or T-cell mediated kidney disease. In some embodiments, the condition is T / B-cell mediated. In some embodiments, the condition is selected from the group consisting of multiple sclerosis, rheumatoid arthritis, myasthenia gravis, Sjögren's syndrome, Graves' disease, allergic diseases (e.g., asthma, allergic contact dermatitis, rhinitis, or contact dermatitis), and autoimmune liver diseases. (e.g., biliary sclerosis or sclerosing cholangitis), chronic inflammatory demyelinating polyradiculoneuropathy, macular degeneration, systemic lupus erythematosus, Hashimoto's thyroiditis, amyloidosis, inflammatory eye disease, pemphigus, systemic lupus erythematosus, chronic graft-versus-host disease, lupus nephritis, pulmonary hypertension, or vasculitis. In some embodiments, the condition is selected from the group consisting of ulcerative colitis, rheumatoid arthritis, psoriasis, multiple sclerosis, myasthenia gravis, cutaneous lupus, or axial spondyloarthritis. In a preferred embodiment, the condition is ulcerative colitis. In some embodiments, the condition is selected from the group consisting of B-cell lymphoma, B-cell leukemia, T-cell lymphoma, T-cell leukemia, or acute myeloid leukemia. In a preferred embodiment, the condition is chronic lymphocytic leukemia.

[0181] On one hand, this disclosure relates to a method for treating ulcerative colitis, rheumatoid arthritis, psoriasis, multiple sclerosis, myasthenia gravis, cutaneous lupus, or axial spondyloarthritis, the method comprising administering to a subject a therapeutically effective amount of a pharmaceutically acceptable salt of a compound. In a preferred embodiment, the condition is ulcerative colitis.

[0182] On one hand, this disclosure relates to a method for treating B-cell lymphoma, B-cell leukemia, T-cell lymphoma, T-cell leukemia, or acute myeloid leukemia, the method comprising administering to a subject a therapeutically effective amount of a pharmaceutically acceptable salt of a compound. In a preferred embodiment, the method is a method for treating chronic lymphocytic leukemia.

[0183] On one hand, this disclosure relates to methods for treating neurological diseases, wherein the neurological diseases include cerebrovascular diseases such as cerebral infarction, neuroimmunological diseases such as multiple sclerosis and neuromyelitis optica, infectious diseases of the central nervous system such as viral encephalitis, and neurodegenerative diseases including Alzheimer's disease (AD), Parkinson's disease (PD), multiple system atrophy (MSA), amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), progressive supranuclear palsy (PSP), Lewy body dementia (DLB), and Huntington's disease (HD). The method includes administering a therapeutically effective amount of a pharmaceutically acceptable salt of the compound to a subject.

[0184] Terminology Explanation

[0185] Unless otherwise stated, the terminology used herein has the common meaning understood by one of ordinary skill in the art. It may vary for those skilled in the art depending on the desired properties and effects sought through this application, and each numerical parameter should be interpreted according to the number of significant figures and conventional rounding methods or as understood by one of ordinary skill in the art. Generally, the nomenclature used herein and the experimental procedures in organic chemistry, medicinal chemistry, and biology described herein are well-known and commonly used in the art. Unless otherwise defined, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which this application pertains. Where multiple definitions exist for terms used herein, the definitions in this section shall prevail unless otherwise stated.

[0186] Unless otherwise stated, all figures used in this specification and claims to indicate content, concentration, proportion, weight, particle size, percentage, technical effect, etc., shall in any event be understood to be modified by the terms “about” or “approximately”. Therefore, unless indicated to the contrary, the numerical parameters listed in the following specification and appended claims are approximate values. “About” or “approximately” can be understood to mean a range of plus or minus 10%, 20%, 30%, 40%, or 50% of the indicated values.

[0187] In this document, the term "embodiment" means that a particular feature, structure, or characteristic described in connection with an embodiment may be included in at least one embodiment of this application. The appearance of this phrase in various places throughout the specification does not necessarily refer to the same embodiment, nor is it a separate or alternative embodiment mutually exclusive with other embodiments. It will be explicitly and implicitly understood by those skilled in the art that the embodiments described herein can be combined with other embodiments.

[0188] When used in this document, the expression “A and / or B” includes three cases: (1) A; (2) B; and (3) A and B. The expression “A, B and / or C” includes seven cases: (1) A; (2) B; (3) C; (4) A and B; (5) A and C; (6) B and C; and (7) A, B and C. The meanings of similar expressions can be deduced by analogy.

[0189] When used in this document, the terms “including,” “contains,” or “comprising” mean that other elements are not excluded in addition to the elements listed.

[0190] A "bond" indicates that the substituent is absent, and the two ends of the substituent are directly connected to form a bond.

[0191] When "alkyl" is used as a group or part of a group, it refers to a group consisting of C1-C2. 20 Straight-chain or branched aliphatic hydrocarbon groups. Preferably C1-C. 10 Alkyl groups, more preferably C1-C8 alkyl groups. Examples of alkyl groups include, but are not limited to, 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.

[0192] "alkylene" refers to a divalent alkyl group, wherein the alkyl group is as defined above, and the alkylene group is preferably an alkylene group having 1 to 12 carbon atoms (i.e., C12). 1-12 Alkylenes, more preferably alkylenes containing 1 to 6 carbon atoms (i.e., C16-64 ... 1-6 Alkylenes, more preferably alkylenes containing 1 to 4 carbon atoms (i.e., C14-44 carbon atoms). 1-4Alkylenes. Non-limiting examples of alkylenes include, but are not limited to, methylene (-CH2-), 1,1-ethylene (-CH(CH3)-), 1,2-ethylene (-CH2CH2)-, 1,1-propylene (-CH(CH2CH3)-), 1,2-propylene (-CH2CH(CH3)-), 1,3-propylene (-CH2CH2CH2-), and 1,4-butylene (-CH2CH2CH2CH2-). Alkylenes can be substituted or unsubstituted, and when substituted, they can be substituted at any usable linking point. Substituents can be selected from one or more of alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkoxy, heterocyclic alkoxy, cycloalkylthio, heterocyclic alkylthio, and oxo.

[0193] "Alkenyl" refers to an aliphatic hydrocarbon group containing a single carbon-carbon double bond, which can be straight-chain or branched. C2-C is preferred. 10 Alkenyl, more preferably C2-C8 alkenyl. Representative examples include, but are not limited to, vinyl, The alkenyl group can be substituted or unsubstituted.

[0194] "Alkyne group" refers to an aliphatic hydrocarbon group containing a carbon-carbon triple bond, which can be straight-chain or branched. C2-C is preferred. 10 The alkynyl group is more preferably C2-C8 alkynyl, and most preferably C2-C4 alkynyl. Examples of alkynyl groups include, but are not limited to, acetyleneyl, ... The alkynyl group can be substituted or unsubstituted.

[0195] "Ideinyl" refers to a divalent straight-chain or branched aliphatic hydrocarbon group containing one or more carbon-carbon double bonds, having a specified number of carbon atoms, such as 2 to 8 carbon atoms, for example -CH=CH-, -CH2CH=CH-, -C(CH3)=CH-, etc., and the imeneyl group may optionally be substituted by one or more (such as 1 to 3) identical or different substituents.

[0196] "Imyynyl" refers to a divalent straight-chain or branched hydrocarbon group having one or more carbon-carbon triple bonds, containing a specified number of carbon atoms, such as 2 to 8 carbon atoms, including but not limited to, etc., and the imynylyl group may optionally be substituted by one or more (such as 1 to 3) identical or different substituents.

[0197] "Cycloalkyl" refers to a saturated or partially saturated monocyclic, fused, bridged, or spirocyclic carbon ring. Preferably, it is C3-C. 12Cycloalkyl groups, more preferably C3-C8 cycloalkyl groups, and most preferably C3-C6 cycloalkyl groups. Examples of monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclohepttrienyl, cyclooctyl, etc., with cyclopropyl and cyclohexenyl being preferred. The cycloalkyl group may be substituted or unsubstituted.

[0198] "Spirocycloalkyl" refers to a polycyclic group with 5 to 18 quintiles, consisting of two or more cyclic structures, where the monocyclic rings share a carbon atom (called a spiro atom) with each other. The rings may contain one or more double bonds, but none of the rings are aromatic. Preferably, it is 6 to 14 quintiles, more preferably 7 to 10 quintiles. Based on the number of spiro atoms shared between the rings, spirocycloalkyl groups are classified as monospiro, bispiro, or polyspirocycloalkyl groups, with monospiro and bispirocycloalkyl groups being preferred, and preferably 4 / 5, 4 / 6, 5 / 5, or 5 / 6 quintiles. Examples of "spirocycloalkyl" include, but are not limited to: spiro[4.5]decyl, spiro[4.4]nonyl, spiro[3.5]nonyl, and spiro[2.4]heptyl.

[0199] "Fused cycloalkyl" refers to a 5- to 18-membered polycyclic aromatic hydrocarbon group containing two or more ring structures sharing a pair of carbon atoms. One or more rings may contain one or more double bonds, but none of the rings are aromatic. It is preferably 6- to 12-membered, and more preferably 7- to 10-membered. Depending on the number of constituent rings, it can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic fused cycloalkyl, preferably bicyclic or tricyclic, and more preferably 5-membered / 5-membered or 5-membered / 6-membered bicyclic alkyl. Examples of "fused cycloalkyl" include, but are not limited to: bicyclo[3.1.0]hexyl, bicyclo[3.2.0]hept-1-enyl, bicyclo[3.2.0]heptyl, decahydronaphthyl, or tetradecahydrophenanthrene.

[0200] "Bridged cycloalkyl" refers to a 5- to 18-membered polycyclic aromatic hydrocarbon group containing two or more ring structures that share two non-directly connected carbon atoms. One or more rings may contain one or more double bonds, but none of the rings are aromatic. It is preferably 6- to 14-membered, more preferably 7- to 10-membered. Depending on the number of rings, it can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic bridged cycloalkyl, preferably bicyclic, tricyclic, or tetracyclic, and more preferably bicyclic or tricyclic. Examples of "bridged cycloalkyl" include, but are not limited to: (1s,4s)-bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl, (1s,5s)-bicyclo[3.3.1]nonyl, bicyclo[2.2.2]octyl, (1r,5r)-bicyclo[3.3.2]decyl, and bicyclo[1.1.1]pentyl.

[0201] "Cycloalkylene" refers to a divalent, saturated or partially saturated monocyclic, fused, bridged, or spirocyclic carbon ring, connected to one group by a single bond and to other groups by another single bond, such as C10.3-10 Cycloalkylene groups contain 3-10 carbon atoms, C 3-6 Cycloalkylene compounds contain 3-6 carbon atoms; common cycloalkylene compounds include (but are not limited to) cyclopropane-1,1-ylene, cyclopropane-1,2-ylene, cyclobutane-1,1-ylene, cyclobutane-1,2-ylene, cyclobutane-1,3-ylene, etc.

[0202] The terms “heterocyclic group,” “heterocyclic,” or “heterocyclic” are used interchangeably in this application and all refer to a non-aromatic heterocyclic group in which one or more cyclic atoms are heteroatoms, such as N, O, S, P, or Se, and the remainder are carbon atoms, wherein the carbon atoms are optionally oxidized (i.e., forming C=O), the nitrogen atom is optionally quaternized, and nitrogen, sulfur, and phosphorus may be optionally oxidized (i.e., NO, S(O)). n n is selected from 1 or 2, P(O) m m is selected from 1, 2 or 3), and the ring includes monocyclic, fused, bridged and spirocyclic rings, which may contain one or more double bonds. Preferably, it has 3 to 12 ring atoms, more preferably a 4 to 7-membered monocyclic or a 7 to 10-membered bis- or tricyclic ring. Examples of "heterocyclic groups" include, but are not limited to, morpholino, oxoheterobutyl, azacyclic butyl, thioheterobutyl, thiomorpholino, tetrahydropyrano (including tetrahydrofuran-2-yl), tetrahydrothiophene (including tetrahydrothiophene-2-yl and tetrahydrothiophene-3-yl, etc.), tetrahydropyrano, 1,1-dioxo-thiomorpholino, piperidinyl, piperazinyl, 2-oxo-piperidinyl, pyrrolyl, pyrazolyl, imidazoyl, 2-oxo-pyrrolyl, piperazin-2-one, 8-oxa-3-aza-bicyclo[3.2.1]octyl, 1,2,3,6-tetrahydropyridinyl, homopiperidinyl, homopiperidinyl, thiaalkyl, isoxazolyl, isothiazolyl, 1,2-azinyl, 1,2-thiaazinyl or hexahydropyridazinyl or 3,6-dihydro-2H-pyrano. The heterocyclic group can be substituted or unsubstituted.

[0203] "Hypo-heterocyclic group" refers to a divalent non-aromatic heterocyclic group in which one or more cyclic atoms are heteroatoms, such as N, O, S, P, and Se. These include monocyclic, fused, bridged, and spirocyclic groups. The ring may contain one or more double bonds, connected to a group via one single bond and to other groups (or ring systems) via another single bond. Examples include 3-10 membered hypo-heterocyclic groups, 3-7 membered hypo-heterocyclic groups, or 4-10 membered hypo-heterocyclic groups. Common hypo-heterocyclic groups include (but are not limited to) oxepane-2,2-ene, oxepane-2,3-ene, aziridine-2,2-ene, aziridine-2,3-ene, and aziridine-2,3-ene. Alkyl-2,4-yl, tetrahydrofuran-2,5-yl, tetrahydro-2H-pyran-2,3-yl, tetrahydro-2H-pyran-2,4-yl, tetrahydro-2H-pyran-2,5-yl, tetrahydro-2H-pyran-2,6-yl, pyrrolidine-1,2-yl, pyrrolidine-1,3-yl, pyrrolidine-2,3-yl, pyrrolidine-2,4-yl, pyrrolidine-2,5-yl, piperidine-1,2-yl, piperidine-1,3-yl, piperidine-1,4-yl, piperidine-2,3-yl, piperidine-2,4-yl, piperidine-2,5-yl, piperidine-2,6-yl, etc.

[0204] "Spirocycloheterocyclic group" refers to a polycyclic group with 5 to 18 members, consisting of two or more rings sharing an atom between the rings. The rings may contain one or more double bonds, but none of the rings are aromatic. One or more ring atoms are selected from N, O, S, P, and Se, while the remainder are carbon atoms. The carbon atoms are optionally oxidized (i.e., forming C=O), the nitrogen atom is optionally quaternized, and nitrogen, sulfur, and phosphorus may be optionally oxidized (i.e., NO, S(O)). n n is selected from 1 or 2, P(O) m m is selected from 1, 2, or 3). Preferably, it is 6 to 14 ternary atoms, more preferably 7 to 10 ternary atoms. Spirocyclic groups are classified into monospirocyclic groups, bispirocyclic groups, or multispirocyclic groups according to the number of shared spiro atoms between rings, preferably monospirocyclic groups and bispirocyclic groups. More preferably, it is a 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered, or 5-membered / 6-membered monospirocyclic group. Examples of “spirocyclic groups” include, but are not limited to: 1,7-dioxaspiro[4.5]decyl, 2-oxa-7-azaspiro[4.4]nonyl, 7-oxaspiro[3.5]nonyl, and 5-oxaspiro[2.4]heptyl.

[0205] A "fused heterocyclic group" refers to a polycyclic aromatic hydrocarbon group containing two or more ring structures that share a pair of atoms. One or more rings may contain one or more double bonds, but none of the rings are aromatic. One or more ring atoms are selected from N, O, S, P, and Se, and the rest are carbon atoms. The carbon atoms are optionally oxidized (i.e., forming C=O), the nitrogen atom is optionally quaternized, and nitrogen, sulfur, and phosphorus can be optionally oxidized (i.e., NO, S(O)). n n is selected from 1 or 2, P(O) m m is selected from 1, 2 or 3), and the remaining ring atoms are carbon. Preferably, it is 6 to 14-membered, more preferably 7 to 10-membered. Depending on the number of constituent rings, it can be classified as bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic group, preferably bicyclic or tricyclic, more preferably 5-membered / 5-membered or 5-membered / 6-membered bicyclic fused heterocyclic group. Non-limiting examples of "fused heterocyclic group" include, but are not limited to: octahydropyrrolo[3,4-c]pyrrole, octahydro-1H-isoindolyl, 3-azabicyclo[3.1.0]hexyl, octahydrobenzo[b][1,4]dioxin.

