Nitrogen oxides, process for their preparation and their use in medicine

Abstract

The present disclosure relates to a nitroxide, a process for its preparation and its use in medicine. In particular, the present disclosure relates to a nitroxide of general formula (I), a process for its preparation, a pharmaceutical composition containing the nitroxide and its use as a therapeutic agent, in particular as a VAV1 inhibitor or degrader and in the manufacture of a medicament for the treatment and / or prevention of a disease or disorder mediated or dependent on VAV1. Wherein the groups in general formula (I) are as defined in the description.

Description

Technical Field

[0001] This disclosure pertains to the pharmaceutical field and relates to a nitrogen oxide of general formula (I), a method for its preparation, a pharmaceutical composition containing the nitrogen oxide, and its use as a therapeutic agent, particularly as a VAV1 inhibitor or degrader, and in the preparation of medicaments for the treatment and / or prevention of VAV1-mediated or dependent diseases or conditions. Background Technology

[0002] The VAV family is a group of signal transduction proteins that act as nucleation-dependent GDP / GTP exchange factors (GEFs) and adaptor molecules for Rho subfamily GTPases. In vertebrates, this family consists of three members: Vav1, Vav2, and Vav3. 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. 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. Regarding the function of VAV1, researchers first discovered Vav1… - / - Mice exhibited severe T cell developmental defects, including a significant reduction in the number of thymic and peripheral T cells; conversely, Vav2... – / – Vav3 – / – and Vav2 – / – / 3 – / – The mouse model showed normal T cell development, indicating the crucial role of Vav1 in T cell development; secondly, Vav1 also affects signal transduction in T / B cells, for example: Vav1 - / - CD4 +Th cells exhibited a deficiency in IL-4 expression. Furthermore, CRISPR screening further validated the crucial role of VAV1 in TCR-mediated activation and T cell effector function. When the TCR, BCR, and other cytokine receptors are activated, Vav1 is rapidly phosphorylated, activating Rac GTPases. Vav1 plays a role in various cellular functions, including actin remodeling, F-actin polymerization, TCR aggregation, integrin-mediated cell adhesion activation, immune synapse formation between T cells and antigen-presenting cells (APCs), and chemokine-mediated cell migration. VAV1 also regulates B cell cytoskeleton remodeling. In addition, Vav1 functions as a scaffold protein in GEF-independent pathways. T cells derived from GEF-inactivated VAV1 mice showed normal TCR-mediated calcium release and NFAT pathway activation in vitro. Conversely, transfection of human VAV1-deficient J.Vav1 T cells with a GEF-retaining N-terminal truncated mutant resulted in incomplete Ca2+ release, calmodulin binding, and NFAT pathway activation in vitro due to the inability to interact with phospholipase C-γ (PLCγ)1. These findings demonstrate the scaffold function of VAV1. Although the exact role of VAV1 in human diseases remains to be clinically validated, multiple pieces of evidence suggest its association with autoimmune and chronic inflammatory diseases. VAV1-deficient mice antagonize MOG(5-55)-induced EAE, a model widely used to evaluate drug efficacy against multiple sclerosis. Genomic screening of primary human T cells using the CRISPRa and CRISPRi methods has also revealed VAV1 as an important positive regulator of T cell function. These findings highlight VAV1's potential as a target in autoimmune and chronic diseases. Because VAV1 lacks a distinct binding pocket, it has long been considered an untreatable target. Molecular glue degraders (MGDs) are oral small molecules that induce ubiquitination and degradation of target proteins by binding to the surface of E3 ligase complexes, representing a novel class of molecules targeting proteins without a clear binding pocket. Monte Rosa Therapeutics has designed a molecular glue, MRT-6160, targeting VAV1. Through MGD-mediated degradation of VAV1 protein, it regulates TCR and BCR-mediated activation, inhibiting T cell proliferation and cytokine production. MRT-6160 has shown excellent preclinical efficacy in animal models of arthritis and colitis, providing a solid foundation for future clinical trials. This disclosure describes a molecular glue specifically for VAV1 degradation. Summary of the Invention

[0003] The purpose of this disclosure is to provide a compound of general formula (I) or a pharmaceutically acceptable salt thereof.

[0004]

[0005] in:

[0006] Ring B is a ring containing at least one N. + -O - cycloalkyl, heterocyclic, aryl, or heteroaryl groups;

[0007] X is N or CR 6a ;

[0008] Y is N or CR 6d ;

[0009] R 1 R 2 R 3 R 4 R 5 R 6a R 6b R 6c and R 6d The same or different, and each independently selected from hydrogen atom, halogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, cyano, amino, hydroxy, nitro, cycloalkyl, heterocyclic, aryl, heteroaryl, -OR 16 -NR 17 R 18 -C(O)R 16 -C(O)OR 16 -C(O)NR 17 R 18 -OC(O)NR 17 R 18 -OC(O)R 16 -OC(O)OR 16 -NR 19 C(O)R 16 -NR 19 C(O)OR 16 -S(O) v R 16 -S(O) v NR 17 R 18 -NR 17 R 18 -S(O) v -NR 19 C(O)NR 17 R 18 -NR 19 S(O) v R 16 =O and =CR 20R 21 The alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each independently and optionally selected by one or more R groups. 0 replace;

[0010] Or, two Rs 1 Together with their respective attached atoms, they form cycloalkyl, heterocyclic, aryl, or heteroaryl groups, each of which is independently and optionally influenced by one or more R groups. 0 replace;

[0011] L is selected from bond, O, S(O). v S(O) v NR c NR c S(O) v C(O), NR c C(O)NR c NR c C(O), alkylene, O(alkylene), (alkylene)O, NR c (alkylene), (alkylene)NR c C(O)NR c (alkylene), (alkylene)C(O)NR c S(O) v (alkylene), (alkylene)S(O) v (alkylene)S(O) v NR c S(O) v NR c (alkylene), NR c C(O)NR c NR c S(O) v NR c C(O) (alkylene) and (alkylene)C(O), wherein the alkylene is optionally mixed with one or more R 0 replace;

[0012] R c Selected from hydrogen atoms, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, and cycloalkylalkyl;

[0013] Or, L and R 6a Together with the adjacent atoms, they form cycloalkyl, heterocyclic, aryl, or heteroaryl groups fused to the ring containing X and Y, wherein each cycloalkyl, heterocyclic, aryl, and heteroaryl group is independently and optionally influenced by one or more R groups. 0 replace;

[0014] Or, L and R 6dTogether with the adjacent atoms, they form cycloalkyl, heterocyclic, aryl, or heteroaryl groups fused to the ring containing X and Y, wherein each cycloalkyl, heterocyclic, aryl, and heteroaryl group is independently and optionally influenced by one or more R groups. 0 replace;

[0015] R 7 Selected from hydrogen atoms, halogens, hydroxyl groups, alkyl groups, haloalkyl groups, hydroxyalkyl groups, alkoxy groups, and haloalkoxy groups;

[0016] R 16 R 17 and R 18 The same or different, and each independently selected from hydrogen atoms, alkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl, wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl is independently optionally selected by one or more R 0 Replace; or R 17 and R 18 Together with the connected nitrogen atom, they form an optional structure with one or more R atoms. 0 Substituted heterocyclic groups;

[0017] R 19 Selected from hydrogen atoms, alkyl groups, and cycloalkyl groups;

[0018] R 20 and R 21 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, alkyl groups, alkoxy groups, hydroxyl groups, and cycloalkyl groups; or, R 20 and R 21 Together with the attached carbon atom, they form cycloalkyl or heterocyclic groups;

[0019] Each R 0 They may be the same or different, and each is independently selected from halogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, aminoalkyl, hydroxyl, cyano, nitro, amino, -NHalkyl, -N(alkyl)2, =O, =S, =CH2, =CHF, =CF2, -C(O)Oalkyl, -C(O)OH, -C(O)NH2, -C(O)NH(alkyl), -C(O)N(alkyl)2, -C(O)halogen, -C(O)alkyl, -S(alkyl), cycloalkyl, cycloalkylalkyl, cycloalkyloxy, heterocyclic, heterocyclic alkyl, heterocyclic oxy, aryl, arylalkyl, aryloxy, heteroaryl, heteroarylalkyl and heteroaryloxy;

[0020] Or, two Rs 0 Together with the attached atoms, they form a 3- to 8-membered cycloalkyl or a 3- to 8-membered heterocyclic group, wherein each of the 3- to 8-membered cycloalkyl and the 3- to 8-membered heterocyclic group is independently and optionally substituted by one or more substituents selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy and oxo.

[0021] n is 0, 1, 2, 3, 4, 5, or 6; and

[0022] v can be 0, 1, or 2.

[0023] In some implementation schemes, R 7 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and hydroxyl; in some embodiments, R 7 It is a hydrogen atom.

[0024] In some embodiments, ring B is selected from pyridine oxynitride, quinoline oxynitride, and isoquinoline oxynitride; in some embodiments, ring B is pyridine oxynitride.

[0025] In some implementation schemes, Selected from , and B 1 B 2 B 3 B 4 and B 5 Each is independently selected from N, N + -O - and CR 1 V 1 V 2 V 3 V 4 V 5 V 6 and V 7 Each is independently selected from N, N + -O - and CR 1 The condition is that B 1 B 2 B 3 B 4 and B 5 At least one of them is N + -O - V 1 V 2 V 3 V 4 V 5 V 6 and V 7 At least one of them is N + -O - ;R 1 As defined in general formula (I); in some implementations, Selected from , , , , , , and n1 is 0, 1, 2, 3, or 4; n2 is 0, 1, 2, 3, 4, 5, or 6; R 1 As defined in general formula (I); in some implementations, for or .

[0026] This disclosure provides a compound of general formula (II) or a pharmaceutically acceptable salt thereof.

[0027]

[0028] in:

[0029] B 1 B 2 B 3 B 4 and B 5 Each is independently selected from N, N + -O - and CR 1 The condition is that B 1 B 2 B 3 B 4 and B 5 At least one of them is N + -O - ;and

[0030] R 1 -R 5 X, R 6b R 6c Y and L are as defined in general formula (I).

[0031] This disclosure provides a compound of general formula (III) or a pharmaceutically acceptable salt thereof.

[0032]

[0033] in:

[0034] V 1 V 2 V 3 V 4 V 5 V 6 and V 7 Each is independently selected from N, N + -O - and CR 1 The condition is that V1 V 2 V 3 V 4 V 5 V 6 and V 7 At least one of them is N + -O - ;and

[0035] R 1 -R 5 X, R 6b R 6c Y and L are as defined in general formula (I).

[0036] In some implementation schemes, B 1 For N + -O - B 2 B 3 B 4 and B 5 Each is independently N or CR 1 Or, B 2 For N + -O - B 1 B 3 B 4 and B 5 Each is independently N or CR 1 Or, B 3 For N + -O - B 1 B 2 B 4 and B 5 Each is independently N or CR 1 In some implementation schemes, B 1 For N + -O - B 2 B 3 B 4 and B 5 Each independently for CR 1 Or, B 2 For N + -O - B 1 B 3 B 4 and B 5 Each independently for CR 1 Or, B 3 For N + -O - B 1 B2 B 4 and B 5 Each independently for CR 1 ;R 1 As defined in general formula (I); in some implementations, B 1 For N + -O - B 2 B 3 B 4 and B 5 For CH; or, B 2 For N + -O - B 1 B 3 B 4 and B 5 For CH; or, B 3 For N + -O - B 1 B 2 B 4 and B 5 For CH.

[0037] In some implementation schemes, V 1 For N + -O - V 2 V 3 V 4 V 5 V 6 and V 7 Each is independently N or CR 1 Or, V 2 For N + -O - V 1 V 3 V 4 V 5 V 6 and V 7 Each is independently N or CR 1 Or, V 7 For N + -O - V 1 V 2 V 3 V 4 V 5 and V 6 Each is independently N or CR 1 In some implementation schemes, V 1 For N + -O - V2 V 3 V 4 V 5 V 6 and V 7 Each independently for CR 1 Or, V 2 For N + -O - V 1 V 3 V 4 V 5 V 6 and V 7 Each independently for CR 1 Or, V 7 For N + -O - V 1 V 2 V 3 V 4 V 5 and V 6 Each independently for CR 1 In some implementation schemes, V 1 For N + -O - V 2 V 3 V 4 V 5 V 6 and V 7 For CH; or, V 2 For N + -O - V 1 V 3 V 4 V 5 V 6 and V 7 For CH; or, V 7 For N + -O - V 1 V 2 V 3 V 4 V 5 and V 6 For CH.

[0038] In some implementations, X is CR 6a ;R 6a As defined in general formula (I); in some implementations, X is CH; in some implementations, X is N.

[0039] In some implementations, Y is CR6d ;R 6d As defined in general formula (I); in some implementations, Y is CH; in some implementations, Y is N.

[0040] In some implementations, X is CR 6a Y is CR 6d ;R 6a and R 6d As defined in general formula (I); in some implementations, X is CH; Y is CH.

[0041] This disclosure provides a compound of general formula (II-1) or a pharmaceutically acceptable salt thereof.

[0042]

[0043] in:

[0044] n1 is 0, 1, 2, 3, or 4; and

[0045] R 1 -R 5 L, R 6a R 6b R 6c and R 6d As defined in general formula (I).

[0046] In some implementation schemes, Selected from , and n² is 0, 1, 2, 3, 4, 5, or 6; R 1 As defined in general formula (I); in some implementations, Selected from , , , and .

[0047] This disclosure provides a compound of general formula (III-1) or a pharmaceutically acceptable salt thereof.

[0048]

[0049] in:

[0050] n² is 0, 1, 2, 3, 4, 5, or 6; and

[0051] R 1 -R 5 L, R 6a R 6b R 6c and R 6dAs defined in general formula (I).

[0052] In some implementations, L is selected from bond, O, C 1-3 Alkylene and OC 1-3 Alkylene; in some embodiments, L is selected from bond, O, CH2 and OCH2; in some embodiments, L is selected from bond, CH2 and OCH2; in some embodiments, L is bond; in some embodiments, L is O; in some embodiments, L is CH2, CH2 and CH2CH2CH2; in some embodiments, L is CH2; in some embodiments, L is OCH2.

