Heterocyclic small molecule compounds and uses thereof

Abstract

This invention discloses a class of heterocyclic small molecule compounds and their applications. This invention provides a compound of formula (I), its stereoisomers, its tautomers, its pharmaceutically acceptable salts, its solvates, its deuterated derivatives, its metabolites, or its prodrugs. The compounds provided by this invention exhibit good degradation activity against VAV1 and can be used to prepare drugs for the treatment or prevention of diseases related to the VAV1 protein signaling pathway.

Description

[0001] This application claims priority to U.S. Patent Application No. 63 / 788,249, filed on April 14, 2025, the entire contents of which are incorporated herein by reference. Technical Field

[0002] This invention relates to novel molecular gel degraders targeting human VAV1 protein (VAV1) and their valuable pharmacological properties, belonging to the field of biomedical technology, specifically involving a class of heterocyclic small molecule compounds and their applications. Background Technology

[0003] VAV1 protein, encoded by the proto-oncogene VAV1, is a hematopoietic system-specific guanylate exchange factor (GEF) that activates Rho / Rac family GTPases (such as Rac1 and RhoA), thereby regulating cytoskeleton dynamics, immune cell activation, and migration. This protein is primarily expressed on T cells, B cells, and NK cells, and can transduce signals from antigen receptors (TCR / BCR) and cytokine receptors, driving key signaling pathways related to lymphocyte development, proliferation, and cytotoxicity (PLCγ, NFAT, MAPK). By remodeling actin, VAV1 promotes immune synapse formation, phagocytosis, and cell motility, playing a central role in the regulation of the body's immune function. Abnormal regulation of VAV1 is closely related to the development and progression of various diseases. Mutations or overexpression of this protein can lead to the development of malignant tumors such as lymphoma (e.g., peripheral T-cell lymphoma), while its functional loss results in impaired immune function. Under both physiological and pathological conditions, the activity of VAV1 is strictly regulated by phosphorylation modifications (such as Lck kinase-mediated phosphorylation), making it a key molecule connecting membrane receptors to downstream effector networks.

[0004] The ubiquitin-proteasome system (UPS) is the core system for targeted protein degradation in the body. It uses E1-E2-E3 enzymes to catalyze ubiquitin labeling of target protein substrates, enabling the proteasome to recognize and degrade the substrates, thereby precisely regulating intracellular protein homeostasis. Molecular glues (also known as molecular glue degraders, MGDs) are a class of small molecule compounds with targeted degradation capabilities. Their mechanism of action involves hijacking the ubiquitin-proteasome system, inducing E3 ubiquitin ligases (such as cereblon) to interact closely with the target protein (new substrate), thereby triggering ubiquitination and degradation of the target protein. MGDs act monovalently, recruiting new substrates by remodeling the surface structure of E3 ubiquitin ligases. These compounds offer a new technological pathway for the treatment of "undruggable" targets in cancer and other diseases. Currently known molecular glue degraders include immunomodulatory drugs (such as thalidomide, which degrades IKZF1 / 3 proteins in myeloma) and natural products (such as cyclosporine A), demonstrating promising clinical application potential.

[0005] This invention discloses a series of novel small molecule structures that have the potential to be used as VAV1 molecular glue degrading agents. These degrading agents can hijack the ubiquitin-proteasome system, recruiting E3 ligases (such as cereblon) to VAV1, inducing VAV1 ubiquitination and degradation by the proteasome, thereby effectively silencing its carcinogenic or overactivated GTPase signals. The compounds of this invention may provide therapeutic strategies for cancers and autoimmune diseases (such as peripheral T-cell lymphoma, chronic lymphocytic leukemia, rheumatoid arthritis, myasthenia gravis, ulcerative colitis, and psoriasis) driven by abnormal VAV1 signaling.

[0006] Given the crucial role of abnormal VAV1 signaling in various diseases, the development of novel molecular glue degraders targeting VAV1 has significant clinical implications and application value for the treatment of related diseases. Summary of the Invention

[0007] The technical problem to be solved by this invention is to develop new small molecule degraders of VAV1 to meet clinical treatment needs. To this end, this application provides a class of heterocyclic small molecule compounds and their applications. The compounds provided in this application have better efficacy and promising application prospects.

[0008] The present invention solves the above-mentioned technical problems through the following solution.

[0009] The compounds of the present invention and pharmaceutically acceptable compositions thereof are capable of effectively degrading VAV1 protein. The compounds have general formula (I), or stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, deuterated derivatives, metabolites, or prodrugs thereof, wherein the variables are defined as described herein: ; in: For connection and A divalent group (located at the Z site). For connection With the divalent group of L. L is the linker. With the divalent group of G.

[0010] In some implementation schemes, " indicates an optional double bond.

[0011] In some embodiments, certain groups in the compound of formula (I) or its stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, deuterated derivatives, metabolites or prodrugs have the following definitions, and the definitions of groups not mentioned are as described in any embodiment of the present invention (hereinafter referred to as "in one embodiment" or "in some embodiments").

[0012] In some implementations, ring Y represents .

[0013] In some implementations, ring X represents .

[0014] In some embodiments, ring Y is independently selected from 5-20 membered monocyclic, bicyclic, or tricyclic aromatic rings, partially saturated 5-20 membered monocyclic, bicyclic, or tricyclic aromatic rings, and 3-15 membered saturated or partially unsaturated monocyclic, fused bicyclic, bridged bicyclic, or spirocyclic alkyl rings, optionally containing 1-6 heteroatoms as part of the ring structure, wherein the heteroatoms are independently selected from nitrogen (N), oxygen (O), and sulfur (S). Each time ring Y occurs, it is optionally substituented by 0 to m substituents R. y replace.

[0015] In some implementations, the linker site with Z may be, where valence allows, a substitute for R. y -H at any site.

[0016] In some implementations, the linking site with ring X may be, where valence allows, a substitution of R. y -H at any site.

[0017] In some implementations, ring Y can be selected from structures including, but not limited to, the following. It should be understood that, " indicates the connection site with Z, and another connection site with ring X can be -H, which can replace any site in ring Y, provided that the valence allows; .

[0018] In some implementations, ring Y and one or more R y Substituents may be selected from, but are not limited to, the following structures. It should be understood that, ", located in one of its R y The substituent indicates the connection site with Z, and another connection site with ring X can be -H at any site on ring Y, provided the valence allows; .

[0019] In some embodiments, ring X is independently selected from 5-20 membered monocyclic, bicyclic, or tricyclic aromatic rings, partially saturated 5-20 membered monocyclic, bicyclic, or tricyclic aromatic rings, and 3-18 membered saturated or partially unsaturated monocyclic, fused bicyclic, bridged bicyclic, or spirocyclic alkyl rings, optionally containing 1-6 heteroatoms as part of the ring structure, wherein the heteroatoms are independently selected from nitrogen (N), oxygen (O), and sulfur (S). Each time ring X occurs, it is optionally substituented by 0-n substituents "R". x "replace.

[0020] In some implementations, the connection site with ring Y may be, where valence allows, a substitution of R. x -H at any position on the upper part.

[0021] In some implementations, the linker site with L can replace R, provided the valence allows. x -H at any position on the upper part.

[0022] In some implementations, ring X can be selected from structures including, but not limited to, the following. It should be understood that, " indicates the connection site with ring Y, and another connection site with L can be a -H that replaces any site on ring X, provided the valence allows;

[0023] “ "Indicates that any double key can be selected.

[0024] In some implementation schemes, R x and R y Each is independently selected from hydrogen, deuterium, -CH3, -C2H5, -CH2F, -CHF2, -CF3, -F, -Cl, -Br, -I, -OH, -SH, -NH2, -NO2, -CN, -C(=O)OH, and -C(=O)NH2. In some embodiments, R x and R y Each is R c .

[0025] In some implementation schemes, any R x Or R y It can form a ring or a double bond with the same carbon atom it is attached to. The double bond can be independently selected from -C=O, -C=S, -C=NR, -C=CHR, and -C=CR2. The ring can be independently selected from C... 3-12 A saturated or partially unsaturated monocyclic, fused bicyclic, bridged bicyclic, or spirocyclic ring, optionally comprising 1 to 4 heteroatoms as components of the ring structure, wherein the heteroatoms are independently selected from nitrogen (N), oxygen (O), and sulfur (S). Each time, the formed ring is optionally independently substituted by one or more substituents selected from: hydrogen, deuterium, -CH3, -C2H5, -CH2F, -CHF2, -CF3, -F, -Cl, -Br, -I, -OH, -SH, -NH2, -NO2, -CN, -C(=O)OH, -C(=O)NH2. In some embodiments, the formed ring is optionally substituted by one or more R... c replace.

[0026] In some implementations, any two R x Or any two R yIt can form a ring together with the carbon atom it is attached to and / or adjacent atoms, through interatomic connections. The resulting ring can be independently selected from C atoms. 3-12 Saturated or partially unsaturated monocyclic, fused bicyclic, bridged bicyclic, or spirocyclic compounds, or C 5-12 An aromatic ring, wherein the ring optionally comprises 1 to 3 heteroatoms as constituent parts of the ring structure, the heteroatoms being independently selected from nitrogen (N), oxygen (O), and sulfur (S). Each time, the formed ring is optionally independently substituted by one or more substituents selected from: hydrogen, deuterium, -CH3, -C2H5, -CH2F, -CHF2, -CF3, -F, -Cl, -Br, -I, -OH, -SH, -NH2, -NO2, -CN, -C(=O)OH, -C(=O)NH2. In some embodiments, the formed ring is optionally substituted by one or more R... c replace.

[0027] In some implementation schemes, R y It is independently selected from -CH3, -C2H5, -CH2F, -CHF2, -CF3, -F, -Cl, -Br, -I, -OH, -SH, -NH2, -NHCH3, N(CH3)2, -NO2, -CN, -C(=O)OH, -C(=O)NH2.

[0028] In some implementation schemes, R y Together with the carbon atom it is attached to, they form a carbonyl group.

[0029] In some implementation schemes, R x Independently selected from -CH3, -C2H5, -CH2F, -CHF2, -CF3, -F, -Cl, -Br, -I, -OH, -SH, -NH2, -NHCH3, N(CH3)2, -NO2, -CN, -C(=O)OH, -C(=O)NH 2。

[0030] In some implementation schemes, R x Together with the carbon atom it is attached to, they form a carbonyl group.

[0031] In some implementations, n and m are each independently selected from 0, 1, 2, 3, 4, 5, and 6.

[0032] In some implementations, Z is independently selected from N, CH, CD, CF, and CR.

[0033] In some implementation schemes, R 1 R 2 and R 3Each is independently selected from hydrogen, deuterium, methyl, ethyl, cyclopropyl, cyclobutyl, cyclopentyl, halogen, -CN, -OR, -SR, -NR2. In some embodiments, R 1 R 2 and R 3 Each is R c .

[0034] In some implementation schemes, any R 1 or R 2 It can form a ring or a double bond with the carbon atom it is attached to. The double bond can be independently selected from C=O, C=S, C=NR, and C=CR2. The ring can be independently selected from C... 3-7 A saturated or partially unsaturated monocyclic, fused bicyclic, bridged bicyclic, or spirocyclic ring, optionally comprising 1 to 3 heteroatoms as components of the ring structure, wherein the heteroatoms are independently selected from nitrogen (N), oxygen (O), and sulfur (S). Each time, the formed ring is optionally substituented by one or more substituents independently selected from the group consisting of: hydrogen, deuterium, -CH3, -C2H5, -CH2F, -CHF2, -CF3, -F, -Cl, -Br, -I, -OH, -SH, -NH2, -NO2, -CN, -C(=O)OH, -C(=O)NH2. In some embodiments, the formed ring is optionally substituented by one or more R... c replace.

[0035] In some implementations, any two R 1 R 2 R 3 Z, along with the carbon atoms they are attached to and / or adjacent atoms, can form rings through the atoms in between. The resulting rings can be independently selected from C. 3-7 Saturated or partially unsaturated monocyclic, fused bicyclic, bridged bicyclic, or spirocyclic compounds, or C 5-6 An aromatic ring, wherein the ring optionally comprises 1 to 3 heteroatoms as constituent parts of the ring structure, the heteroatoms being independently selected from nitrogen (N), oxygen (O), and sulfur (S). Each time, the formed ring is optionally independently substituted by one or more substituents selected from: hydrogen, deuterium, -CH3, -C2H5, -CH2F, -CHF2, -CF3, -F, -Cl, -Br, -I, -OH, -SH, -NH2, -NO2, -CN, -C(=O)OH, -C(=O)NH2. In some embodiments, the formed ring is optionally substituted by one or more R... c replace.

[0036] In some implementation schemes, "Optional from, but not limited to, the following structures. It should be understood that," " indicates the connection point with ring Y; .

[0037] In some implementations, L is a covalent bond, or C 1-10 Straight-chain or branched, saturated or partially unsaturated hydrocarbon chains, or C 3-12 Saturated or partially unsaturated monocyclic, fused bicyclic, bridged bicyclic, or spirocyclic compounds, or C 5-12 A monocyclic or bicyclic aromatic ring comprising 1 to 6 heteroatoms constituting part or all of the chain structure, wherein the heteroatoms are independently selected from nitrogen (N), oxygen (O), and sulfur (S). Each time L appears, L is optionally independently substituted by one or more substituents selected from: hydrogen, deuterium, -CH3, -C2H5, -CH2F, -CHF2, -CF3, -F, -Cl, -Br, -I, -OH, -SH, -NH2, -NO2, -CN, -C(=O)OH, -C(=O)NH2. In some embodiments, L is optionally substituted by one or more R... c replace.

[0038] In some implementation schemes, any R c It can form a ring or a double bond with the same carbon atom it is attached to. The double bond can be independently selected from -C=O, -C=S, -C=NR, -C=CHR, and -C=CR2. The ring can be independently selected from C... 3-7 The ring is a saturated or partially unsaturated monocyclic, fused bicyclic, bridged bicyclic, or spirocyclic ring, wherein the ring optionally contains 1 to 3 heteroatoms as constituents of the ring structure, said heteroatoms being independently selected from nitrogen (N), oxygen (O), and sulfur (S). Each time such heteroatoms are present, the resulting ring is optionally independently substituted by one or more substituents selected from: hydrogen, deuterium, -CH3, -C2H5, -CH2F, -CHF2, -CF3, -F, -Cl, -Br, -I, -OH, -SH, -NH2, -NO2, -CN, -C(=O)OH, -C(=O)NH2. In some embodiments, the resulting ring is optionally substituted by one or more R... a replace.

[0039] In some implementations, any two R c They can form rings, together with the atoms they are connected to and / or adjacent atoms, through intermediate atoms. The resulting rings can be independently selected from C. 3-7 Saturated or partially unsaturated monocyclic, fused bicyclic, bridged bicyclic, or spirocyclic compounds, and C 5-6The aromatic ring optionally contains 1 to 3 heteroatoms as constituent parts of the ring structure, wherein the heteroatoms are independently selected from nitrogen (N), oxygen (O), and sulfur (S). Each time, the formed ring is optionally independently substituted by one or more substituents selected from: hydrogen, deuterium, -CH3, -C2H5, -CH2F, -CHF2, -CF3, -F, -Cl, -Br, -I, -OH, -SH, -NH2, -NO2, -CN, -C(=O)OH, -C(=O)NH2. In some embodiments, the formed ring is optionally substituted by one or more R... a replace.

[0040] In some implementations, G is independently selected from C. 1-10 Straight-chain or branched, saturated or partially unsaturated alkyl, C 3-20 Saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic, tricyclic, or spirocyclic alkyl groups, C 5-20 Monocyclic, bicyclic or tricyclic aryl, C 5-20 A partially unsaturated monocyclic, bicyclic, or tricyclic aryl group, optionally comprising 1 to 6 heteroatoms as components of the ring structure, wherein the heteroatoms are independently selected from nitrogen (N), oxygen (O), and sulfur (S). In each occurrence, G is optionally independently substituted by one or more substituents selected from: hydrogen, deuterium, -CH3, -C2H5, -CH2F, -CHF2, -CF3, -F, -Cl, -Br, -I, -OH, -SH, -NH2, -NO2, -CN, -C(=O)OH, -C(=O)NH2. In some embodiments, G is optionally substituted by one or more R... c replace.

[0041] In some implementation schemes, any R c It can form a ring or a double bond with the same carbon atom it is attached to. The double bond can be independently selected from -C=O, -C=S, -C=NR, -C=CHR, and -C=CR2. The ring can be independently selected from C... 3-7 The ring is a saturated or partially unsaturated monocyclic, fused bicyclic, bridged bicyclic, or spirocyclic ring, wherein the ring optionally contains 1 to 3 heteroatoms as constituents of the ring structure, said heteroatoms being independently selected from nitrogen (N), oxygen (O), and sulfur (S). Each time such heteroatoms are present, the resulting ring is optionally independently substituted by one or more substituents selected from: hydrogen, deuterium, -CH3, -C2H5, -CH2F, -CHF2, -CF3, -F, -Cl, -Br, -I, -OH, -SH, -NH2, -NO2, -CN, -C(=O)OH, -C(=O)NH2. In some embodiments, the resulting ring is optionally substituted by one or more R... a replace.

[0042] In some implementations, any two Rc They can form rings, together with the atoms they are connected to and / or adjacent atoms, through intermediate atoms. The resulting rings can be independently selected from C. 3-7 Saturated or partially unsaturated monocyclic, fused bicyclic, bridged bicyclic, or spirocyclic compounds, and C 5-6 The aromatic ring optionally contains 1 to 3 heteroatoms as constituent parts of the ring structure, wherein the heteroatoms are independently selected from nitrogen (N), oxygen (O), and sulfur (S). Each time, the formed ring is optionally independently substituted by one or more substituents selected from: hydrogen, deuterium, -CH3, -C2H5, -CH2F, -CHF2, -CF3, -F, -Cl, -Br, -I, -OH, -SH, -NH2, -NO2, -CN, -C(=O)OH, -C(=O)NH2. In some embodiments, the formed ring is optionally substituted by one or more R... a replace.

[0043] In some implementations, the following group is defined: R c R b R a 、R; Each R c Independently selected from C 1-6 Straight-chain or branched alkyl groups, C 2-6 Straight-chain or branched alkenyl, C 2-6 Straight-chain or branched alkynyl groups, C 3-7 cycloalkyl, C 3-7 Cycloalkenyl, C 5-6 Aryl, C 5-6 Mixed aromatics, -OR b -SR b -N(R) b )2、-Si(R b 3. -S(=O)R b -S(=O)2R b -S(=O)2N(R) b )2、-C(=O)R b -C(=O)OR b -C(=O)N(R) b )2、-C(=O)NR b (OR b -OC(=O)R b -OC(=O)OR b -OC(=O)N(R) b )2、-NRC(=O)R b -NRC(=O)OR b -NRC(=O)N(R) b )2、-NRS(=O)2R b-P(=O)(R b )2、-P(=O)(OR b )2、-OP(=O)(R b )2、-OP(=O)(OR b 2. The above-mentioned groups optionally contain 1 to 5 heteroatoms as components of the chain or ring structure, wherein the heteroatoms are independently selected from nitrogen (N), oxygen (O), and sulfur (S). Each time R appears... c It may optionally be independently substituted by one or more substituents selected from the following: hydrogen, deuterium, -CH3, -C2H5, -CH2F, -CHF2, -CF3, -F, -Cl, -Br, -I, -OH, -SH, -NH2, -NO2, -CN, -C(=O)OH, -C(=O)NH2. In some embodiments, R c Optional by one or more R b Substituent substitution.

[0044] Each R b Independently selected from C 1-6 Straight-chain or branched alkyl groups, C 2-6 Straight-chain or branched alkenyl, C 2-6 Straight-chain or branched alkynyl groups, C 3-7 cycloalkyl, C 3-7 Cycloalkenyl, C 5-6 The aryl group optionally comprises 1 to 3 heteroatoms as part of a chain or ring structure, wherein the heteroatoms are independently selected from nitrogen (N), oxygen (O), and sulfur (S). Each time it appears, R... b It may be independently substituted by one or more substituents selected from the following: hydrogen, deuterium, -CH3, -C2H5, -CH2F, -CHF2, -CF3, -F, -Cl, -Br, -I, -OH, -SH, -NH2, -NO2, -CN, -C(=O)OH, -C(=O)NH2.

[0045] Each R a Independently selected from hydrogen, deuterium, -CN, -C(=O)OH, -C(=O)NH2, -OH, -SH, -NH2, -NO 2， -OCH3, -NHCH3, -N(CH 3)2 , -CH3, -C2H5, -CH2F, -CHF2, -CF3, -F, -Cl, -Br, -I and R b .

[0046] Each R is independently selected from hydrogen, deuterium, -CN, -C(=O)OH, -C(=O)NH2, -OH, -SH, -NH2, -NO 2， -OCH3, -NHCH3, -N(CH 3)2, -CH3, -C2H5, -CH2F, -CHF2, -CF3, -F, -Cl, -Br, -I, C 1-6 Straight-chain or branched alkyl groups, C 2-6 Straight-chain or branched alkenyl, C 2-6 Straight-chain or branched alkynyl groups, C 3-7 cycloalkyl, C 3-7 Cycloalkenyl, C 5-6 Aryl, C 5-6 The heteroaryl group optionally comprises 1 to 3 heteroatoms as part of a chain or ring structure, wherein the heteroatoms are independently selected from nitrogen (N), oxygen (O), and sulfur (S). Each time R appears, R is optionally independently substituted by one or more substituents selected from: hydrogen, deuterium, halogen, -CN, -NO2, -OR. a -SR a -N(R) a )2、-Si(R a 3. -S(=O)R a -S(=O)2R a -S(=O)2N(R) a )2、-C(=O)R a -C(=O)OR a -C(=O)(NR) a )2、-C(=O)NR a (OR a -OC(=O)R a -OC(=O)OR a -OC(=O)N(R) a )2、-NRC(=O)R a -NRC(=O)OR a -NRC(=O)N(R) a )2、-NRS(=O)2R a -P(=O)(R a )2、-P(=O)(OR a )2、-OP(=O)(R a )2、-OP(=O)(OR a 2. In some implementations, R is optionally controlled by one or more Rs. b Substituent substitution.

[0047] The compounds of the present invention and pharmaceutically acceptable compositions thereof are effective as degraders of VAV1 protein. In one aspect, the present invention provides a compound of formula (II), or a stereoisomer, tautomer, pharmaceutically acceptable salt, solvate, deuterated analog, metabolite, or prodrug thereof. The compound of formula (II) is selected from any of the following compounds:

[0048] In some implementation schemes, R x The terms are independently selected from -CH3, -C2H5, -CH2F, -CHF2, -CF3, -F, -Cl, -Br, -I, -OH, -SH, -NH2, -NHCH3, N(CH3)2, -NO2, -CN, -C(=O)OH, and -C(=O)NH2.

[0049] In some implementation schemes, R x Together with the carbon atom it is attached to, they form a carbonyl group.

[0050] In some implementation schemes, ring X and R x The substituents can be selected from, but are not limited to, the following structures. It should be understood that the "..." on the left side of the structure... The "" indicates the connection point with "L", and the "" on the right side of the structure "Indicates the connection point with ring Y; .

[0051] In some implementations, each R y Independently selected from hydrogen, deuterium, -CH3, -C2H5, -CH2F, -CHF2, -CF3, -F, -Cl, -Br, -I, -OH, -SH, -NH2, -NO2, -CN, -C(=O)OH, -C(=O)NH2. In some embodiments, each R y For R c .

[0052] In some implementation schemes, any R y It can form a ring or a double bond with the same carbon atom it is attached to. The double bond can be independently selected from -C=O, -C=S, -C=NR, -C=CHR, and -C=CR2. The ring can be independently selected from C... 3-12 The ring is a saturated or partially unsaturated monocyclic, fused bicyclic, bridged bicyclic, or spirocyclic ring, wherein the ring optionally contains 1 to 4 heteroatoms as constituent parts of the ring structure, said heteroatoms being independently selected from nitrogen (N), oxygen (O), and sulfur (S). Each time such heteroatoms are present, the resulting ring is optionally independently substituted by one or more substituents selected from: hydrogen, deuterium, -CH3, -C2H5, -CH2F, -CHF2, -CF3, -F, -Cl, -Br, -I, -OH, -SH, -NH2, -NO2, -CN, -C(=O)OH, -C(=O)NH2. In some embodiments, the resulting ring is optionally substituted by one or more R... c replace.

[0053] In some implementations, any two R y They can form rings, together with the carbon atoms they are attached to and / or adjacent atoms, through intermediate atoms. The resulting rings can be independently selected from C atoms. 3-12 Saturated or partially unsaturated monocyclic, fused bicyclic, bridged bicyclic, or spirocyclic compounds, or C 5-12 The aromatic ring optionally contains 1 to 3 heteroatoms as constituent parts of the ring structure, wherein the heteroatoms are independently selected from nitrogen (N), oxygen (O), and sulfur (S). Each time, the formed ring is optionally independently substituted by one or more substituents selected from: hydrogen, deuterium, -CH3, -C2H5, -CH2F, -CHF2, -CF3, -F, -Cl, -Br, -I, -OH, -SH, -NH2, -NO2, -CN, -C(=O)OH, -C(=O)NH2. In some embodiments, the formed ring is optionally substituted by one or more R... c replace.

[0054] The compounds of the present invention and pharmaceutically acceptable compositions thereof are effective as degraders of VAV1 protein. In one aspect, the present invention is characterized by compounds of formula (III), or stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, deuterated analogs, metabolites, or prodrugs thereof. The compound of formula (III) is any one of the following: .

[0055] In some implementations, ring Y and its R y Substituents may be selected from the following structures, but are not limited to them. It should be understood that the "..." on the left side of the structure... "Indicates the connection point with ring X, the right side of the structure " " indicates the connection point with Z; .

[0056] In some implementations, each R x Independently selected from hydrogen, deuterium, -CH3, -C2H5, -CH2F, -CHF2, -CF3, -F, -Cl, -Br, -I, -OH, -SH, -NH2, -NO2, -CN, -C(=O)OH, -C(=O)NH 2. In some implementations, each R x For R c .

[0057] In some implementation schemes, any R xIt can form a ring or a double bond with the same carbon atom it is attached to. The double bond can be independently selected from -C=O, -C=S, -C=NR, -C=CHR, and -C=CR2. The ring can be independently selected from C... 3-12 The ring is a saturated or partially unsaturated monocyclic, fused bicyclic, bridged bicyclic, or spirocyclic ring, wherein the ring optionally contains 1 to 4 heteroatoms as constituent parts of the ring structure, said heteroatoms being independently selected from nitrogen (N), oxygen (O), and sulfur (S). Each time such heteroatoms are present, the resulting ring is optionally independently substituted by one or more substituents selected from: hydrogen, deuterium, -CH3, -C2H5, -CH2F, -CHF2, -CF3, -F, -Cl, -Br, -I, -OH, -SH, -NH2, -NO2, -CN, -C(=O)OH, -C(=O)NH2. In some embodiments, the resulting ring is optionally substituted by one or more R... c replace.

[0058] In some implementations, any two R x They can form rings, together with the carbon atoms they are attached to and / or adjacent atoms, through intermediate atoms. The resulting rings can be independently selected from C atoms. 3-12 Saturated or partially unsaturated monocyclic, fused bicyclic, bridged bicyclic, or spirocyclic compounds, or C 5-12 The aromatic ring optionally contains 1 to 3 heteroatoms as constituent parts of the ring structure, wherein the heteroatoms are independently selected from nitrogen (N), oxygen (O), and sulfur (S). Each time, the formed ring is optionally independently substituted by one or more substituents selected from: hydrogen, deuterium, -CH3, -C2H5, -CH2F, -CHF2, -CF3, -F, -Cl, -Br, -I, -OH, -SH, -NH2, -NO2, -CN, -C(=O)OH, -C(=O)NH2. In some embodiments, the formed ring is optionally substituted by one or more R... c replace.

[0059] The compounds of the present invention and pharmaceutically acceptable compositions thereof are effective as degraders of VAV1 protein. In one aspect, the present invention provides a compound of formula (IV), or a stereoisomer, tautomer, pharmaceutically acceptable salt, solvate, deuterated analog, metabolite, or prodrug thereof. The compound of formula (IV) is any one of the following:

[0060] in: In some preferred embodiments, "The following structures may be selected, but are not limited to. It should be understood that," "Represents the connection point with ring Y; .

[0061] The compounds of the present invention and pharmaceutically acceptable compositions thereof are effective as degraders of VAV1 protein. In one aspect, the present invention provides a compound of formula (V), or a stereoisomer, tautomer, pharmaceutically acceptable salt, solvate, deuterated analog, metabolite, or prodrug thereof. The compound of formula (V) is a compound represented by the following formula:

[0062] in: In some implementations, L represents a covalent bond.

[0063] In some implementations, L can be selected from --C(R) b )2---, --O---, --(S)---, --N(R b )---, --Si(R b )2---, --S(=O)O---, --S(=O)2O---, --S(=O)2N(R b )---, --C(=O)---, --C(=O)O---, --C(=O)N(R b )---, --C(NR b (OR) b )---, --OC(=O)---, --OC(=O)O---, --OC(=O)N(R b )---, --N(R b )C(=O)---, --N(R b )C(=O)O---, --N(R b )C(=O)N(R b )---, --N(R b )S(=O)2R b ---, --P(=O)(R b )2---, --P(=O)(OR b )2---, --OP(=O)(R b )2---, --OP(=O)(OR b )2---, The aforementioned groups optionally contain 1 to 3 heteroatoms as components of the chain or ring structure, wherein the heteroatoms are independently selected from nitrogen (N), oxygen (O), and sulfur (S). Each time such a structure appears, it is optionally independently substituted by one or more substituents selected from: hydrogen, deuterium, -CH3, -C2H5, -CH2F, -CHF2, -CF3, -F, -Cl, -Br, -I, -OH, -SH, -NH2, -NO2, -CN, -C(=O)OH, -C(=O)NH 2。 In some embodiments, the above structures are optionally modified by one or more substituents R. b Replacement. It should be understood that "---" represents the connection site with ring X, and "--" represents the connection site with G.

[0064] In some implementations, L can be selected from the following structures, but is not limited to them. It should be understood that the "..." on the right side of the structure... "Represents the connection point with ring X, on the left side of the structure" " represents the connection site with G; .

[0065] In some implementations, G may be selected from the following structures, but is not limited to them. It should be understood that, " represents the connection point with L; .

[0066] The present invention provides a compound of formula (I), or a stereoisomer, tautomer, pharmaceutically acceptable salt, solvate, deuterated derivative, metabolite or prodrug thereof; , in, It is a divalent group, connecting and (At position Z); It is a divalent group, connecting and L; L is a divalent group, connecting... and G; Y-ring represents ; Ring X represents ; It can be a single bond or a double bond; The ring Y is phenyl or a 5-6 membered heteroaryl group; Ring X is selected from , , , , , , and ,in Represents the connection point with ring Y. Represents the connection point with L; Z is selected from N and CR; L is selected from single bond, -O-, -NH-, -C(=O)-, -S-, -S(=O-, -S(=O)2-, -C(=O)NH- -NHC(=O)- -C 1-3 Alkyl-, -C 2-3 alkenyl-, -C 2-3 alkynyl-, -OC 1-3 alkyl- -NH-C 1-3 alkyl- -C(=O)-C 1-3 alkyl- -NHC(=O)-C 1-3 alkyl- -C(=O)NH-C 1-3 alkyl- -C 1-3 Alkyl-O- -C 1-3 Alkyl-NH- -C 1-3 Alkyl-C(=O)- -C 1-3 Alkyl-C(=O)NH- and -C 1-3 Alkyl-NHC(=O)- The -NH- and -C(=O)NH- -NHC(=O)- -C 1-3 Alkyl-, -C 2-3 alkenyl-, -C 2-3 alkynyl-, -OC 1-3 alkyl- -NH-C 1-3 alkyl- -C(=O)-C 1-3 alkyl- -NHC(=O)-C 1-3 alkyl- -C 1-3 Alkyl-NHC(=O)- -C 1-3 Alkyl-O- -C 1-3 Alkyl-NH- -C 1-3 Alkyl-C(=O)- -C 1-3 Alkyl-C(=O)NH- and -C(=O)NH-C 1-3 alkyl- Each can be independently selected by 1, 2, 3 or 4 Rs. L Replace, among which Indicates the connection point with ring G; G is selected from 3-10 membered heterocyclic alkyl groups, 4-10 membered heterocyclic alkenyl groups, and C. 6-10 aryl or 5-10-membered heteroaryl, wherein the 3-10-membered heterocyclic alkyl, 4-10-membered heterocyclic alkenyl, C 6-10 Aryl and 5-10 heteroaryl groups are each independently and optionally bound by 1, 2, 3 or 4 R groups. G replace; R¹, R², and R³ are each independently selected from H, D, F, Cl, Br, I, CN, NH₂, OH, -CH₃, and -CH₂CH₃; Or, any R 1 Or R 2 It can form a ring with the carbon atom it is attached to, and the formed ring is independently selected from C. 3-7 Saturated monocyclic ring; Each R x and R y The elements are independently selected from H, D, F, Cl, Br, I, CN, NH2, OH, -CH3, -CH2CH3, -CH2CH2CH3, -CH2F, -CHF2, -CF3, -OCH3, -C(=O)OH and -C(=O)NH2, respectively. Each R L Each element is independently selected from H, D, halogens, CN, NH2, OH, and C. 1-6 Alkyl, Halogenated C 1-6 Alkyl-C(=O)C 1-6 Alkyl groups, -C(=O)OH, and -C(=O)NH2; Each R G The elements are independently selected from H, D, F, Cl, Br, I, =O, CN, NH2, OH, -C(=O)OH, -C(=O)NH2, C 1-6 Alkyl, -OC 1-6 Alkyl and C 3-7 cycloalkyl, the C 1-6 Alkyl, -OC 1-6 Alkyl and C 3-7 The cycloalkyl group is independently and optionally surrounded by 1, 2, 3 or 4 R groups.G1 replace; Or, R G Two Rs on the same carbon G They can be connected to form a ring, and the formed ring is independently selected from C. 3-7 Saturated monocyclic ring; Each R G1 Each of the following is independently selected from D, halogen, =O (oxo group), CN, NH2, OH, -NHCH3, -N(CH3)2, and C. 1-3 Alkyl, -OC 1-6 Alkyl and C 3-7 cycloalkyl, the C 1-3 Alkyl, -OC 1-3 Alkyl and C 3-7 Each cycloalkyl group may be independently substituted by 1, 2, 3 or 4 Rs; Each R is independently selected from H, D, F, Cl, Br, I, CN, NH2, OH, -CH3, -CH2CH3, -CH2F, -CHF2, -CF3, -OCH3, -NHCH3 and -N(CH3)2; m is selected from 0, 1, 2, 3, and 4; n is selected from 0, 1, 2, 3, and 4; In the heteroaryl group, the heteroatom / heteroatomic group is independently selected from one or more of N, S, O and C (=O), and the number of heteroatom / heteroatomic groups is independently selected from 1, 2, 3 and 4; In the heterocyclic alkyl group, the heteroatom / heteroatomic group is independently selected from one or more of N, S, O and C (=O), and the number of heteroatoms / heteroatomic groups is independently selected from 1, 2, 3 and 4. And the compound shown in formula (I) satisfies any of the following conditions: (1) When L is -C 1-3 When alkyl-, G is selected from 6-10 membered heterocyclic alkyl, 5-10 membered heterocyclic alkenyl, C 6-10 aryl and 6-10 heteroaryl, wherein the 6-10 heterocyclic alkyl, 5-10 heterocyclic alkenyl, C 6-10 Aryl and 6-10 heteroaryl groups are each independently and optionally co-occupied by 1, 2, 3 or 4 R groups. G replace; (2) When L is a single bond and the ring X is When G is selected from 6-10 N-containing heterocyclic alkyl groups, 6-10 N-containing heterocyclic alkenyl groups, and C 6-10 aryl and 6-10 N-containing heteroaryl, wherein the 6-10 N-containing heterocyclic alkyl, 6-10 N-containing heterocyclic alkenyl, C 6-10 Aryl and 6-10 N-containing heteroaryl groups are each independently and optionally co-occupied by 1, 2, 3, or 4 R groups. G replace; (3) When L is a single bond and the ring X is In this case, G is selected from 4-10-membered heterocyclic alkenyl and 5-10-membered heteroaryl, wherein the 4-10-membered heterocyclic alkenyl and 5-10-membered heteroaryl are independently and optionally surrounded by 1, 2, 3 or 4 Rs. G replace.

[0067] In some embodiments of the present invention, the compound of formula (I), its stereoisomers, or pharmaceutically acceptable salts thereof, wherein the compound of formula (I) is shown in formulas (II-A), (II-B), (II-C), (II-D), (III-A), and (IV-A): , , , , , , in, R 1 R 2 R 3 R x R y Z, L, G, ring X, ring Y, m and n are as defined in this invention.

[0068] In some embodiments of the present invention, the above-mentioned C 1-6 The alkyl group can be selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and tert-butyl, with methyl being preferred.

[0069] In some embodiments of the present invention, the above-mentioned C 1-3 The alkyl group can be selected from methyl, ethyl, n-propyl and isopropyl, with methyl being preferred.

[0070] In some embodiments of the present invention, the above-mentioned C 2-3 The alkenyl group can be selected from vinyl and propenyl groups.

[0071] In some embodiments of the present invention, the above-mentioned C 2-3 The alkynyl group can be selected from ethynyl and propynyl.

[0072] In some embodiments of the present invention, the above-mentioned C 3-7 The cycloalkyl group can be selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

[0073] In some embodiments of the present invention, the heteroatoms / heteroatomic groups of the above-mentioned 3-10 member heterocyclic alkyl groups are selected from one or more of N, O and C (=O), and the number of heteroatoms / heteroatomic groups is selected from 1, 2 and 3.

[0074] In some embodiments of the present invention, the 3-10 member heterocyclic alkyl group is selected from 3-7 member monocyclic heterocyclic alkyl groups and 7-10 member bicyclic heterocyclic alkyl groups.

[0075] In some embodiments of the present invention, the 3-10 membered heterocyclic alkyl group is selected from... , , , , , , , , , , , , , , , , , , , , , , and Preferred from , , , , , , , , , , , , , , , , and .

[0076] In some embodiments of the present invention, the heteroatom / heteroatom group of the above-mentioned 4-10 member heterocyclic alkenyl group is selected from one or more of N, O and C (=O), and the number of heteroatoms / heteroatom groups is selected from 1, 2, 3 and 4.

[0077] In some embodiments of the present invention, the above-mentioned C 6-10 The aryl group is selected from phenyl and naphthyl groups.

[0078] In some embodiments of the present invention, the above-mentioned C 3-7 Saturated monocyclic ring is C 3-7 Cycloalkyl groups, such as cyclopropyl groups.

[0079] In some embodiments of the present invention, the aforementioned 5-6 heteroaryl group is selected from pyridone, pyrimidinone, pyrazinone, pyridazinone, thiophene, pyridyl, pyrimidin, pyrazin, pyridazin, pyrazolyl, imidazolyl, oxazolyl, triazolyl, and imidazolinone, preferably from pyridone, pyrimidinone, and pyridyl, for example, pyridone (e.g.) ), for example, pyridyl.

[0080] In some embodiments of the present invention, the aforementioned 5-10-membered heteroaryl group is selected from 5-6-membered heteroaryl groups and 8-10-membered heteroaryl groups, preferably selected from pyridinone, pyrimidinone, pyrazinone, pyridinone, pyridyl, pyrimidin, pyrazin, pyridazin, pyrazolyl, imidazolyl, oxazolyl, triazolyl, imidazolinone, indole, isoindole, indazole, isoindazole, quinolinyl, isoquinolinyl, benzimidazolyl, and benzimidazolone, more preferably from... , , , , , , , , , , , , , , , , , , , , , , , , , , , , and .

[0081] In some embodiments of the present invention, the halogen is F, Cl, Br or I, for example F or Cl.

[0082] In some embodiments of the invention, the halogenation is replaced by one or more (e.g., 2, 3, 4 or 5) halogens.

[0083] In some embodiments of the present invention, the halogenated C 1-6 Alkyl group is fluorinated C 1-3 Alkyl groups, such as -CH2F, -CHF2, or -CF3.

[0084] In some embodiments of the present invention, Ring Y is phenyl; Ring X Selection , , , , , , ,in Represents the connection point with ring Y. Represents the connection point with L; Z stands for CH; L is selected from single bond, -O-, -NH-, -C(=O)-, -C 1-3 Alkyl-, -C(=O)-C 1-3 alkyl- -C 1-3 Alkyl-C(=O)- and -C 1-3 Alkyl-C(=O)NH- The -NH- and -C 1-3 Alkyl-, -C(=O)-C 1-3 alkyl- -C 1-3 Alkyl-C(=O)- and -C 1-3 Alkyl-C(=O)NH- Each can be independently selected by 1, 2, 3 or 4 Rs. L Replace, among which Indicates the connection point with ring G; G is selected from 3-10 membered heterocyclic alkyl groups, 4-10 membered heterocyclic alkenyl groups, and C. 6-10 aryl or 5-10-membered heteroaryl, wherein the 3-10-membered heterocyclic alkyl, 4-10-membered heterocyclic alkenyl, C 6-10 Aryl and 5-10 heteroaryl groups are each independently and optionally bound by 1, 2, 3 or 4 R groups. G replace; R¹, R², and R³ are each independently selected from H; Or, any R 1 Or R 2 It can form a ring with the carbon atom it is attached to, and the formed ring is independently selected from C. 3-7 Saturated monocyclic ring; Each R x and R y Each of the following is independently selected from H, Cl, -CH3, and -CF3; Each R L Selected independently from C 1-6 Alkyl or halogenated C 1-6 Alkyl-C(=O)C 1-6 alkyl; Each R G Selected independently from F, =O, and C respectively. 1-6 Alkyl, -OC 1-6 Alkyl and C 3-7 cycloalkyl, the C 1-6 Alkyl and C 3-7 The cycloalkyl group is independently and optionally surrounded by 1, 2, 3 or 4 R groups.G1 replace; Each R G1 Selected independently from halogens and C 3-7 cycloalkyl, the C 3-7 Each cycloalkyl group may be independently substituted by 1, 2, 3 or 4 Rs; m is selected from 0, 1, 2, 3, and 4; n is selected from 0, 1, 2, 3, and 4; In the heteroaryl group, the heteroatom is independently selected from one or more of N, S, O and C (=O), and the number of heteroatoms / heteroatomic groups is independently selected from 1, 2, 3 and 4; In the heterocyclic alkyl and heterocyclic alkenyl alkyl groups, the heteroatoms / heteroatomic groups are independently selected from one or more of N, S, O and C (=O), and the number of heteroatoms / heteroatomic groups is independently selected from 1, 2, 3 and 4; And the compound shown in formula (I) satisfies any of the following conditions: (1) When L is -C 1-3 When alkyl-, G is selected from 6-10 membered heterocyclic alkyl, 5-10 membered heterocyclic alkenyl, C 6-10 aryl and 6-10 heteroaryl, wherein the 6-10 heterocyclic alkyl, 5-10 heterocyclic alkenyl, C 6-10 Aryl and 6-10 heteroaryl groups are each independently and optionally co-occupied by 1, 2, 3 or 4 R groups. G replace; (2) When L is a single bond and the ring X is When G is selected from 6-10 N-containing heterocyclic alkyl groups, 6-10 N-containing heterocyclic alkenyl groups, and C 6-10 aryl and 6-10 N-containing heteroaryl, wherein the 6-10 N-containing heterocyclic alkyl, 6-10 N-containing heterocyclic alkenyl, C 6-10 Aryl and 6-10 N-containing heteroaryl groups are each independently and optionally co-occupied by 1, 2, 3, or 4 R groups. G replace; (3) When L is a single bond and the ring X is In this case, G is selected from 4-10-membered heterocyclic alkenyl and 5-10-membered heteroaryl, wherein the 4-10-membered heterocyclic alkenyl and 5-10-membered heteroaryl are independently and optionally surrounded by 1, 2, 3 or 4 Rs. G replace.

[0085] In some embodiments of the present invention, for ; Ring X Selection ,in Represents the connection point with ring Y. Represents the connection point with L; Z stands for CH; L is selected from single bond, -O-, -NH-, -C(=O)-, -C 1-3 Alkyl-, -C(=O)-C 1-3 alkyl- -C 1-3 Alkyl-C(=O)- and -C 1-3 Alkyl-C(=O)NH- The -NH- and -C 1-3 Alkyl-, -C(=O)-C 1-3 alkyl- -C 1-3 Alkyl-C(=O)- and -C 1-3 Alkyl-C(=O)NH- Each can be independently selected by 1, 2, 3 or 4 Rs. L Replace, among which Indicates the connection point with ring G; G is selected from 6-membered heterocyclic alkyl and 6-membered heteroaryl groups, wherein the 6-membered heterocyclic alkyl and 6-membered heteroaryl groups are independently selected by 1, 2, 3 or 4 R groups respectively. G Substitution; preferably, the 6-membered heterocyclic alkyl and 6-membered heteroaryl groups contain at least one N heteroatom; R¹, R², and R³ are each independently selected from H; Each R G Selected independently from H, D, Cl, Br, I, F, O, and C respectively. 1-6 Alkyl, -OC 1-6 Alkyl and C 3-7 cycloalkyl, the C 1-6 Alkyl and C 3-7 The cycloalkyl group is independently and optionally surrounded by 1, 2, 3 or 4 R groups. G1 replace; Each R G1 Selected independently from halogens and C 3-7 cycloalkyl, the C 3-7 Each cycloalkyl group may be independently substituted by 1, 2, 3 or 4 Rs; m is 1; n is selected from 0, 1, 2, 3, and 4; In the heteroaryl group, the heteroatom / heteroatomic group is independently selected from one or more of N, S, O and C (=O), and the number of heteroatom / heteroatomic groups is independently selected from 1, 2, 3 and 4; In the heterocyclic alkyl group, the heteroatom / heteroatomic group is independently selected from one or more of N, S, O and C (=O), and the number of heteroatoms / heteroatomic groups is independently selected from 1, 2, 3 and 4.