[0206] "Bridged heterocyclic groups" refer to polycyclic groups with 5 to 18 members, containing two or more ring structures that share two non-directly connected atoms. One or more rings may contain one or more double bonds, but none of the rings are aromatic. One or more ring atoms are selected from N, O, S, P, and Se, while the rest are carbon atoms. The carbon atoms are optionally oxidized (i.e., forming C=O), the nitrogen atom is optionally quaternized, and nitrogen, sulfur, and phosphorus can be optionally oxidized (i.e., NO, S(O)). n n is selected from 1 or 2, P(O) m m is selected from 1, 2, or 3), preferably 6 to 14 elements, more preferably 7 to 10 elements. Depending on the number of constituent rings, it can be classified as a bicyclic, tricyclic, tetracyclic, or polycyclic bridged heterocyclic group, preferably bicyclic, tricyclic, or tetracyclic, and more preferably bicyclic or tricyclic. Examples of "bridged heterocyclic groups" include, but are not limited to: 2-azabicyclo[2.2.1]heptyl, 2-azabicyclo[2.2.2]octyl, and 2-azabicyclo[3.3.2]decyl.

[0207] "Aryl" refers to a carbocyclic aromatic system containing one or two rings, wherein the rings may be connected together in a fused manner. "Aryl" includes monocyclic or bicyclic aryl groups, such as phenyl, naphthyl, and tetrahydronaphthyl aromatic groups. Preferably, the aryl group is C6-C. 10 Aryl, more preferably phenyl and naphthyl, most preferably phenyl. The aryl group can be substituted or unsubstituted.

[0208] "Arylidene" refers to an aryl group as defined herein, which has two monovalent group centers obtained by removing two hydrogen atoms from the same carbon atom or two different carbon atoms of the parent aryl group. Typical arylidene groups include, but are not limited to, phenylene and naphthylene.

[0209] The terms “heteroaryl” and “heteroary ring” are used interchangeably in this application, both referring to a monocyclic or polycyclic aromatic cyclic group containing 5 to 14 ring atoms, which may contain 1 to 4 atoms selected from N, O, S, and Se. Preferably, it contains 5 to 12 ring atoms, more preferably 5 to 6-membered monocyclic heteroaryl or 8 to 10-membered bicyclic heteroaryl. Examples of "heteroaryl" include, but are not limited to, furanyl, pyridinyl, 2-oxo-1,2-dihydropyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiopheneyl, isoxazolyl, oxazolyl, oxadiazolyl, imidazolyl, pyrroleyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl, benzo[m]dioxacyclopentenyl, benzo[thiophene], benzimidazolyl, indolyl, isoyindolyl, 1,3-dioxo-isoindolyl, quinolinyl, indolyl, benzo[isothiazolyl], benzo[oxazolyl], benzo[isoxazolyl], and heteroaryl can be substituted or unsubstituted.

[0210] "Hypo-heteroaryl" refers to the heteroaryl group as described above, which has two monovalent group centers obtained by removing two hydrogen atoms from the same carbon atom or two different carbon atoms of the parent heteroaryl group, or by removing one hydrogen atom from a carbon atom and one hydrogen atom from a nitrogen atom.

[0211] The heteroaryl group can be substituted or unsubstituted.

[0212] A "fused ring" or "fused cyclic group" refers to a polycyclic group in which two or more cyclic structures share a pair of atoms. One or more rings may contain one or more double bonds, but at least one ring is not aromatic, and at least one ring is aromatic. In this group, 0, 1, or more ring atoms are selected from N, O, S, P, and Se, and the remainder are carbon atoms. The carbon atoms are optionally oxidized (i.e., forming C=O), and the nitrogen atom is optionally quaternized. Nitrogen, sulfur, and phosphorus may be optionally oxidized (i.e., NO, S(O)n, where n is selected from 1 or 2, P(O)m, where m is selected from 1, 2, or 3). The fused ring preferably includes a bicyclic or tricyclic fused ring, wherein the bicyclic fused ring is preferably a fused ring of an aryl or heteroaryl group with a monocyclic heterocyclic group or a monocyclic cycloalkyl group. Preferably, it is 7 to 14 quinary, more preferably 9 to 10 quinary. Examples of "fused rings" or "fused cyclic groups" include, but are not limited to:

[0213] The fused ring can be substituted or unsubstituted.

[0214] "Alkoxy" refers to an (alkyl-O-) group. Alkyl groups are defined in the relevant section of this document. C1-C8 alkoxy groups are preferred. Examples include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, etc. Alkoxy groups can be substituted or unsubstituted.

[0215] "Alkenyloxy group" refers to the (alkenyl-O-) group. The alkenyl group is defined in the relevant section of this document. C2-C8 alkenyloxy groups are preferred. Alkenyloxy groups can be substituted or unsubstituted.

[0216] "Hydroxyalkyl" is a (-alkyl-OH) group. The alkyl group is defined in the relevant section of this document. C1-C8 hydroxyalkyl groups are preferred. Examples include, but are not limited to, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxyisopropyl, and hydroxybutyl. Hydroxyalkyl groups can be substituted or unsubstituted.

[0217] "Alkylamino" refers to a (alkyl-NH-) group. The alkyl group is defined in the relevant section of this document. C1-C8 alkylamino groups are preferred. Examples include, but are not limited to: methylamino, ethylamino, n-propylamino, isopropylamino, n-butylamino, isobutoxy, tert-butoxy, etc. Alkylamino groups can be substituted or unsubstituted, and the substituent can be on the alkyl group or on the nitrogen atom, as in examples such as dimethylamino and diethylamino.

[0218] "Aminoalkyl" refers to a (-alkyl-NH2) group. The alkyl group is defined in the relevant section of this document. Examples include, but are not limited to: aminomethyl, aminoethyl, aminopropyl, aminoisopropyl, aminobutyl, aminopentyl, etc. Aminoalkyl groups can be substituted or unsubstituted, and the substituent can be on the alkyl group or on the nitrogen atom, as in the example of dimethylaminoalkyl.

[0219] "Alkyl carbonyl" refers to a (alkyl-C(O)-) group. The alkyl group is defined in the relevant section of this document. Examples include, but are not limited to: methyl carbonyl, ethyl carbonyl, n-propyl carbonyl, isopropyl carbonyl, n-butyl carbonyl, isobutyl carbonyl, etc. Alkyl carbonyl groups can be substituted or unsubstituted.

[0220] "Alkoxycarbonyl" refers to a (alkyl-OC(O)-) group. The alkyl group is defined in the relevant section of this document. Examples include, but are not limited to, methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, etc. Alkoxycarbonyl groups can be substituted or unsubstituted.

[0221] "Halogenated alkyl" refers to an alkyl group that has been replaced by a halogen. For the definitions of halogen and alkyl group, please refer to the relevant definitions in this document.

[0222] "Haloalkoxy" refers to an alkoxy group that has been replaced by a halogen. For the definitions of halogen and alkoxy group, please refer to the relevant definitions in this article.

[0223] "Halogenated alkylamino" refers to an alkylamino group that has been replaced by a halogen. For the definitions of halogen and alkylamino, please refer to the relevant definitions in this article.

[0224] "Cycloalkoxy" refers to a (cycloalkyl-O-) group. The cycloalkyl group is defined in the relevant section of this document.

[0225] "Heterocyclic group" refers to a group containing (heterocyclic -O-). The definition of heterocyclic group is provided in the relevant section of this document.

[0226] "Hydroxy" refers to the -OH group.

[0227] "Halogens" refer to fluorine, chlorine, bromine, and iodine.

[0228] "Amino" refers to -NH2.

[0229] “Cyano” refers to -CN.

[0230] "Nitro" refers to -NO2.

[0231] "Carboxyl group" refers to -C(O)OH.

[0232] "Amide" refers to -C(O)NH2.

[0233] "Substituted" refers to one or more hydrogen atoms in a group, preferably 1 to 5, more preferably 1 to 3 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 (by experiment or theory) possible or impossible substitutions without much effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom having an unsaturated bond (such as an alkene).

[0234] Unless otherwise specified, the terms "substituted" or "substituted" in this specification refer to the substitution of a group by one or more groups selected from the following: H, deuterium, halogen, C1-C8 alkyl, C1-C8 alkoxy, C2-C8 alkenyl, C2-C8 alkynyl, C2-C8 alkenyloxy, C3-C 12 Cycloalkyl, C3-C8 cycloalkoxy, 3-12 membered heterocyclic, 3-12 membered heterocyclic, aminosulfonyl, C6-C 10 Aryl, 5-12 heteroaryl, cyano, amino, nitro, hydroxy, oxo, carboxyl, amide, hydroxyalkyl, aminoalkyl, alkanecarbonyl, alkoxycarbonyl, C1-C8 alkylamino, C1-C8 haloalkylamino, -OR g -SR g -C1-C8 alkylene-R g -OC(O)R g -C(O)R g -C(O)OR g -C(O)N(R) x )R y -NR x R y -N(CH3)R g -N(R) x)C(O)R y -N(R) x )C(O)NR x R y -N(R) x )C(O)OR g -N(R) x )S(O)NR x R y -N(R) x )S(O)2NR x R y -N(R) x )S(O)2R g -S(O)R g -S(O)2R g -S(O)2NR x R y -P(O)R x R y The alkyl, alkylene, alkoxy, alkenyl, alkynyl, alkenyloxy, cycloalkyl, cycloalkoxy, heterocyclic, heterocyclic, aryl, heteroaryl, 3-12 membered ring, amino, hydroxyl, or amide may optionally be further surrounded by one or more R o replace;

[0235] When 2 R o When two R atoms are substituted on the same atom, o Together with the atoms they are attached to, they form 3-6 membered rings, or when 2 R o When substitution occurs on adjacent atoms, 2 R o Together with the atoms it is attached to, they form 3-12 membered rings;

[0236] R g R x R y R o Each is independently selected from H, deuterium, halogen, C1-C8 alkyl, C1-C8 alkoxy, C2-C8 alkenyl, C2-C8 alkynyl, C2-C8 alkenyloxy, C3-C 12 Cycloalkyl, C3-C8 cycloalkoxy, 3-12 membered heterocyclic, 3-12 membered heterocyclic, aminosulfonyl, C6-C 10 Aryl, 5-12 heteroaryl, cyano, amino, nitro, hydroxy, oxo, carboxyl, amide, hydroxyalkyl, aminoalkyl, alkanecarbonyl, alkoxycarbonyl, C1-C8 alkylamino, C1-C8 haloalkylamino, -OR s -SR s -C1-C8 alkylene-R s -OC(O)R s -C(O)R s -C(O)ORs -C(O)N(R) s )R t -NR s R t -N(CH3)R s -N(R) s )C(O)R t -N(R) s )C(O)NR s R t -N(R) s )C(O)OR t -N(R) s )S(O)NR s R t -N(R) s )S(O)2NR s R t -N(R) s )S(O)2R t -S(O)R s -S(O)2R s -S(O)2NR s R t or -P(O)R s R t The alkyl, alkylene, cycloalkyl, heterocyclic, aryl, or heteroaryl group may optionally be further modified by one or more R groups. r replace;

[0237] When 2 R r When two R atoms are substituted on the same atom, r Together with the atoms they are attached to, they form 3-6 membered rings, or when 2 R r When substitution occurs on adjacent atoms, 2 R r Together with the atoms it is attached to, they form 3-12 membered rings;

[0238] R r R s R t Each is independently selected from H, deuterium, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, halogen, cyano, amino, nitro, hydroxyl, oxo, C1-C8 alkoxy, C1-C8 haloalkyl, hydroxyalkyl, aminoalkyl, C1-C8 alkylamino, alkoxycarbonyl, alkoxycarbonyl, halohydroxyalkyl, C1-C8 haloalkylamino, C3-C 12 Cycloalkyl, 3-12 membered heterocyclic groups, carboxyl groups, amides, C6-C 10 Aryl or 5-12 heteroaryl groups.

[0239] The compounds disclosed herein may contain asymmetric or chiral centers, and thus exist in different stereoisomeric forms. It is contemplated that all stereoisomeric forms of the compounds disclosed herein, including but not limited to diastereomers, enantiomers, atropisomers, and geometric (conformal) isomers and mixtures thereof, such as racemic mixtures, are within the scope of this disclosure.

[0240] Unless otherwise stated, the structures described in this disclosure also include all isomers of this structure (e.g., diastereomers, enantiomers, and trans-isomers and geometric (conformal) isomers; for example, R and S configurations of each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers). Therefore, individual stereoisomers of the compounds disclosed herein, as well as mixtures of enantiomers, mixtures of diastereomers, and mixtures of geometric (conformal) isomers, are all within the scope of this disclosure.

[0241] The C, H, O, S, N, F, Cl, Br, and I components mentioned in the groups and compounds described in this disclosure include their isotopic variations. Furthermore, the C, H, O, S, N, F, Cl, Br, and I components mentioned in the groups and compounds described in this disclosure may optionally be substituted with one or more of their corresponding isotopes, including but not limited to carbon isotopes. 12 C 13 C 14 C, hydrogen isotopes protium (H), deuterium (D), tritium (T), and oxygen isotopes 16 O、 17 O、 18 O, an isotope of sulfur 32 S, 33 S, 34 S, 36 S, an isotope of nitrogen 14 N、 15 N, an isotope of fluorine 17 F, 19 F, an isotope of chlorine 35 Cl、 37 Cl, an isotope of bromine 79 Br、 81 Br, etc.

[0242] It is important to understand that the general description preceding the text and the detailed description following the text are merely illustrative and explanatory, and are not restrictive on any of the claims. It should be noted that in the specification and appended claims, unless otherwise stated in the text, singular forms such as "a," "an," and "this" include plural forms. It should also be noted that unless otherwise stated, "or" means "and / or." Furthermore, terms such as "comprising" and "including" are not restrictive.

[0243] "Medicinal salts" refer to certain salts of the above-mentioned compounds that retain their original biological activity and are suitable for medicinal use. The medicinal salts of the compounds represented by formula (I) can be metal salts, salts formed with suitable acids, or salts formed with suitable bases. A preferred class of salts are salts formed by the compounds of this disclosure with acids. Suitable acids for forming salts include, but are not limited to: inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, and carbonic acid; organic acids such as formic acid, acetic acid, trifluoroacetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, p-toluenesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, camphorsulfonic acid, citric acid, isonicotinic acid, salicylic acid, ascorbic acid, gentian acid, gluconic acid, pyruvic acid, naphthalenesulfonic acid, stearic acid, phenylacetic acid, p-aminobenzenesulfonic acid, hydroxyethanesulfonic acid, dihydroxynaphthalic acid, and tannic acid; and acidic amino acids such as aspartic acid and glutamic acid. A preferred type of salt is the salt formed by the compound of this disclosure with a base. Suitable bases for forming salts include, but are not limited to, inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, and sodium phosphate, and organic bases such as ammonia, triethylamine, diethylamine, piperazine, guanidine, and diethanolamine.

[0244] It is important to understand that the general description preceding the text and the detailed description following the text are merely illustrative and explanatory, and are not restrictive on any of the claims. It should be noted that in the specification and appended claims, unless otherwise stated in the text, singular forms such as "a," "an," and "this" include plural forms. It should also be noted that unless otherwise stated, "or" means "and / or." Furthermore, terms such as "comprising" and "including" are not restrictive.