[0053] In some implementations, R 1 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl and C 1-6 Haloalkoxy; or, two R 1 Together with the attached atoms, they form 3- to 8-membered cycloalkyl, 3- to 8-membered heterocyclic, phenyl, or 5- or 6-membered heteroaryl groups; in some embodiments, R 1 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl and C 1-6 Halogenated alkyl groups; or, two adjacent R groups 1 Together with their respective attached carbon atoms, they form a phenyl group; in some embodiments, R 1 They may be the same or different, and each is independently a hydrogen atom or a carbon atom. 1-6 Alkyl group; or, two adjacent R groups 1 Together with their respective attached carbon atoms, they form a phenyl group; in some embodiments, R 1 It is a hydrogen atom, or two adjacent R atoms. 1 Together with their respective attached carbon atoms, they form a phenyl group; in some embodiments, R 1 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl and C 1-6 Halogenated alkyl; in some embodiments, R 1 They may be the same or different, and each is independently a hydrogen atom or a carbon atom. 1-6 Alkyl; in some embodiments, R 1 They may be the same or different, and each is independently a hydrogen atom or a methyl group; in some embodiments, R 1 For hydrogen atoms; in some implementations, two adjacent R atoms 1 Together with their respective carbon atoms, they form a phenyl group.

[0054] In some implementation schemes, R 2 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl; in some embodiments, R 2 For halogen; in some implementations, R 2 For F or Cl; in some implementations, R 2 It is Cl.

[0055] In some implementation schemes, R 3 Selected from hydrogen atoms, halogens and C 1-6 Alkyl; in some embodiments, R 3 It is a hydrogen atom.

[0056] In some implementation schemes, R 4 Selected from hydrogen atoms, halogens and C 1-6 Alkyl; in some embodiments, R 4 It is a hydrogen atom.

[0057] In some implementation schemes, R 5 Selected from hydrogen atoms, halogens and C 1-6 Alkyl; in some embodiments, R 5 It is a hydrogen atom.

[0058] In some implementation schemes, R 3 It is a hydrogen atom; and / or R 4 It is a hydrogen atom; and / or R 5 It is a hydrogen atom.

[0059] In some implementation schemes, R 6a Selected from hydrogen atoms, halogens and C 1-6 Alkyl; in some embodiments, R 6a It is a hydrogen atom or a carbon atom. 1-6 Alkyl; in some embodiments, R 6a It is a hydrogen atom or a methyl group; in some embodiments, R 6a It is a hydrogen atom.

[0060] In some implementation schemes, R 6b Selected from hydrogen atoms, halogens and C 1-6 Alkyl; in some embodiments, R 6b It is a hydrogen atom or a carbon atom. 1-6 Alkyl; in some embodiments, R 6b It is a hydrogen atom or a methyl group; in some embodiments, R 6b It is a hydrogen atom.

[0061] In some implementation schemes, R 6c Selected from hydrogen atoms, halogens and C 1-6 Alkyl; in some embodiments, R6c It is a hydrogen atom or a carbon atom. 1-6 Alkyl; in some embodiments, R 6c It is a hydrogen atom or a methyl group; in some embodiments, R 6c It is a hydrogen atom.

[0062] In some implementation schemes, R 6d Selected from hydrogen atoms, halogens and C 1-6 Alkyl; in some embodiments, R 6d It is a hydrogen atom or a carbon atom. 1-6 Alkyl; in some embodiments, R 6d It is a hydrogen atom or a methyl group; in some embodiments, R 6d It is a hydrogen atom.

[0063] In some implementation schemes, R 6a It is a hydrogen atom; and / or R 6b It is a hydrogen atom; and / or R 6c It is a hydrogen atom; and / or R 6d It is a hydrogen atom or a carbon atom. 1-6 alkyl.

[0064] In some implementation schemes, R 6a It is a hydrogen atom; and / or R 6b It is a hydrogen atom; and / or R 6c It is a hydrogen atom; and / or R 6d It is a hydrogen atom.

[0065] In some implementations, n is 0, 1, or 2; in some implementations, n is 0 or 1; in some implementations, n is 0; in some implementations, n is 1; in some implementations, n is 2.

[0066] In some implementations, n1 is 0, 1, or 2; in some implementations, n1 is 0 or 1; in some implementations, n1 is 1; in some implementations, n1 is 0; in some implementations, n1 is 2.

[0067] In some implementations, n2 is 0, 1, or 2; in other implementations, n2 is 0.

[0068] In some implementation schemes, for or In some implementation schemes, for In some implementation schemes, for .

[0069] In some implementation schemes, R 16 It is a hydrogen atom or a carbon atom.1-6 Alkyl; in some embodiments, R 16 C 1-6 Alkyl; in some embodiments, R 16 It is a hydrogen atom.

[0070] In some implementation schemes, R 17 and R 18 They may be the same or different, and each is independently a hydrogen atom or a carbon atom. 1-6 alkyl.

[0071] In some implementation schemes, R 19 It is a hydrogen atom.

[0072] In some implementation schemes, R 20 and R 21 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl; in some embodiments, R 20 and R 21 They may be the same or different, and each is independently a hydrogen atom or a halogen; in some embodiments, R 20 and R 21 It is F.

[0073] In some implementations, v is 0; in some implementations, v is 1; and in some implementations, v is 2.

[0074] In some implementation schemes, each R 0 They may be the same or different, and each is independently selected from halogens, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkoxy and oxo groups; or, geminal or two adjacent R groups. 0 Together with the attached atoms, they form 3- to 8-membered cycloalkyl or 3- to 8-membered heterocyclic groups; in some embodiments, each R 0 They may be the same or different, and each is independently selected from halogens, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkoxy and oxo groups; or, R 1 The two Rs on 0 Together with the attached atoms, they form 3- to 8-membered cycloalkyl or 3- to 8-membered heterocyclic groups; or, R 2 The two Rs on 0 Together with the attached atoms, they form 3- to 8-membered cycloalkyl or 3- to 8-membered heterocyclic groups; or, R 3The two Rs on 0 Together with the attached atoms, they form 3- to 8-membered cycloalkyl or 3- to 8-membered heterocyclic groups; or, R 4 The two Rs on 0 Together with the attached atoms, they form 3- to 8-membered cycloalkyl or 3- to 8-membered heterocyclic groups; or, R 5 The two Rs on 0 Together with the attached atoms, they form 3- to 8-membered cycloalkyl or 3- to 8-membered heterocyclic groups; or, R 6a The two Rs on 0 Together with the attached atoms, they form 3- to 8-membered cycloalkyl or 3- to 8-membered heterocyclic groups; or, R 6b The two Rs on 0 Together with the attached atoms, they form 3- to 8-membered cycloalkyl or 3- to 8-membered heterocyclic groups; or, R 6c The two Rs on 0 Together with the attached atoms, they form 3- to 8-membered cycloalkyl or 3- to 8-membered heterocyclic groups; or, R 6d The two Rs on 0 Together with the attached atoms, they form 3- to 8-membered cycloalkyl or 3- to 8-membered heterocyclic groups; in some embodiments, each R 0 They may be the same or different, and each is independently selected from halogens, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Halogenated alkoxy groups and oxo groups; or two R groups on the same carbon atom 0 Together with the attached atoms, they form 3 to 8-membered cycloalkyl groups; in some embodiments, each R 0 They may be the same or different, and each is independently selected from halogens, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkoxy and oxo groups; in some embodiments, each R 0 They may be the same or different, and each is independently selected from halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl; in some embodiments, R 0 It is an oxo group.

[0075] In some embodiments, the compound represented by general formula (II-1) or a pharmaceutically acceptable salt thereof,

[0076] Among them, R 2 It is a halogen; R 3 For hydrogen atoms; R 4 For hydrogen atoms; R5 For hydrogen atoms; R 6a Selected from hydrogen atoms, halogens and C 1-6 Alkyl; R 6b Selected from hydrogen atoms, halogens and C 1-6 Alkyl; R 6c Selected from hydrogen atoms, halogens and C 1-6 Alkyl; R 6d Selected from hydrogen atoms, halogens and C 1-6 Alkyl; L is selected from bond, CH2 and OCH2; R 1 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl and C 1-6 Halogenated alkyl groups; or, two adjacent R groups 1 Together with their respective carbon atoms, they form a phenyl group; n1 is 0, 1, or 2.

[0077] In some embodiments, the compound represented by general formula (II-1) or a pharmaceutically acceptable salt thereof,

[0078] Among them, R 2 It is a halogen; R 3 For hydrogen atoms; R 4 For hydrogen atoms; R 5 For hydrogen atoms; R 6a Selected from hydrogen atoms, halogens and C 1-6 Alkyl; R 6b For hydrogen atoms; R 6c For hydrogen atoms; R 6d Selected from hydrogen atoms, halogens and C 1-6 Alkyl; L is a bond; R 1 They may be the same or different, and each is independently a hydrogen atom or a carbon atom. 1-6 Alkyl; n1 is 0 or 1.

[0079] In some embodiments of this disclosure, the compound represented by general formula (II-1) or a pharmaceutically acceptable salt thereof,

[0080] Among them, R 2 It is a halogen; R 3 For hydrogen atoms; R 4 For hydrogen atoms; R 5 For hydrogen atoms; R 6a Selected from hydrogen atoms, halogens and C 1-6 Alkyl; R 6b For hydrogen atoms; R 6c For hydrogen atoms; R 6d Halogen or C 1-6 Alkyl; L is selected from bond, CH2 and OCH2; R 1They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl and C 1-6 Haloalkyl; or, or, two adjacent Rs 1 Together with their respective carbon atoms, they form a phenyl group; n1 is 0, 1, or 2.

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

[0082] Among them, R 2 It is a halogen; R 3 For hydrogen atoms; R 4 For hydrogen atoms; R 5 For hydrogen atoms; R 6a For hydrogen atoms; R 6b For hydrogen atoms; R 6c For hydrogen atoms; R 6d For hydrogen atoms; L is selected from bond, CH2 and OCH2; R 1 It is a hydrogen atom; or, two adjacent R atoms. 1 Together with their respective carbon atoms, they form a phenyl group; n1 is 0, 1, or 2.

[0083] In some embodiments, the compound represented by general formula (II-1) or a pharmaceutically acceptable salt thereof,

[0084] Among them, R 2 It is a halogen; R 3 For hydrogen atoms; R 4 For hydrogen atoms; R 5 For hydrogen atoms; R 6a For hydrogen atoms; R 6b For hydrogen atoms; R 6c For hydrogen atoms; R 6d For hydrogen atoms; L is selected from bond, CH2 and OCH2; R 1 It is a hydrogen atom.

[0085] In some embodiments, the compound represented by general formula (III-1) or a pharmaceutically acceptable salt thereof, wherein R 2 It is a halogen; R 3 For hydrogen atoms; R 4 For hydrogen atoms; R 5 For hydrogen atoms; R 6a For hydrogen atoms; R 6b For hydrogen atoms; R 6c For hydrogen atoms; R 6d For hydrogen atoms; L represents a bond; R represents a hydrogen atom. 1 It is a hydrogen atom.

[0086] Group A: Typical compounds disclosed herein include, but are not limited to:

[0087] , , , , , , , , ,

[0088] , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and .

[0089] Another aspect of this disclosure relates to a method for preparing a compound of general formula (I) or a pharmaceutically acceptable salt thereof, comprising:

[0090]

[0091] A compound of general formula (IA) or a salt thereof undergoes a coupling reaction with a compound of general formula (IB) or a salt thereof to obtain a compound of general formula (I) or a pharmaceutically usable salt thereof;

[0092] in:

[0093] R w for Or -B(OH)2;

[0094] R L For leaving groups; in some embodiments, R L For halogen; in some implementations, RL It is Br; and

[0095] R 1 -R 5 R 7 X, Y, L, R 6b R 6c Rings B and n are defined as in general formula (I).

[0096] Another aspect of this disclosure relates to a method for preparing a compound of general formula (II) or a pharmaceutically acceptable salt thereof, comprising:

[0097]

[0098] A compound of general formula (IIA) or a salt thereof undergoes a coupling reaction with a compound of general formula (IIB) or a salt thereof to obtain a compound of general formula (II) or a pharmaceutically usable salt thereof;

[0099] in:

[0100] R w for Or -B(OH)2;

[0101] R L For leaving groups; in some embodiments, R L For halogen; in some implementations, R L It is Br; and

[0102] R 2 -R 5 X, R 6b R 6c Y, L, B 1 B 2 B 3 B 4 and B 5 As defined in general formula (II).

[0103] Another aspect of this disclosure relates to a method for preparing a compound of general formula (II-1) or a pharmaceutically acceptable salt thereof, comprising:

[0104]

[0105] The compound of general formula (IIA) or its salt undergoes a coupling reaction with the compound of general formula (II-1B) or its salt to give the compound of general formula (II-1) or its pharmaceutically usable salt.

[0106] in:

[0107] R w for Or -B(OH)2;

[0108] R L For leaving groups; in some embodiments, R L For halogen; in some implementations, R L It is Br; and

[0109] R 1 -R 5 R 6a R 6b R 6c R 6d L and n1 are defined as in general formula (II-1).

[0110] Another aspect of this disclosure relates to a method for preparing a compound of general formula (III) or a pharmaceutically acceptable salt thereof, comprising:

[0111]

[0112] A compound of general formula (IIA) or a salt thereof undergoes a coupling reaction with a compound of general formula (IIIB) or a salt thereof to obtain a compound of general formula (III) or a pharmaceutically usable salt thereof;

[0113] in:

[0114] R w for Or -B(OH)2;

[0115] R L For leaving groups; in some embodiments, R L For halogen; in some implementations, R L It is Br; and

[0116] R 2 -R 5 X, R 6b R 6c Y, L, V 1 V 2 V 3 V 4 V 5 V 6 and V 7 As defined in general formula (III).

[0117] Another aspect of this disclosure relates to a method for preparing a compound of general formula (III-1) or a pharmaceutically acceptable salt thereof, comprising:

[0118]

[0119] The compound of general formula (IIA) or its salt undergoes a coupling reaction with the compound of general formula (III-1B) or its salt to give the compound of general formula (III-1) or its pharmaceutically usable salt.