[0086] In some embodiments of the present invention, each of the above-mentioned R is independently selected from H, D and F.

[0087] In some embodiments of the present invention, each of the above R is independently H.

[0088] In some embodiments of the present invention, R¹, R², and R³ are each independently selected from H, D, and F.

[0089] In some embodiments of the present invention, R¹, R², and R³ are each independently H.

[0090] In some embodiments of the present invention, the aforementioned R² forms a cyclopropyl group with the carbon atom to which it is attached.

[0091] In some embodiments of the present invention, the above-mentioned R x They are selected independently from H, -CH3 and -CF3, for example, H.

[0092] In some embodiments of the present invention, the above-mentioned R y The elements are independently selected from H, D, F, Cl, Br, I, CN, NH2, OH and -CH3, respectively.

[0093] In some embodiments of the present invention, the above-mentioned R y They can be H and Cl, respectively, for example, Cl.

[0094] In some embodiments of the present invention, the above-mentioned R L The elements are independently selected from H, D, F, Cl, Br, I, CN, NH2, OH, -CH3, -CH2CH3, -CH2F, -CHF2, -CF3, -C(=O)CH3, -C(=O)OH and -C(=O)NH2, for example, selected from H, -CH3 and -C(=O)CH3, and for example H.

[0095] In some embodiments of the present invention, the above-mentioned R G1 Each of the following is independently selected from D, F, Cl, Br, I, =O, CN, NH2, OH, -CH3, -CH3, -CH2CH3, -CH2F, -CHF2, -CF3, -OCH3, -NHCH3, -N(CH3)2, and .

[0096] In some embodiments of the present invention, the above-mentioned R G1 Selected from halogens and C 3-7 Cycloalkyl.

[0097] In some embodiments of the present invention, the above-mentioned R G1 Selected from F, and .

[0098] In some embodiments of the present invention, the above-mentioned R G Selected from F, Cl, Br, I, =O, CN, NH2, OH, -C(=O)OH, -C(=O)NH2, C 1-3 Alkyl, -OC 1-3 Alkyl and C 3-5 cycloalkyl, the C 1-3 Alkyl, -OC 1-3 Alkyl and C 3-5 The cycloalkyl group is independently and optionally surrounded by 1, 2, 3 or 4 R groups. G1 replace.

[0099] In some embodiments of the present invention, the above-mentioned R G The derivatives are selected from F, Cl, Br, I, =O, CN, NH2, OH, -C(=O)OH, -C(=O)NH2, -CH3, -CH2CH3, -CH2CH2CH3, and -OCH3, wherein -CH3, -CH2CH3, -CH2CH2CH3, and -OCH3 are each independently and optionally selected by 1, 2, 3, or 4 Rs. G1 replace.

[0100] In some embodiments of the present invention, the above-mentioned R G Selected from F, Cl, Br, I, CN, NH2, OH, =O, -CH3, -CH2CH3, -CH2CH2CH3, -CH2F, -CHF2, -CF3, -OCH3, -OCH2CH3, -OCH2CH2CH3, , , , , and .

[0101] In some embodiments of the present invention, the above-mentioned R G Selected from F, =O, C 1-6 Alkyl, -OC 1-6 Alkyl and C 3-7 cycloalkyl, the C 1-6 Alkyl, -OC 1-6 Alkyl and C 3-7 The cycloalkyl group is independently and optionally surrounded by 1, 2, 3 or 4 R groups. G1 replace.

[0102] In some embodiments of the present invention, the above-mentioned R G Selected from F, =O, -CH3, -CH2CH3, -CF3, -OCH2CH3, -OCH2CH2CH3, , , and .

[0103] In some embodiments of the present invention, the above-mentioned R G Selected from H or methyl, such as methyl.

[0104] In some embodiments of the present invention, m is selected from 0 and 1, for example, 1.

[0105] In some embodiments of the present invention, n is selected from 0 and 1, for example 0.

[0106] In some embodiments of the present invention, the aforementioned cyclic Y is selected from phenyl and thiophene groups.

[0107] In some embodiments of the present invention, the aforementioned ring Y is a phenyl group.

[0108] In some embodiments of the present invention, the above-mentioned structural unit Selected from .

[0109] In some embodiments of the present invention, the above-mentioned structural unit Selected from .

[0110] In some embodiments of the present invention, the above-mentioned structural unit Selected from , and .

[0111] In some embodiments of the present invention, the above-mentioned structural unit for .

[0112] In some embodiments of the present invention, the ring X is selected from... For example, the ring X mentioned above is selected from and Preferred .

[0113] In some embodiments of the present invention, the ring X is selected from... , , , , , , , , , , , , and ,in Represents the connection point with ring Y. Represents the connection point with L, for example, the ring X mentioned above is selected from and Preferred .

[0114] In some embodiments of the present invention, Z is selected from N, CH and CF.

[0115] In some embodiments of the present invention, Z is CH.

[0116] In some embodiments of the present invention, for The C marked with an asterisk represents the S configuration, R configuration, or a mixture thereof.

[0117] In some embodiments of the present invention, the above-mentioned structural unit Selected from , , and .

[0118] In some embodiments of the present invention, the above-mentioned structural unit Selected from and .

[0119] In some embodiments of the present invention, the above-mentioned structural unit Selected from , , , , , , , , , , and ,For example .

[0120] In some embodiments of the present invention, the above-mentioned structural unit Selected from , , , , , and .

[0121] In some embodiments of the present invention, the L mentioned above is selected from single bonds, -O-, -NH-, -C(=O)-, -C 1-3 Alkyl-, -C 2-3 alkenyl-, -C 2-3 alkynyl-, -OC 1-3 alkyl- -C(=O)-C 1-3 alkyl- -NHC(=O)-C 1-3 alkyl- -C1-3 Alkyl-O- -C 1-3 Alkyl-C(=O)- and -C 1-3 Alkyl-C(=O)NH- The -NH- and -C 1-3 Alkyl-, -C 2-3 alkenyl-, -C 2-3 alkynyl-, -OC 1-3 alkyl- -C(=O)-C 1-3 alkyl- -NHC(=O)-C 1-3 alkyl- -C 1-3 Alkyl-O- -C 1-3 Alkyl-C(=O)- and -C 1-3 Alkyl-C(=O)NH- Each can be independently selected by 1, 2, 3 or 4 Rs. L Replace, among which This indicates the connection point with ring G.

[0122] In some embodiments of the present invention, the L mentioned above is selected from single bonds, -O-, -NH-, -C(=O)-, -C 1-3 Alkyl-, -C(=O)-C 1-3 alkyl- -C 1-3 Alkyl-C(=O)- and -C 1-3 Alkyl-C(=O)NH- The -NH- and -C 1-3 Alkyl-, -C(=O)-C 1-3 alkyl- -C 1-3 Alkyl-C(=O)- and -C 1-3 Alkyl-C(=O)NH- Each can be independently selected by 1, 2, 3 or 4 Rs. L replace.

[0123] In some embodiments of the present invention, the L mentioned above is selected from single bonds, , , , , , , , , , , , , , , and ,in Indicates the connection point with G. For example, L is selected from -O- or -C. 1-3 Alkyl group, preferably or Further optimized .

[0124] In some embodiments of the present invention, G is selected from 3-8 membered heterocyclic alkyl, 4-8 membered heterocyclic alkenyl, C 6-10 aryl and 5-10-membered heteroaryl, wherein the 3-8-membered heterocyclic alkyl, 4-8-membered heterocyclic alkenyl, C 6-10 Aryl and 5-10 heteroaryl groups are each independently and optionally bound by 1, 2, 3 or 4 R groups. G replace.

[0125] In some embodiments of the present invention, G is selected from 3-6-membered heterocyclic alkyl, 5-6-membered heterocyclic alkenyl, C 6-10 aryl or 5-6-membered heteroaryl, wherein the 3-6-membered heterocyclic alkyl, 5-6-membered heterocyclic alkenyl, C 6-10 The aryl or 5-6 heteroaryl groups are independently and independently selected to be bound by 1, 2, 3 or 4 R groups. G replace.

[0126] In some embodiments of the present invention, the above-mentioned G is selected from phenyl, pyridinyl, pyrimidinyl, pyrazinyl, pyrazolyl, imidazoleyl, oxazolyl, triazolyl, pyridinoneyl, pyrimidinoneyl, pyrazinoneyl, pyridinoneyl, imidazolinoneyl, pyrrolodinoneyl, piperidinyl, morpholinyl, piperazinyl, piperidinoneyl, tetrahydropyrimidinoneyl, morpholinoneyl, piperidinoneyl, piperidinoneyl, pyrroloalkyl, imidazoalkyl, pyrrolidinoneyl, imidazolinoneyl, pyrrolidinoneyl, indoleyl, isoindoleyl, indazoleyl, isoindazoleyl, quinolinyl, isoquinolinyl, benzimidazoleyl, and benzimidazoleoneyl. The following groups are selected independently and optionally separated by 1, 2, 3, or 4 R groups: phenyl, pyridinyl, pyrimidinyl, pyrazinyl, pyrazinyl, imidazoleyl, oxazolyl, triazolyl, pyridinoneyl, pyrimidinoneyl, pyrazinoneyl, pyridazinoneyl, imidazole, diketoneyl, piperidinyl, morpholinyl, piperazinyl, piperidinoneyl, tetrahydropyrimidinoneyl, morpholinoneyl, piperidinoneyl, piperidinoneyl, pyrrolylalkyl, imidazolealkyl, pyrrolidoneyl, imidazolediketoneyl, indoleyl, isoindoleyl, indazoleyl, isoindazoleyl, quinolinyl, isoquinolinyl, benzimidazoleyl, and benzimidazole ketoneyl. G replace.

[0127] In some embodiments of the present invention, the aforementioned G is selected from 6-membered heterocyclic alkyl groups (e.g., piperidinone group, piperidinedione group) and 6-membered heteroaryl groups (e.g., pyridinyl group, pyridinone group, pyrimidinone group), preferably selected from 6-membered N-containing heterocyclic alkyl groups and 6-membered N-containing heteroaryl groups, wherein the 6-membered N-containing heterocyclic alkyl group and the 6-membered heteroaryl group are each independently and optionally surrounded by 1, 2, 3 or 4 R groups. G Substitution, for example, optional unsubstituted or by 1, 2, 3 or 4 Rs G Replacement , , , or .

[0128] In some embodiments of the present invention, the G is selected from 6-membered heteroaryl groups (e.g., pyridyl, pyridone, pyrimidinone), preferably from 6-membered N-containing heteroaryl groups, wherein each 6-membered heteroaryl group is independently and optionally surrounded by 1, 2, 3, or 4 R groups. G Substitution, such as optional unsubstituted or by one or more R G Replacement , or .

[0129] In some embodiments of the present invention, G is selected from... , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and .

[0130] In some embodiments of the present invention, G is selected from... , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and .

[0131] In some embodiments of the present invention, the compound of formula (I), its stereoisomers, or pharmaceutically acceptable salts thereof, wherein the compound of formula (I) is shown in formulas (IA), (IB), and (IC): , and , Among them, R 1 R 2 R 3 R x R y Z, L, G, ring A, m, and n are as defined in this invention.

[0132] In some embodiments of the present invention, the compound of formula (I), its stereoisomers, or pharmaceutically acceptable salts thereof, wherein the compound of formula (I) is shown in formulas (IA-1), (IB-1), and (IC-1): , and , Among them, R x Ry L, G, ring A, m, and n are as defined in this invention.

[0133] In some embodiments of the present invention, the compound of formula (I), its stereoisomers, or pharmaceutically acceptable salts thereof, wherein the compound of formula (I) is shown in formulas (IA-1a), (IA-1b), (IA-1c), (IA-1d), (IA-1e), (IA-1f), (IB-1a), (IB-1b), (IB-1c), (IB-1d), (IC-1a), and (IC-1b): , , , , , , , , , , and , Among them, R x R y L, G, ring A, m, and n are as defined in this invention.

[0134] Some solutions in this invention are derived from arbitrary combinations of the above-mentioned variables.

[0135] The present invention also provides any of the following stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, deuterated derivatives, metabolites, or prodrugs, as shown in any of the following formulas. .

[0136] The present invention also provides compounds of any of the following formulas, their stereoisomers, their tautomers, their pharmaceutically acceptable salts, their solvates, their deuterated derivatives, their metabolites, or their prodrugs. .

[0137] The present invention also provides a pharmaceutical composition comprising the compound shown in formula (I) above, its stereoisomer or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0138] The present invention also provides the use of the compound shown in formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition thereof in the preparation of a medicament for treating diseases related to the VAV1 signaling pathway.

[0139] In some embodiments of the present invention, the diseases related to the VAV1 signaling pathway are autoimmune diseases and cancer.

[0140] The present invention also provides the use of the compound of formula (I) above, its stereoisomer or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition thereof in the preparation of a medicament for treating autoimmune diseases and cancer.

[0141] In some embodiments of the present invention, the aforementioned autoimmune diseases are selected from multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus, psoriasis, Hashimoto's thyroiditis, myasthenia gravis, type I or type II diabetes and related diseases, vasculitis, pernicious anemia, Sjögren's syndrome, uveitis, psoriasis, Graves' ophthalmopathy, alopecia areata, allergic diseases, inflammatory bowel disease, atherosclerosis, osteoarthritis, inflammatory eye disease, keratoconjunctivitis, myocarditis, and hepatitis, more preferably from multiple sclerosis.

[0142] The present invention also provides the use of the above-mentioned compounds, their stereoisomers or pharmaceutically acceptable salts thereof, or the above-mentioned pharmaceutical compositions in the preparation of VAV1 molecular glue degrading agents.

[0143] This disclosure provides compounds comprising formula (I), (II), (III), (IV) or (V) and pharmaceutically acceptable compositions thereof, said compounds and compositions being effective as degraders of VAV1 protein and having excellent pharmacological properties.

[0144] This invention provides a pharmaceutical composition comprising a compound of formula (I), (II), (III), (IV), or (V), a stereoisomer thereof, a pharmaceutically acceptable salt, a solvate, a deuterated derivative, a metabolite or prodrug, and at least one pharmaceutically acceptable excipient. In a specific embodiment, the compounds of formula (I), (II), (III), (IV), and (V) are present in the pharmaceutical composition in an effective amount. In a specific embodiment, the compounds of formula (I), (II), (III), (IV), and (V) are provided in a therapeutically effective amount. In a specific embodiment, the compounds of formula (I), (II), (III), (IV), or (V) are provided in a preventatively effective amount.

[0145] The present invention provides the use of compounds of formula (I), (II), (III), (IV) or (V), their stereoisomers, pharmaceutically acceptable salts, solvates, deuterated derivatives, metabolites or prodrugs, or pharmaceutical compositions described herein in the preparation of medicaments for the prevention and / or treatment of VAV1 protein-related diseases.

[0146] As used in this article, “VAV1” refers to naturally occurring VAV1, also known as Vav or p95vav, including naturally occurring variants that retain the functional activity of VAV1, such as allelic variants and splice variants.

[0147] In some implementation schemes, the aforementioned related diseases include multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus, Hashimoto's thyroiditis, myasthenia gravis, type I and type II diabetes mellitus, pernicious anemia, uveitis, psoriasis, alopecia areata, ulcerative colitis, Crohn's disease, atherosclerosis, myocarditis, pericarditis, pulmonary fibrosis, systemic sclerosis, morphine scleroderma, inflammatory eye disease, allergic asthma, atopic dermatitis, allergic rhinitis / conjunctivitis, peripheral T-cell lymphoma, and chronic lymphocytic leukemia.

[0148] Definitions and Explanations

[0149] Unless otherwise stated, the definitions of groups and terms recorded in this specification and claims, including those as examples, exemplifications, preferred embodiments, descriptions in tables, and definitions of specific compounds in the examples, can be arbitrarily combined and combined with each other. Therefore, subsequent definitions of groups and compound structures should fall within the scope of the specification.

[0150] The compounds described in this invention may have asymmetric centers. Compounds of this invention containing asymmetric substituted atoms can be isolated in optically active or racemic forms. Unless otherwise specified, all chiral, diastereomeric, racemic, and geometrically isomer forms of the structure apply.

[0151] The term "stereoisomer" as used in this invention refers to isomers resulting from different spatial arrangements of atoms in a molecule, including enantiomers, diastereomers, and conformational isomers.

[0152] The compounds of this invention can exist in specific geometric or stereoisomeric forms. This invention envisions all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, ( R )-and( S - Enantiomers, diastereomers, ( D (L)-isomers, (I)-isomers, and racemic mixtures thereof, as well as other mixtures, such as enantiomers or diastereomer-enriched mixtures, are all within the scope of this invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and mixtures thereof are included within the scope of this invention.

[0153] Unless otherwise stated, the terms "enantiomer" or "optical isomer" refer to stereoisomers that are mirror images of each other.

[0154] Unless otherwise stated, the terms "cis-trans isomers" or "geometric isomers" refer to stereoisomers that result from the different spatial arrangements of certain atoms or groups in a molecule due to factors such as double bonds or cyclization. In cis-trans isomers, the two isomers have different configurations and are not mirror images of each other.

[0155] Unless otherwise stated, the term "diastereomer" refers to a stereoisomer of a molecule having two or more chiral centers and being in a non-mirror relationship with each other.

[0156] Unless otherwise stated, "(+)" indicates right-handed rotation, "(-)" indicates left-handed rotation, and "(±)" indicates racemic rotation.

[0157] Unless otherwise stated, key ( ) indicates that the configuration is not specified, meaning that if chiral isomers exist in the compound structure, the bond ( ) can be " "or" , or both contain " "and" "Two configurations. Using wedge-shaped solid line keys ( ) and wedge-shaped dashed key ( ) represents the absolute configuration of a solid center, using a straight solid line key ( ) and straight dashed key ( The relative configuration of the center of a solid is represented by a wavy line ( ). ) indicates a wedge-shaped solid line key ( ) or wedge-shaped dashed key ( ) or use wavy lines ( ) indicates a straight solid line key ( ) or straight dashed key ( ).

[0158] Unless otherwise stated, items marked with " "The carbon atom is a chiral carbon atom, with ( R )or( S Single enantiomer form or ( R )or( S It exists in mixed forms. For example, express ,or ,or( R )or( S It exists in a mixed form.

[0159] Unless otherwise stated, when the compounds of this invention contain double bond structures, such as carbon-carbon double bonds, carbon-nitrogen double bonds, and nitrogen-nitrogen double bonds, and each atom on the double bond is connected to two different substituents (in a double bond containing a nitrogen atom, the lone pair of electrons on the nitrogen atom is considered as one of the substituents it is connected to), the bond " "" indicates that the configuration is not specified. If the atoms on the double bonds in this compound are separated from their substituents by... If we represent that, then we can represent the ( ) of the compound. Z ) type isomers, ( E ) type isomers or simultaneously containing ( Z )and( E Two isomers.

[0160] As used in this invention, 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.

[0161] As used in this invention, the term "pharmaceutically acceptable salt" refers to a pharmaceutically acceptable organic or inorganic salt of the compounds of this invention as defined above. Such salts are safe and effective in mammalian vivo and possess the desired 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 typically include inorganic bases.

[0162] As used herein, the singular forms of “a,” “an,” and “the” include plural references, and vice versa, unless the context clearly indicates otherwise.

[0163] As used herein, the terms “optional” or “optionally” mean that an event or condition described below may, but is not required, occur, and that the description includes both the occurrence and non-occurrence of said event or condition. For example, the term “optionally substituted by one or more substituents” means that it may or may not be substituted. When substituted, it means that any one or more hydrogen atoms on a particular atom are substituted by substituents that are independent of each other and may be the same or different.

[0164] As used in this invention, the terms "substituted" or "replaced by" refer to the substitution of one or more hydrogen atoms on a specific atom by a substituent. Substituents can include deuterium and hydrogen variants, provided the valence state of the specific atom is normal and the substituted compound is stable, and when multiple substituents are present, they are independent of each other. When the substituent is oxygen (i.e., =O), it means that two hydrogen atoms are substituted. For example, "-C(=O)-3-8-membered heterocyclic alkyl" substituted with =O means that two hydrogen atoms on the "3-8-membered heterocyclic alkyl" are substituted with =O.

[0165] The terms “optionally substituted” or “optionally substituted” as used in this invention mean that a substance may or may not be substituted, unless otherwise specified, and the types and numbers of substituents may be arbitrary and independent of each other on the basis that they are chemically feasible.

[0166] As used herein, the term "pharmaceutical composition" refers to a mixture containing one or more of the compounds described herein, their pharmaceutically acceptable salts, and other chemical components, as well as other 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 the exertion of its biological activity.

[0167] Those skilled in the art will understand that, according to convention in the art, when a group has one or more connectable sites, any one or more sites of that group can be connected to other groups via chemical bonds. When the chemical bond connection is non-directional and the connectable site contains H atoms, the number of H atoms at that site will decrease accordingly with the number of chemical bonds connected, resulting in a group with a corresponding valence. The chemical bond connecting the site to other groups can be a straight solid line bond (…). Straight dashed key ( ) or wavy line (" " "or" The symbol "" indicates that the oxygen atom in the group is connected to other groups. For example, the straight solid line bond in -OCH3 indicates that the oxygen atom in the group is connected to other groups. , or The wavy lines in the middle indicate that the carbon atom in the cyclopentyl group is connected to other groups; the straight dashed lines in the middle indicate that the bonds are connected to other groups through the two ends of the nitrogen atom in the group. This indicates that any connectable site on the piperidinyl group can be linked to other groups via a single chemical bond, including at least... , , and These are the four connection methods.

[0168] When any variable (e.g., R) appears more than once in the composition or structure of a compound, its definition is independent in each case. For example, if a group is substituted by 0-2 Rs, the group may optionally be substituted by up to two Rs, and R has independent options in each case. Furthermore, combinations of substituents and / or their variants are only permitted if such combinations produce stable compounds.

[0169] When the number of a linking group is 0, such as -(CRR)0-, it indicates that the linking group is a single bond.

[0170] When one of the variables is selected as a single bond, it means that the two groups it connects to are directly connected. For example, when L in ALZ represents a single bond, it means that the structure is actually AZ.

[0171] When a substituent is vacant, it means that the substituent does not exist. For example, if X is vacant in AX, it means that the structure is actually A.

[0172] Unless otherwise specified, the term "alkyl" refers to a saturated aliphatic hydrocarbon group comprising a branched or straight chain having a specified number of carbon atoms. For example, "C1-6 alkyl" is defined as a group comprising 1, 2, 3, 4, 5, and 6 carbon atoms in a straight or branched structure, including but not limited to methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, and tert-hexyl.

[0173] Unless otherwise specified, the term "C" 1-6 "alkyl" is used to denote a straight-chain or branched saturated hydrocarbon group consisting of 1 to 6 carbon atoms. The C 1-6 Alkyl groups include C 1-5 C 1-4 C 1-3 C 1-2 C 2-6 C 2-5 C 2-4 C 2-3 C 3-6 C 3-5 C 3-4 C 4-6 C 4-5 C1, C2, C3, C4, C5, and C6 alkyl groups, etc.; they can be monovalent (e.g., methyl), divalent (e.g., methylene), or polyvalent (e.g., methine). 1-6 Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, s-butyl and t-butyl), pentyl (including n-pentyl, isopentyl and neopentyl) and hexyl.

[0174] Unless otherwise specified, the term "C" 1-3 "alkyl" is used to denote a straight-chain or branched saturated hydrocarbon group consisting of 1 to 3 carbon atoms. The C 1-3 Alkyl groups include C 1-2 C 2-3 C1, C2, and C3 alkyl groups, etc.; they can be monovalent (e.g., methyl), divalent (e.g., methylene), or polyvalent (e.g., methine). 1-3 Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), etc.

[0175] Unless otherwise specified, "C 2-3 "Alkenyl" is used to denote a hydrocarbon group consisting of 2 to 3 carbon atoms, either straight-chain or branched, containing at least one carbon-carbon double bond. The carbon-carbon double bond can be located at any position within the group. The C... 2-3 Alkenes include C3 and C2 alkenes, etc.; they can be monovalent, divalent, or polyvalent. 2-3 Examples of alkenyl groups include, but are not limited to, vinyl and propenyl groups.

[0176] Unless otherwise specified, "C 2-3 "Alkyne" is used to denote a straight-chain or branched hydrocarbon group consisting of 2 to 3 carbon atoms containing at least one carbon-carbon triple bond, which can be located at any position within the group. 2-3 Alkynyl groups include C2 and C3 alkynyl groups, etc. They can be monovalent, divalent, or polyvalent. 2-3 Examples of alkynyl groups include, but are not limited to, acetylene and propyne groups.

[0177] Unless otherwise specified, the number of atoms in a ring is usually defined as the elemental number of the ring. For example, a "5-6 elemental ring" refers to a "ring" with 5-6 atoms arranged around it.

[0178] Unless otherwise specified, the term "cycloalkyl" refers to a ring composed of a specified carbon atom (e.g., C12). 3-7 A saturated cyclic hydrocarbon group composed of ) . For example, "C 3-7 "" refers to a saturated cyclic hydrocarbon group composed of 3 to 7 cyclic carbon atoms (e.g., 3-6 cyclic carbon atoms). It can be monovalent, divalent, or polyvalent.

[0179] Unless otherwise specified, the term "C" 3-7 "Cycloalkyl" refers to a saturated cyclic hydrocarbon group consisting of 3 to 7 carbon atoms, which can be monocyclic or bicyclic systems. 3-7 Cycloalkyl groups include C 3-6 C 3-5 C 3-4 C 4-7 C 4-6 C 4-5 C 5-7 C 5-6 C3, C4, C5, C6, and C7 cycloalkyl groups, etc.; they can be monovalent, divalent, or polyvalent. 3-7 Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, and bicyclo[2.2.2]octane.

[0180] Unless otherwise specified, the term "C" 3-5 "Cycloalkyl" refers to a saturated cyclic hydrocarbon group consisting of 3 to 5 carbon atoms, which can be monocyclic or bicyclic. 3-5 Cycloalkyl groups include C3-4 C 4-5 C3, C4, and C5 cycloalkyl groups, etc.; they can be monovalent, divalent, or polyvalent. 3-5 Examples of cycloalkyl groups include, but are not limited to, cyclopropyl and cyclobutyl.

[0181] Unless otherwise specified, the term "heterocyclic alkyl" refers to a cycloalkyl group in which one or more (in some embodiments, 1 to 3, e.g., 1, 2, 3) carbon atoms are replaced by heteroatoms / heteroatom groups, consisting of one or more rings (preferably 1), each ring having an independently defined number of atoms (e.g., 2, 3, 4, 5, or 6), wherein the ring contains at least one (e.g., 1, 2, 3, or 4, preferably 1 or 2) heteroatoms / heteroatom groups selected from N, O, S, and C (=O), with the remainder being carbon atoms. It includes monocyclic and polycyclic systems, wherein polycyclic systems include spirocyclic, fused, and bridged rings (preferably monocyclic). The term "heterocyclic alkyl" may contain 3-8 ring atoms, 6-10 ring atoms, or 3-6 ring atoms, etc. Examples of heterocyclic alkyl groups include, but are not limited to, azahexacyclic butyl, oxacyclobutyl, thiohexacyclic butyl, pyrrolidinyl, pyrazolyl, imidazoalkyl, tetrahydrothiopheneyl (including tetrahydrothiophene-2-yl and tetrahydrothiophene-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperidinyl and 2-piperidinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxyl, dithiaalkyl, isoxazolyl, isothiazolyl, 1,2-oxazinyl, 1,2-thiaazinyl, hexahydropyridazinyl, homopiperidinyl, homopiperidinyl, and dioxacycloheptyl, etc.

[0182] Unless otherwise specified, the term "3-10 membered heterocyclic alkyl" or in combination with other terms refers to a saturated cyclic group consisting of 3 to 10 ring atoms, wherein 1, 2, 3, or 4 ring atoms are heteroatoms / heteroatomic groups independently selected from N, O, S, and C (=O), and the remainder are carbon atoms. It includes monocyclic, bicyclic, and tricyclic systems (preferably monocyclic), wherein bicyclic and tricyclic systems include spirocyclic, fused, and bridged rings. Furthermore, with respect to the term "3-10 membered heterocyclic alkyl," the heteroatom may occupy the bonding position between the heterocyclic alkyl group and the rest of the molecule. The 3-1-membered heterocyclic alkyl groups include 3-9-membered, 3-8-membered, 3-7-membered, 3-6-membered, 3-5-membered, 3-4-membered, 4-10-membered, 4-9-membered, 4-8-membered, 4-7-membered, 4-6-membered, 4-5-membered, 5-10-membered, 5-9-membered, 5-8-membered, 5-7-membered, 5-6-membered, 6-10-membered, 6-9-membered, 6-8-membered, 6-7-membered, 7-10-membered, 7-9-membered, 7-8-membered, 3-membered, 4-membered, 5-membered, 6-membered, 7-membered, 8-membered, 9-membered, 10-membered and heterocyclic alkyl groups, etc. Examples of 3-10 membered heterocyclic alkyl groups include, but are not limited to, azirrobutyl, oxacyclobutyl, thiocyclobutyl, pyrrolidinyl, pyrazolyl, imidazoalkyl, tetrahydrothiopheneyl (including tetrahydrothiophene-2-yl and tetrahydrothiophene-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperidinyl and 2-piperidinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxane, dithiaalkyl, isoxazolyl, isothiazolyl, 1,2-oxazinyl, 1,2-thiaazinyl, hexahydropyridazinyl, homopiperidinyl, homopiperidinyl, and dioxaneheptyl, etc.

[0183] Unless otherwise specified, the term "3-8 membered heterocyclic alkyl" or in combination with other terms refers to a saturated cyclic group consisting of 3 to 8 ring atoms, wherein 1, 2, 3, or 4 ring atoms are heteroatoms / heteroatomic groups independently selected from N, O, S, and C (=O), and the remainder are carbon atoms. It includes monocyclic, bicyclic, and tricyclic systems, wherein bicyclic and tricyclic systems include spirocyclic, fused, and bridged rings (preferably monocyclic). Furthermore, with respect to the term "3-8 membered heterocyclic alkyl," the heteroatom may occupy the connection position between the heterocyclic alkyl group and the rest of the molecule. The 3-8 membered heterocyclic alkyl groups include 3-7, 3-6, 3-5, 3-4, 4-8, 4-7, 4-6, 4-5, 5-8, 5-7, 5-6, 6-8, 6-7, 7-8, 3, 4, 5, 6, 7, and 8 membered heterocyclic alkyl groups, etc. Examples of 3-8 membered heterocyclic alkyl groups include, but are not limited to, azirrobutyl, oxacyclobutyl, thiocyclobutyl, pyrrolidinyl, pyrazolyl, imidazoalkyl, tetrahydrothiopheneyl (including tetrahydrothiophene-2-yl and tetrahydrothiophene-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperidinyl and 2-piperidinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxane, dithiaalkyl, isoxazolyl, isothiazolyl, 1,2-oxazinyl, 1,2-thiaazinyl, hexahydropyridazinyl, homopiperidinyl, homopiperidinyl, and dioxaneheptyl, etc.

[0184] Unless otherwise specified, the term "3-6 membered heterocyclic alkyl" or in combination with other terms refers to a saturated cyclic group consisting of 3 to 6 ring atoms, wherein 1, 2, 3, or 4 ring atoms are heteroatoms / heteroatomic groups independently selected from N, O, S, and C (=O), and the remainder are carbon atoms. Furthermore, with respect to "3-6 membered heterocyclic alkyl," heteroatoms may occupy the bonding positions between the heterocyclic alkyl group and the rest of the molecule. The 3-6 membered heterocyclic alkyl groups include 3-5, 3-4, 4-6, 4-5, 5-6, 3, 4, 5, and 6 membered heterocyclic alkyl groups, etc. Examples of the 3-6 membered heterocyclic alkyl groups include, but are not limited to, azirrobutyl, oxacyclobutyl, thiocyclobutyl, pyrrolidinyl, pyrazolyl, imidazoalkyl, tetrahydrothiophenyl (including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxyl, dithiaalkyl, isoxazolyl, isothiazolyl, 1,2-oxazinyl, 1,2-thiaazinyl, hexahydropyridazinyl, etc.

[0185] Unless otherwise specified, the terms "partially saturated" and "partially unsaturated" refer to the presence of at least one (e.g., 1, 2, or 3) unsaturated double bonds (e.g., carbon-carbon double bonds) but without aromaticity.

[0186] Unless otherwise specified, the term "spiro ring" refers to a ring system in which multiple (preferably two) rings share a single atom. The term "bridged ring" refers to a ring system in which multiple (preferably two) rings share one, two, or more bridging atoms; the number of bridging atoms can be 1, 2, or 3. A bridged bicyclic ring is a ring system in which two rings share one, two, or more bridging atoms. The term "fused" refers to a ring system in which multiple (e.g., two rings) rings share a single edge; a fused bicyclic ring is a ring system in which two rings share a single edge.

[0187] Unless otherwise specified, the term "6-10 membered heterocyclic alkyl" refers to a heterocyclic alkyl that satisfies the condition of having 6 to 10 ring atoms, and the definition of heterocyclic alkyl may be as specific as described in any of the preceding schemes.

[0188] Unless otherwise specified, the term "6-10 N-containing heterocyclic alkyl" refers to a heterocyclic alkyl that satisfies the compositional condition of 6 to 10 ring atoms, wherein at least one (e.g., 1 or 2) N heteroatoms is present, and the definition of heterocyclic alkyl may be as specific as described in any of the preceding schemes.

[0189] Unless otherwise specified, the term "heterocyclic alkenyl" refers to a cycloalkenyl group in which one or more (in some embodiments, 1 to 3, e.g., 1, 2, 3) carbon atoms are replaced by heteroatoms / heteroatom groups, consisting of one or more rings (preferably 1-2, more preferably 1), each ring having 3-7 atoms (e.g., 6), wherein the ring contains at least one (e.g., 1, 2, 3, or 4, preferably 1 or 2) heteroatoms / heteroatom groups selected from N, O, S, and C (=O), with the remainder being carbon atoms. The heterocyclic alkenyl contains at least one (e.g., 1, 2, or 3, preferably 1) unsaturated double bond and is not aromatic as a whole (at least one ring). It includes monocyclic and polycyclic systems, wherein polycyclic systems include spirocyclic, fused, and bridged rings (preferably monocyclic).

[0190] Unless otherwise specified, the term "4-10 membered heterocyclic alkenyl" refers to an unsaturated cyclic group consisting of 4 to 10 (e.g., 6-10) ring atoms, wherein 1, 2, 3, or 4 ring atoms are heteroatoms / heteroatom groups independently selected from N, O, S, and C (=O), and the remainder are carbon atoms. The 4-10 membered heterocyclic alkenyl contains one, two, or three unsaturated double bonds and is not aromatic as a whole. Furthermore, with respect to the "4-10 membered heterocyclic alkenyl," heteroatoms may occupy the connection positions between the heterocyclic alkenyl and the rest of the molecule.

[0191] Unless otherwise specified, the term "4-8 membered heterocyclic alkenyl" refers to an unsaturated cyclic group consisting of 4 to 8 ring atoms, wherein 1, 2, 3, or 4 ring atoms are heteroatoms / heteroatom groups independently selected from N, O, S, and C (=O), and the remainder are carbon atoms. The 4-8 membered heterocyclic alkenyl contains one or two unsaturated double bonds and is not aromatic as a whole. Furthermore, with respect to the "4-8 membered heterocyclic alkenyl," the heteroatom may occupy the bonding position between the heterocyclic alkenyl and the rest of the molecule.

[0192] Unless otherwise specified, the term "5-6 membered heterocyclic alkenyl" refers to an unsaturated cyclic group consisting of 5 to 6 ring atoms, where 1, 2, 3, or 4 ring atoms are heteroatoms / heteroatomic groups independently selected from N, O, S, and C (=O), and the remainder are carbon atoms. The 5-6 membered heterocyclic alkenyl contains one or two unsaturated double bonds and is not aromatic as a whole. Furthermore, with respect to the "5-6 membered heterocyclic alkenyl," the heteroatom can occupy the connection position between the heterocyclic alkenyl and the rest of the molecule. The 5-6 membered heterocyclic alkenyl includes 5-membered and 6-membered heterocyclic alkenyl groups, etc.

[0193] Unless otherwise specified, the term "6-10 membered heterocyclic alkenyl" refers to a heterocyclic alkenyl that satisfies the condition of having 6 to 10 ring atoms, and the definition of a heterocyclic alkenyl can be as specific as described in any of the preceding schemes.

[0194] Unless otherwise specified, the term "6-10 N-containing heterocyclic alkenyl" refers to a heterocyclic alkenyl that satisfies the compositional condition of 6 to 10 ring atoms, wherein at least one (e.g., 1) N heteroatom, and the definition of heterocyclic alkenyl can be as specific as described in any of the preceding schemes.

[0195] Unless otherwise specified, the term "aryl" or "aromatic ring" refers to an aromatic monocyclic or fused polycyclic group containing 6-14 carbon atoms, wherein at least one ring is an aromatic ring. When one of the rings is a non-aromatic ring, the group may be linked by either an aromatic or non-aromatic ring. Examples of aryl groups include, but are not limited to: phenyl, naphthyl, tetrahydronaphthyl, 2,3-dihydroindenyl, biphenyl, phenanthryl, anthracene, and acenaphthene. The aryl group may also be fused to cycloalkenyl, heteroaryl, or heterocyclic alkenyl groups, wherein the linking bonds may be linked by either an aromatic or non-aromatic ring. Examples of aryl groups include, but are not limited to: indolyl, isoyindolyl, indazole, isoyinazole, benzotriazolyl, benzothiophene, benzofuranyl, quinolinyl, isoquinolinyl, benzimidazolyl, and benzimidazolone.

[0196] Unless otherwise specified, the term "C" in this invention refers to... 6-10 "Aromatic ring" and "C" 6-10 "Aryl" can be used interchangeably; the term "C" is used interchangeably. 6-10"Aryl" refers to an aromatic monocyclic or fused polycyclic group containing 6-10 carbon atoms, wherein at least one ring is an aromatic ring. When one of the rings is a non-aromatic ring, the group can be linked by either an aromatic or non-aromatic ring. Examples of aryl groups include, but are not limited to: phenyl, naphthyl, tetrahydronaphthyl, 2,3-dihydroindenyl, biphenyl, phenanthryl, anthracene, and acenaphthene. The aryl group can also be fused to cycloalkenyl, heteroaryl, or heterocyclic alkenyl groups, wherein the linking bonds can be either aromatic or non-aromatic rings.

[0197] Unless otherwise specified, the terms "5-10-membered heteroaryl ring" and "5-10-membered heteroaryl ring" are used interchangeably in this invention. The term "5-10-membered heteroaryl ring" refers to a cyclic group consisting of 5 to 10 (e.g., 6-10) ring atoms / ring groups having a conjugated π-electron system, wherein 1, 2, 3, or 4 ring atoms / ring groups are independently selected from O, S, N, and C (=O), and the remainder are carbon atoms. This also includes keto derivatives of the aforementioned "5-10-membered heteroaryl ring" and their deprotonated aromatic conjugated bases, which can be monocyclic, fused bicyclic, or fused tricyclic systems. The 5-10-membered heteroaryl ring can be attached to the rest of the molecule via heteroatoms or carbon atoms. The 5-10 quinary heteroaryl groups include 5-10 quinary, 5-9 quinary, 5-8 quinary, 5-7 quinary, 5-6 quinary, 5-7 quinary, 6-10 quinary, 6-9 quinary, 6-8 quinary, 6-7 quinary, 7-10 quinary, 7-9 quinary, 7-8 quinary, 8-10 quinary, 8-9 quinary, 9-10 quinary, 10 quinary, 9 quinary, 8 quinary, 7 quinary, 6 quinary, and 5 quinary heteroaryl groups. Examples of the 5-10 quinary heteroaryl groups include, but are not limited to, pyridinone, pyrimidinone, pyrazinone, pyridazinone, imidazolinone, pyrrolodione, pyrrolo (including N-pyrrolo, 2-pyrrolo, and 3-pyrrolo), pyrazol (including 2-pyrazol and 3-pyrazol), and imidazo (including...). N -imidazolium, 2-imidazolium, 4-imidazolium and 5-imidazolium, etc.), oxazolium (including 2-oxazolium, 4-oxazolium and 5-oxazolium, etc.), triazolium (1 H -1,2,3-triazolyl, 2 H -1,2,3-triazolyl, 1 H -1,2,4-triazolyl and 4 H-1,2,4-triazolyl, tetrazolyl, isoxazolyl (3-isooxazolyl, 4-isooxazolyl, and 5-isooxazolyl, etc.), thiazolyl (including 2-thiazolyl, 4-thiazolyl, and 5-thiazolyl, etc.), furanyl (including 2-furanyl and 3-furanyl, etc.), thiophene (including 2-thiophene and 3-thiophene, etc.), pyridyl (including 2-pyridyl, 3-pyridyl, and 4-pyridyl, etc.), pyrazinyl, pyrimidine The groups include benzothiazolyl (including 2-pyrimidinyl and 4-pyrimidinyl, etc.), benzothiazolyl (including 5-benzothiazolyl, etc.), purine, benzimidazolyl (including 2-benzimidazolyl, etc.), benzoxazolyl, indole (including 5-indole, etc.), isoquinolinyl (including 1-isoquinolinyl and 5-isoquinolinyl, etc.), quinoxalinyl (including 2-quinoxalinyl and 5-quinoxalinyl, etc.), and quinolinyl (including 3-quinolinyl and 6-quinolinyl, etc.).

[0198] Unless otherwise specified, the terms "5-6-membered heteroaryl ring" and "5-6-membered heteroaryl group" are used interchangeably in this invention. The term "5-6-membered heteroaryl group" refers to a monocyclic group with a conjugated π-electron system composed of 5 to 6 ring atoms / ring groups, wherein 1, 2, 3, or 4 of the ring atoms / ring groups are heteroatoms / ring groups independently selected from O, S, N, and C (=O), and the remainder are carbon atoms. It also includes keto derivatives of the aforementioned "5-6-membered heteroaryl ring" and their aromatic conjugated bases formed after deprotonation. The 5-6-membered heteroaryl group can be attached to the rest of the molecule via heteroatoms or carbon atoms. The 5-6-membered heteroaryl group includes both 5-membered and 6-membered heteroaryl groups. Examples of the 5-6 membered heteroaryl groups include, but are not limited to, pyridinone, pyrazinone, pyridazinone, imidazolinone, pyrrolodione, pyrrolo (including N-pyrrolo, 2-pyrrolo, and 3-pyrrolo), pyrazol (including 2-pyrazol and 3-pyrazol), and imidazo (including...). N -imidazolium, 2-imidazolium, 4-imidazolium and 5-imidazolium, etc.), oxazolium (including 2-oxazolium, 4-oxazolium and 5-oxazolium, etc.), triazolium (1 H -1,2,3-triazolyl, 2 H -1,2,3-triazolyl, 1 H -1,2,4-triazolyl and 4 H -1,2,4-triazolyl, tetrazolyl, isoxazolyl (3-isooxazolyl, 4-isooxazolyl and 5-isooxazolyl, etc.), thiazolyl (including 2-thiazolyl, 4-thiazolyl and 5-thiazolyl, etc.), furanyl (including 2-furanyl and 3-furanyl, etc.), thiophene (including 2-thiophene and 3-thiophene, etc.), pyridyl (including 2-pyridyl, 3-pyridyl and 4-pyridyl, etc.), pyrazinyl and pyrimidinyl (including 2-pyrimidinyl and 4-pyrimidinyl, etc.).

[0199] Unless otherwise specified, the terms "6-10-membered heteroaryl ring" and "6-10-membered heteroaryl group" are used interchangeably in this invention. The term "6-10-membered heteroaryl group" refers to a cyclic group with a conjugated π-electron system composed of 6 to 10 ring atoms / ring groups, wherein 1, 2, 3, or 4 ring atoms are heteroatoms / ring groups independently selected from O, S, N, and C (=O), and the remainder are carbon atoms. It also includes keto derivatives of the aforementioned "6-10-membered heteroaryl ring" and their deprotonated aromatic conjugated bases, which can be monocyclic or fused bicyclic systems, wherein each ring is aromatic. The 6-10-membered heteroaryl group can be attached to the rest of the molecule via heteroatoms or carbon atoms. The 6-10-membered heteroaryl group includes 6-membered, 6-9-membered, 6-8-membered, and 7-membered heteroaryl groups, etc. Examples of the 6-10 membered heteroaryl groups include, but are not limited to, pyridinone, pyrazinone, pyridazinone, imidazolinone, pyrrolodione, pyridyl (including 2-pyridyl, 3-pyridyl, and 4-pyridyl), pyrazin, pyrimidin (including 2-pyrimidin and 4-pyrimidin), benzothiazolyl (including 5-benzothiazolyl), purine, benzimidazol (including 2-benzimidazol), benzoxazol, indole (including 5-indole), isoquinolinyl (including 1-isoquinolinyl and 5-isoquinolinyl), quinoxalinyl (including 2-quinoxalinyl and 5-quinoxalinyl), and quinolinyl (including 3-quinolinyl and 6-quinolinyl).

[0200] The descriptive phrase "...each / each independently is" used in this application should be interpreted broadly, meaning that the described individuals are independent of each other and can independently be the same or different specific groups. More specifically, the descriptive phrase "...independently is" can mean that in different groups, the specific options expressed by the same symbol do not affect each other; or it can mean that in the same group, the specific options expressed by the same symbol do not affect each other.

[0201] In this invention, the term "pharmaceutical excipient" refers to excipients and additives used in the production of pharmaceuticals and the preparation of prescriptions; it refers to substances contained in pharmaceutical preparations other than the active ingredient. See the Pharmacopoeia of the People's Republic of China (2015 Edition), Volume IV, or the Handbook of Pharmaceutical Excipients (Raymond C Rowe, 2009 Sixth Edition). Unless otherwise specified, the term "treatment" means the elimination of the cause or relief of symptoms.

[0202] Other features and advantages of the invention will be set forth in the following description, and will be apparent in part from the description, or may be learned by practicing the application. Other advantages of the invention can be realized and obtained by means of the methods described in the description.