[0245] "Medicinal salts" refer to certain salts of the above-mentioned compounds that retain their original biological activity and are suitable for medicinal use. The medicinal salts of the compounds represented by formula (I) can be metal salts, salts formed with suitable acids, or salts formed with suitable bases. A preferred class of salts are salts formed by the compounds of this disclosure with acids. Suitable acids for forming salts include, but are not limited to: inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, and carbonic acid; organic acids such as formic acid, acetic acid, trifluoroacetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, p-toluenesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, camphorsulfonic acid, citric acid, isonicotinic acid, salicylic acid, ascorbic acid, gentian acid, gluconic acid, pyruvic acid, naphthalenesulfonic acid, stearic acid, phenylacetic acid, p-aminobenzenesulfonic acid, hydroxyethanesulfonic acid, dihydroxynaphthalic acid, and tannic acid; and acidic amino acids such as aspartic acid and glutamic acid. A preferred type of salt is the salt formed by the compound of this disclosure with a base. Suitable bases for forming salts include, but are not limited to, inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, and sodium phosphate, and organic bases such as ammonia, triethylamine, diethylamine, piperazine, guanidine, and diethanolamine.

[0246] When applied to animals, humans, experimental subjects, cells, tissues, organs, or biological fluids, “administration,” “administering,” “leating,” and “treatment” mean contact between an exogenous agent, therapeutic agent, diagnostic agent, or composition and the animal, human, subject, cell, tissue, organ, or biological fluid. Treatment of cells encompasses contact between the reagent and the cell, as well as contact between the reagent and a fluid, wherein the fluid contacts the cell. The terms “administering” and “treatment” also mean in vitro and ex vivo treatment of, for example, cells by means of a reagent, diagnostic agent, conjugated compound, or another cell. The term “subject” herein includes any organism, preferably an animal, more preferably a mammal (e.g., rat, mouse, dog, cat, and rabbit), and most preferably a human.

[0247] "Effective amount" or "therapeutic effective amount" refers to an amount of an active ingredient (such as a compound) that is sufficient to affect such treatment of a disease, disorder, or symptom when the compound is given to a subject to treat at least one clinical symptom of the disease or disorder. "Therapeutic effective amount" can vary with: the compound, the disease, disorder, and / or the symptoms of the disease or disorder, the severity of the disease, disorder, and / or the symptoms of the disease or disorder, the age of the subject to be treated, and / or the weight of the subject to be treated. In any given example, the appropriate amount will be clear to those skilled in the art or can be determined by routine experiments. In some embodiments, "therapeutic effective amount" is the amount of at least one compound disclosed herein and / or at least one stereoisomer thereof and / or at least one pharmaceutically acceptable salt thereof effective in "treating" (as defined above) a subject's disease or disorder. In the case of combination therapies, "therapeutic effective amount" refers to the total amount of the combination of subjects used to effectively treat the disease, disorder, or symptom.

[0248] "Pharmaceutical carrier" refers to one or more solid or liquid fillers or gel substances suitable for human use. The pharmaceutical carrier can be any conventional carrier and / or diluent in the field of pharmaceutical formulations, preferably having sufficient purity and sufficiently low toxicity, and intended to be compatible with the active ingredient of this disclosure without significantly reducing the efficacy of the active ingredient. For example, a pharmaceutical carrier can be a filler, binder, disintegrant, lubricant, aqueous solvent, or non-aqueous solvent. The amount of active ingredient capable of producing a single dosage form by combination with a carrier substance generally refers to the amount of compound capable of producing a therapeutic effect.

[0249] "Pharmaceutical formulation" refers to any pharmaceutically acceptable dosage form prepared for administration by any suitable route of delivery, such as local, oral, transdermal, rectal, vaginal, non-enteric, intranasal, intrapulmonary, intraocular, intravenous, intramuscular, intraarterial, intrathecal, intradermal, intraperitoneal, subcutaneous, subcutaneous, or inhalation administration to a patient or subject requiring such treatment. Pharmaceutical compositions containing an active ingredient may be in forms suitable for oral administration, such as tablets, sugar tablets, lozenges, liquid formulations such as aqueous or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups, elixirs, solutions, or suspensions. Tablets contain the active ingredient and a non-toxic, pharmaceutically acceptable carrier suitable for tablet preparation for mixing. For parenteral administration, the pharmaceutical composition may be a solution, aqueous solution, oil suspension concentrate, lyophilized powder, etc. Preferably, the formulation of the pharmaceutical composition is selected from tablets, coated tablets, capsules, suppositories, nasal sprays, or injections, more preferably tablets or capsules. The pharmaceutical composition may be administered as a single unit with an accurate dose. In addition, the pharmaceutical composition may contain other active ingredients. Dosage forms for topical or transdermal administration may include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalers. The active compound may be mixed with a pharmaceutically acceptable carrier under sterile conditions, and may be mixed with any preservatives, buffers, or propellants that may be required.

[0250] All formulations of the pharmaceutical compositions disclosed herein can be produced using conventional methods in the pharmaceutical field. For example, the active ingredient can be mixed with one or more excipients to prepare the desired formulation. "Pharmaceutically acceptable excipients" refer to conventional pharmaceutical carriers suitable for the desired pharmaceutical formulation, such as: diluents, media such as water, various organic solvents, fillers such as starch, sucrose, etc., binders such as cellulose derivatives, alginate, gelatin, and polyvinylpyrrolidone (PVP); wetting agents such as glycerin; disintegrants such as agar, calcium carbonate, and sodium bicarbonate; absorption enhancers such as quaternary ammonium compounds; surfactants such as hexadecyl alcohol; absorption carriers such as kaolin and bentonite; lubricants such as talc, calcium stearate, magnesium stearate, polyethylene glycol, etc. In addition, the pharmaceutical compositions may also contain other pharmaceutically acceptable excipients, such as dispersants, stabilizers, thickeners, complexing agents, buffers, penetration enhancers, polymers, flavorings, sweeteners, and dyes.

[0251] The term “disease” refers to any illness, discomfort, ailment, symptom, or indication and is interchangeable with the terms “symptom” or “disorder”.

[0252] This disclosure demonstrates through experiments that the compound disclosed herein has degradation activity against VAV1.

[0253] This disclosure demonstrates through experiments that the compound disclosed herein has the ability to inhibit the secretion of IL-2 by T cells and inhibit TCR activity.

[0254] This disclosure demonstrates through experiments that the compound disclosed herein has the ability to inhibit the secretion of CD69 by B cells and inhibit BCR activity.

[0255] The various embodiments and preferences described above for this application can be combined with each other (as long as they are not inherently contradictory), and all embodiments formed by such combinations are considered part of the disclosure of this application.

[0256] The technical solution of this application will be illustrated more clearly and explicitly below with reference to embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of protection of this application. The scope of protection of this application is defined only by the claims.

[0257] Example

[0258] The embodiments described below are exemplary and are only used to explain this application, and should not be construed as limiting this application. Where specific techniques or conditions are not specified in the embodiments, they shall be performed in accordance with the techniques or conditions described in the literature in the art or according to the product instructions. Reagents or instruments whose manufacturers are not specified are all conventional products that can be obtained commercially. Some abbreviations in this invention represent chemical substances as follows:

[0259] DMF: N,N-dimethylformamide;

[0260] PtO2: Platinum dioxide;

[0261] DCM: Dichloromethane;

[0262] Et3N: Triethylamine;

[0263] DMAP: 4-Dimethylaminopyridine;

[0264] THF: Tetrahydrofuran;

[0265] TFA: Trifluoroacetic acid;

[0266] EA: Ethyl acetate;

[0267] Pd(dppf)Cl2: Palladium dichloride DPPF;

[0268] KOAc: Potassium acetate;

[0269] NBS: N-bromosuccinimide;

[0270] AIBN: Azobisisobutyronitrile;

[0271] ACN: Acetonitrile;

[0272] TMSCN: Trimethylcyanosilane;

[0273] TBAF: Tetrabutylammonium fluoride;

[0274] LiHMDS: Lithium bis(trimethylsilylamine);

[0275] LDA: Lithium diisopropylaminodimethylamine;

[0276] PhMe: p-Methoxyethylphenol;

[0277] Pd2(dba)3: Tris(dibenzylacetone)dipalladium;

[0278] Cu(OAc)2: Copper acetate;

[0279] TEA: Triethylamine;

[0280] DCE: 1,2-Dichloroethane.

[0281] Example 1: Synthesis of Intermediate A1

[0282] Synthesis Step 1: Synthesis of A1-1

[0283] 2-(3-bromo-2-chlorophenyl)acetonitrile (6.6 g, 28.7 mmol) was dissolved in tetrahydrofuran (65 mL), and sodium methyl ester (310 mg, 5.8 mmol) and tert-butyl acrylate (3.67 g, 28.7 mmol) were slowly added at 0 °C. The mixture was stirred at 20 °C for 2 hours. After the reaction was complete, the mixture was quenched with water, extracted with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The solution was then analyzed by column chromatography to obtain Al-1. ESI-MS (M+H) + =358.0.

[0284] Synthesis Step 2: Synthesis of A1-2

[0285] Al-1 (2.4 g, 6.0 mmol) was dissolved in acetic acid (30 mL), and sulfuric acid (2.8 g, 28.2 mmol) was added. The mixture was stirred at 90 °C for 3 hours. After the reaction was complete, the mixture was cooled to room temperature, poured into ice water, and the filtered cake was washed with water. The filter cake was dried under reduced pressure to give Al-2. ESI-MS (M+H) + =302.0.

[0286] Synthesis Step 3: Synthesis of A1

[0287] A1-2 (1.0 g, 3.3 mmol) was dissolved in 1,4-dioxane (16 mL), and pinacol diborate (1.0 g, 4.0 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (0.2 g, 0.3 mmol), and potassium acetate (1.0 g, 9.9 mmol) were added sequentially under nitrogen atmosphere. The mixture was stirred at 85 °C for 3 hours. After the reaction was complete, the mixture was filtered, and the filter cake was washed with ethyl acetate. The combined filtrates were concentrated under reduced pressure. The residue was subjected to column chromatography to give intermediate A1, ESI-MS (M+H). + =350.1.

[0288] Example 2: Synthesis of Intermediate A2

[0289] Synthesis Step 1: Synthesis of A2-1

[0290] 3-Bromo-2-chloroaniline (5.6 g, 27.0 mmol) was dissolved in toluene (50 mL), and acrylic acid (3.9 g, 54.1 mmol) was added to the system. The reaction was carried out at 100 °C for 16 h. After the reaction was completed, the mixture was quenched with water, extracted with ethyl acetate, and the organic phases were combined, dried, concentrated under reduced pressure, and subjected to column chromatography to give A2-1 (5.6 g, 20.3 mmol, 75% yield). ESI-MS (M+H) + =278.0.

[0291] Synthesis Step 2: Synthesis of A2-2

[0292] A2-1 (5.6 g, 20.3 mmol) was dissolved in acetic acid (50 mL), and urea (2.6 g, 43.6 mmol) was added to the system. The reaction was carried out at 110 °C for 16 h. After the reaction was completed, the mixture was quenched with water, extracted with ethyl acetate, and the organic phases were combined, dried, concentrated under reduced pressure, and subjected to column chromatography to obtain A2-2. ESI-MS (M+H) + =303.0.

[0293] Synthesis Step 3: Synthesis of A2

[0294] A2-2 (1.1 g, 3.3 mmol) was dissolved in dioxane (16 mL), and pinacol diborate (1.0 g, 4.0 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (0.2 g, 0.3 mmol), and potassium acetate (1.0 g, 9.9 mmol) were added sequentially under nitrogen atmosphere. The mixture was stirred at 85 °C for 3 hours. After the reaction was complete, the mixture was filtered, and the filter cake was washed with ethyl acetate. The combined filtrates were concentrated under reduced pressure. The residue was subjected to column chromatography to give intermediate A2 (0.80 g, 1.7 mmol, 50% yield), ESI-MS (M+H). + =351.1.

[0295] Example 3: Synthesis of intermediate A3

[0296] Synthesis Step 1: Synthesis of A3-1

[0297] 4-Chloro-3,5-dibromopyridine (3.0 g, 11.0 mmol) was dissolved in a mixture of 1,4-dioxane and water (4:1). Under a nitrogen atmosphere, 2,6-di(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentane-2-yl)pyridine (4.6 g, 11.0 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (804.9 mg, 1.1 mmol), and sodium carbonate (3.5 g, 33.0 mmol) were added sequentially. The mixture was stirred at 85 °C for 3 hours. After the reaction was complete, the reaction mixture was filtered, and the filter cake was washed with ethyl acetate. The combined filtrates were concentrated under reduced pressure. The residue was subjected to column chromatography to give A3-1, ESI-MS (M+H). + =481.0.

[0298] Synthesis Step 2: Synthesis of A3-2

[0299] A3-1 (1.6 g, 3.3 mmol) was dissolved in 1,4-dioxane (16 mL), and pinacol diborate (1.0 g, 4.0 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (0.2 g, 0.3 mmol), and potassium acetate (1.0 g, 9.9 mmol) were added sequentially under nitrogen atmosphere. The mixture was stirred at 85 °C for 3 hours. After the reaction was complete, the reaction mixture was filtered, and the filter cake was washed with ethyl acetate. The combined filtrates were concentrated under reduced pressure. The residue was subjected to column chromatography to give A3-2, ESI-MS (M+H). + =529.20.

[0300] Synthesis Step 2: Synthesis of A3

[0301] A3-2 (1.4 g, 2.6 mmol) was dissolved in ethyl acetate, PtO2 was added, hydrogen was added to replace the precipitate, and the reaction was carried out overnight at room temperature. After the reaction was complete, the mixture was filtered through diatomaceous earth, and the filtrate was concentrated to obtain A3.

[0302] Example 4: Synthesis of intermediate A6

[0303] Synthesis Step 1: Synthesis of Compound A6-1

[0304] Compound A1-2 (10 g, 0.033 mol, 1.0 eq) was dissolved in 200 mL of DCM. Et3N (14 mL, 0.1 mol, 3.0 eq), di-tert-butyl dicarbonate (8.73 g, 0.04 mol, 1.2 eq), and DMAP (2 g, 0.016 mol, 0.5 eq) were added sequentially to the system, and the reaction was carried out at room temperature for 1 h. After the reaction was completed, the mixture was quenched with water, extracted with DCM, and the organic phase was washed once with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and subjected to column chromatography to obtain compound A6-1. ESI-MS (M+H) + =402.0.

[0305] Synthesis Step 2: Synthesis of Compound A6-2

[0306] Compound A6-1 (2 g, 4.97 mmol, 1.0 eq) was dissolved in 20 mL of THF. Under N2 protection, the temperature was lowered to -70 °C. LiHMDS (1.5 mL, 7.455 mmol, 1.5 eq) was added dropwise, maintaining the temperature below -60 °C. After the addition was complete, the temperature was maintained for 1 h. Then, 10 mL of NFSI (2.35 g, 7.455 mmol, 1.5 eq) in THF was added dropwise, maintaining the temperature at -60 °C. After the addition was complete, the reaction was allowed to proceed to room temperature for 2 h. After the reaction was complete, the mixture was quenched with water, extracted with EA, and the organic phase was washed once with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and subjected to column chromatography to obtain compound A6-2. ESI-MS (M+H) + =420.0.

[0307] Synthesis Step 3: Synthesis of Compound A6-3

[0308] Compound A6-2 (150 mg, 0.475 mol, 1.0 eq) was dissolved in 10 mL of DCM. TFA (2 mL, 10 V) was added to the system, and the reaction was allowed to proceed at room temperature for 3 h. After the reaction was complete, the mixture was quenched with water, and the pH was adjusted to approximately 8 at 0 °C with a saturated sodium bicarbonate aqueous solution. DCM was then added for extraction. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain compound A6-3. ESI-MS (M+H) + =319.9.