[0120] in:

[0121] R w for Or -B(OH)2;

[0122] R L For leaving groups; in some embodiments, R L For halogen; in some implementations, R L It is Br; and

[0123] R 1 -R 5 R 6a R 6b R 6c R 6d L and n2 are defined as in general formula (III-1).

[0124] In some embodiments of this disclosure, the preparation methods of compounds of general formulas (I), (II), (II-1), (III), or (III-1) or their pharmaceutically acceptable salts, wherein the coupling reaction is carried out under alkaline conditions and with the action of a metal catalyst; the metal catalyst includes, but is not limited to, [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride; the reagent providing the alkaline conditions includes organic and inorganic bases, wherein the organic bases include, but are not limited to, triethylamine, N,N-diisopropylethylamine, n-butyllithium, diisopropylaminolithium, potassium acetate, sodium tert-butoxide, potassium tert-butoxide, tetrabutylammonium fluoride, tetrahydrofuran solution of tetrabutylammonium fluoride, or 1,8-diazabicycloundec-7-ene, and the inorganic bases include, but are not limited to, sodium hydride, potassium phosphate, sodium carbonate, sodium acetate, potassium acetate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, cesium fluoride, and potassium hydroxide; in some embodiments, the reagent providing the alkaline conditions is potassium phosphate.

[0125] In some embodiments of this disclosure, the preparation methods of compounds of general formulas (I), (II), (II-1), (III) or (III-1) or their pharmaceutically acceptable salts, wherein the coupling reaction is carried out in a solvent, including but not limited to: ethylene glycol dimethyl ether, acetic acid, methanol, ethanol, acetonitrile, n-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide, 1,4-dioxane, water, N,N-dimethylformamide, N,N-dimethylacetamide, and mixtures thereof.

[0126] Another aspect of this disclosure relates to a pharmaceutical composition comprising a compound of the formula (I), (II), (II-1), (III), (III-1) or group A of this disclosure or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

[0127] This disclosure further relates to the use of compounds of the above general formulas (I), (II), (II-1), (III)\(III-1) or group A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising them, in the preparation of medicaments for inhibiting or degrading VAV1.

[0128] This disclosure further relates to the use of compounds of the above general formulas (I), (II), (II-1), (III), (III-1) or group A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising thereof, in the preparation of a medicament for regulating the ubiquitination and degradation of VAV1 protein in a subject.

[0129] This disclosure further relates to the use of compounds of the above general formulas (I), (II), (II-1), (III), (III-1) or group A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising them, in the preparation of medicaments for the treatment and / or prevention of diseases or conditions mediated or dependent on VAV1.

[0130] This disclosure further relates to the use of compounds of the above general formulas (I), (II), (II-1), (III), (III-1) or group A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising thereof, in the preparation of medicaments for the treatment and / or prevention of tumors, autoimmune diseases, and inflammatory diseases.

[0131] In some embodiments, the VAV1-mediated or dependent diseases or conditions described in this disclosure are selected from tumors, autoimmune diseases, and inflammatory diseases; in some embodiments, the VAV1-mediated or dependent diseases or conditions described in this disclosure are autoimmune diseases or inflammatory diseases; in some embodiments, the VAV1-mediated or dependent diseases or conditions described in this disclosure are tumors.

[0132] In some embodiments, the autoimmune or inflammatory diseases described in this disclosure are selected from multiple sclerosis, arthritis, rheumatoid arthritis, pemphigus, systemic lupus erythematosus, Hashimoto's thyroiditis, myasthenia gravis, type I or II diabetes and related diseases, vasculitis, pernicious anemia, Sjögren's syndrome, uveitis, psoriasis, Graves' ophthalmopathy, Graves' disease, alopecia areata, asthma, allergic asthma, atopic dermatitis, allergic dermatitis, rhinitis, conjunctivitis, allergic contact dermatitis, colitis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, intrinsic asthma, inflammatory lung injury, inflammatory liver injury, inflammatory glomerular injury, atherosclerosis, osteoarthritis, irritant contact dermatitis, eczematous dermatitis, seborrheic dermatitis, inflammatory eye disease, keratoconjunctivitis, myocarditis, pericarditis, pulmonary fibrosis, systemic sclerosis, morphine scleroderma, Alzheimer's disease, autoimmune liver disease, hepatitis, amyloidosis, macular degeneration, lupus nephritis, pulmonary hypertension, chronic graft-versus-host disease, cholesclerosis, sclerosing cholangitis, axial spondyloarthritis.

[0133] In some embodiments, the autoimmune or inflammatory diseases described in this disclosure are selected from systemic lupus erythematosus (SLE), ankylosing spondylitis, Chagas disease, chronic obstructive pulmonary disease, dermatomyositis, type 1 diabetes mellitus, endometriosis, Goodpasture's syndrome, Graves' disease, Guillain-Barré syndrome (GBS), Hashimoto's disease, hidradenitis suppurativa, Kawasaki disease, IgA nephropathy, idiopathic thrombocytopenic purpura, interstitial cystitis (IC), mixed connective tissue disease (MCTD), morphine scleroderma, multiple sclerosis, chronic spontaneous urticaria (CSU), neuromuscular myotonia, psoriasis, psoriatic arthritis, psoriasis, polymyositis, primary biliary cirrhosis, relapsing polychondritis, etc. Rheumatoid arthritis, sarcoidosis, scleroderma, Sjögren's syndrome, stiff neck syndrome, ulcerative colitis, vasculitis, vitiligo, Wegener's granulomatosis, atopic dermatitis, asthma, insulin-dependent diabetes mellitus, Hashimoto's thyroiditis, pernicious anemia, myasthenia gravis, pemphigus vulgaris, and Crohn's disease; in some embodiments, the autoimmune diseases described in this disclosure are selected from systemic lupus erythematosus (SLE), rheumatoid arthritis, scleroderma, and Guillain-Barré syndrome (GBS); in some embodiments, the autoimmune diseases described in this disclosure are selected from atopic dermatitis, asthma, insulin-dependent diabetes mellitus, Hashimoto's thyroiditis, pernicious anemia, myasthenia gravis, pemphigus vulgaris, and Crohn's disease.

[0134] In some embodiments, the tumors described in this disclosure are selected from lymphoma, leukemia, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, hepatocellular carcinoma, renal cell carcinoma, bladder cancer, colorectal cancer, breast cancer, cervical cancer, colon cancer, esophageal cancer, kidney cancer, liver cancer, lung cancer, head and neck cancer, ovarian cancer, pancreatic cancer, prostate cancer, gastric cancer, melanoma, sarcoma, Ewing sarcoma, angiosarcoma, Kaposi's sarcoma, liposarcoma, sarcoma, and peripheral neuroepithelial tumor. Neuroepithelial tumor, synovial sarcoma, glioma, astrocytoma, glioblastoma, neuroblastoma, ganglioglioma, medulloblastoma, pineal cell carcinoma, meningioma, meningeal sarcoma, neurofibroma and schwannoma, prostate cancer, endometrial cancer, testicular cancer, thyroid cancer, astrocytoma, carcinosarcoma, Hodgkin's disease, nephroblastoma and teratoma; in some embodiments, the tumors described in this disclosure are selected from leukemia, lymphoma, breast cancer and lung cancer; in some embodiments, the tumors described in this disclosure are leukemia or lymphoma; in some embodiments, the tumors described in this disclosure are lymphoma.

[0135] In some implementations, the tumor described in this disclosure is cancer.

[0136] In some embodiments, the tumors described in this disclosure are hematologic malignancies.

[0137] In some implementations, the lung cancer described in this disclosure is non-small cell lung cancer (NSCLC).

[0138] In some embodiments, the lymphoma described in this disclosure is selected from non-Hodgkin lymphoma (NHL), diffuse large B-cell lymphoma (DIBCLs), Burkitt lymphoma, T-cell lymphoblastic lymphoma (T-LL), peripheral T-cell lymphoma, lymphoblastic lymphoma, pre-B lymphoma, B-cell lymphoma, B-cell ALL, follicular lymphoma, marginal zone lymphoma (MZL), mantle cell lymphoma (MCL), small lymphocytic lymphoma (SLL), intravascular large B-cell lymphoma, and Waldenström macroglobulinemia (WM); in some embodiments, the lymphoma described in this disclosure is B-cell lymphoma; in some embodiments, the lymphoma described in this disclosure is diffuse large B-cell lymphoma; in some embodiments, the lymphoma described in this disclosure is non-Hodgkin lymphoma (NHL); in some embodiments, the lymphoma described in this disclosure is relapsed / refractory non-Hodgkin lymphoma.

[0139] In some embodiments, the leukemia described in this disclosure is selected from T-cell acute lymphoblastic leukemia (T-ALL), adult T-cell leukemia, precursor B-cell acute lymphoblastic leukemia (Pre-B ALL), B-cell acute lymphoblastic leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia (CLL), B-cell leukemia, and chronic myeloid leukemia.

[0140] The active compound can be formulated into a form suitable for administration via any appropriate route, in some embodiments in the form of a unit dose or in a form that a patient can self-administer as a single dose. The unit dose of the disclosed compound or composition can be expressed as tablets, capsules, sachets, bottled liquids, powders, granules, lozenges, suppositories, regenerated powders, or liquid formulations. In some embodiments, a suitable unit dose may be 0.001 mg to 1000 mg. In some embodiments, a suitable unit dose may be 0.1 to 1000 mg. In addition to the active compound, the pharmaceutical compositions of this disclosure may contain one or more excipients selected from the following: fillers (diluents), binders, wetting agents, disintegrants, or excipients. Depending on the method of administration, the composition may contain 0.1 to 99% by weight of the active compound.

[0141] In some embodiments, the pharmaceutical composition contains 0.01-99.99% of the aforementioned compound or its pharmaceutically acceptable salt or isotopic substitution, based on the total weight of the composition. In some embodiments, the pharmaceutical composition contains 0.1-99.9% of the aforementioned compound or its pharmaceutically acceptable salt or isotopic substitution. In some embodiments, the pharmaceutical composition contains 0.5%-99.5% of the aforementioned compound or its pharmaceutically acceptable salt or isotopic substitution. In some embodiments, the pharmaceutical composition contains 1%-99% of the aforementioned compound or its pharmaceutically acceptable salt or isotopic substitution. In some embodiments, the pharmaceutical composition contains 2%-98% of the aforementioned compound or its pharmaceutically acceptable salt or isotopic substitution.

[0142] In some embodiments, the pharmaceutical composition contains 0.01% to 99.99% pharmaceutically acceptable excipients based on the total weight of the composition. In some embodiments, the pharmaceutical composition contains 0.1% to 99.9% pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical composition contains 0.5% to 99.5% pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical composition contains 1% to 99% pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical composition contains 2% to 98% pharmaceutically acceptable excipients.

[0143] The pharmaceutically acceptable salts of the compounds described in this disclosure may be selected from inorganic or organic salts.

[0144] Pharmaceutical compositions containing active ingredients may be in forms suitable for oral administration, such as tablets, sugar lozenges, tablets, aqueous or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Oral compositions may be prepared according to any method known in the art for preparing pharmaceutical compositions, and such compositions may contain one or more ingredients selected from sweeteners, flavoring agents, coloring agents, and preservatives to provide an appealing and palatable pharmaceutical formulation.

[0145] Tablets contain an active ingredient and non-toxic, pharmaceutically acceptable excipients suitable for tablet preparation, used for mixing. These excipients may be inert excipients, granulating agents, disintegrants, binders, and lubricants. These tablets may be uncoated or coated using known techniques that mask the taste of the drug or delay disintegration and absorption in the gastrointestinal tract, thus providing sustained release over a longer period.

[0146] Oral formulations can also be provided using soft gelatin capsules in which the active ingredient is mixed with an inert solid diluent or in which the active ingredient is mixed with a water-soluble carrier or an oil solvent.

[0147] Aqueous suspensions contain active substances and excipients suitable for preparing aqueous suspensions for mixing. These excipients are suspending agents, dispersing agents, or wetting agents. Aqueous suspensions may also contain one or more preservatives, one or more coloring agents, one or more flavoring agents, and one or more sweeteners.

[0148] Oil suspensions are formulated by suspending the active ingredient in vegetable or mineral oil. Oil suspensions may contain thickeners. Sweeteners and flavoring agents mentioned above may be added to provide palatable formulations. These compositions may be preserved by adding antioxidants.

[0149] The pharmaceutical compositions disclosed herein may also be in the form of an oil-in-water emulsion. The oil phase may be vegetable oil, mineral oil, or a mixture thereof. Suitable emulsifiers may be naturally occurring phospholipids, and the emulsion may also contain sweeteners, flavoring agents, preservatives, and antioxidants. Such formulations may also contain modifiers, preservatives, colorants, and antioxidants.

[0150] The pharmaceutical compositions disclosed herein may be in the form of sterile injectable aqueous solutions. Acceptable solvents or media that can be used include water, Ringer's solution, and isotonic sodium chloride solution. The sterile injectable formulation may be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in the oil phase, which can be injected into the patient's bloodstream via local large-volume injection. Alternatively, the solution and microemulsion are preferably administered in a manner that maintains a constant circulating concentration of the disclosed compounds. To maintain such a constant concentration, a continuous intravenous delivery device can be used. An example of such a device is the Deltec CADD-PLUS™ 5400 intravenous infusion pump.

[0151] The pharmaceutical compositions disclosed herein may be in the form of sterile injectable aqueous or oil suspensions for intramuscular and subcutaneous administration. These suspensions may be formulated using suitable dispersants or wetting agents and suspending agents according to known techniques. The sterile injectable formulations may also be sterile injectable solutions or suspensions prepared in parenteral acceptable non-toxic diluents or solvents. Furthermore, sterile fixative oils can be conveniently used as solvents or suspension media. Any blended fixative oil may be used for this purpose. Additionally, fatty acids may also be used to prepare injectable formulations.

[0152] The disclosed compounds can be administered in suppository form for rectal administration. These pharmaceutical compositions can be prepared by mixing the drug with a suitable, non-irritating excipient that is solid at normal temperatures but liquid in the rectum, and thus dissolves in the rectum to release the drug.

