Heterocyclic compound and pharmaceutical use thereof

Abstract

The present invention relates to the technical field of medicine, and specifically relates to a VAV1 degrader, a preparation method therefor, and the pharmaceutical use thereof. Provided in the present invention are a VAV1 degrader of formula (I), and a composition thereof and the use thereof. The compound can be used for treating or preventing VAV1-mediated diseases or conditions and related diseases or conditions.

Description

A heterocyclic compound and its pharmaceutical applications Technical Field

[0001] This invention relates to the field of pharmaceutical technology, and more specifically to a heterocyclic compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, and its use in the preparation of medicaments for treating related diseases. Background Technology

[0002] The VAV family is a group of signal transduction proteins that act as phosphorylation-dependent GDP / GTP exchange factors (GEFs) and adaptor molecules for Rho subfamily GTPases. This family includes three members: VAV1, VAV2, and VAV3. VAV1 is primarily expressed in human hematopoietic cells, including T cells, B cells, monocytes, natural killer (NK) cells, granulocytes, and dendritic cells, while VAV2 and VAV3 are widely distributed throughout the body. VAV1 participates in T / B lymphocyte antigen receptor signaling, promoting actin polymerization, immune synapse formation, T cell activation and differentiation, and cytokine production. VAV1 activates Rac1 through its GEF function, triggering downstream effects including actin remodeling and F-actin polymerization, T cell signaling pathway aggregation, integrin-mediated activation of cell adhesion, immune synapse formation between T cells and antigen-presenting cells (APCs), and chemokine-mediated cell migration. In addition to its GEF-dependent function, VAV1 protein also functions as a scaffold protein. In vitro studies have shown that transfection of N-terminally truncated mutant VAV1 protein into human J.Vav1 T cells lacking VAV1 can restore GEF activity, but it cannot interact with phospholipase C-γ (PLCγ)1, leading to downstream Ca2+ deficiency. 2+ Processes such as flow, calmodulin binding, and NFAT activation are impossible. In vivo studies show that VAV1- / - mice have severe T cell developmental defects, with significantly reduced numbers of thymic and peripheral T cells; compared with wild-type mice, VAV1- / - mice have reduced susceptibility to antigen (methylated BSA)-induced arthritis. Furthermore, the mRNA level of VAV1 in the lamina propria mononuclear cells of patients with inflammatory bowel disease is significantly increased compared with the non-inflammatory control group.

[0003] Multiple research findings and clinical data indicate that targeted intervention of VAV1 physiological function has great potential in the treatment of T-cell and B-cell mediated autoimmune diseases and chronic inflammatory diseases. However, VAV1 has numerous functional domains and a complex protein structure, and has long been considered an undruggable target. In recent years, the development of molecular glue technology has made intervention on this protein possible. Molecular glues are a class of small molecules that can induce or stabilize protein-protein interactions. Unlike traditional drugs, molecular glues mediate the degradation or functional modification of target proteins by specifically regulating protein function and interactions, thereby achieving therapeutic effects. This mechanism provides a new approach to targeting "undruggable" proteins. Molecular glues targeting VAV1 can degrade the protein, not only disrupting its GEF function but also eliminating its function as a scaffold protein, thereby achieving better inhibitory effects. This invention aims to provide a novel heterocyclic derivative and its uses. The described compound has excellent VAV1 degradation activity and can be used as a VAV1 degrading agent for the treatment of autoimmune diseases and chronic inflammatory diseases. Summary of the Invention

[0004] The technical problem to be solved by this invention is to provide a novel heterocyclic compound that can be used as a VAV1 degrading agent for the preparation of drugs for treating VAV1-mediated diseases or symptoms and related diseases or symptoms. To solve the above technical problem, the technical solution provided by this invention is as follows:

[0005] On the one hand, the present invention provides heterocyclic compounds with the structure shown in formula (I) or their pharmaceutically acceptable salts, isotope derivatives, solvates, or their stereoisomers, geometric isomers, tautomers, or their prodrug molecules or metabolites:

[0006] in,

[0007] X is selected from CR a Or N;

[0008] R a Selected from hydrogen, deuterium, fluorine, or methyl;

[0009] R1 is selected from hydrogen, deuterium, halogen, cyano, methyl, difluoromethyl, trifluoromethyl, or methoxy;

[0010] R2, R3, and R4 are each independently selected from hydrogen, deuterium, halogen, cyano, and C. 1-6 Alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl, C 3-6 alkynyl or C 1-4 Alkoxy;

[0011] W and Y are each independently selected from N or CR e ;

[0012] Each R e R5 is independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 1-6 Alkyl sulfone group, C 1-6 Alkylthio, C 1-6 alkylamine group, C 1-6 alkyl ester group, C 1-6 Alkyl acyl, C 1-6 Alkylamide group, C 1-6 alkylsulfonyl, C 1-6 alkylsulfonamide group, 3-8 membered heterocyclic group, 5-14 membered heteroaryl group or C 6-12 Aryl; the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 1-6 Alkyl sulfone group, C 1-6 Alkylthio, C 1-6 alkylamine group, C 1-6 alkyl ester group, C 1-6 Alkyl acyl, C 1-6 Alkylamide group, C 1-6 alkylsulfonyl, C 1-6 alkylsulfonamide group, 3-8 membered heterocyclic group, 5-14 membered heteroaryl group or C 6-12 The aryl group may optionally be affected by one or more R groups. b replace;

[0013] n is selected from 0, 1, or 2;

[0014] Ring A is selected from 9-14 membered heteroaryl or heterocyclic groups;

[0015] R6 and R7 can be attached to the same carbon atom, or to different carbon atoms or heteroatoms. R6, R7, and the atoms directly attached to them together form C. 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-8 Aryl or 5-8 quinone heteroaryl, wherein C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-8 Aryl or 5-8 heteroaryl groups may optionally be replaced by one or more R groups. c replace;

[0016] Each R8 group is independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, oxo, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 1-6 Alkyl sulfone group, C 1-6 Alkylthio, C 1-6 alkylamine group, C 1-6 alkyl ester group, C 1-6 Alkyl acyl, C 1-6 Alkylamide group, C 1-6 alkylsulfonyl, C 1-6 alkylsulfonamide group, 3-8 membered heterocyclic group, 5-14 membered heteroaryl group or C 6-12 Aryl; the C 1-6 Alkyl, C 2- 6-olefin, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 1-6 Alkyl sulfone group, C 1-6 Alkylthio, C 1-6 alkylamine group, C 1-6 alkyl ester group, C 1-6 Alkyl acyl, C 1-6 Alkylamide group, C 1-6 alkylsulfonyl, C 1-6 alkylsulfonamide group, 3-8 membered heterocyclic group, 5-14 membered heteroaryl group or C 6-12 The aryl group may optionally be affected by one or more R groups. d replace;

[0017] m is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

[0018] Each R b R d Each is independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, mercapto, oxo, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 1-6 Alkyl sulfone group, C 1-6 Alkylthio, C 1-6 alkylamine group, C 1-6 alkyl ester group, C 1-6 Alkyl acyl, C 1-6 Alkylamide group, C 1-6 alkylsulfonyl, C 1-6 alkylsulfonamide group, C1-6 Phosphoryl group, 3-8 membered heterocyclic group, 5-14 membered heteroaryl group or C 6-12 Aryl; the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 1-6 Alkyl sulfone group, C 1-6 Alkylthio, C 1-6 alkylamine group, C 1-6 alkyl ester group, C 1-6 Alkyl acyl, C 1-6 Alkylamide group, C 1-6 alkylsulfonyl, C 1-6 alkylsulfonamide group, C 1-6 Phosphoryl group, 3-8 membered heterocyclic group, 5-14 membered heteroaryl group or C 6-12 The aryl group may optionally be further reacted with one or more hydrogens, deuteriums, halogens, cyano groups, hydroxyl groups, amino groups, mercapto groups, oxo groups, or C groups. 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 1-6 Alkyl sulfone group, C 1-6 Alkylthio, C 1-6 alkylamine group, C 1-6 Alkyl acyl, 4-10 membered heterocyclic, 5-14 membered heteroaryl or C 6-12 Aryl groups are replaced;

[0019] Each R c Each is independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, oxo group, C 1-6 Alkyl, C 2-6 alkenyl, C 3-6 alkynyl group, C 1-6 Alkoxy, C 3-6 cycloalkyl or C 1-6 Halogenated alkyl groups.

[0020] In some embodiments, in the compound represented by formula (I), or its pharmaceutically acceptable salt, isotope derivative, solvate, or its stereoisomer, geometric isomer, tautomer, or its prodrug molecule or metabolite, R6 and R7 may be attached to the same carbon atom or to different carbon atoms or heteroatoms, and R6, R7 and the atoms directly attached to them together form C 3-8 Cycloalkyl, 3-8 membered heterocyclic or 5-8 membered heteroaryl, wherein C 3-8Cycloalkyl, 3-8 membered heterocyclic or 5-8 membered heteroaryl groups may optionally be coupled with one or more R groups. c replace;

[0021] Each R c Each is independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C 1-6 Alkyl, C 2-6 alkenyl, C 3-6 alkynyl group, C 1-6 Alkoxy, C 3-6 cycloalkyl or C 1-6 Halogenated alkyl groups.

[0022] In some embodiments, the compound represented by formula (I), or a pharmaceutically acceptable salt, isotope derivative, solvate thereof, or a stereoisomer, geometric isomer, tautomer thereof, or a prodrug molecule or metabolite thereof, has a structure represented by formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Im), (In), (Io), (Ip), (Iq), (Ir), (Is), (It), (Iu), (Iv), or (Iw):

[0023] in,

[0024] It can be a single bond or a double bond;

[0025] Ring B is selected from phenyl, 5-8 membered heteroaryl, or 5-8 membered heterocyclic group;

[0026] Ring C is C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-8 Aryl or 5-8 quinone heteroaryl, wherein C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-8 Aryl or 5-8 heteroaryl groups may optionally be replaced by one or more R groups. c Substitution; preferably, ring C is C 3-8 Cycloalkyl, 3-8 membered heterocyclic or 5-8 membered heteroaryl, wherein C 3-8 Cycloalkyl, 3-8 membered heterocyclic or 5-8 membered heteroaryl groups may optionally be coupled with one or more R groups. c replace;

[0027] J2 is selected from C, CH, or N; J3 is selected from C, CH, or N;

[0028] J1, J4, and J5 are each independently selected from -(C=O)-, -SO2-, -O-, and -CR-. 81 R 82 -or-NR83 -;

[0029] Each R 81 R 82 R 83 Each is independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 1-6 Alkyl sulfone group, C 1-6 Alkylthio, C 1-6 alkylamine group, C 1-6 alkyl ester group, C 1-6 Alkyl acyl, C 1-6 Alkylamide group, C 1-6 alkylsulfonyl, C 1-6 alkylsulfonamide group, 3-8 membered heterocyclic group, 5-14 membered heteroaryl group or C 6-12 Aryl; the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 1-6 Alkyl sulfone group, C 1-6 Alkylthio, C 1-6 alkylamine group, C 1-6 alkyl ester group, C 1-6 Alkyl acyl, C 1-6 Alkylamide group, C 1-6 alkylsulfonyl, C 1-6 alkylsulfonamide group, 3-8 membered heterocyclic group, 5-14 membered heteroaryl group or C 6- 12 The aryl group may optionally be affected by one or more R groups. d replace;

[0030] m1 and m2 are each independently selected from 0, 1, 2, 3, 4, 5 or 6;

[0031] X, Y, W, R1, R2, R3, R4, R5, R8, R c R d The definitions of and n are as described in general formula (I).

[0032] In one practical application, a compound of formula (I), a chemically accessible substance, an isotopic compound, a soluble compound, or a Its three-dimensional different structure, how many different structures, mutually different structure, some its predecessor, substitute, material as below formula (I-1), ( I-2), (I-3), (I-4), (I-5), (I-6), (I-7), (I-8), (I-9), (I-10), (I-11), (I-12), (I-13), (I-14), (I-15) , (I-16), (I-17), (I-18), (I-19), (I-20), (I-21), (I-22), (I-23), (I-24), (I-25), (I-26), (I-27), (I- 28), (I-29), (I-30), (I-31), (I-32), (I-33), (I-34), (I-35), (I-36), (I-37), (I-38), (I-39), (I-40), ( I-41), (I-42), (I-43), (I-44), (I-45), (I-46), (I-47), (I-48), (I-49), (I-50), (I-51), (I-52), (I-53 ), (I-54), (I-55), (I-56), (I-57), (I-58), (I-59), (I-60), (I-61), (I-62), (I-63), (I-64), (I-65), (I Structures shown in (-66), (I-67), (I-68), (I-69), (I-70), (I-71), (I-72), (I-73), (I-74), (I-75), (I-76), (I-77), (I-78), (I-79), (I-80), (I-81), (I-82), (I-83), (I-84), (I-85), (I-86), (I-87), (I-88), (I-89), or (I-90):

[0033] Among them, X, Y, W, R1, R2, R3, R4, R5, R8, R 81 , R 82 , R 83 , R c , n's fixed order as described in (Ia).

[0034] In some embodiments, X is CH in the compounds represented by formulas (I), (Ia) to (Iw), (I-1) to (I-90), or their pharmaceutically acceptable salts, isotope derivatives, solvates, or their stereoisomers, geometric isomers, tautomers, or their prodrug molecules or metabolites.

[0035] In some embodiments, in the compounds represented by formulas (I), (Ia) to (Iw), (I-1) to (I-90), or their pharmaceutically acceptable salts, isotope derivatives, solvates, or their stereoisomers, geometric isomers, tautomers, or their prodrug molecules or metabolites, the Y is CH.

[0036] In some embodiments, in the compounds represented by formulas (I), (Ia) to (Iw), (I-1) to (I-90), or their pharmaceutically acceptable salts, isotope derivatives, solvates, or their stereoisomers, geometric isomers, tautomers, or their prodrug molecule or metabolite, wherein W is a CR e The R e Selected from hydrogen or C 1-6 Alkyl group; preferably, the W is CH.

[0037] In some embodiments, R1 is a halogen in the compounds represented by formulas (I), (Ia) to (Iw), (I-1) to (I-90), or their pharmaceutically acceptable salts, isotope derivatives, solvates, or their stereoisomers, geometric isomers, tautomers, or their prodrug molecules or metabolites.

[0038] In a further embodiment, R1 is chlorine or fluorine; preferably, R1 is chlorine.

[0039] In some embodiments, R2 is hydrogen in the compounds represented by formulas (I), (Ia) to (Iw), (I-1) to (I-90), or their pharmaceutically acceptable salts, isotope derivatives, solvates, or their stereoisomers, geometric isomers, tautomers, or their prodrug molecules or metabolites.

[0040] In some embodiments, R3 is hydrogen in the compounds represented by formulas (I), (Ia) to (Iw), (I-1) to (I-90), or their pharmaceutically acceptable salts, isotope derivatives, solvates, or their stereoisomers, geometric isomers, tautomers, or their prodrug molecules or metabolites.

[0041] In some embodiments, R4 is hydrogen in the compounds represented by formulas (I), (Ia) to (Iw), (I-1) to (I-90), or their pharmaceutically acceptable salts, isotope derivatives, solvates, or their stereoisomers, geometric isomers, tautomers, or their prodrug molecules or metabolites.

[0042] In some embodiments, R5 is hydrogen in the compounds represented by formulas (I), (Ia) to (Iw), (I-1) to (I-90), or their pharmaceutically acceptable salts, isotope derivatives, solvates, or their stereoisomers, geometric isomers, tautomers, or their prodrug molecules or metabolites.

[0043] In some embodiments, in the compounds represented by formulas (I), (Ia) to (Iw), (I-1) to (I-90), or their pharmaceutically acceptable salts, isotope derivatives, solvates, or their stereoisomers, geometric isomers, tautomers, or their prodrug molecules or metabolites, the R8 is independently selected from hydrogen, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-8 membered heterocyclic or C 1-6 alkylamine group, the C 1-6 Alkyl groups may optionally be C 1-6 Alkylamine substitution.

[0044] In some embodiments, in the compounds represented by formulas (I), (Ia) to (Iw), (I-1) to (I-90), or their pharmaceutically acceptable salts, isotope derivatives, solvates, or their stereoisomers, geometric isomers, tautomers, or their prodrug molecules or metabolites, the R8 group is independently selected from hydrogen, cyano, C... 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-8 membered heterocyclic or C 1- 6-alkylamine group, the C 1-6 Alkyl groups may optionally be C 1-6 Alkylamine substitution.

[0045] In some embodiments, in the compounds represented by formulas (I), (Ia) to (Iw), (I-1) to (I-90), or their pharmaceutically acceptable salts, isotope derivatives, solvates, or their stereoisomers, geometric isomers, tautomers, or their prodrug molecules or metabolites, the R8 group is independently selected from hydrogen, cyano, C... 1-6 Alkyl, C 1-6 Alkoxy, C 1-6Haloalkyl, C 3-6 Cycloalkyl, 3-8 membered heterocyclic or C 1- 6-alkylamine group.

[0046] In some embodiments, in the compounds represented by formulas (I), (Ia) to (Iw), (I-1) to (I-90), or their pharmaceutically acceptable salts, isotope derivatives, solvates, or their stereoisomers, geometric isomers, tautomers, or their prodrug molecules or metabolites, the R8 group is independently selected from hydrogen, cyano, C... 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 3-6 cycloalkyl or C 1-6 Alkylamine group.

[0047] In some embodiments, in the compounds represented by formulas (I), (Ia) to (Iw), (I-1) to (I-90), or their pharmaceutically acceptable salts, isotope derivatives, solvates, or their stereoisomers, geometric isomers, tautomers, or their prodrug molecules or metabolites, the R8 group is independently selected from hydrogen, cyano, C... 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl or C 1-6 Alkylamine group.

[0048] In some embodiments, in the compounds represented by formulas (I), (Ia) to (Iw), (I-1) to (I-90), or their pharmaceutically acceptable salts, isotope derivatives, solvates, or their stereoisomers, geometric isomers, tautomers, or their prodrug molecules or metabolites, the R8 group is independently selected from hydrogen, oxo groups, C... 1-6 Alkyl, C 1-6 Halogenated alkyl or C 1-6 Alkylamine group.