[0309] Synthesis Step 4: Synthesis of Compound A6

[0310] Compound A6-3 (150 mg, 0.437 mmol, 1.0 eq) was dissolved in 5 mL of 1,4-dioxane. Pinaryl diboronate (122 mg, 0.48 mmol), Pd(dppf)Cl2 (32 mg, 0.0437 mmol), and KOAc (129 mg, 1.311 mmol) were added sequentially to the system. After replacing N2, the mixture was heated to 90 °C and reacted for 16 h. After the reaction was complete, water and EA were added for extraction. The organic phases were combined and concentrated under reduced pressure to obtain compound A6. ESI-MS (M+H) + =368.1.

[0311] Example 5: Synthesis of intermediate A7

[0312] Synthesis Step 1: Synthesis of Compound A7-2

[0313] A7-1 (100 g, 487 mmol, 1.0 eq) was dissolved in 1000 mL of carbon tetrachloride, and NBS (90.9 g, 511 mmol) and AIBN (2.4 g, 14.6 mmol) were added. The mixture was sealed in a tube at 90 °C for 2 h. After the reaction was complete, water and EA were added for extraction. The organic phases were combined, concentrated under reduced pressure, and subjected to column chromatography to obtain compound A7-2. ESI-MS (M+H) + =282.8.

[0314] Synthesis Step 2: Synthesis of Compound A7-3

[0315] A7-2 (44 g, 156.1 mmol) was dissolved in 1000 mL of ACN, and TMSCN (18.5 g, 187.3 mmol) and TBAF (187.3 mL, 187.3 mmol) were added. The mixture was sealed at 50 °C and reacted for 2 h. After the reaction was complete, water and EA were added for extraction. The organic phases were combined, concentrated under reduced pressure, pulped, filtered, and the solid was given as compound A7-3. ESI-MS (M+H) + =229.9.

[0316] Synthesis Step 3: Synthesis of Compound A7-4

[0317] A7-3 (30 g, 132 mmol) was dissolved in 300 mL of THF, cooled to -70 °C, and LiHMDS (132 mL, 132 mmol) was added dropwise while maintaining the temperature at -70 °C. Iodomethane (6.24 g, 132 mmol) was then added dropwise while maintaining the temperature at -70 °C. The reaction was allowed to proceed for 30 min, followed by 12 h at room temperature. After the reaction was complete, water and EA were added for extraction. The organic phases were combined, concentrated under reduced pressure, and purified by column chromatography to obtain compound A7-4. ESI-MS (M+H) + =244.0.

[0318] Synthesis Step 4: Synthesis of Compound A7-6

[0319] Dissolve 11.4 g (46.9 mmol) of A7-4 in 120 mL of THF, cool to -65 °C, add 25.8 mL (51.6 mmol) of LDA dropwise while maintaining the temperature at -65 °C, then add 9.3 g (51.6 mmol) of A7-5 dropwise while maintaining the temperature at -65 °C. React for 30 min, then allow to cool to room temperature for 2 h. After the reaction is complete, extract with ammonium chloride water and EA, combine the organic phases, concentrate under reduced pressure, and obtain compound A7-6 by column chromatography. ESI-MS (M+H) + =444.0.

[0320] Synthesis Step 5: Synthesis of Compound A7-7

[0321] A7-6 (4.0 g, 11.6 mmol) was dissolved in a 40 mL / 12 mL THF / H₂O mixture, and LiOH (839 mL, 34.98 mmol, 3.0 eq) was added. The mixture was reacted at room temperature for 12 h. After the reaction was complete, the pH was adjusted to 6-7 with 0.5 N HCl, and the mixture was extracted with ethyl acetate. The liquid-liquid phase was extracted with saturated sodium chloride and dried over anhydrous sodium sulfate to obtain compound A7-7.

[0322] ESI-MS(M+H) + =316.0.

[0323] Synthesis Step 6: Synthesis of Compounds A7-8

[0324] Compound A7-7 (2.6 g, 8.2 mmol, 1.0 eq) was dissolved in 30 mL of PhMe solution, and concentrated sulfuric acid (0.5 mL, 9.25 mmol) was added. The mixture was reacted at room temperature for 2 h. After the reaction was complete, the pH was adjusted to 7-8 with saturated sodium bicarbonate, and the mixture was extracted with ethyl acetate. The liquid-liquid phase was extracted with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain compound A7-8. ESI-MS (M+H) + =316.0.

[0325] Synthesis Step 7: Synthesis of Compound A7

[0326] A7-8 (800 mg, 2.53 mmol) was dissolved in 30 mL of dioxane, and pinacol diboronic acid ester (707 mg, 2.78 mmol), Pd(dppf)Cl2 (185 mg, 0.253 mmol), and KAcO (743 mg, 7.59 mmol) were added. After replacing N2, the mixture was reacted at 90 °C for 2 h. After the reaction was completed, the mixture was filtered through diatomaceous earth and evaporated to dryness to obtain compound A7. ESI-MS (M+H) + =364.1.

[0327] Example 6: Synthesis of Intermediate B1

[0328] Synthesis Step 1: Synthesis of B1-1

[0329] (4-Bromophenyl)boronic acid (3.0 g, 14.9 mmol), 5-cyclopropoxypyridin-2(1H)-one (2.7 g, 17.9 mmol), copper acetate (2.7 g, 14.9 mmol), and triethylamine (4.5 g, 44.8 mmol) were added to dichloroethane (5 mL), and the mixture was subjected to three evacuations followed by oxygen purging. The mixture was then stirred at 25 °C for 3 hours. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was subjected to column chromatography to give B1-1 (1.6 g, 6.3 mmol), ESI-MS (M+H). + =306.0.

[0330] Synthesis Step 2: Synthesis of B1

[0331] B1-1 (2.7 g, 8.81 mmol) was dissolved in dioxane. Pinaryl borate (3.3 g, 13.2 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (644.0 mg, 0.9 mmol), and potassium acetate (2.6 g, 26.4 mmol) were added sequentially to the system. The reaction was carried out at 80 °C under nitrogen protection for 4 hours. After the reaction was complete, the mixture was quenched with water, extracted with dichloromethane, and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Column chromatography yielded B1 (1.2 g, 3.2 mmol). ESI-MS (M+H) + =354.2.

[0332] Following the synthetic route and method of intermediate B1, the following intermediate compounds were synthesized:

[0333] Example 7: Synthesis of intermediate B33

[0334] 1-Methyltetrahydropyridin-2(1H)-one (500.0 mg, 4.4 mmol), 1-bromo-4-iodobenzene (1.5 g, 5.3 mmol), copper iodide (167.0 mg, 876.0 μmol), potassium phosphate (1.9 g, 8.8 mmol), and N',N'-dimethylethylene-1,2-diamine (154.0 mg, 1.8 mmol) were added to dioxane (7 mL), and the mixture was subjected to three evacuations followed by nitrogen purging. The mixture was then stirred at 110 °C for 16 hours under nitrogen. The reaction mixture was cooled to 25 °C, diluted with water, and extracted with ethyl acetate. The combined filtrates were concentrated under reduced pressure. The residue was subjected to column chromatography to give intermediate B33 (592.1 mg, 2.2 mmol), ESI-MS (M+H). + =269.0.

[0335] Following the synthetic route and method of intermediate B33, the following intermediate compounds were synthesized:

[0336] Example 8: Synthesis of intermediate B59

[0337] 1-Bromo-4-(bromomethyl)benzene (791.0 mg, 3.2 mmol) was added dropwise under nitrogen to a tetrahydrofuran suspension of active zinc (2.1 g, 31.7 mmol). 2-Bromopyridine (500.0 mg, 3.2 mmol) was added at 25 °C, followed by dropwise addition of tetraphenylphosphine palladium (731.0 mg, 633.0 μmol) under nitrogen. The mixture was stirred at 25 °C for 12 hours. The mixture was filtered. The filtrate was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product. The crude product was subjected to column chromatography to give intermediate B59 (592.1 mg, 2.2 mmol, 15% yield), ESI-MS (M+H). + =248.0.

[0338] Following the synthetic route and method of intermediate B59, the following intermediate compounds were synthesized:

[0339] Example 9: Synthesis of intermediate B63

[0340] 3-Bromo-1-methylpyridin-2-one (500.0 mg, 2.7 mmol), (4-bromophenyl)boronic acid (641.0 mg, 3.2 mmol), potassium phosphate (1.7 g, 8.0 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (195.0 mg, 266.0 μmol) were dissolved in N,N-dimethylformamide. The mixture was purged three times with nitrogen, and then stirred at 100 °C for 6 h under nitrogen. The reaction mixture was cooled to 25 °C, filtered, and concentrated to give the crude product. The crude product was subjected to column chromatography to obtain B63 (320.0 mg, 848.0 μmol) ESI-MS (M+H). + =278.0.

[0341] Following the synthetic route and method of intermediate B63, the following intermediate compounds were synthesized:

[0342] Example 10: Synthesis of intermediate B65

[0343] 3-Iodo-1-methylpyridin-2(1H)-one (2.0 g, 8.5 mmol) was dissolved in toluene, and 7-bromo-2,3,4,5-tetrahydro-1H-benzo[B]azapyrrolidone (1.9 g, 8.5 mmol), sodium tert-butoxide (1.6 g, 17.0 mmol), tris(dibenzylacetone)dipalladium (824.1 mg, 0.9 mmol), and tri-tert-butylphosphine (182.1 mg, 0.9 mmol) were added sequentially. The mixture was purged with nitrogen three times, and then stirred at 100 °C for 6 h under nitrogen. The reaction mixture was cooled to 25 °C, filtered, and concentrated to give the crude product. The crude product was subjected to column chromatography to give intermediate B65 (1.1 g, 3.4 mmol) ESI-MS (M+H). + =334.2.

[0344] Following the synthetic route and method of intermediate B65, the following intermediate compounds were synthesized:

[0345] Example 11: Synthesis of intermediate B67

[0346] 5-Bromodihydroindole (5.0 g, 25.2 mmol) was dissolved in tetrahydrofuran. Sodium hydroxide (1.2 g, 50.4 mmol) was added under ice bath conditions, and the mixture was stirred for 30 minutes. Then, 3-bromomethyl-1-methylpyrazole (4.4 g, 25.2 mmol) was added, and the mixture was heated to 60 °C overnight. After the reaction was complete, the reaction mixture was cooled to 25 °C, filtered, and concentrated to obtain the crude product. The crude product was subjected to column chromatography to obtain B67 (5.7 g, 19.6 mmol). ESI-MS (M+H) +=292.0.

[0347] Following the synthetic route and method of intermediate B67, the following intermediate compounds were synthesized:

[0348] Example 12: Synthesis of intermediate B73

[0349] p-Bromoaniline (5.0 g, 29.1 mmol) was dissolved in tetrahydrofuran. Cesium carbonate (9.5 g, 29.1 mmol) and 2-chloro-5-cyclopropoxypyrimidine (5.0 g, 29.1 mmol) were added under ice bath conditions, and the mixture was stirred at room temperature. After the reaction was complete, the solution was filtered and concentrated, and column chromatography was performed to obtain B73 (6.9 g, 22.7 mmol). ESI-MS (M+H) + =306.0.

[0350] Following the synthetic route and method of intermediate B73, the following intermediate compounds were synthesized:

[0351] Example 13: Synthesis of Intermediate D1

[0352] Synthesis Step 1: Synthesis of D1-1

[0353] 2-Benzyloxy-5-hydroxypyridine (8.99 g, 44.68 mmol) was dissolved in N-methylpyrrolidone (100 mL), followed by the addition of cyclobutyl bromide (30 g, 223.39 mmol) and cesium carbonate (43.67 g, 134.03 mmol). The reaction mixture was placed in a sealed container and reacted at 150 °C for 8 hours. After the reaction was complete, the mixture was cooled to room temperature and diluted with water, then extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The solution was then analyzed by column chromatography to obtain D1-1. ESI-MS (M+H) + =256.1.

[0354] Synthesis Step 2: Synthesis of D1-2

[0355] D1-1 (2.00 g, 7.81 mmol) was dissolved in a mixed solvent of tetrahydrofuran (25 mL) and methanol (25 mL), and palladium on carbon (10%, 1.00 g) was added. The reaction mixture was reacted at 10 °C for 2 hours under a hydrogen atmosphere. After the reaction was complete, the mixture was filtered, and the filtrate was concentrated. The crude product was purified by reversed-phase column chromatography to obtain D1-2, ESI-MS (M+H). + =166.1.

[0356] Synthesis Step 3: Synthesis of D1

[0357] (4-Bromophenyl)boric acid (730 mg, 4.83 mmol) was dissolved in dichloromethane (40 mL), and D1-2 (1.94 g, 9.66 mmol), copper acetate (66 mg, 0.33 mmol), pyridine (764 mg, 9.66 mmol), and pyridine-N-oxide (505 mg, 5.31 mmol) were added sequentially. The reaction was carried out at 10 °C for 16 hours under an oxygen atmosphere. After the reaction was completed, the reaction solution was diluted with dichloromethane and filtered. The filtrate was washed with saturated ammonium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography to give D1A (0–60% ethyl acetate / petroleum ether; V / V), and ESI-MS (M+H). + =320.0; D1 (60% ethyl acetate / petroleum ether), ESI-MS (M+H) + =320.0.

[0358] Following the synthetic route and method of intermediate D1A, the following intermediate compounds were synthesized:

[0359] Example 14: Synthesis of intermediate D52

[0360] Synthesis Step 1: Synthesis of D52-1

[0361] 2-Z-cyclohexanone (20 g, 0.2 mol) was dissolved in cyclopropanol (150 mL), and tetraethyl-p-toluenesulfonate ammonium (2 g, 7 mmol) was added. The solution was cooled to 10-20 °C, stirred continuously, and electrolyzed for 20 h. After the reaction was completed, the solution was concentrated under reduced pressure and the result was obtained by column chromatography as D52-1, ESI-MS (M+H). + =156.1.

[0362] Synthesis Step 2: Synthesis of D52

[0363] The synthesis of D52 follows the same procedure as step 3 in the synthesis of intermediate D1.

[0364] Example 15: Synthesis of intermediate D53

[0365] Synthesis Step 1: Synthesis of D53-1

[0366] 2,4-Difluoro-3-iodopyridine (10.76 g, 44.68 mmol) was dissolved in N-methylpyrrolidone (100 mL), followed by the addition of cyclobutanol (16 g, 223.39 mmol) and cesium carbonate (43.67 g, 134.03 mmol). The reaction mixture was placed in a sealed container and reacted at 150 °C for 8 hours. After the reaction was complete, the mixture was cooled to room temperature and diluted with water, then extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The solution was then analyzed by column chromatography to obtain D53-1. ESI-MS (M+H) + =294.0.

[0367] Synthesis Step 2: Synthesis of D53-2

[0368] D53-1 (6.5 g, 2.34 mmol) was dissolved in acetic acid (100 mL), and sodium acetate (5.5 g, 67.02 mmol) was added. The reaction mixture was placed in a sealed container and reacted at 120 °C for 12 hours. After the reaction was complete, the reaction mixture was cooled to room temperature and diluted with water, then extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. D53-2 was obtained by column chromatography and analyzed by ESI-MS (M+H). + =292.0. Synthesis Step 3: Synthesis of D53-3

[0369] D53-2 (10 g, 34.36 mmol) was dissolved in THF (100 mL), and NaH (1.2 g, 51.55 mmol) was added under ice bath conditions. The mixture was stirred under ice bath conditions for 30 min, and then 4-methylbenzenesulfonic acid-3-methyloxetane-3-yl ester (16.63 g, 68.73 mmol) was slowly added. The reaction was carried out at room temperature for 4 hours. After the reaction was completed, the mixture was quenched with water and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. D53-3 was obtained by column chromatography and analyzed by ESI-MS (M+H). + =362.0.

[0370] Synthesis Step 4: Synthesis of D53

[0371] The synthesis of D53 follows the same procedure as step 3 in the synthesis of intermediate D1.