[0153] As is well known to those skilled in the art, the dosage of a drug depends on a variety of factors, including but not limited to: the activity of the specific compound used, the patient's age, the patient's weight, the patient's health status, the patient's behavior, the patient's diet, the timing of administration, the route of administration, the rate of excretion, the combination of drugs, the severity of the disease, etc.; in addition, the optimal treatment mode, such as the treatment pattern, the daily dosage of the compound, or the type of medicinal salt can be validated based on conventional treatment protocols.

[0154] Terminology Explanation

[0155] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0156] The term "alkyl" refers to a saturated, straight-chain or branched aliphatic hydrocarbon group having 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) carbon atoms (i.e., C2). 1-20 Alkyl group). In some embodiments, the alkyl group is an alkyl group having 1 to 12 carbon atoms (i.e., C12). 1-12 Alkyl groups, in some embodiments, have 1 to 6 carbon atoms (i.e., C1646 ... 1-6Alkyl groups). Non-limiting examples include: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2 3-Dimethylpentyl, 2,4-Dimethylpentyl, 2,2-Dimethylpentyl, 3,3-Dimethylpentyl, 2-Ethylpentyl, 3-Ethylpentyl, n-Octyl, 2,3-Dimethylhexyl, 2,4-Dimethylhexyl, 2,5-Dimethylhexyl, 2,2-Dimethylhexyl, 3,3-Dimethylhexyl, 4,4-Dimethylhexyl, 2-Ethylhexyl, 3-Ethylhexyl, 4-Ethylhexyl, 2-Methyl-2-Ethylpentyl, 2-Methyl-3-Ethylpentyl, n-Nonyl, 2-Methyl-2-Ethylhexyl, 2-Methyl-3-Ethylhexyl, 2,2-Diethylpentyl, n-Decyl, 3,3-Diethylhexyl, 2,2-Diethylhexyl, and their various branched isomers, etc. Alkyl groups can be substituted or unsubstituted, and when substituted, they can be substituted at any usable connection point. In some embodiments, the substituents are selected from one or more of the following: D atom, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0157] The term "alkenyl" refers to an alkyl group in which the molecule contains at least one carbon-carbon double bond, wherein the alkyl group is defined as described above and has 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12) carbon atoms (i.e., C atoms). 2-12 Alkenyl group). In some embodiments, the alkenyl group has 2 to 6 carbon atoms (i.e., C64-64 carbon atoms). 2-6 Alkenyl). Non-limiting examples include vinyl, propenyl, isopropenyl, butenyl, etc. Alkenyl groups can be substituted or unsubstituted, and when substituted, they can be substituted at any usable connection point; in some embodiments, the substituent is selected from one or more of the following: D atom, alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0158] The term "alkynyl" refers to an alkyl group in a molecule that contains at least one carbon-carbon triple bond, wherein the alkyl group is defined as described above and has 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12) carbon atoms (i.e., C64, C74, C84, C9 ... 2-12 (Alkyne group). In some embodiments, the alkynyl group has 2 to 6 carbon atoms (i.e., C64). 2-6 (Alynyl). Non-limiting examples include: ethynyl, propynyl, butynyl, pentyynyl, hexynyl, etc. The alkynyl group can be substituted or unsubstituted, and when substituted, it can be substituted at any usable linker; in some embodiments, the substituent is selected from one or more of the following: D atom, alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0159] The term "alkylene" refers to a divalent alkyl group, wherein the alkyl group, as defined above, has 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) carbon atoms (i.e., C2). 1-20 Alkylene). In some embodiments, the alkylene has 1 to 10 carbon atoms (i.e., C10). 1-10 Alkylenes), in some embodiments, alkylenes having 1 to 8 carbon atoms (i.e., C1646-C ... 1-8 Alkylenes), in some embodiments, are selected having 2 to 7 carbon atoms (i.e., C164-C ... 2-7 Alkylene); in some embodiments, an alkylene having 1, 2, or 3 carbon atoms (i.e., C14) 1-6 Alkylenes. Non-limiting examples include: -CH2-, -CH(CH3)-, -C(CH3)2-, -CH2CH2-, -CH(CH2CH3)-, -CH2CH(CH3)-, -CH2C(CH3)2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, etc. Alkylenes can be substituted or unsubstituted, and when substituted, they can be substituted at any usable linking point. In some embodiments, the substituent is selected from one or more of the following: D atom, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0160] The term "bridged alkylene" refers to an alkylene ring formed by the connection of two non-adjacent atoms, as defined above. Non-limiting examples include: bridged ethylene (-CH2CH2-) and bridged methylene (-CH2-).

[0161] The term "alkoxy" refers to -O-(alkyl), where alkyl is defined as described above. Non-limiting examples include methoxy, ethoxy, propoxy, and butoxy, etc. Alkoxy groups can be substituted or unsubstituted, and when substituted, they can be substituted at any usable link. In some embodiments, the substituent is selected from one or more of the following: D atom, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0162] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic carbocyclic (i.e., monocyclic cycloalkyl) or polycyclic system (i.e., polycyclic cycloalkyl) having 3 to 20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., 3 to 20 membered cycloalkyl). In some embodiments, the cycloalkyl is a cycloalkyl having 3 to 12 ring atoms (i.e., 3 to 12 membered cycloalkyl) or a cycloalkyl having 4 to 11 ring atoms (i.e., 4 to 11 membered cycloalkyl). In some embodiments, it is a cycloalkyl having 3 to 8 ring atoms (i.e., 3 to 8 membered cycloalkyl). In some embodiments, it is a cycloalkyl having 4 to 8 ring atoms (i.e., 4 to 8 membered cycloalkyl). In some embodiments, it is a cycloalkyl having 4 to 6 ring atoms (i.e., 4 to 6 membered cycloalkyl). In some embodiments, it is a cycloalkyl having 3 to 6 ring atoms (i.e., 3 to 6 membered cycloalkyl).

[0163] Non-limiting examples of the monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclohepttrienyl, and cyclooctyl.

[0164] The polycyclic alkyl groups include: spirocyclic alkyl groups, fused cyclic alkyl groups, and bridged cyclic alkyl groups.

[0165] The term "spirocycloalkyl" refers to a polycyclic system in which rings share a single carbon atom (called a spiro atom), and the ring may contain one or more double bonds, or one or more heteroatoms selected from nitrogen, oxygen, and sulfur (the nitrogen may optionally be oxidized, i.e., to form nitrogen oxides; the sulfur may optionally be oxidized, i.e., to form sulfoxides or sulfones, but excluding -OO-, -OS-, or -SS-), provided that it contains at least one full carbon ring with a bonding point on that full carbon ring, having 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., 5 to 20-membered spirocycloalkyl). In some embodiments, the spirocycloalkyl is a spirocycloalkyl having 6 to 14 ring atoms (i.e., 6 to 14-membered spirocycloalkyl), and in some embodiments, it is a spirocycloalkyl having 7 to 10 ring atoms (i.e., 7 to 10-membered spirocycloalkyl). The spirocyclic alkyl group includes monospirocyclic alkyl and polyspirocyclic alkyl (such as bispirocyclic alkyl, etc.). In some embodiments, it is a monospirocyclic alkyl or a bispirocyclic alkyl. In some embodiments, the spirocyclic alkyl group is a 3-membered / 4-membered, 3-membered / 5-membered, 3-membered / 6-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 3-membered, 5-membered / 4-membered, 5-membered / 5-membered, 5-membered / 6-membered, 5-membered / 7-membered, 6-membered / 3-membered, 6-membered / 4-membered, 6-membered / 5-membered, 6-membered / 6-membered, 6-membered / 7-membered, 7-membered / 5-membered, or 7-membered / 6-membered monospirocyclic alkyl group. Non-limiting examples include:

[0166] Its connection point can be anywhere;

[0167] wait.

[0168] The term "fused cycloalkyl" refers to a polycyclic system in which two adjacent carbon atoms are shared between rings. This system is a monocyclic cycloalkyl group fused with one or more monocyclic cycloalkyl groups, or a monocyclic cycloalkyl group fused with one or more heterocyclic, aryl, or heteroaryl groups, wherein the bonding point is on the monocyclic cycloalkyl group, which may contain one or more double bonds and has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., 5 to 20-membered fused cycloalkyl). In some embodiments, the fused cycloalkyl group is a fused cycloalkyl group having 6 to 14 ring atoms (i.e., 6 to 14-membered fused cycloalkyl), and in some embodiments, it is a fused cycloalkyl group having 7 to 10 ring atoms (i.e., 7 to 10-membered fused cycloalkyl). The fused cyclic alkyl group includes bicyclic fused cyclic alkyl groups and polycyclic fused cyclic alkyl groups (such as tricyclic fused cyclic alkyl groups, tetracyclic fused cyclic alkyl groups, etc.). In some embodiments, it is a bicyclic fused cyclic alkyl group or a tricyclic fused cyclic alkyl group. In some embodiments, it is a ternary / quadrivalent, ternary / quinary, ternary / six-membered, quadrivalent / quadrivalent, quadrivalent / quinary, quadrivalent / six-membered, quinary / tertiary, quinary / quadrivalent, quinary / quinary, quinary / six-membered, quinary / seven-membered, quinary / tertiary, quinary / quadrivalent, quinary / quadrivalent, quinary / six-membered, quinary / seven-membered, quinary / tertiary, quinary / tertiary, quinary / six-membered, quinary / seven-membered, or quinary / six-membered bicyclic fused cyclic alkyl group. Non-limiting examples include:

[0169] Its connection point can be anywhere; wait.

[0170] The term "bridged cycloalkyl" refers to a fully carbon polycyclic system in which two non-directly connected carbon atoms are shared between rings, and the ring may contain one or more double bonds and have 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) carbon atoms (i.e., 5 to 20-membered bridged cycloalkyl). In some embodiments, the bridged cycloalkyl is a bridged cycloalkyl with 6 to 14 carbon atoms (i.e., 6 to 14-membered bridged cycloalkyl), and in some embodiments, it is a bridged cycloalkyl with 7 to 10 carbon atoms (i.e., 7 to 10-membered bridged cycloalkyl). The bridged cycloalkyl includes bicyclic bridged cycloalkyl and polycyclic bridged cycloalkyl (e.g., tricyclic bridged cycloalkyl, tetracyclic bridged cycloalkyl, etc.), and in some embodiments, it is a bicyclic bridged cycloalkyl or a tricyclic bridged cycloalkyl. Non-limiting examples include:

[0171] Its connection point can be anywhere.

[0172] The cycloalkyl group can be substituted or unsubstituted. When substituted, it can be substituted at any usable connection point. In some embodiments, the substituent is selected from one or more of the following: D atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, alkylthio, haloalkylthio, cycloalkylthio, heterocyclic thio, heterocyclic oxy, hydroxy, hydroxyalkyl, oxo, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0173] The term "heterocyclic group" refers to a saturated or partially unsaturated monocyclic heterocycle (i.e., monocyclic heterocyclic group) or polycyclic heterocyclic system (i.e., polycyclic heterocyclic group) containing at least one (e.g., 1, 2, 3 or 4) heteroatoms selected from nitrogen, oxygen and sulfur (the nitrogen may optionally be oxidized, i.e., to form nitrogen oxides; the sulfur may optionally be oxidized, i.e., to form sulfoxides or sulfones, but excluding -OO-, -OS- or -SS-), and having 3 to 20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (i.e., 3 to 20 membered heterocyclic groups). In some embodiments, the heterocyclic group is a heterocyclic group having 3 to 12 ring atoms (i.e., a 3 to 12-membered heterocyclic group) or a heterocyclic group having 4 to 11 ring atoms (i.e., a 4 to 11-membered heterocyclic group); in some embodiments, a heterocyclic group having 3 to 8 ring atoms (i.e., a 3 to 8-membered heterocyclic group); in some embodiments, a heterocyclic group having 4 to 8 ring atoms (i.e., a 4 to 8-membered heterocyclic group); in some embodiments, a heterocyclic group having 4 to 6 ring atoms (i.e., a 4 to 6-membered heterocyclic group); in some embodiments, a heterocyclic group having 3 to 6 ring atoms (i.e., a 3 to 6-membered heterocyclic group); in some embodiments, a heterocyclic group having 5 to 7 ring atoms (i.e., a 5 to 7-membered heterocyclic group); in some embodiments, a heterocyclic group having 5 or 6 ring atoms (i.e., a 5 or 6-membered heterocyclic group); in some embodiments, a heterocyclic group having 6 ring atoms (i.e., a 6-membered heterocyclic group).

[0174] Non-limiting examples of the monocyclic heterocyclic group include: pyrrolidinyl, tetrahydropyranyl, 1,2,3,6-tetrahydropyridyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, and homopiperazinyl, etc.

[0175] The polycyclic heterocyclic groups include spirocyclic heterocyclic groups, fused heterocyclic groups, and bridged heterocyclic groups.

[0176] The term "spiroheterocyclic group" refers to a polycyclic heterocyclic system in which rings share a single atom (called a spiro atom), which may contain one or more double bonds and at least one (e.g., 1, 2, 3 or 4) heteroatoms selected from nitrogen, oxygen and sulfur (the nitrogen may optionally be oxidized to form nitrogen oxides; the sulfur may optionally be oxidized to form sulfoxides or sulfones, but excluding -OO-, -OS- or -SS-), provided that it contains at least one monocyclic heterocyclic group with a connecting point on the monocyclic heterocyclic group, which has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (i.e., 5 to 20-membered spiroheterocyclic groups). In some embodiments, the spiroheterocyclic group is a spiroheterocyclic group having 6 to 14 ring atoms (i.e., a 6 to 14-membered spiroheterocyclic group), and in some embodiments, it is a spiroheterocyclic group having 7 to 11 ring atoms (i.e., a 7 to 11-membered spiroheterocyclic group). The spiroheterocyclic group includes monospirocyclic and polyspirocyclic groups (such as bispirocyclic groups). In some embodiments, it is a monospirocyclic or bispirocyclic group. In some embodiments, it is a 3-membered / 4-membered, 3-membered / 5-membered, 3-membered / 6-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 3-membered, 5-membered / 4-membered, 5-membered / 5-membered, 5-membered / 6-membered, 5-membered / 7-membered, 6-membered / 3-membered, 6-membered / 4-membered, 6-membered / 5-membered, 6-membered / 6-membered, 6-membered / 7-membered, 7-membered / 5-membered, or 7-membered / 6-membered monospirocyclic group. Non-limiting examples include:

[0177] wait.