[0203] The compounds of the present invention can be prepared by a variety of synthetic methods known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthetic methods, and equivalent substitutions known to those skilled in the art. Preferred embodiments include, but are not limited to, the embodiments of the present invention.

[0204] Without violating common sense in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain various preferred embodiments of the present invention.

[0205] The reagents and raw materials used in this invention are all commercially available.

[0206] The positive and progressive effects of this invention are that the compound provided by this invention has good degradation activity against VAV1. Detailed Implementation

[0207] The present invention is further illustrated below by way of embodiments, but the invention is not limited to the scope of the embodiments described herein. Experimental methods in the following embodiments that do not specify specific conditions were performed according to conventional methods and conditions, or as selected according to the product instructions.

[0208] 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 increments. -6 The units are given. NMR measurements were performed using a BRUKER AVANCE III (400 MHz) nuclear magnetic resonance spectrometer, with deuterated dimethyl sulfoxide (DMSO-d6) or deuterated chloroform (CDCl3) as the solvent and tetramethylsilane (TMS) as the internal standard.

[0209] LCMS measurements were performed using a Shimadzu LC-20AB &MS 2020.

[0210] Thin-layer chromatography silica gel plates were prepared using West Asia Reagent GF254 silica gel plates.

[0211] Column chromatography used 200-300 mesh silica gel from Qingdao Ocean Chemical Co., Ltd. as the carrier.

[0212] The known starting materials used in this application can be synthesized using or according to methods known in the art, or can be purchased from companies such as Aladdin, Bidex Pharmaceuticals, WuXi AppTec, and Lanbo.com.

[0213] The abbreviations used in this article have the following meanings: AcOH: Acetic acid; ACN, MeCN: Acetonitrile; DCM: Dichloromethane; DIEA: N,N-Diisopropylethylamine; DMF: N,N-Dimethylformamide; DPPA: Diphenyl azidophosphate; EtOAc: Ethyl acetate; MTBE: Methyl tert-butyl ether; NaBH3CN: Sodium cyanoborohydride; NIS: N-Iodosuccinimide; TEA: Triethylamine; TFA: Trifluoroacetic acid; THF: Tetrahydrofuran; SFC: Supercritical fluid chromatography; % MPE: Maximum potential effect percentage; LC-MS, LCMS: Liquid chromatography-mass spectrometry; NMR: Nuclear magnetic resonance; HPLC: High performance liquid chromatography; TMS: Tetramethylsilane; min: minute; mmol: millimole; mg: milligram; μg: microgram; g: gram; kg: kilogram; eq: equivalent; mm: millimeter; µm: micrometer; nm: nanometer; mL: milliliter; μL: microliter; hr / h, h: hour; M: mole / liter; μM: micromole / liter; μmol: micromole; mV: millivolt; ms: millisecond; MHz: megahertz; TLC: Thin-layer chromatography; Rt: retention time; Rf: Rf value; EtOH: ethanol; HATU: 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b] Pyridinium-3-oxide hexafluorophosphate; ESI: electrospray ionization; HCl: hydrogen chloride; NH4Cl: ammonium chloride; NaHMDS: sodium bis(trimethylsilyl)amino; Na2SO4: sodium sulfate; HClO4: perchloric acid; K2CO3: potassium carbonate; silica gel; H2: hydrogen; PdCl2(PPh3)2: palladium(II) di(triphenylphosphine) dichloride; MeOH: methanol; t-BuOK: potassium tert-butoxide; NaHCO3: sodium bicarbonate; NH2NH2 H2O: hydrazine hydrate; KOH: potassium hydroxide; t-BuONa: sodium tert-butoxide; NH4HCO3: ammonium bicarbonate; Pd(dppf)Cl2: [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) dichloride; Pd / C: palladium on carbon; Cs2CO3: cesium carbonate; t-BuOH: tert-butanol; DMEM: Duchenne modified Eagle medium; FBS: fetal bovine serum; DMSO: dimethyl sulfoxide; NaCl: sodium chloride; KCl: potassium chloride; MgCl2: magnesium chloride; CaCl2: calcium chloride; NaH2PO4 2H₂O: Sodium dihydrogen phosphate dihydrate; EDTA: Disodium ethylenediaminetetraacetate; rpm: revolutions per minute; SPF: Specific pathogen-free; ICR: ICR mouse; SD: SD rat; SnCl₂ 2H2O: Stannous chloride dihydrate; CbzCl: Benzyl chloroformate; N2: Nitrogen gas; ip: Intraperitoneal injection; 11H NMR: Proton nuclear magnetic resonance spectrum; NMP: N-methylpyrrolidone; Select F: 1-chloromethyl-4-fluoro-1,4-diazabicyclo[2.2.2]octane di(tetrafluoroborate) salt; DMAP: 4-dimethylaminopyridine; TMPMgCl LiCl: Lithium magnesium chloride (2,2,6,6-tetramethylpiperidinyl)chloride; t-BuXPhos: 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl; t-BuXPhos Pd G3: Methanesulfonic acid (2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II); Pd(dppf)Cl2·DCM: dichlorobis(1,1'-diphenylphosphine)ferrocene palladium dichloromethane complex; DIC: N,N'-diisopropylcarbodiimide; CDI: N,N'-carbonyldiimidazole; DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene; SEM-Cl: 2-(trimethylsilyl)ethoxymethyl chloride; DCC: dicyclohexylcarbodiimide; Pd-PEPPSI-IHept Cl2: Dichloro[1,3-bis(2,6-di-4-heptylphenyl)imidazol-2-yl](3-chloropyridyl)palladium(II); NBS: N-bromosuccinimide; TMSCN: Trimethylcyanosilane; TBAF: Tetrabutylammonium fluoride; Na2SO4: Sodium sulfate; NH4Cl: Ammonium chloride; LDA: Lithium diisopropylamino; H2SO4: Sulfuric acid; KOAc: Potassium acetate; BF3.Et2O: Boron trifluoride diethyl ether; i -PrMgCl-LiCl: Isopropyl magnesium chloride-lithium chloride; PBr3: Boron tribromide; DCE: 1,2-dichloroethane; Et3SiH: Triethylsilane; NaH: Sodium hydride; NaBH4: Sodium borohydride; SOCl2: Sulfoxide; TFAA: Trifluoroacetic anhydride.

[0214] Intermediate A: 3-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)phenyl)piperidine-2,6-dione (A)

[0215] Step 1: 1-Bromo-2-chloro-3-methylbenzene (89 g) and NBS (80.95 g) were dissolved in MeCN (900 mL) to obtain a solution, which was pumped into a pipeline at a rate of 10 mL / min under 45 °C and irradiated with a blue LED lamp. After the reaction was complete, the reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate gradient from 100% to 5%) to give 1-bromo-3-(bromomethyl)-2-chlorobenzene (120 g, yield 97.4%) as a white solid. 1 H NMR (400MHz, CDCl3- d ): d 7.60 (dd, J = 1.2, 8.0 Hz, 1H), 7.40 (dd, J = 1.2, 7.6 Hz, 1H), 7.13 (t, J = 8.0 Hz, 1H), 4.62 (s, 2H).

[0216] Step 2: At 0 °C, TBAF (1 M, 263 mL) was added dropwise to a DCM (1 L) solution of 50 g of 1-bromo-3-(bromomethyl)-2-chlorobenzene and 26.1 g of TMSCN. The mixture was stirred at 20 °C for 12 hours. After the reaction was complete, the mixture was washed with water (500 mL × 3), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate gradient from 100% to 10%) to give 35.0 g of 2-(3-bromo-2-chlorophenyl)acetonitrile (86.3% yield) as a brown solid. 1 H NMR (400 MHz, CDCl3-) d ): d 7.66 (d, J = 8.0 Hz, 1H), 7.51 (d, J = 8.0 Hz, 1H), 7.21 (t, J = 8.0 Hz, 1H), 3.90 (s, 2H).

[0217] Step 3: Under a nitrogen atmosphere at -70°C, LDA (2 M, 47.7 mL) was slowly added to a THF (300 mL) solution of 2-(3-bromo-2-chlorophenyl)acetonitrile (20.0 g). The reaction mixture was stirred at -70°C for 1 hour under a nitrogen atmosphere, followed by dropwise addition of a THF (50 mL) solution of tert-butyl 3-bromopropionate (18.1 g) at -70°C. The resulting mixture was stirred at -70°C for 1 hour, then heated to 20°C and stirred again at 20°C for 1 hour under a nitrogen atmosphere. After the reaction was complete, the mixture was quenched with a saturated NH4Cl solution (500 mL) and extracted with EtOAc (200 mL × 3). The combined organic phases were washed with brine (50 mL), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate gradient from 100% to 10%) to give tert-butyl 4-(3-bromo-2-chlorophenyl)-4-cyanobutyrate (30.0 g, yield 96.4%) as a colorless oil. LC-MS: Rt = 0.643 min, m / z = 358.2 [M+H] + . 1 H NMR (400 MHz, CDCl3- d ): d 7.65 (dd, J = 1.2, 8.0 Hz, 1H), 7.53 (dd, J = 1.2, 7.6 Hz, 1H), 7.22 (t, J = 8.0 Hz, 1H), 4.55 -4.44 (m, 1H), 2.55 - 2.39 (m, 2H), 2.31 - 2.09 (m, 2H), 1.47 - 1.45 (m, 9H).

[0218] Step 4: At 20 °C, 38.7 g of H₂SO₄ was added to a solution of 30.0 g of tert-butyl 4-(3-bromo-2-chlorophenyl)-4-cyanobutyrate in 300 mL of AcOH. The mixture was stirred at 90 °C for 3 hours. After the reaction was complete, the reaction mixture was diluted with water (1 L), and then filtered to remove insoluble solids. The filtrate was concentrated under reduced pressure to give 13 g of 3-(3-bromo-2-chlorophenyl)piperidine-2,6-dione (yield 51.37%) as a white solid. LC-MS: Rt = 0.421 min, m / z = 304.0 [M+H] + . 1 H NMR (400MHz, DMSO- d 6): d10.94 (s, 1H), 7.72 (dd, J = 1.6, 8.0 Hz, 1H), 7.38 (dd, J =1.6, 7.6 Hz, 1H), 7.32 - 7.23 (m, 1H), 4.32 (dd, J = 5.2, 12.4 Hz, 1H), 2.83- 2.71 (m, 1H), 2.56 (t, J = 3.2 Hz, 1H), 2.38 - 2.27 (m, 1H), 2.05 - 1.95 (m, 1H).

[0219] Step 5: In a nitrogen atmosphere at 20°C, KOAc (1.30 g) and Pd(dppf)Cl2 (483.69 mg) were added to a solution of 2.00 g of 3-(3-bromo-2-chlorophenyl)piperidine-2,6-dione and 2.52 g of 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxoborhexacyclopentan-2-yl)-1,3,2-dioxoborhexacyclopentane (2.52 g) in dioxane (20 mL). The mixture was stirred at 80°C for 2 hours in a nitrogen atmosphere. After the reaction was complete, the reaction mixture was filtered to remove insoluble solids. The filtrate was diluted with water (50 mL) and extracted with EtOAc (500 mL × 3). The combined organic phases were washed with brine (100 mL), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate gradient from 50% to 33%) to give intermediate A (2.60 g, yield 64.1%, purity 57%). LC-MS: Rt = 0.493 min, m / z = 350.2 [M+H] + . 1 H NMR (400MHz, DMSO- d 6): d 10.90 (s, 1H), 7.52 (dd, J = 2.0, 7.2 Hz, 1H), 7.41 (dd, J =1.6, 7.6 Hz, 1H), 7.32 (d, J = 7.6 Hz, 1H), 5.76 (s, 1H), 4.31 - 4.19 (m,1H), 2.82 - 2.72 (m, 1H), 2.56 - 2.53 (m, 1H), 2.37 - 2.25 (m, 1H), 1.31 (s,12H).

[0220] Intermediate B: (2-chloro-3-(2,6-dioxopiperidin-3-yl)phenyl)boronic acid (compound B)

[0221] In a nitrogen atmosphere at 20 °C, Pd(dppf)Cl2 (24.1 mg), KOAc (64.8 mg), and 5,5,5',5'-tetramethyl-2,2'-bi(1,3,2-dioxoborhexane) (149 mg) were added to a solution of 100 mg of 3-(3-bromo-2-chlorophenyl)piperidine-2,6-dione in dioxane (2 mL). The mixture was stirred at 60 °C for 12 hours in a nitrogen atmosphere. After the reaction was complete, the reaction mixture was filtered to remove insoluble solids. The filtrate was diluted with water (5 mL) and extracted with EtOAc (5 mL × 3). The combined organic phases were washed with brine (10 mL), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate gradient from 50% to 10%) to give intermediate B (69 mg, yield 70.1%, purity 90%) as a brown solid. LC-MS: Rt = 0.248 min, m / z = 268.1[M+H] + .

[0222] Example 1: 3-(3-(3-benzylimidazo[1,2-a]pyridin-7-yl)-2-chlorophenyl)piperidin-2,6-dione (Compound 1)

[0223] Step 1: A mixture of 4-bromopyridin-2-amine (3.00 g), copper chloride (867 μmol), bis(trifluoromethanesulfonyloxy)copper (313.58 mg), and 4A molecular sieve (3 g) dissolved in toluene (60 mL) was degassed and purged three times with N2. Phenylacetylene (2.66 g) and formaldehyde (18.2 mmol, 1.36 mL, purity 37%) were added to the above solution at 25 °C under N2 atmosphere, and the mixture was then stirred at 120 °C for 16 hours under N2 atmosphere. The reaction mixture was concentrated under reduced pressure. The residue was diluted with ethyl acetate (100 mL) and filtered through a neutral alumina stopper using ethyl acetate. The filtrate was concentrated under reduced pressure. The residue was analyzed by preparative HPLC (column: CD27-Phenomenex luna C18 250 mm). 70mm Purification was performed using a mobile phase of [H₂O (containing 0.225% FA)-ACN] and a gradient of 10%-40% ACN, eluting for 20.0 min, yielding 3-benzyl-7-bromoimidazolo[1,2-a]pyridine (270 mg, yield 5.42%) as a white solid. LCMS: Rt = 0.285 min, m / z = 287.0 [M+H]. + . 1 H NMR (400 MHz, CDCl3-) d ): d 7.91 (s, 1H), 7.74 - 7.63 (m, 1H), 7.59 - 7.42 (m, 1H), 7.37 -7.28 (m, 3H), 7.24 - 7.14 (m, 2H), 6.93 - 6.84 (m, 1H), 4.32 - 4.20 (m, 2H).

[0224] Step 2: In a nitrogen atmosphere at 20°C, cyclopentyl(diphenyl)phosphine dichloropalladium iron (25 mg) and K₂CO₃ (96.2 mg) were added to a solution of 100 mg of 3-benzyl-7-bromo-imidazo[1,2-a]pyridine and 0.8 mL of dioxane and H₂O in 3-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxoboron-2-yl)phenyl)piperidine-2,6-dione (214 mg). The mixture was stirred at 80°C for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was analyzed by preparative HPLC (column: CD24-WePure Biotech XPT C18 150 mm). 25mm 7 μm; mobile phase: [H2O (containing 10 mM NH4HCO3)-ACN]; gradient: 32%-62% ACN, elution for 15.0 min) purification, yielding compound 1 (29.59 mg, yield 19.7%) as a white solid. LCMS: Rt = 2.205 min, m / z = 430.1 [M+H] + . 1 H NMR: (400 MHz, DMSO- d 6): d11.04- 10.81 (m, 1H), 8.34 - 8.21 (m, 1H), 7.59 - 7.54 (m, 1H), 7.53 - 7.48 (m,1H), 7.46 - 7.38 (m, 3H), 7.36 - 7.28 (m, 4H), 7.27 - 7.21 (m, 1H), 6.98 -6.94 (m, 1H), 4.43 - 4.29 (m, 3H), 2.86 - 2.72 (m, 1H), 2.68 - 2.58 (m, 1H),2.37 - 2.31 (m, 1H), 2.10 - 2.02 (m, 1H).

[0225] Example 2: 3-(3-(2-benzylimidazo[1,2-a]pyridin-7-yl)-2-chlorophenyl)piperidin-2,6-dione (Compound 2)

[0226] Step 1: In a nitrogen atmosphere, a tetrahydrofuran solution (1 M, 888 μL) of magnesium phenyl bromide was added to a tetrahydrofuran solution (8 mL) of 0.20 g of 7-bromoimidazolo[1,2-a]pyridin-2-carboxaldehyde in a nitrogen atmosphere at 0 °C. The mixture was stirred for 1 hour at 20 °C in a nitrogen atmosphere. After the reaction was complete, the mixture was quenched with saturated NH4Cl (8 mL), extracted with EtOAc (20 mL × 3), and the combined organic phases were washed with brine (25 mL), dried over Na2SO4, and concentrated under reduced pressure to give (7-bromoimidazolo[1,2-a]pyridin-2-yl)(phenyl)methanol (290 mg, 90% yield) as a colorless oil. LC-MS: Rt = 0.291 min, m / z = 303.0 [M+H] + .

[0227] Step 2: BF3·Et2O (411 μL) and Et3SiH (381 μL) were added dropwise to a DCM solution of (7-bromoimidazolo[1,2-a]pyridin-2-yl)(phenyl)methanol (290 mg) in 10 mL at 0 °C. The mixture was stirred at 40 °C for 12 hours. After the reaction was complete, the mixture was cooled to room temperature, quenched with NH4Cl (30 mL), extracted with EtOAc (20 mL × 3), and the combined organic phases were washed with brine (25 mL), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate gradient from 5:1 to 1:1) to give compound 2-benzyl-7-bromoimidazolo[1,2-a]pyridine (200 mg, yield 72.8%) as a brown oil. LC-MS: Rt = 0.580 min, m / z = 287.0 [M+H] + .

[0228] Step 3: In a nitrogen atmosphere at 20°C, Pd(dppf)Cl2 (7.64 mg) and K2CO3 (29 mg) were added to a solution of 2-benzyl-7-bromoimidazolo[1,2-a]pyridine (30.0 mg), (27.9 mg) dioxane (1 mL), and H2O (0.1 mL). The mixture was stirred at 80°C for 1 hour in a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure. The residue was analyzed by preparative HPLC (column: CD19-Daisogel SP-100-8-ODS-PK 200 mm). 50mm The mobile phase was [H₂O (containing 10 mM NH₄OAc)-ACN]; gradient: 29%-59% ACN, elution for 10.0 min) to purify compound 2 (10.15 mg, yield 22.2%, purity 98.6%), as a white solid. LC-MS: Rt = 2.211 min, m / z = 430.1 [M+H] + . 1 H NMR (400 MHz, DMSO- d 6): d 10.93 (s, 1H), 8.52 (d, J= 7.2 Hz,1H), 7.71 (s, 1H), 7.46 (s, 1H), 7.44 - 7.38 (m, 3H), 7.35 - 7.27 (m, 4H),7.24 - 7.17 (m, 1H), 6.90 (dd, J = 1.6, 7.0 Hz, 1H), 4.36 (dd, J = 4.8 12.0Hz, 1H), 4.06 (s, 2H), 2.85 - 2.73 (m, 1H), 2.59 - 2.55 (m, 1H), 2.39 - 2.28 (m, 1H), 2.11 - 1.99 (m, 1H).

[0229] Example 3: 3-(2-chloro-3-(3-(pyridin-4-ylmethyl)imidazo[1,2-a]pyridin-7-yl)phenyl)piperidin-2,6-dione (compound 3)

[0230] Step 1: In a nitrogen atmosphere at 0°C, add 4-bromopyridine (300 mg) to a THF solution (6 mL) i A 1.30 M, 1.61 mL THF solution of PrMgCl-LiCl was added, and the mixture was stirred at 0 °C for 0.5 h. Then, a 3 mL THF solution of 7-bromoimidazole[1,2-a]pyridine-3-carboxaldehyde (384 mg) was added to the mixture under a N2 atmosphere at 0 °C, and the mixture was stirred at 25 °C for 0.5 h under a N2 atmosphere. After the reaction was complete, the mixture was quenched with NH4Cl (20 mL), extracted with EtOAc (10 mL × 3), and the combined organic phases were washed with brine (20 mL), dried over Na2SO4, and concentrated. The residue was analyzed by preparative HPLC (column: CD45-Waters Xbridge BEH C18 150 mm). 40mm 10 μm; mobile phase: [H2O (containing 10 mM NH4HCO3)-ACN]; gradient: 6%-36% ACN, elution for 11.0 min) purification, yielding (7-bromoimidazolo[1,2-a]pyridin-3-yl)(pyridin-4-yl)methanol (300 mg, yield 51.0%), as a white solid. LCMS: Rt = 0.412 min, m / z = 304.1 M+H + . 1 H NMR (400 MHz, CDCl3): d 8.64 (d, J= 4.4 Hz, 2H), 8.05 - 7.97 (m, 1H), 7.82 -7.74 (m, 1H), 7.38 (d, J = 4.8 Hz, 2H), 6.93 - 6.86 (m, 1H), 6.25 - 6.17 (m, 1H), 3.47 - 3.08 (m, 1H).

[0231] Step 2: In a nitrogen atmosphere at 20°C, PBr3 (373 mg) was added to a THF (1.50 mL) solution of (7-bromoimidazolo[1,2-a]pyridin-3-yl)(pyridin-4-yl)methanol (140 mg). The mixture was stirred at 20°C for 0.5 h, followed by stirring at 80°C for 2 h. After the reaction was complete, the mixture was quenched with saturated NaHCO3 (10 mL) at 25°C, extracted with EtOAc (10 mL × 3), and the combined organic phases were washed with brine (10 mL), dried over Na2SO4, and concentrated. The residue was analyzed by preparative HPLC (column: CD24-WePure Biotech XPT C18 150 mm). 25mm The solution was purified by elution with a mobile phase of [H₂O (containing 10 mM NH₄HCO₃)-ACN] and a gradient of 13%-43% ACN for 10.0 min to give 7-bromo-3-(pyridin-4-ylmethyl)imidazo[1,2-a]pyridine (35.0 mg, yield 26.3%) as an orange solid. LCMS: Rt = 0.447 min, m / z = 287.9 ​​[M+H]. + . 1 H NMR (400 MHz, DMSO-) d 6): d 8.49 - 8.46 (m, 2H), 8.20 (d, J = 7.2 Hz, 1H), 7.90 (d, J = 1.6 Hz, 1H), 7.48 (s, 1H), 7.23 (d, J = 6.0 Hz, 2H), 7.07 (dd, J = 2.0,7.2 Hz, 1H), 4.36 (s, 2H).

[0232] Step 3: To a solution of 30.0 mg of 7-bromo-3-(pyridin-4-ylmethyl)imidazo[1,2-a]pyridine and 0.5 mL of dioxane and 0.05 mL of H₂O, K₂CO₃ (28.7 mg) and Pd(dppf)Cl₂ (7.62 mg) were added, and the mixture was stirred at 80 °C for 1 hour under a nitrogen atmosphere. The reaction mixture was diluted with 5 mL of H₂O and extracted with EtOAc (5 mL × 4). The combined organic phases were washed with 10 mL of brine, dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was subjected to preparative HPLC (column: CD24-WePureBiotech XPT C18 150 mm). 25mm 7 μm; mobile phase: [H2O (containing 10 mM NH4HCO3)-ACN]; gradient: 13%-43% ACN, elution for 10.0 min) purification, yielding compound 3 (13.5 mg, yield 29.9%, purity 99.5%) as a white solid. LCMS: Rt = 1.653 min, m / z: 431.1 [M+H] + . 1 H NMR: (400 MHz, DMSO- d 6): d 10.94 (s,1H), 8.53 - 8.49 (m, 2H), 8.30 (d, J = 7.2 Hz, 1H), 7.60 - 7.54 (m, 2H), 7.46- 7.39 (m, 3H), 7.31 (d, J = 5.6 Hz, 2H), 6.98 (dd, J = 1.6, 7.2 Hz, 1H),4.41 (s, 2H), 4.39 - 4.33 (m, 1H), 2.88 - 2.73 (m, 1H), 2.60 - 2.54 (m, 1H),2.38 - 2.29 (m, 1H), 2.06 (dd, J = 4.0, 8.8 Hz, 1H).

[0233] Example 4: 3-(2-chloro-3-(2-(pyridin-4-ylmethyl)imidazo[1,2-a]pyridin-7-yl)phenyl)piperidin-2,6-dione (compound 4)

[0234] Step 1: In a nitrogen atmosphere at 0°C, a THF solution of i-PrMgCl-LiCl (2 M, 1.39 mL) was added to an 8 mL THF solution of 4-bromopyridine (400 mg). The mixture was stirred at 20°C for 1 hour. Subsequently, a THF solution of 7-bromoimidazolo[1,2-a]pyridine-2-carboxaldehyde (512 mg) (2 mL) was added to the mixture in a nitrogen atmosphere at 0°C. The mixture was then stirred at 20°C for 1 hour in a nitrogen atmosphere. After the reaction was complete, the mixture was quenched with saturated NH4Cl (1 mL), and then the resulting mixture was concentrated under reduced pressure. The residue was analyzed by preparative HPLC (column: CD45-Waters Xbridge BEH C18 150 mm). 40mm Purification was performed using a mobile phase of [H₂O (containing 10 mM NH₄HCO₃)-ACN] and a gradient of 2%-32% ACN, eluting for 15.0 min, to give the compound (7-bromoimidazolo[1,2-a]pyridin-2-yl)(pyridin-4-yl)methanol (170 mg, yield 22.0%) as an off-white solid. LC-MS: Rt = 0.726 min, m / z = 305.8 [M+H] + .

[0235] Step 2: At 20°C, PBr3 (267 mg) was added to a THF (3 mL) solution of (7-bromoimidazolo[1,2-a]pyridin-2-yl)(pyridin-4-yl)methanol (100 mg). The mixture was stirred at 20°C for 0.5 h, followed by stirring at 80°C for 12 h. After the reaction was complete, the mixture was cooled to room temperature, quenched with NH4Cl (15 mL), extracted with EtOAc (15 mL × 3), and the combined organic phases were washed with brine (15 mL), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate gradient from 5:1 to 1:1) to give 7-bromo-2-(pyridin-4-ylmethyl)imidazo[1,2-a]pyridine (92.0 mg, yield 97.11%) as a brown oil. LC-MS: Rt = 0.456 min, m / z = 288.0[M+H] + . 1 H NMR (400MHz, CDCl3- d): δ 8.58 - 8.50 (m, 2H), 7.94 - 7.88 (m, 1H), 7.78 - 7.73 (m,1H), 7.30 - 7.29 (m, 1H), 7.27 - 7.25 (m, 2H), 6.92 - 6.85 (m, 1H), 4.14 -4.13 (m, 2H).

[0236] Step 3: In a nitrogen atmosphere at 20°C, Pd(dppf)Cl2 (22.8 mg) and K2CO3 (86.3 mg) were added to a solution of 7-bromo-2-(pyridin-4-ylmethyl)imidazo[1,2-a]pyridine (90.0 mg) and (2-chloro-3-(2,6-dioxoperidin-3-yl)phenyl)boronic acid (83.5 mg) in dioxane (1 mL) and H2O (0.1 mL). The mixture was stirred at 80°C for 1 hour in a nitrogen atmosphere. After the reaction was complete, the reaction mixture was concentrated under reduced pressure. The residue was analyzed by preparative HPLC (column: CD04-Welch Ultimate C18 150 mm). 25mm The mobile phase was [H₂O (containing 0.225% FA)-ACN]; gradient: 0%-23% ACN, elution for 15.0 min. The compound 4 (3.05 mg, yield 2.24%, purity 98.6%) was purified as a white solid. LC-MS: Rt = 0.914 min, m / z = 431.1 [M+H] + . 1 H NMR (400 MHz, DMSO- d 6): d 10.93 (s, 1H), 8.53 (dd, J = 0.8, 7.2 Hz, 1H), 8.50 - 8.44 (m, 2H), 8.25 (s, 1H), 7.80 (s, 1H),7.48 - 7.46 (m, 1H), 7.46 - 7.37 (m, 3H), 7.36 - 7.31 (m, 2H), 6.91 (dd, J =1.6, 7.2 Hz, 1H), 4.36 (dd, J= 5.2, 12.4 Hz, 1H), 4.09 (s, 2H), 2.86 - 2.74(m, 1H), 2.58 - 2.56 (m, 1H), 2.41 - 2.28 (m, 1H), 2.11 - 2.01 (m, 1H).

[0237] Example 5: 3-(2-chloro-3-(3-(pyridin-3-ylmethyl)imidazo[1,2-a]pyridin-7-yl)phenyl)piperidin-2,6-dione (Compound 5)

[0238] Step 1: In a nitrogen atmosphere at 0°C, a THF solution of i-PrMgCl-LiCl (1.30 M, 1.61 mL) was added to a THF solution of 3-bromopyridine (0.30 g) in 6 mL of THF. The mixture was stirred at 20°C for 1 hour, followed by the addition of a THF solution of 7-bromoimidazolo[1,2-a]pyridine-3-carboxaldehyde (427 mg) in 3 mL of THF in a nitrogen atmosphere at 0°C. The resulting mixture was stirred at 20°C in a nitrogen atmosphere for 1 hour. After the reaction was complete, the mixture was quenched with NH4Cl (20 mL), extracted with EtOAc (10 mL × 3), and the combined organic phases were washed with brine (20 mL), dried over Na2SO4, and concentrated under reduced pressure. The residue was analyzed by preparative HPLC (column: CD45-WatersXbridge BEH C18 150 mm). 40 mm 10 μm; mobile phase: [H2O (containing 10 mM NH4HCO3)-ACN]; gradient: 5%-35% ACN, elution for 11.0 min) purification, yielding (7-bromoimidazolo[1,2-a]pyridin-3-yl)(pyridin-3-yl)methanol (210 mg, yield 36.3%), as a white solid. LCMS: Rt = 0.725 min, m / z = 303.9 M+H + . 1 H NMR: (400MHz, CDCl3): d 8.62 (d, J = 1.6 Hz, 1H), 8.57 - 8.50 (m, 1H), 8.10 (d, J =7.2 Hz, 1H), 7.77 (d, J= 8.0 Hz, 1H), 7.67 - 7.58 (m, 1H), 7.38 - 7.29 (m,1H), 7.01 (s, 1H), 6.92 - 6.86 (m, 1H), 6.22 - 6.14 (m, 1H), 5.30 (s, 1H).

[0239] Step 2: At 20°C, triethylsilane (1.79 mL) and TFA (732 μL) were added to a DCE (2 mL) solution of (7-bromoimidazolo[1,2-a]pyridin-3-yl)(pyridin-3-yl)methanol (200 mg). The mixture was stirred at 100°C for 16 hours. After the reaction was complete, the mixture was quenched with saturated NaHCO3 (10 mL) in a N2 atmosphere at 25°C, extracted with EtOAc (10 mL × 3), and the combined organic phases were washed with brine (10 mL), dried over Na2SO4, and concentrated. The residue was analyzed by preparative HPLC (column: CD24-WePure Biotech XPT C18 150 mm). 25mm The solution was purified by elution with a mobile phase of [H₂O (containing 10 mM NH₄HCO₃)-ACN] and a gradient of 14%-44% ACN for 12.0 min to give 7-bromo-3-(pyridin-3-ylmethyl)imidazo[1,2-a]pyridine (80.0 mg, yield 42.2%) as a pale yellow solid. LCMS: Rt = 0.860 min, m / z = 287.9 ​​[M+H]. + . 1 HNMR: (400 MHz, DMSO- d 6): d 8.55 (d, J = 1.6 Hz, 1H), 8.44 (dd, J = 1.6, 4.8Hz, 1H), 8.27 (d, J = 7.2 Hz, 1H), 7.89 (dd, J = 0.4, 2.0 Hz, 1H), 7.62 (td, J = 2.0, 7.6 Hz, 1H), 7.42 (s, 1H), 7.35 - 7.30 (m, 1H), 7.07 (dd, J = 2.0,7.2 Hz, 1H), 4.33 (s, 2H).

[0240] Step 3: In a nitrogen atmosphere at 20°C, K₂CO₃ (76.7 mg) and Pd(dppf)Cl₂ (20.3 mg) were added to a solution of 80.0 mg 7-bromo-3-(pyridin-3-ylmethyl)imidazo[1,2-a]pyridine and 3-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborpentan-2-yl)phenyl)piperidin-2,6-dione (341 mg) in dioxane (1 mL) and H₂O (0.1 mL). The mixture was stirred at 80°C for 1 hour in a nitrogen atmosphere. The reaction mixture was diluted with H₂O (5 mL) and extracted with EtOAc (5 mL × 4). The combined organic phases were washed with brine (10 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was subjected to preparative HPLC (column: CD24-WePure Biotech XPT C18 150 mm). 25mm 7 μm; mobile phase: [H₂O (containing 10 mM NH₄HCO₃)-ACN]; gradient: 13%-43% ACN, elution for 10.0 min) purification, yielding compound 5 (54.4 mg, yield 45.3%, purity 99.7%) as a white solid. LCMS: Rt = 1.688 min, m / z: 431.1 [M+H] + . 1 H NMR: (400 MHz, DMSO- d 6): d 10.93 (s, 1H), 8.61 (d, J = 2.0 Hz, 1H), 8.46 (dd, J = 1.6, 4.8 Hz, 1H), 8.37 (d, J = 7.2 Hz, 1H), 7.73 - 7.65 (m, 1H), 7.57 (s, 1H), 7.49 (s,1H), 7.44 - 7.40 (m, 3H), 7.35 (dd, J = 4.8, 7.6 Hz, 1H), 6.98 (dd, J = 1.6,7.2 Hz, 1H), 4.38 (s, 2H), 4.38 - 4.33 (m, 1H), 2.86 - 2.74 (m, 1H), 2.56 (d, J = 3.6 Hz, 1H), 2.34 (dd, J = 4.0, 12.4 Hz, 1H), 2.09 - 2.01 (m, 1H).

[0241] Example 6: 3-(2-chloro-3-(3-((1-methyl-1H-pyrazol-3-yl)methyl)imidazo[1,2-a]pyridin-7-yl)phenyl)piperidin-2,6-dione (Compound 6)

[0242] Step 1: In a N2 atmosphere at 0°C, a THF solution of i-PrMgCl-LiCl (1.30 M, 4.07 mL) was added to a THF solution of 10 mL of 3-iodo-1-methyl-1H-pyrazole (1.00 g). The mixture was stirred at 20°C for 1 hour. Subsequently, a THF solution of 973 mg of 7-bromoimidazolo[1,2-a]pyridine-3-carboxaldehyde (973 mg) was added to a THF solution of 5 mL in a N2 atmosphere at 0°C. The resulting mixture was stirred at 20°C in a N2 atmosphere for 1 hour. After the reaction was complete, the mixture was quenched with 20 mL of NH4Cl, extracted with EtOAc (10 mL × 3), and the combined organic phases were washed with 20 mL of brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, isocratic elution DCM:MeOH = 10:1) to give (7-bromoimidazolo[1,2-a]pyridin-3-yl)(1-methyl-1H-pyrazol-3-yl)methanol (1.00 g, 3.26 mmol, yield 67.7%) as a pale yellow solid. LCMS: Rt = 0.219 min, m / z = 306.9 M+H + . 1 H NMR (400 MHz, DMSO- d 6): d 8.37 (d, J = 7.2 Hz, 1H), 7.87 (d, J = 1.6 Hz, 1H), 7.65 (d, J = 2.0 Hz, 1H), 7.37 (s, 1H), 7.07 (dd, J = 2.0, 7.2Hz, 1H), 6.31 (d, J = 2.0 Hz, 1H), 6.12 - 6.04 (m, 2H), 3.77 (s, 3H).

[0243] Step 2: In a nitrogen atmosphere at 0°C, Et3SiH (1.51 g) and TFA (1.48 g) were added to a DCE (17 mL) solution of (7-bromoimidazolo[1,2-a]pyridin-3-yl)(1-methyl-1H-pyrazol-3-yl)methanol (500 mg). The mixture was stirred at 80°C for 12 hours. After the reaction was complete, the mixture was quenched with saturated NaHCO3 (10 mL) at 25°C, extracted with EtOAc (10 mL × 3), and the combined organic phases were washed with brine (10 mL), dried over Na2SO4, and concentrated to give 7-bromo-3-((1-methyl-1H-pyrazol-3-yl)methyl)imidazo[1,2-a]pyridine (400 mg, yield 84.4%) as a pale yellow solid. LCMS: Rt = 0.242 min, m / z = 292.8 [M+H] + Step 3: In a nitrogen atmosphere at 20 °C, K₂CO₃ (94.9 mg) and Pd(dppf)Cl₂ (25.1 mg) were added to a solution of 7-bromo-3-((1-methyl-1H-pyrazol-3-yl)methyl)imidazo[1,2-a]pyridine (100 mg) and 3-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborone-2-yl)phenyl)piperidine-2,6-dione (240 mg) in dioxane (1 mL) and H₂O (0.1 mL). The mixture was stirred at 80 °C for 1 hour in a nitrogen atmosphere. The reaction mixture was diluted with H₂O (5 mL) and extracted with EtOAc (5 mL × 4). The combined organic phases were washed with brine (10 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was analyzed by preparative HPLC (column: CD19-Daisogel SP-100-8-ODS-PK 200mm). 50mm Purification was performed using a mobile phase of [H₂O (containing 10 mM NH₄HCO₃)-ACN] and a gradient of 15%-45% ACN, eluting for 11.0 min, yielding compound 6 (70.8 mg, yield 47.3%, purity 99.5%) as a white solid. LCMS: Rt = 1.695 min, m / z: 434.1 [M+H]. + . 1 H NMR (400MHz, DMSO- d 6): d 8.33 (dd, J = 0.8, 7.2 Hz, 1H), 7.59 (d, J = 2.0 Hz, 1H), 7.55 (dd, J= 0.8, 1.6 Hz, 1H), 7.49 (s, 1H), 7.46 - 7.40 (m, 3H), 6.98 (dd, J = 1.6, 7.2 Hz, 1H), 6.08 (d, J = 2.0 Hz, 1H), 4.37 (dd, J = 5.2, 12.0 Hz,1H), 4.26 (s, 2H), 3.78 (s, 3H), 2.85 - 2.76 (m, 1H), 2.61 - 2.56 (m, 1H),2.41 - 2.28 (m, 1H), 2.10 - 2.02 (m, 1H).

[0244] Example 7: 3-(2-chloro-3-(2-((1-methyl-1H-pyrazol-3-yl)methyl)imidazo[1,2-a]pyridin-7-yl)phenyl)piperidin-2,6-dione (Compound 7)

[0245] Step 1: In a nitrogen atmosphere at 0°C, a THF solution of i-PrMgCl·LiCl (1.3 M) was added to an 8 mL THF solution of 3-iodo-1-methyl-1H-pyrazole (550 mg). The mixture was stirred at 20°C for 2 hours. Subsequently, a THF solution of 7-bromoimidazolo[1,2-a]pyridine-2-carboxaldehyde (535 mg) (2 mL) was added in a nitrogen atmosphere at 0°C. The resulting mixture was stirred at 20°C for 1 hour in a nitrogen atmosphere. After the reaction was complete, the mixture was quenched with saturated NH4Cl (1 mL) and then concentrated under reduced pressure. The residue was analyzed by preparative HPLC (column: CD45-Waters Xbridge BEH C18 150 mm). 40mm Purification was performed using a mobile phase of [H₂O (containing 10 mMNH₄HCO₃)-ACN] and a gradient of 3%-33% ACN, eluting for 11.0 min, yielding (7-bromoimidazolo[1,2-a]pyridin-2-yl)(1-methyl-1H-pyrazol-3-yl)methanol (0.40 g, yield 49.2%) as a white solid. LC-MS: Rt = 0.706 min, m / z = 309.0 [M+H] + .

[0246] Step 2: Et3SiH (454 mg) and TFA (445 mg) were added to a DCM (5 mL) solution of (7-bromoimidazolo[1,2-a]pyridin-2-yl)(1-methyl-1H-pyrazol-3-yl)methanol (150 mg) at 20 °C under a N2 atmosphere. The mixture was stirred at 80 °C for 12 hours. After the reaction was complete, the mixture was cooled to room temperature, quenched with NaHCO3 (5 mL), and extracted with EtOAc (5 mL × 3). The combined organic phases were washed with brine (5 mL), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate gradient from 5:1 to 1:1) to give 7-bromo-2-((1-methyl-1H-pyrazol-3-yl)methyl)imidazolo[1,2-a]pyridine (120 mg, yield 84.4%) as a brown solid. LC-MS: Rt = 0.440 min, m / z = 291.1[M+H] + . 1 H NMR (400 MHz, CDCl3- d ): d 7.87 (d, J = 7.2 Hz, 1H), 7.73 (s, 1H), 7.36 (s,1H), 7.29 (d, J = 1.8 Hz, 1H), 6.83 (dd, J = 1.6, 7.2 Hz, 1H), 6.17 (d, J =2.0 Hz, 1H), 4.16 (s, 2H), 3.88 (s, 3H).

[0247] Step 3: At 20°C and under a N2 atmosphere, K2CO3 (94.94 mg) and Pd(dppf)Cl2 (25.1 mg) were added to a solution of 7-bromo-2-((1-methyl-1H-pyrazol-3-yl)methyl)imidazo[1,2-a]pyridine (100 mg) and (2-chloro-3-(2,6-dioxopiridine-3-yl)phenyl)boronic acid (91.8 mg) in dioxane (1 mL) and H2O (0.1 mL). The mixture was stirred at 80°C and under a N2 atmosphere for 1 hour. After the reaction was complete, the reaction mixture was concentrated under reduced pressure. The residue was analyzed by preparative HPLC (column: CD25-WePure Biotech XPT PHS C18 150 mm). 25mm 7 μm; mobile phase: [H₂O (containing 0.225% FA)-ACN]; gradient: 8%-38% ACN, elution for 10.0 min) purification, yielding compound 8 (12.7 mg, yield 8.27%, purity 96.6%) as a white solid. LC-MS: Rt = 1.711 min, m / z = 434.1 [M+H] + . 1 H NMR (400 MHz, DMSO- d 6): d 10.94 (s, 1H), 8.56 - 8.44 (m, 1H), 8.22 (s, 1H), 7.69 (s, 1H), 7.56 (d, J =2.0 Hz, 1H), 7.48 - 7.38 (m, 4H), 6.89 (dd, J = 1.6, 6.8 Hz, 1H), 6.08 (d, J = 2.0 Hz, 1H), 4.36 (dd, J = 5.2, 12.0 Hz, 1H), 3.98 (s, 2H), 3.78 (s, 3H), 2.85 - 2.74 (m, 1H), 2.59 - 2.55 (m, 1H), 2.30 (s, 1H), 2.12 - 2.02 (m, 1H).

[0248] Example 8: 4-((7-(2-chloro-3-(2-oxopiperidin-3-yl)phenyl)imidazo[1,2-a]pyridin-3-yl)methyl)-4-azaspiro[2.5]octane-5-one (Compound 8)

[0249] Step 1: Under a nitrogen atmosphere at 25°C, NaH (81.5 mg, 60% mineral oil dispersion) was added in portions to a DMF (12.0 mL) solution of 153 mg of 4-azaspiro[2.5]octane-5-one. The mixture was stirred at 25°C under a nitrogen atmosphere for 0.5 h. Subsequently, 7-bromo-3-(chloromethyl)imidazo[1,2-a]pyridine (100 mg) was added in portions to the mixture under a nitrogen atmosphere at 25°C. The resulting mixture was stirred at 25°C for another 0.5 h. The reaction mixture was quenched with saturated NH4Cl (10.0 mL) and extracted with EtOAc (10.0 mL × 3). The combined organic phases were washed with brine (5.00 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, dichloromethane / methanol gradient 0% to 10%) to give 4-((7-bromoimidazolo[1,2-a]pyridin-3-yl)methyl)-4-azaspiro[2.5]octane-5-one (100 mg, yield 73.5%) as a brown solid. LCMS: Rt = 0.270 min, m / z = 334.1 [M+H] + .

[0250] Step 2: At 20°C and under a N2 atmosphere, Pd(dppf)Cl2 (21.9 mg) and K2CO3 (82.7 mg) were added to a solution of 1 mL dioxane and 0.100 mL H2O containing 100 mg of 4-((7-bromoimidazolo[1,2-a]pyridin-3-yl)methyl)-4-azaspiro[2.5]octane-5-one, 80.0 mg of (2-chloro-3-(2,6-dioxopiridin-3-yl)phenyl)boronic acid. The mixture was stirred at 80°C for 1 hour under a N2 atmosphere. The reaction mixture was filtered to remove insoluble solids, and the filtrate was concentrated under reduced pressure. The residue was subjected to preparative HPLC (column: CD12-WePure Biotech Phenyl-Hexyl 150). 25mm 7 μm; mobile phase: [H2O (containing 0.225% FA)-ACN]; gradient: ACN gradient 10%-40% over 15.0 min), yielding compound 8 (0.01991 g, yield 12.7%, purity 99.5%), a white solid. LCMS: Rt = 1.308 min, m / z = 477.0 M+H + . 1 H NMR (400 MHz, DMSO- d 6 ): d 10.95 (s, 1H), 8.48 (d, J= 7.2 Hz, 1H), 8.25 (s, 1H), 7.63 - 7.53 (m,2H), 7.48 - 7.36 (m, 3H), 7.03 (dd, J = 2.0, 7.2 Hz, 1H), 4.74 (s, 2H), 4.37(dd, J = 5.2, 12.0 Hz, 1H), 2.87 - 2.75 (m, 1H), 2.57 (d, J = 3.6 Hz, 1H),2.49 - 2.45 (m, 2H), 2.35 (dd, J = 4.4, 12.8 Hz, 1H), 2.12 - 2.01 (m, 1H),1.77 (quin, J = 6.8 Hz, 2H), 1.42 (t, J = 6.8 Hz, 2H), 1.13 - 1.03 (m, 2H), 0.72 - 0.63 (m, 2H).