[0372] Following the synthetic route and method of intermediate D53, the following intermediate compounds were synthesized:

[0373] Following steps 1 and 4 of the synthesis of intermediate D53, the following intermediate compounds were synthesized:

[0374] Example 16: Synthesis of intermediate D79

[0375] Synthesis Step 1: Synthesis of D79-1

[0376] 2,3,4,5-Tetrahydro-1H-benzo[D]azapyrrolidone (1.00 g, 6.79 mmol) was dissolved in DMF (21 mL), cooled to 0 °C, and a solution of NBS (1.27 g, 7.13 mmol) in DMF (9 mL) was slowly added. The reaction was carried out at 10 °C for 1.5 h. After the reaction was complete, the mixture was quenched with water and extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, concentrated under reduced pressure, and subjected to column chromatography to obtain D79-1. ESI-MS (M+H) + =226.0.

[0377] Synthesis Step 2: Synthesis of D79

[0378] D79-1 (1.00 g, 3.26 mmol) was dissolved in dichloromethane (10 mL), and 2,2,2-trifluoroacetaldehyde (639 mg, 6.51 mmol) and acetic acid (384 mg, 6.51 mmol) were added. The reaction was carried out at 35 °C for 2 hours, then cooled to 0 °C, and sodium triacetoxyborohydride (2.07 g, 9.77 mmol) was added. The reaction was continued at 0 °C for 2 hours, then heated to 20 °C and reacted for 16 hours. After the reaction was complete, saturated ammonium chloride was added to quench the reaction, and the mixture was extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, concentrated under reduced pressure, and subjected to column chromatography to obtain D79. ESI-MS (M+H) + =308.0.

[0379] Following the synthetic route and method of intermediate D79, the following intermediate compounds were synthesized:

[0380] Example 17: Synthesis of intermediate D90

[0381] D79-1 (394 mg, 1.50 mmol) and m-iodobenzonitrile (412 mg, 1.80 mmol) were dissolved in toluene (12 mL), followed by the addition of sodium tert-butoxide (432 mg, 4.50 mmol), Xantphos (104 mg, 0.18 mmol), and Pd2(dba)3 (84 mg, 0.09 mmol). The reaction was carried out at 110 °C for 12 hours under nitrogen protection. After the reaction was completed, the mixture was quenched with water, extracted with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain D90. ESI-MS (M+H) + =327.0.

[0382] Example 18: Synthesis of intermediates D91 and D92

[0383] Synthesis Step 1: Synthesis of D91-1

[0384] 16.88 g (75.00 mmol) of 6-bromo-3,4-dihydro-1H-2-naphthone was dissolved in 78 mL of methanesulfonic acid and cooled to 0 °C in an ice bath. Sodium azide (6.34 g, 97.50 mmol) was added in portions. The reaction mixture was reacted at 10 °C for 5 hours. After the reaction was complete, the reaction mixture was slowly poured into an aqueous solution of potassium hydroxide, extracted with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and analyzed by column chromatography to obtain D91-1. ESI-MS (M+H) + =240.0.

[0385] Synthesis Step 2: Synthesis of D91

[0386] D91-1 (12.00 g, 50.00 mmol) was dissolved in tetrahydrofuran (50 mL). Under nitrogen protection, the solution was cooled to 0 °C in an ice bath, and a borane-tetrahydrofuran solution (1 M, 150 mL, 150.00 mmol) was slowly added. The reaction mixture was incubated at 65 °C for 16 hours. After the reaction was complete, excess borane was quenched by slowly adding methanol. The reaction mixture was then incubated at 80 °C for another 40 hours. After the reaction was complete, the solution was cooled to room temperature and concentrated to obtain D91. ESI-MS (M+H) + =226.0.

[0387] Synthesis Step 3: Synthesis of D92

[0388] The synthesis of D92 follows the same procedure as step 2 in the synthesis of intermediate D79.

[0389] Example 19: Synthesis of intermediate D93

[0390] Synthesis Step 1: Synthesis of D93

[0391] The synthesis of D93 is performed in accordance with the synthesis of intermediate D90.

[0392] Example 20: Synthesis of intermediate D115

[0393] Synthesis Step 1: Synthesis of D115-3

[0394] Compound D115-1 (23 g, 0.084 mol, 1 eq) was dissolved in 250 mL of DMAC. D115-2 (9.95 g, 0.092 mol, 1.1 eq) and cesium carbonate (55 g, 0.168 mol, 2.0 eq) were added to the system. The reaction was stirred at room temperature for 16 h. After the reaction was complete, water was added to quench the reaction mixture, and the mixture was extracted with EA. The organic phases were combined, washed three times with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and subjected to column chromatography to obtain compound D115-3. ESI-MS (M+H) + =346.9.

[0395] Synthesis Step 2: Synthesis of D115-5

[0396] Compound D115-4 (13 g, 0.216 mol, 5.0 eq) was dissolved in 500 mL of THF under nitrogen protection and cooled to 0 °C. Potassium tert-butoxide (9.7 g, 0.087 mol, 2.0 eq) was slowly added to the system, maintaining the temperature between 0 and 5 °C. The mixture was stirred for 20 min. Then, D115-3 (15 g, 0.043 mol, 1.0 eq) and 100 mL of THF were added dropwise to the reaction solution, maintaining the temperature between 0 and 5 °C. After the addition was complete, the mixture was transferred to room temperature and allowed to react for 1 h. After the reaction was complete, the mixture was quenched with water, extracted with EA, and the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain compound D115-5. ESI-MS (M+H) + =369.0.

[0397] Synthesis Step 3: Synthesis of D115-6

[0398] Compound D115-5 (1 g, 2.72 mmol, 1 eq) was dissolved in 60 mL of 1,4-dioxane. Cyclopropylboronic acid (1.4 g, 16.29 mmol, 6 eq) was added in three batches, along with sodium carbonate (720 mg, 6.8 mmol, 2.5 eq), water (10 mL), and Pd(dppf)Cl2 (200 mg, 0.272 mmol, 0.1 eq). The reaction was carried out under nitrogen protection at 100 °C for 30 min. Cyclopropylboronic acid and 1,4-dioxane were then added to the reaction solution in batches, with 30-minute intervals between each addition. After all additions were completed, the reaction was allowed to proceed for 1 h. The reaction mixture was then cooled to room temperature, extracted with EA, and the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and analyzed by column chromatography to obtain compound D115-6. ESI-MS (M+H) yielded the compound D115-6. + =283.1.

[0399] Synthesis Step 4: Synthesis of D115-7

[0400] Compound D115-6 (680 mg, 2.41 mmol, 1 eq) was dissolved in 10 mL of methanol. Pd / C (70 mg, 10% W) and hydrogen gas were added to the system. The reaction was carried out at room temperature for 1 h. After the reaction was complete, Pd / C was filtered off, and the filtrate was concentrated under reduced pressure and subjected to column chromatography to obtain compound D115-7. ESI-MS (M+H) + =193.1.

[0401] Synthesis Step 5: Synthesis of D115

[0402] Compound D115-7 (100 mg, 0.52 mmol, 1 eq) was dissolved in 15 mL of DCE. D115-8 (418 mg, 2.08 mmol), TEA (288 μL, 2.08 mmol), and Cu(OAc)₂ (114 mg, 0.624 mmol) were added to the system. Oxygen was replaced, and the reaction was carried out at 50 °C for 12 h. After the reaction was complete, water was added to quench the reaction, the solid was filtered off, and the mixture was extracted with EA. The organic phases were combined, concentrated under reduced pressure, and purified by column chromatography to obtain compound D115. ESI-MS (M+H) + =347.0.

[0403] Following the synthetic route and method of D115, and using the corresponding intermediates and reagents, the following intermediate compounds were synthesized. The intermediate structures and characterization data are as follows:

[0404] The intermediate compound is synthesized according to the steps outlined in D115:

[0405] Following the synthetic routes and methods of steps 1, 2, 4, and 5 of D115, and using the corresponding intermediates and reagents, the following intermediate compounds were synthesized:

[0406] Example 21: Synthesis of intermediate D30

[0407] Synthesis Step 1: Synthesis of D30-3

[0408] Compound D30-1 (23 g, 0.084 mol) was dissolved in 250 mL of DMAC. D30-2 (9.95 g, 0.092 mol) and cesium carbonate (55 g, 0.168 mol) were added to the system. The reaction was stirred at room temperature for 16 h. After the reaction was complete, water was added to quench the reaction mixture, and the mixture was extracted with EA. The organic phases were combined, washed three times with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and subjected to column chromatography to obtain compound D30-3. ESI-MS (M+H) + =345.9.

[0409] Synthesis Step 2: Synthesis of D30-5

[0410] Compound D115-4 (13 g, 0.216 mol, 5.0 eq) was dissolved in 500 mL of THF under nitrogen protection and cooled to 0 °C. Potassium tert-butoxide (9.7 g, 0.087 mol, 2.0 eq) was slowly added to the system, maintaining the temperature between 0 and 5 °C. The mixture was stirred for 20 min. Then, D30-3 (15 g, 0.043 mol, 1.0 eq) and 100 mL of THF were added dropwise to the reaction solution, maintaining the temperature between 0 and 5 °C. After the addition was complete, the mixture was transferred to room temperature and allowed to react for 1 h. After the reaction was complete, the mixture was quenched with water, extracted with EA, and the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain compound D30-5. ESI-MS (M+H) + =368.0.

[0411] Synthesis Step 3: Synthesis of D30-6

[0412] Compound D30-5 (1 g, 2.72 mmol, 1 eq) was dissolved in 60 mL of 1,4-dioxane. Cyclopropylboronic acid (1.4 g, 16.29 mmol) was added in three portions, along with sodium carbonate (720 mg, 6.8 mmol), water (10 mL), and Pd(dppf)Cl2 (200 mg, 0.272 mmol). The reaction was carried out under nitrogen protection at 100 °C for 30 min. Cyclopropylboronic acid and 1,4-dioxane were then added to the reaction solution in batches, with 30-minute intervals between each addition. After all additions were completed, the reaction was allowed to proceed for 1 h. The reaction was then cooled to room temperature, extracted with EA, and the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain compound D30-6. ESI-MS (M+H) + =282.1.

[0413] Synthesis Step 4: Synthesis of D30-7

[0414] Compound D30-6 (680 mg, 2.41 mmol, 1 eq) was dissolved in 10 mL of methanol. Pd / C (70 mg, 10% W) and hydrogen gas were added to the system. The reaction was carried out at room temperature for 1 h. After the reaction was complete, Pd / C was filtered off, and the filtrate was concentrated under reduced pressure and subjected to column chromatography to obtain compound D30-7. ESI-MS (M+H) + =192.1.

[0415] Synthesis Step 5: Synthesis of D30

[0416] Compound D30-7 (100 mg, 0.52 mmol, 1 eq) was dissolved in 15 mL of DCE. D115-8 (418 mg, 2.08 mmol), TEA (288 μL, 2.08 mmol), and Cu(OAc)₂ (114 mg, 0.624 mmol) were added to the system, followed by oxygen replacement. The reaction was carried out at 50 °C for 12 h. After the reaction was completed, water was added to quench the reaction mixture, the solid was filtered off, and the mixture was extracted with EA. The organic phases were combined, concentrated under reduced pressure, and purified by column chromatography to obtain compound D30. ESI-MS (M+H) + =346.0.

[0417] Following the synthetic route and method of D30, and using the corresponding intermediates and reagents, the following intermediate compounds were synthesized:

[0418] Following the synthetic routes and methods of D30, steps 1, 2, 4, and 5, and using the corresponding intermediates and reagents, the following intermediate compounds were synthesized:

[0419] Example 22: Synthesis of intermediate D179

[0420] Synthesis Step 1: Synthesis of D179-1

[0421] Compound D115-5 (7 g, 19 mmol, 1 eq) was dissolved in 70 mL of toluene. Tributyl(1-ethoxyethylene)tin (13.7 g, 38 mmol, 2.0 eq) and Pd(PPh3)4 (1.1 g, 0.95 mmol, 0.05 eq) were added to the system. Under nitrogen protection, the reaction was carried out at 110 °C for 16 h. After the reaction was completed, the mixture was cooled to room temperature, extracted with EA, and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give crude intermediate D179-1. ESI-MS (M+H) + =313.1.

[0422] Synthesis Step 2: Synthesis of D179-2

[0423] Compound D179-1 was dissolved in 70 mL of tetrahydrofuran. 70 mL of 2N HCl aqueous solution was added to the system. The reaction was allowed to proceed at room temperature for 1 h. After the reaction was complete, EA was added for extraction. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to give intermediate 179-2. ESI-MS (M+H) + =285.1.0.

[0424] Synthesis Step 3: Synthesis of D179-3

[0425] Compound D179-2 (4 g, 14.07 mmol, 1.0 eq) was dissolved in 100 mL of tetrahydrofuran, and the solution was heated to -30 °C by replacing N2. 42 mL of a tetrahydrofuran solution of methylmagnesium bromide (1 mol / L, 42.21 mmol, 3.0 eq) was added dropwise to the system. After the addition was complete, the reaction mixture was reacted at -30 °C for 2 h. Upon completion of the reaction, the reaction solution was quenched dropwise in an aqueous HCl solution, extracted with EA, and the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and subjected to column chromatography to obtain intermediate D179-3. ESI-MS (M+H) + =301.1. Synthesis Step 4: Synthesis of D179-4

[0426] Compound D179-3 (1 g, 3.33 mmol, 1 eq) was dissolved in 10 mL of methanol. Pd / C (100 mg, 10% W) and hydrogen gas were added to the system. The reaction was carried out at room temperature for 1 h. After the reaction was complete, Pd / C was filtered off, and the filtrate was concentrated under reduced pressure and subjected to column chromatography to obtain intermediate D179-4. ESI-MS (M+H) + =211.1.

[0427] Synthesis Step 5: Synthesis of D179

[0428] Compound D179-4 (270 mg, 1.284 mmol, 1 eq) was dissolved in 15 mL of DCE. D179-4 (1.03 g, 5.137 mmol), pyridine (400 μL, 5.137 mmol), and Cu(OAc)₂ (280 mg, 1.541 mmol) were added to the system. Oxygen was replaced, and the reaction was carried out at 50 °C for 12 h. After the reaction was complete, water was added to quench the reaction mixture, the solid was filtered off, and the mixture was extracted with EA. The organic phases were combined, concentrated under reduced pressure, and the solution was obtained by column chromatography (M+H). + =365.0.

[0429] Example 23: Synthesis of Compound 1

[0430] Synthesis Step 1:

[0431] Intermediate A1-2 (2.8 g, 9.2 mmol), B1 (3.6 g, 10.1 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (672.0 mg, 918.0 μmol), and sodium carbonate (2.9 g, 27.5 mmol) were added to DMF (60 mL) and purged with nitrogen. The mixture was then stirred at 100 °C for 16 hours under nitrogen. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was subjected to column chromatography to give compound 1, as shown in ESI-MS (M+H). + =449.1. 1 H NMR (400MHz, DMSO-d6) δ10.94(s,1H),7.57(s,4H),7.47–7.36(m,5H),6.54–6.47(m,1H),4.38(dd,J=12.2,5.0Hz,1H),3.8 6–3.79(m,1H),2.81(t,J=17.7Hz,1H),2.61–2.53(m,1H),2.43–2.30(m,1H),2.08(t,J=13.1Hz,1H),0.70(d,J=6.4Hz,4H).

[0432] Following the synthetic route and method of compound 1, the following compounds were synthesized:

[0433] Example 24: Synthesis of Compound 87

[0434] Synthesis Step 1:

[0435] Intermediate A1 (3.2 g, 9.2 mmol), B65 (3.37 g, 10.1 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (672.0 mg, 918.0 μmol), and sodium carbonate (2.9 g, 27.5 mmol) were added to DMF (60 mL) and subjected to three nitrogen purgings. The mixture was then stirred at 100 °C for 16 hours under a nitrogen atmosphere. The reaction mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was subjected to column chromatography to give compound 87 (949.6 mg, 2.3 mmol) as ESI-MS (M+H). + =476.2.