[0178] The term "fused heterocyclic group" refers to a polycyclic heterocyclic system in which two adjacent atoms are shared between rings. The ring may contain one or more double bonds and at least one (e.g., 1, 2, 3, or 4) heteroatoms selected from nitrogen, oxygen, and sulfur (the nitrogen may optionally be oxidized to form nitrogen oxides; the sulfur may optionally be oxidized to form sulfoxides or sulfones, but excluding -OO-, -OS-, or -SS-). It is a monocyclic heterocyclic group fused with one or more monocyclic heterocyclic groups, or a monocyclic heterocyclic group fused with one or more cycloalkyl, aryl, or heteroaryl groups, wherein the bonding point is on the monocyclic heterocyclic group and has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., 5 to 20 membered fused heterocyclic groups). In some embodiments, the fused heterocyclic group has 6 to 14 ring atoms (i.e., 6 to 14-membered fused heterocyclic group), in some embodiments it has 7 to 11 ring atoms (i.e., 7 to 11-membered fused heterocyclic group), and in some embodiments it has 9 ring atoms (i.e., 9-membered fused heterocyclic group). The fused heterocyclic group includes bicyclic and polycyclic fused heterocyclic groups (such as tricyclic fused heterocyclic groups, tetracyclic fused heterocyclic groups, etc.). In some embodiments, it is a bicyclic or tricyclic fused heterocyclic group. In some embodiments, it is a 3-membered / 4-membered, 3-membered / 5-membered, 3-membered / 6-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 3-membered, 5-membered / 4-membered, 5-membered / 5-membered, 5-membered / 6-membered, 5-membered / 7-membered, 6-membered / 3-membered, 6-membered / 4-membered, 6-membered / 5-membered, 6-membered / 6-membered, 6-membered / 7-membered, 7-membered / 5-membered, or 7-membered / 6-membered bicyclic fused heterocyclic group. Non-limiting examples include:

[0179] wait.

[0180] The term "bridged heterocyclic group" refers to a polycyclic heterocyclic system in which two non-directly bonded atoms are shared between the rings. The rings may contain one or more double bonds and at least one (e.g., 1, 2, 3, or 4) heteroatoms selected from nitrogen, oxygen, and sulfur (the nitrogen may optionally be oxidized to form nitrogen oxides; the sulfur may optionally be oxidized to form sulfoxides or sulfones, but excluding -OO-, -OS-, or -SS-), having 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., 5 to 20-membered bridged heterocyclic groups). In some embodiments, the bridged heterocyclic group has 6 to 14 ring atoms (i.e., 6 to 14-membered bridged heterocyclic groups), and in some embodiments, it has 7 to 10 ring atoms (i.e., 7 to 10-membered bridged heterocyclic groups). Based on the number of constituent rings, heterocyclic groups can be classified into bicyclic bridged heterocyclic groups and multicyclic bridged heterocyclic groups (such as tricyclic bridged heterocyclic groups, tetracyclic bridged heterocyclic groups, etc.). In some embodiments, they are bicyclic bridged heterocyclic groups or tricyclic bridged heterocyclic groups. Non-limiting examples include:

[0181] wait.

[0182] The heterocyclic group can be substituted or unsubstituted. When substituted, it can be substituted at any usable connection point. In some embodiments, the substituent is selected from one or more of the following: D atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, alkylthio, haloalkylthio, cycloalkylthio, heterocyclic thio, hydroxy, hydroxyalkyl, oxo, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0183] The term "aryl" refers to a monocyclic all-carbon aromatic ring (i.e., monocyclic aryl) or a polycyclic aromatic ring system (i.e., polycyclic aryl) having a conjugated π-electron system, having 6 to 14 (e.g., 6, 7, 8, 9, 10, 11, 12, 13, or 14) ring atoms (i.e., 6 to 14-membered aryl). In some embodiments, the aryl group has 6 to 10 ring atoms (i.e., 6 to 10-membered aryl). The monocyclic aryl group is, for example, phenyl. Non-limiting examples of the polycyclic aryl group include naphthyl, anthraceneyl, phenanthrene, etc. The polycyclic aryl group further includes fusion of the phenyl group with one or more heterocyclic groups or cycloalkyl groups, or fusion of the naphthyl group with one or more heterocyclic groups or cycloalkyl groups, wherein the bonding point is on the phenyl or naphthyl group, and in this case, the number of ring atoms continues to represent the number of ring atoms in the polycyclic aromatic ring system, non-limiting examples including:

[0184] wait.

[0185] The aryl group can be substituted or unsubstituted. When substituted, it can be substituted at any usable connection point. In some embodiments, the substituent is selected from one or more of the following: D atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxyl, alkylthio, haloalkylthio, cycloalkylthio, heterocyclic thio, hydroxyalkyl, oxo, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl. The term "heteroaryl" refers to a monocyclic heteroaryl ring (i.e., monocyclic heteroaryl) or a polycyclic heteroaryl ring system (i.e., polycyclic heteroaryl) having a conjugated π-electron system, containing at least one (e.g., 1, 2, 3, or 4) heteroatoms selected from nitrogen, oxygen, and sulfur (the nitrogen may optionally be oxidized, i.e., to form nitrogen oxides; the sulfur may optionally be oxidized, i.e., to form sulfoxides or sulfones, but excluding -OO-, -OS-, or -SS-), having 5 to 14 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14) ring atoms (i.e., 5 to 14-membered heteroaryl). In some embodiments, the heteroaryl has 5 to 10 ring atoms (i.e., 5 to 10-membered heteroaryl), and in some embodiments, it has 5 or 6 ring atoms (i.e., 5 or 6-membered heteroaryl).

[0186] Non-limiting examples of the aforementioned monocyclic heteroaryl groups include: furanyl, thiopheneyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, furazonyl, pyrroleyl, N-alkylpyrroleyl, pyridyl, pyrimidinyl, pyridoneyl, N-alkylpyridone (e.g.) (etc.), pyrazinyl, pyridazinyl, etc.

[0187] Non-limiting examples of the polycyclic heteroaryl groups include: indolyl, indazole, quinolinyl, isoquinolinyl, quinoxalinyl, phthalazinyl, benzimidazolyl, benzothiophene, quinazolinyl, benzothiazolyl, carbazole, etc. The polycyclic heteroaryl groups also include monocyclic heteroaryl groups fused with one or more aryl groups, wherein the connecting point is on the aromatic ring, and in this case, the number of ring atoms continues to represent the number of ring atoms in the polycyclic heteroaryl ring system. The polycyclic heteroaryl groups also include monocyclic heteroaryl groups fused with one or more cycloalkyl or heterocyclic groups, wherein the connecting point is on the monocyclic heteroaryl ring, and in this case, the number of ring atoms continues to represent the number of ring atoms in the polycyclic heteroaryl ring system. Non-limiting examples include:

[0188]

[0189] , , , , wait.

[0190] The heteroaryl group can be substituted or unsubstituted. When substituted, it can be substituted at any usable connection point. In some embodiments, the substituent is selected from one or more of the following: D atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxyl, alkylthio, haloalkylthio, cycloalkylthio, heterocyclic thio, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0191] The aforementioned cycloalkyl, heterocyclic, aryl, and heteroaryl groups include residues derived from removing one hydrogen atom from a parent ring atom, or residues derived from removing two hydrogen atoms from the same ring atom or two different ring atoms of the parent ring, i.e., "cycloalkylene", "heterocyclicene", "arylene", and "heteroarylene". Non-limiting examples include: wait.

[0192] The term "cycloalkylalkyl" refers to an alkyl group that is substituted by one or more cycloalkyl groups, wherein the cycloalkyl and alkyl groups are as defined above.

[0193] The term "heterocyclic alkyl" refers to an alkyl group that is substituted by one or more heterocyclic groups, wherein the heterocyclic group and the alkyl group are as defined above.

[0194] The term "arylalkyl" refers to an alkyl group that is substituted with one or more aryl groups, wherein the aryl and alkyl groups are as defined above.

[0195] The term "heteroarylalkyl" refers to an alkyl group that is substituted by one or more heteroaryl groups, wherein the heteroaryl and alkyl groups are as defined above.

[0196] The term "cycloalkyloxy" refers to -O-cycloalkyl, where the cycloalkyl is as defined above.

[0197] The term "heterocyclic oxygen group" refers to an -O-heterocyclic group, wherein the heterocyclic group is as defined above.

[0198] The term "aryloxy group" refers to -O-aryl, where the aryl group is as defined above.

[0199] The term "heteroaryloxy" refers to -O-heteroaryl, where the heteroaryl is as defined above.

[0200] The term "aminoalkyl" refers to an alkyl group that is substituted with one or more amino groups, wherein the alkyl group is as defined above.

[0201] The term "alkoxyalkyl" refers to an alkyl group that is substituted with one or more alkoxy groups, wherein the alkoxy groups and alkyl groups are as defined above.

[0202] The term "halogenated alkyl" refers to an alkyl group that has been substituted with one or more halogens, wherein the alkyl group is as defined above.

[0203] The term "haloalkoxy" refers to an alkoxy group that is substituted by one or more halogens, wherein the alkoxy group is as defined above.

[0204] The term "hydroxyalkyl" refers to an alkyl group that is replaced by one or more hydroxyl groups, wherein the alkyl group is as defined above.

[0205] The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0206] The term "hydroxyl group" refers to -OH.

[0207] The term "thiol" refers to -SH.

[0208] The term "amino" refers to -NH2.

[0209] The term "cyano" refers to -CN.

[0210] The term "nitro" refers to -NO2.

[0211] The term "oxo" or "oxo group" refers to "=O".

[0212] The term "carbonyl" refers to C=O.

[0213] The term "alkylthio" refers to -S-alkyl, where the alkyl group is as defined above.

[0214] The term "haloalkylthio" refers to an alkylthio group that is replaced by one or more halogens, wherein the alkylthio group is as defined above.

[0215] The term "cycloalkylthio" refers to -S-cycloalkyl, where the cycloalkyl group is as defined above.

[0216] The term "heterocyclic thio" refers to a -S-heterocyclic group, where the heterocyclic group is as defined above.

[0217] “TBS” refers to tert-butyldimethylsilyl substituent.

[0218] “Boc” refers to the tert-butyloxycarbonyl substituent.

[0219] “SEM” refers to the (trimethylsilyl)ethoxymethyl substituent. A “leaving group” is an atom or functional group that breaks off from a larger molecule in a chemical reaction; it is a term used in nucleophilic substitution and elimination reactions. In a nucleophilic substitution reaction, the reactant attacked by the nucleophile is called the substrate, and the atom or group of atoms that breaks off with a pair of electrons from the substrate molecule is called the leaving group. Groups that readily accept electrons and have a strong ability to accept negative charges are good leaving groups. The smaller the pKa of the conjugate acid of the leaving group, the easier it is for the leaving group to break off from other molecules. This is because the smaller the pKa of its conjugate acid, the stronger the tendency for the corresponding leaving group to exist as an anion (or an electrically neutral leaving group) without needing to combine with other atoms. Common leaving groups include, but are not limited to, halogens, -OTs, or -OH. The compounds disclosed herein can exist in specific stereoisomer forms. The term “stereoisomer” refers to isomers with the same structure but different spatial arrangements of atoms. This includes cis and trans (or Z and E) isomers, (-)- and (+)- isomers, (R)- and (S)- enantiomers, diastereomers, (D)- and (L)- isomers, tautomers, trans-blocking isomers, conformational isomers, and mixtures thereof (such as racemates and mixtures of diastereomers). Substituents in the compounds disclosed herein may contain additional asymmetric atoms. All such stereoisomers and mixtures thereof are included within the scope of this disclosure. Optically active (-)- and (+)- isomers, (R)- and (S)- enantiomers, and (D)- and (L)- isomers can be prepared by chiral synthesis, chiral reagents, or other conventional techniques. This disclosure discloses an isomer of a compound, which can be prepared by asymmetric synthesis or with chiral auxiliaries, or, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), by forming a salt of the diastereomer with a suitable optically active acid or base, followed by diastereomer resolution using conventional methods known in the art to obtain the pure isomer. Furthermore, the separation of enantiomers and diastereomers is typically performed by chromatography. In the chemical structure of the compound described in this disclosure, the bond " "" indicates that the configuration is not specified, meaning that if a chiral isomer exists in the chemical structure, the bond " "can be " "or" , or both contain " "and" "Two configurations. For all carbon-carbon double bonds, even if only one configuration is named, both the Z-type and the E-type are included."

[0220] The compounds disclosed herein may exist in various tautomer forms, and all such forms are included within the scope of this disclosure. The terms "tautomer" or "tautomer form" refer to a structural isomer that exists in equilibrium and readily transforms from one isomer to another. This includes all possible tautomers, i.e., existing as a single isomer or as a mixture of said tautomers in any proportion. Non-limiting examples include: keto-enols, imine-enamines, lactam-lactamimides, etc. Examples of lactam-lactamimide equilibrium are shown below:

[0221] .

[0222] When referring to the pyrazolyl group, it should be understood to include any one or a mixture of two tautomers of the following two structures:

[0223] .

[0224] All tautomers are within the scope of this disclosure, and the naming of compounds does not exclude any tautomers.

[0225] The compounds disclosed herein may comprise transisomers. The term "transisomer" refers to a conformational stereoisomer resulting from restricted or significantly slowed rotation around a single bond in a molecule (as a result of spatial interactions with other parts of the molecule and asymmetric substituents at the ends of the single bond), whose interconversion is slow enough to allow separation and isolation under predetermined conditions. For example, some compounds of this disclosure may exist as mixtures of transisomers (e.g., equal-proportion mixtures, mixtures enriched with one transisomer, etc.) or as a purified transisomer.