[0251] Example 9: 3-(2-chloro-3-(2-((5-oxo-4-azaspiro[2.5]octane-4-yl)methyl)imidazo[1,2-a]pyridin-7-yl)phenyl)piperidin-2,6-dione (compound 9)

[0252] Step 1: At 0 °C, NaBH4 (148 mg) was added in portions to a solution of 800 mg of 7-bromoimidazolo[1,2-a]pyridin-2-carboxaldehyde in EtOH (16.0 mL). The reaction mixture was stirred at 25 °C for 1 hour. The mixture was quenched with saturated NH4Cl solution (10 mL) and extracted with EtOAc (10 mL × 3). The combined organic phases were washed with brine (10.0 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give (7-bromoimidazolo[1,2-a]pyridin-2-yl)methanol (800 mg, 99.1% yield) as a yellow solid.

[0253] Step 2: At 0 °C, SOCl2 (419 mg) was added to a DCM (10.0 mL) solution of (7-bromoimidazolo[1,2-a]pyridin-2-yl)methanol (800 mg). The mixture was stirred at 20 °C for 1 hour. The mixture was quenched with saturated NH4Cl solution (10.0 mL) and extracted with EtOAc (10 mL × 3). The combined organic phases were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give 7-bromo-2-(chloromethyl)imidazolo[1,2-a]pyridine (800 mg, yield 92.49%) as a yellow solid. LCMS: Rt = 0.204 min, m / z = 244.9 [M+H] + .

[0254] Step 3: Under a nitrogen atmosphere at 0°C, NaH (78.2 mg, 60% mineral oil dispersion) was added in portions to a DMF (4.00 mL) solution of 224 mg azirospiro[2.5]octane-5-one. The mixture was stirred at 0°C under a nitrogen atmosphere for 0.5 h, followed by the addition of 400 mg 7-bromo-2-(chloromethyl)imidazo[1,2-a]pyridine in portions under a nitrogen atmosphere at 0°C. The resulting mixture was stirred at 25°C for 12 h. The reaction mixture was quenched with saturated NH4Cl solution (5 mL) and extracted with EtOAc (5.00 mL × 3). The combined organic phases were washed with brine (5.00 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: CD02-Waters Xbridge BEH C18 100 mm). 25mm 10 μm; mobile phase: [H2O (containing 10 mM NH4HCO3)-ACN]; gradient: ACN gradient 17%-47% over 13.0 min), yielding compound 4-((7-bromoimidazolo[1,2-a]pyridin-2-yl)methyl)-4-azaspiro[2.5]octane-5-one (250 mg, yield 45.9%), as a yellow solid. LCMS: Rt = 0.962 min, m / z = 334.0 [M+H] + Step 4: At 20°C and under a N2 atmosphere, Pd(dppf)Cl2 (21.9 mg) and K2CO3 (82.7 mg) were added to a solution of 1 mL of dioxane and 0.100 mL of (2-chloro-3-(2,6-dioxopiridin-3-yl)phenyl)boronic acid (80.0 mg) in 1 mL of dioxane and H2O. The mixture was stirred at 80°C for 1 hour under a N2 atmosphere. The reaction mixture was filtered to remove insoluble solids, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: CD02-Waters Xbridge BEH C18 100 mm). 25mm 10 μm; mobile phase: [H2O (containing 10 mMNH4HCO3)-ACN]; gradient: ACN gradient 17%-47% over 13.0 min), yielding compound 9 (46.0 mg, yield 32.0%, purity 99.3%), as an off-white solid. LCMS: Rt = 1.310 min, m / z = 477.1 M+H + . 1 H NMR (400 MHz, DMSO- d 6 ): d 10.93 (s, 1H), 8.52 (dd, J = 0.8, 7.2 Hz, 1H), 7.77 (s, 1H), 7.48(s, 1H), 7.45 - 7.38 (m, 3H), 6.92 (dd, J = 1.6, 7.2 Hz, 1H), 4.42 (s, 2H), 4.36 (dd, J = 5.2, 12.4 Hz, 1H), 2.86 - 2.75 (m, 1H), 2.57 (d, J = 3.6 Hz, 1H), 2.45 (t, J = 6.8 Hz, 2H), 2.39 - 2.30 (m, 1H), 2.11 - 2.02 (m, 1H), 1.84(q, J = 6.8 Hz, 2H), 1.70 - 1.64 (m, 2H), 1.09 - 1.03 (m, 2H), 0.63 - 0.57 (m, 2H).

[0255] Example 10: 3-(2-chloro-3-(3-((2-oxopiperidin-1-yl)methyl)imidazo[1,2-a]pyridin-7-yl)phenyl)piperidin-2,6-dione (Compound 10)

[0256] Step 1: At 0 °C, NaBH4 (148 mg) was added in portions to a solution of 800 mg of 7-bromoimidazolo[1,2-a]pyridin-3-carboxaldehyde in EtOH (16.0 mL). The reaction mixture was stirred at 20 °C for 1 hour, then quenched with saturated NH4Cl solution (10 mL) and extracted with EtOAc (10.0 mL × 3). The combined organic phases were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give (7-bromoimidazolo[1,2-a]pyridin-3-yl)methanol (800 mg, yield 99.1%) as a white solid.

[0257] Step 2: At 0 °C, SOCl2 (314 mg) was added to a DCM (10.0 mL) solution of (600 mg) of (7-bromoimidazolo[1,2-a]pyridin-3-yl)methanol. The mixture was stirred at 20 °C for 1 hour, then quenched with saturated NH4Cl solution (10.0 mL) and extracted with EtOAc (10.0 mL × 3). The combined organic phases were washed with brine (10.0 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give 7-bromo-3-(chloromethyl)imidazolo[1,2-a]pyridine (800 mg, yield 92.5%) as a yellow solid. LCMS: Rt = 0.205 min, m / z = 241.0 [M+H] + .

[0258] Step 3: NaH (489 mg, 60% purity) was added in portions to a DMF (12.0 mL) solution of piperidin-2-one (727 mg) under a N2 atmosphere. The mixture was stirred at 25 °C for 0.5 h under a N2 atmosphere, followed by the addition of 7-bromo-3-(chloromethyl)imidazo[1,2-a]pyridine (600 mg) in portions under a N2 atmosphere at 0 °C. The resulting mixture was stirred at 25 °C for 0.5 h, then quenched with saturated NH4Cl solution (10 mL) and extracted with EtOAc (10 mL × 3). The combined organic phases were washed with brine (5 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, dichloromethane / methanol gradient 0% to 10%) to give compound 1-((7-bromoimidazolo[1,2-a]pyridin-3-yl)methyl)piperidin-2-one (430 mg, yield 57.1%) as a yellow solid. LCMS: Rt = 0.230 min, m / z = 308.1 [M+H] + .

[0259] Step 4: At 20°C and under a N2 atmosphere, Pd(dppf)Cl2 (23.7 mg) and K2CO3 (89.7 mg) were added to a solution of 1-((7-bromoimidazolo[1,2-a]pyridin-3-yl)methyl)piperidin-2-one (100 mg) and (2-chloro-3-(2,6-dioxopiperidin-3-yl)phenyl)boronic acid (86.8 mg) in dioxane (1 mL) and H2O (0.100 mL). The mixture was stirred at 80°C for 1 hour under a N2 atmosphere. The reaction mixture was filtered to remove insoluble solids, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: CD07-Daisogel SP-100-8-ODS-PK 150 mm). 25mm 10 μm; mobile phase: [H₂O (containing 10 mM NH₄HCO₃)-ACN]; gradient: ACN gradient 15%-45% over 13.0 min), yielding compound 10 (46.4 mg, yield 31.7%, purity 100%), as an off-white solid. LCMS: Rt = 1.171 min, m / z = 451.0 [M+H] + . 1 H NMR (400 MHz, DMSO- d 6 ): d 10.94 (s, 1H), 8.60 (d, J = 7.2 Hz, 1H), 7.67 (s, 1H), 7.58 (d, J= 0.8 Hz,1H), 7.48 - 7.38 (m, 3H), 7.04 (dd, J = 1.6, 7.2 Hz, 1H), 4.90 (s, 2H), 4.37(dd, J = 4.8, 12.4 Hz, 1H), 3.23 (s, 2H), 2.80 (ddd, J = 5.2, 12.4, 17.6 Hz,1H), 2.60 - 2.55 (m, 1H), 2.37 - 2.27 (m, 3H), 2.11 - 2.01 (m, 1H), 1.68 (t, J = 3.2 Hz, 4H).

[0260] Example 11: 3-(2-chloro-3-(2-((2-oxopiperidin-1-yl)methyl)imidazo[1,2-a]pyridin-7-yl)phenyl)piperidin-2,6-dione (Compound 11)

[0261] Step 1: Under a nitrogen atmosphere at 0°C, NaH (78.2 mg, 60% mineral oil dispersion) was added in portions to a DMF (4.00 mL) solution of piperidin-2-one (178 mg). The mixture was stirred at 0°C under a nitrogen atmosphere for 0.5 h, followed by the addition of 7-bromo-2-(chloromethyl)imidazo[1,2-a]pyridine (400 mg) in portions under a nitrogen atmosphere at 25°C. The resulting mixture was stirred at 25°C for 0.5 h. The reaction mixture was quenched with saturated NH4Cl solution (10 mL) and extracted with EtOAc (10 mL × 3). The combined organic phases were washed with brine (5 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: CD02-WatersXbridge BEH C18 100 mm). 25mm 10 μm; mobile phase: [H2O (containing 10 mM NH4HCO3)-ACN]; gradient: ACN gradient 11%-45% over 13.0 min), yielding compound 1-((7-bromoimidazolo[1,2-a]pyridin-2-yl)methyl)piperidin-2-one (250 mg, yield 49.8%), as a yellow solid. LCMS: Rt = 0.825 min, m / z = 307.9 [M+H] + .

[0262] Step 2: Pd(dppf)Cl2 (23.7 mg) and K2CO3 (89.7 mg) were added to a solution of 1-((7-bromoimidazolo[1,2-a]pyridin-2-yl)methyl)piperidin-2-one (100 mg) and (2-chloro-3-(2,6-dioxopiperidin-3-yl)phenyl)boronic acid (86.8 mg) in H2O (0.100 mL) at 20 °C and under a N2 atmosphere. The mixture was stirred at 80 °C for 1 hour under a N2 atmosphere. The reaction mixture was filtered to remove insoluble solids, and the filtrate was concentrated. The residue was purified by preparative HPLC (column: CD02-Waters XbridgeBEH C18 100 mm). 25mm 10 μm; mobile phase: [H₂O (containing 10 mM NH₄HCO₃)-ACN]; gradient: ACN gradient of 11%-41% within 13.0 min), yielding compound 11 (52.0 mg, yield 35.0%, purity 98.4%), as a white solid. LCMS: Rt = 1.184 min, m / z = 451.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6): δ 10.93 (s, 1H), 8.59- 8.49 (m, 1H), 7.84 (s, 1H), 7.50 (s, 1H), 7.47 - 7.38 (m, 3H), 6.93 (dd, J =1.6, 7.2 Hz, 1H), 4.60 (s, 2H), 4.36 (dd, J = 5.2, 12.0 Hz, 1H), 3.40 - 3.35(m, 2H), 2.87 - 2.73 (m, 1H), 2.59 - 2.55 (m, 1H), 2.38 - 2.31 (m, 1H), 2.27(t, J = 6.0 Hz, 2H), 2.10 - 2.00 (m, 1H), 1.77 - 1.68 (m, 4H).

[0263] Example 12: 3-(2-chloro-3-(3-(5-oxo-4-azaspiro[2.5]octane-4-yl)imidazo[1,2-a]pyridin-7-yl)phenyl)piperidin-2,6-dione (compound 12)

[0264] Step 1: Under a nitrogen atmosphere at 20°C, bis[(Z)-1-methyl-3-oxobut-1-enoxy]copper (162.12 mg) was added to a solution of 7-bromo-3-ioimidazolo[1,2-a]pyridine (1.00 g), 4-azaspiro[2.5]octane-5-one (310 mg), and Cs₂CO₃ (3.03 g) in toluene (50 mL). The mixture was stirred at 120°C for 16 hours under a nitrogen atmosphere, then cooled to room temperature and quenched with H₂O (50 mL). The resulting mixture was extracted with EtOAc (20 mL × 4). The combined organic phases were washed with brine (20 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: CD02-Waters XbridgeBEH C18 100 mm). 25mm 10 μm; mobile phase: [H2O (containing 10 mM NH4HCO3)-ACN]; gradient: ACN gradient of 14%-48% within 13.0 min), yielding 4-(7-bromoimidazolo[1,2-a]pyridin-3-yl)-4-azaspiro[2.5]octane-5-one (130 mg, 406 μmol, yield 13.1%), as a green solid. LCMS: Rt = 0.460 min, m / z = 320.0 [M+H] + .

[0265] Step 2: Under a nitrogen atmosphere at 20°C, K₂CO₃ (69.1 mg) and Pd(dppf)Cl₂ (36.5 mg) were added to a solution of 4-(7-bromoimidazolo[1,2-a]pyridin-3-yl)-4-azaspiro[2.5]octane-5-one (80.0 mg) and (2-chloro-3-(2,6-dioxoperidin-3-yl)phenyl)boronic acid (66.8 mg) in dioxane (1 mL) and H₂O (0.1 mL). The mixture was stirred at 80°C for 1 hour under a nitrogen atmosphere, then diluted with H₂O (5 mL) and extracted with EtOAc (5 mL × 4). The combined organic phases were washed with brine (10 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: CD24-WePureBiotech XPT C18 150 mm). 25mm 7 μm; mobile phase: [H₂O (containing 10 mM NH₄HCO₃)-ACN]; gradient: ACN gradient 18%-48% over 12.0 min, yielding compound 12 (13.8 mg, yield 11.18%, purity 93.1%), as a white solid. LCMS: Rt = 0.31 min, m / z: 463.1 [M+H] + . 1 H NMR (400 MHz, DMSO- d 6): d 10.94 (s, 1H), 8.17 (d, J = 7.2 Hz, 1H), 7.59 (s, 1H), 7.50 (s, 1H), 7.47 - 7.41 (m, 3H), 7.03 (d, J = 7.2 Hz, 1H), 4.38 (dd, J = 4.8, 12.4 Hz, 1H), 2.86 - 2.56 (m,4H), 2.35 (dq, J = 36, 12.8 Hz, 1H), 2.21 (d, J = 7.6 Hz, 1H), 2.10 - 1.96(m, 3H), 1.77 (d, J = 5.2 Hz, 1H), 0.84 - 0.55 (m, 3H), 0.05 (s, 1H).

[0266] Example 13: 3-(2-chloro-3-(2-(2-oxopiperidin-1-yl)imidazo[1,2-a]pyridin-7-yl)phenyl)piperidin-2,6-dione (Compound 13)

[0267] Step 1: 4-Bromopyridin-2-amine (5 g) and 4-methylbenzenesulfonyl chloride (6.1 g) were dissolved in pyridine (100 mL) at 20 °C, and the mixture was heated at 80 °C for 4 hours. Pyridine was removed under reduced pressure. The residue was milled with EtOAc (100 mL) at 20 °C for 30 minutes to give N-(4-bromopyridin-2-yl)-4-methylbenzenesulfonamide (8 g, yield 84.6%) as an orange solid. LCMS: m / z = 326.7 [M+H] + . 1 H NMR (400 MHz, DMSO- d 6): d 7.99 (d, J= 5.6 Hz, 1H), 7.78 (d, J = 8.4Hz, 2H), 7.37 (d, J = 8.0 Hz, 2H), 7.27 - 7.26 (m, 1H), 7.18 - 7.14 (m, 1H), 2.35 (s, 3H).

[0268] Step 2: At 25 °C, DIEA (6.08 g) and 2-iodoacetamide (8.70 g) were added to a DMF (120 mL) solution of N-(4-bromopyridin-2-yl)-4-methylbenzenesulfonamide (7.00 g). The mixture was stirred at 25 °C for 16 hours, followed by concentration under reduced pressure. The residue was diluted with water (300 mL), and the precipitated solid was collected by filtration and washed with ethyl acetate (20 mL) to give (Z)-2-(4-bromo-2-(4-methylbenzenesulfonylimino)pyridin-1(2H)-yl)acetamide (5.70 g, yield 69.3%) as a red solid. LCMS: Rt = 0.368 min, m / z = 385.9 [M+H] + . 1 H NMR: (400 MHz, DMSO- d 6): d 7.97 (d, J = 7.2 Hz, 1H), 7.82 - 7.76 (m, 1H), 7.66 (d, J = 8.0 Hz, 2H), 7.52 (d, J =2.0 Hz, 1H), 7.39 (s, 1H), 7.30 (d, J = 8.0 Hz, 2H), 7.01 (dd, J = 2.0, 7.2Hz, 1H), 4.78 (s, 2H), 2.35 (s, 3H).

[0269] Step 3: At 20 °C, TFAA (120 mL) was added in portions to a DCM (120 mL) solution of (Z)-2-(4-bromo-2-(4-methylbenzenesulfonylimino)pyridin-1(2H)-yl)acetamide (5.70 g). The mixture was stirred at 50 °C for 2 hours. All volatile substances were removed under reduced pressure, and the residue was partitioned in ethyl acetate (200 mL) and saturated NaHCO3 solution (200 mL). The organic phase was washed with saturated NaHCO3 solution (200 mL) and brine (100 mL), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, hexane / ethyl acetate gradient 100% to 50%) to give N-(7-bromoimidazolo[1,2-a]pyridin-2-yl)-2,2,2-trifluoroacetamide (1.75 g, yield 38.3%) as a yellow solid. LCMS: Rt = 0.408 min, m / z = 307.9[M+H] + . 1 H NMR (400 MHz, DMSO- d 6): d 12.53 (s, 1H), 8.57 (dd, J = 0.8, 7.2 Hz,1H), 8.28 (s, 1H), 7.88 - 7.83 (m, 1H), 7.13 (dd, J = 2.0, 7.2 Hz, 1H).

[0270] Step 4: At 20 °C, K₂CO₃ (3.36 g) was added to a solution of N-(7-bromoimidazolo[1,2-a]pyridin-2-yl)-2,2,2-trifluoroacetamide (1.50 g) in MeOH (75.0 mL) and H₂O (45.0 mL). The mixture was stirred at 70 °C for 3 hours, then diluted with H₂O (50 mL) and extracted with EtOAc (100 mL × 3). The combined organic phases were washed with brine (100 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give 7-bromoimidazolo[1,2-a]pyridin-2-amine (1.00 g, yield 96.8%, as a yellow solid). LCMS: Rt = 0.144 min, m / z = 213.8 [M+H] + . 1 H NMR (400 MHz, DMSO- d 6): d 8.24 (d, J = 7.2 Hz, 1H), 7.42 (d, J= 1.6 Hz, 1H), 7.01 (s, 1H), 6.84 (dd, J = 2.0, 7.2 Hz, 1H), 5.21 (s, 2H).

[0271] Step 5: TEA (286 mg) was added to a DCM (4 mL) solution of 200 mg 7-bromoimidazolo[1,2-a]pyridin-2-amine and 225 mg 5-bromopentanoyl chloride (225 mg). The mixture was stirred at 20 °C for 3 h, then diluted with 10 mL H₂O and extracted with EtOAc (5 mL × 4). The combined organic phases were washed with 10 mL brine, dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, hexane / ethyl acetate gradient 100% to 50%) to give 5-bromo-N-(7-bromoimidazolo[1,2-a]pyridin-2-yl)pentanoamide (200 mg, yield 56.5%) as an off-white solid. LCMS: Rt = 0.405 min, m / z = 373.8 [M+H] + .

[0272] Step 6: Under a nitrogen atmosphere at 0°C, 31.9 mg of NaH (60.0% in mineral oil) was added to a THF (13.0 mL) solution of 200 mg of 5-bromo-N-(7-bromoimidazolo[1,2-a]pyridin-2-yl)pentanamide. The mixture was stirred at 20°C for 1 hour under a nitrogen atmosphere, then quenched with 20.0 mL of saturated NH4Cl solution and extracted with EtOAc (10 mL × 4). The combined organic phases were washed with 20 mL of brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, hexane / ethyl acetate gradient 100% to 50%) to give 1-(7-bromoimidazolo[1,2-a]pyridin-2-yl)piperidin-2-one (140 mg, 89.2% yield) as a pale yellow solid. LCMS: Rt = 0.502 min, m / z = 293.8 [M+H] + .

[0273] Step 7: Under a nitrogen atmosphere at 20°C, K₂CO₃ (93.9 mg) and Pd(dppf)Cl₂ (49.7 mg) were added to a solution of 1-(7-bromoimidazolo[1,2-a]pyridin-2-yl)piperidin-2-one (100 mg) and (2-chloro-3-(2,6-dioxopiperidin-3-yl)phenyl)boronic acid (90.9 mg) in dioxane (2.00 mL) and H₂O (0.2 mL). The mixture was stirred at 80°C for 2 hours under a nitrogen atmosphere, then diluted with H₂O (5 mL) and extracted with EtOAc (5 mL × 4). The combined organic phases were washed with brine (10 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by prep-HPLC (column: CD24-WePure Biotech XPTC18 150 mm). 25mm 7 μm; mobile phase: [H2O (containing 10 mM NH4HCO3)-ACN]; gradient: ACN content 19%-39% within 15.0 min), yielding compound 13 (47.04 mg, yield 30.28%, purity 95.6%), as an off-white solid. LCMS: Rt = 1.797 min, m / z: 437.1 [M+H] + . 1 H NMR (400 MHz, DMSO- d 6): d 10.94 (s, 1H), 8.64 (dd, J = 0.8, 6.8 Hz, 1H), 8.42 (s, 1H), 7.52 - 7.49 (m, 1H), 7.46 - 7.39 (m,3H), 6.97 (dd, J = 1.6, 7.2 Hz, 1H), 4.38 (dd, J = 4.8, 12.0 Hz, 1H), 4.05(t, J = 6.0 Hz, 2H), 2.87 - 2.74 (m, 1H), 2.60 - 2.53 (m, 3H), 2.41 - 2.30(m, 1H), 2.11 - 2.02 (m, 1H), 1.96 - 1.88 (m, 2H), 1.86 - 1.79 (m, 2H).

[0274] Example 14: 3-(2-chloro-3-(3-(2-oxopiperidin-1-yl)imidazo[1,2-a]pyridin-7-yl)phenyl)piperidin-2,6-dione (compound 14)

[0275] Step 1: CuI (117 mg) was added to a solution of 7-bromo-3-iodoimidazolo[1,2-a]pyridine (1.00 g), piperidin-2-one (460 mg), (1R,2R)-N1,N2-dimethylcyclohexane-1,2-diamine (352 mg), and Cs2CO3 (2.02 g) in dioxane (10 mL) at 20 °C under N2 atmosphere. The mixture was stirred at 80 °C for 16 hours under N2 atmosphere, then diluted with H2O (10 mL) and extracted with EtOAc (10 mL × 4). The combined organic phases were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by prep-HPLC (column: CD05-Phenomenex Luna C18 100). 40mm 10 μm; mobile phase: [H₂O (containing 0.225% FA)-ACN]; gradient: ACN content 0%-29% over 13.0 min), yielding 1-(7-bromoimidazolo[1,2-a]pyridin-3-yl)piperidin-2-one (280 mg, 951 μmol, yield 30.7%), as a white solid. LCMS: Rt = 0.212 min, m / z = 293.8 [M+H] + .

[0276] Step 2: 20℃, N 2. Under N2 atmosphere, K2CO3 (93.9 mg) and Pd(dppf)Cl2 (49.7 mg) were added to a solution of 1-(7-bromoimidazolo[1,2-a]pyridin-3-yl)piperidin-2-one (100 mg) and (2-chloro-3-(2,6-dioxopiperidin-3-yl)phenyl)boronic acid (90.9 mg) in dioxane (1 mL) and H2O (0.1 mL). The mixture was stirred at 80 °C for 1 hour under N2 atmosphere, then diluted with H2O (5 mL) and extracted with EtOAc (5 mL × 4). The combined organic phases were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by prep-HPLC (column: CD24-WePure Biotech XPT C18 150 mm). 25mm 7 μm; mobile phase: [H2O (containing 10 mM NH4HCO3)-ACN]; gradient: ACN content 14%-44% within 12.0 min), yielding compound 14 (46.3 mg, yield 29.8%, purity 95.8%), a white solid. LCMS: Rt = 1.628 min, m / z: 437.1 [M+H] + . 1 H NMR (400 MHz, DMSO- d 6): d 10.94 (s, 1H), 8.10 - 8.06 (m, 1H), 7.61 - 7.57 (m, 2H), 7.47 - 7.40 (m, 3H), 7.00 (dd, J = 1.6, 7.2 Hz, 1H), 4.38 (dd, J = 4.8, 12.0 Hz, 1H), 3.70 (t, J = 5.2 Hz, 2H), 2.86 - 2.74(m, 1H), 2.60 - 2.52 (m, 3H), 2.35 (dd, J = 4.4, 12.8 Hz, 1H), 2.13 - 2.02 (m, 1H), 1.99 - 1.90 (m, 4H).

[0277] Example 15: 3-(3-(1-benzyl-2-oxo-1,2-dihydropyridin-4-yl)-2-chlorophenyl)piperidin-2,6-dione (Compound 15)

[0278] Step 1: At 20 °C, Cs₂CO₃ (5.62 g) was added to a DMF (15 mL) solution of 4-bromopyridin-2(1H)-one (1.00 g) and bromomethylbenzene (2.95 g). The mixture was stirred at 20 °C for 12 hours. After the reaction was complete, the mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL × 3). The combined organic phases were washed with brine (50 mL), dried over Na₂SO₄, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate gradient 10:1 to 5:1) to give 1-benzyl-4-bromopyridin-2(1H)-one (1.20 g, yield 79.0%) as a white solid. LC-MS: Rt = 0.428 min, m / z = 266.0 [M+H] + . 1H NMR (400 MHz, CDCl3- d ): d 7.40 - 7.28 (m, 5H), 7.12 (d, J = 7.2 Hz, 1H), 6.87 (d, J = 2.0 Hz, 1H), 6.31 (dd, J = 2.0, 7.2 Hz, 1H), 5.10 (s, 2H).

[0279] Step 2: N 2. Under a nitrogen atmosphere at 20°C, Pd(dppf)Cl2 (27.7 mg) and K2CO3 (104 mg) were added to a solution of 1-benzyl-4-bromopyridin-2(1H)-one (100 mg) and (2-chloro-3-(2,6-dioxopiridin-3-yl)phenyl)boronic acid (101 mg) in dioxane (1 mL) and H2O (0.1 mL). The mixture was stirred at 80°C for 1 hour under a nitrogen atmosphere. After the reaction was complete, the reaction mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (column: CD19-Daisogel SP-100-8-ODS-PK 200). 50 10 μm; mobile phase: [H₂O (containing 10 mM NH₄OAc)-ACN]; gradient: ACN content 21%-51% within 10.0 min), yielding compound 15 (56.67 mg, yield 36.1%, purity 98.2%), as a white solid. LC-MS: Rt = 1.808 min, m / z = 407.0 [M+H] + . 1 H NMR (400 MHz, DMSO- d 6): d 10.99 - 10.88 (m, 1H), 7.87 (d, J =7.2 Hz, 1H), 7.43 - 7.40 (m, 2H), 7.39 - 7.28 (m, 6H), 6.40 (d, J = 1.6 Hz, 1H), 6.31 (dd, J = 1.8, 6.8 Hz, 1H), 5.14 (s, 2H), 4.34 (dd, J = 5.2, 12.4Hz, 1H), 2.84 - 2.73 (m, 1H), 2.55 (d, J= 3.6 Hz, 1H), 2.32 (dq, J = 4.0,12.8 Hz, 1H), 2.06 - 1.99 (m, 1H).

[0280] Example 16: 3-(3-(2-(benzyloxy)pyridin-4-yl)-2-chlorophenyl)piperidin-2,6-dione (Compound 16)

[0281] Step 1: t-BuOK (1 M, 5.68 mL) was added to a THF (10 mL) solution of 4-bromo-2-fluoropyridine (1.00 g) and benzyl alcohol (614 mg) under a N2 atmosphere at 0 °C. The mixture was stirred at 20 °C for 12 hours. After the reaction was complete, the reaction mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL × 3). The combined organic phases were washed with brine (50 mL), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate gradient 10:1 to 5:1) to give 2-(benzyloxy)-4-bromopyridine (1.60 g, yield 74.6%, purity 70%) as a colorless oil. LC-MS: Rt = 0.621 min, m / z = 264.0 [M+H] + . 1 H NMR (400 MHz, CDCl3- d ): d 8.01 (d, J = 5.6 Hz, 1H), 7.48 -7.43 (m, 2H), 7.42 - 7.33 (m, 3H), 7.09 - 7.01 (m, 2H), 5.38 (s, 2H).

[0282] Step 2: 20℃, N 2. Under N2 atmosphere, Pd(dppf)Cl2 (27.70 mg) and K2CO3 (104.65 mg) were added to a solution of 2-(benzyloxy)-4-bromopyridine (100 mg) and (2-chloro-3-(2,6-dioxopiridin-3-yl)phenyl)boronic acid (101 mg) in dioxane (1 mL) and H2O (0.1 mL). The mixture was stirred at 80 °C for 1 hour under N2 atmosphere. After the reaction was completed, the reaction mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (column: CD19-Daisogel SP-100-8-ODS-PK 200). 50 10 μm; mobile phase: [H₂O (containing 10 mM NH₄OAc)-ACN]; gradient: ACN content 38%-68% within 10.0 min), yielding compound 16 (38.01 mg, yield 22.95%, purity 93.0%), as a white solid. LC-MS: Rt = 2.584 min, m / z = 407.0 [M+H] + . 1 H NMR (400 MHz, DMSO- d 6): d 10.93 (s, 1H), 8.26 (d, J = 5.4 Hz, 1H),7.52 - 7.29 (m, 8H), 7.06 (dd, J = 1.2, 5.2 Hz, 1H), 6.90 (d, J = 0.6 Hz,1H), 5.40 (s, 2H), 4.35 (dd, J = 4.8, 12.0 Hz, 1H), 2.85 - 2.74 (m, 1H), 2.56(d, J = 3.6 Hz, 1H), 2.36 - 2.30 (m, 1H), 2.10 - 2.00 (m, 1H).

[0283] Example 17: 3-(2-chloro-3-(2-oxo-1-(thiophen-3-ylmethyl)-1,2-dihydropyridin-4-yl)phenyl)piperidin-2,6-dione (Compound 17)

[0284] Step 1: At 20 °C, 1.97 g of Cs₂CO₃ was added to a DMF (5 mL) solution of 0.35 g of 4-bromopyridin-2(1H)-one and 1.07 g of 3-(bromomethyl)thiophene. The mixture was stirred at 20 °C for 12 hours. After the reaction was complete, the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (20 mL × 3). The combined organic phases were washed with brine (20 mL), dried over Na₂SO₄, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate gradient 20:1 to 5:1) to give 4-bromo-1-(thiophene-3-ylmethyl)pyridin-2(1H)-one (400 mg, yield 73.6%) as a white solid. LC-MS: Rt = 0.412 min, m / z = 270.0 [M+H] + . 1H NMR (400 MHz, CDCl3- d ): d 7.33 (dd, J = 2.8, 4.8 Hz,1H), 7.26 - 7.24 (m, 1H), 7.13 (d, J = 7.2 Hz, 1H), 7.05 (dd, J = 1.2, 4.8Hz, 1H), 6.86 (d, J = 2.0 Hz, 1H), 6.31 (dd, J = 2.0, 7.2 Hz, 1H), 5.09 (s, 2H).

[0285] Step 2: Under a nitrogen atmosphere at 20°C, Pd(dppf)Cl2 (27.1 mg) and K2CO3 (102 mg) were added to a solution of 100 mg 4-bromo-1-(thiophene-3-ylmethyl)pyridin-2(1H)-one and 99.0 mg (2-chloro-3-(2,6-dioxopiridin-3-yl)phenyl)boronic acid in H2O (0.1 mL). The mixture was stirred at 80°C for 1 hour under a nitrogen atmosphere. After the reaction was complete, the reaction mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (column: CD20-Waters Xbidge BEH C18 250). 25 10 μm; mobile phase: [H2O (containing 10 mM NH4HCO3)-ACN]; gradient: ACN content 20%-50% within 11.0 min), yielding compound 17 (55.63 mg, yield 36.1%, purity 99.2%), as a white solid. LC-MS: Rt = 1.864 min, m / z = 413.0 [M+H] + . 1 H NMR (400 MHz, DMSO- d 6): d 10.93 (s, 1H), 7.85 (d, J = 7.2 Hz, 1H), 7.53 (dd, J = 3.2, 4.8 Hz, 1H), 7.50 (d, J = 1.6 Hz, 1H), 7.41 (d, J = 4.8 Hz,2H), 7.37 - 7.31 (m, 1H), 7.16 (dd, J= 1.2, 4.8 Hz, 1H), 6.39 (d, J = 1.6Hz, 1H), 6.29 (dd, J = 1.8, 7.2 Hz, 1H), 5.11 (s, 2H), 4.34 (dd, J = 5.2,12.4 Hz, 1H), 2.84 - 2.73 (m, 1H), 2.57 - 2.54 (m, 1H), 2.32 (dq, J = 4.2,12.8 Hz, 1H), 2.07 - 1.98 (m, 1H).

[0286] Example 18: 3-(2-chloro-3-(2-(pyridin-3-yloxy)pyridin-4-yl)phenyl)piperidin-2,6-dione (Compound 18)

[0287] Step 1: At 20 °C, Cs₂CO₃ (3.70 g) was added to a DMF (10 mL) solution of pyridine-3-ol (540 mg) and 4-bromo-2-fluoropyridine (1.00 g). The mixture was stirred at 80 °C for 12 hours. After the reaction was complete, the reaction mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL × 3). The combined organic phases were washed with brine (50 mL × 3), dried over Na₂SO₄, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate gradient 10:1 to 5:1) to give 4-bromo-2-(pyridin-3-yloxy)pyridine (370 mg, 1.47 mmol, yield 25.9%) as a colorless oil. LC-MS: Rt = 0.326 min, m / z = 251.0 [M+H] + .

[0288] Step 2: Under a nitrogen atmosphere at 20°C, Pd(dppf)Cl2 (23.3 mg) and K2CO3 (88.07 mg) were added to a solution of 4-bromo-2-(pyridin-3-yloxy)pyridine (80.0 mg) and (2-chloro-3-(2,6-dioxopiridin-3-yl)phenyl)boronic acid (85.2 mg) in H2O (0.1 mL) and dioxane (2 mL). The mixture was stirred at 80°C for 1 hour. After the reaction was complete, the reaction mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (column: CD19-Daisogel SP-100-8-ODS-PK 200). 50 10 μm; mobile phase: [H₂O (containing 10 mM NH₄OAc)-ACN]; gradient: ACN content 20%-50% within 10.0 min), yielding compound 18 (51.76 mg, yield 40.8%, purity 99.0%), as a white solid. LC-MS: Rt = 1.863 min, m / z = 394.4 [M+H] + . 1 H NMR (400 MHz, DMSO- d 6): d 11.10 - 10.75 (m, 1H), 8.51 (d, J =2.4 Hz, 1H), 8.46 (dd, J = 1.2, 4.6 Hz, 1H), 8.22 (d, J = 5.6 Hz, 1H), 7.69 (dd, J = 1.2, 2.6 Hz, 1H), 7.52 - 7.49 (m, 1H), 7.48 - 7.47 (m, 1H), 7.47 -7.46 (m, 1H), 7.43 - 7.40 (m, 1H), 7.24 (dd, J = 1.2, 5.2 Hz, 1H), 7.19 (d, J = 0.4 Hz, 1H), 4.38 (dd, J = 5.2, 12.4 Hz, 1H), 2.86 - 2.75 (m, 1H), 2.59 -2.56 (m, 1H), 2.36 - 2.29 (m, 1H), 2.10 - 2.01 (m, 1H).

[0289] Example 19: 3-(2-chloro-3-(1-(furan-3-ylmethyl)-2-oxo-1,2-dihydropyridin-4-yl)phenyl)piperidin-2,6-dione (Compound 19)

[0290] Step 1: SOCl2 (1.21 g) was added to a DCM (10.0 mL) solution of furan-3-ylmethanol (1.00 g) at 0 °C. The mixture was stirred at 20 °C for 2 hours, and then concentrated to give compound 3-(chloromethyl)furan (1.00 g, yield 84.2%) as a dark brown oil.

[0291] Step 2: Cs₂CO₃ (14.0 g) was added to a DMF (10.0 mL) solution of 3-(chloromethyl)furan (1.00 g) and 4-bromopyridin-2(1H)-one (1.49 g) at 20 °C. The mixture was stirred at 80 °C for 12 h, followed by filtration to remove insoluble solids. The filtrate was diluted with H₂O (10 mL) and extracted with EtOAc (10 mL × 3). The combined organic phases were washed with brine (10 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, hexane / ethyl acetate gradient 100% to 50%) to give 4-bromo-1-(furan-3-ylmethyl)pyridin-2(1H)-one (900 mg, yield 41.3%) as a yellow solid. LCMS: Rt = 0.377 min, m / z = 254.0 [M+H] + . 1 H NMR (400 MHz, DMSO- d 6 ): d 7.74 (d, J = 7.2 Hz, 1H), 7.67 (dd, J = 0.8, 1.6 Hz, 1H), 7.61 (t, J = 1.6 Hz, 1H), 6.73(d, J = 2.0 Hz, 1H), 6.49 - 6.45 (m, 2H), 4.89 (s, 2H).

[0292] Step 3: Under a nitrogen atmosphere at 20°C, Pd(dppf)Cl2 (28.8 mg) and K2CO3 (109 mg) were added to a solution of 100 mg 4-bromo-1-(furan-3-ylmethyl)pyridin-2(1H)-one and 105 mg (2-chloro-3-(2,6-dioxopiridin-3-yl)phenyl)boronic acid in H2O (0.100 mL). The mixture was stirred at 80°C for 1 hour under a nitrogen atmosphere, followed by filtration to remove insoluble solids. The filtrate was concentrated, and the residue was purified by prep-HPLC (column: CD24-WePure Biotech XPT C18 150 mm). 25mm 7 μm; mobile phase: [H₂O (containing 0.225% FA)-ACN]; gradient: ACN content 22%-42% within 10.0 min), yielding compound 19 (0.02604 g, yield 14.7%, purity 98.5%, FA), a white solid. LCMS: Rt = 1.620 min, m / z = 397.1 [M+H] + . 1 H NMR (400 MHz, DMSO- d 6 ): d 10.93 (s, 1H), 7.81 (d, J = 7.2 Hz, 1H), 7.74 (d, J = 0.8 Hz, 1H), 7.64 (t, J = 1.6 Hz, 1H), 7.41 (d, J = 4.8 Hz,2H), 7.36 - 7.31 (m, 1H), 6.54 (d, J = 1.2 Hz, 1H), 6.38 (d, J = 2.0 Hz, 1H), 6.28 (dd, J = 2.0, 7.2 Hz, 1H), 4.96 (s, 2H), 4.34 (dd, J = 5.2, 12.0 Hz,1H), 2.84 - 2.74 (m, 1H), 2.55 (d, J = 4.0 Hz, 1H), 2.32 (dd, J = 4.0, 12.8Hz, 1H), 2.10 - 1.95 (m, 1H).

[0293] Example 20: 3-(2-chloro-3-(2-oxo-1-(pyridin-3-ylmethyl)-1,2-dihydropyridin-4-yl)phenyl)piperidin-2,6-dione (Compound 20)

[0294] Step 1: At 20 °C, Cs₂CO₃ (3.75 g) was added to a DMF (10.0 mL) solution of 4-bromopyridin-2(1H)-one (1.00 g) and 3-(bromomethyl)pyridine (989 mg). The mixture was stirred at 80 °C for 12 hours, followed by filtration to remove insoluble solids. The filtrate was diluted with H₂O (10.0 mL) and extracted with EtOAc (10 mL × 3). The combined organic phases were washed with brine (5 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, hexane / ethyl acetate gradient 100% to 0%) to give 4-bromo-1-(pyridin-3-ylmethyl)pyridin-2(1H)-one (600 mg, yield 39.4%) as a yellow solid. LCMS: Rt = 0.216 min, m / z = 266.9 [M+H] + . 1 H NMR (400 MHz, DMSO- d 6 ): d 8.56 (d, J = 2.0 Hz, 1H), 8.49 (dd, J = 1.6, 4.8 Hz, 1H), 7.89 (d, J = 7.2 Hz, 1H), 7.69 (td, J = 2.0, 8.0 Hz, 1H), 7.37 (dd, J = 4.4, 7.6 Hz, 1H), 6.76 (d, J =2.0 Hz, 1H), 6.53 (dd, J = 2.0, 7.2 Hz, 1H), 5.10 (s, 2H).

[0295] Step 2: Under a nitrogen atmosphere at 20°C, Pd(dppf)Cl2 (27.6 mg) and K2CO3 (104 mg) were added to a solution of 100 mg of 4-bromo-1-(pyridin-3-ylmethyl)pyridin-2(1H)-one and 100 mg of (2-chloro-3-(2,6-dioxopiridin-3-yl)phenyl)boronic acid in H2O (0.100 mL). The mixture was stirred at 80°C for 1 hour under a nitrogen atmosphere, followed by filtration to remove insoluble solids. The filtrate was concentrated under reduced pressure, and the residue was purified by prep-HPLC (column: CD07-Daisogel SP-100-8-ODS-PK150mm). 25mm 10 μm; mobile phase: [H₂O (containing 10 mM NH₄HCO₃)-ACN]; gradient: ACN content 10%-40% within 13.0 min), yielding compound 20 (0.04203 g, yield 26.9%, purity 98.6%), a white solid. LCMS: Rt = 1.058 min, m / z = 408.0 [M+H] + . 1 H NMR (400 MHz, DMSO- d 6 ): d 10.93 (s, 1H), 8.64 (d, J =12.0 Hz, 1H), 8.52 (dd, J = 1.6, 4.8 Hz, 1H), 7.96 (d, J = 7.2 Hz, 1H), 7.79(td, J = 2.0, 7.8 Hz, 1H), 7.43 - 7.38 (m, 3H), 7.37 - 7.33 (m, 1H), 6.41 (d, J = 2.0 Hz, 1H), 6.33 (dd, J = 2.0, 7.2 Hz, 1H), 5.17 (s, 2H), 4.34 (dd, J =5.2, 12.4 Hz, 1H), 2.84 - 2.74 (m, 1H), 2.55 (d, J = 3.6 Hz, 1H), 2.37 - 2.27 (m, 1H), 2.08 - 1.98 (m, 1H).

[0296] Example 21: 3-(4'-amino-2-chloro-3'-(2-(pyridin-3-yl)ethyl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione (Compound 21)

[0297] Step 1: TEA (339 mg) and Pd(OAc)₂ (3.77 mg) were added to a mixture of 4-bromo-2-iodoaniline (500 mg) and 3-vinylpyridine (264 mg) in MeCN (5 mL) at 20 °C under a N₂ atmosphere. The mixture was stirred at 90 °C for 7 hours under a N₂ atmosphere. After the reaction was complete, the reaction mixture was concentrated under reduced pressure. The residue was then diluted with water (20 mL) and extracted with DCM (3 × 20 mL). The organic phase was washed with brine (10 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, hexane / ethyl acetate gradient 100% to 33%) to give (E)-4-bromo-2-(2-(pyridin-3-yl)vinyl)aniline (350 mg, yield 75.7%) as a green solid. LCMS: Rt = 0.327 min, m / z = 274.9 [M+H] + .

[0298] Step 2: A THF (17.5 mL) solution of 0.35 g of 4-bromo-2-[(E)-2-(3-pyridyl)vinyl]aniline was pumped through a fixed bed (FLR1, 6.350 (1 / 4'') mm, 35 °C, 5 mL volume) completely packed with particulate catalyst Pt / C (1%, 248 mg) at a flow rate of 0.301 mL / min. The H2 back pressure was adjusted to 0.6 MPa, and the H2 flow rate was 30 mL / min. The reaction mixture was then collected from the reactor outlet, and the fixed bed was washed with THF (200 mL). The resulting mixtures were combined and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, hexane / ethyl acetate gradient 100% to 33%) to give 4-bromo-2-(2-(pyridyl-3-yl)ethyl)aniline (50.0 mg, 180 μmol, yield 14.1%) as a colorless solid. LCMS: Rt = 0.297 min, m / z = 276.9[M+H] + .

[0299] Step 3: Under a nitrogen atmosphere at 20 °C, K₂CO₃ (49.8 mg) and Pd(dppf)Cl₂ (49.8 mg) were added to a solution of 4-bromo-2-[2-(3-pyridyl)ethyl]aniline (50.0 mg) and 3-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborpentan-2-yl)phenyl)piperidine-2,6-dione (94.1 mg) in dioxane (1 mL) and H₂O (0.1 mL). The mixture was stirred at 80 °C for 1 hour under a nitrogen atmosphere, then diluted with H₂O (5 mL) and extracted with EtOAc (5 mL × 4). The combined organic phases were washed with brine (10 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by prep-HPLC (column: CD24-WePure Biotech XPT C18 150 mm). 25mm 7 μm; mobile phase: [H2O (containing 10 mM NH4HCO3)-ACN]; gradient: ACN content 21%-51% within 12.0 min), yielding compound 21 (43.0 mg, yield 56.3%, purity 99.1%), as a white solid. LCMS: Rt = 1.925 min, m / z: 420.2 [M+H] + . 1 H NMR (400 MHz, DMSO- d 6): d 10.89 (s, 1H), 8.48 (d, J = 1.6 Hz, 1H), 8.38 (dd, J = 1.6, 4.8 Hz, 1H), 7.73 - 7.67(m, 1H), 7.33 - 7.27 (m, 2H), 7.25 - 7.21 (m, 1H), 7.17 (dd, J = 1.6, 7.6 Hz,1H), 6.99 - 6.93 (m, 2H), 6.69 (d, J = 8.0 Hz, 1H), 5.16 (s, 2H), 4.30 (dd, J = 5.2, 12.0 Hz, 1H), 2.89 - 2.83 (m, 2H), 2.81 - 2.72 (m, 3H), 2.54 (d, J =3.6 Hz, 1H), 2.36 - 2.26 (m, 1H), 2.07 - 1.98 (m, 1H).