[0049] In a further embodiment, each of the R8 groups is independently selected from hydrogen, fluorine, methoxy, methyl, trifluoromethyl, difluoromethyl, cyclopropyl, cyano, etc.

[0050] In a further embodiment, each of the R8 groups is independently selected from hydrogen, methoxy, methyl, trifluoromethyl, difluoromethyl, cyclopropyl, cyano, etc.

[0051] In a further embodiment, each of the R8 groups is independently selected from hydrogen, methoxy, methyl, trifluoromethyl, difluoromethyl, cyclopropyl, cyano, or...

[0052] In a further embodiment, each of the R8 groups is independently selected from hydrogen, methoxy, methyl, cyclopropyl, cyano, or...

[0053] In some embodiments, the compound represented by formulas (I), (Ia) to (Iw), (I-1) to (I-90), or a pharmaceutically acceptable salt, isotope derivative, solvate thereof, or its stereoisomer, geometric isomer, tautomer, or its prodrug molecule or metabolite, wherein the R 81 Selected from hydrogen, R 82 Selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 1-6 alkylthio or C 1-6 Alkylamine group; the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 1- 6-alkylthio or C 1-6 The alkylamine group may optionally be replaced by one or more radicals selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, mercapto, oxo, or C. 1- 6-alkyl substituents.

[0054] Preferably, R 82 Selected from hydrogen.

[0055] In some embodiments, the compound represented by formulas (I), (Ia) to (Iw), (I-1) to (I-90), or a pharmaceutically acceptable salt, isotope derivative, solvate thereof, or its stereoisomer, geometric isomer, tautomer, or its prodrug molecule or metabolite, wherein the R 83 Selected from hydrogen, C 1-6 Alkyl, C 1-6 Alkyl acyl, C 3-6 cycloalkyl or C 1-6 alkylsulfonyl, the C 1-6 Alkyl groups may optionally be substituted with one or more R groups. d Replace, each R d Each is independently selected from hydrogen, hydroxyl, or C. 1-6 Alkyl group.

[0056] Preferably, the R 83 Selected from hydrogen, C 1-6 Alkyl, C 1-6 alkyl acyl or C 1-6alkylsulfonyl, the C 1-6 Alkyl groups may optionally be substituted with one or more R groups. d Replace, each R d Each is independently selected from hydrogen, hydroxyl, or C. 1-6 Alkyl group.

[0057] In a further implementation, the R 83 Each is independently selected from hydrogen, methyl, Preferably, the R 83 Each is independently selected from hydrogen, methyl,

[0058] In some embodiments, the compound represented by formulas (I), (Ia) to (Iw), (I-1) to (I-90), or a pharmaceutically acceptable salt, isotope derivative, solvate thereof, or its stereoisomer, geometric isomer, tautomer, or its prodrug molecule or metabolite, wherein the R c It is hydrogen, halogen or C 1-6 Alkyl; preferably, the R c It is hydrogen.

[0059] In some embodiments, the compounds represented by formulas (I), (Ia) to (Iw), (I-1) to (I-90), or their pharmaceutically acceptable salts, isotope derivatives, solvates, or their stereoisomers, geometric isomers, tautomers, or their prodrug molecules or metabolites are selected from the following structural compounds:

[0060] On the other hand, the present invention provides heterocyclic compounds with the structure shown in formula (II) or their pharmaceutically acceptable salts, isotope derivatives, solvates, or their stereoisomers, geometric isomers, tautomers, or their prodrug molecules or metabolites:

[0061] in,

[0062] X is selected from CR a Or N;

[0063] R a Selected from hydrogen, deuterium, fluorine, or methyl;

[0064] R1 is selected from hydrogen, deuterium, halogen, cyano, methyl, difluoromethyl, trifluoromethyl, or methoxy;

[0065] R2, R3, and R4 are each independently selected from hydrogen, deuterium, halogen, cyano, and C. 1-6 Alkyl, C3-6 cycloalkyl, C 2-6 alkenyl, C 3-6 alkynyl or C 1-4 Alkoxy;

[0066] W and Y are each independently selected from N or CH;

[0067] U, V, Q, and Z are each independently selected from -(C=O)-, -SO2-, -O-, and -CR-. 12 R 13 -、-NR 14 -or-(CR) 15 R 16 ) p - and at least one of U, V, Q, and Z is selected from -CR 12 R 13 -;

[0068] R 12 R 13 Together with the atoms they are attached to, they form C 3-8 cycloalkyl or 3-8 membered heterocyclic groups, wherein the C 3-8 Cycloalkyl or 3-8 membered heterocyclic groups may optionally be surrounded by one or more R groups. y replace;

[0069] R 14 Selected from hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 1-6 Alkyl acyl, C 1-6 alkylsulfonyl, C 1-6 Phosphoryl group, 3-8 membered heterocyclic group, 5-14 membered heteroaryl group or C 6-12 Aryl; the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 1-6 Alkyl acyl, C 1-6 alkylsulfonyl, C 1-6 Phosphoryl group, 3-8 membered heterocyclic group, 5-14 membered heteroaryl group or C 6-12 The aryl group may optionally be affected by one or more R groups. z Replaced;

[0070] R 15 and R 16 Each element is independently selected from hydrogen, deuterium, halogens, and carbon. 1-6 Alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl, C 3-6 alkynyl or C 1-4Alkoxy;

[0071] p is selected from 0, 1, or 2;

[0072] Each R y Each is independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C 1-6 Alkyl, C 2-6 alkenyl, C 3-6 alkynyl group, C 1-6 Alkoxy, C 3-6 cycloalkyl or C 1-6 Halogenated alkyl groups;

[0073] Each R z Each independently contains hydrogen, deuterium, halogen, cyano, hydroxyl, amino, mercapto, oxo, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 2- 6-olefin, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 1-6 Alkyl sulfone group, C 1-6 Alkylthio, C 1-6 alkylamine group, C 1-6 Alkyl acyl, C 1-6 alkylsulfonyl, C 1-6 Phosphoryl, 4-10 membered heterocyclic group, 5-14 membered heteroaryl or C 6-12 Aryl group replaced, the C 3-6 Cycloalkyl, 4-10 membered heterocyclic, 5-14 membered heteroaryl or C 6-12 The aryl group may optionally be reacted with one or more hydrogens, deuteriums, halogens, or C atoms. 1-6 Alkyl or C 1-6 Alkyl halogenates are substituted.

[0074] In some embodiments, the compound represented by formula (II), or a pharmaceutically acceptable salt, isotope derivative, solvate thereof, or its stereoisomer, geometric isomer, tautomer, or its prodrug molecule or metabolite, has the structure represented by formula (IIA):

[0075] Among them, U, V, and Z are each independently selected from -(C=O)-, -SO2-, -O-, and -CR-. 12 R 13 -、-NR 14 -or-CR 15 R 16- And at least one of U, V, and Z is selected from -CR 12 R 13 -;

[0076] X, Y, W, R1, R2, R3, R4, R 12 R 13 R 14 R 15 R 16 The definition is as stated in general formula (II).

[0077] In some embodiments, the compound represented by formula (II), or a pharmaceutically acceptable salt, isotope derivative, solvate thereof, or a stereoisomer, geometric isomer, tautomer thereof, or a prodrug molecule or metabolite thereof, has a structure represented by formula (IIa), (IIb) or (IIc) below:

[0078] T is selected from O, S, SO2, and CHR. y or NR y The R y Each is independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl or C 1-6 Haloalkyl; q and r are each independently selected from 0, 1, 2, 3, 4 or 5, and q and r are not both 0;

[0079] The definitions of X, Y, W, U, V, Z, R1, R2, R3, and R4 are as described in general formula (IIA).

[0080] In some embodiments, the compound represented by formula (II), or a pharmaceutically acceptable salt, isotope derivative, solvate thereof, or a stereoisomer, geometric isomer, tautomer thereof, or a prodrug molecule or metabolite thereof, has a structure represented by formula (II-1), (II-2), (II-3), (II-4), (II-5), (II-6), or (II-16):

[0081] Among them, X, Y, W, R1, R2, R3, R4, R 14 The definition is as stated in general formula (II).

[0082] In some embodiments, the compound represented by formula (II), or a pharmaceutically acceptable salt, isotope derivative, solvate thereof, or its stereoisomer, geometric isomer, tautomer, or its prodrug molecule or metabolite, has the structure shown in formula (IIB):

[0083] Among them, U, V, Q, and Z are each independently selected from -(C=O)-, -SO2-, -O-, and -CR-. 12 R 13-、-NR 14 -or-CR 15 R 16 - and at least one of U, V, Q, and Z is selected from -CR 12 R 13 -;

[0084] X, Y, W, R1, R2, R3, R4, R 12 R 13 R 14 R 15 R 16 The definition is as stated in general formula (II).

[0085] In some embodiments, the compound represented by formula (II), or a pharmaceutically acceptable salt, isotope derivative, solvate thereof, or a stereoisomer, geometric isomer, tautomer thereof, or a prodrug molecule or metabolite thereof, has a structure represented by formula (IId), (IIe), (IIIf) or (IIg):

[0086] T is selected from O, S, SO2, and CHR. y or NR y The R y Each is independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl or C 1-6 Haloalkyl; q and r are each independently selected from 0, 1, 2, 3, 4 or 5, and q and r are not both 0;

[0087] The definitions of X, Y, W, U, V, Q, Z, R1, R2, R3, and R4 are as described in general formula (IIB).

[0088] In some embodiments, the compound represented by formula (II), or a pharmaceutically acceptable salt, isotope derivative, solvate thereof, or a stereoisomer, geometric isomer, tautomer thereof, or a prodrug molecule or metabolite thereof, has the structure shown in formulas (II-7), (II-8), (II-9), (II-10), (II-11), (II-12), (II-13), (II-14), or (II-15):

[0089] Among them, X, Y, W, R1, R2, R3, R4, R 14 The definition is as stated in general formula (II).

[0090] In some embodiments, X is CH in the compounds of formulas (II), (IIA), (IIB), (IIa) to (IIg), (II-1) to (II-16), or their pharmaceutically acceptable salts, isotope derivatives, solvates, or their stereoisomers, geometric isomers, tautomers, or their prodrug molecules or metabolites.

[0091] In some embodiments, Y is CH in the compounds represented by formulas (II), (IIA), (IIB), (IIa) to (IIg), (II-1) to (II-16), or their pharmaceutically acceptable salts, isotope derivatives, solvates, or their stereoisomers, geometric isomers, tautomers, or their prodrug molecules or metabolites.

[0092] In some embodiments, Y is N in the compounds of formulas (II), (IIA), (IIB), (IIa) to (IIg), (II-1) to (II-16), or their pharmaceutically acceptable salts, isotope derivatives, solvates, or their stereoisomers, geometric isomers, tautomers, or their prodrug molecules or metabolites.

[0093] In some embodiments, the W in the compounds of formulas (II), (IIA), (IIB), (IIa) to (IIg), (II-1) to (II-16), or their pharmaceutically acceptable salts, isotope derivatives, solvates, or their stereoisomers, geometric isomers, tautomers, or their prodrug molecules or metabolites, is CH.

[0094] In some embodiments, R1 is a halogen in the compounds of formulas (II), (IIA), (IIB), (IIa) to (IIg), (II-1) to (II-16), or their pharmaceutically acceptable salts, isotope derivatives, solvates, or their stereoisomers, geometric isomers, tautomers, or their prodrug molecules or metabolites.

[0095] In a further embodiment, R1 is chlorine.

[0096] In some embodiments, R2 is hydrogen in the compounds of formulas (II), (IIA), (IIB), (IIa) to (IIg), (II-1) to (II-16), or their pharmaceutically acceptable salts, isotope derivatives, solvates, or their stereoisomers, geometric isomers, tautomers, or their prodrug molecules or metabolites.

[0097] In some embodiments, R3 is hydrogen in the compounds of formulas (II), (IIA), (IIB), (IIa) to (IIg), (II-1) to (II-16), or their pharmaceutically acceptable salts, isotope derivatives, solvates, or their stereoisomers, geometric isomers, tautomers, or their prodrug molecules or metabolites.

[0098] In some embodiments, R4 is hydrogen in the compounds of formulas (II), (IIA), (IIB), (IIa) to (IIg), (II-1) to (II-16), or their pharmaceutically acceptable salts, isotope derivatives, solvates, or their stereoisomers, geometric isomers, tautomers, or their prodrug molecules or metabolites.

[0099] In some embodiments, the compounds represented by formulas (II), (IIA), (IIB), (IIa) to (IIg), (II-1) to (II-16), or their pharmaceutically acceptable salts, isotope derivatives, solvates, or their stereoisomers, geometric isomers, tautomers, or their prodrug molecules or metabolites, wherein the R... 14 Selected from hydrogen, C 1-6 Alkyl or 5-14-membered heteroaryl, wherein the C 1-6 Alkyl or 5-14-membered heteroaryl groups may optionally be surrounded by one or more R groups. z Replaced;

[0100] Each R z Each is independently selected from hydrogen, halogen, oxo group, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, 4-10 membered heterocyclic group or 5-14 membered heteroaryl, wherein the C 3-6 Cycloalkyl, 4-10-membered heterocyclic or 5-14-membered heteroaryl groups may further optionally be converted by one or more hydrogens, C-terminals, or C-terminals. 1-6 Alkyl or C 1-6 Halogenated alkyl substitution.

[0101] In a further implementation, the R 14 Selected from hydrogen, methyl, ethyl,

[0102] In a further implementation, the R 14 Selected from hydrogen, methyl, ethyl,

[0103] In some embodiments, the compounds represented by formulas (II), (IIA), (IIB), (IIa) to (IIg), (II-1) to (II-16), or their pharmaceutically acceptable salts, isotope derivatives, solvates, or their stereoisomers, geometric isomers, tautomers, or their prodrug molecules or metabolites are selected from the following structural compounds:

[0104] On the other hand, the present invention provides a pharmaceutical composition containing a therapeutically effective amount of the compounds represented by the above general formulas or their pharmaceutically acceptable salts, isotope derivatives, solvates, or their stereoisomers, geometric isomers, tautomers, or their prodrug molecules or metabolites.

[0105] In another aspect, the present invention provides the use of compounds represented by the above general formulas or pharmaceutically acceptable salts, isotope derivatives, solvates, or stereoisomers, geometric isomers, tautomers, or prodrug molecules, metabolites, or pharmaceutical compositions thereof in the preparation of medicaments for treating VAV1-related diseases or conditions and related diseases or conditions.

[0106] In another aspect, the present invention provides the use of compounds represented by the above general formulas or their pharmaceutically acceptable salts, isotope derivatives, solvates, or stereoisomers, geometric isomers, tautomers, or their prodrug molecules, metabolites, or pharmaceutical compositions described above for the treatment of VAV1-related diseases or conditions and related diseases or conditions.

[0107] The present invention also provides a method for treating and / or preventing diseases, comprising administering to a therapeutically effective amount of the compounds represented by the above general formulas or their pharmaceutically acceptable salts, isotope derivatives, solvates, or their stereoisomers, geometric isomers, tautomers, or their prodrug molecules, metabolites, or the pharmaceutical compositions described above.

[0108] In some implementations, the disease being treated and / or prevented is a VAV1-related disease or condition and related diseases or conditions.

[0109] In some implementations, the VAV1-related diseases or conditions and related diseases or conditions are diseases caused by abnormalities in the T-cell signaling pathway (TCR) or B-cell signaling pathway (BCR), including autoimmune diseases, inflammatory diseases and hematologic malignancies.

[0110] In some implementations, the autoimmune diseases include multiple sclerosis, arthritis, systemic lupus erythematosus, chronic autoimmune thyroiditis, myasthenia gravis, type I / II diabetes and its complications, vasculitis, pernicious anemia, Sjögren's syndrome, uveitis, psoriasis, Graves' ophthalmopathy, alopecia areata, allergic asthma, atopic dermatitis, allergic rhinitis, allergic conjunctivitis, etc.; the inflammatory diseases include inflammatory bowel disease, Crohn's disease, endogenous asthma, inflammatory lung injury, inflammatory liver injury, inflammatory kidney injury, atherosclerosis, osteoarthritis, irritant dermatitis, eczema, seborrheic dermatitis, keratitis, myocarditis, and hepatitis, etc.; the hematologic malignancies include leukemia, lymphoma, acute myeloid leukemia (A1), etc. ML), T-cell lymphoblastic lymphoma, T-cell chronic lymphocytic leukemia, aggressive NK-cell leukemia, hairy cell leukemia, extranodal NK / T-cell lymphoma, mycosis fungoides, Sézary syndrome, angioimmunoblastic T-cell lymphoma, peripheral T-cell lymphoma, adult T-cell leukemia (HTLV1+), anaplastic large cell lymphoma, cutaneous T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, intestinal T-cell lymphoma, hepatosplenic T-cell lymphoma, non-Hodgkin lymphoma (e.g., B-cell non-Hodgkin lymphoma, Burkitt lymphoma, chronic lymphocytic leukemia / small lymphocytic lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, and mantle cell lymphoma).

[0111] In some embodiments, the present invention provides intermediate compounds M3-1, M3, or pharmaceutically acceptable salts, isotopic derivatives, solvates thereof, or stereoisomers, geometric isomers, tautomers thereof, or prodrug molecules thereof:

[0112] This manual states “the above-mentioned general formulas indicate compounds” refer to the self-selected formulas (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (I g), (Ih), (Ii), (Ij), (Ik), (Im), (In), (Io), (Ip), (Iq), (Ir), (Is), ( It), (Iu), (Iv), (Iw), (I-1), (I-2), (I-3), (I-4), (I-5), (I-6), (I-7 ), (I-8), (I-9), (I-10), (I-11), (I-12), (I-13), (I-14), (I-15), (I-1 6), (I-17), (I-18), (I-19), (I-20), (I-21), (I-22), (I-23), (I-24), (I-25), (I-26), (I-27), (I-28), (I-29), (I-30), (I-31), (I-32), (I-3 3), (I-34), (I-35), (I-36), (I-37), (I-38), (I-39), (I-40), (I-41), (I-42), (I-43), (I-44), (I-45), (I-46), (I-47), (I-48), (I-49), (I-5 0), (I-51), (I-52), (I-53), (I-54), (I-55), (I-56), (I-57), (I-58), (I-59), (I-60), (I-61), (I-62), (I-63), (I-64), (I-65), (I-66), (I-6 7), (I-68), (I-69), (I-70), (I-71), (I-72), (I-73), (I-74), (I-75), (I-76), (I-77), (I-78), (I-79), (I-80), (I-81), (I-82), (I-83), (I-8 4), (I-85), (I-86), (I-87), (I-88), (I-89), (I-90), (II), (IIA), (IIB), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (II-1), (II-2), ( II-3), (II-4), (II-5), (II-6), (II-7), (II-8), (II-9), (II-10), (II-11), (II-12), (II-13), (II-14), (II-15), (II-16) Any one or more of the following general formulas.