[0436] Following the synthetic route and method of compound 87, the following compounds were synthesized:

[0437] Example 25: Synthesis of Compound 24

[0438] Compound A5 (51.7 mg, 127 μmol), 2-bromo-4-cyclopropoxypyridine (40.9 mg, 191 μmol), and cesium carbonate were added.

[0439] A mixture of N,N-dimethylacetamide (82.9 mg, 255 μmol), sodium iodide (7.25 mg, 48.4 μmol), nickel chloride ethylene glycol dimethyl ether complex (7.27 mg, 33.1 μmol), and pyridine-2-carboxyaminochloride (5.22 mg, 33.1 μmol) was dissolved in 1.00 mL of N,N-dimethylacetamide. Zinc powder (20.8 mg, 318 μmol) was added, and the reaction was carried out under nitrogen protection. The reaction was stirred at 60 °C for 4 hours. After cooling to room temperature, the reaction mixture was filtered, and the precipitate was washed with 1 M hydrochloric acid to remove the zinc powder. The filtrate was poured into water and extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The crude product was purified to give compound 24 (11.7 mg, 25.4 μmol), ESI-MS (M+H). + =461.2.

[0440] Example 26: Synthesis of Compound 104

[0441] Synthesis Step 1: Synthesis of 104-1:

[0442] 2,3-Dichloro-4-iodopyridine (2.5 g, 9.2 mmol), B1 (3.6 g, 10.1 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (672.0 mg, 918.0 μmol), and sodium carbonate (2.9 g, 27.5 mmol) were added to DMF (60 mL) and subjected to three nitrogen purgings. The mixture was then stirred at 100 °C for 16 hours under a nitrogen atmosphere. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The combined filtrates were concentrated under reduced pressure. The residue was subjected to column chromatography to give compound 104-1 (1.7 g, 4.6 mmol) as ESI-MS (M+H). + =373.0.

[0443] Synthesis Step 2: Synthesis of 104-2:

[0444] Compound 104-1 (4.1 g, 11.0 mmol) was dissolved in a mixture of 1,4-dioxane and water (4:1). Under a nitrogen atmosphere, 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentane-2-yl)pyridine (4.6 g, 11.0 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (804.9 mg, 1.1 mmol), and sodium carbonate (3.5 g, 33.0 mmol) were added sequentially. The mixture was stirred at 85 °C for 3 hours. After the reaction was complete, the reaction mixture was filtered, and the filter cake was washed with ethyl acetate. The combined filtrates were concentrated under reduced pressure. The residue was subjected to column chromatography to give 104-2 (3.8 g, 6.2 mmol), ESI-MS (M+H). + =628.2. Synthesis Step 3: Synthesis of Compound 104

[0445] 104-2 (3.8 g, 6.2 mmol) was dissolved in ethyl acetate, PtO2 was added, hydrogen was purged, and the reaction was carried out overnight at room temperature. After the reaction was complete, the mixture was filtered through diatomaceous earth, and the filtrate was concentrated and purified to give compound 104 (2.2 g, 4.8 mmol). ESI-MS (M+H) was then performed. + =450.1.

[0446] Following the synthetic route and method of compound 104, and using the corresponding intermediates and reagents, the following intermediate compounds were synthesized:

[0447] Example 27: Synthesis of Compound 115

[0448] Synthesis Step 1: Synthesis of 115-1

[0449] Al (126 mg, 0.36 mmol) was dissolved in tetrahydrofuran (4 mL), and D91 (79 mg, 0.30 mmol), Pd(dtbpf)Cl2 (19 mg, 0.03 mmol), and potassium phosphate (191 mg, 0.90 mmol) in water (1 mL) were added sequentially. The reaction was carried out at 70 °C for 3 hours under nitrogen protection. After the reaction was complete, the reaction solution was cooled to room temperature and quenched with water, then extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The solution was then analyzed by column chromatography to obtain 115 μL. ESI-MS (M+H) + =369.1. 1H NMR (400MHz, DMSO-d6) δ10.93(s,1H),8.30(s,1H),7.43–7.37(m,1H),7.36(dd,J=7.7,2.1Hz,1H ),7.31(d,J=7.7Hz,1H),7.28(dd,J=7.1,2.1Hz,1H),7.24(d,J=1.5Hz,1H),7.18(dd,J=7.6,1.7 Hz,1H),4.34(dd,J=12.2,5.0Hz,1H),4.05(s,2H),3.24–3.13(m,2H),2.98(d,J=10.1Hz,2H),2. 85–2.73(m,1H),2.60–2.52(m,1H),2.34(dd,J=12.7,4.0Hz,1H),2.10–2.00(m,1H),1.75(s,2H).

[0450] Following the synthetic route and method of compound 115, and using the corresponding intermediates and reagents, the following intermediate compounds were synthesized:

[0451] Example 28: Synthesis of Compound 148

[0452] Synthesis Step 1: Synthesis of 148

[0453] Al (100 mg, 0.31 mmol) was dissolved in tetrahydrofuran (4 mL), and D15 (119 mg, 0.34 mmol), Pd(dtbpf)Cl2 (10 mg, 0.02 mmol), and potassium phosphate (132 mg, 0.62 mmol) in water (1 mL) were added sequentially. The reaction was carried out at 70 °C for 3 hours under nitrogen protection. After the reaction was complete, the reaction solution was cooled to room temperature and quenched with water, then extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The solution was then analyzed by column chromatography to obtain 148 μL of the solution. ESI-MS (M+H) + =465.1.

[0454] Example 29: Synthesis of Compound 309

[0455] Synthesis Step 1: Synthesis of Compound 309

[0456] D178 (120 mg, 0.317 mmol, 1 eq) was dissolved in 8 mL of THF. Al (133 mg, 0.380 mmol), potassium phosphate (168 mg, 0.79 mmol), water (2 mL), and Pd(dtbpf)Cl2 (21 mg, 0.032 mmol) were added to the system. Under nitrogen protection, the reaction was carried out at 70 °C for 1 h. After the reaction was complete, EA was added, followed by water extraction. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to give compound 309. ESI-MS (M+H) + =520.2.

[0457] Referring to the synthetic routes and methods of compounds 148 or 309, and using the corresponding intermediates and reagents, the following intermediate compounds were synthesized:

[0458] Example 30: Synthesis of compounds 17, 311 and 312

[0459] Compound D181 (300 mg, 0.98 mmol) was dissolved in tetrahydrofuran (8 mL), followed by the addition of compound A1 (514 mg, 1.47 mmol), Pd(dtbpf)Cl2 (96 mg, 0.15 mmol), and potassium phosphate (624 mg, 2.94 mmol) in water (2 mL). The reaction mixture was incubated at 70 °C for 3 hours under nitrogen protection. After the reaction, the mixture was cooled to room temperature and diluted with water (40 mL), then extracted with ethyl acetate (2 x 50 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by column chromatography (dichloromethane / methanol = 35 / 1; V / V) to give compound 17.

[0460] Compound 17 (285 mg) was separated by SFC (column: Daicel ChiralCel OD*40 mm ID×250 mm*10 μm; mobile phase A: n-hexane, mobile phase B: ethanol; gradient ratio: 100% B; flow rate: 40 mL / min) to obtain compound 311 (43.2 mg, white solid), yield: 15.2%; and compound 312 (54.2 mg, white solid), yield: 19.0%.

[0461] Single configuration compound (shorter retention time): 311 (43.2 mg, yield 15.2%).

[0462] Chiral HPLC analysis: Retention time 7.513 min, purity 99.49% (Column: Daicel_ChiralPak-OD-H 4.6mm I.D.*150mm, 5μm, BS021; Mobile phase A: n-hexane, Mobile phase B: ethanol; Gradient ratio: 100% B; Flow rate: 1 mL / min). ESI-MS (M+H) + =449.0,

[0463] 1 H NMR: N251473-170-P1 (400MHz, DMSO-d6) δ10.93 (s, 1H), 7.54 (dd, J = 9.2, 7.6Hz, 1H), 7.52– 7.47(m,2H),7.46–7.36(m,3H),7.31–7.21(m,2H),6.12(dd,J=9.2,0.8Hz,1H),6.08(dd,J =7.6,0.8Hz,1H),4.37(dd,J=12.4,5.2Hz,1H),4.04–3.92(m,1H),2.87–2.74(m,1H),2.62 –2.53(m,1H),2.42–2.28(m,1H),2.14–2.00(m,1H),0.80–0.71(m,2H),0.64–0.55(m,2H).

[0464] Single configuration compound (longer retention time): 312 (54.2 mg, yield 19.0%).

[0465] Chiral HPLC analysis: retention time 9.426 min, purity 98.57% (column: Daicel_ChiralPak-OD-H4.6mm I.D.*150mm, 5μm, BS021; mobile phase A: n-hexane, mobile phase B: ethanol; gradient ratio: 100% B; flow rate: 1 mL / min).

[0466] Example 31: Synthesis of compounds 293 and 294

[0467] Compound 232 was separated by a chiral column (column: Daicel ChiralCel OD, 40 mm ID × 250 mm, 10 μm; mobile phase A: n-hexane, mobile phase B: ethanol, gradient ratio: A:B = 40:60, flow rate: 60 mL / min) to obtain compounds 293 (3.04 g, yield: 47.8%) and 294 (2.94 g, yield: 46.3%).

[0468] Single configuration compound (shorter retention time): 293 (3.04 g, yield: 47.8%).

[0469] Chiral HPLC analysis: retention time 8.4 min, purity 99.49% (column: DAICL CHIRALPAK-IC 4.6×250 mm, 5 μm, catalog number 83325; mobile phase: ethanol-methyl tert-butyl ether (55:45); flow rate: 1 mL / min).

[0470] 1 H NMR(400MHz,Chloroform-d)δ8.12(s,1H),7.51–7.46(m,3H),7.35(d,J=1.6Hz,1H),7.33(s,1H),7.22(dd,J=5.4,4.0Hz,1H),7.19(d,J=8.6Hz,2H),4 .41–4.21(m,2H),2.87–2.23(m,3H),1.92–1.77(m,1H),1.26–1.21(m,1H), 0.91–0.84(m,2H),0.78–0.72(m,2H),0.72–0.66(m,2H),0.65–0.59(m,2H).

[0471] Single configuration compound (longer retention time): 294 (2.94 g, yield: 46.3%).

[0472] Chiral HPLC analysis: retention time 9.8 min, purity 98.57% (column: DAICL CHIRALPAK-IC 4.6×250 mm, 5 μm, catalog number 83325; mobile phase: ethanol-methyl tert-butyl ether (55:45); flow rate: 1 mL / min)

[0473] 1 H NMR(400MHz,Chloroform-d)δ8.24(s,1H),7.54–7.44(m,3H),7.34(d,J=1.5Hz,1H),7.33(s,1H),7.21(dd,J=5.3,4.1Hz,1H),7.18(d,J=8.6Hz,1H),4 .41–4.24(m,2H),2.89–2.26(m,3H),1.90–1.79(m,1H),1.31–1.17(m,1H), 0.93–0.80(m,2H),0.78–0.71(m,2H),0.70–0.65(m,2H),0.65–0.59(m,2H).

[0474] ESI-MS(M+H) + =504.1.

[0475] Example 32: Synthesis of 295 and 296:

[0476] Following the synthetic routes of compounds 311 and 312, compounds 295 and 296 were obtained by SFC resolution. Chiral HPLC analysis revealed that the single-configuration compound (shorter retention time) was 295, and the single-configuration compound (longer retention time) was 296. ESI-MS (M+H) + =508.1.

[0477] Example 33: Synthesis of 297 and 298:

[0478] Following the synthetic routes of compounds 311 and 312, compounds 297 and 298 were obtained by SFC resolution. Chiral HPLC analysis revealed that the single-configuration compound (shorter retention time) was 297, and the single-configuration compound (longer retention time) was 298. ESI-MS (M+H) + =504.1.

[0479] Example 34: Synthesis of 299 and 300:

[0480] Following the synthetic routes of compounds 311 and 312, 299 and 300 were obtained by SFC resolution.

[0481] Among them, single-configuration compounds (shorter retention time): 299;

[0482] Chiral HPLC analysis: retention time 22.2 min, purity 98.09% (DAICEL CHIRALPAK-IC 4.6×250 mm, 5 μm, catalog number 83325; mobile phase: n-hexane-ethanol (35:65); flow rate: 0.8 mL / min).

[0483] Among them, single-configuration compounds (longer retention time): 300;

[0484] Chiral HPLC analysis: retention time 31.6 min, purity 99.15% (column: DAICEL CHIRALPAK-IC 4.6×250 mm, 5 μm, catalog number 83325; mobile phase: n-hexane-ethanol (35:65); flow rate: 0.8 mL / min).

[0485] ESI-MS(M+H) + =518.1.

[0486] Example 34: Synthesis of 301 and 302:

[0487] Following the synthetic routes of compounds 311 and 312, compounds 301 and 302 were obtained by SFC resolution. Chiral HPLC analysis revealed that 301 was the single-configuration compound (shorter retention time), and 302 was the single-configuration compound (longer retention time). ESI-MS (M+H) + =536.1.

[0488] Example 35: Synthesis of 303 and 304:

[0489] Following the synthetic routes of compounds 311 and 312, 303 and 304 were obtained by SFC resolution. Chiral HPLC analysis showed that the single-configuration compound (shorter retention time) was 303, and the single-configuration compound (longer retention time) was 304.

[0490] ESI-MS(M+H) + =532.1.

[0491] Example 36: Synthesis of compound a

[0492] Compound a was obtained using the synthetic route of example 24 of WO2024 / 151547A1.

[0493] The NMR results of the compound are as follows:

[0494] Biological testing

[0495] Test Example 1: VAV1 Degradation in hPBMCs

[0496] VAV1 protein blot analysis. Human peripheral blood mononuclear cells (hPBMCs) were blotted at 5 × 10⁶ cells per well. 5Cells were seeded at a density of [number] cells per well in 24-well plates. Cells were treated with different concentrations of the compound according to experimental conditions. 24 hours after treatment, the cell suspension was transferred to 1 mL EP tubes, centrifuged, and the cell culture supernatant was discarded, collecting the cell pellet. Each tube was washed twice with 1 mL PBS, then the PBS was discarded. 60 μL of prepared lysis buffer (RIPA:PMSF:protease inhibitor:phosphatase inhibitor = 100:1:1:1:1) was added to each tube for resuspending. Lysis was performed on ice for 30 min, followed by centrifugation at 12000 rpm for 10 min, collecting the supernatant. 5× loading buffer was added, vortexed, and heated in a 100°C metal bath for 10 min. The protein was then analyzed using FuturePAGE. TM Separation was performed on a 10% precast gel and transferred to a nitrocellulose membrane. After transfer, the target and reference proteins were cut according to the label, and the membrane was blocked with TBST containing 5% skim milk powder for 2 hours. Subsequently, the membrane was incubated overnight at 4°C with a specific primary antibody. After incubation, the membrane was washed three times with 1×TBST for 10 minutes each time. The membrane was then incubated with HRP-labeled secondary antibody at room temperature for 1 hour, followed by washing three times with 1×TBST for 10 minutes each time. The target protein was then visualized using ECL detection reagents and a chemiluminescence imaging system (SH-Cute100). The primary antibodies used in this invention include VAV1 (CST, 2502S) and GAPDH (Immunoway, YM8016), and the secondary antibody is HRP-labeled goat anti-rabbit IgG (Abbkine, A21020).

[0497] Table 1 shows the degradation of VAV1 in hPBMCs by the compounds.

[0498] The results in Table 1 show that the compounds of this application have a strong ability to degrade VAV1 in hPBMCs.

[0499] Test Example 2: Jurkat T cell VAV1 degradation test

[0500] After cell resuscitation, cells were cultured to the logarithmic growth phase and seeded into 24-well plates. Drug solutions were prepared in four concentration gradients, and cells were collected and washed after 4 or 24 hours of treatment. Cells were lysed using total protein extract, and protein concentration was determined using a BCA kit. Protein samples were boiled in loading buffer in preparation for electrophoresis. After electrophoresis, proteins were transferred to PVDF membranes and blocked for 1 hour. The membranes were washed with TBST and then incubated with primary antibody (1:1000) and secondary antibody (1:5000), with washing after each incubation step. Finally, the cells were developed using ECL and the results were recorded using a gel imaging system. Data analysis was performed using GraphPad Prism 9 and ImageJ software.