[0300] Example 22: 3-(3'-((1H-pyrazol-1-yl)methyl)-2-chloro-4'-methyl-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione (Compound 22)

[0301] Step 1: At 0 °C, PBr3 (660 mg) was added to a THF (10 mL) solution of (5-bromo-2-methylphenyl)methanol (1.00 g). The mixture was stirred at 0 °C for 2 hours. After the reaction was complete, the reaction mixture was quenched with saturated NaHCO3 solution (50 mL) and extracted with EtOAc (50 mL × 3). The combined organic phases were washed with brine (50 mL × 3), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate gradient 1:0 to 20:1) to give compound 4-bromo-2-(bromomethyl)-1-methylbenzene (1.00 g, yield 83%) as a white solid.

[0302] Step 2: At 20 °C, Cs₂CO₃ (555 mg) was added to a DMF (1 mL) solution of 4-bromo-2-(bromomethyl)-1-methylbenzene (300 mg) and 1H-pyrazole (77.3 mg). The mixture was stirred at 80 °C for 1.5 h. After the reaction was complete, the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (20 mL × 3). The combined organic phases were washed with brine (20 mL × 3), dried over Na₂SO₄, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate gradient 5:1 to 1:1) to give 1-(5-bromo-2-methylbenzyl)-1H-pyrazole (0.24 g, yield 84.0%) as a colorless oil. LC-MS: m / z = 253.1 [M+H] + . 1 H NMR (400 MHz, DMSO- d 6): d 7.80 (d, J = 2.0 Hz, 1H), 7.50 (d, J = 1.2Hz, 1H), 7.38 (dd, J = 2.0, 8.0 Hz, 1H), 7.16 (d, J = 8.0 Hz, 1H), 6.97 (d, J = 2.0 Hz, 1H), 6.30 (t, J= 2.0 Hz, 1H), 5.35 (s, 2H), 2.25 (s, 3H).

[0303] Step 3: Under a nitrogen atmosphere (N2), Pd(dppf)Cl2 (29.14 mg) and K2CO3 (110.07 mg) were added to a solution of 1-(5-bromo-2-methylbenzyl)-1H-pyrazole (100 mg) and 3-[2-chloro-3-(2-chloro-3-(2,6-dioxopiperidin-3-yl)phenyl)boronic acid (208 mg) in dioxane (2 mL) and H2O (0.1 mL). The mixture was stirred at 80 °C for 2 hours under a nitrogen atmosphere. After the reaction was complete, the reaction mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (column: CD19-Daisogel SP-100-8-ODS-PK 200). 50 10 μm; mobile phase: [H₂O (containing 10 mM NH₄HCO₃)-ACN]; gradient: ACN content 29%-59% within 11.0 min), yielding compound 22 (42.83 mg, yield 26.7%, purity 97.8%) as a white solid. LC-MS: Rt = 2.073 min, m / z = 394.1 [M+H] + . 1 H NMR: (400 MHz, DMSO- d 6): d 10.91 (s, 1H), 7.77 (d, J = 2.0 Hz, 1H), 7.46 (d, J = 1.2 Hz, 1H), 7.39 - 7.30 (m, 2H), 7.29 -7.17 (m, 3H), 6.91 (s, 1H), 6.26 (t, J = 1.8 Hz, 1H), 5.40 (s, 2H), 4.31 (dd, J = 4.8, 12.0 Hz, 1H), 2.82 - 2.72 (m, 1H), 2.54 (d, J = 3.6 Hz, 1H), 2.38 -2.33 (m, 3H), 2.33 - 2.24 (m, 1H), 2.06 - 1.97 (m, 1H).

[0304] Example 23: 3-(2-chloro-4'-hydroxy-3'-(pyridin-3-ylethynyl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione (Compound 23)

[0305] Step 1: At 25 °C, Pd(PPh3)2Cl2 (449 mg) and CuI (122 mg) were added to a solution of 4-bromo-2-iodo-1-methoxybenzene (1.00 g) and 3-ethynylpyridine (494 mg) in THF (5.00 mL) and TEA (5.00 mL). The mixture was degassed and purged three times with N2, and the resulting mixture was stirred at 25 °C for 12 hours under N2 atmosphere. The reaction mixture was filtered to remove insoluble solids. The filtrate was diluted with H2O (10 mL) and extracted with EtOAc (10 mL × 3). The combined organic phases were washed with brine (5 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, hexane / ethyl acetate gradient 100% to 0%) to give compound 3-((5-bromo-2-methoxyphenyl)ethynyl)pyridine (900 mg, yield 97.7%) as a yellow solid. LCMS: Rt = 0.470 min, m / z = 288.1[M+H] + . LCMS: Rt = 0.470 min, m / z = 288.1, [M+H] + . 1 H NMR (400 MHz, DMSO- d 6 ): d 8.73 (dd, J = 0.8, 2.0 Hz, 1H), 8.59 (dd, J= 1.6, 4.8 Hz, 1H), 7.95 (td, J = 2.0, 8.0 Hz, 1H), 7.70 (d, J = 2.4 Hz, 1H), 7.59 (dd, J = 2.4, 8.8 Hz, 1H), 7.47 (ddd, J = 0.8, 4.8, 8.0 Hz, 1H), 7.09 (d, J = 9.2 Hz, 1H), 3.87 (s, 3H).

[0306] Step 2: 20℃, N 2.Under a nitrogen atmosphere, Pd(dppf)Cl2 (50.8 mg) and K2CO3 (192 mg) were added to a solution of 3-((5-bromo-2-methoxyphenyl)ethynyl)pyridine (200 mg) and (2-chloro-3-(2,6-dioxopiperidin-3-yl)phenyl)boronic acid (364 mg) in H2O (0.100 mL). The mixture was stirred at 80 °C for 1 hour under a nitrogen atmosphere, followed by filtration to remove insoluble solids. The filtrate was diluted with H2O (10 mL) and extracted with EtOAc (10 mL × 3). The combined organic phases were washed with brine (5 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, hexane / ethyl acetate gradient from 100% to 0%) to give 3-(2-chloro-4'-methoxy-3'-(pyridin-3-ylethynyl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione (240 mg, 80.3% yield) as a yellow solid. LCMS: m / z = 431.0 [M+H] + .

[0307] Step 3: At 0 °C, BBr3 (1.00 M, 348 μL) was added to a DCM (2.00 mL) solution of 100 mg of 3-(2-chloro-4'-methoxy-3'-(pyridin-3-ylethynyl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione. The mixture was stirred at 0 °C for 1 hour. The reaction mixture was diluted with H2O (5 mL) and extracted with DCM (5 mL × 3). The combined organic phases were washed with brine (5 mL × 2), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by prep-HPLC (column: CD07-Daisogel SP-100-8-ODS-PK 150 mm). 25mm 10 μm; mobile phase: [H2O (containing 10 mM NH4HCO3)-ACN]; gradient: ACN content 22%-52% within 13.0 min), yielding compound 23 (0.00925 g, yield 9.56%, purity 100%), as an off-white solid. LCMS: Rt = 1.566 min, m / z = 417.0 [M+H] + . 1 H NMR (400 MHz, DMSO- d 6 ): d 11.00 - 10.86 (m, 1H), 10.50 - 9.96 (m, 1H), 8.72 (d, J= 1.6 Hz, 1H), 8.57 (dd, J = 1.6, 4.8 Hz, 1H), 7.95 (td, J = 2.0, 8.0 Hz, 1H), 7.47 - 7.42 (m,2H), 7.41 - 7.32 (m, 3H), 7.31 - 7.28 (m, 1H), 7.02 (d, J = 8.4 Hz, 1H), 4.33(dd, J = 5.2, 12.0 Hz, 1H), 2.79 (ddd, J = 5.2, 12.4, 17.2 Hz, 1H), 2.56 (d, J = 4.0 Hz, 1H), 2.36 - 2.31 (m, 1H), 2.09 - 2.00 (m, 1H).

[0308] Example 24: 3-(2-chloro-3-(2-(pyridin-3-yl)benzofuran-5-yl)phenyl)piperidin-2,6-dione (Compound 24)

[0309] Step 1: At 20 °C, Pd(PPh3)2Cl2 (470 mg) and CuI (127 mg) were added to a TEA (5.00 mL) and THF (5.00 mL) solution of 4-bromo-2-iodophenol (1.00 g) and 3-ethynylpyridine (518 mg). The mixture was degassed and purged three times with N2. The resulting mixture was stirred at 20 °C for 12 hours under N2 atmosphere, and then filtered to remove insoluble solids. The filtrate was diluted with H2O (10 mL) and extracted with EtOAc (10 mL × 3). The combined organic phases were washed with brine (5 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, hexane / ethyl acetate gradient 100% to 0%) to give compound 3-(5-bromobenzofuran-2-yl)pyridine (300 mg, yield 32.7%) as a white solid. LCMS: Rt = 0.395 min, m / z= 274.0[M+H] + . 1 H NMR (400 MHz, DMSO- d 6 ): d 9.16 (d, J = 1.6 Hz, 1H), 8.63 (dd,J = 1.6, 4.8 Hz, 1H), 8.30 (td, J = 2.0, 8.0 Hz, 1H), 7.93 (d, J = 2.0 Hz, 1H), 7.66 (d, J = 8.8 Hz, 1H), 7.60 (s, 1H), 7.56 (dd, J = 4.8, 8.0 Hz, 1H), 7.51 (dd, J = 2.0, 8.8 Hz, 1H).

[0310] Step 2: Pd(dppf)Cl2 (10.7 mg) and K2CO3 (40.3 mg) were added to a solution of 3-(5-bromobenzofuran-2-yl)pyridine (40.0 mg) and (2-chloro-3-(2,6-dioxopiridin-3-yl)phenyl)boronic acid (39.0 mg) in H2O (0.100 mL) at 20 °C and under a N2 atmosphere. The mixture was stirred at 80 °C for 1 hour under a N2 atmosphere, followed by filtration to remove insoluble solids. The filtrate was concentrated under reduced pressure. The residue was purified by prep-HPLC (column: CD24-WePure Biotech XPT C18 150 mm). 25mm 7 μm; mobile phase: [H2O (containing 10 mM NH4HCO3)-ACN]; gradient: ACN content 31%-61% within 12.0 min), yielding compound 24 (4.18 mg, yield 6.10%, purity 88.8%), as a white solid. LCMS: Rt = 1.765 min, m / z = 416.9 [M+H] + . 1 H NMR: (400 MHz, DMSO- d 6 ): d 10.93 (s, 1H), 9.18 (s, 1H), 8.62 (d, J =3.2 Hz, 1H), 8.31 (d, J= 7.2 Hz, 1H), 7.78 - 7.68 (m, 2H), 7.66 (s, 1H), 7.58 - 7.54 (m, 1H), 7.39 (s, 4H), 4.41 - 4.33 (m, 1H), 2.92 - 2.69 (m, 2H), 2.39 - 2.30 (m, 1H), 2.08 (s, 1H).

[0311] Example 25: 3-(4'-amino-2-chloro-3'-phenethyl-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (Compound 25)

[0312] Step 1: Under a nitrogen atmosphere at 20°C, Pd(OAc)₂ (15.1 mg) and TEA (1.36 g) were added to a MeCN mixture of 2-bromo-2-iodoaniline (2.00 g) and styrene (1.05 g) in 20.0 mL. The mixture was stirred at 90°C for 12 hours under a nitrogen atmosphere. After the reaction was complete, the reaction mixture was concentrated. The residue was diluted with H₂O (20 mL) and extracted with EtOAc (20 mL × 3). The combined organic phases were washed with brine (20 mL × 3), dried over Na₂SO₄, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, hexane / ethyl acetate gradient 100% to 0%) to give compound (E)-4-bromo-2-styrenicoaniline (1.00 g, yield 54.3%) as a dark brown oil. LCMS: Rt = 0.589 min, m / z = 274.1 [M+H] + . 1 H NMR (400 MHz, DMSO- d 6 ): d 7.65 (d, J = 7.2 Hz, 2H), 7.57 (d, J = 2.4 Hz, 1H), 7.40 - 7.30(m, 3H), 7.28 - 7.21 (m, 1H), 7.12 - 7.04 (m, 2H), 6.62 (d, J = 8.8 Hz, 1H), 5.57 (s, 2H).

[0313] Step 2: A THF (12.5 mL) solution of (E)-4-bromo-2-phenylethylaniline (500 mg) was pumped at a rate of 0.300 mL / min through a fixed bed (FLR1, SS, 1 / 4'', 5.00 mL, 40 °C) completely packed with particulate catalyst Pt / C (1%, 2.50 g). The H2 back pressure regulator was adjusted to 1.0 MPa, and the H2 flow rate was 30.0 mL / min. The reaction mixture was collected from the reactor outlet, and the fixed bed was washed with THF (200 mL). The combined mixture was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, n-hexane / ethyl acetate, elution gradient 100% to 0%) to give 4-bromo-2-phenylethylaniline (430 mg, yield 85.4%) as a yellow solid. LCMS: Rt = 0.560 min, m / z = 276.1 [M+H] + . 1 H NMR: (400 MHz, DMSO- d 6 ): d 7.31 - 7.25 (m, 4H), 7.18 (dt, J = 2.8, 5.6 Hz, 1H), 7.06 - 6.99(m, 2H), 6.58 (d, J = 8.4 Hz, 1H), 5.10 (s, 2H), 2.82 - 2.77 (m, 2H), 2.72 -2.66 (m, 2H).

[0314] Step 3: Under a nitrogen atmosphere at 20°C, K₂CO₃ (100 mg) and Pd(dppf)Cl₂ (26.5 mg) were added to a solution of 4-bromo-2-phenylethylaniline (100 mg) and (2-chloro-3-(2,6-dioxopiperidin-3-yl)phenyl)boronic acid (190 mg) in dioxane (2.00 mL) and H₂O (0.200 mL). The mixture was stirred at 80°C for 1 hour under a nitrogen atmosphere. The insoluble solids were then removed by filtration. The filtrate was concentrated under reduced pressure. The residue was purified by prep-HPLC using a CD24-WePure Biotech XPT C18 150mm column. 25mm 7 μm; mobile phase: [H2O (containing 10 mM NH4HCO3)-ACN]; gradient: ACN content 35%-65% within 10.0 min), yielding compound 25 (27.9 mg, yield 18.4%, purity 99.8%) as a white solid. LCMS: Rt = 2.08 min, m / z = 419.0 [M+H] + . 1 H NMR (400 MHz, DMSO- d 6 ): d 10.90 (s, 1H), 7.41 - 7.11 (m,8H), 7.04 - 6.92 (m, 2H), 6.69 (d, J = 8.8 Hz, 1H), 5.11 (s, 2H), 4.30 (dd, J = 4.8, 11.6 Hz, 1H), 2.87 - 2.81 (m, 2H), 2.77 - 2.72 (m, 2H), 2.54 (d, J =0.8 Hz, 2H), 2.38 - 2.25 (m, 1H), 2.09 - 1.98 (m, 1H).

[0315] Example 26: Synthesis of Compound 26

[0316] Compound 26-1 (100 mg) was dissolved in THF (2 mL), and 260 μL of diisopropylaminolithium was added at -70 °C under nitrogen protection. The mixture was stirred at -70 °C for 1 hour. Subsequently, a THF (1 mL) solution of methyl 1-(bromomethyl)cyclopropane-1-carboxylate (83.7 mg) was slowly added dropwise at -70 °C. After the addition was complete, stirring was continued at -70 °C for 1 hour, followed by heating to 20 °C and stirring for another hour. The reaction was quenched with saturated ammonium chloride solution (20 mL), and the mixture was extracted with ethyl acetate (10 mL × 3 times). The organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (elution gradient: n-hexane / ethyl acetate = 2:1 to 1:1) to give compound 26-2. LCMS: 366.1 [M + Na] + 1 H NMR: (400 MHz, CDCl3- d ) d = 7.64 (dd, J= 1.2, 8.0 Hz, 1H), 7.50 (dd, J = 1.2, 7.6Hz, 1H), 7.22 - 7.17 (m, 1H), 4.92 (dd, J = 5.6, 9.6 Hz, 1H), 3.73 - 3.67 (m,3H), 2.38 (dd, J = 5.6, 14.4 Hz, 1H), 1.85 (dd, J = 9.6, 14.4 Hz, 1H), 1.49 -1.42 (m, 1H), 1.30 - 1.24 (m, 1H), 1.18 - 1.10 (m, 1H), 0.64 (ddd, J = 4.4, 7.2, 9.2 Hz, 1H).

[0317] Compound 26-2 (130 mg) was dissolved in acetic acid (1.3 mL), and sulfuric acid (186 mg) was added. The reaction mixture was stirred at 90 °C for 3 hours. The reaction mixture was diluted with water (20 mL), filtered, and the filter cake was collected. After concentration under reduced pressure, the mixture was slurried with ethyl acetate (0.5 mL) for 10 minutes to give compound 26-3. LCMS: 328.1 [M+H] + . 1 H NMR: (400 MHz, DMSO- d 6) δ = 11.05 (s, 1H), 7.72 (dd, J = 1.2, 8.0 Hz, 1H), 7.42 (dd, J = 1.6, 7.6Hz, 1H), 7.32 - 7.25 (m, 1H), 4.39 (dd, J = 5.2, 12.8 Hz, 1H), 1.56 (dd, J =5.2, 13.6 Hz, 1H), 1.38 (ddd, J = 3.6, 6.8, 9.6 Hz, 1H), 1.06 - 0.94 (m, 2H), 0.91 - 0.83 (m, 1H), 0.82 - 0.74 (m, 1H).

[0318] Compound 26-3 (60.0 mg) and (4-(2-oxopyridin-1(2H)-yl)phenyl)boronic acid (81.4 mg) were dissolved in a mixed solvent of 1,4-dioxane (2 mL) and water (0.2 mL), followed by the addition of potassium carbonate (50.4 mg) and Pd(dppf)Cl2 (13.3 mg). The reaction mixture was stirred at 80 °C for 2 hours under nitrogen protection. The reaction solution was concentrated under reduced pressure. The crude product was purified by preparative high-performance liquid chromatography (HPLC) (column: CD24-WePure Biotech XPT C18 150-257 μm; mobile phase: [10 mM ammonium bicarbonate aqueous solution-acetonitrile]; gradient elution program: 23%-53% acetonitrile, 12.0 min) to give compound 26. LCMS: 419.1 [M+H] + . 1 H NMR: (400 MHz, DMSO- d 6) d = 11.05 (s, 1H), 7.73 (dd, J = 1.6, 6.8 Hz, 1H), 7.57 - 7.49 (m, 5H), 7.47 - 7.42 (m, 2H), 7.40 - 7.35 (m,1H), 6.51 (d, J = 9.2 Hz, 1H), 6.38 - 6.30 (m, 1H), 4.45 (dd, J = 5.2, 12.4Hz, 1H), 2.75 (t, J = 13.2 Hz, 1H), 1.63 (dd, J = 4.8, 13.2 Hz, 1H), 1.39(dt, J = 3.6, 8.0 Hz, 1H), 1.08 - 0.95 (m, 2H), 0.86 - 0.75 (m, 1H).

[0319] Example 27: Synthesis of Compound 27

[0320] Compound 27-1 (1.00 g) was dissolved in tetrahydrofuran (10 mL), and a boron trifluoride diethyl ether complex (792 mg) was slowly added dropwise at 0 °C. After stirring the reaction mixture at 0 °C for 15 min, a solution of lithium magnesium chloride (2,2,6,6-tetramethylpiperidinyl) chloride (1 M) was slowly added dropwise at -78 °C, and stirring was continued at -78 °C for another 15 min. Subsequently, iodine (1.93 g) dissolved in THF (5 mL) was slowly added dropwise at -78 °C. The mixture was slowly heated to 20 °C and stirred for 2 h. The reaction mixture was quenched in a saturated ammonium chloride solution (20 mL) under nitrogen protection and at 0 °C, and extracted with ethyl acetate (20.0 mL × 3). The combined organic phases were washed with saturated brine (20.0 mL × 2), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (elution gradient of petroleum ether / ethyl acetate = 1:0 to 20:1) to give compound 27-2. LCMS: 324.8 [M+H] + . 1 H NMR: (400 MHz, DMSO- d 6 ) d 8.64 (d, J = 7.2 Hz, 1H), 7.97 (d, J = 1.6 Hz, 1H), 7.00 (dd, J =2.4, 7.2 Hz, 1H), 6.81 (s, 1H).

[0321] Compound 27-2 (100 mg) and 4-azaspiro[2.5]oct-5-one (31.01 mg) were dissolved in toluene (5.00 mL), followed by the addition of cesium carbonate (302 mg) and bis[(Z)-1-methyl-3-oxobut-1-enoxy]copper (16.2 mg). The reaction mixture was stirred at 120 °C for 12 hours. The reaction mixture was extracted separately with water (10 mL) and ethyl acetate (100 mL × 4). The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by preparative thin-layer chromatography (petroleum ether / ethyl acetate = 0:1) to give compound 27-3. LCMS: 320.1 [M+H] + .

[0322] Compound 27-3 (30.0 mg) and intermediate A (65.5 mg) were dissolved in a mixed solvent of 1,4-dioxane (1.00 mL) and water (0.1 mL), followed by the sequential addition of Pd(dppf)Cl2 (13.7 mg) and potassium carbonate (25.9 mg). The reaction mixture was stirred at 80 °C for 1 hour under nitrogen protection. After filtration, the filtrate was concentrated, and the residue was purified by preparative high-performance liquid chromatography (HPLC) (column: CD24-WePure Biotech XPT C18 150×25×7 μm; mobile phase: [water (containing 10 mM NH4HCO3)-acetonitrile]; gradient: 18%-48% B phase, 15.0 min) to obtain compound 27. LCMS: 463.1 [M+H] + LCMS: m / z: 463.2 [M+H] + . 1 H NMR: (400 MHz, DMSO- d 6 ) d 10.94 (s, 1H), 8.65 (d, J = 7.2 Hz, 1H), 7.66 (d, J = 1.2 Hz, 1H), 7.46 - 7.40 (m,3H), 6.93 (dd, J = 2.0, 7.2 Hz,1H), 6.47 (s, 1H), 4.37 (dd, J = 4.8, 12.4 Hz, 1H), 2.86 - 2.76 (m, 1H), 2.56(t, J = 6.8Hz, 4H), 2.09 - 2.03 (m, 1H), 1.99 - 1.93 (m, 2H), 1.90 - 1.84 (m, 2H), 0.69 (s, 4H).

[0323] Example 28: Synthesis of Compound 28

[0324] Compound 28-1 (1.00 g) was dissolved in dichloromethane (20.0 mL), and a solution of O-(tris(methyltris(methyltris(methyltris(methyltris(methyltris(methyltris(methyltris(methyltris(methyltris(methyltris(methyltris(methyltris(methyltris(methyltris(methyltris(methyltris(methyltris(methyltris(methyltris(methyltris(methyltris(methyltris(methyltris(s(t)))))))))))))))))))))))))))))) was smeared in dichloromethane))))""")))"""")')""")'"")', "")'""'")'"")'"")'""'"")'""")'""""""""" "" ...+ .

[0325] Compound 28-2 (1.60 g) was dissolved in methanol (50.0 mL), and potassium carbonate (5.19 g) was added. The reaction mixture was stirred at 25 °C for 12 hours under nitrogen protection. The reaction mixture was diluted with water (10.0 mL) and extracted with ethyl acetate (10.0 mL × 3 times). The combined organic phases were washed with saturated brine (10.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The crude product was purified by silica gel column chromatography (elution gradient: n-hexane / ethyl acetate = 100 / 1 to 1 / 1) to give compound 28-3. LCMS: 213.9 [M + H] + .

[0326] Compound 28-3 (630 mg) was dissolved in sulfuric acid (150 mL), and the reaction mixture was stirred at 100 °C for 2 hours. The pH was adjusted to 7 with saturated sodium bicarbonate solution (50.0 mL), and then extracted with ethyl acetate (20.0 mL × 5 times). The combined organic phases were washed with saturated brine (30.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 28-4. LCMS: 214.8 [M+H] + . 1 H NMR: (400 MHz, DMSO- d 6) d 10.67 (s, 1H), 8.32 (d, J =7.2 Hz, 1H), 7.67 (d, J = 2.0 Hz, 1H), 6.76 (dd, J = 2.4, 7.2 Hz, 1H), 5.75 (s, 1H).

[0327] Compound 28-4 (400 mg) and 3-(chloromethyl)pyridine hydrochloride (462 mg) were dissolved in N,N-dimethylformamide (4.00 mL), and potassium carbonate (1.30 g) was added. The reaction mixture was stirred at 25 °C for 12 hours. The reaction mixture was diluted with water (50.0 mL) and extracted with ethyl acetate (100 mL × 3 times). The combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The crude product was purified by silica gel column chromatography (elution gradient: n-hexane / ethyl acetate = 100 / 1 to 0 / 1) to give compound 28-5. LCMS: 305.9 [M+H] + . 1 H NMR: (400MHz, DMSO- d 6) d8.51 - 8.45 (m, 2H), 8.22 (d, J = 7.4 Hz, 1H), 7.56 - 7.48(m, 2H), 7.35 (dd, J = 4.8, 7.9 Hz, 1H), 6.67 (dd, J = 2.2, 7.3 Hz, 1H), 5.42(s, 2H), 5.24(s, 1H).

[0328] Compound 28-5 (80.0 mg) and intermediate A (138 mg) were dissolved in a mixed solvent of 1,4-dioxane (1.00 mL) and water (0.100 mL), followed by the addition of potassium carbonate (72.7 mg) and Pd(dppf)Cl2 (19.3 mg). The reaction mixture was stirred at 80 °C for 2 hours under nitrogen protection. The reaction mixture was diluted with water (5.00 mL) and extracted with ethyl acetate (5.00 mL × 4). The combined organic phases were washed with saturated brine (10.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by preparative high-performance liquid chromatography (column: CD24-WePure Biotech XPT C18150 257 μm; mobile phase: [10 mM ammonium bicarbonate aqueous solution-acetonitrile]; gradient elution program: 5%-35% acetonitrile, 12.0 min) to give compound 28. LCMS:447.0 [M+H] + . 1 H NMR: (400 MHz, DMSO- d 6) d 10.98 - 10.85(m, 1H), 8.56 (d, J = 2.0 Hz, 1H), 8.50 (dd, J = 1.6, 4.8 Hz, 1H), 8.34 (d, J= 7.2 Hz, 1H), 7.66 - 7.60 (m, 1H), 7.42 - 7.34 (m, 4H), 7.23 (d, J = 1.6 Hz,1H), 6.56 (dd, J = 2.0, 7.2 Hz, 1H), 5.47 (s, 2H), 5.30 (s, 1H), 4.38 - 4.28(m, 1H), 2.84 - 2.72 (m, 1H), 2.55 (s, 1H), 2.35 - 2.26 (m, 1H), 2.05 - 1.97 (m, 1H).

[0329] Example 29: Synthesis of compounds 29 and 30

[0330] Compound 29-1 (1.00 g) was dissolved in THF (10 mL), and boron trifluoride diethyl ether complex (792 mg) was slowly added dropwise at 0 °C. After stirring the reaction mixture at 0 °C for 15 minutes, TMPMgCl was slowly added dropwise at -78 °C. LiCl solution (1 M, 6.09 mL) was stirred at -78 °C for 15 minutes. Then, pyridine-3-carboxymethyl chloride hydrochloride (1.17 g) dissolved in tetrahydrofuran (5 mL) was slowly added dropwise at -78 °C. The mixture was slowly heated to 20 °C and stirred for 2 hours. The reaction mixture was quenched under nitrogen protection and at 0 °C in a saturated ammonium chloride solution (20 mL), and extracted with ethyl acetate (20.0 mL × 3). The combined organic phases were washed with saturated brine (20.0 mL × 2), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:0 to 0:1 gradient elution) to give compound 29-2. LCMS: 301.9 [M + H] + . 1 H NMR: (400 MHz, DMSO- d 6 ) d 9.39 - 9.32 (m, 1H), 8.87 - 8.80 (m, 2H), 8.54 (td, J = 2.0, 8.0Hz, 1H), 8.21 (d, J = 1.6 Hz, 1H), 7.63 (ddd, J = 0.8, 4.8, 8.0 Hz, 1H), 7.27(dd, J = 2.0, 7.2 Hz, 1H), 7.23 (s, 1H).

[0331] Compound 29-2 (60.0 mg) was dissolved in ethylene glycol (1.00 mL), followed by the addition of potassium hydroxide (33.4 mg) and hydrazine hydrate (99.4 mg). The reaction mixture was stirred at 140 °C for 2 hours. The reaction mixture was extracted separately with water (5 mL) and ethyl acetate (5 mL). The organic phase was washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by preparative thin-layer chromatography (petroleum ether / ethyl acetate = 0:1) to give compound 29-3. LCMS: 288.0 [M+H] + .

[0332] Compound 29-3 (20.0 mg) and intermediate A (48.5 mg) were dissolved in a mixed solvent of 1,4-dioxane (1.00 mL) and water (0.1 mL), followed by the sequential addition of Pd(dppf)Cl2 (5.08 mg) and potassium carbonate (19.9 mg). The reaction mixture was stirred at 80 °C for 1 hour under nitrogen protection. After filtration, the filtrate was concentrated, and the residue was purified by preparative high-performance liquid chromatography (HPLC) (column: CD24-WePure Biotech XPT C18 150×25×7 μm; mobile phase: [water (containing 10 mM NH4HCO3)-acetonitrile]; gradient: 17%-47% B phase, 15.0 min) to obtain compound 29. LCMS: 431.3 [M+H] + . 1 H NMR: (400MHz, DMSO- d 6 ) d 10.92 (s, 1H), 8.65 (d, J = 7.2 Hz, 1H), 8.57 (d, J = 1.6 Hz, 1H), 8.43 (dd, J = 1.2, 4.8 Hz, 1H), 7.72 (d, J = 7.6 Hz, 1H), 7.61 (s, 1H), 7.45 - 7.38 (m, 3H), 7.33 (dd, J = 4.8, 7.6 Hz, 1H), 6.85 (dd, J =2.0, 7.2Hz, 1H), 6.46 (s, 1H), 4.35 (dd, J = 5.2, 12.4 Hz, 1H), 4.16 (s, 2H), 2.87 -2.74 (m, 1H), 2.59 - 2.55 (m, 1H), 2.32 (d, J = 3.6 Hz, 1H), 2.08 - 2.03 (m,1H).

[0333] Compound 30 was obtained by referring to the preparation method of compound 29:

[0334] Example 30: Synthesis of Compound 31

[0335] Compound 31-1 (50.0 mg) and 3-(chloromethyl)pyridine hydrochloride (57.8 mg) were dissolved in N,N-dimethylformamide (1.00 mL), and potassium carbonate (130 mg) was added. The reaction mixture was stirred at 20 °C for 12 hours. The reaction mixture was diluted with water (10.0 mL) and extracted with ethyl acetate (10.0 mL × 3 times). The combined organic phases were washed with saturated brine (10.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The crude product was purified by silica gel column chromatography (elution gradient: n-hexane / ethyl acetate = 10 / 1 to 0 / 1) to give compound 31-2. LCMS: 305.9 [M + H] + . 1 H NMR: (400MHz, DMSO- d 6 ) d 8.70 (d, J = 1.6 Hz, 1H), 8.56 (dd, J = 1.6, 4.8 Hz, 1H), 8.46 (d, J = 7.2 Hz, 1H), 7.91 (td, J = 2.0, 7.6 Hz, 1H), 7.80 (d, J = 1.6 Hz,1H), 7.47 - 7.41 (m, 1H), 6.88 (dd, J = 2.4, 7.2 Hz, 1H), 6.06 (s, 1H), 5.36(s, 2H).

[0336] Compound 31-2 (50.0 mg) and intermediate B (86.2 mg) were dissolved in a mixed solvent of 1,4-dioxane (0.5 mL) and water (0.1 mL), followed by the addition of potassium carbonate (45.4 mg) and Pd(dppf)Cl2 (12.0 mg). The reaction mixture was stirred at 80 °C for 1 hour under nitrogen protection. The reaction mixture was diluted with water (5.00 mL) and extracted with ethyl acetate (5.00 mL × 3 times). The combined organic phases were washed with saturated brine (5.00 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by preparative high-performance liquid chromatography (column: CD24-WePure Biotech XPT C18 150-257 μm; mobile phase: [10 mM ammonium bicarbonate aqueous solution-acetonitrile]; gradient elution program: 23%-53% acetonitrile, 11.0 min) to give compound 31. LCMS:447.1[M+H] + . 1 H NMR: (400 MHz, DMSO- d 6 ) d10.94 (s, 1H), 8.72 (d,J = 1.6 Hz, 1H), 8.57 - 8.53 (m, 2H), 7.92 (td, J = 1.6, 7.6 Hz, 1H), 7.50(d, J = 1.2 Hz, 1H), 7.46 - 7.38 (m, 4H), 6.79 (d, J = 2.0 Hz, 1H), 6.12 (s,1H), 5.38 (s, 2H), 4.36 (dd, J = 4.8, 12.4 Hz, 1H), 2.86 - 2.74 (m, 1H), 2.56(d, J = 3.6 Hz, 1H), 2.39 - 2.30 (m, 1H), 2.10 - 1.99 (m, 1H).

[0337] Example 31: Synthesis of Compound 32

[0338] Compound 29-2 (120 mg) and intermediate A (167 mg) were dissolved in a mixed solvent of 1,4-dioxane (2.00 mL) and water (0.200 mL), followed by the sequential addition of Pd(dppf)Cl2 (29.1 mg) and potassium carbonate (110 mg). The reaction mixture was stirred at 80 °C for 1 hour under nitrogen protection. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain the residue. The crude product was purified by preparative high-performance liquid chromatography (HPLC) (column: CD24-WePure Biotech XPT C18 150-257 μm; mobile phase: [10 mM ammonium bicarbonate aqueous solution-acetonitrile]; gradient elution program: 22%-52% acetonitrile, 10.0 min) to give compound 32. LCMS: 445.1 [M+H] + . 1 H NMR: (400 MHz, DMSO- d 6 ) d10.94 (s, 1H), 9.39 (d, J = 1.6 Hz, 1H), 8.91 (d, J = 7.2 Hz, 1H), 8.86 (dd, J = 1.6, 4.8 Hz, 1H), 8.57 (td, J =2.0, 8.0 Hz, 1H), 7.91 (d, J = 0.8 Hz, 1H), 7.65 (dd, J = 4.8, 8.0 Hz, 1H), 7.49 - 7.44 (m, 3H), 7.34 (s, 1H), 7.18 (dd, J = 2.0, 7.2 Hz, 1H), 4.38 (dd,J = 5.2, 12.4 Hz, 1H), 2.86 - 2.76 (m, 1H), 2.59 - 2.53 (m, 1H), 2.43 - 2.29 (m, 1H), 2.13 - 2.00 (m, 1H).

[0339] Example 32: Synthesis of Compound 33

[0340] Intermediate A (300 mg) and tert-butyl-4-bromo-3,6-dihydropyridine-1(2H)-carboxylate (337 mg) were dissolved in a mixed solvent of 1,4-dioxane (3.00 mL) and water (0.300 mL), followed by the addition of potassium carbonate (237 mg) and Pd(dppf)Cl2 (62.8 mg). The reaction mixture was stirred at 80 °C for 2 hours. The reaction mixture was diluted with water (5.00 mL) and extracted with ethyl acetate (5.00 mL × 3 times). The combined organic phases were washed with saturated brine (5.00 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The crude product was purified by silica gel column chromatography (elution gradient: n-hexane / ethyl acetate = 100 / 1 to 1 / 1) to give compound 33-2. LCMS: 348.9 [M-Boc+H] + . 1 H NMR: (400 MHz, DMSO- d 6) d10.90 (s, 1H), 7.32 - 7.24 (m, 2H), 7.18 (dd, J = 2.0, 7.2 Hz, 1H), 5.68(br s, 1H), 4.28 (dd, J = 5.2, 12.0 Hz, 1H), 3.96 (s, 2H), 3.53 (t, J = 5.2Hz, 2H), 2.84 - 2.71 (m, 1H), 2.56 - 2.52 (m, 1H), 2.35 (s, 2H), 2.31 - 2.22(m, 1H), 2.03 - 1.96 (m, 1H), 1.43 (s, 9H).

[0341] Compound 33-2 (180 mg) was dissolved in a hydrogen chloride / dioxane solution (2.00 mL), and the reaction mixture was stirred at 25 °C for 2 hours. The reaction solution was concentrated under reduced pressure to give compound 33-3. LCMS: 305.0 [M+H] + . 1 H NMR: (400MHz, DMSO- d 6) d 10.92 (s, 1H), 9.24 (s, 2H), 7.38 - 7.29 (m, 2H), 7.18 (dd, J= 2.0, 7.2 Hz, 1H), 5.72 (s, 1H), 4.30 (dd, J = 5.2, 12.4 Hz, 1H), 3.73 (s,2H), 3.29 - 3.26 (m, 1H), 2.77 (d, J = 12.4 Hz, 1H), 2.56 (d, J = 3.6 Hz,3H), 2.37 - 2.23 (m, 1H), 2.06 - 1.95 (m, 1H).

[0342] Under nitrogen protection, sodium hydride (95.9 mg) was slowly added dropwise to a tetrahydrofuran (2.00 mL) solution of 200 mg of 4-azaspiro[2.5]octane-5-one at 0 °C, and the mixture was stirred at 0 °C for 0.5 h. Subsequently, a tetrahydrofuran (2.00 mL) solution of 468 mg of compound 33-4 was slowly added dropwise under nitrogen protection at 0 °C, and the temperature was raised to 20 °C and stirring was continued for 1.5 h. The reaction mixture was quenched with a saturated ammonium chloride aqueous solution (10.0 mL) at 0 °C under nitrogen protection. The mixture was extracted with ethyl acetate (10.0 mL × 3 times), and the combined organic phases were washed with saturated brine (10.0 mL × 3 times), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the residue. The crude product was purified by silica gel column chromatography (elution gradient: n-hexane / ethyl acetate = 100 / 1 to 1 / 1) to give compound 33-5. LCMS:240.1[M+H] + .

[0343] Compound 33-5 (100 mg) was dissolved in DCM (1.00 mL), and TFA (461 mg) was added. The reaction mixture was stirred at 25 °C for 1 hour. The reaction solution was concentrated under reduced pressure to give compound 33-6. LCMS: 183.9 [M+H] + .

[0344] Compounds 33-6 (50.0 mg) and 33-3 (45.1 mg) were dissolved in N,N-dimethylformamide (1.00 mL), followed by the addition of HATU (93.6 mg) and DIEA (42.4 mg). The reaction mixture was stirred at 25 °C for 1 hour. The reaction mixture was filtered, and the filtrate was concentrated to obtain the residue. The crude product was purified by preparative high-performance liquid chromatography (HPLC) (column: CD24-WePureBiotech XPT C18 150). 25 7 μm; mobile phase: [10 mM ammonium bicarbonate aqueous solution-acetonitrile]; gradient elution program: 17%-47% acetonitrile, 11.0 min), to give compound 33. LCMS: 470.1 [M+H] + . 1 H NMR: (400 MHz, DMSO- d 6) d10.90 (s, 1H), 7.34 - 7.25 (m, 2H), 7.21 - 7.18 (m, 1H), 5.73 - 5.66(m, 1H), 4.32 - 4.23 (m, 1H), 4.13 (s, 1H), 4.09 (s, 1H), 4.06 - 4.02 (m,2H), 3.63 (d, J = 8.0 Hz, 2H), 2.82 - 2.72 (m, 1H), 2.54 (d, J = 3.6 Hz, 1H), 2.44 (d, J = 2.0 Hz, 1H), 2.39 (t, J = 6.8 Hz, 2H), 2.35 - 2.24 (m, 2H), 2.05- 1.96 (m, 1H), 1.82 (t, J = 6.8 Hz, 2H), 1.72 - 1.66 (m, 2H), 0.92 - 0.86(m, 2H), 0.61 - 0.55 (m, 2H).

[0345] Example 33: Synthesis of Compound 34

[0346] Compound 33-3 (40.0 mg) and 2-chloropyrimidine (22.6 mg) were dissolved in N,N-dimethylformamide (1.00 mL), and potassium carbonate (54.4 mg) was added. The reaction mixture was stirred at 60 °C for 1 hour. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain the residue. The crude product was purified by preparative high-performance liquid chromatography (HPLC) (column: CD24-WePure Biotech XPTC18 150). 25 7 μm; mobile phase: [10 mM ammonium bicarbonate aqueous solution-acetonitrile]; gradient elution program: 27%-57% acetonitrile, 11.0 min), yielding compound 34. LCMS: 383.1 [M+H] + . 1 H NMR: (400 MHz, DMSO- d 6) d10.93 -10.88 (m, 1H), 8.40 (d, J = 4.8 Hz, 2H), 7.34 - 7.25 (m, 2H), 7.23 - 7.18 (m,1H), 6.65 (t, J = 4.8 Hz, 1H), 5.84 - 5.78 (m, 1H), 4.32 - 4.25 (m, 3H), 4.04- 3.98 (m, 2H), 2.77 (ddd, J = 5.2, 12.8, 17.2 Hz, 1H), 2.57 - 2.52 (m, 1H), 2.45 (d, J = 0.8 Hz, 2H), 2.35 - 2.23 (m, 1H), 2.05 - 1.97 (m, 1H).

[0347] Example 34: Synthesis of Compound 35

[0348] Under nitrogen protection, lithium hexamethyldisilamide (1.00 M) was slowly added dropwise to a tetrahydrofuran (4.50 mL) solution of compound 35-1 (300 mg) at -78 °C, and the mixture was stirred at -78 °C for 1 hour. Subsequently, a tetrahydrofuran (4.50 mL) solution of 1,1,1-trifluoro-N-phenyl-N-(trifluoromethylsulfonyl)methanesulfonamide (608 mg) was slowly added dropwise at -78 °C under nitrogen protection. After the addition was complete, the temperature was raised to 25 °C and stirring was continued for 1 hour. The reaction mixture was quenched with a saturated ammonium chloride aqueous solution (10.0 mL) at 0 °C under nitrogen protection. The mixture was extracted with ethyl acetate (10.0 mL × 3 times), and the combined organic phases were washed with saturated brine (10.0 mL × 3 times), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (elution gradient: n-hexane / ethyl acetate = 10 / 1 to 0 / 1) to give compound 35-2. LCMS: 309.0 [M+H] + .

[0349] Compound 35-2 (100 mg) and intermediate A (170 mg) were dissolved in a mixed solvent of 1,4-dioxane (1.00 mL) and water (0.100 mL), followed by the addition of potassium carbonate (89.7 mg) and Pd(dppf)Cl2 (23.7 mg). The reaction mixture was stirred at 80 °C for 2 hours under nitrogen protection. The reaction mixture was diluted with water (5.00 mL) and extracted with ethyl acetate (5.00 mL × 3 times). The combined organic phases were washed with saturated brine (5.00 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The crude product was purified by preparative high-performance liquid chromatography (HPLC) (column: CD24-WePure Biotech XPT C18 150). 25 7 μm; mobile phase: [10 mM ammonium bicarbonate aqueous solution-acetonitrile]; gradient elution program: 31%-51% acetonitrile, 12.0 min), to give compound 35. LCMS: 382.1 [M+H] + . 1 H NMR: (400 MHz, DMSO- d 6 ) d 8.13(dd, J = 1.4, 4.9 Hz, 1H), 7.55 (ddd, J = 2.0, 7.2, 8.8 Hz, 1H), 7.34 - 7.25(m, 2H), 7.24 - 7.19 (m, 1H), 6.82 (d, J = 8.8 Hz, 1H), 6.64 (dd, J = 5.2,6.8 Hz, 1H), 5.81 (s, 1H), 4.29 (dd, J = 5.2, 12.4 Hz, 1H), 4.07 (d, J = 2.8Hz, 2H), 3.83 (t, J = 5.6 Hz, 2H), 2.83 - 2.72 (m, 1H), 2.56 - 2.53 (m, 1H), 2.49 - 2.43 (m, 2H), 2.35 - 2.23 (m, 1H), 2.05 - 1.96 (m, 1H).

[0350] Example 35: Synthesis of Compound 36

[0351] Compound 33-3 (50.0 mg) and 2-(pyridin-3-yl)acetic acid (33.8 mg) were dissolved in N,N-dimethylformamide (1.00 mL), followed by the addition of HATU (93.6 mg) and N,N-diisopropylethylamine (42.4 mg). The reaction mixture was stirred at 25 °C for 1 hour. After the reaction was complete, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain the residue. The crude product was purified by preparative high-performance liquid chromatography (HPLC) (column: CD24-WePure Biotech XPT C18 150). 25 7 μm; mobile phase: [10 mM ammonium bicarbonate aqueous solution-acetonitrile]; gradient elution program: 14%-44% acetonitrile, 11.0 min), yielding compound 36. LCMS: 424.1 [M+H] + . 1 H NMR: (400 MHz, DMSO- d 6 ) d 10.91 (s, 1H), 8.49 - 8.41 (m, 2H), 7.69 - 7.62 (m, 1H), 7.37 - 7.25 (m, 3H), 7.19 (dd, J = 1.6, 7.2 Hz, 1H), 5.72 (s, 1H), 4.33 - 4.23 (m, 2H), 4.11 (d, J = 2.0 Hz, 1H), 3.85 (d, J =11.6 Hz, 2H), 3.78 - 3.69 (m, 2H), 2.85 - 2.72 (m, 1H), 2.55 (d, J = 3.6 Hz, 1H), 2.42 - 2.34 (m, 2H), 2.34 - 2.24 (m, 1H), 2.06 - 1.96 (m, 1H).