[0113] Unless otherwise stated, the general chemical terms used in the structural formulas have their usual meanings.

[0114] For example, unless otherwise stated, the term "halogen" as used in this invention refers to fluorine, chlorine, bromine, or iodine.

[0115] In this invention, unless otherwise stated, "alkyl" includes straight-chain or branched monovalent saturated hydrocarbon groups. For example, alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 3-(2-methyl)butyl, 2-pentyl, 2-methylbutyl, neopentyl, n-hexyl, 2-hexyl, 2-methylpentyl, etc. Similarly, "C 1-6 "alkyl" 1-6 "" refers to a group consisting of 1, 2, 3, 4, 5 or 6 carbon atoms arranged in a straight or branched form.

[0116] The term "alkoxy" refers to the oxygen ether form of the aforementioned straight-chain or branched alkyl group, i.e., -O-alkyl.

[0117] The term "halogenated alkyl" refers to an alkyl group in which one or more H atoms have been replaced by halogen atoms.

[0118] The term "oxo" or "oxo group" refers to an oxygen atom in the form of a divalent substituent, which forms a carbonyl group when attached to a carbon atom, and a sulfoxide group, sulfone group, or N-oxide group when attached to a heteroatom.

[0119] The term "cycloalkyl" refers to a cyclic system having at least one cycloalkyl group. Preferably, C 3-12 Cycloalkyl, wherein the "C" 3-12 The term "cycloalkyl" refers to the fact that a cycloalkyl group can have 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 cyclic atoms. The cycloalkyl group can include monocyclic and polycyclic rings (e.g., having 2, 3, or 4 fused rings, spirocyclic, bridged rings, etc.). In some embodiments, the cycloalkyl group includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, etc.; the cycloalkyl group can also be fused to an aryl, heterocyclic, or heteroaryl ring, wherein the ring connected to the parent structure is a cycloalkyl group.

[0120] The term "alkenyl" refers to an alkyl group having one or more carbon-carbon double bonds, such as vinyl, propenyl, 1,3-butadiene, cis-butenyl, trans-butenyl, etc.

[0121] The term "alkynyl" refers to an alkyl group having one or more carbon-carbon triple bonds, such as ethynyl, propynyl, etc.

[0122] The term "alkathioyl" refers to a straight-chain or branched alkyl group linked by sulfur atoms, i.e., -S-alkyl, such as C 1-6Alkylthio groups include, but are not limited to, methylthio, ethylthio, propylthio (including n-propylthio and isopropylthio), butylthio (including n-butylthio, isobutylthio, sec-butylthio, and tert-butylthio), pentylthio (including n-pentylthio, isopentylthio, and neopentylthio), and hexylthio (n-hexylthio, 2-methylpentylthio, 3-methylpentylthio, 2,3-dimethylbutylthio, and 2,2-dimethylbutylthio).

[0123] The term "alkylsulfonyl" refers to a straight-chain or branched alkyl group linked by a sulfone group, i.e., -SO2-alkyl, such as C 1-6 Alkyl sulfone groups, including but not limited to methyl sulfone, ethyl sulfone, propane sulfone (including n-propane sulfone and isopropane sulfone), butyl sulfone (including n-butyl sulfone, isobutyl sulfone, sec-butyl sulfone, and tert-butyl sulfone), pentyl sulfone (including n-pentyl sulfone, isopentyl sulfone, and neopentyl sulfone), and hexyl sulfone (n-hexyl sulfone, 2-methylpentyl sulfone, 3-methylpentyl sulfone, 2,3-dimethylbutyl sulfone, and 2,2-dimethylbutyl sulfone), etc.

[0124] The term "alkylamine" refers to an open-chain alkyl group containing a nitrogen atom, such as C... 1-6 Alkylamine groups, including but not limited to methylamino, ethylamino, isopropylamino, dimethylamino, methylethylamino, diethylamino, etc.

[0125] The term "alkyl ester group" refers to a straight-chain or branched alkyl group linked by an ester group, i.e., -alkyl-CO2-, such as C 1-6 Alkyl ester group, including but not limited to methyl ester group, ethyl ester group, propyl ester group (including n-propyl ester group and isopropyl ester group), butyl ester group (including n-butyl ester group, isobutyl ester group, sec-butyl ester group, and tert-butyl ester group), pentyl ester group (including n-pentyl ester group, isopentyl ester group, and neopentyl ester group), and hexyl ester group (n-hexyl ester group, 2-methylpentyl ester group, 3-methylpentyl ester group, 2,3-dimethylbutyl ester group, and 2,2-dimethylbutyl ester group), etc.

[0126] The term "alkyl acyl" refers to a straight-chain or branched alkyl group linked by an acyl group, i.e., -alkyl-CO-, such as C 1-6 Alkyl groups, including but not limited to formyl, acetyl, propionyl (including n-propionyl and isopropionyl), butyryl (including n-butyryl, isobutyryl, sec-butyryl, and tert-butyryl), valeryl (including n-valeryl, isovaleryl, and neovaleryl), and hexanoyl (n-hexanoyl, 2-methylvaleryl, 3-methylvaleryl, 2,3-dimethylbutyryl, and 2,2-dimethylbutyryl).

[0127] The term "alkylamide group" refers to a straight-chain or branched alkyl group linked by an amide group, i.e., -alkyl-CONH-, such as C 1-6Alkylamide groups include, but are not limited to, formamido, acetamido, propionamido (including n-propionamido and isopropionamido), butyamido (including n-butyamido, isobutyamido, sec-butyamido, and tert-butyamido), pentamido (including n-pentamido, isovaleramido, and neopentamido), and hexamido (n-hexamido, 2-methylpentamido, 3-methylpentamido, 2,3-dimethylbutyamido, and 2,2-dimethylbutyamido).

[0128] The term "alkylsulfonyl" refers to a straight-chain or branched alkyl group linked by a sulfonyl group, i.e., -alkyl-SO2-, such as C 1-6 Alkyl sulfonyl groups, including but not limited to methanesulfonyl, ethanesulfonyl, propanesulfonyl (including n-propanesulfonyl and isopropanesulfonyl), butanesulfonyl (including n-butanesulfonyl, isobutanesulfonyl, sec-butanesulfonyl, and tert-butanesulfonyl), pentylesulfonyl (including n-pentanesulfonyl, isopentanesulfonyl, and neopentanesulfonyl), and hexanesulfonyl (n-hexanesulfonyl, 2-methylpentanesulfonyl, 3-methylpentanesulfonyl, 2,3-dimethylbutanesulfonyl, and 2,2-dimethylbutanesulfonyl).

[0129] The term "alkylsulfonamide" refers to a straight-chain or branched alkyl group linked by a sulfonamide group, i.e., -alkyl-SO2N-, such as C 1-6 Alkyl sulfonamide groups include, but are not limited to, methanesulfonamide, ethanesulfonamide, propanesulfonamide (including n-propanesulfonamide and isopropanesulfonamide), butanesulfonamide (including n-butanesulfonamide, isobutanesulfonamide, sec-butanesulfonamide, and tert-butanesulfonamide), pentasulfonamide (including n-pentanesulfonamide, isopentanesulfonamide, and neopentanesulfonamide), and hexanesulfonamide (n-hexanesulfonamide, 2-methylpentanesulfonamide, 3-methylpentanesulfonamide, 2,3-dimethylbutanesulfonamide, and 2,2-dimethylbutanesulfonamide).

[0130] The term "phosphoryl group" refers to -PO2-, such as C 1-6 Phosphoryl groups include, but are not limited to, methylphosphoryl, ethphosphoryl, propionic phosphoryl (including n-propionic phosphoryl and isopropionic phosphoryl), butylphosphoryl (including n-butylphosphoryl, isobutylphosphoryl, sec-butylphosphoryl, and tert-butylphosphoryl), pentaphosphoryl (including n-pentaphosphoryl, isopentapionic phosphoryl, and neopentaphosphoryl), and hexophosphoryl (n-hexophosphoryl, 2-methylpentaphosphoryl, 3-methylpentaphosphoryl, 2,3-dimethylbutionic phosphoryl, and 2,2-dimethylbutionic phosphoryl).

[0131] The term "aryl," in this invention, unless otherwise stated, refers to an unsubstituted or substituted monocyclic or fused-ring aromatic group comprising a carbide ring atom. Preferably C 6-12 Aryl, more preferably aryl, is C 6-10Aromatic ring groups, either monocyclic or bicyclic. Preferably phenyl or naphthyl. The aryl ring may be fused to a heteroaryl, heterocyclic, or cycloalkyl group, wherein the ring attached to the parent structure is an aryl ring; non-limiting examples include, but are not limited to, benzocyclopentyl.

[0132] The term "heteroaryl" in this invention, unless otherwise stated, refers to a monocyclic or polycyclic (e.g., fused bicyclic) aromatic heterocycle having at least one heteroatom selected from N, O, and / or S, wherein the nitrogen or sulfur heteroatom is selectively oxidized, and the nitrogen heteroatom is selectively quaternized. Preferably, it is a 5-14 membered heteroaryl, wherein "5-14" in 5-14 membered heteroaryl refers to a heteroaryl containing 5-14 cyclic atoms of C, N, O, or S. More preferably, it is a 5-10 membered heteroaryl, and even more preferably, it is a 5-6 membered heteroaryl. Examples of heteroaryl groups include, but are not limited to, thienyl, furanyl, imidazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyrroloyl, thiazolyl, thiadiazolyl, triazolyl, pyridinyl, pyridazinyl, indolyl, azaindolyl, indolyl, benzimidazolyl, benzofuranyl, benzothiophene, benzoisoxazolyl, benzothiazolyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyladenine, quinolinyl, or isoquinolinyl. The heteroaryl group may be fused to an aryl, heterocyclic, or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring.

[0133] The term "heterocyclic group" refers to a ring system having at least one cyclic alkyl or cyclic alkenyl group containing a heterocycle, wherein the heteroatom is selected from N, O, and / or S. The heterocyclic group can include monocyclic or polycyclic groups (e.g., having 2, 3, or 4 fused rings, spirocyclic, bridged rings, etc.). The heterocyclic group can be connected to other parts of the compound via cyclic carbon atoms or cyclic heteroatoms. Preferably, it is a 3-14 membered heterocyclic group, where "3-14" refers to a heterocyclic group consisting of 3-14 cyclic atoms of C, N, O, or S; more preferably, it is a 3-8 membered heterocyclic group, and even more preferably, a 5-6 membered heterocyclic group; wherein the nitrogen or sulfur heteroatom can be selectively oxidized, and the nitrogen heteroatom can be selectively quaternized. Examples of these heterocyclic groups include, but are not limited to, aza-butyl, pyrrolyl, piperidinyl, 1,2,3,6-tetrahydropyridine, piperazinyl, oxoperazinyl, oxoperridinyl, tetrahydrofuranyl, dioxopentyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydrooxazolyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, and tetrahydrooxadiazolyl. Spiroheterocycles can be 6- to 12-membered spiroheterocycles, including, but not limited to, 4-azaspiro[2,4]heptane and 4-azaspiro[2,4]heptane. Heterocyclic groups also include cyclic systems in which the above-mentioned heterocyclic ring is fused with one or more cycloalkyl, aryl, or heteroaryl groups, including but not limited to: dihydroindolyl, isodihydroindolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, benzoxazolinone, tetrahydroquinolinyl, tetrahydroisoquinolinyl, tetrahydrobenzopyranyl, and tetrahydropyranopyridyl.

[0134] The term "substituted" refers to a group in which one or more hydrogen atoms are replaced by the same or different substituents. Typical substituents include, but are not limited to, halogens (F, Cl, Br, or I), C... 1-8 Alkyl, C 3-12 cycloalkyl, -OR 1 -SR 1 =O, =S, -C(O)R 1 -C(S)R 1 =NR 1 -C(O)OR 1 -C(S)OR 1 -NR 1 R 2 -C(O)NR 1 R 2 , cyano, nitro, -S(O)2R 1 -OS(O2)OR 1 -OS(O)2R 1 -OP(O)(OR) 1 (OR) 2 ); where R 1 and R 2Independently selected from -H, C 1-6 Alkyl, C 1-6 Halogenated alkyl or C 3-6 Cycloalkyl. In some embodiments, the substituents are independently selected from groups comprising -F, -Cl, -Br, -I, -OH, trifluoromethoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, -SCH3, -SC2H5, formaldehyde, -C(OCH3), cyano, nitro, trifluoromethyl, -OCF3, amino, dimethylamino, methylthio, sulfonyl, and acetyl.

[0135] The "compound" described in this invention includes, but is not limited to, compounds in the following forms: free base, stereoisomer, geometric isomer, tautomer, isotope, pharmaceutically acceptable salt, solvate, hydrate, prodrug (ester), etc.

[0136] The "compound" described in this invention can be asymmetric, for example, having one or more stereoisomers. Unless otherwise stated, all stereoisomers include, for example, enantiomers and diastereomers. Compounds containing asymmetric carbon atoms in this invention can be isolated in optically active pure form or in racemic form. Optically active pure form can be obtained by resolution of racemic mixtures, synthesis using chiral starting materials or chiral reagents.

[0137] The term “pharmaceutically acceptable” as used herein refers to compounds, materials, compositions, and / or dosage forms that, within the bounds of reliable medical judgment, are suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, in proportion to a reasonable benefit / risk ratio.

[0138] The term "pharmaceutically acceptable salt" refers to a salt of the compounds of this invention, prepared by reacting a compound with a relatively non-toxic acid or base, as discovered in this invention, with a specific substituent. When the compounds of this invention contain relatively acidic functional groups, a base addition salt can be obtained by contacting the neutral form of such compounds with a sufficient amount of base in a pure solution or a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine, or magnesium salts, or similar salts. When the compounds of this invention contain relatively basic functional groups, an acid addition salt can be obtained by contacting the neutral form of such compounds with a sufficient amount of acid in a pure solution or a suitable inert solvent. Certain specific compounds of this invention contain both basic and acidic functional groups, and thus can be converted into either a base or acid addition salt.

[0139] The pharmaceutically acceptable salts of the present invention can be synthesized from parent compounds containing acid radicals or bases by conventional chemical methods. Generally, such salts are prepared by reacting these compounds in water or an organic solvent, or a mixture thereof, with a stoichiometric amount of a suitable base or acid in the form of a free acid or base.

[0140] Unless otherwise stated, the term "isomer" is intended to include geometric isomers, cis-trans isomers, stereoisomers, enantiomers, optical isomers, diastereomers and tautomers.

[0141] In addition to the salt form, the compounds provided by this invention also exist in prodrug form. The prodrugs of the compounds described herein readily undergo chemical changes under physiological conditions to be converted into the compounds of this invention. Furthermore, the prodrugs can be converted into the compounds of this invention in the in vivo environment via chemical or biochemical methods.

[0142] The compounds of this invention may contain atomic isotopes in non-natural proportions on one or more atoms constituting the compound. For example, the compounds may be labeled with radioactive isotopes, such as tritium. 3 H), Iodine-125 125 I) or C-14 14 C). For example, deuterium can be used to replace hydrogen to form deuterated drugs. The bond between deuterium and carbon is stronger than that between ordinary hydrogen and carbon. Compared with undeuterated drugs, deuterated drugs have advantages such as reduced toxicity, increased drug stability, enhanced efficacy, and prolonged drug biological half-life. All isotopic variations of the compounds of this invention, regardless of radioactivity, are included within the scope of this invention.

[0143] When the compounds provided by this invention are acids, their corresponding salts can be conveniently prepared from pharmaceutically acceptable, non-toxic bases, including inorganic and organic bases. Salts derived from inorganic bases include salts of aluminum, ammonium, calcium, copper (high and low valence), ferric iron, ferrous iron, lithium, magnesium, manganese (high and low valence), potassium, sodium, zinc, etc. Salts of ammonium, calcium, magnesium, potassium, and sodium are particularly preferred. Non-toxic organic bases capable of being derived into pharmaceutically acceptable salts include primary, secondary, and tertiary amines, as well as cyclic amines and amines containing substituents, such as naturally occurring and synthetic amines containing substituents. Other pharmaceutically acceptable non-toxic organic bases that can form salts include ion exchange resins, as well as arginine, betaine, caffeine, choline, N',N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, reduced glucosamine, glucosamine, histidine, isopropylamine, lysine, methylglucosamine, morpholine, piperazine, piperidine, polyamine resins, procaine, chloroprocaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, etc.

[0144] When the compound provided by this invention is a base, pharmaceutically acceptable non-toxic acids, including inorganic and organic acids, can be used to conveniently prepare their corresponding salts. Such acids include, for example, acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, formic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, hydroxyethanesulfonic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucilage, nitric acid, pyric acid, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, oxalic acid, propionic acid, glycolic acid, hydroiodic acid, perchloric acid, cyclohexanesulfonic acid, salicylic acid, 2-naphthalenesulfonic acid, saccharinic acid, trifluoroacetic acid, tartaric acid, and p-toluenesulfonic acid. More preferably, citric acid, hydrobromic acid, formic acid, hydrochloric acid, maleic acid, phosphoric acid, sulfuric acid, and tartaric acid. More preferably, formic acid and hydrochloric acid.

[0145] The drug prodrugs of the compounds of this invention are included within the scope of protection of this invention. Generally, a drug prodrug refers to a functional derivative that is readily converted into the desired compound in vivo. For example, any pharmaceutically acceptable salt, ester, salt of ester, or other derivative of the compounds of this application, which, upon administration to a receptor, can directly or indirectly provide the compound of this application or its pharmaceutically active metabolites or residues.