[0226] The compounds disclosed herein, or pharmaceutically acceptable salts thereof, include solvates (e.g., hydrates, non-aqueous solvates) or non-solvents of the compounds thereof or pharmaceutically acceptable salts thereof.

[0227] The compounds disclosed herein include all suitable isotopic derivatives thereof. The term "isotopic derivative" refers to a compound in which at least one atom is replaced by an atom having the same atomic number but a different atomic mass. Examples of isotopes that may be introduced into the compounds of this disclosure include stable and radioactive isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine, and iodine, for example, […]. 2 H (deuterium, D) 3 H (tritium, T) 11 C 13 C 14 C 15 N、 17 O、 18 O、 32 p、33 p、 33 S, 34 S, 35 S, 36 S, 18 F, 36 Cl、 82 Br、 123 I, 124 I, 125 I, 129 I and 131 I In some implementation schemes, it is deuterium.

[0228] Compared to undeuterated drugs, deuterated drugs offer advantages such as reduced toxicity, increased drug stability, enhanced efficacy, and prolonged biological half-life. All isotopic variations of the compounds disclosed herein, regardless of radioactivity, are included within the scope of this disclosure. Each available hydrogen atom bonded to a carbon atom can be independently replaced by a deuterium atom, wherein the deuterium substitution can be partial or complete; partial deuterium substitution refers to the replacement of at least one hydrogen atom with at least one deuterium atom.

[0229] When a position is specifically designated as deuterium D, the position should be understood as having a deuterium abundance of at least 1,000 times greater than the natural abundance of deuterium (which is 0.015%) (i.e., at least 15% deuterium incorporation). The compounds in the examples having a natural abundance greater than deuterium can be at least 1000 times abundant deuterium (i.e., at least 15% deuterium doping), at least 2000 times abundant deuterium (i.e., at least 30% deuterium doping), at least 3000 times abundant deuterium (i.e., at least 45% deuterium doping), at least 3340 times abundant deuterium (i.e., at least 50.1% deuterium doping), at least 3500 times abundant deuterium (i.e., at least 52.5% deuterium doping), at least 4000 times abundant deuterium (i.e., at least 60% deuterium doping), or at least 4500 times abundant deuterium (i.e., at least 67.5% deuterium doping). The abundance of deuterium is at least 5000 times (i.e., at least 75% deuterium doping), at least 5500 times (i.e., at least 82.5% deuterium doping), at least 6000 times (i.e., at least 90% deuterium doping), at least 6333.3 times (i.e., at least 95% deuterium doping), at least 6466.7 times (i.e., at least 97% deuterium doping), at least 6600 times (i.e., at least 99% deuterium doping), at least 6633.3 times (i.e., at least 99.5% deuterium doping), or higher.

[0230] "Optional" or "optional" means that the event or situation described below may but is not necessarily to occur; it includes both the possibility that the event or situation may occur or not occur. For example, "C that is optionally substituted with a halogen or cyano group..." 1-6"Alkyl" includes cases where the alkyl group is substituted with a halogen or cyano group and cases where the alkyl group is not substituted with a halogen or cyano group.

[0231] "Substitution" or "substituted" refers to one or more hydrogen atoms in a group, in some embodiments 1 to 6, and in some embodiments 1 to 3 hydrogen atoms, which are independently substituted by the corresponding number of substituents. Those skilled in the art can determine possible or improbable substitutions without much effort (through experimentation or theory). For example, an amino or hydroxyl group having free hydrogen may be unstable when combined with a carbon atom having an unsaturated bond (such as an alkene).

[0232] "Pharmaceutical composition" means a mixture containing one or more of the compounds described herein or their pharmaceutically acceptable salts, along with other chemical components, such as pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to a living organism, thereby promoting the absorption of the active ingredient and its biological activity.

[0233] "Pharmacologically acceptable salt" refers to the salt of the compounds disclosed herein, which may be selected from inorganic or organic salts. Such salts are safe and effective when used in mammals and possess the expected biological activity. They can be prepared separately during the final isolation and purification of the compound, or by reacting a suitable group with a suitable base or acid. Bases commonly used to form pharmaceutically acceptable salts include inorganic bases, such as sodium hydroxide and potassium hydroxide, and organic bases, such as ammonia. Acids commonly used to form pharmaceutically acceptable salts include both inorganic and organic acids.

[0234] As used herein, the term "pharmaceutically acceptable" means that these compounds, materials, compositions, and / or dosage forms are suitable for contact with patient tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, within reasonable medical judgment, have a reasonable benefit / risk ratio, and are effective for their intended use.

[0235] As used herein, the singular forms of “a,” “an,” and “the” include plural references, and vice versa, unless the context clearly indicates otherwise.

[0236] When the term "about" is applied to parameters such as pH, concentration, temperature, etc., it indicates that the parameter can vary by ±10%, and in some embodiments within ±5%. As those skilled in the art will understand, when a parameter is not critical, figures are typically given for illustrative purposes only and not as limitations. Detailed Implementation

[0237] The following embodiments are used to further describe this disclosure, but these embodiments are not intended to limit the scope of this disclosure.

[0238] Example

[0239] The structure of the compound was determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts (δ) were expressed in 10⁻¹⁰ ohms. -6 The unit (ppm) is given. NMR determination was performed using a Bruker AVANCE-400 NMR spectrometer or a Bruker AVANCE NEO 500M. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD). The internal standard was tetramethylsilane (TMS).

[0240] MS measurements were performed using an Agilent 1200 / 1290 DAD-6110 / 6120 Quadrupole MS liquid chromatography-mass spectrometry system (manufacturer: Agilent, MS model: 6110 / 6120 Quadrupole MS).

[0241] waters ACQuity UPLC-QD / SQD (Manufacturer: waters, MS model: waters ACQuity QdaDetector / waters SQ Detector)

[0242] THERMO Ultimate 3000-Q Exactive (Manufacturer: THERMO, MS Model: THERMO QExactive)

[0243] High-performance liquid chromatography (HPLC) analysis was performed using an Agilent HPLC 1200DAD, an Agilent HPLC 1200VWD, and a Waters HPLC e2695-2489 HPLC system.

[0244] Chiral HPLC analysis was performed using an Agilent 1260 DAD high-performance liquid chromatograph.

[0245] High performance liquid chromatography (HPLC) was performed using Waters 2545-2767, Waters 2767-SQ Detecor2, Shimadzu LC-20AP, and Gilson GX-281 preparative chromatographs.

[0246] Chiral preparation was performed using a Shimadzu LC-20AP preparative chromatograph.

[0247] The CombiFlash rapid preparation system uses a CombiFlash Rf200 (TELEDYNE ISCO).

[0248] Thin-layer chromatography silica gel plates are Yantai Huanghai HSGF254 or Qingdao GF254. The silica gel plates used in thin-layer chromatography (TLC) have a size of 0.15 mm to 0.2 mm, and the size used for thin-layer chromatography separation and purification of products is 0.4 mm to 0.5 mm.

[0249] Silica gel column chromatography generally uses Yantai Huanghai silica gel with a mesh size of 200-300 as the carrier.

[0250] Mean inhibition rate of kinases and IC 50 The values ​​were determined using a NovoStar microplate reader (BMG GmbH, Germany).

[0251] The known starting materials disclosed herein can be synthesized using or in accordance with methods known in the art, or can be purchased from companies such as ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, and Darui Chemicals.

[0252] Unless otherwise specified in the examples, all reactions can be carried out under an argon or nitrogen atmosphere.

[0253] Argon or nitrogen atmosphere refers to a reaction flask connected to an argon or nitrogen gas balloon with a volume of approximately 1L.

[0254] A hydrogen atmosphere refers to a reaction flask connected to a hydrogen balloon with a volume of approximately 1L.

[0255] The pressurized hydrogenation reaction was performed using a Parr 3916EKX hydrogenator and a Qinglan QL-500 hydrogen generator or an HC2-SS hydrogenator.

[0256] The hydrogenation reaction is usually carried out under vacuum, filled with hydrogen gas, and repeated 3 times.

[0257] The microwave reaction was performed using a CEM Discover-S 908860 microwave reactor.

[0258] Unless otherwise specified in the examples, "solution" refers to an aqueous solution.

[0259] Unless otherwise specified in the examples, the reaction temperature is room temperature.

[0260] The reaction process in the examples was monitored using thin-layer chromatography (TLC). The developing solvent used in the reaction, the eluent system for column chromatography used to purify the compounds, and the developing solvent system for TLC included: A: dichloromethane / methanol system, B: n-hexane / ethyl acetate system. The volume ratio of the solvent was adjusted according to the polarity of the compounds, and small amounts of basic or acidic reagents such as triethylamine and acetic acid could also be added for adjustment.

[0261] Example 1

[0262] 2-(2'-chloro-3'-(2,6-dioxopiperidin-3-yl)-[1,1'-biphenyl]-4-yl)pyridine 1-oxide

[0263]

[0264]

[0265] first step

[0266] 2-(4-bromophenyl)pyridine 1b

[0267] 2-Bromopyridine 1a (2 g, 12.66 mmol, Bio-Tech) was dissolved in 1,4-dioxane (40 mL) and water (8 mL). (4-Bromophenyl)boronic acid (2.2 g, 10.95 mmol, Sinopharm), tetrakis(triphenylphosphine)palladium (800 mg, 0.69 mmol, Adamas), and sodium carbonate (2.7 g, 25.47 mmol, Sinopharm) were added, and the mixture was stirred at 80 °C for 2 hours. After returning to room temperature, the reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system B to give title compound 1b (1.9 g, yield: 64.1%).

[0268] MS m / z (ESI): 234.1 [M+1].

[0269] Step 2

[0270] 2-(4-bromophenyl)pyridine 1-oxide 1c

[0271] Compound 1b (1 g, 4.27 mmol) was dissolved in dichloromethane (20 mL), and then added... m-chloroperoxybenzoic acid (1.05 g, 5.17 mmol, Sinopharm), the reaction was stirred at room temperature for 2 hours. Then, 10 mL of saturated sodium sulfite solution was added to quench the reaction, the organic phase was separated, and the mixture was concentrated under reduced pressure to give the title compound 1c (600 mg, yield: 56.2%).

[0272] MS m / z (ESI): 250.1 [M+2].

[0273] Step 3

[0274] 2-(2'-chloro-3'-(2,6-dioxopiperidin-3-yl)-[1,1'-biphenyl]-4-yl)pyridine 1-oxide

[0275] Compound 1c (200 mg, 0.80 mmol), 3-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxoborhexacyclopentan-2-yl)phenyl)piperidin-2,6-dione 1d (560 mg, 1.6 mmol, prepared by the method disclosed in Intermediate A on page 182 of patent application WO2024151547A1), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (60 mg, 0.08 mmol, Adamas), and potassium phosphate (340 mg, 1.6 mmol, Adamas) were dissolved in 1,4-dioxane (5 mL) and water (0.5 mL), purged with nitrogen three times, heated to 100 °C, and stirred for 16 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system A to give title compound 1 (50 mg, yield: 15.9%).

[0276] MS m / z (ESI): 393.2 [M+1].

[0277] 1 H NMR (500 MHz, DMSO-d6): δ 10.95 (s, 1H), 8.39-8.38 (m, 1H), 7.95-7.94 (m, 2H), 7.73-7.72 (m, 1H), 7.55-7.37 (m, 7H), 4.40-4.36 (m, 1H), 2.85-2.78 (m, 1H), 2.59-2.50 (m, 1H), 2.41-2.33 (m, 1H), 2.10-2.05 (m, 1H).

[0278] Examples 1-1 and 1-2

[0279] (S)-2-(2'-chloro-3'-(2,6-dioxopiperidin-3-yl)-[1,1'-biphenyl]-4-yl)pyridine 1-oxide 1-1

[0280] (R)-2-(2'-chloro-3'-(2,6-dioxopiperidin-3-yl)-[1,1'-biphenyl]-4-yl)pyridine 1-oxide 1-2

[0281]

[0282] Compound 1 (380 mg, 0.97 mmol) was prepared chirally (separation conditions: chiral preparation column ChiralCelOD-H5um, 20mm ID* 250mm LDaicel); mobile phase 1: acetonitrile (24%); mobile phase 2: ethanol / dichloromethane = 95 / 5 (70%), flow rate: 20 mL / min). The corresponding fractions were collected and concentrated under reduced pressure to obtain title compounds 1-1 (80 mg) and 1-2 (80 mg).

[0283] Single-configuration compounds:

[0284] MS m / z (ESI): 393.2 [M+1].

[0285] Chiral HPLC analysis: retention time 7.716 min, chiral purity: 100% (column: CHIRALCEL OD-H, 150*4, 6 mm (Phenomenex, 5 µm); mobile phase: ethanol / acetonitrile = 90 / 10 (V / V), flow rate: 1 mL / min).

[0286] 1 H NMR (500 MHz, DMSO-d6): δ 10.95 (s, 1H), 8.39-8.38 (m, 1H), 7.95-7.94 (m, 2H), 7.73-7.72 (m, 1H), 7.55-7.37 (m, 7H), 4.40-4.36 (m, 1H), 2.85-2.78 (m, 1H), 2.59-2.50 (m, 1H), 2.41-2.33 (m, 1H), 2.10-2.05 (m, 1H).

[0287] Single-configuration compounds:

[0288] MS m / z (ESI): 393.2 [M+1].

[0289] Chiral HPLC analysis: retention time 23.339 min, chiral purity: 99.9% (column: CHIRALCEL OD-H, 150*4, 6 mm (Phenomenex, 5 µm); mobile phase: ethanol / acetonitrile = 90 / 10 (V / V), flow rate: 1 mL / min).

[0290] 1H NMR (500 MHz, DMSO-d6): δ 10.95 (s, 1H), 8.39-8.38 (m, 1H), 7.95-7.94 (m, 2H), 7.73-7.72 (m, 1H), 7.55-7.37 (m, 7H), 4.40-4.36 (m, 1H), 2.85-2.78 (m, 1H), 2.59-2.50 (m, 1H), 2.41-2.33 (m, 1H), 2.10-2.05 (m, 1H).