[0352] Example 36: Synthesis of Compound 37

[0353] Under nitrogen protection, lithium hexamethyldisilamide (1.00 M, 6.48 mL) was slowly added dropwise to a tetrahydrofuran (15.0 mL) solution of compound 37-1 (1.00 g) at -78 °C, and the mixture was stirred at -78 °C for 1 hour. Subsequently, a tetrahydrofuran (15.0 mL) solution of 1,1,1-trifluoro-N-phenyl-N-(trifluoromethylsulfonyl)methanesulfonamide (1.93 g) was slowly added dropwise at -78 °C under nitrogen protection, and the mixture was stirred at -78 °C for another 1 hour. The reaction was quenched with ammonium chloride solution (10.0 mL) and extracted with ethyl acetate (10.0 mL × 3). The combined organic phases were washed with saturated brine (5.00 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The crude product was purified by silica gel column chromatography (elution gradient: n-hexane / ethyl acetate = 1 / 0 to 20 / 1) to give compound 37-2. 1 H NMR: (400 MHz, DMSO- d 6 ) d 6.09 (d, J = 19.2Hz, 1H), 4.19 (dd, J = 4.8, 10.0 Hz, 2H), 4.15 - 4.08 (m, 2H), 1.42 (s, 9H).

[0354] Compound 37-2 (400 mg) and intermediate A (529 mg) were dissolved in a mixed solvent of 1,4-dioxane (4.00 mL) and water (0.400 mL), followed by the sequential addition of Pd(dppf)Cl2 (92.3 mg) and potassium carbonate (348 mg). The reaction mixture was stirred at 80 °C for 2 hours under nitrogen protection. The reaction solution was filtered, and the filtrate was concentrated to obtain the residue. The crude product was purified by silica gel column chromatography (elution gradient: n-hexane / ethyl acetate = 1 / 0 to 0 / 1) to give compound 37-3. LCMS: 334.7 [M+H] + . 1 HNMR: (400 MHz, DMSO- d 6 ) d10.91 (s, 1H), 7.35 - 7.30 (m, 3H), 6.17 - 6.11 (m,1H), 4.42 - 4.36 (m, 2H), 4.34 - 4.27 (m, 1H), 4.26 - 4.19 (m, 2H), 2.83 -2.73 (m, 1H), 2.55 (s, 1H), 2.32 - 2.25 (m, 1H), 2.03 - 1.97 (m, 1H), 1.44 (d, J = 4.0 Hz, 9H).

[0355] Compound 37-3 (250 mg) was dissolved in DCM (3.00 mL), and trifluoroacetic acid (1.54 g) was added. The reaction mixture was stirred at 20 °C for 1 hour. The reaction solution was concentrated to give compound 37-4. LCMS: 291.0 [M-CF3COOH] + H] + .

[0356] Compound 37-4 (50.0 mg) and 2-chloropyrimidine (17.0 mg) were dissolved in N,N-dimethylformamide (1.00 mL), and N,N-diisopropylethylamine (31.9 mg) was added. The reaction mixture was stirred at 60 °C for 1 hour. The reaction mixture was filtered, and the filtrate was concentrated to obtain the residue. The crude product was purified by preparative high-performance liquid chromatography (HPLC) (column: CD24-WePure Biotech XPT C18 150). 25 7 μm; mobile phase: [10 mM ammonium bicarbonate aqueous solution-acetonitrile]; gradient elution program: 15%-45% acetonitrile, 15.0 min), yielding compound 37. LCMS: 369.1 [M+H] + . 1 H NMR: (400 MHz, DMSO- d 6 ) d10.92(s, 1H), 8.40 (d, J = 4.8 Hz, 2H), 7.45 - 7.41 (m, 1H), 7.39 - 7.32 (m, 2H), 6.68 (t, J = 4.8 Hz, 1H), 6.33 (t, J = 2.0 Hz, 1H), 4.68 - 4.62 (m, 2H), 4.49- 4.44 (m, 2H), 4.34 (dd, J = 5.2, 12.4 Hz, 1H), 2.85 - 2.74 (m, 1H), 2.59 -2.54 (m, 1H), 2.37 - 2.27 (m, 1H), 2.08 - 1.98 (m, 1H).

[0357] Example 37: Synthesis of Compound 38

[0358] Compound 37-4 (50.0 mg) and 2-(pyridin-3-yl)acetic acid (20.3 mg) were dissolved in N,N-dimethylformamide (1.00 mL), followed by the addition of HATU (70.5 mg) and DIEA (31.9 mg). The reaction mixture was stirred at 20 °C for 1 hour. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the residue. The crude product was purified by preparative high-performance liquid chromatography (HPLC) (column: CD24-WePure Biotech XPT C18 150). 25 7 μm; mobile phase: [10 mM ammonium bicarbonate aqueous solution-acetonitrile]; gradient elution program: 11%-35% acetonitrile, 17.0 min), to give compound 38. LCMS: 410.0 [M+H] + . 1 H NMR: (400MHz, DMSO- d 6 ) d10.91 (s, 1H), 8.45 (d, J = 7.2 Hz, 2H), 7.72 - 7.63 (m, 1H), 7.42 - 7.31 (m, 4H), 6.30 - 6.17 (m, 1H), 4.78 (d, J = 2.0 Hz, 1H), 4.59 (d,J = 2.4 Hz, 1H), 4.49 (d, J = 2.4 Hz, 1H), 4.36 - 4.28 (m, 2H), 3.76 (d, J =1.6 Hz, 2H), 2.79 (tdd, J = 5.2, 12.4, 17.2 Hz, 1H), 2.55 (dd, J = 2.8, 5.6Hz, 1H), 2.38 - 2.24 (m, 1H), 2.05 - 1.94 (m, 1H).

[0359] Example 38: Synthesis of Compound 39

[0360] Compound 39-1 (1.00 g) was dissolved in tetrahydrofuran (15.0 mL), and hexamethyldisilamide lithium (1.00 M, 5.01 mL) was slowly added dropwise at -78 °C under nitrogen protection, with the mixture stirred at -78 °C for 1 hour. Subsequently, a solution of 1,1,1-trifluoro-N-phenyl-N-(trifluoromethylsulfonyl)methanesulfonamide (1.49 g) in tetrahydrofuran (15.0 mL) was slowly added dropwise at -78 °C under nitrogen protection, and the mixture was stirred at -78 °C for 11 hours. The reaction was quenched with ammonium chloride solution (10.0 mL) and extracted with ethyl acetate (10.0 mL × 3 times). The combined organic phases were washed with saturated brine (5.00 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The crude product was purified by silica gel column chromatography (elution gradient: n-hexane / ethyl acetate = 1 / 0 to 20 / 1) to give compound 39-2. 1 H NMR: (400 MHz, DMSO- d 6 ) d 5.82 (s, 1H), 3.67 - 3.48 (m, 4H), 2.42 - 2.37 (m, 4H), 1.89 (t, J = 6.0 Hz, 2H), 1.37 (s, 9H).

[0361] Compound 39-2 (200 mg) and intermediate A (226 mg) were dissolved in a mixed solvent of 1,4-dioxane (2.00 mL) and water (0.200 mL), followed by the sequential addition of Pd(dppf)Cl2·DCM (44.0 mg) and potassium carbonate (149 mg). The reaction mixture was stirred at 80 °C for 2 hours under nitrogen protection. The reaction solution was filtered, and the filtrate was concentrated to obtain the residue. The crude product was purified by silica gel column chromatography (elution gradient: n-hexane / ethyl acetate = 1 / 0 to 0 / 1) to give compound 39-3. LCMS: 389.1 [M+H] + . 1 H NMR: (400 MHz, DMSO- d 6 ) d 10.89 (s, 1H), 7.29 - 7.20 (m, 2H), 7.12 (dd,J = 2.0, 7.2 Hz, 1H), 5.52 (s, 1H), 4.25 (dd,J = 5.2, 12.0 Hz, 1H), 3.64 (s,4H), 2.83 - 2.69 (m, 1H), 2.40 - 2.19 (m, 6H), 2.02 - 1.95 (m, 1H), 1.85 (t,J = 6.0 Hz, 2H), 1.38 (s, 9H).

[0362] Compound 39-3 (160 mg) was dissolved in DCM (2.00 mL), and TFA (1.54 g) was added. The reaction mixture was stirred at 20 °C for 1 hour. The reaction solution was concentrated to give compound 39-4. LCMS: 344.9 [M+H] + .

[0363] Compound 39-4 (50.0 mg) and 2-chloropyrimidine (15.0 mg) were dissolved in N,N-dimethylformamide (1.00 mL), and potassium carbonate (45.2 mg) was added. The reaction mixture was stirred at 60 °C for 1 hour. The reaction solution was filtered, and the filtrate was concentrated to obtain the residue. The crude product was purified by preparative high-performance liquid chromatography (HPLC) (column: CD24-WePure Biotech XPT C18150). 25 7 μm; mobile phase: [10 mM ammonium bicarbonate aqueous solution-acetonitrile]; gradient elution program: 26%-56% acetonitrile, 12.0 min), yielding compound 39. LCMS: 423.1 [M+H] + . 1 H NMR: (400 MHz, DMSO- d6 ) d 10.89 (s,1H), 8.33 (d, J = 4.8 Hz, 2H), 7.31 - 7.21 (m, 2H), 7.15 (dd, J = 2.0, 7.2Hz, 1H), 6.65 (t, J = 4.8 Hz, 1H), 5.57 (s, 1H), 4.28 (dd, J = 5.2, 12.0 Hz,1H), 3.89 - 3.84 (m, 2H), 3.81 - 3.77 (m, 2H), 2.82 - 2.72 (m, 1H), 2.54 (d,J = 4.0 Hz, 1H), 2.45 (s, 2H), 2.37 (s, 2H), 2.28 (dd, J = 4.0, 12.4 Hz, 1H), 2.04 - 1.97 (m, 1H), 1.94 (t, J = 6.0 Hz, 2H).

[0364] Example 39: Synthesis of Compound 40

[0365] Compound 40-1 (1.00 g) was dissolved in DCM (10.0 mL), and a hydrogen chloride / dioxane solution (2.00 M, 5.00 mL) was added. The reaction mixture was stirred at 25 °C for 1 hour. After the reaction was complete, the reaction solution was concentrated to give compound 40-2.

[0366] Compound 40-2 (320 mg) was dissolved in a mixed solvent of tert-butanol (6.00 mL) and water (0.600 mL), followed by the addition of t-BuXPhos (35.9 mg), palladium acetate (6.33 mg), and potassium phosphate (838 mg). The reaction mixture was stirred at 100 °C for 1 hour under nitrogen protection. The reaction solution was filtered, and the filtrate was concentrated to obtain the residue. The crude product was purified by preparative high-performance liquid chromatography (HPLC) (column: CD51-WePure Biotech XPT C18 150). 40 7 μm; mobile phase: [10 mM ammonium bicarbonate aqueous solution-acetonitrile]; gradient elution program: 8%-38% acetonitrile, 11.0 min), yielding compound 40-3. LCMS: 217.1 [M+H] + . 1 H NMR: (400 MHz, CDCl3) d8.08 - 8.01 (m, 1H), 7.91 (d, J = 2.4 Hz, 1H), 7.14 (dd, J = 4.8, 8.4 Hz, 1H), 6.80 - 6.74 (m, 1H), 3.81 (s, 4H), 2.42 (t, J =6.8 Hz, 4H), 2.20 - 2.15 (m, 4H).

[0367] Under nitrogen protection, compound 40-3 (80.0 mg) was dissolved in tetrahydrofuran (1.00 mL), and hexamethyldisilamide lithium (1.00 M, 444 μL) was slowly added dropwise at -78 °C. The mixture was stirred at -78 °C for 1 hour. Subsequently, a solution of 1,1,1-trifluoro-N-phenyl-N-(trifluoromethylsulfonyl)methanesulfonamide (132 mg) in tetrahydrofuran (0.500 mL) was slowly added dropwise at -78 °C under nitrogen protection. After the addition was complete, the temperature was raised to 25 °C and stirring was continued for 12 hours. The reaction mixture was quenched with saturated ammonium chloride aqueous solution (2.00 mL) at 0 °C under nitrogen protection. The mixture was extracted with ethyl acetate (2.00 mL × 3 times), and the combined organic phases were washed with saturated brine (2.00 mL × 3 times), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product. The crude product was purified by preparative thin-layer chromatography (developing solvent: n-hexane / ethyl acetate = 0:1) to give compound 40-4. LCMS: 349.0 [M+H] + . 1 H NMR: (400 MHz, DMSO- d 6 ) d 7.74 (dd, J = 1.2, 4.4 Hz, 1H), 7.65 (d, J= 2.4 Hz, 1H), 7.00 (dd, J = 4.4, 8.4 Hz, 1H), 6.67 (ddd, J = 1.2, 2.8, 8.4Hz, 1H), 5.71 (t, J = 4.0 Hz, 1H), 3.53 (d, J = 7.2 Hz, 2H), 3.44 (d, J = 7.2Hz, 2H), 2.36 (d, J = 2.0 Hz, 2H), 2.31 - 2.25 (m, 2H), 1.84 (t, J = 6.4 Hz, 2H).

[0368] Compound 40-4 (30.0 mg) and intermediate A (45.2 mg) were dissolved in a mixed solvent of 1,4-dioxane (1.00 mL) and water (0.100 mL), followed by the addition of Pd(dppf)Cl2 (6.30 mg) and potassium carbonate (23.8 mg). The reaction mixture was stirred at 80 °C for 1 hour under nitrogen protection. The reaction solution was filtered, and the filtrate was concentrated to obtain the residue. The crude product was purified by preparative high-performance liquid chromatography (HPLC) (column: CD24-WePure Biotech XPT C18 150). 25 7 μm; mobile phase: [10 mM ammonium bicarbonate aqueous solution-acetonitrile]; gradient elution program: 32%-62% acetonitrile, 11.0 min), yielding compound 40. LCMS: 422.1 [M+H] + . 1 H NMR: (400 MHz, DMSO- d 6 ) d 10.89 (s, 1H), 7.92 - 7.87 (m, 1H),7.84 (d, J = 2.4 Hz, 1H), 7.31 - 7.22 (m, 2H), 7.19 - 7.11 (m, 2H), 6.86 -6.80 (m, 1H), 5.58 (s, 1H), 4.32 - 4.23 (m, 1H), 3.75 - 3.71 (m, 2H), 3.69 -3.65 (m, 2H), 2.77 (ddd, J = 5.2, 12.4, 17.6 Hz, 1H), 2.54 (d, J = 3.6 Hz,1H), 2.47 (s, 2H), 2.37 (s, 2H), 2.33 - 2.24 (m, 1H), 2.01 (dd, J = 4.0, 9.2Hz, 1H), 1.98 - 1.93 (m, 2H).

[0369] Example 40: Synthesis of Compound 41

[0370] Compound 41-1 (50.0 mg) and nicotinic acid (14.0 mg) were dissolved in DCM (1.00 mL), and acetic acid (6.54 mg) was added. The reaction mixture was stirred at 20 °C for 0.5 h. Then, sodium triacetoxyborohydride (69.3 mg) was added to the mixture, and stirring was continued at 20 °C for 1 h. The reaction mixture was concentrated under reduced pressure to obtain the residue. The crude product was purified by preparative high-performance liquid chromatography (pHPLC) (column: CD24-WePure Biotech XPT C18 150). 25 7 μm; mobile phase: [10 mM ammonium bicarbonate aqueous solution-acetonitrile]; gradient elution program: 23%-53% acetonitrile, 12.0 min), yielding compound 41. LCMS: / z = 436.1 [M+H] + . 1 H NMR: (400 MHz, DMSO- d 6 ) d 10.88 (s, 1H), 8.53 - 8.40 (m, 2H), 7.68 (d, J = 8.0 Hz, 1H), 7.34 (dd, J = 4.8, 7.6 Hz, 1H), 7.28 - 7.18 (m, 2H), 7.10 (dd, J = 1.6, 7.2 Hz, 1H), 5.52 (s, 1H), 4.24 (dd, J = 5.2, 12.0 Hz,1H), 3.62 (s, 2H), 3.06 - 2.98 (m, 4H), 2.80 - 2.70 (m, 1H), 2.54 - 2.52 (m,1H), 2.35 (s, 2H), 2.27 (s, 3H), 2.03 - 1.94 (m, 1H), 1.85 (t, J = 6.0 Hz, 2H).

[0371] Example 41: Synthesis of Compound 42

[0372] 7-Bromo-3-ioimidazolo[1,2-a]pyridine (1.00 g) and pyridine-2(1H)-one (442 mg) were dissolved in DMSO (20.0 mL), and cuprous iodide (118 mg), potassium carbonate (856 mg), and 2-(dimethylamino)acetic acid (575 mg) were added sequentially. The reaction mixture was stirred at 100 °C for 5 hours under nitrogen protection. The reaction mixture was diluted with water (10.0 mL) and extracted with ethyl acetate (10.0 mL × 3). The combined organic phases were washed with saturated brine (10.0 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (elution gradient of petroleum ether / ethyl acetate = 100:1 to 1:2) to give compound 42-1. LCMS: m / z = 290.0 [M+H] + ¹H NMR: (400 MHz, DMSO-d⁶) d 8.04 (d, J = 1.4 Hz, 1H), 7.88 (d, J= 7.3 Hz, 1H), 7.78 (s, 1H), 7.69 (dd, J = 1.4, 6.8 Hz, 1H), 7.64 (ddd, J =2.0, 6.8, 9.1 Hz, 1H), 7.14 (dd, J = 1.9, 7.3 Hz, 1H), 6.59 (d, J = 9.3 Hz, 1H), 6.42 (dt, J = 1.2, 6.7 Hz, 1H).

[0373] Compound 42-1 (70.0 mg) and intermediate A (127 mg) were dissolved in a mixed solvent of 1,4-dioxane (2.00 mL) and water (0.200 mL), followed by the addition of potassium carbonate (66.7 mg) and Pd(dppf)Cl2 (17.7 mg). The reaction mixture was stirred at 80 °C for 2 hours under nitrogen protection. The reaction mixture was diluted with water (5.00 mL) and extracted with ethyl acetate (5.00 mL × 4). The combined organic phases were washed with saturated brine (5.00 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by preparative high-performance liquid chromatography (HPLC) (column: CD07-Daisogel SP-100-8-ODS-PK 150×25×10 μm; mobile phase: [water (containing 10 mM NH4HCO3)-acetonitrile]; gradient: 8%-38% B phase, 12.0 min) to give compound 42. LCMS: 433.0 [M+H] + . 1 H NMR: (400 MHz, DMSO- d 6) d10.94 (s, 1H), 7.96 (dd, J = 0.8, 7.2 Hz, 1H), 7.83 (s, 1H), 7.74 (dd, J = 1.6, 6.8 Hz, 1H), 7.71 (d, J = 1.6 Hz, 1H), 7.66(ddd, J = 2.0, 6.8, 9.2 Hz, 1H), 7.48 - 7.43 (m, 3H), 7.05 (dd, J = 1.6, 7.2Hz, 1H), 6.61 (d, J = 9.2 Hz, 1H), 6.44 (dt, J = 1.2, 6.8 Hz, 1H), 4.38 (dd,J = 5.2, 12.4 Hz, 1H), 2.86 - 2.75 (m, 1H), 2.60 - 2.54 (m, 1H), 2.43 - 2.30 (m, 1H), 2.11 - 2.02 (m, 1H).

[0374] Example 42: Synthesis of Compound 43

[0375] 7-Bromo-3-ioimidazolo[1,2-a]pyridine (1.00 g) and pyridine-2(1H)-one (442 mg) were dissolved in DMSO (20.0 mL), followed by the addition of cuprous iodide (118 mg), potassium carbonate (856 mg), and 2-(dimethylamino)acetic acid (575 mg). The reaction mixture was stirred at 100 °C for 5 hours under nitrogen protection. The reaction mixture was diluted with water (10.0 mL) and extracted with ethyl acetate (10.0 mL × 3). The combined organic phases were washed with saturated brine (10.0 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (elution gradient of petroleum ether / ethyl acetate = 100:1 to 1:2) to give compound 43-1. LCMS: m / z = 290.0 [M+H] + ¹H NMR: (400 MHz, DMSO-d⁶) d 8.11 (ddd, J = 0.4, 2.0, 4.8 Hz,1H), 8.02 (dd, J = 0.8, 7.2 Hz, 1H), 7.96 (ddd, J = 2.0, 7.2, 8.4 Hz, 1H),7.92 - 7.89 (m, 1H), 7.49 (s, 1H), 7.29 (d, J= 8.4 Hz, 1H), 7.23 (ddd, J =0.8, 5.2, 7.2 Hz, 1H), 7.03 (dd, J = 2.0, 7.2 Hz, 1H).

[0376] Compound 43-1 (100 mg) and intermediate A (180 mg) were dissolved in a mixed solvent of 1,4-dioxane (1.00 mL) and water (0.10 mL), followed by the sequential addition of potassium carbonate (95.2 mg) and Pd(dppf)Cl2 (25.2 mg). The reaction mixture was stirred at 80 °C for 2 hours under nitrogen protection. The reaction mixture was diluted with water (5 mL) and extracted with ethyl acetate (5 mL × 4). The combined organic phases were washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by preparative high-performance liquid chromatography (HPLC) (column: CD24-WePure Biotech XPT C18 150×25×7 μm; mobile phase: [water (containing 10 mMNH4HCO3)-acetonitrile]; gradient: 13%-43% B phase, 15.0 min) to give compound 43. LCMS: 433.5 [M+H] + . 1 HNMR: (400 MHz, DMSO- d 6) d 10.93 (s, 1H), 8.17 - 8.13 (m, 1H), 8.09 (dd, J =0.8, 7.2 Hz, 1H), 8.01 - 7.95 (m, 1H), 7.60 - 7.57 (m, 1H), 7.53 (s, 1H),7.47 - 7.43 (m, 2H), 7.43 - 7.40 (m, 1H), 7.33 (d, J = 8.4 Hz, 1H), 7.24(ddd, J = 0.8, 5.2, 7.2 Hz, 1H), 6.96 (dd, J = 1.6, 7.2 Hz, 1H), 4.37 (dd, J = 4.8, 12.4 Hz, 1H), 2.86 - 2.75 (m, 1H), 2.54 (s, 1H), 2.41 - 2.29 (m, 1H), 2.12 - 2.02 (m, 1H).

[0377] Example 43: Synthesis of Compound 44

[0378] 7-Bromo-3-iodomizo[1,2-a]pyridine (1.00 g) and 6-methylpyridin-2(1H)-one (507 mg) were dissolved in DMSO (20.0 mL), followed by the addition of cuprous iodide (18.0 mg), potassium carbonate (856 mg), and 2-(dimethylamino)acetic acid (575 mg). The reaction mixture was stirred at 100 °C for 5 hours under nitrogen protection. The reaction mixture was diluted with water (10.0 mL) and extracted with ethyl acetate (10.0 mL × 3). The combined organic phases were washed with saturated brine (10.0 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (elution gradient of petroleum ether / ethyl acetate = 100:1 to 1:2) to give compound 44-1. LCMS: m / z = 304.0 [M+H] + . 1 H NMR: (400 MHz, DMSO- d 6) d 8.03 (d, J = 1.3 Hz, 1H), 7.89 (d, J = 7.3 Hz, 1H), 7.77 (s, 1H), 7.53 (dd, J = 6.8, 9.3 Hz, 1H), 7.12 (dd, J = 1.9, 7.2 Hz, 1H), 6.43 (d, J = 9.3 Hz, 1H), 6.36 (d, J = 6.8 Hz, 1H), 1.97 (s, 3H).

[0379] Compound 44-1 (90 mg) and intermediate A (155.18 mg) were dissolved in a mixed solvent of 1,4-dioxane (2.00 mL) and water (0.100 mL), followed by the addition of potassium carbonate (81.79 mg) and Pd(dppf)Cl2 (21.65 mg). The reaction mixture was stirred at 80 °C for 2 hours under nitrogen protection. The reaction mixture was diluted with water (5.00 mL) and extracted with ethyl acetate (5.00 mL × 4). The combined organic phases were washed with saturated brine (5.00 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by preparative high-performance liquid chromatography (column: CD24-WePure Biotech XPT C18 150×25×7 μm; mobile phase: [water (containing 10 mM NH4HCO3)-acetonitrile]; gradient: 18%-48% B phase, 15.0 min) to give compound 44-1. LCMS:447.1[M+H] + . 1 H NMR: (400 MHz, DMSO- d6) d 10.94 (s, 1H), 7.99 - 7.93 (m, 1H), 7.82 (s, 1H), 7.71 (d, J = 0.8 Hz, 1H), 7.54 (dd, J = 6.8, 9.2 Hz, 1H), 7.49 - 7.41 (m,3H), 7.04 (td, J = 2.0, 7.2 Hz, 1H), 6.45 (d, J = 9.2 Hz, 1H), 6.38 (d, J =6.8 Hz, 1H), 4.38 (dd, J = 4.8, 12.4 Hz, 1H), 2.86 - 2.74 (m, 1H), 2.59 -2.53 (m, 1H), 2.41 - 2.30 (m, 1H), 2.11 - 2.03 (m, 1H), 2.01 (s, 3H).

[0380] Example 44: Synthesis of compounds 45 and 46

[0381] 7-Bromo-3-iodoimidazolo[1,2-a]pyridine (100 mg) and (1-methyl-2-oxo-1,2-dihydropyridin-3-yl)boronic acid (71.0 mg) were dissolved in a mixed solvent of 1,4-dioxane (1.00 mL) and water (0.100 mL), followed by the addition of potassium carbonate (90.9 mg) and Pd(dppf)Cl2 (22.7 mg). The reaction mixture was stirred at 80 °C for 1 hour. The reaction mixture was diluted with water (10.0 mL) and extracted with ethyl acetate (10.0 mL × 3 times). The combined organic phases were washed with saturated brine (10.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The crude product was purified by silica gel column chromatography (elution gradient: dichloromethane / methanol = 1 / 1 to 10 / 1) to give compound 45-1. LCMS: 305.9 [M + H] + .

[0382] Compound 451 (100 mg) and intermediate A (172 mg) were dissolved in a mixed solvent of 1,4-dioxane (2.00 mL) and water (0.200 mL), followed by the addition of potassium carbonate (90.9 mg) and Pd(dppf)Cl2 (24.1 mg). The reaction mixture was stirred at 80 °C for 2 hours under nitrogen protection. The reaction mixture was diluted with water (5.00 mL) and extracted with ethyl acetate (5.00 mL × 3 times). The combined organic phases were washed with saturated brine (5.00 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The crude product was purified by preparative high-performance liquid chromatography (HPLC) (column: CD45-Waters XbridgeBEH C18 150). 40 mm 10 μm; mobile phase: [10 mM ammonium bicarbonate aqueous solution-acetonitrile]; gradient elution program: 14%-44% acetonitrile, 12.0 min), yielding compound 45. LCMS: 447.2 [M+H] + . 1 H NMR: (400 MHz, DMSO- d 6 ) d 10.94 (s, 1H), 8.11 - 8.08 (m, 1H), 7.92 (dd, J = 2.0, 6.8 Hz, 1H), 7.76 -7.72 (m, 2H), 7.64 - 7.62 (m, 1H), 7.47 - 7.41 (m, 3H), 6.98 (dd, J = 1.6,7.2 Hz, 1H), 6.42 (t, J = 6.8 Hz, 1H), 4.38 (dd, J = 5.2, 12.0 Hz, 1H), 3.58(s, 3H), 2.86 - 2.75 (m, 1H), 2.60 - 2.54 (m, 1H), 2.42 - 2.30 (m, 1H), 2.12-2.03 (m, 1H).

[0383] Compound 46 was obtained by referring to the preparation method of compound 45:

[0384] Example 45: Synthesis of compounds 47, 48 and 49

[0385] 7-Bromo-3-ioimidazolo[1,2-a]pyridine (1.00 g) and 7-oxa-4-azaspiro[2.5]octane-5-one (591 mg) were dissolved in DMSO (20.0 mL), followed by the addition of dimethylglycine (575 mg), bis[(Z)-1-methyl-3-oxo-but-1-enoxy]copper (162 mg), and potassium carbonate (856 mg). The reaction mixture was stirred at 100 °C for 4 hours under nitrogen protection. The reaction mixture was diluted with water (10.0 mL) and extracted with ethyl acetate (10.0 mL × 3 times). The combined organic phases were washed with saturated brine (10.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The crude product was purified by silica gel column chromatography (elution gradient: n-hexane / ethyl acetate = 1 / 0 to 0 / 1) to give compound 47-1. LCMS: 324.7 [M + H] + .

[0386] Compound 47-1 (30.0 mg) and intermediate A (65.1 mg) were dissolved in a mixed solvent of 1,4-dioxane (0.500 mL) and water (0.0500 mL), followed by the addition of potassium carbonate (25.7 mg) and Pd(dppf)Cl2 (6.81 mg). The reaction mixture was stirred at 80 °C for 2 hours under nitrogen protection. The reaction mixture was diluted with water (5.00 mL) and extracted with ethyl acetate (5.00 mL × 3 times). The combined organic phases were washed with saturated brine (5.00 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The crude product was purified by preparative high-performance liquid chromatography (HPLC) (column: CD24-WePure Biotech XPT C18 150). 25 7 μm; mobile phase: [10 mM ammonium bicarbonate aqueous solution-acetonitrile]; gradient elution program: 7%-37% acetonitrile, 12.0 min), to give compound 47. LCMS: 465.1 [M+H] + . 1 H NMR: (400 MHz, DMSO- d 6 ) d10.94(s, 1H), 8.33 (dd, J = 0.8, 7.2 Hz, 1H), 7.63 (s, 2H), 7.48 - 7.41 (m, 3H),7.10 - 7.05 (m, 1H), 4.58 - 4.44 (m, 2H), 4.42 - 4.34 (m, 2H), 3.74 (d, J =11.6 Hz, 1H), 2.86 - 2.76 (m, 1H), 2.59 - 2.53 (m, 1H), 2.41 - 2.31 (m, 1H),2.11 - 2.02 (m, 1H), 0.99 - 0.85 (m, 2H), 0.72 - 0.63 (m, 1H), -0.04 (td, J =6.4, 10.4 Hz, 1H).

[0387] The following compounds were prepared using the same method as compound 47 to obtain compounds 48 and 49.

[0388]

[0389] Example 46: Synthesis of Compound 50

[0390] 7-Bromo-3-ioimidazolo[1,2-a]pyridine (200 mg) and 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)pyridin-2(1H)-one (218 mg) were dissolved in a mixed solvent of 1,4-dioxane (2.00 mL) and water (0.200 mL), followed by the addition of potassium carbonate (171 mg) and Pd(dppf)Cl2 (90.6 mg). The reaction mixture was stirred at 60 °C for 2 hours under nitrogen protection. After the reaction was complete, the reaction mixture was diluted with water (10.0 mL) and extracted with ethyl acetate (10.0 mL × 3 times). The combined organic phases were washed with saturated brine (10.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The crude product was purified by silica gel column chromatography (elution gradient: n-hexane / ethyl acetate = 1 / 0 to 10 / 1) to give compound 50-1. LCMS: 303.9 [M+H] + .

[0391] Compound 501 (100 mg) and intermediate A (172 mg) were dissolved in a mixed solvent of 1,4-dioxane (2.00 mL) and water (0.200 mL), followed by the addition of potassium carbonate (90.9 mg) and Pd(dppf)Cl2 (24.1 mg). The reaction mixture was stirred at 80 °C for 2 hours under nitrogen protection. After the reaction was complete, the reaction mixture was diluted with water (5.00 mL) and extracted with ethyl acetate (5.00 mL × 3 times). The combined organic phases were washed with saturated brine (5.00 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The crude product was purified by preparative high-performance liquid chromatography (HPLC) (column: CD02-WatersXbridge BEH C18 100). 25 mm 10 μm; mobile phase: [10 mM ammonium bicarbonate aqueous solution-acetonitrile]; gradient elution program: 7%-37% acetonitrile, 12.0 min), to give compound 50. LCMS: 447.2 [M+H] + . 1 H NMR: (400 MHz, DMSO-d6) δ 10.95 (s, 1H), 8.50 (d, J = 7.2 Hz, 1H), 8.14 (d, J = 2.4 Hz, 1H), 7.75- 7.70 (m, 2H), 7.65 (s, 1H), 7.48 - 7.41 (m, 3H), 7.03 (dd, J = 1.6, 7.2 Hz,1H), 6.57 (d, J = 9.2 Hz, 1H), 4.38 (dd, J = 5.2, 12.4 Hz, 1H), 3.53 (s, 3H),2.88 - 2.75 (m, 1H), 2.58 (d, J = 3.6 Hz, 1H), 2.42 - 2.30 (m, 1H), 2.13 -2.02 (m, 1H).

[0392] Example 47: Synthesis of compounds 51 and 52

[0393] Compound 51-1 (1.00 g) was dissolved in N,N-dimethylformamide (10.0 mL), and N-iodosuccinimide (1.36 g) was added in portions. The reaction mixture was stirred at 90 °C for 12 hours. The reaction mixture was then slowly poured into ice water (30 mL) while stirring vigorously. After filtration, washing with water, and vacuum drying, compound 51-2 was obtained. LCMS: 323.8 [M+H] + . 1H NMR: (400 MHz, DMSO- d 6) d 8.25 (d, J = 7.2 Hz, 1H), 8.21 (d, J = 0.8 Hz, 1H), 7.18 (dd, J =1.6, 7.2 Hz, 1H).

[0394] Compound 51-2 (1.00 g) and pyridin-2(1H)-one (440 mg) were dissolved in DMSO (10.0 mL), and cuprous iodide (118 mg), potassium carbonate (853 mg), and N,N-dimethylglycine (573 mg) were added sequentially. The reaction mixture was stirred at 80 °C for 16 hours under nitrogen protection. The reaction mixture was diluted with water (10.0 mL) and extracted with ethyl acetate (10.0 mL × 3). The combined organic phases were washed with saturated brine (10.0 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by preparative high-performance liquid chromatography (column: CD03-Welch Xtimate C18 150 × 25 mm × 5 μm; mobile phase: [water (containing 0.225% formic acid) - acetonitrile]; gradient: 0%-30% B phase, 10.0 min) to give compound 51-3. LCMS: Rt = 0.249 min, 291.0 [M+H] + .

[0395] Compound 51-2 (500 mg) and pyridine-2(1H)-one (220 mg) were dissolved in DMSO (10.0 mL), followed by the addition of cuprous iodide (58.8 mg), potassium carbonate (426 mg), and 2-(dimethylamino)acetic acid (286 mg). The reaction mixture was stirred at 80 °C for 12 hours under nitrogen protection. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (30 mL, 10 mL divided into three portions). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (elution gradient of petroleum ether / ethyl acetate = 100:1 to 0:1) to give compound 51-4. LCMS: Rt = 0.344 min, 290.9 [M+H] + . 1 H NMR: (400 MHz, DMSO- d 6) d 8.17 (s, 1H), 8.13 - 8.09 (m, 2H), 8.06 - 8.01 (m, 1H), 7.43 (d, J= 8.4 Hz, 1H), 7.31 (dd, J = 5.2, 7.2 Hz, 1H), 7.08 (dd, J = 1.6, 7.2 Hz, 1H).

[0396] Compound 51-3 (20.0 mg) and intermediate A (18.0 mg) were dissolved in a mixed solvent of 1,4-dioxane (0.500 mL) and water (0.100 mL), followed by the addition of potassium carbonate (9.50 mg) and Pd(dppf)Cl2 (2.51 mg). The reaction mixture was stirred at 80 °C for 2 hours under nitrogen protection. The reaction mixture was diluted with water (5.00 mL) and extracted with ethyl acetate (5.00 mL × 3). The combined organic phases were washed with saturated brine (5.00 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by preparative high-performance liquid chromatography (pHPLC) (column: CD24-WePure Biotech XPT C18 150 × 25 × 7 μm; mobile phase: [water (containing 10 mMNH4HCO3)-acetonitrile]; gradient: 5%-35% B phase, 10.0 min) to give compound 51. LCMS: 434.1 [M+H] + . 1 HNMR: (400 MHz, DMSO- d 6 ) d 10.95 (s, 1H), 8.16 (dd, J = 0.8, 7.2 Hz, 1H), 7.95(s, 1H), 7.83 (dd, J = 1.6, 6.8 Hz, 1H), 7.72 (ddd, J = 2.0, 6.8, 9.2 Hz,1H), 7.51 - 7.47 (m, 3H), 7.13 (dd, J = 1.6, 7.2 Hz, 1H), 6.65 (d, J = 9.2Hz, 1H), 6.56 - 6.50 (m, 1H), 4.39 (dd, J = 5.2, 12.0 Hz, 1H), 2.79 (dd, J =4.8, 12.8 Hz, 1H), 2.58 (d, J = 3.6 Hz, 1H), 2.39 - 2.32 (m, 1H), 2.11 - 2.02 (m, 1H).

[0397] Compound 51-4 (80.0 mg) and intermediate A (192 mg) were dissolved in a mixed solvent of 1,4-dioxane (2.00 mL) and water (0.20 mL), followed by the addition of potassium carbonate (75.9 mg) and Pd(dppf)Cl2 (20.1 mg). The reaction mixture was stirred at 80 °C for 2 hours under nitrogen protection. The reaction mixture was diluted with water (5 mL) and extracted with ethyl acetate (5 mL × 4). The combined organic phases were washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by preparative high-performance liquid chromatography (HPLC) (column: CD07-Daisogel SP-100-8-ODS-PK 150 × 25 × 10 μm; mobile phase: [water (containing 10 mMNH4HCO3)-acetonitrile]; gradient: 15%-45% B phase, 13.0 min) to give 52. LCMS: 434.1 [M+H] + . 1 H NMR: (400 MHz, DMSO- d 6) d 10.98 - 10.90 (m, 1H), 8.19 (dd, J = 0.8, 7.2 Hz, 1H),8.16 - 8.13 (m, 1H), 8.05 (ddd, J = 2.0, 7.2, 8.4 Hz, 1H), 7.79 (t, J = 1.2Hz, 1H), 7.51 - 7.44 (m, 4H), 7.32 (ddd, J = 0.8, 5.2, 7.2 Hz, 1H), 7.00 (dd, J = 1.6, 7.2 Hz, 1H), 4.38 (dd, J = 5.2, 12.4 Hz, 1H), 2.81 (ddd, J = 5.2,12.4, 17.6 Hz, 1H), 2.60 - 2.54 (m, 1H), 2.35 (dq, J = 4.4, 12.8 Hz, 1H), 2.12 - 2.01 (m, 1H).

[0398] Example 48: Synthesis of Compound 53

[0399] Compound 53-1 (15.0 g) was dissolved in water (300 mL), and 1-bromo-2,2-dimethoxypropane (106 g) and p-toluenesulfonic acid (4.16 g) were added sequentially. The reaction mixture was stirred at 100 °C for 16 hours. After the reaction was complete, the reaction mixture was diluted with water (10.0 mL) and extracted with ethyl acetate (10.0 mL × 3 times). The combined organic phases were washed with saturated brine (10.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The crude product was purified by silica gel column chromatography (elution gradient: n-hexane / ethyl acetate = 100 / 1 to 1 / 1) to give compound 53-2. LCMS: 163.1 [M+H] + .

[0400] Compound 53-2 (2.70 g) was dissolved in THF (30.0 mL), and N-bromosuccinimide (2.96 g) was added. The reaction mixture was stirred at -78 °C for 0.5 h. After the reaction was complete, the reaction mixture was diluted with water (10.0 mL) and extracted with ethyl acetate (10.0 mL × 3 times). The combined organic phases were washed with saturated brine (10.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The crude product was purified by silica gel column chromatography (elution gradient: n-hexane / ethyl acetate = 100 / 1 to 1 / 1) to give compound 53-3. LCMS: 241.0 [M+H] + . 1 H NMR: (400 MHz, DMSO- d 6) d 8.07 (d, J = 7.5 Hz, 1H), 6.91 (d, J = 2.4 Hz, 1H), 6.70 (dd, J = 2.5, 7.5 Hz, 1H), 3.83 (s, 3H), 2.27 (s, 3H).

[0401] Compound 53-3 (1.00 g) and pyridin-2(1H)-one (592 mg) were dissolved in DMSO (20.0 mL), and cuprous iodide (158 mg), potassium carbonate (1.15 g), and dimethylglycine (770 mg) were added sequentially. The reaction system was stirred at 100 °C for 12 hours under nitrogen protection. After the reaction was complete, the pH was adjusted to 7 with saturated sodium bicarbonate solution (50.0 mL), and the mixture was extracted with ethyl acetate (20.0 mL × 5 times). The combined organic phases were washed with saturated brine (30.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The crude product was purified by preparative high performance liquid chromatography (column: CD19-Daisogel SP-100-8-ODS-PK 200). 50 10 μm; mobile phase: [10 mM ammonium bicarbonate aqueous solution-acetonitrile]; gradient elution program: 0%-30% acetonitrile, 11.0 min), to give compounds 53-4. LCMS: 256.0 [M+H] + . 1 H NMR: (400 MHz, DMSO- d 6) d 7.66 - 7.59 (m, 3H), 6.93 (d, J = 2.4 Hz, 1H), 6.62 - 6.56 (m, 2H), 6.40 (d, J = 1.2 Hz, 1H), 3.84 (s, 3H), 2.16 (s, 3H).

[0402] Compound 53-4 (90.0 mg) was dissolved in dichloroethane (2.00 mL) and cooled to 0°C in an ice bath under nitrogen protection. Boron tribromide (1.76 mL) was slowly added dropwise using a syringe over 5 minutes, maintaining an internal temperature of 0°C. The reaction mixture was then heated to 70°C and stirred under nitrogen protection for 12 hours. The reaction was quenched by slowly adding saturated sodium bicarbonate solution (30.0 mL) over 15 minutes at 25°C to avoid violent gas release and temperature rise. The reaction mixture was extracted with a 10 / 10 dichloromethane / methanol mixture (6 × 20.0 mL). After drying the aqueous phase, it was added to a 5 / 10 dichloromethane / methanol mixture (20.0 mL), stirred at 25°C for 0.5 hours, filtered, and the filtrate was concentrated under reduced pressure to give compound 53-5. LCMS: 242.1 [M+H] + .

[0403] In a 10 mL double-necked round-bottom flask equipped with a magnetic stirrer, compound 53-5 (270 mg) and anhydrous dichloromethane (6.00 mL) were added. The flask was sealed with a rubber diaphragm and purged three times with nitrogen. The solution was cooled to 0°C using a dry ice / ethanol bath. Under nitrogen protection, N,N-diisopropylethylamine (217 mg) was slowly added dropwise using a syringe over a period of 1 minute, maintaining an internal temperature of 0°C. Subsequently, 1,1,1-trifluoro-N-phenyl-N-(trifluoromethylsulfonyl)methanesulfonamide (400 mg) was slowly added dropwise using a syringe over a period of 10 minutes. The reaction mixture was heated to 25°C and stirred for 12 hours. After the reaction was complete, the reaction was quenched by slowly adding water (10.0 mL) dropwise at 0±5°C under nitrogen protection, with strict temperature control to avoid exothermic reactions. The mixture was extracted with ethyl acetate (10.0 mL × 3 times), and the combined organic phases were washed with saturated brine (10.0 mL × 3 times). After drying over anhydrous sodium sulfate, the mixture was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (elution gradient: n-hexane / ethyl acetate = 100 / 1 to 1 / 1) to give compounds 53-6. LCMS: 374.1 [M+H] + .

[0404] Compound 53-6 (40.0 mg) and intermediate A (56.2 mg) were dissolved in a mixed solvent of 1,4-dioxane (1.00 mL) and water (0.100 mL), followed by the addition of potassium carbonate (29.6 mg) and Pd(dppf)Cl2 (7.84 mg). The reaction mixture was stirred at 80 °C for 2 hours under nitrogen protection. After the reaction was complete, the reaction mixture was diluted with water (5.00 mL) and extracted with ethyl acetate (5.00 mL × 4 times). The combined organic phases were washed with saturated brine (10.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by preparative high-performance liquid chromatography (HPLC) (column: CD24-WePure Biotech XPT C18 150). 25 7 μm; mobile phase: [10 mM ammonium bicarbonate aqueous solution-acetonitrile]; gradient elution program: 9%-39% acetonitrile, 10.0 min), to give compound 53. LCMS: 447.1 [M+H] + . 1 H NMR: (400 MHz, DMSO- d 6) d10.94(s, 1H), 7.88 (d, J = 7.2 Hz, 1H), 7.73 (dd, J = 1.6, 6.8 Hz, 1H), 7.66 (ddd,J = 2.0, 6.8, 9.2 Hz, 1H), 7.59 (s, 1H), 7.47 - 7.41 (m, 3H), 7.01 - 6.97 (m,1H), 6.62 (d, J = 9.2 Hz, 1H), 6.45 (dt, J = 1.2, 6.8 Hz, 1H), 4.37 (dd, J =5.2, 12.0 Hz, 1H), 2.80 (ddd, J = 5.2, 12.4, 17.6 Hz, 1H), 2.59 - 2.53 (m,1H), 2.41 - 2.30 (m, 1H), 2.26 (s, 3H), 2.12 - 2.01 (m, 1H).

[0405] Example 49: Synthesis of Compound 54

[0406] Compound 54-1 (1 g) was suspended in methanol (15 mL), and ethyl 2-oxoacetate (1.30 g, 50% purity) was added. The mixture was heated to 60 °C and stirred for 2 hours, then cooled to 25 °C and concentrated under reduced pressure. The residue was dissolved in dichloromethane (15 mL) and cooled to 0 °C, and [acetoxy(phenyl)iodonium]acetate (2.23 g) was added in portions. After the addition was complete, the reaction mixture was transferred to 25 °C and stirred. LCMS analysis showed complete conversion of the starting material. After concentration under reduced pressure, the residue was purified by rapid silica gel column chromatography (20 g silica gel column, petroleum ether / ethyl acetate = 0-50% gradient elution, flow rate 40 mL / min) to give compound 54-2. LCMS: 269.9 [M+H] + .

[0407] Compound 54-2 (0.91 g) was dissolved in a mixed solvent of tetrahydrofuran (5 mL) and methanol (1 mL), and sodium borohydride (255 mg) was added at 0 °C. The reaction mixture was stirred at 25 °C. LC-MS analysis showed complete conversion of the starting material. The reaction mixture was quenched with saturated ammonium chloride solution (10 mL), and the aqueous phase was extracted with ethyl acetate (25 mL × 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give compound 54-3, which was used directly in the next reaction without purification. LC-MS: 229.9 [M+H] + .