[0146] The so-called metabolites produced by the breakdown of the compounds of the present invention in the body are also included within the scope of the claims of this application. The "metabolites" of the compounds disclosed in this invention are derivatives formed during the metabolism of the compounds. The metabolites of the compounds disclosed in this invention may optionally be identified by administering the compounds to a host and analyzing tissue samples from the host, or by incubating the compounds with hepatocytes in vitro and analyzing the resulting compounds.

[0147] The compounds described in this invention may contain one or more asymmetric centers, and may thereby produce diastereomers and optical isomers. This invention includes all possible diastereomers and their racemic mixtures, their substantially pure enantiomers, all possible geometric isomers, and their pharmaceutical salts.

[0148] When the compounds represented by the above general formulas have tautomers, unless otherwise stated, the present invention includes any possible tautomers and their pharmaceutical salts, and mixtures thereof.

[0149] This invention also includes atoms of all isotopes, whether in intermediates or final compounds. Isotopic atoms include those having the same number of atoms but different mass numbers. For example, isotopes of hydrogen include tritium and deuterium.

[0150] The term "pharmaceutical composition" refers to a mixture of one or more compounds of this application or their pharmaceutical salts with pharmaceutically acceptable excipients. The purpose of a pharmaceutical composition is to facilitate the administration of the compounds of this application to an organism.

[0151] In this invention, the terms "a," "an," "the," "at least one," and "one or more" are used interchangeably. Thus, for example, a mixture comprising "a" pharmaceutically acceptable excipient can be interpreted as indicating that the pharmaceutical composition includes "one or more" pharmaceutically acceptable excipients.

[0152] The term "pharmaceuticalally acceptable excipient" refers to excipients that do not cause significant irritation to the organism and do not impair the biological activity and properties of the active compound. Suitable excipients are well known to those skilled in the art, such as carbohydrates, waxes, water-soluble and / or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, etc.

[0153] The pharmaceutical compositions of the present invention can be prepared by combining the compounds of the present application with suitable pharmaceutically acceptable excipients, for example, in solid, semi-solid, liquid or gaseous formulations, such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, suppositories, injections, inhalers, gels, microspheres and aerosols.

[0154] Typical routes of administration for the compounds of the present invention or their pharmaceutical salts or pharmaceutical compositions include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, vaginal, nasal, ocular, intraperitoneal, intramuscular, subcutaneous, and intravenous administration.

[0155] The term “treatment” generally refers to achieving the desired pharmacological and / or physiological effect. This effect can be therapeutic, depending on whether it partially or completely stabilizes or cures the disease and / or causes side effects due to the disease. As used herein, “treatment” covers any treatment of a patient’s disease, including: (a) suppressing the symptoms of the disease, i.e., preventing its progression; or (b) alleviating the symptoms of the disease, i.e., causing the disease or symptoms to regress.

[0156] The term "effective amount" means the amount of the compound of this application used to (i) treat or prevent a particular disease, condition, or disorder; (ii) alleviate, improve, or eliminate one or more symptoms of a particular disease, condition, or disorder; or (iii) prevent or delay the onset of one or more symptoms of a particular disease, condition, or disorder described herein. The amount of the compound of this application constituting a "therapeutic effective amount" varies depending on the compound, the disease state and its severity, the route of administration, and the age of the mammal to be treated, but may routinely be determined by a person skilled in the art based on their own knowledge and the present disclosure.

[0157] Based on the VAV1 target, this invention developed a series of novel heterocyclic compounds and conducted related biological experiments. The results showed that the compounds significantly degraded VAV1 protein and significantly inhibited CD69 upregulation, IL-2 secretion, and T cell proliferation. These compounds exhibited low hERG toxicity and favorable pharmacokinetic properties, with high plasma and tissue exposures in animals. They also showed no significant inhibitory effect on various cytochrome P450 (CYP450) enzymes, demonstrating good drug-like properties and significant clinical application potential. Furthermore, the synthetic routes provided by this invention are novel, safe, environmentally friendly, and feasible for production. Attached Figure Description

[0158] Figure 1 shows the results of the in vitro degradation activity test of compound 1 VAV1. Detailed Implementation

[0159] To make the above content clearer and more explicit, the technical solution of the present invention will be further illustrated by the following embodiments. The following embodiments are only used to illustrate specific implementation methods of the present invention so that those skilled in the art can understand the present invention, but are not intended to limit the scope of protection of the present invention. In the specific implementation methods of the present invention, the technical means or methods, etc., not specifically described, are conventional technical means or methods in the art.

[0160] Unless otherwise stated, all temperatures in this invention refer to degrees Celsius.

[0161] The following abbreviations were used in the examples:

[0162] H2O: Water; LC-MS: Liquid Chromatography-Mass Spectrometry; In the embodiments of this invention, x mL×y: indicates y repetitions, x mL each time, such as extraction with EA (10 mL×3), which means extraction with 10 mL of ethyl acetate each time, repeated 3 times; In the embodiments of this invention, the eluent is used in volume ratio, such as PE:EA=20:1, which means the volume ratio of petroleum ether to ethyl acetate is 20:1; NBS: N-bromosuccinimide; BPO: benzoyl peroxide; TMSCN: trimethylcyanosilane; TBAF: tetrabutylammonium fluoride; DCM: dichloromethane; AcOH: acetic acid; PE: petroleum ether; EA: acetic acid Ethyl acetate; DMF: N,N-dimethylformamide; PPh3: triphenylphosphine; DIAD: diisopropyl azodicarboxylate; THF: tetrahydrofuran; Bpin2 / B2pin2: pinacolyl diboronate; Pd(dppf)Cl2: [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride; KOAc / AcOK: potassium acetate; TFA: trifluoroacetic acid; Pd(OAc)2: palladium acetate; Xantphos: 4,5-bisdiphenylphosphine-9,9-dimethyloxa Anthracene; Pd2(dba)3: Tris(dibenzylacetone)dipalladium; TfOH: Trifluoromethanesulfonic acid; CMBP: Cyanomethylenetri-n-butylphosphine; Tol: Toluene; TEA: Triethylamine; Cu(OAc)2: Copper acetate; DCE: 1,2-Dichloroethane; t-BuONa: Sodium tert-butoxide; DMAC: N,N-Dimethylacetamide; dppf: 1,1'-Bis(diphenylphosphine)ferrocene; LiHMDS: Bistrimethylsilylaminolithium; ACN: Acetonitrile; Tf2O: Trifluoromethanesulfonic anhydride; PCy3: tricyclohexylphosphine; Brettphos: 2-(dicyclohexylphosphine)3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl; Brettphos-Pd-G3: methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II); DBU: 1,8-diazabicyclo[5.4].0] Undec-7-ene; PMBCl: 4-methoxybenzyl chloride; EtOH: ethanol; MeOH: methanol; MeCN: acetonitrile; Bipy: 2,2'-bipyridine; SEMCl: 2-(trimethylsilyl)ethoxymethyl chloride; HATU: 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate; DIPEA / DIEA: N,N-diisopropylethylamine; Zn(OTf)2: Zinc trifluoromethanesulfonate; BBA: tetrahydroxydiboron; TIPT: tetraisopropyl titanate; TMSOI: trimethyl sulfoxide; PPA: polyphosphoric acid; TsOH: p-toluenesulfonic acid; LDA: lithium diisopropylamino; TMSCl: trimethylchlorosilane; HFIP: hexafluoroisopropanol; XPhos: 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl; Ac2O: acetic anhydride; DEAD: diethyl azodicarbonate.

[0163] Furthermore, all operations involving easily oxidized or hydrolyzed raw materials are performed under nitrogen protection. Unless otherwise stated, the raw materials used in this invention are commercially available and can be used directly without further purification.

[0164] All reaction raw materials and common intermediates involved in the embodiments of the present invention can be obtained commercially or by self-production. The preparation process of raw materials and common intermediates that need to be self-produced is described in detail below.

[0165] Preparation Example 1: Synthesis of Intermediate M1

[0166] Step 1: Synthesis of 1-bromo-3-(bromomethyl)-2-chlorobenzene (M1-1)

[0167] 1-Bromo-2-chloro-3-toluene (2.0 g, 10.0 mmol), N-bromosuccinimide (2.0 g, 11.0 mmol), and benzoyl peroxide (121 mg, 0.5 mmol) were dissolved in carbon tetrachloride (150 mL) and reacted at 80 °C for 16 h. After the reaction was complete, the mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by column chromatography (PE elution) to give 1-bromo-3-(bromomethyl)-2-chlorobenzene (1.4 g), in 55.6% yield.

[0168] Step 2: Synthesis of 2-(3-bromo-2-chlorophenyl)acetylcyanide (M1-2)

[0169] 1-Bromo-3-(bromomethyl)-2-chlorobenzene (M1-1, 1.40 g, 4.96 mmol) and tetrabutylammonium fluoride (1.95 g, 7.45 mmol) were dissolved in dichloromethane (20 mL). Trimethylcyanosilane (0.74 g, 7.45 mmol) was slowly added under ice bath conditions, and the reaction was carried out overnight at room temperature. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography (PE:EA = 20:1) to give 2-(3-bromo-2-chlorophenyl)acetylcyanine (1.0 g), with a yield of 88.1%.

[0170] Step 3: Synthesis of tert-butyl 4-(3-bromo-2-chlorophenyl)-4-cyanobutyrate (M1-3)

[0171] 2-(3-bromo-2-chlorophenyl)acetylcyanide (M1-2, 1.0 g, 4.37 mmol) and cesium carbonate (3.3 g, 8.74 mmol) were dissolved in ultra-dry acetonitrile (20 mL). The system was purged with nitrogen, and tert-butyl acrylate (0.56 g, 4.37 mmol) was slowly added under ice bath conditions. The reaction was carried out at room temperature for 4 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography (PE:EA = 20:1) to give tert-butyl 4-(3-bromo-2-chlorophenyl)-4-cyanobutyrate (1.0 g), with a yield of 64.1%.

[0172] LC-MS (m / z): 358.0, 360.0 [M+H] + .

[0173] Step 4: Synthesis of 3-(3-bromo-2-chlorophenyl)piperidine-2,6-dione (M1)

[0174] 4-(3-bromo-2-chlorophenyl)-4-cyanobutyrate tert-butyl ester (M1-3, 1.0 g, 0.28 mmol) was added to acetic acid (9 mL) and concentrated sulfuric acid (1 mL), and the system was heated to 90 °C and reacted for 3 h. After the reaction was completed, the reaction solution was dropped into ice water, filtered, the filter cake was washed with water, and dried to give 3-(3-bromo-2-chlorophenyl)piperidine-2,6-dione (550 mg), yield 65.2%.

[0175] LC-MS (m / z): 302.0, 304.0 [M+H] + .

[0176] Preparation Example 2: Synthesis of Intermediate M2

[0177] Step 1: Synthesis of 3-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)-1-(4-methoxybenzyl)piperidine-2,6-dione (M2)

[0178] 3-(3-bromo-2-chlorophenyl)piperidin-2,6-dione (M1, 30 mg, 0.10 mmol), pinacol diboronate (30 mg, 0.12 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (7 mg, 0.01 mmol), and potassium acetate (29 mg, 0.30 mmol) were dissolved in dioxane (3 mL). The system was purged with nitrogen, and the temperature was raised to 85 °C for 6 h. After the reaction was completed, the mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by column chromatography (PE:EA = 3:2) to give 3-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)-1-(4-methoxybenzyl)piperidin-2,6-dione (27 mg), yield 77.4%.

[0179] LC-MS (m / z): 350.0 [M+H] + .

[0180] Preparation Example 3: Synthesis of Intermediate M3

[0181] Step 1: Synthesis of 3-(3-bromo-2-chlorophenyl)-1-(4-methoxybenzyl)piperidine-2,6-dione (M3-1)

[0182] 3-(3-bromo-2-chlorophenyl)piperidin-2,6-dione (M1, 5.0 g, 16.61 mmol) and potassium carbonate (4.6 g, 33.33 mmol) were dissolved in DMF (25 mL), followed by the addition of 4-methoxybenzyl chloride (2.5 g, 16.03 mmol). The mixture was stirred overnight at room temperature. After the reaction was complete, the mixture was quenched with saturated ammonium chloride solution (50 mL), extracted with EA (50 mL × 3), and the organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography (PE:EA = 9:1) to give 3-(3-bromo-2-chlorophenyl)-1-(4-methoxybenzyl)piperidin-2,6-dione (M3-1, 5.8 g), with a yield of 82.9%.

[0183] LC-MS (m / z): 422.0, 424.0 [M+H] + .

[0184] Step 2: Synthesis of 3-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)phenyl)-1-(4-methoxybenzyl)piperidine-2,6-dione (M3)

[0185] 3-(3-bromo-2-chlorophenyl)-1-(4-methoxybenzyl)piperidine-2,6-dione (M3-1, 3.6 g, 8.55 mmol), pinacol diboronate (2.4 g, 9.45 mmol), KOAc (2.5 g, 2.55 mmol), and Pd(dppf)Cl2 (314 mg, 0.43 mmol) were added to dioxane (36 mL), and the mixture was heated to 100 °C for 4 hours under nitrogen protection. After the reaction was completed, the mixture was concentrated under reduced pressure. The residue was purified by column chromatography (PE:DCM = 4:6) to give 3-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)phenyl)-1-(4-methoxybenzyl)piperidine-2,6-dione (M3, 1.8 g), yield 44.9%.

[0186] LC-MS (m / z): 470.0 [M+H] + .

[0187] Example 1: Synthesis of 3-(2-chloro-3-(1'-(1-methyl-1H-imidazol-4-yl)methyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-5'-yl)phenyl)piperidine-2,6-dione (compound 1)

[0188] Step 1: Synthesis of 5'-bromospiro[cyclopropane-1,3'-indoline]-2'-one (1-2)

[0189] 5-Bromoindolin-2-one (1-1, 500 mg, 2.36 mmol) was dissolved in DMF (10 mL), and zinc trifluoromethanesulfonate (1.71 g, 4.72 mmol) and triethylamine (715 mg, 7.08 mmol) were added sequentially. After stirring at room temperature for 15 minutes, (2-bromoethyl)diphenylsulfonium trifluoromethanesulfonate (1.25 mg, 2.83 mmol) was added, and the reaction mixture was stirred for another 3 hours. The reaction mixture was diluted with water (40 mL), extracted with EA (15 mL × 3), and the combined organic phases were washed with saturated NaCl (20 mL), dried over anhydrous Na₂SO₄, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA = 4:1) to give 5'-bromospiro[cyclopropane-1,3'-indolin]-2'-one (480 mg), yield 85.5%.

[0190] LC-MS (m / z): 237.0, 239.0 [M+H] + .

[0191] Step 2: Synthesis of 5'-bromo-1'-((1-methyl-1H-imidazol-4-yl)methyl)spiro[cyclopropane-1,3'-indoline]-2'-one (1-3)

[0192] 5'-Bromospiro[cyclopropane-1,3'-indoline]-2'-one (1-2, 1.20 g, 5.04 mmol), (1-methyl-1H-imidazol-4-yl)methanol (678 mg, 6.05 mmol), and triphenylphosphine (1.98 g, 7.56 mmol) were dissolved in THF (15 mL). Diisopropyl azodicarbonate (1.53 g, 7.56 mmol) was slowly added dropwise under ice bath, and the reaction was stirred at room temperature for 5 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography (DCM:MeOH = 20:1) to give 5'-bromo-1'-((1-methyl-1H-imidazol-4-yl)methyl)spiro[cyclopropane-1,3'-indoline]-2'-one (1.0 g), yield 35.8%.

[0193] LC-MS (m / z): 332.0, 334.0 [M+H] + .

[0194] Step 3: Synthesis of 1'-((1-methyl-1H-imidazol-4-yl)methyl)-5'-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)spiro[cyclopropane-1,3'-indoline]-2'-one (1-4)

[0195] 5'-bromo-1'-((1-methyl-1H-imidazol-4-yl)methyl)spiro[cyclopropane-1,3'-indoline]-2'-one (1-3, 200 mg, 0.60 mmol), pinacol diboronate (168 mg, 0.66 mmol), potassium acetate (118 mg, 1.20 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (43 mg, 0.06 mmol) were dissolved in dioxane (3 mL). The system was purged with nitrogen three times, and the mixture was heated to 100 °C and stirred for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography (DCM:MeOH = 25:1) to give 1'-((1-methyl-1H-imidazol-4-yl)methyl)-5'-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)spiro[cyclopropane-1,3'-indoline]-2'-one (150 mg), yield 65.6%.

[0196] LC-MS (m / z): 380.0 [M+H] + .

[0197] Step 4: Synthesis of 3-(2-chloro-3-(1'-(1-methyl-1H-imidazol-4-yl)methyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-5'-yl)phenyl)piperidine-2,6-dione (compound 1)

[0198] 1'-((1-methyl-1H-imidazol-4-yl)methyl)-5'-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)spiro[cyclopropane-1,3'-indoline]-2'-one (1-4, 94 mg, 0.25 mmol), 3-(3-bromo-2-chlorophenyl)piperidin-2,6-dione (M1, 50 mg, 0.17 mmol), potassium acetate (32 mg, 0.33 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (15 mg, 0.02 mmol) were dissolved in DMF (2 mL). The system was purged with nitrogen three times, and the mixture was heated to 100 °C and stirred for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography (DCM:MeOH = 25:1) to give 5'-bromo-1'-((1-methyl-1H-imidazol-4-yl)methyl)spiro[cyclopropane-1,3'-indoline]-2'-one (6 mg), yield 7.64%.

[0199] LC-MS (m / z): 475.0 [M+H] + .

[0200] 1 H NMR (600MHz, DMSO-d6): δ10.91(s,1H),7.50(s,1H),7.37(t,J=7.2Hz,1H),7.32(dd,J1=7.8 Hz,J1=1.8Hz,1H),7.29(dd,J1=7.2Hz,J1=1.8Hz,1H),7.22(s,2H),7.08(s,1H),7.05(s,1H) ,4.81(s,2H),4.34(dd,J1=12.6Hz,J1=5.4Hz,1H),3.59(s,3H),2.81-2.75(m,1H),2.55-2.5 0(m,1H),2.36-2.28(m,1H),2.05-2.00(m,1H),1.67(q,J=4.2Hz,2H),1.56(q,J=4.2Hz,2H).

[0201] Example 5: Synthetic route of 3-(2-chloro-3-(1'-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-2'-oxospiro[cyclopropane-1,3'-indoline]-5'-yl)phenyl)piperidin-2,6-dione (compound 5):

[0202] The preparation of compounds 1-2 is described in step 1 of Example 1.