[0501] Table 2. VAV1 degradation activity of the compounds in this application (cell incubation for 24 hours)

[0502] Table 3. VAV1 degradation activity of the compounds in this application (cell incubation for 4 hours)

[0503] The results in Tables 2 and 3 demonstrate that the compounds of this application exhibit excellent VAV1 degradation activity in Jurkat T cells. Test Example 3: VAV1 degradation led to TCR-mediated inhibition of IL-2 and CXCL10 secretion.

[0504] Pan T cells were distributed at a rate of 1 × 10⁶ per well. 5 Cells were seeded at a density of 100 cells / well in 96-well U-shaped plates. Cells were treated with different concentrations of the compound according to experimental conditions. After 24 h of drug treatment, cells were transferred to anti-CD3 (5 μg / mL) coated plates and co-stimulated with anti-CD28 (1 μg / mL). Cells were incubated at 37°C with 5% CO2. After 48 h of anti-CD3 / anti-CD28 co-stimulation, the supernatant was collected for the detection of IL-2 and CXCL10 cytokines. IL-2 in the cell supernatant was assessed using the Startech Human IL-2 OneStep ELISA Kit (S0C3001) according to the manufacturer's protocol, and CXCL10 in the cell supernatant was assessed using the Sizhengbai Human CXCL10 / IP10 (chemokine CXCL10) ELISA KIT Kit (CHE0091-096) according to the manufacturer's protocol. The main reagents used in this study included anti-CD3 (biogems, 05121-25) and anti-CD28 (biogems, 10311-25).

[0505] Table 4 shows the TCR-mediated inhibition of IL-2 secretion caused by the compounds in this application.

[0506] A:IC 50 <0.01nM; B: 0.01nM <IC 50 <0.1 nM; C: 0.1 nM < IC 50 <1nM; D:1nM<IC 50

[0507] The results in Table 4 show that the compound of this application has an inhibitory effect on TCR-mediated IL-2 secretion.

[0508] Table 5 shows the TCR-mediated inhibition of CXCL10 secretion caused by the compounds in this application.

[0509] A:IC 50 <0.1nM; B: 0.1nM <IC 50 <1nM; C:1nM<IC 50

[0510] The results in Table 5 show that the compound of this application has the ability to inhibit TCR-mediated CXCL10 secretion.

[0511] Test Example 4: VAV1 degradation leads to BCR-mediated inhibition of CD69 expression.

[0512] CD19+B cells were distributed at a rate of 1×10⁶ cells per well. 5 Cells were seeded at a density of 1000 cells / well in 96-well U-shaped plates. Cells were treated with different concentrations of the compound according to experimental conditions. After 24 h of drug treatment, cells were co-stimulated with anti-IgM (1 mg / mL; BD; 555780) and recombinant human IL-4 (10 ng / mL; UA; UA040026) for 24 h. Cells were then collected, stained with APC Mouse Anti-Human CD69 (FN50) (BD; 555533), and finally evaluated by flow cytometry. The mean fluorescence intensity (MFI) of CD69-APC in the CD19+B cell population was calculated using FlowJo (BD) software. The CD69 MFI of the compound-treated samples was normalized to that of the DMSO-stimulated and unstimulated controls. The normalized data were imported into Prism 8.0.1 (GraphPad) and fitted using a four-parameter model.

[0513] Table 6 shows the BCR-mediated inhibition of CD69 expression caused by the compounds in this application.

[0514] A:IC 50 ≤0.5nM; B: 0.5nM < IC 50 <1.5nM; C: 1.5nM ≤ IC 50 .

[0515] The results in Table 6 show that the compound of this application has an inhibitory effect on BCR-mediated CD69 expression.

[0516] Test Example 5: In vivo efficacy data

[0517] Twenty-three DBA / 1 mice, aged approximately 7-9 weeks, were divided into six groups based on body weight. Six mice were selected as normal controls and did not undergo modeling. The remaining animals underwent two immunizations to establish the model, as detailed below:

[0518] First immunization (Day 0): An immunization emulsion was prepared using Freund's complete adjuvant (CFA) and type II collagen solution (concentration 2 mg / ml, dissolved in 50 mM acetic acid) at a 1:1 ratio. All animals except the normal group were injected subcutaneously with 0.1 mL of the emulsion into the tail.

[0519] Second immunization (Day 21): An immunization emulsion was prepared using Freund's incomplete adjuvant (IFA) and type II collagen solution (concentration 2 mg / ml, dissolved in 50 mM acetic acid). All animals except the normal group were injected subcutaneously with 0.1 mL of the emulsion into the tail.

[0520] Five days after the second immunization, the animals were observed daily, and clinical arthritis scores were performed. The appearance of clinical symptoms of arthritis indicated successful modeling.

[0521] All animals were given medication on the day of grouping, with a volume of 10 mL / kg and a dose of 0.3 mg / kg. The model group was given the appropriate solvent. All compounds were prepared fresh for use and administered for a total of 14 days.

[0522] After administration to the groups, body weight was measured three times a week and clinical scores were performed three times a week. The experimental endpoint was reached after 14 days of administration, and the pharmacodynamic evaluation of the test compound in a mouse model of type II collagen-induced arthritis (CIA) was conducted.

[0523] Table 7. Pharmacodynamic studies of the compounds in this application on a CIA mouse model.

[0524] The results in Table 7 show that the compounds in this application have excellent alleviating effects on the CIA mouse model.

[0525] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of this application, and not to limit them. Although this application has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some or all of the technical features therein. These modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of this application, and they should all be covered within the scope of the claims and specification of this application. In particular, as long as there is no structural conflict, the various technical features mentioned in the embodiments can be combined in any way. This application is not limited to the specific embodiments disclosed herein, but includes all technical solutions falling within the scope of the claims.

Claims

1. A compound of general formula (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof: in: Cy1 is selected from C6-C 10 Aryl, 5-12 heteroaryl, C3-C 12 Cycloalkyl, 4-12 membered heterocyclic groups, or 7-14 membered fused cyclic groups; Cy2is selected from the group consisting of absent, C6-Ci2aryl, 3-12 membered 10 heteroaryl, C3-C12cycloalkyl, or 4-12 membered heterocyclyl; each of which is substituted with 0, 1, 2, 3, or 4 Rb; 12 heteroaryl, C3-C12cyc X1 is selected from CR6 and N; X2 is selected from CR7 and N; X3 is selected from CR8 and N; X4 is selected from CR9 and N; R1 is selected from H, halogen, cyano, nitro, amino, hydroxyl, C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, or C3-C6 cycloalkyl; R2 and R3 are each independently selected from H, halogen, cyano, nitro, amino, hydroxyl, carboxyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C1-C6 alkylamino, halogenated C1-C6 alkylamino, oxo, C6-C 10 Aryl, 5-10 heteroaryl, C3-C 12 Cycloalkyl, 3-12 membered heterocyclic groups, -OR g -SR g -OC(O)R g -C(O)R g -C(O)OR g -C(O)N(R) x )R y -NR x R y -N(CH3)R g -N(R) x )C(O)R y -N(R) x )C(O)NR x R y -N(R) x )C(O)OR g -C1-C8 alkylene-R g -N(R) x )S(O)NR x R y -N(R) x )S(O)2NR x R y -N(R) x )S(O)2R g -S(O)R g -S(O)2R g -S(O)2NR x R y -S(O)NR x R y or -P(O)R x R y The alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocyclic groups are optionally selected from one or more of R. r Substituents; R4is selected from -O-C3-C8cycloalkyl, -O-3-8 membered heterocyclyl, -O-C1-C2alkylene-3-8 membered heterocyclyl, -NR5-C3-C8cycloalkyl, -NR5-3-8 membered heterocyclyl, said cycloalkyl, heterocyclyl groups being optionally further substituted by one or more substituents selected from R r substituents; R5 is selected from H, C1-C6 alkyl, halo-C1-C6 alkyl, C3-C8 cycloalkyl or 3-12 membered heterocyclic groups; R6, R7, R8, R9are each independently selected from H, halogen, cyano, nitro, amino, hydroxy, carboxy, Ci-C6alkyl, Ci-C6alkoxy, Ci-C6alkylamino, haloCi-C6alkyl, haloCi-C6alkoxy, haloCi-C6alkylamino, C3-C8cycloalkyl, or 3- to 12-membered heterocyclyl; said alkyl, cycloalkyl, heterocyclyl are optionally further substituted by one or more substituents selected from R r substituents; or, R7and R8or R8and R9together with the atoms to which they are attached form a 4-8 membered ring containing 0, 1, or 2 heteroatoms selected from N, O, S, P, and the 4-8 membered ring is optionally further substituted with one or more substituents selected from halo, C1-C8alkyl, C1-C8haloalkyl, C3-C8cycloalkyl, 3-12 membered heterocyclyl, C1-C8alkoxy, C1-C8haloalkoxy, C1-C8alkylamino, haloalkylamino, di(C1-C8alkyl)amino, amino, hydroxyl, oxo, nitro, or cyano; 12 C1-C8alkyl, C1-C8haloalkyl, C3-C8cycloalkyl, 3-12 membered heterocyclyl, C1-C8alkoxy, C1-C8haloalkoxy, C1-C8alkylamino, haloalkylamino, di(C1-C8alkyl)amino, amino, hydroxyl, oxo, nitro, or cyano; L1 is selected from: -Y1-Y2-Y3-Y4-Y5-Y6-, Ra; Y1, Y2, Y3, Y4, Y5, Y6are each independently selected from the group consisting of a chemical bond, -CR 01 R 02 -, -C(R 01 )=C(R 02 )-, -C≡C-, -NR 03 -, -O-, -CO, -S-, -S(O)-, -SO2-, -POR 04 -, 3-6 membered heterocyclylenyl, C3-C6cycloalkylenyl, phenyl, 5-12 membered heteroaryl; Ra is selected from -NR 05 -SO2-R 06 , -SO2-NR 07 R 08 , -NR 05 -C(O)-R 09 , -NR 05 -C(O)-NR 010 ; R 01 R 02 Each is independently selected from H, halogen, hydroxyl, amino, cyano, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, C3-C 12 Cycloalkyl, phenyl, 5-12-membered heteroaryl or 3-12-membered heterocyclic; R 03 , R 04 , R 05 each independently is selected from H, halogen, hydroxyl, amino, cyano, C1-C6alkyl, haloC1-C6alkyl, C1-C6alkoxy, C1-C6alkylamino, C3-C7cycloalkyl, phenyl, 5-12 membered heteroaryl, or 3-12 membered heterocyclyl, said alkyl, cycloalkyl, phenyl, heteroaryl, heterocyclyl optionally further substituted with one or more substituents selected from R 12 r substituents;​ R 06 selected from H, C1-C6 alkyl, haloC1-C6 alkyl, -C1-C6 alkylene-R b ; R 07 , R 08 each independently is selected from H, halogen, hydroxyl, amino, cyano, C1-C6alkyl, haloC1-C6alkyl, C3-C8cycloalkyl, 3-12 membered heterocyclyl; R 09 selected from haloC1-C4alkyl, C3-C6cycloalkyl, 3-12 membered heterocyclyl; R 010 selected from H, C1-C6 alkyl, haloC1-C6 alkyl, C3-C8 cycloalkyl, 3-12 membered heterocyclyl; R b selected from H, halogen, hydroxyl, amino, cyano, C1-C6alkyl, haloC1-C6alkyl, C1-C6alkoxy, C1-C6alkylamino, C3-C6cycloalkyl, phenyl, 5-12 membered heteroaryl, or 3-12 membered heterocyclyl, said alkyl, cycloalkyl, phenyl, heteroaryl, heterocyclyl optionally substituted with one or more substituents selected from R 12 selected from H, halogen, hydroxyl, amino, cyano, C1-C6alkyl, haloC1-C6alkyl, C1-C6alkoxy, C1-C6alkylamino, C3-C6cycloalkyl, phenyl, 5-12 membered heteroaryl, or 3-12 membered heterocyclyl, said alkyl, cycloalkyl, phenyl, heteroaryl, heterocyclyl optionally substituted with one or more substituents selected from R r substituents; or R 01 and R 02 with the carbon atom to which they are both attached form a 3-12 membered ring containing 0, 1 or 2 heteroatoms selected from N, O, S, P; R r R g R x R y Each group is independently selected from H, halogen, cyano, nitro, amino, hydroxyl, carboxyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkoxy, halogenated C1-C6 alkoxy, C1-C6 alkylamino, halogenated C1-C6 alkylamino, oxo, C6-C 10 Aryl, 5-10 heteroaryl, C3-C 12 Cycloalkyl, 3-12 membered heterocyclic groups, -OR s -SR s -C1-C8 alkylene-R s -OC(O)R s -C(O)R s -C(O)OR s -C(O)N(R) s )R t -NR s R t -N(CH3)R s -N(R) s )C(O)R t -N(R) s )C(O)NR s R t -N(R) s )C(O)OR t -N(R) s )S(O)NR s R t -N(R) s )S(O)2NR s R t -N(R) s )S(O)2R t -S(O)R s -S(O)2R s -S(O)2NR s R t or -P(O)R s R t The alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocyclic groups are optionally selected from one or more of R. w Substituents; R w R s R t Each is independently selected from H, deuterium, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, halogen, cyano, amino, nitro, hydroxyl, oxo, C1-C8 alkoxy, C1-C8 haloalkyl, hydroxyC1-C8 alkyl, aminoC1-C8 alkyl, C1-C8 alkylamino, C1-C8 alkylcarbonyl, C1-C8 alkoxycarbonyl, haloC1-C8 hydroxyalkyl, C1-C8 haloalkylamino, C3-C 12 Cycloalkyl, 3-12 membered heterocyclic groups, carboxyl groups, amides, C6-C 10 Aryl or 5-12 heteroaryl groups; o can be selected from 0, 1, 2, 3, or 4; p is selected from 0, 1, 2, 3 or 4; m is selected from 0, 1, 2, 3 or 4; n is selected from 0, 1, or 2; when X1is selected from CR6, X2is selected from CR7, X3is selected from CR8, and X4is selected from CR9, Cy1is selected from 5-membered heteroaryl, 7-8 membered heteroaryl, 11-12 membered heteroaryl, C3-C 12 cycloalkyl, 4-12 membered heterocyclyl, 6-membered and 7-membered fused ring group, 6-membered and 8-membered fused ring group, 5-membered and 6-membered fused ring group, 5-membered and 7-membered fused ring group; the * indicates attachment to the ring connect; Alternatively, when X1 is selected from CR6, X2 is selected from CR7, X3 is selected from CR8, and X4 is selected from CR9, Cy2 is selected when it exists, and p is selected from 1 and 2; Alternatively, when X1 is selected from CR6, X2 is selected from CR7, X3 is selected from CR8, X4 is selected from CR9, Cy2 is selected when it does not exist, and L1 is selected from Ra.