[0408] Compound 54-3 (300 mg) was dissolved in dichloromethane (5 mL), and thionyl chloride (235 mg) was added at 0 °C. The reaction mixture was stirred at 25 °C for 16 hours. LCMS analysis showed that there was still a starting material residue, but the target product was detected. After the reaction mixture was concentrated under reduced pressure, the residue was purified by rapid silica gel column chromatography (20 g silica gel column, dichloromethane / methanol gradient elution of 0–5%, flow rate 30 mL / min) to give compound 54-4. LCMS: 245.9 [M+H] + .

[0409] 75 mg of methylpyridinone was dissolved in 2 mL of DMF, and sodium hydride (41 mg, 60% purity) was added at 0 °C under nitrogen protection. After stirring at 0 °C for 0.5 hours, 85 mg of compound 187-4 was added. The mixture was stirred at 25 °C. LC-MS analysis showed complete conversion of the starting material. After the reaction was complete, the reaction solution was quenched by slowly pouring it into a saturated ammonium chloride solution (10 mL) under nitrogen protection and an ice-water bath (0–5 °C), and extracted with ethyl acetate (5 mL × 5). The combined organic phases were washed with saturated brine (5 mL × 3), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 10:1) to give compound 54-5. LC-MS: 318.9 [M+H] + .

[0410] Compound 54-5 (85 mg) and compound A (140 mg) were dissolved in a mixed solvent of 1,4-dioxane (4 mL) and water (0.01 mL), followed by the sequential addition of Pd(dppf)Cl2 (19 mg) and potassium carbonate (74 mg). The reaction mixture was stirred at 80 °C. After filtration, the reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative high-performance liquid chromatography (HPLC) (column: CD24-WePureBiotech XPT C18 150×25×7 μm; mobile phase: [water (containing 0.225% formic acid)-acetonitrile]; gradient: 6%-36% B phase, 16.0 min) to obtain compound 54. LCMS: 462.1 [M+H ]+ ; 1 H NMR: (400 MHz, DMSO- d6)δ10.95 (s,1H), 8.79 (dd, J = 0.8, 7.2 Hz, 1H), 7.88 - 7.75 (m, 2H), 7.47 (s, 3H), 7.38- 7.32 (m, 1H), 7.16 (dd, J = 1.6, 7.2 Hz, 1H), 6.26 (t, J = 6.8 Hz, 1H), 5.67 (s, 2H), 4.38 (dd, J = 5.2, 12.4 Hz, 1H), 2.87 - 2.75 (m, 1H), 2.55 -2.52 (m, 1H), 2.40 - 2.32 (m, 1H), 2.09 - 2.02 (m, 1H), 1.98 (s, 3H).

[0411] Example 50: Synthesis of Compound 55

[0412] Compound 55-1 (2.00 g) was dissolved in ethanol (10.0 mL), and 3-bromo-1,1,1-trifluoroprop-2-one (4.61 g) was added. The reaction mixture was stirred at 100 °C for 16 hours. The reaction mixture was quenched with saturated sodium bicarbonate solution (15.0 mL), filtered through a Buchner funnel, and washed with ethanol (10.0 mL) to remove unreacted starting material. The residue was concentrated under reduced pressure and purified by silica gel column chromatography (elution with petroleum ether / ethyl acetate at a gradient of 100:1 to 2:1) to give compound 55-2. LCMS: 217.0 [M+H] + . 1 H NMR: (400 MHz, DMSO- d 6) d 8.43 (d, J = 7.6 Hz, 1H), 8.31 (s, 1H), 7.01 (d, J = 2.4 Hz, 1H), 6.78 (dd, J = 2.4, 7.6 Hz, 1H), 3.85 (s, 3H).

[0413] Compound 55-2 (700 mg) was dissolved in acetic acid (7.00 mL), and N-bromosuccinimide (691 mg) was added. The reaction mixture was stirred at 25 °C for 12 hours. After the acetic acid was removed by vacuum distillation, saturated sodium bicarbonate solution (20.0 mL) was added, and the mixture was extracted with ethyl acetate (10.0 mL × 3). The organic phase was washed with saturated brine (20.0 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (elution with a gradient of petroleum ether / ethyl acetate = 100:1 to 2:1) to give compound 55-3. LCMS: 295.0 [M+H] + . 1 H NMR: (400 MHz, DMSO- d 6) d 8.30 (d, J = 7.6 Hz, 1H), 7.13 (d, J = 2.4 Hz, 1H), 6.92 (dd, J = 2.4, 7.6 Hz, 1H), 3.88 (s, 3H).

[0414] Compound 55-3 (730 mg) and pyridin-2(1H)-one (352 mg) were dissolved in DMSO (14.0 mL), and cuprous iodide (94.2 mg), potassium carbonate (1.03 g), and 2-(dimethylamino)acetic acid (459 mg) were added sequentially. The reaction mixture was stirred at 100 °C for 12 hours under nitrogen protection. The reaction mixture was diluted with water (10.0 mL) and extracted with ethyl acetate (10.0 mL × 4). The combined organic phases were washed with saturated brine (10.0 mL × 2), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (elution gradient of petroleum ether / ethyl acetate = 100:1 to 0:1) to give compound 55-4. LCMS: 310.1 [M + H] + . 1 H NMR: (400MHz, DMSO- d 6) d 8.09 (dd, J = 1.6, 4.8 Hz, 1H), 8.02 - 7.96 (m, 2H), 7.35 (d, J = 8.4 Hz, 1H), 7.26 (dd, J = 5.2, 6.4 Hz, 1H), 7.03 (d, J = 2.4 Hz, 1H), 6.73 (dd, J= 2.4, 7.6 Hz, 1H), 3.87 (s, 3H).

[0415] Compound 55-4 (100 mg) was dissolved in dichloroethane (2.00 mL) and cooled to 0 °C under nitrogen protection and an ice bath. Boron tribromide (0.808 mL) was slowly added dropwise using a syringe over 5 minutes, maintaining an internal temperature of 0–5 °C. The mixture was heated to 70 °C and stirred under nitrogen protection for 12 hours. The reaction was quenched by slowly adding saturated sodium bicarbonate solution (10.0 mL) at 25 °C (completed over 5 minutes), controlling gas release and temperature rise. The mixture was extracted with ethyl acetate (3 × 10.0 mL), and the combined organic phases were washed with saturated brine (2 × 10.0 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (elution gradient of petroleum ether / ethyl acetate = 100:1 to 1:1) to give compound 55-5. LCMS: 296.0 [M+H] + .

[0416] Compound 55-5 (40.0 mg) and tetrahydrofuran (0.600 mL) were added to a 10 mL double-necked round-bottom flask, and a magnetic stir bar was installed. The flask was sealed with a rubber diaphragm and purged three times with nitrogen. The solution was cooled to -78°C using a dry ice / ethanol bath. Under nitrogen protection, bis(trimethylsilyl)aminolithium (0.325 mL) was slowly added dropwise using a syringe over 10 minutes, maintaining the internal temperature at -78°C. The mixture was stirred at -78°C for 1 hour. Subsequently, 1,1,1-trifluoro-N-phenyl-N-(trifluoromethylsulfonyl)methanesulfonamide (96.8 mg) dissolved in tetrahydrofuran (0.600 mL) was slowly added dropwise using a syringe at the same temperature over 10 minutes. The reaction mixture was slowly heated to 25°C and stirred for 1 hour. After the reaction was complete, the reaction was quenched by slowly adding 20.0 mL of saturated ammonium chloride solution under nitrogen protection and at 0°C, with strict temperature control to avoid violent exothermic reactions. The mixture was extracted with ethyl acetate (10.0 mL × 3), and the combined organic phases were washed with saturated brine (10.0 mL × 3), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (elution gradient of petroleum ether / ethyl acetate = 100:1 to 1:1) to give compound 55-6. LCMS: 428.0 [M+H] + .

[0417] Compound 55-6 (30.0 mg) and intermediate A (36.8 mg) were dissolved in a mixed solvent of water (0.10 mL) and 1,4-dioxane (0.50 mL), followed by the addition of potassium carbonate (19.4 mg) and Pd(dppf)Cl2 (5.14 mg). The reaction mixture was stirred at 80 °C for 2 hours under nitrogen protection. The reaction mixture was diluted with water (5.00 mL) and extracted with ethyl acetate (5.00 mL × 4). The combined organic phases were washed with saturated brine (5.00 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by preparative high-performance liquid chromatography (HPLC) (column: CD02-Waters Xbridge BEH C18 100 × 25 mm × 10 μm; mobile phase: [water (containing 10 mM NH4HCO3) - acetonitrile]; gradient: 30%-60% B phase, 12.0 min) to give compound 55. LCMS: 501.1 [M+H] + . 1 HNMR: (400 MHz, DMSO- d 6) d 10.99 - 10.88 (m, 1H), 8.25 (d, J = 7.2 Hz, 1H),8.16 - 8.10 (m, 1H), 8.07 - 7.99 (m, 1H), 7.74 (s, 1H), 7.50 - 7.40 (m, 4H),7.29 (dd, J = 5.2, 7.2 Hz, 1H), 7.12 (dd, J = 1.6, 7.2 Hz, 1H), 4.38 (dd, J =5.2, 12.4 Hz, 1H), 2.86 - 2.74 (m, 1H), 2.57 (d, J = 3.6 Hz, 1H), 2.41 - 2.29 (m, 1H), 2.12 - 2.01 (m, 1H).

[0418] Example 51: Synthesis of Compound 56

[0419] 7-Bromo-3-ioimidazolo[1,2-a]pyridine (300 mg) and pyridazin-3(2H)-one (134 mg) were dissolved in DMSO (6.00 mL), followed by the addition of cuprous iodide (35.4 mg), potassium carbonate (257 mg), and dimethylglycine (172 mg). The reaction mixture was stirred at 80 °C for 12 hours under nitrogen protection. After the reaction was complete, the reaction mixture was diluted with water (10.0 mL) and extracted with ethyl acetate (10.0 mL × 3 times). The combined organic phases were washed with saturated brine (10.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The crude product was purified by preparative thin-layer chromatography (electrolyte: n-hexane / ethyl acetate = 0 / 1) to give compound 56-1. LCMS: 291.0 [M+H] + . 1 H NMR: (400 MHz, DMSO- d 6 ) d 8.16(dd, J = 1.6, 3.8 Hz, 1H), 8.12 (d, J = 7.2 Hz, 1H), 8.05 (d, J = 1.2 Hz,1H), 7.81 (s, 1H), 7.59 (dd, J = 4.2, 9.6 Hz, 1H), 7.19 (dd, J = 1.6, 4.8 Hz, 1H), 7.17 (t, J = 2.0 Hz, 1H).

[0420] Compound 56-1 (70.0 mg) and intermediate A (168 mg) were dissolved in a mixed solvent of 1,4-dioxane (2.00 mL) and water (0.200 mL), followed by the addition of potassium carbonate (66.5 mg) and Pd(dppf)Cl2 (17.6 mg). The reaction mixture was stirred at 80 °C for 2 hours under nitrogen protection. After the reaction was complete, the reaction mixture was diluted with water (5.00 mL) and extracted with ethyl acetate (5.00 mL × 3 times). The combined organic phases were washed with saturated brine (5.00 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The crude product was purified by preparative high-performance liquid chromatography (HPLC) (column: CD24-WePureBiotech XPT C18 150). 25 7 μm; mobile phase: [10 mM ammonium bicarbonate aqueous solution-acetonitrile]; gradient elution program: 5%-35% acetonitrile, 12.0 min), to give compound 56. LCMS: 434.1 [M+H] + . 1 H NMR: (400 MHz, DMSO-d 6 ) d 10.98 - 10.88 (m, 1H), 8.20 - 8.17 (m, 2H), 7.87 (s, 1H), 7.72 - 7.70 (m,1H), 7.61 (dd, J = 4.0, 9.6 Hz, 1H), 7.49 - 7.43 (m, 3H), 7.21 (dd, J = 1.6, 9.6 Hz, 1H), 7.07 (dd, J = 1.6, 7.2 Hz, 1H), 4.38 (dd, J = 5.2, 12.4 Hz, 1H), 2.87 - 2.75 (m, 1H), 2.61 - 2.56 (m, 1H), 2.41 - 2.30 (m, 1H), 2.11 - 2.03 (m, 1H).

[0421] Example 52: Synthesis of compounds 57 and 58

[0422] 7-Bromo-3-ioimidazolo[1,2-a]pyridine (500 mg), compound 57-1 (223 mg), and potassium carbonate (428 mg) were dissolved in DMSO (10.0 mL). Cuprous iodide (59.0 mg) and dimethylglycine (287 mg) were added under nitrogen protection. The reaction mixture was stirred at 90 °C for 12 hours under nitrogen protection. After the reaction was complete, the reaction mixture was diluted with water (10.0 mL) and extracted with ethyl acetate (10.0 mL × 3 times). The combined organic phases were washed with saturated brine (10.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The crude product was purified by silica gel column chromatography (elution gradient: n-hexane / ethyl acetate = 10 / 1 to 0 / 1) to give compounds 57-2 and 58-2. LCMS: 291.0 [M+H] + Rt = 0.713 min, compound 57-2: 1 H NMR: (400 MHz, DMSO- d 6 ) d8.22 (d, J = 1.2 Hz, 1H), 8.16 (d, J = 7.2 Hz, 1H), 8.06 (d, J = 2.0 Hz, 1H), 7.84 (s, 1H), 7.68 (dd, J = 1.2, 4.4 Hz, 1H), 7.46 (d, J = 4.4 Hz, 1H), 7.20 (dd, J = 2.0, 7.2 Hz, 1H). Rt = 0.788 min, compound 58-2: 1 H NMR: (400 MHz, DMSO- d 6 ) d 8.80 (d, J = 1.0 Hz, 1H), 8.49 (d,J = 2.4 Hz, 1H), 8.22 - 8.18 (m, 2H), 7.93 (d, J = 1.2 Hz, 1H), 7.54 (s, 1H),7.07 (dd, J = 2.0, 7.2 Hz, 1H).

[0423] Compound 57-2 (30.0 mg) and intermediate A (54.1 mg) were dissolved in a mixed solvent of 1,4-dioxane (1.00 mL) and water (0.100 mL), followed by the addition of potassium carbonate (28.5 mg) and Pd(dppf)Cl2 (7.54 mg). The reaction mixture was stirred at 80 °C for 2 hours under nitrogen protection. After the reaction was complete, the reaction mixture was diluted with water (5.00 mL) and extracted with ethyl acetate (5.00 mL × 3 times). The combined organic phases were washed with saturated brine (5.00 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The crude product was purified by preparative high-performance liquid chromatography (HPLC) (column: CD24-WePureBiotech XPT C18 150). 25 7 μm; mobile phase: [10 mM ammonium bicarbonate aqueous solution-acetonitrile]; gradient elution program: 9%-39% acetonitrile, 12.0 min), to give compound 57. LCMS: 434.1 [M+H] + . 1 H NMR: (400 MHz, DMSO- d 6 ) d10.94 (s, 1H), 8.25 - 8.22 (m, 2H), 7.89 (s, 1H), 7.73 (d, J = 1.2 Hz, 2H), 7.49 - 7.44 (m, 4H), 7.09 (dd, J = 1.6, 7.2 Hz, 1H), 4.41 - 4.35 (m, 1H), 2.86 - 2.74 (m, 1H), 2.57 (d, J = 3.6 Hz, 1H), 2.39 - 2.32 (m, 1H), 2.10 -2.02 (m, 1H).

[0424] Compound 58-2 (80.0 mg) and intermediate A (144 mg) were dissolved in a mixed solvent of 1,4-dioxane (2.00 mL) and water (0.200 mL), followed by the addition of potassium carbonate (76.0 mg) and Pd(dppf)Cl2 (20.1 mg). The reaction mixture was stirred at 80 °C for 2 hours under nitrogen protection. After the reaction was complete, the reaction mixture was diluted with water (5.00 mL) and extracted with ethyl acetate (5.00 mL × 3 times). The combined organic phases were washed with saturated brine (5.00 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The crude product was purified by preparative high-performance liquid chromatography (HPLC) (column: CD24-WePureBiotech XPT C18 150). 25 7 μm; mobile phase: [10 mM ammonium bicarbonate aqueous solution-acetonitrile]; gradient elution program: 13%-43% acetonitrile, 12.0 min), to give compound 58. LCMS: 434.1 [M+H] + . 1 H NMR: (400 MHz, DMSO- d 6 ) d7.61 - 7.60 (m,1H), 7.59 (s, 1H), 7.48 - 7.41 (m, 3H), 6.99 (dd, J = 1.6, 7.2 Hz, 1H), 4.37(dd, J = 5.2, 12.4 Hz, 1H), 2.85 - 2.75 (m, 1H), 2.59 - 2.53 (m, 1H), 2.42 -2.29 (m, 1H), 2.11 - 2.01 (m, 1H).

[0425] Example 53: Synthesis of compounds 59 and 60

[0426] 7-Bromo-3-iodomizo[1,2-a]pyridine (500 mg) and compound 59-1 (253 mg) were dissolved in DMSO (10.0 mL), followed by the addition of potassium carbonate (428 mg), dimethylglycine (287 mg), and cuprous iodide (56.0 mg). The reaction mixture was stirred at 90 °C for 12 hours. After the reaction was complete, the reaction mixture was diluted with water (10.0 mL) and extracted with ethyl acetate (10.0 mL × 3 times). The combined organic phases were washed with saturated brine (10.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The crude product was purified by silica gel column chromatography (elution gradient: n-hexane / ethyl acetate = 10 / 1 to 0 / 1) to give compounds 59-2 and 60-2. LCMS: 304.0 [M+H] + Rt = 0.650 min, compound 59-2: 1 HNMR: (400 MHz, DMSO- d 6 ) d8.01 (d, J = 7.2 Hz, 1H), 7.91 - 7.88 (m, 2H), 7.80 (dd, J = 0.8, 7.2 Hz, 1H), 7.48 (s, 1H), 7.13 (dd, J = 5.2, 7.2 Hz, 1H), 7.03 (dd, J = 2.0, 7.2 Hz, 1H), 2.44 (s, 3H). Rt = 0.866 min, compound 60-2: 1 H NMR: (400 MHz, DMSO- d 6 ) d 8.03 (d, J = 1.2 Hz, 1H), 7.86 (d, J = 7.2 Hz, 1H), 7.75(s, 1H), 7.52 (dd, J = 6.8, 12.4 Hz, 2H), 7.13 (dd, J = 2.0, 7.2 Hz, 1H), 6.34 (t, J = 6.8 Hz, 1H), 2.08 (s, 3H).

[0427] Compound 59-2 (50.0 mg) and intermediate A (86.2 mg) were dissolved in a mixed solvent of 1,4-dioxane (2.00 mL) and water (0.200 mL), followed by the addition of potassium carbonate (45.4 mg) and Pd(dppf)Cl2 (12.0 mg). The reaction mixture was stirred at 80 °C for 2 hours under nitrogen protection. After the reaction was complete, the reaction mixture was diluted with water (5.00 mL) and extracted with ethyl acetate (5.00 mL × 3 times). The combined organic phases were washed with saturated brine (5.00 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The crude product was purified by preparative high-performance liquid chromatography (HPLC) (column: CD24-WePureBiotech XPT C18 150). 25 7 μm; mobile phase: [10 mM ammonium bicarbonate aqueous solution-acetonitrile]; gradient elution program: 21%-51% acetonitrile, 12.0 min), yield compound 59. LCMS: 447.1 [M+H] + . 1 H NMR: (400 MHz, DMSO- d 6 ) d10.93 (s, 1H), 8.09 (d, J = 7.2 Hz, 1H), 7.95 - 7.91 (m, 1H), 7.81 (d, J =7.2 Hz, 1H), 7.58 (s, 1H), 7.53 (s, 1H), 7.47 - 7.44 (m, 2H), 7.43 - 7.40 (m,1H), 7.15 (dd, J = 4.8, 7.2 Hz, 1H), 6.96 (dd, J = 1.6, 7.2 Hz, 1H), 4.37(dd, J = 4.8, 12.0 Hz, 1H), 2.80 (ddd, J = 5.2, 12.4, 17.6 Hz, 1H), 2.60 -2.53 (m, 1H), 2.47 (s, 3H), 2.40 - 2.30 (m, 1H), 2.14 - 2.00 (m, 1H).

[0428] Compound 60-2 (50.0 mg) and intermediate A (86.2 mg) were dissolved in a mixed solvent of 1,4-dioxane (2.00 mL) and water (0.200 mL), followed by the addition of potassium carbonate (45.4 mg) and Pd(dppf)Cl2 (12.0 mg). The reaction mixture was stirred at 80 °C for 2 hours under nitrogen protection. After the reaction was complete, the reaction mixture was diluted with water (5.00 mL) and extracted with ethyl acetate (5.00 mL × 3 times). The combined organic phases were washed with saturated brine (5.00 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The crude product was purified by preparative high-performance liquid chromatography (HPLC) (column: CD24-WePureBiotech XPT C18 150). 25 7 μm; mobile phase: [10 mM ammonium bicarbonate aqueous solution-acetonitrile]; gradient elution program: 10%-40% acetonitrile, 12.0 min), to give compound 60. LCMS: 447.1 [M+H] + . 1 H NMR: (400 MHz, DMSO- d 6 ) d10.94 (s, 1H), 7.93 (d, J = 7.2 Hz, 1H), 7.81 (s, 1H), 7.70 (s, 1H), 7.59 (d, J = 6.4 Hz, 1H), 7.53 (d, J = 7.2 Hz, 1H), 7.48 - 7.42 (m, 3H), 7.05 (dd,J = 1.6, 7.2 Hz, 1H), 6.36 (t, J = 6.8 Hz, 1H), 4.38 (dd, J = 5.2, 12.0 Hz,1H), 2.86 - 2.76 (m, 1H), 2.57 (d, J = 3.6 Hz, 1H), 2.39 - 2.31 (m, 1H), 2.11(s, 3H), 2.09 - 2.03(m, 1H).

[0429] Example 54: Synthesis of Compound 61

[0430] Compound 61-1 (2 g) and 2-bromo-1,1-dimethoxyethane (10.66 g) were dissolved in N,N-dimethylacetamide (20 mL), and cesium carbonate (34.26 g) was added at 25 °C. The reaction mixture was stirred at 100 °C for 12 hours. After cooling to room temperature, the reaction mixture was diluted with water (150 mL) and extracted with ethyl acetate (100 mL × 3 times). The combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The crude product was purified by silica gel column chromatography (elution gradient: n-hexane / ethyl acetate = 1 / 0 to 0 / 1) to give compound 61-2. 1 H NMR: (400MHz, DMSO- d 6 ) δ 8.31 (d, J = 2.8 Hz, 1H), 8.18 (dd, J = 1.2, 4.8 Hz, 1H), 7.42(ddd, J = 1.2, 2.8, 8.4 Hz, 1H), 7.32 (dd, J = 4.8, 8.4 Hz, 1H), 4.70 (s,1H), 4.05 (d, J = 5.2 Hz, 2H), 3.35 (s, 6H).

[0431] Compound 61-2 (1.1 g) was dissolved in formic acid (11 mL), and the mixture was stirred at 45 °C for 48 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure at 25 °C to give compound 61-3. LCMS: 138.3 [M+H] + . 1 H NMR: (400 MHz, DMSO- d 6 ) δ 9.68 (s, 1H), 8.31 (d, J = 3.2 Hz, 1H), 8.28 (br d, J = 3.2 Hz, 1H), 7.40 - 7.36 (m, 2H), 4.99 (s, 2H).

[0432] Compound 61-3 (450 mg) was dissolved in dichloroethane (50 mL), and 4-bromopyridine-2-amine (1.70 g) and elemental iodine (1.67 g) were added sequentially at 25 °C. The mixture was stirred at 100 °C for 12 hours. After cooling to room temperature, the reaction mixture was diluted with an aqueous sodium sulfite solution (100 mL) and extracted with dichloromethane (100 mL × 3). The combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified sequentially by column chromatography (silica gel column, mobile phase: hexane / ethyl acetate = 1 / 0 to 0 / 1 gradient elution) and preparative thin-layer chromatography (ethyl acetate system) to obtain compound 61-4. LCMS: 290.0 [M+H] + . 1 H NMR: (400 MHz, DMSO- d 6 ) δ 8.54 (d, J = 2.8 Hz, 1H), 8.40 (dd, J = 1.2, 4.8 Hz, 1H), 8.18 (d, J = 7.2 Hz, 1H), 7.94 (d, J = 1.2 Hz, 1H), 7.49 (s, 1H), 7.51 - 7.46 (m, 1H), 7.43 - 7.40 (m,1H), 7.09 (dd, J = 2.0, 7.2 Hz, 1H).

[0433] Compound 61-4 (30 mg) was dissolved in a mixed solution of dioxane (1 mL) and water (0.05 mL). Intermediate A (54.23 mg), Pd(dppf)Cl2 (7.57 mg), and potassium carbonate (28.58 mg) were added sequentially under nitrogen protection and at 25 °C. The mixture was stirred at 80 °C for 1 hour under nitrogen protection. After cooling to room temperature, the reaction solution was diluted with water (20 mL) and extracted with ethyl acetate (10 mL × 3). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative high-performance liquid chromatography (pHPLC) (column: CD04-Welch Ultimate C18 150 × 25 mm × 7 μm; mobile phase: [water (containing 0.225% formic acid) - acetonitrile]; gradient: 5%-35% acetonitrile, 15.0 min) to obtain compound 61. LCMS: 433.1 [M +H] + . 1 H NMR: (400 MHz, DMSO- d 6 ) d 10.94 (s, 1H), 8.58 (d, J = 2.8 Hz, 1H), 8.45 - 8.38 (m, 1H), 8.27 (d, J = 7.2 Hz,1H), 7.61 (s, 1H), 7.57 (s, 1H), 7.55 - 7.51 (m, 1H), 7.47 - 7.42 (m, 4H),7.02 (dd, J = 1.6, 7.2 Hz, 1H), 4.37 (dd, J = 5.2, 12.0 Hz, 1H), 2.85 - 2.76(m, 1H), 2.57 (br d, J = 3.6 Hz, 1H), 2.35 (br dd, J = 4.2, 13.2 Hz, 1H), 2.09 - 2.03 (m, 1H).

[0434] Example 55: Synthesis of Compound 62

[0435] Compound 62-1 (1.00 g) was dissolved in tetrahydrofuran (10.0 mL), and sodium hydride (535 mg) was added in portions at 0 °C under nitrogen protection. After stirring the mixture at 0 °C for 0.5 hours, 2-(trimethylsilyl)ethoxymethyl chloride (2.23 g) was added at the same temperature, followed by stirring at 25 °C for 2 hours. The reaction mixture was quenched with saturated ammonium chloride aqueous solution (10.0 mL) at 0 °C and extracted with ethyl acetate (10.0 mL × 3). The combined organic phases were washed with saturated brine (10.0 mL × 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (hexane:ethyl acetate = 1 / 0 to 1 / 1 gradient elution) to give compound 62-2. LCMS: 243.3 [M+H] + . 1 H NMR: (400 MHz, DMSO- d 6 ) d 7.64 (s, 1H), 5.15 (s, 2H), 3.42 (t, J = 8.0 Hz, 2H), 2.10 (s, 3H), 2.00 (s,3H), 0.78 (t, J = 8.0 Hz, 2H), -0.06 (s, 9H).

[0436] Compound 62-2 (380 mg) and ethyl 7-bromo-3-fluoroimidazolo[1,2-a]pyridine-2-carboxylate (300 mg) were dissolved in N,N-dimethylformamide (2.50 mL), and potassium carbonate (289 mg) was added. The mixture was stirred at 80 °C for 1 hour. The reaction mixture was diluted with water (2.00 mL) and extracted with ethyl acetate (5.00 mL × 3). The combined organic phases were washed with saturated brine (5.00 mL × 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (hexane:ethyl acetate = 1 / 0 to 1 / 1 gradient elution) to give compound 62-3. LCMS: 509.3 [M+H] + .

[0437] Compound 62-3 (500 mg) was dissolved in a mixed solvent of tetrahydrofuran (2.50 mL) and water (2.50 mL), and lithium hydroxide monohydrate (82.4 mg) was added. The mixture was stirred at 25 °C for 1 hour. The reaction solution was adjusted to pH 7 with 1 N hydrochloric acid and filtered. The filter cake was concentrated to obtain compound 62-4. LCMS: 481.0 [M+H] + .

[0438] Compound 62-4 (400 mg) and DBU (253 mg) were dissolved in N,N-dimethylacetamide (4.00 mL) to prepare solution 1. Solution 1 was pumped to flow reactor 1 (FLR1, stainless steel coil reactor, inner diameter 3.18 mm (1 / 8 inch), volume 10.0 mL, temperature 230 °C) via pump 1 (S1, P1, flow rate 1.00 mL / min). The reactor volume was 10 mL (1 / 8 inch PFA material), the cooling temperature was 20.0 °C, and the system pressure was set to 4.00 MPa. The residence time in flow reactor 1 was 10.0 min. The reaction solution was diluted with water (5.00 mL) and extracted with ethyl acetate (5.00 mL × 3). The combined organic phases were washed with saturated brine (5.00 mL × 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (hexane:ethyl acetate = 1 / 0 to 1 / 1 gradient elution) to give compound 62-5. LCMS: 437.2 [M+H] + .

[0439] Compound 62-5 (150 mg) was dissolved in dichloromethane (1.00 mL), and trifluoroacetic acid (39.1 mg) was added. The mixture was stirred at 25 °C for 1 hour. The reaction solution was concentrated to obtain a residue, which was adjusted to pH 7 with saturated sodium carbonate solution and then concentrated again. The residue was washed with ethyl acetate (3.00 mL), and the filtrate was concentrated to give compound 62-6. LCMS: 309.2 [M+H] + .

[0440] 62-6 (100 mg) and 5,5,5',5'-tetramethyl-2,2'-bis(1,3,2-dioxaborane) (147 mg) were dissolved in dioxane (1.00 mL), followed by the addition of potassium acetate (63.9 mg) and Pd(dppf)Cl2 (23.8 mg). The mixture was stirred at 100 °C for 1 hour under nitrogen protection. The reaction solution was used directly for the next reaction. LCMS: 273.0 [M+H] + .

[0441] The reaction solution containing compound 62-7 (crude product) was dissolved in dioxane (1.00 mL) with 108 mg of 3-(3-bromo-2-chlorophenyl)piperidine-2,6-dione, followed by the addition of Pd(dppf)Cl2 (23.7 mg) and potassium carbonate (89.4 mg). The mixture was stirred at 80 °C for 3 hours under nitrogen protection. The reaction solution was filtered through a diatomaceous earth mat, and the filtrate was concentrated to obtain the crude product. The crude product was purified by preparative high-performance liquid chromatography (HPLC) (column: CD24-WePure Biotech XPT C18 150). 25 7 μm; mobile phase: [water (containing 0.225% formic acid) - acetonitrile]; gradient: 9%-39% acetonitrile, 11.0 min), yielding compound 62. LCMS: 450.1 [M + H] + . 1 H NMR: (400 MHz, DMSO- d 6 ) d 12.56 - 12.15 (m, 1H), 10.94 (s,1H), 8.33 (dd, J = 0.8, 7.2 Hz, 1H), 7.51 - 7.47 (m, 1H), 7.47 - 7.38 (m,3H), 7.01 (dd, J = 1.6, 7.2 Hz, 1H), 6.85 (s, 1H), 4.37 (dd, J = 5.2, 12.4Hz, 1H), 2.88 - 2.74 (m, 1H), 2.56 (td, J = 3.6, 17.2 Hz, 2H), 2.42 - 2.29(m, 1H), 2.12 - 2.04 (m, 6H).

[0442] Example 56: Synthesis of Compound 63

[0443] Compound 63-1 (200 mg) and 2-bromo-1,1-dimethoxyethane (804 mg) were dissolved in N,N-dimethylacetamide (4 mL), and cesium carbonate (2.58 g) was added. The mixture was stirred at 100 °C for 12 hours. The reaction solution was diluted with water (5.00 mL) and extracted with ethyl acetate (5.00 mL × 3). The combined organic phases were washed with saturated brine (5.00 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (hexane:ethyl acetate = 100:1 to 1:1 gradient elution) to give compound 63-2. LCMS: 215.1 [M+H] + .

[0444] Compound 63-2 (200 mg) was dissolved in formic acid (5.00 mL), and the mixture was stirred at 50 °C for 20 hours. The reaction solution was concentrated under reduced pressure to give compound 63-3. LCMS: 169.1 [M+H] + .

[0445] Compound 63-3 (309 mg) and 4-bromopyridin-2-amine (309 mg) were dissolved in dichloroethane (10.0 mL), and elemental iodine (453 mg) was added. The mixture was stirred at 100 °C for 12 hours. After the reaction was complete, the reaction was quenched with a saturated ammonium chloride aqueous solution (10.0 mL) at 0 °C under nitrogen protection, and extracted with ethyl acetate (10.0 mL × 3). The combined organic phases were washed with saturated brine (10.0 mL × 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (elution gradient of n-hexane:ethyl acetate = 100:1 to 1:1) to give compound 63-4. LCMS: 323.0 [M + H] + .

[0446] Compound 63-4 (100 mg) and intermediate A were dissolved in a mixed solvent of dioxane (2.00 mL) and water (0.200 mL), followed by the sequential addition of potassium carbonate (86.1 mg) and Pd(dppf)Cl2 (22.8 mg). The mixture was stirred at 80 °C for 2 hours under nitrogen protection. After filtration, the filtrate was concentrated to obtain the crude product. The crude product was purified by preparative high-performance liquid chromatography (HPLC) (column: CD04-Welch Ultimate C18 150). 25 mm 7 μm; mobile phase: [water (containing 0.225% formic acid) - acetonitrile]; gradient: 5%-35% acetonitrile, 15.0 min), yielding compound 63. LCMS: 464.1 [M+H] + . 1 H NMR: (400 MHz, DMSO- d 6) d 10.94 (s, 1H), 8.34 (dd, J = 0.8, 7.2 Hz, 1H), 7.49 (dd, J = 1.2,1.6 Hz, 1H), 7.46 - 7.40 (m, 3H), 7.01 (dd, J = 1.6, 7.2 Hz, 1H), 6.84 (s,1H), 4.37 (dd, J = 5.2, 12.4 Hz, 1H), 3.68 (s, 3H), 2.88 - 2.75 (m, 1H), 2.59- 2.53 (m, 1H), 2.41 - 2.30 (m, 1H), 2.17 (s, 3H), 2.11 - 2.04 (m, 1H), 2.02 (s, 3H).

[0447] Example 57: Synthesis of compounds 64 and 65

[0448] Compound 64-1 (100 mg) was dissolved in anhydrous tetrahydrofuran (4.00 mL). The reaction system was deoxygenated by three cycles of vacuum-nitrogen purging and then cooled to 0°C in an ice-water bath. Sodium hexamethyldisilamide (2.36 mL) was slowly added with stirring, and the mixture was kept at 0°C and stirred for 10 minutes. Subsequently, a tetrahydrofuran solution of 2-fluoropyridine (68.7 mg) (1.00 mL) was added dropwise to the reaction system using a syringe. After the addition was complete, the ice bath was removed, and the reaction was continued to be stirred at 25°C for 1 hour under nitrogen protection. After the reaction was complete, the mixture was quenched with a saturated ammonium chloride aqueous solution (10.0 mL) at 0°C under nitrogen protection and extracted with ethyl acetate (10.0 mL × 3). The combined organic phases were washed with saturated brine (10.0 mL × 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (elution with a gradient of n-hexane:ethyl acetate = 100:1 to 1:1) to give compound 64-2. LCMS: 291.0 [M+H] + . 1 H NMR: (400 MHz, DMSO- d 6) d 8.89 (s, 1H), 8.00 (d, J =4.4 Hz, 1H), 7.93 - 7.85 (m, 2H), 7.57 (t, J = 7.2 Hz, 1H), 7.51 (s, 1H),7.03 (d, J = 7.2 Hz, 1H), 6.74 (t, J = 6.0 Hz, 1H), 6.69 (d, J = 8.0 Hz, 1H).

[0449] Compound 64-2 (80.0 mg) was dissolved in tetrahydrofuran (4.00 mL), and sodium hydride (16.6 mg) was added at 0 °C under nitrogen protection. After stirring the mixture at 0 °C for 20 min, a tetrahydrofuran solution of iodomethane (31.4 mg) (1.00 mL) was slowly added dropwise under the same conditions. The ice bath was removed, and the reaction mixture was stirred at 25 °C for another 40 min. After the reaction was complete, the mixture was quenched with a saturated ammonium chloride aqueous solution (10.0 mL) at 0 °C under nitrogen protection and extracted with ethyl acetate (10.0 mL × 3). The combined organic phases were washed with saturated brine (10.0 mL × 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography (developing solvent: n-hexane / ethyl acetate = 1 / 2) to give compound 64-3. LCMS: 303.0 [M+H] + . 1 H NMR: (400MHz, DMSO- d 6) d 8.14 (dd, J = 1.2, 4.8 Hz, 1H), 7.95 (d, J = 1.2 Hz, 1H), 7.86 (d, J = 7.2 Hz, 1H), 7.58 (s, 1H), 7.56 - 7.50 (m, 1H), 7.05 (dd, J =2.0, 7.2 Hz, 1H), 6.78 (dd, J = 5.2, 6.8 Hz, 1H), 6.35 (d, J = 8.8 Hz, 1H), 3.42 (s, 3H).

[0450] Compound 64-3 (40.0 mg) and intermediate A (69.2 mg) were dissolved in a mixed solvent of dioxane (1.00 mL) and water (0.100 mL), followed by the addition of potassium carbonate (36.5 mg) and Pd(dppf)Cl2 (9.65 mg). The mixture was stirred at 80 °C for 2 hours under nitrogen protection. After filtration, the filtrate was concentrated to obtain the crude product. The crude product was purified by preparative high-performance liquid chromatography (HPLC) (column: CD24-WePure Biotech XPT C18 150). 25 7 μm; mobile phase: [water (containing 10 mM ammonium bicarbonate) - acetonitrile]; gradient: 18%-48% acetonitrile, 12.0 min), yielding compound 64. LCMS: 446.1 [M+H] + . 1 H NMR: (400 MHz, DMSO- d 6) d 10.93 (s, 1H), 8.19 - 8.16 (m, 1H), 7.97 (dd,J = 0.8, 7.2 Hz, 1H), 7.64 (s, 2H), 7.55 (ddd, J = 2.0, 7.2, 8.4 Hz, 1H),7.46 - 7.40 (m, 3H), 6.98 (dd, J = 1.6, 7.2 Hz, 1H), 6.82 - 6.76 (m, 1H), 6.38 (d, J = 8.4 Hz, 1H), 4.37 (d, J = 7.2 Hz, 1H), 3.46 (s, 3H), 2.80 (ddd,J = 5.2, 12.4, 17.6 Hz, 1H), 2.57 (d, J = 3.6 Hz, 1H), 2.39 - 2.29 (m, 1H), 2.11 - 2.02 (m, 1H).

[0451] Compound 65 was obtained by referring to the preparation method of compound 64:

[0452] Example 58: Synthesis of Compound 66

[0453] Compound 66-1 (200 mg) and 5-hydroxy-1-methylpyridin-2(1H)-one (131 mg) were dissolved in N,N-dimethylformamide (4.00 mL), and potassium carbonate (193 mg) was added. The mixture was stirred at 80 °C for 1 hour. The reaction mixture was diluted with water (10.0 mL) and extracted with ethyl acetate (10.0 mL × 3). The combined organic phases were washed with saturated brine (10.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (elution gradient of n-hexane:ethyl acetate = 100:1 to 0:1) to give compound 66-2. LCMS: 392.0 [M+H] + .

[0454] Compound 66-2 (180 mg) was dissolved in a mixed solvent of tetrahydrofuran (1.50 mL) and water (0.500 mL), and lithium hydroxide monohydrate (57.8 mg) was added. The mixture was stirred at 25 °C for 1 hour. After filtration, the filter cake was concentrated under reduced pressure to give compound 66-3. LCMS: 364.0 [M+H] + .

[0455] Compound 66-3 (70.0 mg) and DBU (58.5 mg) were dissolved in N,N-dimethylacetamide (0.700 mL) to prepare solution 1. Solution 1 was pumped to flow reactor 1 (FLR1, stainless steel coil reactor, inner diameter 3.175 mm (1 / 8 inch), volume 10.0 mL, temperature 230 °C) via pump 1 (S1, P1, flow rate 1.00 mL / min). The reactor volume was 5.00 mL (1 / 8 inch PFA material), the cooling temperature was 20 °C, and the system pressure was set to 4 MPa. The residence time in flow reactor 1 was 20.0 min. The reaction solution was diluted with water (5.00 mL) and extracted with ethyl acetate (5.00 mL × 3). The combined organic phases were washed with saturated brine (5.00 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 100:1 to 10:1 gradient elution) to give compound 66-4. LCMS: 320.0 [M+H] + .

[0456] Compound 66-4 (20.0 mg) and intermediate A were dissolved in a mixed solvent of dioxane (1.00 mL) and water (0.100 mL), followed by the sequential addition of potassium carbonate (17.3 mg) and Pd(dppf)Cl2 (4.57 mg). The mixture was stirred at 80 °C for 2 hours under nitrogen protection. The reaction solution was diluted with water (5.00 mL) and extracted with ethyl acetate (5.00 mL × 3). The combined organic phases were washed with saturated brine (5.00 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by preparative high-performance liquid chromatography (HPLC) (column: CD52-Wepure Prepulite Platinum C18 150). 25 7 μm; mobile phase: [water (containing 0.225% formic acid) - acetonitrile]; gradient: 5%-35% acetonitrile, 11.0 min), yielding compound 66. LCMS: 463.2 [M+H] + . 1 H NMR: (400 MHz, DMSO- d 6 ) d 10.95 - 10.92 (m, 1H), 8.33 (d, J = 7.2 Hz,1H), 7.95 (d, J = 3.2 Hz, 1H), 7.63 (dd, J = 3.2, 10.0 Hz, 1H), 7.55 (s, 1H),7.46 - 7.40 (m, 3H), 7.36 (s, 1H), 7.02 (d, J = 7.2 Hz, 1H), 6.44 (d, J =10.0 Hz, 1H), 4.37 (dd, J = 4.8, 12.0 Hz, 1H), 3.42 - 3.39 (m, 3H), 2.86 -2.73 (m, 1H), 2.59 - 2.56 (m, 1H), 2.38 - 2.29 (m, 1H), 2.11 - 2.01 (m, 1H).

[0457] Example 59: Synthesis of Compound 67

[0458] Compound 67-1 (2.00 g) was dissolved in acetonitrile (40.0 mL), cooled to 0 °C, and then Select F (5.27 g) and DMAP (908 mg) were added sequentially. The mixture was stirred at 25 °C for 2 hours. After removing acetonitrile by concentration under reduced pressure, the residue was diluted with water (20.0 mL) and extracted with ethyl acetate (20.0 mL × 3). The combined organic phases were washed with saturated brine (20.0 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by reversed-phase high-performance liquid chromatography (0.1% formic acid) to give compound 67-2. LCMS: 288.9 [M+H] + . 1 H NMR: (400 MHz, DMSO- d 6 ) d 8.31(d, J = 7.2 Hz, 1H), 7.95 (s, 1H), 7.22 (dd, J = 1.6, 7.2 Hz, 1H), 4.33 (q, J= 7.2 Hz, 2H), 1.31 (t, J = 7.2 Hz, 3H).

[0459] Compound 67-2 (200 mg) and 1-methyl-1H-indazole-3-ol (155 mg) were dissolved in N,N-dimethylformamide (3.00 mL), and potassium carbonate (193 mg) was added. The mixture was stirred at 80 °C for 1 hour. The reaction solution was diluted with water (5.00 mL) and extracted with ethyl acetate (5.00 mL × 3). The combined organic phases were washed with saturated brine (5.00 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (elution gradient of n-hexane:ethyl acetate = 100:1 to 1:2) to give compound 67-3. LCMS: 415.0 [M+H] + . 1 H NMR: (400 MHz, DMSO- d 6 ) d 8.31 (d,J = 7.2 Hz, 1H), 8.05 (d, J = 1.2 Hz, 1H), 7.68 (d, J = 8.0 Hz, 1H), 7.60 (d,J = 8.4 Hz, 1H), 7.48 (t, J = 7.6 Hz, 1H), 7.21 - 7.16 (m, 2H), 4.09 (q, J =7.2 Hz, 2H), 3.79 (s, 3H), 0.95 (t, J = 7.2 Hz, 3H).

[0460] Compound 67-3 (120 mg) and sodium hydroxide (57.8 mg) were dissolved in NMP (0.960 mL) and water (0.240 mL) to prepare solution 1. Solution 1 was pumped to flow reactor 1 (FLR1, stainless steel coil reactor, inner diameter 3.175 mm (1 / 8 inch), volume 15.0 mL, temperature 240 °C) via pump 1 (S1, P1, flow rate 1.00 mL / min). The reactor volume was 5.00 mL (1 / 8 inch PFA material), the cooling temperature was 20 °C, and the system pressure was set to 4 MPa. The residence time in flow reactor 1 was 15.0 min. The reaction solution was diluted with water (5.00 mL) and extracted with ethyl acetate (5.00 mL × 3). The combined organic phases were washed with saturated brine (5.00 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (elution with a gradient of n-hexane:ethyl acetate = 100:1 to 1:2) to give compound 67-4. LCMS: 342.9 [M+H] + .