[0203] Step 1: Synthesis of 5'-bromo-1'-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)spiro[cyclopropane-1,3'-indoline]-2'-one (5-1)

[0204] 5'-Bromospiro[cyclopropane-1,3'-indoline]-2'-one (1-2, 400 mg, 1.69 mmol), (1-methyl-2-oxo-1,2-dihydropyridin-3-yl)boronic acid (284 mg, 1.86 mmol), copper acetate (307 mg, 1.69 mmol), and triethylamine (564 mg, 5.58 mmol) were dissolved in dichloroethane (10 mL). The system was replaced with an oxygen atmosphere, and the mixture was heated to 80 °C and reacted for 48 h. After the reaction was completed, the mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by column chromatography (PE:EA = 3:1) to give 5'-bromo-1'-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)spiro[cyclopropane-1,3'-indoline]-2'-one (150 mg), yield 25.8%.

[0205] LC-MS (m / z): 345.0, 347.0 [M+H] + .

[0206] Step 2: Synthesis of 1'-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-5'-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)spiro[cyclopropane-1,3'-indoline]-2'-one (5-2)

[0207] 5'-bromo-1'-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)spiro[cyclopropane-1,3'-indoline]-2'-one (5-1, 150 mg, 0.44 mmol), pinacol diboronate (220 mg, 0.87 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (35 mg, 0.04 mmol), and potassium acetate (130 mg, 1.31 mmol) were dissolved in dioxane (5 mL), the system was purged with nitrogen, and the temperature was raised to 100 °C for 3 h. After the reaction was completed, the mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by column chromatography (PE:EA = 3:1) to give 1'-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-5'-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)spiro[cyclopropane-1,3'-indoline]-2'-one (70 mg), with a yield of 40.9%.

[0208] LC-MS (m / z): 393.0 [M+H] + .

[0209] Step 3: Synthesis of 3-(2-chloro-3-(1'-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-2'-oxospiro[cyclopropane-1,3'-indole]-5'-yl)phenyl)piperidin-2,6-dione (compound 5)

[0210] 1'-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-5'-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)spiro[cyclopropane-1,3'-indoline]-2'-one (5-2, 70 mg, 0.18 mmol), 3-(3-bromo-2-chlorophenyl)piperidin-2,6-dione (M1, 42 mg, 0.14 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (13 mg, 0.02 mmol) and potassium acetate (52 mg, 0.53 mmol) were dissolved in DMF (5 mL), the system was purged with nitrogen, and the temperature was raised to 100 °C for 2 h. After the reaction was completed, the mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by column chromatography (DCM:MeOH = 30:1) to give 3-(2-chloro-3-(1'-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-2'-oxospiro[cyclopropane-1,3'-indole]-5'-yl)phenyl)piperidin-2,6-dione (10 mg), yield 11.5%.

[0211] LC-MS (m / z): 488.0 [M+H] + .

[0212] 1 H NMR (600MHz, DMSO-d6): δ10.92(s,1H),7.92(dd,J1=7.2Hz,J2=1.8Hz,1H),7.73(dd,J1=7.2Hz,J2= 2.4Hz,1H),7.39(t,J=7.2Hz,1H),7.34-7.30(m,2H),7.20-7.19(m,1H),7.13(d,J=1.8Hz,1H),6.66 (d,J=7.8Hz,1H),6.41(t,J=7.2Hz,1H),4.35(dd,J1=12.6Hz,J2=5.4Hz,1H),3.54(s,3H),2.82-2. 76(m,1H),2.37-2.30(m,1H),2.04-2.02(m,1H),1.77-1.75(m,2H),1.63-1.59(m,2H),1.23(s,1H).

[0213] Example 12: Synthesis of 3-(2-chloro-3-(1'-(2-methoxyethyl)-2'-oxospiro[cyclopropane-1,3'-indole]-5'-yl)phenyl)piperidine-2,6-dione (compound 12)

[0214] The preparation of compounds 1-2 is described in step 1 of Example 1.

[0215] Step 1: Synthesis of 5'-bromo-1'-(2-methoxyethyl)spiro[cyclopropane-1,3'-indole]-2'-one (12-1)

[0216] 5'-Bromospiro[cyclopropane-1,3'-indoline]-2'-one (1-2, 300 mg, 1.26 mmol) was dissolved in DMF (5 mL), and 1-iodo-2-methoxyethane (469 mg, 2.52 mmol) and Cs₂CO₃ (821 mg, 2.52 mmol) were added. The reaction was carried out at room temperature for 2 h. After the reaction was completed, water (20 mL) was added, and the mixture was extracted with ethyl acetate (15 mL × 3). The organic phases were combined, washed with saturated NaCl (20 mL × 3), dried over anhydrous Na₂SO₄, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (PE / EA = 5:1) to give 5'-bromo-1'-(2-methoxyethyl)spiro[cyclopropane-1,3'-indoline]-2'-one (350 mg), yield 94.0%.

[0217] LC-MS (m / z): 296.0, 298.0 [M+H] + .

[0218] Step 2: Synthesis of 1'-(2-methoxyethyl)-5'-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)spiro[cyclopropane-1,3'-indoline]-2'-one (12-2)

[0219] 5'-Bromo-1'-(2-methoxyethyl)spiro[cyclopropane-1,3'-indoline]-2'-one (12-1, 2.02 g, 9.38 mmol) was dissolved in dioxane (10 mL), and pinacol diboronate (300 mg, 1.18 mmol), potassium acetate (231 mg, 2.36 mmol), and Pd(dppf)Cl2 (80 mg, 0.12 mmol) were added. The system was purged with nitrogen, and the temperature was raised to 100 °C for 2 h. After the reaction was completed, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (PE / EA = 4:1) to give 1'-(2-methoxyethyl)-5'-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)spiro[cyclopropane-1,3'-indoline]-2'-one (300 mg), yield 74.0%.

[0220] LC-MS (m / z): 344.0 [M+H] + .

[0221] Step 3: Synthesis of 3-(2-chloro-3-(1'-(2-methoxyethyl)-2'-oxospiro[cyclopropane-1,3'-indole]-5'-yl)phenyl)piperidine-2,6-dione (compound 12)

[0222] 3-(3-bromo-2-chlorophenyl)piperidin-2,6-dione (M1, 90 mg, 0.29 mmol) was dissolved in DMF (2 mL), and 1'-(2-methoxyethyl)-5'-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)spiro[cyclopropane-1,3'-indoline]-2'-one (12-2, 150 mg, 0.45 mmol) and potassium acetate (58 mg, 0.59 mmol) were added. The system was purged with nitrogen and the temperature was raised to 100 °C for 2 h. The reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography (DCM / MeOH = 20:1) to give 3-(2-chloro-3-(1'-(2-methoxyethyl)-2'-oxospiro[cyclopropane-1,3'-indole]-5'-yl)phenyl)piperidine-2,6-dione (26 mg), yield 19.9%.

[0223] LC-MS (m / z): 439.0 [M+H] + .

[0224] 1 H NMR (600MHz, DMSO-d6): δ10.92(s,1H),7.39(t,J=7.2Hz,1H),7.33-7.30(m,2H),7.27(dd,J1 =8.4Hz,J2=1.8Hz,1H),7.21(d,J=7.8Hz,1H),7.07(d,J=1.8Hz,1H),4.34(dd,J1=12.0Hz,J2= 4.8Hz,1H),3.96(t,J=5.4Hz,2H),3.60(t,J=5.4Hz,2H),3.26(s,3H),2.82-2.76(m,1H),2.56 -2.52(m,1H),2.36-2.29(m,1H),2.05-2.01(m,1H),1.68-1.66(m,2H),1.55(q,J=3.6Hz,2H).

[0225] Example 49: Synthesis of 3-(2-chloro-3-(4-(1-methyl-1H-pyrazol-3-yl)methyl)-3-oxo-3,4-dihydrospiro[benzo[b][1,4]oxazine-2,1'-cyclopropane]-7-yl)phenyl)piperidine-2,6-dione (compound 49)

[0226] Step 1: Synthesis of ethyl 1-(5-bromo-2-nitrophenoxy)cyclopropane-1-carboxylate (49-2)

[0227] Ethyl 1-hydroxycyclopropanecarboxylate (244 mg, 2.10 mmol) was dissolved in THF (10 mL). Under nitrogen protection, sodium hydride (96 mg, 2.40 mmol) was added in an ice bath. After maintaining the temperature for 0.5 h, 4-bromo-2-fluoro-1-nitrobenzene (49-1, 440 mg, 2.00 mmol) was added, and the reaction was brought to room temperature for 2 h. The reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography (PE:EA = 5:1) to give ethyl 1-(5-bromo-2-nitrobenoxy)cyclopropane-1-carboxylate (450 mg), with a yield of 68.1%.

[0228] LC-MS (m / z): 330.0, 332.0 [M+H] + .

[0229] Step 2: Synthesis of 7-bromospiro[benzo[b][1,4]oxazine-2,1'-cyclopropane]-3(4H)-one (49-3)

[0230] Ethyl 1-(5-bromo-2-nitrophenoxy)cyclopropane-1-carboxylic acid (49-2, 200 mg, 0.63 mmol) was dissolved in AcOH (5 mL), and iron powder (353 mg, 6.30 mmol) was added under ice bath conditions. The mixture was heated to 90 °C and reacted for 0.5 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure, water (10 mL) was added, the pH was adjusted to 7 with saturated NaHCO3 aqueous solution, and the mixture was extracted with EA (20 mL × 3). The organic phases were combined, washed with saturated NaCl (20 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to obtain crude 7-bromospiro[benzo[b][1,4]oxazine-2,1'-cyclopropane]-3(4H)-one (130 mg).

[0231] LC-MS (m / z): 254.0, 256.0 [M+H] + .

[0232] Step 3: Synthesis of 7-bromo-4-((1-methyl-1H-pyrazol-3-yl)methyl)spiro[benzo[b][1,4]oxazine-2,1'-cyclopropane]-3(4H)-one (49-4)

[0233] The crude product (49-3) obtained in the previous step was dissolved in DMF (5 mL), and 3-(chloromethyl)-1-methyl-1H-pyrazole (100 mg, 0.56 mmol) and cesium carbonate (140 mg, 1.02 mmol) were added sequentially. The reaction was carried out at room temperature for 16 h. After the reaction was completed, the system was diluted with water (10 mL), extracted with EA (30 mL × 3), and the combined organic phases were washed with saturated NaCl (30 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA = 4:1) to give 7-bromo-4-((1-methyl-1H-pyrazole-3-yl)methyl)spiro[benzo[b][1,4]oxazine-2,1'-cyclopropane]-3(4H)-one (120 mg), with a two-step yield of 56.9%.

[0234] LC-MS (m / z): 348.0, 350.0 [M+H] + .

[0235] Step 4: Synthesis of 4-((1-methyl-1H-pyrazol-3-yl)methyl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)spiro[benzo[b][1,4]oxazine-2,1'-cyclopropane]-3-(4H)-one (49-5)

[0236] 7-Bromo-4-((1-methyl-1H-pyrazol-3-yl)methyl)spiro[benzo[b][1,4]oxazine-2,1'-cyclopropane]-3(4H)-one (49-4, 120 mg, 0.35 mmol), pinacol diboronate (178 mg, 0.70 mmol), potassium acetate (69 mg, 0.70 mmol), and Pd(dppf)Cl2 (26 mg, 0.04 mmol) were added sequentially to the flask, followed by dioxane (10 mL). The reaction was carried out at 100 °C for 6 hours under nitrogen protection. After the reaction was completed, the reaction solution was concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA = 3:1) to give 4-((1-methyl-1H-pyrazol-3-yl)methyl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)spiro[benzo[b][1,4]oxazine-2,1'-cyclopropane]-3-(4H)-one (65 mg), yield 47.6%.

[0237] LC-MS (m / z): 396.0 [M+H] + .

[0238] Step 5: Synthesis of 3-(2-chloro-3-(4-(1-methyl-1H-pyrazol-3-yl)methyl)-3-oxo-3,4-dihydrospiro[benzo[b][1,4]oxazine-2,1'-cyclopropane]-7-yl)phenyl)piperidine-2,6-dione (compound 49)

[0239] 4-((1-methyl-1H-pyrazol-3-yl)methyl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)spiro[benzo[b][1,4]oxazine-2,1'-cyclopropane]-3-(4H)-one (49-5, 65 mg, 0.17 mmol) was dissolved in DMF (5 mL), and 3-(3-bromo-2-chlorophenyl)piperidin-2,6-dione (M1, 40 mg, 0.13 mmol), KOAc (49 mg, 0.50 mmol), and Pd(dppf)Cl2 (12 mg, 0.02 mmol) were added sequentially. The reaction was carried out at 100 °C for 1 hour under nitrogen protection. The reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography (DCM:MeOH = 20:1) to give 3-(2-chloro-3-(4-(1-methyl-1H-pyrazol-3-yl)methyl)-3-oxo-3,4-dihydrospiro[benzo[b][1,4]oxazine-2,1'-cyclopropane]-7-yl)phenyl)piperidin-2,6-dione (10 mg), yield 12.4%.

[0240] LC-MS (m / z): 491.0 [M+H] + .

[0241] 1 H NMR (600MHz, DMSO-d6): δ10.92 (s, 1H), 7.61 (d, J = 1.8Hz, 1H), 7.38-7.28 (m, 4H), 7.10 (dd, J1=8.4Hz, J2=2.4Hz, 1H), 6.96 (d, J=1.8Hz, 1H), 6.10 (d, J=2.4Hz, 1H), 5.08 (s, 2 H),4.34(dd,J1=12.0Hz,J2=4.8Hz,1H),3.79(s,3H),2.81-2.73(m,1H),2.56(t,J=3. 6Hz,1H),2.35-2.28(m,1H),2.05-1.99(m,1H),1.34-1.31(m,2H),1.28-1.25(m,2H).

[0242] Example 51: Synthesis of 3-(2-chloro-3-(4-((1-methyl-1H-pyrazol-3-yl)methyl)-3,4-dihydrospiro[benzo[b][1,4]oxazine-2,1'-cyclopropane]-7-yl)phenyl)piperidine-2,6-dione (compound 51)

[0243] Step 1: Synthesis of 7-bromo-3,4-dihydrospiro[benzo[b][1,4]oxazine-2,1'-cyclopropane](51-1)

[0244] The synthesis of compound 49-3 is described in steps 1-2 of Example 49.

[0245] 7-Bromospiro[benzo[b][1,4]oxazine-2,1'-cyclopropane]-3(4H)-one (49-3, 400 mg, 1.57 mmol) was dissolved in THF (5 mL), and boranetetrahydrofuran (15.7 mL) was added. The reaction was carried out at 60 °C for 2 h under N2 atmosphere. After the reaction was completed, the mixture was cooled to 0 °C, and 2 mL of methanol and 10 mL of hydrochloric acid (1 N) were added. The mixture was stirred for 0.5 h, and the pH was adjusted to 8 with saturated sodium bicarbonate solution. The mixture was extracted with ethyl acetate (15 mL × 3), and the organic phases were combined. The mixture was washed with saturated NaCl (20 mL × 3), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE / EA = 2:1) to give 7-bromo-3,4-dihydrospiro[benzo[b][1,4]oxazine-2,1'-cyclopropane] (350 mg), with a yield of 92.6%.

[0246] LC-MS (m / z): 240.0, 242.0 [M+H] + .

[0247] Step 2: Synthesis of 7-bromo-4-((1-methyl-1H-pyrazol-3-yl)methyl)-3,4-dihydrospiro[benzo[b][1,4]oxazine-2,1'-cyclopropane](51-2)

[0248] 7-Bromo-3,4-dihydrospiro[benzo[b][1,4]oxazine-2,1'-cyclopropane] (51-1, 350 mg, 1.46 mmol) was dissolved in acetonitrile (10 mL), and 3-(chloromethyl)-1-methyl-1H-pyrazole (950 mg, 7.29 mmol) and potassium carbonate (1010 mg, 7.29 mmol) were added. The mixture was heated to 70 °C and reacted for 24 h. After the reaction was completed, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE / EA = 1:1) to give 7-bromo-4-((1-methyl-1H-pyrazole-3-yl)methyl)-3,4-dihydrospiro[benzo[b][1,4]oxazine-2,1'-cyclopropane] (364 mg), with a yield of 74.7%.

[0249] LC-MS (m / z): 334.0 [M+H] + .

[0250] Step 3: Synthesis of 4-((1-methyl-1H-pyrazol-3-yl)methyl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-3,4-dihydrospiro[benzo[b][1,4]oxazine-2,1'-cyclopropane](51-3)

[0251] 7-Bromo-4-((1-methyl-1H-pyrazol-3-yl)methyl)-3,4-dihydrospiro[benzo[b][1,4]oxazine-2,1'-cyclopropane] (51-2, 364 mg, 1.09 mmol) was dissolved in dioxane (3 mL), and pinacol diboronate (415 mg, 1.63 mmol), potassium acetate (213 mg, 2.18 mmol), and Pd(dppf)Cl2 (80 mg, 0.11 mmol) were added. The system was purged with nitrogen and heated to 100 °C for 2 h. After the reaction was completed, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE / EA = 1:1) to give 4-((1-methyl-1H-pyrazol-3-yl)methyl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-3,4-dihydrospiro[benzo[b][1,4]oxazine-2,1'-cyclopropane] (364 mg), with a yield of 87.7%.

[0252] LC-MS (m / z): 382.0 [M+H] + .

[0253] Step 4: Synthesis of 3-(2-chloro-3-(4-((1-methyl-1H-pyrazol-3-yl)methyl)-3,4-dihydrospiro[benzo[b][1,4]oxazine-2,1'-cyclopropane]-7-yl)phenyl)piperidine-2,6-dione (compound 51)

[0254] 3-(3-bromo-2-chlorophenyl)piperidin-2,6-dione (M1, 120 mg, 0.40 mmol) was dissolved in DMF (2 mL), and 4-((1-methyl-1H-pyrazol-3-yl)methyl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-3,4-dihydrospiro[benzo[b][1,4]oxazine-2,1'-cyclopropane] (51-3, 166 mg, 0.44 mmol), Pd(dppf)Cl2 (29 mg, 0.04 mmol), and potassium phosphate (168 mg, 0.79 mmol) were added. The system was purged with nitrogen, and the temperature was raised to 100 °C for 1 h. After the reaction was completed, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (DCM / MeOH = 20:1) to give 3-(2-chloro-3-(4-((1-methyl-1H-pyrazol-3-yl)methyl)-3,4-dihydrospiro[benzo[b][1,4]oxazine-2,1'-cyclopropane]-7-yl)phenyl)piperidine-2,6-dione (13 mg), yield 6.9%.