2. The compound according to claim 1, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein which is a compound represented by the general formula (II) or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof: in: Cy1is selected from phenyl, 5-12 membered heteroaryl, C3-C 12 cycloalkyl, 4-12 membered heterocyclyl, or 9-14 membered fused cyclyl; Cy2 is selected from non-existent C6-C. 10 Aryl, 5-10 heteroaryl, C3-C 12 Cycloalkyl or 4-12 membered heterocyclic groups; X1 is selected from CR6 and N; X2 is selected from CR7 and N; X3 is selected from CR8 and N; X4 is selected from CR9 and N; R2 and R3 are each independently selected from H, halogen, cyano, nitro, amino, hydroxyl, carboxyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C1-C6 alkylamino, halogenated C1-C6 alkylamino, oxo, C6-C 10 Aryl, 5-10 heteroaryl, C3-C 12 Cycloalkyl, 3-12 membered heterocyclic groups, -OR g -SR g -OC(O)R g -C(O)R g -C(O)OR g -C(O)N(R) x )R y -NR x R y -N(CH3)R g -N(R) x )C(O)R y -N(R) x )C(O)NR x R y -N(R) x )C(O)OR g -C1-C8 alkylene-R g -N(R) x )S(O)NR x R y -N(R) x )S(O)2NR x R y -N(R) x )S(O)2R g -S(O)R g -S(O)2R g -S(O)2NR x R y -S(O)NR x R y or -P(O)R x R y The alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocyclic groups may optionally be substituted by one or more substituents selected from Rr. R4is selected from -O-C3-C8cycloalkyl, -O-3-8 membered heterocyclyl, -O-C1-C2alkylene-3-8 membered heterocyclyl, -NR5-C3-C8cycloalkyl, -NR5-3-8 membered heterocyclyl, said cycloalkyl, heterocyclyl groups being optionally further substituted by one or more substituents selected from R r substituents; R5 is selected from H, C1-C6 alkyl, halo-C1-C6 alkyl, C3-C8 cycloalkyl or 3-12 membered heterocyclic groups; R6, R7, R8, R9are each independently selected from H, halogen, cyano, nitro, amino, hydroxyl, carboxyl, C1-C6alkyl, C1-C6alkoxy, C1-C6alkylamino, haloC1-C6alkyl, haloC1-C6alkoxy, haloC1-C6alkylamino, C3-C8cycloalkyl or 3-12 membered heterocyclyl; said alkyl, cycloalkyl, heterocyclyl are optionally substituted with one or more selected from R r substituents; or, R7and R8or R8and R9together with the atoms to which they are attached form a 4-8 membered ring containing 0, 1, or 2 heteroatoms selected from N, O, S, P, and the 4-8 membered ring is optionally further substituted with one or more substituents selected from halo, C1-C8alkyl, C1-C8haloalkyl, C3-C8cycloalkyl, 3-12 membered heterocyclyl, C1-C8alkoxy, C1-C8haloalkoxy, C1-C8alkylamino, haloalkylamino, di(C1-C8alkyl)amino, amino, hydroxyl, oxo, nitro, or cyano; 12 C1-C8alkyl, C1-C8haloalkyl, C3-C8cycloalkyl, 3-12 membered heterocyclyl, C1-C8alkoxy, C1-C8haloalkoxy, C1-C8alkylamino, haloalkylamino, di(C1-C8alkyl)amino, amino, hydroxyl, oxo, nitro, or cyano; L1 is selected from: -Y1-Y2-Y3-Y4-Y5-Y6-, Ra; Y1, Y2, Y3, Y4, Y5, Y6are each independently selected from the group consisting of a chemical bond, -CR 01 R 02 -, -C(R 01 ) = C(R 02 )-, -C≡C-, -NR 03 -, -O-, -CO, -S-, -S(O)-, -SO2-, -POR 04 -, 3-6 membered heterocyclylenyl, C3-C6cycloalkylenyl, phenyl, 5-12 membered heteroaryl; Ra is selected from -NR 05 -SO2-R 06 , -SO2-NR 07 R 08 , -NR 05 -C(O)-R 09 , -NR 05 -C(O)-NR 010 ; R 01 R 02 Each is independently selected from H, halogen, hydroxyl, amino, cyano, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, C3-C 12 Cycloalkyl, phenyl, 5-12-membered heteroaryl or 3-12-membered heterocyclic; R 03 , R 04 , R 05 each independently is selected from H, halogen, hydroxyl, amino, cyano, C1-C6alkyl, haloC1-C6alkyl, C1-C6alkoxy, C1-C6alkylamino, C3-C7cycloalkyl, phenyl, 5-12 membered heteroaryl, or 3-12 membered heterocyclyl, said alkyl, cycloalkyl, phenyl, heteroaryl, heterocyclyl optionally further substituted with one or more substituents selected from R 12 r each independently is selected from H, halogen, hydroxyl, amino, cyano, C1-C6alkyl, haloC1-C6alkyl, C1-C6alkoxy, C1-C6alkylamino, C3-C7cycloalkyl, phenyl, 5-12 membered heteroaryl, or 3-12 membered heterocyclyl, said alkyl, cycloalkyl, phenyl, heteroaryl, heterocyclyl optionally further substituted with one or more substituents selected from R​ R 06 selected from H, C1-C6 alkyl, haloC1-C6 alkyl, -C1-C6 alkylene-R b ; R 07 , R 08 each independently is selected from H, halogen, hydroxyl, amino, cyano, C1-C6alkyl, haloC1-C6alkyl, C3-C8cycloalkyl, 3-12 membered heterocyclyl; R 09 selected from haloC1-C4alkyl, C3-C6cycloalkyl, 3-12 membered heterocyclyl; R 010 selected from H, C1-C6 alkyl, haloC1-C6 alkyl, C3-C8 cycloalkyl, 3-12 membered heterocyclyl; R b selected from H, halogen, hydroxyl, amino, cyano, C1-C6alkyl, haloC1-C6alkyl, C1-C6alkoxy, C1-C6alkylamino, C3-C6cycloalkyl, phenyl, 5-12 membered heteroaryl, or 3-12 membered heterocyclyl, said alkyl, cycloalkyl, phenyl, heteroaryl, 3-12 membered heterocyclyl optionally substituted with one or more substituents selected from R 12 r substituents selected from R​ or R 01 and R 02 with the carbon atom to which they are both attached form a 3-12 membered ring containing 0, 1 or 2 heteroatoms selected from N, O, S, P; R r R g R x R y Each group is independently selected from H, halogen, cyano, nitro, amino, hydroxyl, carboxyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkoxy, halogenated C1-C6 alkoxy, C1-C6 alkylamino, halogenated C1-C6 alkylamino, oxo, C6-C 10 Aryl, 5-10 heteroaryl, C3-C 12 Cycloalkyl, 3-12 membered heterocyclic groups, -OR s -SR s -C1-C8 alkylene-R s -OC(O)R s -C(O)R s -C(O)OR s -C(O)N(R) s )R t -NR s R t -N(CH3)R s -N(R) s )C(O)R t -N(R) s )C(O)NR s R t -N(R) s )C(O)OR t -N(R) s )S(O)NR s R t -N(R) s )S(O)2NR s R t -N(R) s )S(O)2R t -S(O)R s -S(O)2R s -S(O)2NR s R t or -P(O)R s R t The alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocyclic groups are optionally selected from one or more of R. w Substituents; R w R s R t Each is independently selected from H, deuterium, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, halogen, cyano, amino, nitro, hydroxyl, oxo, C1-C8 alkoxy, C1-C8 haloalkyl, hydroxyC1-C8 alkyl, aminoC1-C8 alkyl, C1-C8 alkylamino, C1-C8 alkylcarbonyl, C1-C8 alkoxycarbonyl, haloC1-C8 hydroxyalkyl, C1-C8 haloalkylamino, C3-C 12 Cycloalkyl, 3-12 membered heterocyclic groups, carboxyl groups, amides, C6-C 10 Aryl or 5-12 heteroaryl groups; o can be selected from 0, 1, 2, 3, or 4; p is selected from 0, 1, 2, 3 or 4; m is selected from 0, 1, 2, 3 or 4; when X1is selected from CR6, X2is selected from CR7, X3is selected from CR8, and X4is selected from CR9, Cy1is selected from a 5-membered heteroaryl, a 6-membered and 7-membered fused ring group, a 6-membered and 8-membered fused ring group, a 5-membered and 6-membered fused ring group, or a 5-membered and 7-membered fused ring group; said * indicates a bond to connect; Alternatively, when X1 is selected from CR6, X2 is selected from CR7, X3 is selected from CR8, and X4 is selected from CR9, Cy2 is selected when it exists, and p is selected from 1 and 2; Alternatively, when X1 is selected from CR6, X2 is selected from CR7, X3 is selected from CR8, X4 is selected from CR9, Cy2 is selected when it does not exist, and L1 is selected from Ra.

3. The compound according to claim 2, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein, (VIIa-VIIb) or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof: Ra is selected from -NR 05 -SO2-R 06 , -SO2-NR 07 R 08 , -NR 05 -C(O)-R 09 , -NR 05 -C(O)-NR 010 ; R 05 selected from H, halogen, hydroxyl, amino, cyano, Ci-C6alkyl, haloCi-C6alkyl, Ci-C6alkoxy, Ci-C6alkylamino; R 06 selected from the group consisting of C1-C4alkyl, haloC1-C4alkyl; R 07 selected from H, C1-C4 alkyl, C3-C6 cycloalkyl; R 08 selected from H, C1-C4 alkyl, C3-C6 cycloalkyl; R 09 selected from haloC1-C4alkyl, C3-C6cycloalkyl, 3-12 membered heterocyclyl; R 010 selected from H, C1-C4 alkyl; L1is selected from a chemical bond, methylene, -0-, -NH-, Cy2 is selected from a 6-membered heteroaryl group; R3is selected from H, halogen, cyano, amino, oxo, C1-C4alkyl, C1-C4alkoxy, haloC1-C4alkyl, C3-C6cycloalkyl, 4-6 membered heterocyclyl, or -C1-C3alkylene-R 3a C2-C4alkenyl, C2-C4alkynyl; said alkyl, cycloalkyl, heterocyclyl, alkenyl, alkynyl are optionally further substituted by one or more substituents selected from C1-C4alkyl, haloC1-C4alkyl, halogen, cyano, C3-C6cycloalkyl, 4-6 membered heterocyclyl; R 3a selected from H, halogen, cyano, amino, hydroxyl, oxo, C1-C4alkyl, C1-C4alkoxy, haloC1-C4alkyl, C3-C6cycloalkyl, or 4-6 membered heterocyclyl; said alkyl, cycloalkyl, heterocyclyl are optionally further substituted with one or more substituents selected from C1-C4alkyl, haloC1-C4alkyl, halogen, cyano, C3-C6cycloalkyl, 4-6 membered heterocyclyl substituents; R4 is selected from -O-C3-C6 cycloalkyl, -O-4-6-membered heterocyclic group, -O-C1-C2 alkylene-4-6-membered heterocyclic group, -NH-C3-C6 cycloalkyl, -NH-4-6-membered heterocyclic group; wherein the cycloalkyl or heterocyclic group is optionally further substituted by one or more substituents selected from C1-C4 alkyl, halogen, cyano, halo-C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl or 4-6-membered heterocyclic group; Preferably, Cy2is selected from Connect to R4, Connected to L1; Preferably, R4 is selected from Preferably, selected from the group consisting of 4. The compound according to claim 2, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein (VIII) or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof. CyB is selected from 7- to 8-membered heterocycles, wherein the heterocycle contains one or two heteroatoms selected from N or O; selected from the group consisting of L1 is selected from chemical bonds, methylene, -O- or -NH-; selected from the absence, W1, W2, W3, W4, and W5 are each independently selected from: CH, N, or CO; j is selected from 1, 2, 3, or 4; R3 is selected from H, oxo, halogen, cyano, C1-C4 alkyl or halo-C1-C4 alkyl; R4 is selected from -O-C3 to C6 cycloalkyl, -O-4 to 6-membered heterocyclic, -NH-C3 to C6 cycloalkyl or -NH-4 to 6-membered heterocyclic; wherein the cycloalkyl or heterocyclic group is optionally further substituted by one or more substituents selected from halogen, C1-C4 alkyl, C1-C4 alkoxy or halo-C1-C4 alkyl. Preferably, selected from the absence, Preferably, selected from the group consisting of 5. The compound according to claim 2, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein, which is a compound represented by General Formula (IXa-IXb) or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof: in: T1is selected from CR 10 , N; T2is selected from CR 11 , N; T3is selected from CR 12 , N; T4is selected from CR 13 , N; R 10 , R 11 , R 12 , R 13 are each independently selected from H, halogen, cyano, nitro, amino, hydroxyl, carboxyl, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylamino, haloC1-C3 alkyl, haloC1-C3 alkoxy, haloC1-C3 alkylamino, C3-C6 cycloalkyl, 4-6 membered heterocyclyl, C2-C4 alkenyl, C2-C4 alkynyl, haloC2-C4 alkenyl, or haloC2-C4 alkynyl; R2 is selected from H, halogen, C1-C3 alkyl, or halo-C1-C3 alkyl; R3is selected from H, halogen, cyano, amino, oxo, C1-C4alkyl, C2-C4alkenyl, C2-C4alkynyl C1-C4alkoxy, haloC1-C4alkyl, C3-C6cycloalkyl, 4-6 membered heterocyclyl, -C1-C3alkylene-R 3a said alkyl, cycloalkyl, heterocyclyl, alkenyl, alkynyl are optionally further substituted by one or more substituents selected from C1-C4alkyl, haloC1-C4alkyl, halogen, cyano, C3-C6cycloalkyl, 4-6 membered heterocyclyl substituents; R 3a selected from H, halogen, cyano, amino, hydroxyl, oxo, C1-C4alkyl, C1-C4alkoxy, haloC1-C4alkyl, C3-C6cycloalkyl, 4-6 membered heterocyclyl, said alkyl, cycloalkyl, heterocyclyl optionally further substituted with one or more substituents selected from C1-C4alkyl, haloC1-C4alkyl, halogen, cyano, C3-C6cycloalkyl, 4-6 membered heterocyclyl; R 4a C3-C6cycloalkyl, 4- to 6-membered heterocyclyl, -Ci-C2alkylene-4- to 6-membered heterocyclyl, said cycloalkyl, heterocyclyl groups being optionally further substituted by one or more substituents selected from the group consisting of Ci-C4alkyl, haloCi-C4alkyl, halogen, cyano, Ci-C4alkoxy, C3-C6cycloalkyl, 4- to 6-membered heterocyclyl; m is selected from 0, 1, or 2; o can be selected from 0, 1, or 2.

6. The compound according to claim 1, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein which is a compound represented by the general formula (X) or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof: in: R2 is selected from H or halogen; R3is selected from H, halogen, cyano, C1-C4alkyl, ethynyl, trifluoromethyl, difluoromethyl, cyclopropyl or T3 is selected from CH or N; R 4a selected from C3-C6cycloalkyl or 4-6 membered heterocyclyl.

7. The compound according to claim 6, or its stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, characterized in that, R2 is selected from H or fluorine; R3is selected from H, chloro, fluoro, cyano, methyl, isopropyl, trifluoromethyl, difluoromethyl, cyclopropyl or R 4a selected from C3-C6cycloalkyl, 8. The compound according to claim 1, wherein the compound is selected from: ###0009### or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof. Or its stereoisomers, or mixtures thereof, or pharmaceutically acceptable salts thereof.

9. A pharmaceutical composition, characterized by, The pharmaceutical composition contains an effective dose of the compound or its stereoisomer, or a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 8, and a pharmaceutically acceptable carrier, excipient, or combination thereof.

10. The use of the compound or stereoisomer of any one of claims 1 to 8, a mixture of stereoisomers thereof, a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 9 in the preparation of a medicament for treating diseases related to VAV1.

11. Use according to claim 10, characterized in that, The diseases associated with VAV1 include autoimmune diseases, malignant tumors, chronic and acute inflammation, neurological diseases, and transplant-related diseases.

12. The use of the compound or stereoisomer of any one of claims 1 to 8, or a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 9, in the preparation of a medicament for treating autoimmune diseases, malignant tumors, chronic and acute inflammation, nervous system diseases, and transplant-related diseases.

13. A method for treating or preventing a disease or condition related to VAV1 in an individual, the method comprising administering to the individual an effective amount of any one of claims 1 to 8, a stereoisomer thereof, a mixture of stereoisomers thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 9.

14. The method of claim 13, wherein, The diseases associated with VAV1 include autoimmune diseases, malignant tumors, chronic and acute inflammation, neurological diseases, and transplant-related diseases.

Images