[0291] Example 2

[0292] 2-(2'-chloro-3'-(2,6-dioxopiperidin-3-yl)-3-methyl-[1,1'-biphenyl]-4-yl)pyridine 1-oxide 2

[0293]

[0294] Following the synthetic route of Example 1, (4-bromophenyl)boronic acid was replaced with (4-bromo-2-methylphenyl)boronic acid to obtain title compound 2 (30 mg, yield: 23.5%).

[0295] MS m / z (ESI): 407.3 [M+1].

[0296] 1 H NMR (500 MHz, DMSO-d6): δ 10.94 (s, 1H), 8.40-8.38 (m, 1H), 7.55-7.32 (m, 9H), 4.40-4.36 (m, 1H), 2.85-2.78 (m, 1H), 2.59-2.50 (m, 1H), 2.40-2.36 (m, 1H), 2.33 (s, 3H), 2.10-2.06 (m, 1H).

[0297] Example 3

[0298] 2-(2'-chloro-3'-(2,6-dioxopiperidin-3-yl)-3-methyl-[1,1'-biphenyl]-4-yl)-3-methylpyridine 1-oxide 3

[0299]

[0300] Following the synthetic route of Example 1, 1a and (4-bromophenyl)boronic acid were replaced with 2-bromo-3-methylpyridine and (4-bromo-2-methylphenyl)boronic acid, respectively, to obtain title compound 3 (40 mg, yield: 33.1%).

[0301] MS m / z (ESI): 421.3 [M+1].

[0302] 1 H NMR (500 MHz, DMSO-d6): δ 10.94 (s, 1H), 8.26-8.25 (m, 1H), 7.45-7.34 (m, 7H), 7.25-7.23 (m, 1H), 4.40-4.37 (m, 1H), 2.85-2.78 (m, 1H), 2.59-2.50 (m, 1H), 2.40-2.35 (m, 1H), 2.33-2.03 (m, 7H).

[0303] Example 4

[0304] 2-(2'-chloro-3'-(2,6-dioxopiperidin-3-yl)-[1,1'-biphenyl]-4-yl)-3-methylpyridine 1-oxide 4

[0305]

[0306] Using the synthetic route of Example 1, the first-step compound 1a was replaced with 2-bromo-3-methylpyridine to obtain title compound 4 (8 mg, yield: 5.2%).

[0307] MS m / z (ESI): 407.3 [M+1]

[0308] 1 H NMR (500 MHz, DMSO-d6): δ 10.95 (s, 1H), 8.26-8.20 (m, 1H), 7.57-7.52 (m, 2H), 7.47-7.42 (m, 3H), 7.42-7.39 (m, 2H), 7.37-7.33 (m, 2H), 4.44-4.33 (m, 1H), 2.88-2.77 (m, 1H), 2.65-2.53 (m, 2H), 2.41-2.32 (m, 1H), 2.12(s, 3H).

[0309] Example 5

[0310] 2-(2'-chloro-3'-(2,6-dioxopiperidin-3-yl)-[1,1'-biphenyl]-4-yl)quinoline 1-oxide 5

[0311]

[0312] Following the synthetic route of Example 1, compound 1a was replaced with 2-bromoquinoline to obtain title compound 5 (8 mg, yield: 6.5%).

[0313] MS m / z (ESI): 443.3 [M+1].

[0314] 1 H NMR (500 MHz, DMSO-d6): δ 10.95 (s, 1H), 8.69-8.67 (m, 1H), 8.16-8.13 (m, 3H), 8.05-8.03 (m, 1H), 7.90-7.77 (m, 3H), 7.61-7.59 (m, 2H), 7.47-7.41(m, 3H), 4.48-4.37 (m, 1H), 2.85-2.78 (m, 1H), 2.60-2.55 (m, 1H), 2.40-2.37 (m, 1H), 2.11-2.09 (m, 1H).

[0315] Example 6

[0316] 1-(2'-chloro-3'-(2,6-dioxopiperidin-3-yl)-[1,1'-biphenyl]-4-yl)isoquinoline 2-oxide 6

[0317]

[0318] Following the synthetic route of Example 1, compound 1a was replaced with 1-bromoisoquinoline to obtain title compound 6 (102 mg, yield: 34.5%).

[0319] MS m / z (ESI): 443.2 [M+1].

[0320] 1 H NMR (500 MHz, DMSO-d6): δ 10.96 (s, 1H), 8.36 – 8.31 (m, 1H), 8.06– 7.96 (m, 2H), 7.68 – 7.58 (m, 6H), 7.52 – 7.38 (m, 4H), 4.45 – 4.38 (m,1H), 2.89 – 2.78 (m, 1H), 2.61 – 2.54 (m, 1H), 2.45 – 2.38 (m, 1H), 2.14 –2.07 (m, 1H).

[0321] Biological evaluation

[0322] The following test examples further describe and explain this disclosure, but these test examples are not intended to limit the scope of this disclosure.

[0323] Test Example 1: VAV1 Degradation Experiment in T Cells

[0324] The degradation rate of VAV1 protein in compound-treated T cells (Jurkat) was detected using Meso Scale Discovery (MSD) to assess the degradation activity of the compound on intracellular VAV1.

[0325] Experimental steps:

[0326] Electrochemiluminescence (ECL) is a specific chemiluminescent reaction initiated by electrochemistry on an electrode surface, offering higher sensitivity and a wider linear range for the detection of target proteins. In this experiment, Jurkat cells (ATCC, catalog number TIB-152) resuspended in RPMI 1640 medium containing 10% FBS were seeded into 96-well plates and cultured at 37°C with 5% CO2. Then, compounds of different concentration gradients were added, and the cells were treated at 37°C with 5% CO2 for 24 hours, after which lysed cells were collected. VAV1 was labeled using a VAV1-specific antibody sandwich method (Thermo, MA5-17198, Proteintech, 16364-1-AP), and the VAV1-antibody complex was tagged with a SULFO label using Anti-Rabbit AntibodyGoat SULFO-TAG Labeled (MSD, R32AB-1). Using a MESOSECTOR S 600 instrument, the electrochemical excitation of the SULFO-TAG™ label resulted in a strong light signal, allowing for the determination of VAV1. The content of VAV1 recombinant protein was calculated using a standard curve. DMSO-treated wells were used as negative controls, and blank cell lysates were used as positive controls. Concentration-response curves of compound concentration versus VAV1 degradation rate were obtained using four-parameter nonlinear fitting with GraphPad PRISM software (version 9.00; GraphPad San Diego, CA), and the relative DC content was calculated. 50 The value reflects the degradation activity of different compounds on VAV1.

[0327] Table 1. Degradation activity of the compounds disclosed herein against VAV1

[0328]

[0329] Conclusion: The compound disclosed herein exhibits good degradation activity against VAV1.

[0330] Test Example 2: VAV1 Degradation Experiment in Human PBMC Cells

[0331] The degradation rate of VAV1 protein in human PBMC cells treated with the compound was detected using Meso Scale Discovery (MSD) technology, thereby evaluating the degradation activity of the compound on VAV1 in human PBMC cells.

[0332] Experimental steps:

[0333] Electrochemiluminescence (ECL) is a specific chemiluminescent reaction initiated by electrochemistry on an electrode surface, offering higher sensitivity and a wider linear range for the detection of target proteins. In this experiment, cryopreserved human PBMC cells (Xuanfeng, #SLB-HP050B) were revived and resuspended in RPMI 1640 medium containing 10% FBS. The cells were seeded at 500,000 viable cells per well in 90 µL of 96-well round-bottom plates (Corning #3788). Then, 10 µL of compounds diluted 4-fold with different concentration gradients were added, and the plates were treated at 37°C with 5% CO2 for 24 hours. After lysing the cells with HTRF lysis buffer (Revvity, #64KL1FDF), the cells were incubated at -80°C. o Stored in a C refrigerator. VAV1 was labeled using a VAV1-specific antibody sandwich method (Thermo, MA5-17198, Proteintech, #16364-1-AP), and the VAV1-antibody complex was tagged with SULFO using Anti-Rabbit Antibody Goat SULFO-TAGLabeled (MSD, #R32AB-1). VAV1 was measured using a MESO SECTOR S 600 instrument, where electrochemical excitation of the SULFO-TAG™ label produced a strong light signal. The content of recombinant VAV1 protein was calculated using a standard curve. DMSO-treated wells were used as positive controls, and blank cell lysates were used as negative controls. A concentration-response curve of compound concentration versus VAV1 degradation rate was obtained using four-parameter nonlinear fitting with GraphPad PRISM software (version 10.00; GraphPad San Diego, CA), and the absolute DC-DC ratio was calculated. 50 The value reflects the degradation activity of different compounds on VAV1.

[0334] Conclusion: The compound disclosed herein exhibits good degradation activity against VAV1 in human PBMC cells.

[0335] Test Example 3: Degradation Experiment of VAV1 in Human Whole Blood Cells

[0336] The ability of the compound to degrade VAV1 protein in human whole blood was evaluated by flow cytometry.

[0337] Experimental steps:

[0338] Fresh whole blood (Xuanfeng, #XFB-HWB-10A) was seeded at 90 µL per well into 96-well round-bottom plates (Corning, #3788). 10 µL of compounds diluted 4-fold with culture medium at different concentrations were added and thoroughly mixed. The plates were incubated at 37°C with 5% CO2 for 24 hours. APC-anti-CD45 antibody (Biolegend, #304037) (final concentration 0.2 µg / mL) was added to the whole blood samples. The mixture was stirred at 900 rpm for 2 min and stained at 4°C for 1 hour. Red blood cells were then lysed. Each whole blood sample was added to 1.8 mL of red blood cell lysis buffer (Thermal, #00-4333-54), and the mixture was shaken at room temperature for 10-15 min until the red blood cells were fully lysed. The cells were then centrifuged at 500g for 5 minutes, and the supernatant was discarded. Add 1.2 mL of pre-chilled FACS buffer (PBS buffer containing 2% heat-sterilized FBS), centrifuge at 4°C, 500 g, for 5 minutes, and discard the supernatant. Resuspend the cell pellet in 200 µL of pre-chilled FACS buffer, centrifuge at 500 g, for 5 minutes, and discard the supernatant, washing the cells twice. Then add 100 µL of cell fixation and permeabilization buffer (BD, # 554714) to each well and incubate at room temperature for 20 minutes. Centrifuge the fixed and permeabilized cell samples, discard the supernatant, and wash twice with BD Perm / Wash Buffer (BD, # 554714), 200 µL per well. Prepare VAV1 antibody (Proteintech, #16364-1-AP) with BD Perm / Wash Buffer to a concentration of 1 µg / mL, resuspend the cells in 50 µL, and incubate overnight at 4°C. Wash the cells three times with BD Perm / Wash Buffer, 200 µL per well, and centrifuge at 500 g for 5 minutes. Cells were resuspended in 50 µL of BD Perm / Wash Buffer containing 1 µg / mL PE-labeled anti-rabbit antibody (Biolegend, #406421) and incubated at 4°C for 1 hour. Cells were washed three times with BD Perm / Wash Buffer, 200 µL per well, and centrifuged at 500g for 5 min. Flow cytometry analysis was performed. FlowJo software (version 10.9.0; Becton, Dickinson and Company; 2023) was used to process the flow cytometry data. The detection value for each well was calculated as the mean VAV1 fluorescence signal multiplied by the VAV1 positivity rate. Positive control wells were DMSO-treated blood sample wells, and negative control wells were DMSO-treated blood sample wells, but only stained with secondary antibody, not primary antibody for VAV1.The concentration-effect curves of compound concentration versus VAV1 degradation rate were obtained using GraphPad PRISM software (version 10.00; GraphPad San Diego, CA) with four-parameter nonlinear fitting, and the absolute DC was calculated. 50 The value reflects the degradation activity of different compounds on VAV1.

[0339] Conclusion: The compound disclosed herein exhibits good degradation activity against VAV1 in human whole blood cells.

[0340] Test Example 4: Pharmacokinetic Evaluation

[0341] I. SD Rat Experiment

[0342] 1. Abstract

[0343] Using SD rats as test animals, the plasma drug concentration of the disclosed compound at different time points after gavage (ig) administration to SD rats was determined by LC / MS / MS. The pharmacokinetic behavior of the disclosed compound in SD rats was investigated to evaluate its pharmacokinetic characteristics.

[0344] 2. Test Plan

[0345] 2.1 Test Drugs

[0346] This compound is disclosed.

[0347] 2.2 Experimental Animals

[0348] SD rats. After fasting overnight, the drugs were administered by gavage.

[0349] 2.3 Drug Preparation

[0350] Weigh out a certain amount of the test compound, add 5% DMSO + 5% Tween 80 + 90% physiological saline, and prepare a colorless and clear solution of 0.2 mg / mL.

[0351] 2.4. Administration

[0352] The dosage is 2.0 mg / kg, and the administration volume is 10.0 mL / kg.

[0353] 3. Operation

[0354] Blood samples of 0.1 mL were collected from the orbital cavity before administration and at 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 11.0, and 24.0 hours after administration. The samples were placed in EDTA-K2 anticoagulant tubes and centrifuged at 10,000 rpm for 1 minute (4°C). Plasma was separated within 1 hour and stored at -20°C for analysis. The entire process, from blood collection to centrifugation, was performed under ice bath conditions. Patients ate 2 hours after administration.

[0355] The levels of the target compound in the plasma of SD rats were determined after administration of different concentrations of the drug.

[0356] Conclusion: The compound disclosed herein has a high exposure level in SD rats and exhibits pharmacokinetic advantages.

[0357] II. C57 Mouse Experiment

[0358] 1. Abstract

[0359] Using C57 mice as test animals, the plasma drug concentrations of the disclosed compound at different time points after administration by gavage (ig) / intravenous injection (iv) in C57 mice were determined by LC / MS / MS. The pharmacokinetic behavior of the disclosed compound in C57 mice was investigated to evaluate its pharmacokinetic characteristics.

[0360] 2. Test Plan

[0361] 2.1 Test Drugs

[0362] This compound is disclosed.

[0363] 2.2 Experimental Animals

[0364] C57 mice. The drugs were administered via gavage and intravenous injection, respectively.