[0255] LC-MS (m / z): 477.0 [M+H] + .

[0256] 1 H NMR (600MHz, DMSO-d6): δ10.90(s,1H),7.59(d,J=2.4Hz,1H),7.33(t,J=7.8Hz,1H),7.25(t,J =8.4Hz,2H),6.94(d,J=8.4Hz,1H),6.83-6.81(m,1H),6.66(d,J=1.8Hz,1H),6.16(d,J=1.8Hz ,1H),4.43(s,2H),4.32-4.29(m,1H),3.79(s,3H),3.40(s,2H),2.80-2.74(m,1H),2.54(t,J= 3.6Hz,1H),2.34-2.26(m,1H),2.04-2.01(m,1H),0.93(t,J=6.6Hz,2H),0.74(t,J=6.0Hz,2H).

[0257] Example 52: Synthesis of 3-(2-chloro-3-(4-(2-(1-methyl-1H-pyrazol-3-yl)ethyl)-3-oxo-3,4-dihydrospiro[benzo[b][1,4]oxazine-2,1'-cyclopropane]-7-yl)phenyl)piperidine-2,6-dione (compound 52)

[0258] Step 1: Synthesis of 7-bromo-4-(2-(1-methyl-1H-pyrazol-3-yl)ethyl)spiro[benzo[b][1,4]oxazine-2,1'-cyclopropane]-3(4H)-one (52-1)

[0259] The synthesis of compound 49-3 is described in steps 1-2 of Example 49.

[0260] 2-(1-methyl-1H-pyrazol-3-yl)ethanol-1-ol (500 mg, 3.97 mmol) was dissolved in THF (10 mL), and 7-bromospiro[benzo[b][1,4]oxazine-2,1'-cyclopropane]-3(4H)-one (49-3, 1.2 g, 4.76 mmol), triphenylphosphine (1.56 g, 5.96 mmol), and diethyl azodicarbonate (1.2 g, 5.96 mmol) were added sequentially. The reaction was carried out at room temperature for 16 h. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (PE:EA = 3:1) to give 7-bromo-4-(2-(1-methyl-1H-pyrazol-3-yl)ethyl)spiro[benzo[b][1,4]oxazine-2,1'-cyclopropane]-3(4H)-one (600 mg), yield 41.7%.

[0261] LC-MS (m / z): 362.0, 364.0 [M+H] + .

[0262] Step 2: Synthesis of 4-(2-(1-methyl-1H-pyrazol-3-yl)ethyl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)spiro[benzo[b][1,4]oxazine-2,1'-cyclopropane]-3(4H)-one (52-2)

[0263] 7-Bromo-4-(2-(1-methyl-1H-pyrazol-3-yl)ethyl)spiro[benzo[b][1,4]oxazine-2,1'-cyclopropane]-3(4H)-one (52-1, 600 mg, 1.66 mmol) was dissolved in 1,4-dioxane (10 mL), and then pinacol diboronic acid ester (650 mg, 2.49 mmol), KOAc (500 mg, 4.98 mmol) and Pd(dppf)Cl2 (120 mg, 0.166 mmol) were added sequentially. The reaction was carried out at 100 °C for 3 h under nitrogen protection. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography (DCM:MeOH = 20:1) to give 4-(2-(1-methyl-1H-pyrazol-3-yl)ethyl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)spiro[benzo[b][1,4]oxazine-2,1'-cyclopropane]-3(4H)-one (500 mg), yield 73.7%.

[0264] LC-MS (m / z): 410.0 [M+H] + .

[0265] Step 3: Synthesis of 3-(2-chloro-3-(4-(2-(1-methyl-1H-pyrazol-3-yl)ethyl)-3-oxo-3,4-dihydrospiro[benzo[b][1,4]oxazine-2,1'-cyclopropane]-7-yl)phenyl)piperidine-2,6-dione (compound 52)

[0266] 4-(2-(1-methyl-1H-pyrazol-3-yl)ethyl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)spiro[benzo[b][1,4]oxazine-2,1'-cyclopropane]-3(4H)-one (52-2, 200 mg, 0.49 mmol) was dissolved in DMF (10 mL), and 3-(3-bromo-2-chlorophenyl)piperidin-2,6-dione (147 mg, 0.49 mmol), KOAc (144 mg, 1.47 mmol), and Pd(dppf)Cl2 (35 mg, 0.049 mmol) were added sequentially. The reaction was carried out at 100 °C for 3 h under nitrogen protection. After the reaction was completed, the mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by column chromatography (DCM:MeOH = 20:1) to give 3-(2-chloro-3-(4-(2-(1-methyl-1H-pyrazol-3-yl)ethyl)-3-oxo-3,4-dihydrospiro[benzo[b][1,4]oxazine-2,1'-cyclopropane]-7-yl)phenyl)piperidine-2,6-dione (70 mg), yield 28.5%.

[0267] LC-MS (m / z): 505.0 [M+H] + .

[0268] 1 H NMR (600MHz, DMSO-d6): δ10.93(s,1H),7.57(d,J=2.4Hz,1H),7.40-7.31(m,3H),7.29(d,J=8.4 Hz,1H),7.17(dd,J1=7.8,J2=1.8Hz,1H),6.98(d,J=1.8Hz,1H),6.14(d,J=1.8Hz,1H),4.35(dd, J1=12.6Hz, J2=4.8Hz,1H),4.19-4.14(m,2H),3.77(s,3H),2.87-2.85(m,2H),2.82-2.76(m,1H) ,2.56-2.52(m,1H),2.38-2.30(m,1H),2.06-2.02(m,1H),1.31-1.27(m,2H),1.24-1.22(m,2H).

[0269] Example 200: Synthesis of 3-(2-chloro-3-(1'-((1-methyl-1H-imidazol-4-yl)methyl)spiro[cyclopropane-1,3'-indole]-5'-yl)phenyl)piperidine-2,6-dione (200)

[0270] Step 1: Synthesis of 5'-bromospiro[cyclopropane-1,3'-dihydroindole](200-1)

[0271] Intermediates 1-2 were prepared according to step 1 of Example 1.

[0272] 5'-Bromospiro[cyclopropane-1,3'-dihydroindole]-2'-one (1-2, 4.0 g, 16.88 mmol) was dissolved in THF (30 mL). Boranetetrahydrofuran solution (1 M, 101.27 mmol, 101 mL) was added dropwise under nitrogen protection and an ice bath. After the addition was complete, the temperature was raised to 70 °C and the reaction was carried out for 2 hours. After the reaction was complete, methanol (20 mL) was slowly added dropwise under an ice bath, followed by 2N dilute hydrochloric acid (10 mL). The mixture was stirred at room temperature for 3 hours. The solution was concentrated under reduced pressure, extracted with ethyl acetate (20 mL × 3), and the combined organic phases were dried over anhydrous Na₂SO₄. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA = 10:1) to give 5'-Bromospiro[cyclopropane-1,3'-dihydroindole] (200-1, 1.5 g), with a yield of 39.5%.

[0273] LC-MS (m / z): 224.0 / 226.0 [M+H] + .

[0274] Step 2: Synthesis of 5'-bromo-1'-((1-methyl-1H-imidazol-4-yl)methyl)spiro[cyclopropane-1,3'-indole](200-2)

[0275] 5'-bromospiro[cyclopropane-1,3'-dihydroindole] (200-1, 1.0 g, 4.48 mmol), potassium carbonate (2.5 g, 17.92 mmol), and 4-(chloromethyl)-1-methyl-1H-imidazole (1.5 g, 8.96 mmol) were added to a flask, followed by 10 mL of DMF. The reaction mixture was reacted at 60 °C for 6 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography (DCM:MeOH = 20:1) to give 5'-bromo-1'-((1-methyl-1H-imidazole-4-yl)methyl)spiro[cyclopropane-1,3'-indole] (200-2, 1.0 g), with a yield of 70.4%.

[0276] LC-MS (m / z): 318.0 / 320.0 [M+H] + .

[0277] Step 3: Synthesis of 3-(2-chloro-3-(1'-((1-methyl-1H-imidazol-4-yl)methyl)spiro[cyclopropane-1,3'-indole]-5'-yl)phenyl)-1-(4-methoxybenzyl)piperidine-2,6-dione (200-3)

[0278] 5'-Bromo-1'-((1-methyl-1H-imidazol-4-yl)methyl)spiro[cyclopropane-1,3'-indole] (200-2, 300.0 mg, 0.95 mmol), 3-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)phenyl)-1-(4-methoxybenzyl)piperidine-2,6-dione (M3, 441.0 mg, 0.95 mmol), cesium carbonate (926.0 mg, 2.85 mmol), and Pd(dppf)Cl2 (73.0 mg, 0.10 mmol) were added sequentially to DMF (4 mL), and the reaction was carried out at 100 °C for 6 hours under nitrogen protection. The reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography (DCM:MeOH = 20:1) to give 3-(2-chloro-3-(1'-((1-methyl-1H-imidazol-4-yl)methyl)spiro[cyclopropane-1,3'-indole]-5'-yl)phenyl)-1-(4-methoxybenzyl)piperidine-2,6-dione (200-3, 250.0 mg), yield 45.3%.

[0279] LC-MS (m / z): 581.0 [M+H] + .

[0280] Step 4: Synthesis of 3-(2-chloro-3-(1'-((1-methyl-1H-imidazol-4-yl)methyl)spiro[cyclopropane-1,3'-indole]-5'-yl)phenyl)piperidine-2,6-dione (200)

[0281] 3-(2-chloro-3-(1'-((1-methyl-1H-imidazol-4-yl)methyl)spiro[cyclopropane-1,3'-indole]-5'-yl)phenyl)-1-(4-methoxybenzyl)piperidine-2,6-dione (200-3, 250.0 mg, 0.45 mmol) was dissolved in trifluoroacetic acid (2 mL), and trifluoromethanesulfonic acid (0.5 mL) was added. The mixture was reacted at 40 °C for 3 hours. The reaction solution was adjusted to pH 7–8 with saturated sodium bicarbonate solution, extracted with ethyl acetate (10 mL × 3), the organic phases were combined and washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, and the residue was purified by column chromatography (DCM:MeOH = 20:1) to give 3-(2-chloro-3-(1'-((1-methyl-1H-imidazol-4-yl)methyl)spiro[cyclopropane-1,3'-indole]-5'-yl)phenyl)piperidin-2,6-dione (200, 8.0 mg), yield 3.9%.

[0282] LC-MS (m / z): 461.0 [M+H] + .

[0283] 1 H NMR (600MHz, DMSO-d6) δ10.90(s,1H),7.49(m,1H),7.31(m,1H),7.23(m,2H),7.03(m,1H),6.98(m,1H),6.64(d,J=12.0Hz,1H),6.58(d,J=1. 8Hz,1H),4.30(m,1H),4.20(s,2H),3.60(s,3H),3.49(s,2H),2.77(m, 1H),2.54(m,1H),2.30(m,7.4Hz,1H),2.06–1.99(m,1H),0.92(s,4H).

[0284] Example 30: Synthesis of 3-(2-chloro-4'-(2'H,4'H-spiro[cyclopropane-1,3'-pyrido[3,2-b][1,4]oxazine]-4'-yl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (compound 30)

[0285] Step 1: Synthesis of (1-(((2-iodopyridin-3-yl)oxy)methyl)cyclopropyl)tert-butyl carbamate (30-2)

[0286] (1-(hydroxymethyl)cyclopropyl)tert-butyl carbamate (2.06 g, 10.00 mmol) and 3-hydroxy-2-iodopyridine (30-1, 2.2 g, 11.00 mmol) were dissolved in THF (20 mL). Under nitrogen protection, triphenylphosphine (3.93 g, 15.00 mmol) was added, and DIAD (3.03 g, 15.00 mmol) was added dropwise under ice bath conditions. The mixture was slowly heated to room temperature and reacted for 16 hours. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (PE:EA = 5:1) to give (1-(((2-iodopyridine-3-yl)oxy)methyl)cyclopropyl)tert-butyl carbamate (1.2 g), yield 30.1%.

[0287] LC-MS (m / z): 391.0 [M+H] + .

[0288] Step 2: Synthesis of 1-(((2-iodopyridin-3-yl)oxy)methyl)cyclopropane-1-amine (30-3)

[0289] (1-(((2-iodopyridin-3-yl)oxy)methyl)cyclopropyl)carbamate tert-butyl ester (30-2, 1.2 g, 3.10 mmol) was dissolved in DCM (15 mL), and 5 mL was added to the system. The reaction was carried out at room temperature for 4 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain trifluoroacetate of 1-(((2-iodopyridin-3-yl)oxy)methyl)cyclopropane-1-amine (1.2 g), crude product.

[0290] LC-MS (m / z): 291.0 [M+H] + .

[0291] Step 3: Synthesis of 2'H,4'H-spiro[cyclopropane-1,3'-pyrido[3,2-b][1,4]oxazine] (30-4)

[0292] The trifluoroacetate of 1-(((2-iodopyridin-3-yl)oxy)methyl)cyclopropane-1-amine (30-3, 388 mg, 1.00 mmol) was dissolved in 1,4-dioxane (10 mL), followed by the addition of palladium acetate (92 mg, 0.10 mmol), 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthracene (116 mg, 0.20 mmol), and cesium carbonate (974 mg, 3.00 mmol). The reaction was carried out under nitrogen protection at 100 °C for 1 hour. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (DCM:MeOH = 20:1) to give 2'H,4'H-spiro[cyclopropane-1,3'-pyrido[3,2-b][1,4]oxazine] (100 mg), with a two-step yield of 83.0%.

[0293] LC-MS (m / z): 163.0 [M+H] + .

[0294] Step 4: Synthesis of 4'-(4-bromophenyl)-2'H,4'H-spiro[cyclopropane-1,3'-pyrido[3,2-b][1,4]oxazine] (30-5)

[0295] Add 2'H,4'H-spiro[cyclopropane-1,3'-pyrido[3,2-b][1,4]oxazine] (30-4, 100 mg, 0.62 mmol) dissolved in dioxane (10 mL) to the flask in sequence. Then add p-bromoiodobenzene (192 mg, 0.68 mmol), tris(dibenzylideneacetone)palladium (55 mg, 0.06 mmol), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (70 mg, 0.12 mmol), and cesium carbonate (610 mg, 1.87 mmol) in sequence. Under nitrogen protection, the system was heated to 100 °C and reacted for 4 hours. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (PE:EA = 5:1) to give 4'-(4-bromophenyl)-2'H,4'H-spiro[cyclopropane-1,3'-pyrido[3,2-b][1,4]oxazine] (120 mg), with a yield of 61.5%.

[0296] LC-MS (m / z): 317.0 [M+H] + .

[0297] Step 5: Synthesis of 3-(2-chloro-4'-(2'H,4'H-spiro[cyclopropane-1,3'-pyrido[3,2-b][1,4]oxazine]-4'-yl)-[1,1'-biphenyl]-3-yl)-1-(4-methoxybenzyl)piperidine-2,6-dione (30-6)

[0298] 4'-(4-bromophenyl)-2'H,4'H-spiro[cyclopropane-1,3'-pyrido[3,2-b][1,4]oxazine] (30-5, 100 mg, 0.32 mmol) was dissolved in dioxane (5 mL), and 3-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)-1-(4-methoxybenzyl)piperidin-2,6-dione (M3, 150 mg, 0.32 mmol), K2CO3 (132 mg, 0.96 mmol) and Pd(dppf)Cl2 (25 mg, 0.03 mmol) were added sequentially. The system was protected with nitrogen and the temperature was raised to 100 °C for 10 hours. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (DCM:MeOH = 20:1) to give 3-(2-chloro-4'-(2'H,4'H-spiro[cyclopropane-1,3'-pyrido[3,2-b][1,4]oxazine]-4'-yl)-[1,1'-biphenyl]-3-yl)-1-(4-methoxybenzyl)piperidine-2,6-dione (50 mg), yield 27.3%.

[0299] LC-MS (m / z): 580.0 [M+H] + .

[0300] Step 6: Synthesis of 3-(2-chloro-4'-(2'H,4'H-spiro[cyclopropane-1,3'-pyrido[3,2-b][1,4]oxazine]-4'-yl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (compound 30)

[0301] 3-(2-chloro-4'-(2'H,4'H-spiro[cyclopropane-1,3'-pyrido[3,2-b][1,4]oxazine]-4'-yl)-[1,1'-biphenyl]-3-yl)-1-(4-methoxybenzyl)piperidin-2,6-dione (30-6, 50 mg, 0.09 mmol) was dissolved in TFA (4 mL), and trifluoromethanesulfonic acid (1 mL) was added to the system. The mixture was heated to 60 °C and reacted for 4 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography (DCM:MeOH = 20:1) to give 3-(2-chloro-4'-(2'H,4'H-spiro[cyclopropane-1,3'-pyrido[3,2-b][1,4]oxazine]-4'-yl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione (8 mg), yield 20.2%.

[0302] LC-MS (m / z): 460.0 [M+H] + .

[0303] 1H NMR (600MHz, DMSO-d6): δ10.93 (s, 1H), 7.72 (d, J = 4.8Hz, 1H), 7.42-7.39 (m, 5H), 7. 36(t,J=6.6Hz,2H),7.23(d,J=7.8Hz,1H),6.81(dd,J1=7.8Hz,J2=4.8Hz,1H),4.37 (dd,J1=12.6Hz, J2=5.4Hz,1H),4.18(s,2H),2.83-2.73(m,1H),2.57-2.53(m,1H), 2.38-2.30(m,1H),2.08-2.03(m,1H),0.96(d,J=6.0Hz,2H),0.82(d,J=6.0Hz,2H).