[0461] Compound 67-4 (50.0 mg) and intermediate A (102 mg) were dissolved in a mixed solvent of dioxane (2.00 mL) and water (0.200 mL), followed by the sequential addition of potassium carbonate (40.3 mg) and Pd(dppf)Cl2 (10.7 mg). The mixture was stirred at 80 °C for 2 hours under nitrogen protection. The reaction solution was diluted with water (5.00 mL) and extracted with ethyl acetate (5.00 mL × 3). The combined organic phases were washed with saturated brine (5.00 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by preparative high-performance liquid chromatography (HPLC) (column: CD24-WePure Biotech XPT C18 150). 25 7 μm; mobile phase: [water (containing 10 mM ammonium bicarbonate) - acetonitrile]; gradient: 27%-57% acetonitrile, 12.0 min), yielding compound 69. LCMS: 486.2 [M+H] + . 1 H NMR: (400 MHz, DMSO- d 6 ) d10.94 (s, 1H), 8.38 - 8.31 (m, 1H), 7.76 (d, J = 8.0 Hz, 1H), 7.66 - 7.57 (m, 3H), 7.51 - 7.40 (m, 4H), 7.19 (t, J =7.6 Hz, 1H), 7.03 (dd, J = 1.6, 7.2 Hz, 1H), 4.37 (dd, J = 4.8, 12.0 Hz, 1H), 3.90 (s, 3H), 2.78 (dd, J = 5.2, 12.8 Hz, 1H), 2.57 (d, J = 3.6 Hz, 1H), 2.39- 2.30 (m, 1H), 2.12 - 2.02 (m, 1H).

[0462] Example 60: Synthesis of Compound 68

[0463] 1.40 g of 6-bromo-1H-indole-1-carboxylic acid tert-butyl ester was dissolved in 15 mL of tert-butanol. Under nitrogen protection, sodium tert-butoxide (906 mg), tBuXPhos Pd G3 (374.62 mg), t-BuXPhos (400 mg), and compound 68-1 (1 g) were added sequentially at 25 °C. The reaction mixture was stirred at 60 °C for 16 hours. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by rapid silica gel column chromatography (20 g silica gel column, elution gradient: 0–80% ethyl acetate / n-hexane, flow rate 30 mL / min) to give compound 68-2. LCMS: 327.2 [M+H] + .

[0464] Compound 68-2 (47 mg) was dissolved in dioxane (1 mL), and 5,5,5',5'-tetramethyl-2,2'-bis(1,3,2-dioxoborane) (65 mg), potassium acetate (28 mg), and Pd(dppf)Cl2 (11 mg) were added sequentially. The mixture was stirred at 100 °C for 1 hour under nitrogen protection. After filtration, the filtrate was concentrated under reduced pressure to give compound 68-3. LCMS: 293.0 [M+H] + .

[0465] The crude compound 68-3 (41 mg) was dissolved in dioxane (1 mL), and 3-(3-bromo-2-chlorophenyl)piperidine-2,6-dione (42 mg), potassium carbonate (39 mg), and Pd(dppf)Cl2 (10 mg) were added sequentially at 25 °C. The reaction mixture was heated to 80 °C and stirred for 16 hours. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative high-performance liquid chromatography (HPLC) (column: CD24-WePure Biotech XPT C18 150). 25 7 μm; mobile phase: [water (containing 0.225% formic acid) - acetonitrile]; gradient: 14%-44% acetonitrile, 16.0 min), yielding compound 68. LCMS: 470.1 [M + H] + . 1 H NMR: (400MHz, CDCl3) δ 8.03 (br s, 1H), 7.98 - 7.90 (m, 2H), 7.71 (s, 1H), 7.63 (s,1H), 7.52 (d, J = 8.4 Hz, 1H), 7.43 - 7.33 (m, 2H), 7.08 - 7.03 (m, 1H), 6.92(d, J = 6.8 Hz, 1H), 6.73 - 6.61 (m, 1H), 6.47 (d, J = 7.2 Hz, 2H), 5.64 -5.48 (m, 1H), 4.34 (dd, J = 6.0, 10.0 Hz, 1H), 2.92 - 2.67 (m, 2H), 2.42 -2.20 (m, 2H).

[0466] Example 61: Synthesis of Compound 69

[0467] 7-Bromo-3-iodomidazo[1,2-a]pyridine (660 mg) and compound 69-1 (828.74 mg) were dissolved in DMSO (16 mL), followed by the addition of potassium phosphate (1.30 g), 1,10-phenanthroline-4,7-diol (216.85 mg), and bis[(Z)-1-methyl-3-oxo-but-1-enoxy]copper (267.49 mg). The mixture was stirred at 100 °C for 12 hours under nitrogen protection. After cooling to room temperature, the reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 1 / 0 to 0 / 1 gradient elution) and preparative thin-layer chromatography (ethyl acetate system) to give compound 69-2. 1 HNMR: (400 MHz, DMSO- d 6 ) δ 7.98 (d, J = 7.2 Hz, 1H), 7.89 (s, 1H), 7.78 (t, J =7.8 Hz, 1H), 7.44 (s, 1H), 7.14 (d, J = 7.2 Hz, 1H), 7.04 (dd, J = 1.6, 7.2Hz, 1H), 6.97 (d, J = 8.0 Hz, 1H), 2.00 - 1.91 (m, 2H), 0.81 - 0.73 (m, 3H).

[0468] Compound 69-2 (23 mg), intermediate A (36.53 mg), potassium carbonate (19.25 mg), and Pd(dppf)Cl2 (5.10 mg) were dissolved in a mixed solvent of dioxane (1 mL) and water (0.1 mL). The mixture was stirred at 80 °C for 2 hours under nitrogen protection. After cooling to room temperature, the reaction solution was diluted with water (10 mL) and extracted with ethyl acetate (10 mL × 3). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative high-performance liquid chromatography (column: CD52-Wepure Prepulite Platinum C18 150). 25 7 μm; mobile phase: [water (containing 0.225% formic acid) - acetonitrile]; gradient: 10%-40% acetonitrile, 13.0 min), yielding compound 69. LCMS: 473.2 [M+H] + . 1 H NMR: (400 MHz, DMSO- d 6 ) d 10.94 (s, 1H), 8.08 - 8.00 (m, 1H), 7.79 (t, J = 7.6 Hz, 1H), 7.56 (s, 1H), 7.50 (s, 1H), 7.47 - 7.39 (m, 3H),7.15 (d, J = 7.2 Hz, 1H), 7.02 - 6.93 (m, 2H), 4.37 (dd, J = 5.2, 12.0 Hz,1H), 2.87 - 2.74 (m, 1H), 2.57 (br s, 1H), 2.36 (br dd, J = 4.0, 12.8 Hz,1H), 2.11 - 2.03 (m, 1H), 2.01 - 1.93 (m, 1H), 0.80 - 0.73 (m, 2H), 0.53 -0.46 (m, 2H).

[0469] Example 62: Synthesis of Compound 70

[0470] 7-Bromo-3-iodoimidazolo[1,2-a]pyridine (500 mg), 1-methyltetrahydropyrimidin-2(1H)-one (265 mg), (1R,2R)-N1,N2-dimethylcyclohexane-1,2-diamine (176 mg), and cesium carbonate (1.01 g) were dissolved in dioxane (5.00 mL), and cuprous iodide (59.0 mg) was added under nitrogen protection. The mixture was stirred at 90 °C for 16 hours under nitrogen protection. The reaction solution was diluted with water (10.0 mL) and extracted with ethyl acetate (10.0 mL × 3). The combined organic phases were washed with saturated brine (10.0 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (gradient elution of dichloromethane:methanol = 100:1 to 10:1) to give compound 70-1. LCMS: 311.0 [M+H] + . 1 H NMR: (400 MHz, DMSO- d6 ) d 7.99 (d, J = 7.2 Hz, 1H), 7.85 (s, 1H), 7.46 (s, 1H), 7.06 (d, J =7.2 Hz, 1H), 3.63 (s, 2H), 3.40 (t, J = 5.2 Hz, 2H), 2.88 (s, 3H), 2.14 -2.06 (m, 2H).

[0471] Compound 70-1 (50.0 mg) and intermediate A (84.8 mg) were dissolved in a mixed solvent of dioxane (1.00 mL) and water (0.100 mL), followed by the addition of potassium carbonate (44.7 mg) and Pd(dppf)Cl2 (11.8 mg). The mixture was stirred at 80 °C for 2 hours under nitrogen protection. The reaction solution was diluted with water (5.00 mL) and extracted with ethyl acetate (5.00 mL × 3). The combined organic phases were washed with saturated brine (5.00 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by preparative high-performance liquid chromatography (HPLC) (column: CD24-WePure Biotech XPT C18 150). 25 7 μm; mobile phase: [water (containing 10 mM ammonium bicarbonate) - acetonitrile]; gradient: 14%-34% acetonitrile, 11.0 min), yielding compound 70. LCMS: 452.2 [M+H] + . 1 H NMR: (400 MHz, DMSO- d 6 ) d 10.96 - 10.92 (m, 1H), 8.08 (d, J =7.2 Hz, 1H), 7.53 (s, 1H), 7.52 - 7.50 (m, 1H), 7.46 - 7.40 (m, 3H), 6.98(dd, J = 1.6, 7.2 Hz, 1H), 4.37 (dd, J = 4.8, 12.0 Hz, 1H), 3.68 (t, J = 5.6Hz, 2H), 3.43 (t, J = 5.6 Hz, 2H), 2.90 (s, 3H), 2.85 - 2.75 (m, 1H), 2.57(d, J = 3.6 Hz, 1H), 2.40 - 2.31 (m, 1H), 2.18 - 2.11 (m, 2H), 2.10 - 2.02 (m, 1H).

[0472] Example 63: Synthesis of Compound 71

[0473] Compound 71-1 (203 mg) and glutaric acid (115 mg) were dissolved in ethyl acetate (8.00 mL), and DIC (220 mg) and DMAP (10.6 mg) were added at 25 °C. The mixture was stirred at 60 °C for 12 hours. The reaction solution was diluted with water (10.0 mL) and extracted with ethyl acetate (10.0 mL × 3). The combined organic phases were washed with saturated brine (10.0 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (elution gradient of n-hexane:ethyl acetate = 10:1 to 0:1) to give compound 71-2. LCMS: 308.0 [M+H] + . 1 H NMR: (400 MHz, DMSO- d 6 ) d 8.28 (d,J = 7.2 Hz, 1H), 7.96 (d, J = 1.2 Hz, 1H), 7.49 (s, 1H), 7.15 (dd, J = 2.0,7.2 Hz, 1H), 2.88 - 2.78 (m, 4H), 2.17 - 1.99 (m, 2H).

[0474] Compound 71-2 (70.0 mg) and intermediate B (60.8 mg) were dissolved in dioxane (2.00 mL), followed by the addition of potassium carbonate (62.8 mg) and Pd(dppf)Cl2 (16.6 mg). The mixture was stirred at 80 °C for 2 hours under nitrogen protection. The reaction solution was diluted with water (5.00 mL) and extracted with ethyl acetate (5.00 mL × 3). The combined organic phases were washed with saturated brine (5.00 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by preparative high-performance liquid chromatography (HPLC) (column: CD02-Waters Xbridge BEH C18 100). 25 mm 10 μm; mobile phase: [water (containing 10 mM ammonium bicarbonate) - acetonitrile]; gradient: 10%-40% acetonitrile, 13.0 min), yielding compound 71. LCMS: 451.2 [M+H] + . 1 H NMR: (400 MHz, DMSO- d 6 ) d10.94 (s, 1H), 8.34 (d, J = 7.2 Hz, 1H), 7.62 (s, 1H), 7.54 (s, 1H), 7.48 - 7.42 (m, 3H), 7.03 (d, J = 7.2 Hz, 1H), 4.38 (dd, J =4.8, 12.0 Hz, 1H), 2.90 - 2.78 (m, 5H), 2.58 (s, 1H), 2.33 (s, 1H), 2.19 -2.11 (m, 1H), 2.10 - 2.03 (m, 2H).

[0475] Example 64: Synthesis of compounds 72 and 73

[0476] 7-Bromo-3-ioimidazolo[1,2-a]pyridine (500 mg) and compound 72-1 (253 mg) were dissolved in DMSO (10.0 mL), and cuprous iodide (56.0 mg), potassium carbonate (428 mg), and dimethylglycine (287 mg) were added sequentially. The mixture was stirred at 100 °C for 12 hours under nitrogen protection. The reaction solution was diluted with water (10.0 mL) and extracted with ethyl acetate (10.0 mL × 3). The combined organic phases were washed with saturated brine (10.0 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution gradient of n-hexane:ethyl acetate = 10:1 to 0:1) to give compounds 72-2 and 73-2. LCMS: 306.0 [M+H] + Rt = 0.250 min, compound 72-2: 1 H NMR: (400 MHz, DMSO- d 6 ) d 8.03 (d, J = 1.2 Hz, 1H), 7.86 (d, J = 7.2 Hz, 1H), 7.76 (s, 1H), 7.56 - 7.48 (m, 2H), 7.13 (dd, J = 2.0, 7.2 Hz, 1H), 6.54 (d, J = 9.2 Hz, 1H), 2.07 (s, 3H). Rt = 0.315 min, compound 73-2: 1 H NMR: (400 MHz, DMSO- d 6 ) d7.98 (dd, J = 0.8, 7.2 Hz, 1H), 7.92 (dd, J = 0.8, 1.6 Hz, 1H), 7.90 (dd, J = 0.8, 1.8 Hz, 1H), 7.78 (dd, J = 2.4, 8.4 Hz, 1H), 7.46 (s, 1H), 7.19 (d, J = 8.4 Hz, 1H), 7.02 (dd, J = 2.0, 7.2 Hz, 1H), 2.25 (s, 3H).

[0477] Compound 72-2 (50.0 mg) and intermediate A (86.2 mg) were dissolved in a mixed solvent of dioxane (1.00 mL) and water (0.100 mL), followed by the addition of potassium carbonate (45.4 mg) and Pd(dppf)Cl2 (12.0 mg). The mixture was stirred at 80 °C for 2 hours under nitrogen protection. The reaction solution was diluted with water (5.00 mL) and extracted with ethyl acetate (5.00 mL × 3). The combined organic phases were washed with saturated brine (5.00 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by preparative high-performance liquid chromatography (HPLC) (column: CD24-WePure Biotech XPT C18 150). 25 7 μm; mobile phase: [water (containing 10 mM ammonium bicarbonate) - acetonitrile]; gradient: 12%-42% acetonitrile, 10.0 min), yield compound 72. LCMS: 447.0 [M+H] + . 1 H NMR: (400 MHz, DMSO- d 6 ) d 10.94 (s, 1H), 7.94 (d, J = 7.2 Hz,1H), 7.81 (s, 1H), 7.70 (d, J = 0.8 Hz, 1H), 7.57 - 7.53 (m, 2H), 7.49 - 7.41(m, 3H), 7.04 (dd, J = 1.6, 7.2 Hz, 1H), 6.56 (d, J = 10.4 Hz, 1H), 4.38 (dd,J = 4.8, 12.4 Hz, 1H), 2.86 - 2.75 (m, 1H), 2.57 (d, J = 4.0 Hz, 1H), 2.41 -2.31 (m, 1H), 2.08 (s, 3H), 2.06 (dd, J = 3.2, 4.8 Hz, 1H).

[0478] Compound 73-2 (50.0 mg) and intermediate A (86.2 mg) were dissolved in a mixed solvent of dioxane (1.00 mL) and water (0.100 mL), followed by the addition of potassium carbonate (45.4 mg) and Pd(dppf)Cl2 (12.0 mg). The mixture was stirred at 80 °C for 2 hours under nitrogen protection. The reaction solution was diluted with water (5.00 mL) and extracted with ethyl acetate (5.00 mL × 3). The combined organic phases were washed with saturated brine (5.00 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by preparative high-performance liquid chromatography (HPLC) (column: CD24-WePure Biotech XPT C18 150). 25 7 μm; mobile phase: [water (containing 0.225% formic acid) - acetonitrile]; gradient: 10%-40% acetonitrile, 10.0 min), yielding compound 73. LCMS: 447.1 [M+H] + . 1 H NMR: (400 MHz, DMSO- d 6 ) d 10.94 (s, 1H), 8.06 (d, J = 7.2 Hz, 1H), 7.97 - 7.94 (m, 1H), 7.80 (dd, J = 2.4, 8.4 Hz, 1H), 7.58 (d, J = 0.8Hz, 1H), 7.51 (s, 1H), 7.47 - 7.40 (m, 3H), 7.23 (d, J = 8.4 Hz, 1H), 6.96 (dd, J = 1.6, 7.2 Hz, 1H), 4.37 (dd, J = 5.2, 12.0 Hz, 1H), 2.80 (ddd, J =5.6, 12.4, 17.6 Hz, 1H), 2.57 (d, J = 3.6 Hz, 1H), 2.39 - 2.30 (m, 1H), 2.26 (s, 3H), 2.11 - 2.02 (m, 1H).

[0479] Example 65: Synthesis of compounds 74 and 75

[0480] 500 mg of 7-bromo-3-ioimidazolo[1,2-a]pyridine and 74-1286.02 mg were dissolved in DMSO (10 mL), followed by the addition of cuprous iodide (58.98 mg), potassium carbonate (427.98 mg), and 2-(dimethylamino)acetic acid (287.40 mg). The mixture was stirred at 100 °C for 2 hours. After cooling to room temperature, the reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 1 / 0 to 0 / 1 gradient elution) to give compounds 74-2 and 75-2. LCMS: 317.9 [M+H] + Rt = 0.454 min, compound 74-2: 1 H NMR: (400 MHz, DMSO- d 6 ) d 8.02 (s, 1H), 7.83 (d, J = 7.2 Hz, 1H), 7.74 (s, 1H), 7.45 (s, 1H), 7.11 (d, J =7.2 Hz, 1H), 6.44 (s, 1H), 2.20 (s, 3H), 2.00 (s, 3H). Rt = 0.507 min, compound 75-2: 1 H NMR: (400 MHz, DMSO- d 6 ) d 7.95 (d, J = 7.2 Hz, 1H), 7.89 (d, J = 1.6 Hz, 1H), 7.81 (s, 1H), 7.43 (s, 1H), 7.10 (s, 1H), 7.02 (dd, J = 2.0,7.2 Hz, 1H), 2.30 (s, 3H), 2.15 (s, 3H).

[0481] Compound 74-2 (40.0 mg), intermediate A (87.9 mg), potassium carbonate (34.7 mg), and Pd(dppf)Cl2 (9.20 mg) were dissolved in a mixed solution of 1,4-dioxane (1 mL) and water (0.1 mL), and the mixture was stirred at 80 °C for 2 hours under nitrogen protection. After cooling to room temperature, the reaction solution was diluted with water (5 mL) and extracted with ethyl acetate (5 mL × 3). The combined organic phases were washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative high-performance liquid chromatography (column: CD52-Wepure Prepulite Platinum C18 150 × 25 × 7 μm; mobile phase: [water (containing 0.225% formic acid) - acetonitrile]; gradient: 6%-36% B phase, 11.0 min) to obtain compound 74. LCMS: 461.2 [M+H] + . 1 H NMR: (400 MHz, DMSO- d 6 ) d 10.94 (s, 1H), 7.91 (d, J = 7.2 Hz, 1H), 7.79 (s, 1H), 7.69 (s, 1H), 7.49 (s, 1H),7.47 - 7.42 (m, 3H),7.03 (dd, J = 1.6, 7.2 Hz, 1H), 6.46 (s, 1H), 4.37 (dd, J = 4.8, 12.0 Hz,1H), 2.86 - 2.76 (m, 1H),2.59 - 2.54 (m, 1H), 2.40 - 2.31 (m, 1H), 2.21 (s,3H), 2.10 - 2.04 (m, 1H), 2.02 (s, 3H).

[0482] Compound 75-2 (40 mg), intermediate A (65.93 mg), potassium carbonate (34.75 mg), and Pd(dppf)Cl2 (9.20 mg) were dissolved in a mixed solution of 1,4-dioxane (1 mL) and water (0.1 mL). The mixture was stirred at 80 °C for 2 hours under nitrogen protection. After cooling to room temperature, the reaction solution was diluted with water (50 mL) and extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative high-performance liquid chromatography (column: CD52-Wepure Prepulite Platinum C18 150 × 25 × 7 μm; mobile phase: [water (containing 0.225% formic acid) - acetonitrile]; gradient: 15%–45% B phase, 11.0 min) to obtain compound 75. LCMS: 461.2 [M+H] + . 1 H NMR: (400 MHz, DMSO- d 6 ) d 10.93 (s, 1H), 8.07 -7.98 (m, 1H), 7.84 (s, 1H), 7.57 (s, 1H), 7.49 - 7.40 (m, 4H), 7.14 (s, 1H), 6.94 (dd, J = 1.6, 7.2 Hz, 1H), 4.37 (dd, J = 4.8, 12.0 Hz, 1H), 2.86 - 2.76(m, 1H), 2.56 (d, J = 13.2 Hz, 1H), 2.37 - 2.31 (m, 4H), 2.16 (s, 3H), 2.10 -2.03 (m, 1H).

[0483] Example 66: Synthesis of Compoun...

Claims

1. A compound of formula (I), its stereoisomer, its tautomer, its pharmaceutically acceptable salt, its solvate, its deuterated derivative, its metabolite or its prodrug; ， in, It is a divalent group, connecting and ; It is a divalent group, connecting and L; L is a divalent group, connecting... and G; Y-shaped ring represents ; Ring X represents ; It can be a single bond or a double bond; The ring Y is phenyl or a 5-6 membered heteroaryl group; Ring X is selected from , , , , , , and ,in Represents the connection point with ring Y. Represents the connection point with L; Z is selected from N and CR; L is selected from single bond, -O-, -NH-, -C(=O)-, -S-, -S(=O-, -S(=O)2-, -C(=O)NH- -NHC(=O)- -C 1-3 Alkyl-, -C 2-3 alkenyl-, -C 2-3 alkynyl-, -OC 1-3 alkyl- -NH-C 1-3 alkyl- -C(=O)-C 1-3 alkyl- -NHC(=O)-C 1-3 alkyl- -C(=O)NH-C 1-3 alkyl- -C 1-3 Alkyl-O- -C 1-3 Alkyl-NH- -C 1-3 Alkyl-C(=O)- -C 1-3 Alkyl-C(=O)NH- and -C 1-3 Alkyl-NHC(=O)- The -NH- and -C(=O)NH- -NHC(=O)- -C 1-3 Alkyl-, -C 2-3 alkenyl-, -C 2-3 alkynyl-, -OC 1-3 alkyl- -NH-C 1-3 alkyl- -C(=O)-C 1-3 alkyl- -NHC(=O)-C 1-3 alkyl- -C 1-3 Alkyl-NHC(=O)- -C 1-3 Alkyl-O- -C 1-3 Alkyl-NH- -C 1-3 Alkyl-C(=O)- -C 1-3 Alkyl-C(=O)NH- and -C(=O)NH-C 1-3 alkyl- Each of the 1, 2, 3, or 4 R's can be independently selected. L Replace, among which Indicates the connection point with ring G; G is selected from 3-10 membered heterocyclic alkyl groups, 4-10 membered heterocyclic alkenyl groups, and C. 6-10 aryl and 5-10 heteroaryl, wherein the 3-10 heterocyclic alkyl, 4-10 heterocyclic alkenyl, C 6-10 Aryl and 5-10 heteroaryl groups are each independently and optionally bound by 1, 2, 3 or 4 R groups. G replace; R¹, R², and R³ are each independently selected from H, D, F, Cl, Br, I, CN, NH₂, OH, -CH₃, and -CH₂CH₃; Or, any R 1 Or R 2 It can form a ring with the carbon atom it is attached to, and the formed ring is independently selected from C. 3-7 Saturated monocyclic ring; Each R x and R y The elements are independently selected from H, D, F, Cl, Br, I, CN, NH2, OH, -CH3, -CH2CH3, -CH2CH2CH3, -CH2F, -CHF2, -CF3, -OCH3, -C(=O)OH and -C(=O)NH2, respectively. Each R L Each element is independently selected from H, D, halogens, CN, NH2, OH, and C. 1-6 Alkyl, Halogenated C 1-6 Alkyl-C(=O)C 1-6 Alkyl groups, -C(=O)OH, and -C(=O)NH2; Each R G The elements are independently selected from H, D, F, Cl, Br, I, =O, CN, NH2, OH, -C(=O)OH, -C(=O)NH2, C 1-6 Alkyl, -OC 1-6 Alkyl and C 3-7 cycloalkyl, the C 1-6 Alkyl, -OC 1-6 Alkyl and C 3-7 The cycloalkyl group is independently and optionally surrounded by 1, 2, 3 or 4 R groups. G1 replace; Or, R G Two Rs on the same carbon G They can be connected to form a ring, and the formed ring is independently selected from C. 3-7 Saturated monocyclic ring; Each R G1 Each of the following is independently selected from D, halogen, =O (oxo group), CN, NH2, OH, -NHCH3, -N(CH3)2, and C. 1-3 Alkyl, -OC 1-6 Alkyl and C 3-7 cycloalkyl, the C 1-3 Alkyl, -OC 1-3 Alkyl and C 3-7 Each cycloalkyl group may be independently substituted by 1, 2, 3 or 4 Rs; Each R is independently selected from H, D, F, Cl, Br, I, CN, NH2, OH, -CH3, -CH2CH3, -CH2F, -CHF2, -CF3, -OCH3, -NHCH3 and -N(CH3)2; m is selected from 0, 1, 2, 3, and 4; n is selected from 0, 1, 2, 3, and 4; In the heteroaryl group, the heteroatom / heteroatomic group is independently selected from one or more of N, S, O and C (=O), and the number of heteroatom / heteroatomic groups is independently selected from 1, 2, 3 and 4; In the heterocyclic alkyl and heterocyclic alkenyl alkyl groups, the heteroatoms / heteroatomic groups are independently selected from one or more of N, S, O and C (=O), and the number of heteroatoms / heteroatomic groups is independently selected from 1, 2, 3 and 4; And the compound shown in formula (I) satisfies any of the following conditions: (1) When L is -C 1-3 When alkyl-, G is a 6-10 membered heterocyclic alkyl, a 5-10 membered heterocyclic alkenyl, or C 6-10 aryl or 6-10 heteroaryl, wherein the 6-10 heterocyclic alkyl, 5-10 heterocyclic alkenyl, C 6-10 Aryl and 6-10 heteroaryl groups are each independently and optionally co-occupied by 1, 2, 3 or 4 R groups. G replace; (2) When L is a single bond and the ring X is When G is selected from 6-10 N-containing heterocyclic alkyl groups, 6-10 N-containing heterocyclic alkenyl groups, and C 6-10 aryl or 6-10 N-containing heteroaryl, wherein the 6-10 N-containing heterocyclic alkyl, 6-10 N-containing heterocyclic alkenyl, C 6-10 Aryl and 6-10 N-containing heteroaryl groups are each independently and optionally substituted with 1, 2, 3, or 4 R groups. G replace; (3) When L is a single bond and the ring X is In this case, G is a 4-10-membered heterocyclic alkenyl or a 5-10-membered heteroaryl, wherein the 4-10-membered heterocyclic alkenyl and the 5-10-membered heteroaryl are independently and optionally surrounded by 1, 2, 3 or 4 Rs. G replace.

2. The compound of formula (I) as claimed in claim 1, its stereoisomers, its tautomers, its pharmaceutically acceptable salts, its solvates, its deuterated derivatives, its metabolites, or its prodrugs, characterized in that, It satisfies one or more of the following conditions: (1) Ring X is selected from ,in Represents the connection point with ring Y. Represents the connection point with L; (2) Selected from , , and ; (3) L is selected from single bond, -O-, -NH-, -C(=O)-, -C 1-3 Alkyl-, -C 2-3 alkenyl-, -C 2-3 alkynyl-, -OC 1-3 alkyl- -C(=O)-C 1-3 alkyl- -NHC(=O)-C 1-3 alkyl- -C 1-3 Alkyl-O- -C 1-3 Alkyl-C(=O)- and -C 1-3 Alkyl-C(=O)NH- The -NH- and -C 1-3 Alkyl-, -C 2-3 alkenyl-, -C 2-3 alkynyl-, -OC 1-3 alkyl- -C(=O)-C 1-3 alkyl- -NHC(=O)-C 1-3 alkyl- -C 1-3 Alkyl-O- -C 1-3 Alkyl-C(=O)- and -C 1-3 Alkyl-C(=O)NH- Each of the 1, 2, 3, or 4 R's can be independently selected. L Replace, among which Indicates the connection point with ring G; (4) G is selected from 6-membered N-containing heterocyclic alkyl groups and 6-membered N-containing heteroaryl groups, wherein the 6-membered N-containing heterocyclic alkyl groups and 6-membered N-containing heteroaryl groups are independently selected by 1, 2, 3 or 4 R groups respectively. G replace.

3. The compound of formula (I) as claimed in claim 1, its stereoisomers, its tautomers, its pharmaceutically acceptable salts, its solvates, its deuterated derivatives, its metabolites, or its prodrugs, characterized in that, It is either Option 1 or Option 2 as follows: Option 1: ， in, It is a divalent group, connecting and ; It is a divalent group, connecting and L; L is a divalent group, connecting... and G; Y-ring represents ; Ring X represents ; Selected from single and double bonds; Cycloyl Y is selected from phenyl and 5-6-membered heteroaryl groups; Ring X is selected from , , , , , , and ,in Represents the connection point with ring Y. Represents the connection point with L; Z is selected from N and CR; L is selected from single bond, -O-, -NH-, -C(=O)-, -S-, -S(=O-, -S(=O)2-, -C(=O)NH- -NHC(=O)- -C 1-3 Alkyl-, -C 2-3 alkenyl-, -C 2-3 alkynyl-, -OC 1-3 alkyl- -NH-C 1-3 alkyl- -C(=O)-C 1-3 alkyl- -NHC(=O)-C 1-3 alkyl- -C(=O)NH-C 1-3 alkyl- -C 1-3 Alkyl-O- -C 1-3 Alkyl-NH- -C 1-3 Alkyl-C(=O)- -C 1-3 Alkyl-C(=O)NH- and -C 1-3 Alkyl-NHC(=O)- The -NH- and -C(=O)NH- -NHC(=O)- -C 1-3 Alkyl-, -C 2-3 alkenyl-, -C 2-3 alkynyl-, -OC 1-3 alkyl- -NH-C 1-3 alkyl- -C(=O)-C 1-3 alkyl- -NHC(=O)-C 1-3 alkyl- -C 1-3 Alkyl-NHC(=O)- -C 1-3 Alkyl-O- -C 1-3 Alkyl-NH- -C 1-3 Alkyl-C(=O)- -C 1-3 Alkyl-C(=O)NH- and -C(=O)NH-C 1-3 alkyl- Each of the 1, 2, 3, or 4 R's can be independently selected. L Replace, among which Indicates the connection point with ring G; G is selected from 3-10 membered heterocyclic alkyl groups, 4-10 membered heterocyclic alkenyl groups, and C. 6-10 aryl and 5-10 heteroaryl, wherein the 3-10 heterocyclic alkyl, 4-10 heterocyclic alkenyl, C 6-10 Aryl and 5-10 heteroaryl groups are each independently and optionally bound by 1, 2, 3 or 4 R groups. G replace; R¹, R², and R³ are each independently selected from H, D, F, Cl, Br, I, CN, NH₂, OH, -CH₃, and -CH₂CH₃; Alternatively, any R¹ or R² can form a cyclopropyl group with the carbon atom to which it is attached; Each R x and R y The elements are independently selected from H, D, F, Cl, Br, I, CN, NH2, OH, -CH3, -CH2CH3, -CH2CH2CH3, -CH2F, -CHF2, -CF3, -OCH3, -C(=O)OH and -C(=O)NH2, respectively. Each R L The elements are independently selected from H, D, F, Cl, Br, I, CN, NH2, OH, -CH3, -CH2CH3, -CH2F, -CHF2, -CF3, -C(=O)CH3, -C(=O)OH and -C(=O)NH2, respectively. Each R G The elements are independently selected from H, D, F, Cl, Br, I, =O, CN, NH2, OH, -C(=O)OH, -C(=O)NH2, C 1-6 Alkyl, -OC 1-6 Alkyl and C 3-7 cycloalkyl, the C 1-6 Alkyl, -OC 1-6 Alkyl and C 3-7 The cycloalkyl group is independently and optionally surrounded by 1, 2, 3 or 4 R groups. G1 replace; Each R G1 Each of the following is independently selected from D, F, Cl, Br, I, =O, CN, NH2, OH, -NHCH3, -N(CH3)2, C 1-3 Alkyl, -OC 1-3 Alkyl and C 3-7 cycloalkyl, the C 1-3 Alkyl, -OC 1-3 Alkyl and C 3-7 Each cycloalkyl group may be independently substituted by 1, 2, 3 or 4 Rs; Each R is independently selected from H, D, F, Cl, Br, I, CN, NH2, OH, -CH3, -CH2CH3, -CH2F, -CHF2, -CF3, -OCH3, -NHCH3 and -N(CH3)2; m is selected from 0, 1, 2, 3, and 4; n is selected from 0, 1, 2, 3, and 4; In the 5-6 membered heteroaryl and 5-10 membered heteroaryl, the heteroatom / heteroatomic group is independently selected from one or more of N, S, O and C (=O), and the number of heteroatoms / heteroatoms is independently selected from 1, 2, 3 and 4; In the 3-10 membered heterocyclic alkyl group and the 4-10 membered heterocyclic alkenyl alkyl group, the heteroatom / heteroatomic group is independently selected from N, S, O and C (=O), and the number of heteroatom / heteroatomic groups is independently selected from 1, 2, 3 and 4. And the compound shown in formula (I) satisfies any of the following conditions: (1) When L is -C 1-3 When alkyl-, G is a 6-10 membered heterocyclic alkyl, a 5-10 membered heterocyclic alkenyl, or C 6-10 aryl or 6-10 heteroaryl, wherein the 6-10 heterocyclic alkyl, 5-10 heterocyclic alkenyl, C 6-10 Aryl and 6-10 heteroaryl groups are each independently and optionally co-occupied by 1, 2, 3 or 4 R groups. G replace; (2) When L is a single bond and the ring X is When G is selected from 6-10 N-containing heterocyclic alkyl groups, 6-10 N-containing heterocyclic alkenyl groups, and C 6-10 aryl or 6-10 N-containing heteroaryl, wherein the 6-10 N-containing heterocyclic alkyl, 6-10 N-containing heterocyclic alkenyl, C 6-10 Aryl and 6-10 N-containing heteroaryl groups are each independently and optionally substituted with 1, 2, 3, or 4 R groups. G replace; (3) When L is a single bond and the ring X is In this case, G is a 4-10-membered heterocyclic alkenyl or a 5-10-membered heteroaryl, wherein the 4-10-membered heterocyclic alkenyl and the 5-10-membered heteroaryl are independently and optionally surrounded by 1, 2, 3 or 4 Rs. G replace; Option 2: for ; Ring X Selection ,in Represents the connection point with ring Y. Represents the connection point with L; Z stands for CH; L is selected from single bond, -O-, -NH-, -C(=O)-, -C 1-3 Alkyl-, -C(=O)-C 1-3 alkyl- -C 1-3 Alkyl-C(=O)- and -C 1-3 Alkyl-C(=O)NH- The -NH- and -C 1-3 Alkyl-, -C(=O)-C 1-3 alkyl- -C 1-3 Alkyl-C(=O)- and -C 1-3 Alkyl-C(=O)NH- Each of the 1, 2, 3, or 4 R's can be independently selected. L Replace, among which Indicates the connection point with ring G; G is selected from 6-membered heterocyclic alkyl and 6-membered heteroaryl groups, wherein the 6-membered heterocyclic alkyl and 6-membered heteroaryl groups are independently selected by 1, 2, 3 or 4 R groups respectively. G Substitution; preferably, the 6-membered heterocyclic alkyl and 6-membered heteroaryl groups contain at least one N heteroatom; R¹, R², and R³ are each independently selected from H; Each R G Selected independently from H, D, Cl, Br, I, F, O, and C respectively. 1-6 Alkyl, -OC 1-6 Alkyl and C 3-7 cycloalkyl, the C 1-6 Alkyl and C 3-7 The cycloalkyl group is independently and optionally surrounded by 1, 2, 3 or 4 R groups. G1 replace; Each R G1 Selected independently from halogens and C 3-7 cycloalkyl, the C 3-7 Each cycloalkyl group may be independently substituted by 1, 2, 3 or 4 Rs; m is 1; n is selected from 0, 1, 2, 3, and 4; In the heteroaryl group, the heteroatom / heteroatomic group is independently selected from one or more of N, S, O and C (=O), and the number of heteroatom / heteroatomic groups is independently selected from 1, 2, 3 and 4; In the heterocyclic alkyl and heterocyclic alkenyl alkyl groups, the heteroatoms / heteroatomic groups are independently selected from one or more of N, S, O and C (=O), and the number of heteroatoms / heteroatomic groups is independently selected from 1, 2, 3 and 4.

4. The compound of formula (I) as claimed in claim 1, its stereoisomers, its tautomers, its pharmaceutically acceptable salts, its solvates, its deuterated derivatives, its metabolites, or its prodrugs, characterized in that, One or more of the following conditions must be met: (1) The C 1-6 The alkyl group is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and tert-butyl, preferably methyl; (2) The C 1-3 The alkyl group is selected from methyl, ethyl, n-propyl, and isopropyl, preferably methyl; (3) The C 2-3 The alkenyl group is selected from vinyl and propenyl groups; (4) The C 2-3 The alkynyl group is selected from ethynyl and propynyl; (5) The C 3-7 The cycloalkyl group is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl; (6) The heteroatoms / heteroatom groups of the 3-10 membered heterocyclic alkyl group are selected from N, O, and C (=O), and the number of heteroatoms / heteroatom groups is selected from 1, 2, and 3; preferably, the 3-10 membered heterocyclic alkyl group is selected from 3-7 membered monocyclic heterocyclic alkyl group and 7-10 membered bicyclic heterocyclic alkyl group; more preferably, the 3-10 membered heterocyclic alkyl group is selected from , , , , , , , , , , , , , , , , , , , , , , and Preferred from , , , , , , , , , , , , , , , , and ; (7) The C 6-10 The aryl group is selected from phenyl and naphthyl groups; (8) The 5-6 aryl heteroaryl group is selected from pyridone, pyrimidinone, pyrazinone, pyridazinone, thiophene, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl, imidazolyl, oxazolyl, triazolyl and imidazolinone, preferably from pyridone, pyrimidinone and pyridinyl; (9) The 5-10 member heteroaryl group is selected from 5-6 member heteroaryl groups and 8-10 member heteroaryl groups, preferably from pyridinone, pyrimidinone, pyrazinone, pyridinone, pyridinyl, pyrimidinyl, pyrazinyl, pyridinyl, pyrazolyl, imidazolyl, oxazolyl, triazolyl, imidazolinone, indole, isoindole, indazole, isoindazole, quinolinyl, isoquinolinyl, benzimidazolyl, and benzimidazolone, more preferably from , , , , , , , , , , , , , , , , , , , , , , , , , , , , and ; (10) The halogen is F, Cl, Br or I, for example F or Cl; (11) The halogenated C 1-6 Alkyl group is fluorinated C 1-3 Alkyl groups, such as -CH2F, -CHF2, or -CF3; (12) The C 3-7 Saturated monocyclic ring is C 3-7 Cycloalkyl groups, such as cyclopropyl groups.

5. The compound of formula (I) as claimed in any one of claims 1-4, its stereoisomers, its tautomers, its pharmaceutically acceptable salts, its solvates, its deuterated derivatives, its metabolites, or its prodrugs, characterized in that, The compound of formula (I) is a compound represented by formula (II-A), (II-B), (II-C), (II-D), (III-A), or (IV-A): 、 、 、 、 、 ， Among them, R 1 R 2 R 3 R x R y The definitions of Z, L, G, ring X, ring Y, m, and n are as described in any one of claims 1-4.

6. The compound of formula (I) as claimed in claim 1, its stereoisomers, its tautomers, its pharmaceutically acceptable salts, its solvates, its deuterated derivatives, its metabolites, or its prodrugs, characterized in that, One or more of the following conditions must be met: (1) Z is selected from N, CH and CF; (2) R¹, R² and R³ are each independently selected from H, D and F; or, R² forms a cyclopropyl group with the carbon atom to which it is attached; (3) Ring Y is phenyl; (4) R x They are independently selected from H, -CH3, and -CF3, respectively; (5) R y Each of the following is independently selected from H, D, F, Cl, Br, I, CN, NH2, OH, and -CH3; (6) m is selected from 0 and 1; (7) n is selected from 0 and 1; (8) L is selected from single bond, -O-, -NH-, -C(=O)-, -C 1-3 Alkyl-, -C(=O)-C 1-3 alkyl- -C 1-3 Alkyl-C(=O)- and -C 1-3 Alkyl-C(=O)NH- The -NH- and -C 1-3 Alkyl-, -C(=O)-C 1-3 alkyl- -C 1-3 Alkyl-C(=O)- and -C 1-3 Alkyl-C(=O)NH- Each of the 1, 2, 3, or 4 R's can be independently selected. L replace; (9) R L The elements are independently selected from H, D, F, Cl, Br, I, CN, NH2, OH, -CH3, -CH2CH3, -CH2F, -CHF2, -CF3, -C(=O)CH3, -C(=O)OH and -C(=O)NH2, respectively. (10) G is selected from phenyl, pyridinyl, pyrimidinyl, pyrazinyl, pyrazolyl, imidazolyl, oxazolyl, triazolyl, pyridinoneyl, pyrimidinoneyl, pyrazinoneyl, pyridazinoneyl, imidazolinoneyl, pyrrolodinoneyl, piperidinyl, morpholinyl, piperazinyl, piperidinoneyl, tetrahydropyrimidinoneyl, morpholinoneyl, piperidinoneyl, piperidinoneyl, pyrroloalkyl, imidazoalkyl, pyrrolidinoneyl, imidazolidinoneyl, pyrrolidinoneyl, indoleyl, isoindoleyl, indazoleyl, isoindazoleyl, quinolinyl, isoquinolinyl, benzimidazolyl, and benzimidazoloneyl, wherein the phenyl, Pyridyl, pyrimidinyl, pyrazinyl, pyrazinyl, pyrazolyl, imidazolyl, oxazolyl, triazolyl, pyridinoneyl, pyrimidinoneyl, pyrazinoneyl, pyrazinoneyl, imidazolinoneyl, pyrrolodinoneyl, piperidinyl, morpholinyl, piperazinyl, piperidinoneyl, tetrahydropyrimidinoneyl, morpholinoneyl, piperidinoneyl, piperidinoneyl, pyrrolidinyl, imidazolyl, pyrrolidinoneyl, imidazolinoneyl, indoleyl, isoindoleyl, indazoleyl, isoindazoleyl, quinolinyl, isoquinolinyl, benzimidazolyl, and benzimidazoloneyl are each independently and optionally separated by 1, 2, 3, or 4 R groups. G replace; (11) R G Selected from F, Cl, Br, I, =O, CN, NH2, OH, -C(=O)OH, -C(=O)NH2, C 1-3 Alkyl, -OC 1-3 Alkyl and C 3-5 cycloalkyl, the C 1-3 Alkyl, -OC 1-3 Alkyl and C 3-5 The cycloalkyl group is independently and optionally surrounded by 1, 2, 3 or 4 R groups. G1 replace; (12) R G1 Each of the following is independently selected from D, F, Cl, Br, I, =O, CN, NH2, OH, -CH3, -CH3, -CH2CH3, -CH2F, -CHF2, -CF3, -OCH3, -NHCH3, -N(CH3)2, and .

7. The compound of formula (I) as claimed in claim 1, its stereoisomers, its tautomers, its pharmaceutically acceptable salts, its solvates, its deuterated derivatives, its metabolites, or its prodrugs, characterized in that, It satisfies at least one of the following conditions: (1) for The C marked with an asterisk represents the S configuration, R configuration, or a mixture thereof; (2) R¹, R², and R³ are each independently H; (3) Selected from ,For example ; (4) n is 0; (5) R x For H; (6) L is selected from -O- or -C 1-3 alkyl-; (7) G is selected from unsubstituted or substituted by 1, 2, 3 or 4 Rs. G Replacement , , , or ; (8) R G Selected from H or methyl, such as methyl.

8. The compound of formula (I) as claimed in claim 1, its stereoisomers, its tautomers, its pharmaceutically acceptable salts, its solvates, its deuterated derivatives, its metabolites, or its prodrugs, characterized in that, It satisfies at least one of the following conditions: (1) Selected from , , , , , , , , , , and ; (2) Selected from , and ; (3) Ring X is selected from , , , , , , , , , , , , and ,in Represents the connection point with ring Y. Represents the connection point with L; (4) L is selected from single bonds, , , , , , , , , , , , , , , and ,in Indicates the connection point with G; (5) G is selected from , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and .

9. A heterocyclic compound, its stereoisomers, its tautomers, its pharmaceutically acceptable salts, its solvates, its deuterated derivatives, its metabolites, or its prodrugs, characterized in that, The compound is any one of the following compounds: 。 10. A pharmaceutical composition comprising a compound as claimed in any one of claims 1-9, a stereoisomer thereof, a tautomer thereof, a pharmaceutically acceptable salt thereof, a solvate thereof, a deuterated derivative thereof, a metabolite thereof, or a prodrug thereof, and a pharmaceutical excipient.

11. The use of a compound as claimed in any one of claims 1-9, its stereoisomers, its tautomers, its pharmaceutically acceptable salts, its solvates, its deuterated derivatives, its metabolites, or its prodrugs, or a pharmaceutical composition as claimed in claim 10, wherein the use is any one of the following: (1) Application in the preparation of drugs for treating diseases related to the VAV1 signaling pathway; (2) Application in the preparation of drugs for treating autoimmune diseases and cancer; (3) Application in the preparation of VAV1 molecular adhesive degrading agent; Preferably, the application satisfies one or more of the following conditions: (1) The diseases associated with the VAV1 signaling pathway are autoimmune diseases and cancer; (2) The autoimmune diseases mentioned are selected from multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus, psoriasis, Hashimoto's thyroiditis, myasthenia gravis, type I or type II diabetes and related diseases, vasculitis, pernicious anemia, Sjögren's syndrome, uveitis, psoriasis, Graves' ophthalmopathy, alopecia areata, allergic diseases, inflammatory bowel disease, atherosclerosis, osteoarthritis, inflammatory eye disease, keratoconjunctivitis, myocarditis and hepatitis, more preferably from multiple sclerosis.

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