[0365] 2.3 Drug Preparation

[0366] Weigh out a certain amount of the test compound and add 5% DMSO + 5% Tween 80 + 90% physiological saline to prepare a 0.1 mg / mL colorless clear solution (gavage administration group) and a 0.1 mg / mL colorless clear solution (intravenous injection group).

[0367] 2.4. Administration

[0368] Gavage administration group: The dosage was 2.0 mg / kg, and the administration volume was 0.2 mL / 10g.

[0369] Intravenous administration group: The dosage was 1.0 mg / kg, and the administration volume was 0.1 mL / 10g.

[0370] 3. Operation

[0371] In the gavage administration group: 0.1 mL of blood was collected before administration and at 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 11.0, and 24.0 hours after administration. The blood was placed in an EDTA-K2 anticoagulant tube, centrifuged at 10,000 rpm for 1 minute (4℃), and the plasma was separated within 1 hour and stored at -80℃ for analysis. The blood collection and centrifugation process was performed under ice bath conditions.

[0372] Intravenous injection group: Blood samples were collected before administration and 5 minutes after administration, and at 0.25, 0.5, 1.0, 2.0, 4.0, 8.0, 11.0 and 24 hours after administration. The treatment was the same as that of the gavage group.

[0373] The levels of the target compound in the plasma of C57 mice were determined after administration of different concentrations of the drug.

[0374] Conclusion: The compound disclosed herein exhibits high exposure levels in C57 mice and demonstrates pharmacokinetic advantages.

[0375] Test Example 5: Solubility of the Compounds Disclosed

[0376] 1. Experimental Materials

[0377] Reagents: Dimethyl sulfoxide (chromatographic grade, Adamas-beta, catalog number 75927E), acetonitrile (chromatographic grade, Merck, catalog number 1.00030.4008), ammonium acetate (ACS reagent, Sigma-Aldrich, catalog number 32301-100G), FaSSIF / FeSSIF / FaSSGF powder (Biorelevant, catalog number FFF02), FaSSIF buffer concentrate (Biorelevant, FASBUF), FeSSIF buffer concentrate (Biorelevant, FESBUF), sodium dihydrogen phosphate dihydrate (analytical grade, Sinopharm, 20040718), disodium hydrogen phosphate dodecahydrate (analytical grade, Sinopharm, 10020318), sodium chloride (analytical grade, Sinopharm, 10019318), sodium hydroxide (analytical grade, Sinopharm, 10019718), hydrochloric acid (analytical grade, Sinopharm, 10011018), and ultrapure water (ELGA). (DIY CHORUS laboratory ultrapure water system).

[0378] Instrument: Agilent 1200 DAD liquid chromatograph (Agilent Technologies, Inc.)

[0379] 2. Material preparation

[0380] 2.1 Preparation of FassIF solution

[0381] Weigh 2.0825g of FaSSIF medium solution and 48.055g of ultrapure water into a 50mL beaker, then add 0.112g of FaSSIF / FeSSIF / FaSSGF powder. Stir to dissolve and let stand for equilibration for 2 hours before use (the solution should be used within 48 hours).

[0382] 2.2 Preparation of FessIF solution

[0383] Weigh 4.0705g of FeSSIF medium solution and 45.97g of ultrapure water into a 50mL beaker, then add 0.56g of FaSSIF / FeSSIF / FaSSGF powder and stir to dissolve (the solution should be used within 48 hours).

[0384] 2.3 Preparation of PBS solution

[0385] Weigh 0.57 g NaH2PO4•2H2O, 5.55 g Na2HPO4•12H2O, and 6.48 g NaCl, add them to ultrapure water, adjust the pH to 7.4±0.05 with 1 M NaOH or 1 M HCl, and then add water to a final volume of 1 L. Store at 4°C (shelf life is 6 months).

[0386] 3. Experimental Procedure

[0387] 3.1 Solubility test in FassIF and FessIF solutions

[0388] 3.1.1 Weigh an appropriate amount of the analyte and prepare a 10 mM stock solution using DMSO as the solvent. Accurately measure 10 μL of the stock solution (10 mM concentration, dissolved in DMSO) and 990 μL of DMSO into a 1.5 mL PE tube, mix well, and obtain a clear 100 μM sample solution as the reference solution.

[0389] 3.1.2 Dissolve 1 mg of the sample to be tested in 900 μL of FassIF solution (or FessIF solution), mix vigorously, and prepare two parallel solutions; shake in a constant temperature shaker at 37°C for 24 hours, transfer the mixed solution to a 1.5 mL PE tube, centrifuge at 12000 rpm for 30 min, and use the supernatant as the sample solution, transfer it to a 2 mL vial for liquid chromatography analysis.

[0390] 3.2 Solubility test in PBS solution

[0391] 3.2.1 Weigh an appropriate amount of the analyte and prepare a 10 mM stock solution using DMSO as the solvent. Accurately measure 10 μL of the stock solution (10 mM concentration, dissolved in DMSO) and 990 μL of DMSO into a 1.5 mL PE tube, mix well, and obtain a clear 100 μM sample solution as the reference solution.

[0392] 3.2.2 Accurately transfer 10 μL of the sample stock solution (10 mM concentration, dissolved in DMSO) and 990 μL of PBS solution into a 96-well deep-well plate (2 mL). Cover the plate with the silicone sealant and mix well. Prepare four parallel aliquots. Shake the plate at 1200 rpm at room temperature for 24 hours on a THERMO-SHAKER microplate shaker. Centrifuge the entire plate at 4000 rpm for 1 hour. Transfer 300 μL of the supernatant into a 96-well shallow-well plate (0.5 mL), cover with the 96-well plate sealant, and transfer to liquid chromatography for analysis.

[0393] 4. Experimental Results

[0394] Solubility (μM) = Peak area of ​​sample / Peak area of ​​reference × Concentration of reference solution (μM) × Dilution factor of sample solution × Injection volume of reference solution ÷ Injection volume of sample solution

[0395] The average of the two measurements was taken as the final solubility in FassIF, FessIF, and PBS solutions.

[0396] Conclusion: The disclosed compound has good solubility in PBS, FastsIF, or FessIF solutions.

Claims

1. A compound of general formula (I) or a pharmaceutically acceptable salt thereof, in: Ring B is a ring containing at least one N. + -O - cycloalkyl, heterocyclic, aryl, or heteroaryl groups; X is N or CR 6a ; Y is N or CR 6d ; R 1 R 2 R 3 R 4 R 5 R 6a R 6b R 6c and R 6d The same or different, and each independently selected from hydrogen atom, halogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, cyano, amino, hydroxy, nitro, cycloalkyl, heterocyclic, aryl, heteroaryl, -OR 16 -NR 17 R 18 -C(O)R 16 -C(O)OR 16 -C(O)NR 17 R 18 -OC(O)NR 17 R 18 -OC(O)R 16 -OC(O)OR 16 -NR 19 C(O)R 16 -NR 19 C(O)OR 16 -S(O) v R 16 -S(O) v NR 17 R 18 -NR 17 R 18 -S(O) v -NR 19 C(O)NR 17 R 18 -NR 19 S(O) v R 16 =O and =CR 20 R 21 The alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each independently and optionally selected by one or more R groups. 0 replace; Or, two Rs 1 Together with their respective attached atoms, they form cycloalkyl, heterocyclic, aryl, or heteroaryl groups, each of which is independently and optionally influenced by one or more R groups. 0 replace; L is selected from bond, O, S(O). v S(O) v NR c NR c S(O) v C(O), NR c C(O)NR c NR c C(O), alkylene, O(alkylene), (alkylene)O, NR c (alkylene), (alkylene)NR c C(O)NR c (alkylene), (alkylene)C(O)NR c S(O) v (alkylene), (alkylene)S(O) v (alkylene)S(O) v NR c S(O) v NR c (alkylene), NR c C(O)NR c NR c S(O) v NR c C(O) (alkylene) and (alkylene)C(O), wherein the alkylene is optionally mixed with one or more R 0 replace; R c Selected from hydrogen atoms, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, and cycloalkylalkyl; Or, L and R 6a Together with the adjacent atoms, they form cycloalkyl, heterocyclic, aryl, or heteroaryl groups fused to the ring containing X and Y, wherein each cycloalkyl, heterocyclic, aryl, and heteroaryl group is independently and optionally influenced by one or more R groups. 0 replace; Or, L and R 6d Together with the adjacent atoms, they form cycloalkyl, heterocyclic, aryl, or heteroaryl groups fused to the ring containing X and Y, wherein each cycloalkyl, heterocyclic, aryl, and heteroaryl group is independently and optionally influenced by one or more R groups. 0 replace; R 7 Selected from hydrogen atoms, halogens, hydroxyl groups, alkyl groups, haloalkyl groups, hydroxyalkyl groups, alkoxy groups, and haloalkoxy groups; R 16 R 17 and R 18 The same or different, and each independently selected from hydrogen atoms, alkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl, wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl is independently optionally selected by one or more R 0 Replace; or R 17 and R 18 Together with the connected nitrogen atom, they form an optional structure with one or more R atoms. 0 Substituted heterocyclic groups; R 19 Selected from hydrogen atoms, alkyl groups, and cycloalkyl groups; R 20 and R 21 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, alkyl groups, alkoxy groups, hydroxyl groups, and cycloalkyl groups; or, R 20 and R 21 Together with the attached carbon atom, they form cycloalkyl or heterocyclic groups; Each R 0 They may be the same or different, and each is independently selected from halogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, aminoalkyl, hydroxyl, cyano, nitro, amino, -NHalkyl, -N(alkyl)2, =O, =S, =CH2, =CHF, =CF2, -C(O)Oalkyl, -C(O)OH, -C(O)NH2, -C(O)NH(alkyl), -C(O)N(alkyl)2, -C(O)halogen, -C(O)alkyl, -S(alkyl), cycloalkyl, cycloalkylalkyl, cycloalkyloxy, heterocyclic, heterocyclic alkyl, heterocyclic oxy, aryl, arylalkyl, aryloxy, heteroaryl, heteroarylalkyl and heteroaryloxy; Or, two Rs 0 Together with the attached atoms, they form a 3- to 8-membered cycloalkyl or a 3- to 8-membered heterocyclic group, wherein each of the 3- to 8-membered cycloalkyl and the 3- to 8-membered heterocyclic group is independently and optionally substituted by one or more substituents selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy and oxo. n is 0, 1, 2, 3, 4, 5, or 6; and v can be 0, 1, or 2.

2. The compound of general formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, is a compound of general formula (II) or a pharmaceutically acceptable salt thereof. in: B 1 B 2 B 3 B 4 and B 5 Each is independently selected from N, N + -O - and CR 1 The condition is that B 1 B 2 B 3 B 4 and B 5 At least one of them is N + -O - ;and R 1 -R 5 X, R 6b R 6c Y and L are as defined in claim 1.

3. The compound of general formula (I) according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein the compound is of general formula (II-1) or a pharmaceutically acceptable salt thereof. in: n1 is 0, 1, 2, 3, or 4; and R 1 -R 5 L, R 6a R 6b R 6c and R 6d As defined in claim 1.

4. The compound of general formula (I) according to any one of claims 1 to 3, or a pharmaceutically usable salt thereof, wherein L is selected from bond, CH2 and OCH2; preferably, L is bond.

5. The compound of general formula (I) according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein R 1 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl and C 1-6 Halogenated alkyl groups; or, two adjacent R groups 1 Together with their respective attached carbon atoms, they form a phenyl group; Preferably, R 1 It is a hydrogen atom.

6. The compound of general formula (I) according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein R 2 It is a halogen; preferably, R 2 It is Cl.

7. The compound of formula (I) according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R 3 It is a hydrogen atom; and / or R 4 It is a hydrogen atom; and / or R 5 It is a hydrogen atom.

8. The compound of general formula (I) according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein R 6a It is a hydrogen atom; and / or R 6b It is a hydrogen atom; and / or R 6c It is a hydrogen atom; and / or R 6d It is a hydrogen atom or a carbon atom. 1-6 alkyl.

9. The compound of formula (I) according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, selected from the group consisting of: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and .

10. A method for preparing a compound of general formula (I) according to claim 1, comprising: A compound of general formula (IA) or a salt thereof undergoes a coupling reaction with a compound of general formula (IB) or a salt thereof to obtain a compound of general formula (I) or a pharmaceutically usable salt thereof; in: R w for Or -B(OH)2; R L It is a leaving group; preferably, R L Halogen; more preferably, R L For Br; R 1 -R 5 R 7 X, Y, L, R 6b R 6c Ring B and n are as defined in claim 1.

11. A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 9, and one or more pharmaceutically acceptable carriers, diluents or excipients.

12. Use of the compound of any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of claim 11 in the preparation of a medicament for inhibiting or degrading VAV1.

13. Use of the compound of any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of claim 11 in the preparation of a medicament for the treatment and / or prevention of diseases or conditions mediated or dependent on VAV1.

14. Use of the compound of any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 11, in the preparation of a medicament for treating and / or preventing tumors, autoimmune diseases, and inflammatory diseases; wherein the autoimmune disease or inflammatory disease is preferably selected from multiple sclerosis, arthritis, rheumatoid arthritis, pemphigus, systemic lupus erythematosus, Hashimoto's thyroiditis, myasthenia gravis, type I or II diabetes and related diseases, vasculitis, pernicious anemia, Sjögren's syndrome, uveitis, psoriasis, Graves' ophthalmopathy, Graves' disease, alopecia areata, asthma, allergic asthma, atopic dermatitis, allergic dermatitis, rhinitis, conjunctivitis, allergic contact dermatitis, colitis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, intrinsic asthma, inflammatory lung injury, inflammatory liver injury, inflammatory glomerular injury, atherosclerosis, osteoarthritis, irritant contact dermatitis, eczematous dermatitis, seborrheic dermatitis, inflammatory eye disease, keratoconjunctivitis, myocarditis, pericarditis, pulmonary fibrosis, systemic sclerosis, morphine scleroderma, Alzheimer's disease, autoimmune liver disease, hepatitis, amyloidosis, macular degeneration, lupus nephritis, pulmonary hypertension, chronic graft-versus-host disease, cholesclerosis, sclerosing cholangitis, axial spondyloarthritis.

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