[0304] Example 33: Synthesis of 3-(2-chloro-4'-(2'H,4'H-spiro[cyclobutane-1,3'-pyrido[3,2-b][1,4]oxazine]-4'-yl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (compound 33)

[0305] Step 1: Synthesis of tert-butyl (1-(((2-iodopyridin-3-yl)oxy)methyl)cyclobutyl)carbamate (33-2)

[0306] 2.5 g (12.44 mmol) of tert-butyl (1-(hydroxymethyl)cyclobutyl)carbamate, 2-iodopyridin-3-ol (33-1, 4.2 g, 18.66 mmol), and cyanomethylenetri-n-butylphosphine (6.0 g, 24.88 mmol) were dissolved in toluene (30 mL), and the mixture was heated to 110 °C and reacted for 16 h. After the reaction was completed, the mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by column chromatography (PE:EA = 5:1) to give 400 mg (1-(((2-iodopyridin-3-yl)oxy)methyl)cyclobutyl)carbamate, with a yield of 7.9%.

[0307] LC-MS (m / z): 405.0 [M+H] + .

[0308] Step 2: Synthesis of 1-(((2-iodopyridin-3-yl)oxy)methyl)cyclobutane-1-amine (33-3)

[0309] (1-(((2-iodopyridin-3-yl)oxy)methyl)cyclobutyl)carbamate tert-butyl ester (33-2, 400 mg, 0.99 mmol) was dissolved in DCM (6 mL), and TFA (2 mL) was added to the system. The reaction was carried out at room temperature for 4 h. After the reaction was completed, the solution was concentrated under reduced pressure to obtain crude 1-(((2-iodopyridin-3-yl)oxy)methyl)cyclobutane-1-amine (300 mg).

[0310] LC-MS (m / z): 305.0 [M+H] + .

[0311] Step 3: Synthesis of 2'H,4'H-spiro[cyclobutane-1,3'-pyrido[3,2-b][1,4]oxazine] (33-4)

[0312] 1-(((2-iodopyridin-3-yl)oxy)methyl)cyclobutane-1-amine (33-3, 300 mg, 0.98 mmol) was dissolved in 1,4-dioxane (10 mL), and Pd(OAc)₂ (22 mg, 0.10 mmol), Xantphos (114.0 mg, 0.20 mmol), and cesium carbonate (961 mg, 2.95 mmol) were added sequentially. The reaction was carried out at 100 °C for 2 h under nitrogen protection. After the reaction was completed, the mixture was concentrated under reduced pressure. The residue was purified by column chromatography (DCM:MeOH = 20:1) to give 2'H,4'H-spiro[cyclobutane-1,3'-pyrido[3,2-b][1,4]oxazine] (110 mg), with a two-step yield of 63.6%.

[0313] LC-MS (m / z): 177.0 [M+H] + .

[0314] Step 4: Synthesis of 4'-(4-bromophenyl)-2'H,4'H-spiro[cyclobutane-1,3'-pyrido[3,2-b][1,4]oxazine] (33-5)

[0315] 2'H,4'H-spiro[cyclobutane-1,3'-pyrido[3,2-b][1,4]oxazine] (33-4, 100 mg, 0.57 mmol) dissolved in 1,4-dioxane (10 mL) was added to the flask in sequence, followed by p-bromoiodobenzene (240 mg, 0.86 mmol), Pd2(dba)3 (55.0 mg, 0.06 mmol), Xantphos (70.0 mg, 0.12 mmol), and cesium carbonate (550.0 mg, 1.69 mmol). The reaction was carried out at 100 °C for 16 h under nitrogen protection. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (PE:EA = 5:1) to give 4'-(4-bromophenyl)-2'H,4'H-spiro[cyclobutane-1,3'-pyrido[3,2-b][1,4]oxazine] (70 mg), with a yield of 37.2%.

[0316] LC-MS (m / z): 311.0, 313.0 [M+H] + .

[0317] Step 5: Synthesis of 4'-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)-2'H,4'H-spiro[cyclobutane-1,3'-pyrido[3,2-b][1,4]oxazine] (33-6)

[0318] 4'-(4-bromophenyl)-2'H,4'H-spiro[cyclobutane-1,3'-pyrido[3,2-b][1,4]oxazine] (33-5, 60.0 mg, 0.18 mmol) was dissolved in 1,4-dioxane (5 mL), and then pinacol diboronic acid ester (70 mg, 0.27 mmol), KOAc (60 mg, 0.54 mmol) and Pd(dppf)Cl2 (15 mg, 0.02 mmol) were added sequentially. The mixture was reacted at 100 °C for 6 h under nitrogen protection. After the reaction was completed, the compound was concentrated under reduced pressure, and the residue was purified by column chromatography (DCM:MeOH = 20:1) to give 4'-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)-2'H,4'H-spiro[cyclobutane-1,3'-pyrido[3,2-b][1,4]oxazine] (50 mg), with a yield of 73.5%.

[0319] LC-MS (m / z): 379.0 [M+H] + .

[0320] Step 6: Synthesis of 3-(2-chloro-4'-(2'H,4'H-spiro[cyclobutane-1,3'-pyrido[3,2-b][1,4]oxazine]-4'-yl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione (compound 33)

[0321] 4'-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)-2'H,4'H-spiro[cyclobutane-1,3'-pyrido[3,2-b][1,4]oxazine] (33-5, 50 mg, 0.13 mmol) was dissolved in DMF (5 mL), and 3-(3-bromo-2-chlorophenyl)piperidin-2,6-dione (M1, 40 mg, 0.13 mmol), KOAc (40 mg, 0.40 mmol), and Pd(dppf)Cl2 (15 mg, 0.02 mmol) were added sequentially. The reaction was carried out at 100 °C for 16 h under nitrogen protection. After the reaction was completed, the mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by column chromatography (DCM:MeOH = 20:1) to give 3-(2-chloro-4'-(2'H,4'H-spiro[cyclobutane-1,3'-pyrido[3,2-b][1,4]oxazine]-4'-yl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione (6.3 mg), yield 10.1%.

[0322] LC-MS (m / z): 474.0 [M+H] + .

[0323] 1 H NMR (600MHz, DMSO-d6): δ10.94(s,1H),7.55(d,J=4.8Hz,1H),7.52(d,J=7.8Hz,2H),7.45-7 .37(m,3H),7.27(d,J=7.8Hz,2H),7.11(d,J=7.8Hz,1H),6.60(dd,J1=7.8Hz,J2=4.8Hz,1H), 4.41-4.36(m,1H),4.31(s,2H),2.84-2.78(m,1H),2.58-2.53(m,1H),2.39-2.32(m,1H),2. 19-2.14(m,2H),2.11-2.04(m,1H),1.99-1.95(m,2H),1.80-1.75(m,1H),1.57-1.52(m,1H).

[0324] Example 50: Synthesis of 3-(2-chloro-4'-(1',3'-dimethyl-5'-oxo-1'H-spiro[cyclopropane-1,6'-pyrazolo[3,4-b][1,4]oxazine]-4'(5'H)-yl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (compound 50)

[0325] Step 1: Synthesis of methyl 1-((1,3-dimethyl-4-nitro-1H-pyrazol-5-yl)oxy)cyclopropane-1-carboxylic acid (50-2)

[0326] Ethyl 1-hydroxycyclopropanecarboxylate (700 mg, 4.63 mmol) was dissolved in THF (10 mL). Under nitrogen protection, sodium hydride (223 mg, 5.56 mmol) was added in an ice bath. After maintaining the temperature for 0.5 h, 5-chloro-1,3-dimethyl-4-nitro-1H-pyrazole (50-1, 860 mg, 4.86 mmol) was added, and the reaction was continued at room temperature for 2 h. After the reaction was complete, the reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA = 5:1) to give methyl 1-((1,3-dimethyl-4-nitro-1H-pyrazole-5-yl)oxy)cyclopropane-1-carboxylate (600 mg), yield 42.9%.

[0327] LC-MS (m / z): 256.0 [M+H] + .

[0328] Step 2: Synthesis of 1',3'-dimethyl-1',4'-dihydro-5'H-spiro[cyclopropane-1,6'-pyrazolo[3,4-b][1,4]oxazine]-5'-one (50-3)

[0329] Methyl 1-((1,3-dimethyl-4-nitro-1H-pyrazol-5-yl)oxy)cyclopropane-1-carboxylic acid (50-2, 510 mg, 2.00 mmol) was dissolved in AcOH (10 mL), and Fe (1.12 g, 20.00 mmol) was added under ice bath conditions. The mixture was heated to 90 °C and reacted for 0.5 h. After the reaction was completed, the mixture was concentrated under reduced pressure, water (10 mL) was added, the pH was adjusted to 7 with saturated NaHCO3 aqueous solution (20 mL), and extracted with EA (20 mL × 3). The combined organic phases were washed with saturated NaCl (20 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give 1',3'-dimethyl-1',4'-dihydro-5'H-spiro[cyclopropane-1,6'-pyrazolo[3,4-b][1,4]oxazine]-5'-one (250 mg), yield 64.8%.

[0330] LC-MS (m / z): 194.0 [M+H] + .

[0331] Step 3: Synthesis of 4'-(4-bromophenyl)-1',3'-dimethyl-1',4'-dihydro-5'H-spiro[cyclopropane-1,6'-pyrazolo[3,4-b][1,4]oxazine]-5'-one (50-4)

[0332] 1',3'-Dimethyl-1',4'-dihydro-5'H-spiro[cyclopropane-1,6'-pyrazolo[3,4-b][1,4]oxazine]-5'-one (50-3, 193 mg, 1.00 mmol) and p-bromoiodobenzene (310 mg, 1.10 mmol) were dissolved in 1,4-dioxane (10 mL), and Pd2(dba)3 (92 mg, 0.10 mmol), Xantphos (115 mg, 0.20 mmol) and cesium carbonate (984 mg, 3.00 mmol) were added sequentially. The reaction was carried out at 100 °C for 1 hour under nitrogen protection. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (DCM:MeOH = 20:1) to give 4'-(4-bromophenyl)-1',3'-dimethyl-1',4'-dihydro-5'H-spiro[cyclopropane-1,6'-pyrazolo[3,4-b][1,4]oxazine]-5'-one (250 mg), yield 72.0%.

[0333] LC-MS (m / z): 348.0 [M+H] + .

[0334] Step 4: Synthesis of 1',3'-dimethyl-4'-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)-1',4'-dihydro-5'H-spiro[cyclopropane-1,6'-pyrazolo[3,4-b][1,4]oxazine]-5'-one (50-5)

[0335] 4'-(4-bromophenyl)-1',3'-dimethyl-1',4'-dihydro-5'H-spiro[cyclopropane-1,6'-pyrazolo[3,4-b][1,4]oxazine]-5'-one (50-4, 250 mg, 0.72 mmol), pinacol diboronate (360 mg, 1.44 mmol), KOAc (130 mg, 1.44 mmol), and Pd(dppf)Cl2 (52 mg, 0.07 mmol) were added sequentially to the flask, followed by 10 mL of dioxane. The reaction mixture was reacted at 100 °C for 6 hours under nitrogen protection. After the reaction was completed, the reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA = 3:1) to give crude product of 1',3'-dimethyl-4'-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)-1',4'-dihydro-5'H-spiro[cyclopropane-1,6'-pyrazolo[3,4-b][1,4]oxazine]-5'-one (240 mg).

[0336] LC-MS (m / z): 396.0 [M+H] + .

[0337] Step 5: Synthesis of 3-(2-chloro-4'-(1',3'-dimethyl-5'-oxo-1'H-spiro[cyclopropane-1,6'-pyrazolo[3,4-b][1,4]oxazine]-4'(5'H)-yl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (compound 50)

[0338] 1',3'-Dimethyl-4'-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)phenyl)-1',4'-dihydro-5'H-spiro[cyclopropane-1,6'-pyrazolo[3,4-b][1,4]oxazine]-5'-one (50-5, 240 mg, 0.61 mmol) was dissolved in DMF (5 mL), and 3-(3-bromo-2-chlorophenyl)piperidin-2,6-dione (M1, 139 mg, 0.46 mmol), KOAc (180 mg, 0.83 mmol), and Pd(dppf)Cl2 (45 mg, 0.06 mmol) were added sequentially. The reaction was carried out at 100 °C for 16 hours under nitrogen protection. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (DCM:MeOH = 20:1) to give 3-(2-chloro-4'-(1',3'-dimethyl-5'-oxo-1'H-spiro[cyclopropane-1,6'-pyrazolo[3,4-b][1,4]oxazine]-4'(5'H)-yl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione (26 mg), with a two-step yield of 7.4%.

[0339] LC-MS (m / z): 491.0 [M+H] + .

[0340] 1 H NMR (600MHz, DMSO-d6): δ10.93(s,1H),7.54(d,J=7.8Hz,2H),7.47(d,J=7.8Hz,2H),7.44-7.38(m,3H),4.37(dd,J1=12.0Hz,J2=4.8Hz,1H), 3.52(s,3H),2.82-2.77(m,1H),2.57-2.53(m,1H),2.38-2.32(m,1H), 2.07-2.04(m,1H),1.49(s,3H),1.43-1.41(m,2H),1.39-1.36(m,2H).

[0341] Example 54: Synthesis of 3-(2-chloro-4'-(7'-methyl-2'H,4'-spiro[cyclopropane-1,3'-pyrido[3,2-b][1,4]oxazine]-4'-yl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (compound 54)

[0342] Step 1: Synthesis of (1-(((5-bromo-2-iodopyridin-3-yl)oxy)methyl)cyclopropyl)tert-butyl carbamate (54-2)

[0343] (1-(bromomethyl)cyclopropyl)carbamate tert-butyl ester (2.0 g, 8.00 mmol) was dissolved in DMF (20 mL), and 5-bromo-2-iodopyridin-3-ol (54-1, 2.4 g, 8.03 mmol) and potassium carbonate (2.2 g, 15.94 mmol) were added at room temperature. The reaction mixture was reacted at 70 °C for 24 h. After the reaction was complete, the reaction mixture was diluted with water (20 mL), extracted with EA (20 mL × 3), and the combined organic phases were washed with saturated NaCl (20 mL), dried over anhydrous Na₂SO₄, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA = 10:1) to give (1-(((5-bromo-2-iodopyridin-3-yl)oxy)methyl)cyclopropyl)carbamate tert-butyl ester (54-2, 1.5 g), yield 39.9%.

[0344] LC-MS (m / z): 469.0, 471.0 [M+H] + .

[0345] Step 2: Synthesis of 7'-bromo-2'H,4'-spiro[cyclopropane-1,3'-pyrido[3,2-b][1,4]oxazine]-4'-carboxylic acid tert-butyl ester (54-3)

[0346] (1-(((5-bromo-2-iodopyridin-3-yl)oxy)methyl)cyclopropyl)tert-butyl carbamate (54-2, 1.4 g, 3.00 mmol) and L-proline (35 mg, 0.31 mmol) were dissolved in 1,4-dioxane (10 mL), followed by the addition of cuprous iodide (114 mg, 0.59 mmol) and sodium tert-butoxide (433 mg, 4.51 mmol). The system was protected under nitrogen atmosphere and heated to 100 °C for 1 hour under microwave conditions. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (PE:EA = 10:1) to give 7'-bromo-2'H,4'-spiro[cyclopropane-1,3'-pyrido[3,2-b][1,4]oxazine]-4'-carboxylic acid tert-butyl ester (54-3, 400 mg), with a yield of 39.6%.

[0347] LC-MS (m / z): 341.0, 343.0 [M+H] + .

[0348] Step 3: Synthesis of 7'-methyl-2'H,4'-spiro[cyclopropane-1,3'-pyrido[3,2-b][1,4]oxazine]-4'-carboxylic acid tert-butyl ester (54-4)

[0349] 7'-bromo-2'H,4'-spiro[cyclopropane-1,3'-pyrido[3,2-b][1,4]oxazine]-4'-carboxylic acid tert-butyl ester (54-3, 500 mg, 1.47 mmol), methylboronic acid (170 mg, 2.65 mmol), potassium phosphate (935 mg, 4.41 mmol), Pd(OAc)2 (33 mg, 0.15 mmol), and tricyclohexylphosphine (83 mg, 0.29 mmol) were added sequentially to the flask, followed by toluene (20 mL) and water (1 mL). The mixture was heated to 100 °C under nitrogen protection and reacted for 16 hours. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (PE:EA = 5:1) to give tert-butyl 7'-methyl-2'H,4'-spiro[cyclopropane-1,3'-pyrido[3,2-b][1,4]oxazine]-4'-carboxylic acid (54-4,230 mg), yield 39.6%.

[0350] LC-MS (m / z): 277.0 [M+H] + .

[0351] Step 4: Synthesis of 7'-methyl-2'H,4'-spiro[cyclopropane-1,3'-pyrido[3,2-b][1,4]oxazine] (54-5)

[0352] 7'-Methyl-2'H,4'-spiro[cyclopropane-1,3'-pyrido[3,2-b][1,4]oxazine]-4'-carboxylic acid tert-butyl ester (54-4, 230 mg, 0.83 mmol) was dissolved in DCM (5 mL), and TFA (1 mL) was added to the system. The reaction was carried out at room temperature for 6 hours. After the reaction was completed, the solution was concentrated under reduced pressure to give crude 7'-methyl-2'H,4'-spiro[cyclopropane-1,3'-pyrido[3,2-b][1,4]oxazine] (54-5, 177 mg).

[0353] LC-MS (m / z): 177.0 [M+H] + .

[0354] Step 5: Synthesis of 4'-(4-bromophenyl)-7'-methyl-2'H,4'H-spiro[cyclopropane-1,3'-pyrido[3,2-b][1,4]oxazine] (54-6)

[0355] The product obtained in the previous step (54-5) and p-bromoiodobenzene (310 mg, 1.1 mmol) were dissolved in 1,4-dioxane (10 mL), and Pd2(dba)3 (92 mg, 0.10 mmol), Xantphos (115 mg, 0.20 mmol), and cesium carbonate (984 mg, 3.00 mmol) were added sequentially. The system was protected with nitrogen and the temperature was raised to 100 °C for 1 hour. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (DCM:MeOH = 20:1) to give 4'-(4-bromophenyl)-7'-methyl-2'H,4'H-spiro[cyclopropane-1,3'-pyrido[3,2-b][1,4]oxazine] (54-6, 140 mg), with a two-step yield of 50.9%.

[0356] LC-MS (m / z): 331.0 [M+H] + .

[0357] Step 6: Synthesis of 7'-methyl-4'-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)-2'H,4'H-spiro[cyclopropane-1,3'-pyrido[3,2-b][1,4]oxazine] (54-7)

[0358] 4'-(4-bromophenyl)-7'-methyl-2'H,4'H-spiro[cyclopropane-1,3'-pyrido[3,2-b][1,4]oxazine] (54-6, 80 mg, 0.24 mmol), pinacol diboronate (122 mg, 0.48 mmol), KOAc (47 mg, 0.48 mmol), and Pd(dppf)Cl2 (17 mg, 0.02 mmol) were added sequentially to the flask, followed by dioxane (50 mL). The mixture was heated to 100 °C under nitrogen protection and reacted for 6 hours. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (PE:EA = 3:1) to give crude 7'-methyl-4'-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)-2'H,4'H-spiro[cyclopropane-1,3'-pyrido[3,2-b][1,4]oxazine] (54-7, 100 mg).

[0359] LC-MS (m / z): 379.0 [M+H] + .

[0360] Step 7: Synthesis of 3-(2-chloro-4'-(7'-methyl-2'H,4'-spiro[cyclopropane-1,3'-pyrido[3,2-b][1,4]oxazine]-4'-yl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (compound 54)

[0361] 7'-Methyl-4'-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)-2'H,4'H-spiro[cyclopropane-1,3'-pyrido[3,2-b][1,4]oxazine] (54-7, 50 mg, 0.13 mmol) was dissolved in DMF (5 mL), and 3-(3-bromo-2-chlorophenyl)piperidin-2,6-dione (M1, 39 mg, 0.13 mmol), KOAc (38 mg, 0.39 mmol), and Pd(dppf)Cl2 (10 mg, 0.01 mmol) were added sequentially. The reaction was carried out at 100 °C for 16 hours under nitrogen protection. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (DCM:MeOH = 20:1) to give 3-(2-chloro-4'-(7'-methyl-2'H,4'-spiro[cyclopropane-1,3'-pyrido[3,2-b][1,4]oxazine]-4'-yl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione (6 mg), with a two-step yield of 12.0%.

[0362] LC-MS (m / z): 474.0 [M+H] + .

[0363] Example 55: Synthesis of 3-(2-chloro-4'-(7'-methoxy-2'H,4'-spiro[cyclopropane-1,3'-pyrido[3,2-b][1,4]oxazine]-4'-yl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (compound 55)

[0364] Step 1: Synthesis of 7'-hydroxy-2'H,4'-spiro[cyclopropane-1,3'-pyrido[3,2-b][1,4]oxazine]-4'-carboxylic acid tert-butyl ester (55-1)

[0365] Compound 54-3 was prepared according to steps 1 to 2 of Example 54.

[0366] 7'-bromo-2'H,4'-spiro[cyclopropane-1,3'-pyrido[3,2-b][1,4]oxazine]-4'-carboxylic acid tert-butyl ester (54-3, 550 mg, 1.62 mmol), potassium hydroxide (545 mg, 9.72 mmol), t-BuBrettphos-PdG3 (150 mg, 0.16 mmol), and Brettphos (90 mg, 0.16 mmol) were added sequentially to the flask. Dioxane (20 mL) and water (1 mL) were then added, and the mixture was heated to 90 °C for 6 hours under nitrogen protection. After the reaction was completed, the reaction solution was cooled to room temperature, acetic acid (1 mL) was added, and the mixture was stirred for 0.2 hours. The reaction mixture was then concentrated under reduced pressure, and the residue was purified by column chromatography (PE:EA = 3:1) to give tert-butyl 7'-hydroxy-2'H,4'-spiro[cyclopropane-1,3'-pyrido[3,2-b][1,4]oxazine]-4'-carboxylic acid (55-1, 100 mg), with a yield of 22.2%.

[0367] LC-MS (m / z): 279.0 [M+H] + .

[0368] Step 2: Synthesis of 7'-methoxy-2'H,4'-spiro[cyclopropane-1,3'-pyrido[3,2-b][1,4]oxazine]-4'-carboxylic acid tert-butyl ester (55-2)

[0369] 7'-hydroxy-2'H,4'-spiro[cyclopropane-1,3'-pyrido[3,2-b][1,4]oxazine]-4'-carboxylic acid tert-butyl ester (55-1, 100 mg, 0.36 mmol) was dissolved in DMF (5 mL), followed by the addition of iodomethane (153 mg, 1.08 mmol) and potassium carbonate (149 mg, 1.08 mmol). The reaction mixture was reacted at room temperature for 16 hours under nitrogen protection. After the reaction was complete, the reaction mixture was diluted with water (10 mL), extracted with EA (10 mL × 3), the organic phases were combined, washed with saturated NaCl (10 mL), dried over anhydrous Na₂SO₄, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA = 5:1) to give tert-butyl 7'-methoxy-2'H,4'-spiro[cyclopropane-1,3'-pyrido[3,2-b][1,4]oxazine]-4'-carboxylic acid (55-2, 100 mg), yield 95.2%.

[0370] LC-MS (m / z): 293.0 [M+H] + .

[0371] Step 3: Synthesis of 7'-methoxy-2'H,4'-spiro[cyclopropane-1,3'-pyrido[3,2-b][1,4]oxazine] (55-3)

[0372] 7'-Methoxy-2'H,4'-spiro[cyclopropane-1,3'-pyrido[3,2-b][1,4]oxazine]-4'-carboxylic acid tert-butyl ester (55-2, 100 mg, 0.34 mmol) was dissolved in DCM (5 mL), and TFA (1 mL) was added to the system. The reaction was carried out at room temperature for 6 hours. The reaction was completely concentrated under reduced pressure to give crude 7'-methoxy-2'H,4'-spiro[cyclopropane-1,3'-pyrido[3,2-b][1,4]oxazine] (55-3, 100 mg).

[0373] LC-MS (m / z): 193.0 [M+H] + .

[0374] Step 4: Synthesis of 4'-(4-bromophenyl)-7'-methoxy-2'H,4'H-spiro[cyclopropane-1,3'-pyrido[3,2-b][1,4]oxazine] (55-4) The product (55-3) obtained in the previous step was dissolved in dioxane (5 mL), and p-bromoiodobenzene (192 mg, 0.57 mmol), Pd2(dba)3 (46 mg, 0.05 mmol), Xantphos (58 mg, 0.10 mmol) and cesium carbonate (512 mg, 1.56 mmol) were added sequentially. The reaction was carried out at 100 °C for 16 hours under nitrogen protection. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (PE:EA = 5:1) to give 4'-(4-bromophenyl)-7'-methoxy-2'H,4'H-spiro[cyclopropane-1,3'-pyrido[3,2-b][1,4]oxazine] (55-4, 80 mg), with a two-step yield of 44.4%.

[0375] LC-MS (m / z): 347.0 [M+H] + .

[0376] Step 5: Synthesis of 7'-methoxy-4'-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)-2'H,4'H-spiro[cyclopropane-1,3'-pyrido[3,2-b][1,4]oxazine] (55-5)

[0377] 4'-(4-bromophenyl)-7'-methoxy-2'H,4'H-spiro[cyclopropane-1,3'-pyrido[3,2-b][1,4]oxazine] (55-4, 80 mg, 0.23 mmol) was dissolved in 1,4-dioxane (5 mL), and then pinacol diboronate (117 mg, 0.46 mmol), KOAc (45 mg, 0.46 mmol), and Pd(dppf)Cl2 (16 mg, 0.02 mmol) were added sequentially. The mixture was heated to 100 °C and reacted for 6 hours under nitrogen protection. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (PE:EA = 3:1) to give 7'-methoxy-4'-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)-2'H,4'H-spiro[cyclopropane-1,3'-pyrido[3,2-b][1,4]oxazine] (55-5,50 mg), yield 54.9%.

[0378] LC-MS (m / z): 395.0 [M+H] + .

[0379] Step 6: Synthesis of 3-(2-chloro-4'-(7'-methoxy-2'H,4'H-spiro[cyclopropane-1,3'-pyrido[3,2-b][1,4]oxazine]-4'-yl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (compound 55)

[0380] 7'-Methoxy-4'-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)-2'H,4'H-spiro[cyclopropane-1,3'-pyrido[3,2-b][1,4]oxazine] (55-5, 50 mg, 0.13 mmol) was dissolved in DMF (5 mL), and 3-(3-bromo-2-chlorophenyl)piperidin-2,6-dione (M1, 39 mg, 0.13 mmol), KOAc (38 mg, 0.39 mmol), and Pd(dppf)Cl2 (10 mg, 0.01 mmol) were added sequentially. The mixture was heated to 100 °C and reacted for 16 hours under nitrogen protection. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (DCM:MeOH = 20:1) to give 3-(2-chloro-4'-(7'-methoxy-2'H,4'-spiro[cyclopropane-1,3'-pyrido[3,2-b][1,4]oxazine]-4'-yl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione (55.6 mg), yield 9.6%.

[0381] LC-MS (m / z): 490.0 [M+H] + .

[0382] Example 60: Synthesis of 3-(2-chloro-4'-(6'H,8'H-spiro[cyclopropane-1,7'-pyrimidino[5,4-b][1,4]oxazine]-8'-yl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (compound 60)

[0383] Step 1: Synthesis of (1-(bromomethyl)cyclopropyl)carbamate tert-butyl ester (60-2)

[0384] tert-butyl (1-hydroxymethylcyclopropyl)carbamate (60-1, 5.0 g, 26.74 mmol) was dissolved in DCM (50 mL), and the mixture was cooled to 0 °C under nitrogen protection. Carbon tetrabromide (11.9 g, 35.95 mmol) and triphenylphosphine (9.5 g, 36.26 mmol) were added to the system, and the mixture was slowly heated to room temperature under nitrogen protection for 24 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA = 10:1) to give tert-butyl (1-(bromomethyl)cyclopropyl)carbamate (60-2, 2.5 g), in 37.6% yield.

[0385] LC-MS (m / z): 250.0, 251.0 [M+H] + .

[0386] Step 2: Synthesis of (1-((4,6-dichloropyrimidin-5-yl)oxy)methyl)cyclopropyl)tert-butyl carbamate (60-3)

[0387] (1-(bromomethyl)cyclopropyl)carbamate tert-butyl ester (60-2, 2.49 g, 10.00 mmol), 4,6-dichloropyrimidin-5-ol (1.64 g, 10.00 mmol), and potassium carbonate (4.1 g, 30.00 mmol) were added sequentially to a flask. DMF (20 mL) was then added, and the mixture was heated to 60 °C under nitrogen protection for 16 hours. After the reaction was complete, the reaction mixture was diluted with water (20 mL), extracted with EA (20 mL × 3), and the combined organic phases were washed with saturated NaCl (20 mL), dried over anhydrous Na₂SO₄, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA = 10:1) to give (1-((4,6-dichloropyrimidin-5-yl)oxy)methyl)cyclopropyl)carbamate tert-butyl ester (60-3, 1.0 g), yield 30.3%.

[0388] LC-MS (m / z): 334.0, 336.0 [M+H] + .

[0389] Step 3: Synthesis of 1-((4,6-dichloropyrimidin-5-yl)oxy)methyl)cyclopropane-1-amine (60-4)

[0390] (60-3, 1.0 g, 3.00 mmol) of tert-butyl (1-((4,6-dichloropyrimidin-5-yl)oxy)methyl)cyclopropyl)carbamate was dissolved in DCM (5 mL), and TFA (1 mL) was added to the system. The reaction was carried out at room temperature for 6 hours. After the reaction was complete, the pH was adjusted to neutral with saturated sodium bicarbonate solution, and the mixture was extracted with DCM (10 mL × 3). The combined organic phases were washed with saturated NaCl (10 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give crude 1-((4,6-dichloropyrimidin-5-yl)oxy)methyl)cyclopropane-1-amine (60-4, 800 mg).

[0391] LC-MS (m / z): 234.0, 236.0 [M+H] + .

[0392] Step 4: Synthesis of 4'-chloro-6'H,8'H-spiro[cyclopropane-1,7'-pyrimidino[5,4-b][1,4]oxazine] (60-5)

[0393] 1-((4,6-dichloropyrimidin-5-yl)oxy)methyl)cyclopropane-1-amine (60-4, 630 mg, 2.70 mmol) was dissolved in 1,4-dioxane (10 mL), and Pd2(dba)3 (247 mg, 0.27 mmol), Xantphos (313 mg, 0.54 mmol), and cesium carbonate (2.66 g, 8.16 mmol) were added sequentially. The mixture was heated to 100 °C for 1 hour under nitrogen protection. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (PE:EA = 3:1) to give 4'-chloro-6'H,8'H-spiro[cyclopropane-1,7'-pyrimidino[5,4-b][1,4]oxazine] (60-5, 300 mg), with a yield of 56.2%.

[0394] LC-MS (m / z): 198.0, 200.0 [M+H] + .

[0395] Step 5: Synthesis of 6'H,8'H-spiro[cyclopropane-1,7'-pyrimido[5,4-b][1,4]oxazine] (60-6)

[0396] 4'-Chloro-6'H,8'H-spiro[cyclopropane-1,7'-pyrimidino[5,4-b][1,4]oxazine] (60-5, 300 mg, 1.52 mmol) was dissolved in EtOH (5 mL), and TEA (1 mL) and 10% Pd / C (30 mg) were added to the system. The reaction was carried out at room temperature for 24 hours. After the reaction was complete, the mixture was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA = 2:1) to give 6'H,8'H-spiro[cyclopropane-1,7'-pyrimidino[5,4-b][1,4]oxazine] (60-6, 160 mg), in a yield of 64.5%.

[0397] LC-MS (m / z): 164.0 [M+H] + .

[0398] Step 6: Synthesis of 8'-(4-bromophenyl)-6'H,8'H-spiro[cyclopropane-1,7'-pyrimidino[5,4-b][1,4]oxazine] (60-7)

[0399] 6'H,8'H-spiro[cyclopropane-1,7'-pyrimidino[5,4-b][1,4]oxazine] (60-6, 65 mg, 0.40 mmol) and p-bromoiodobenzene (226 mg, 0.80 mmol) were dissolved in dioxane (10 mL), and Pd2(dba)3 (37 mg, 0.04 mmol), Xantphos (46 mg, 0.08 mmol), and sodium tert-butoxide (58 mg, 0.60 mmol) were added sequentially. The mixture was heated to 100 °C and reacted for 16 hours under nitrogen protection. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (PE:EA = 1:1) to give 8'-(4-bromophenyl)-6'H,8'H-spiro[cyclopropane-1,7'-pyrimidino[5,4-b][1,4]oxazine] (60-7, 80 mg), with a yield of 63.3%.

[0400] LC-MS (m / z): 318.0 [M+H] + .

[0401] Step 7: Synthesis of 8'-(4-((4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)-6'H,8'H-spiro[cyclopropane-1,7'-pyrimidino[5,4-b][1,4]oxazine](60-8)

[0402] 8'-(4-bromophenyl)-6'H,8'H-spiro[cyclopropane-1,7'-pyrimidino[5,4-b][1,4]oxazine] (60-7, 80 mg, 0.25 mmol), pinacol diboronate (127 mg, 0.50 mmol), KOAc (49 mg, 0.50 mmol), and Pd(dppf)Cl2 (18.0 mg, 0.03 mmol) were added sequentially to the flask, followed by dioxane (10 mL). The mixture was heated to 100 °C under nitrogen protection and reacted for 6 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA = 3:1) to give 8'-(4-((4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)-6'H,8'H-spiro[cyclopropane-1,7'-pyrimidino[5,4-b][1,4]oxazine] (60-8,80 mg), yield 86.9%.

[0403] LC-MS (m / z): 366.0 [M+H] + .

[0404] Step 8: Synthesis of 3-(2-chloro-4'-(6'H,8'H-spiro[cyclopropane-1,7'-pyrimidino[5,4-b][1,4]oxazine]-8'-yl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (compound 60)

[0405] Dissolve 8'-(4-((4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)-6'H,8'H-spiro[cyclopropane-1,7'-pyrimidino[5,4-b][1,4]oxazine] (60-8, 65 mg, 0.18 mmol) in DMF (5 mL), then add 3-(3-bromo-2-chlorophenyl)piperidin-2,6-dione (M1, 49 mg, 0.16 mmol), KOAc (36 mg, 0.36 mmol), and Pd ( The solvent was removed by reducing the pressure of dppf)Cl2 (15 mg, 0.02 mmol) at 100 °C for 16 hours under nitrogen protection. After the reaction, the solvent was removed by reducing the pressure. The residue was purified by column chromatography (DCM:MeOH = 20:1) to give 3-(2-chloro-4'-(6'H,8'H-spiro[cyclopropane-1,7'-pyrimidino[5,4-b][1,4]oxazine]-8'-yl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione (60, 6 mg), yield 7.3%.

[0406] LC-MS (m / z): 461.0 [M+H] + .

[0407] 1H NMR(600MHz,DMSO-d6):10.94(s,1H),8.09(s,1H),8.04(s,1H),7.50(d,J=8.4Hz ,2H),7.44-7.41(m,1H),7.39(s,1H),7.38(s,1H),7.33(d,J=8.4Hz,2H),4.38(dd ,J1=12.0Hz, J2=4.8Hz,1H),4.25(s,2H),2.83-2.77(m,1H),2.61-2.59(m,1H),2 .39-2.32(m,1H),2.07-2.05(m,1H),0.94(m,J=7.2Hz,2H),0.86(m,J=7.2Hz,2H).

[0408] Example 62: Synthesis of 3-(2-chloro-4'-(3'-oxospiro[cyclopropane-1,2'-pyrido[3,2-b][1,4]oxazine]-4'(3'H)-yl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (compound 62)

[0409] Step 1: Synthesis of methyl 1-((2-nitropyridin-3-yl)oxy)cyclopropane-1-carboxylate (62-2)

[0410] 1-Hydroxycyclopropane-1-carboxylic acid methyl ester (2.0 g, 17.2 mmol) was dissolved in THF (30 mL), and sodium hydride (860 mg, 21.5 mmol) was slowly added under ice bath conditions with stirring for 30 min. Then, 3-fluoro-2-nitropyridine (62-1, 2.0 g, 14.3 mmol) was added in portions, and the reaction was allowed to proceed to room temperature for 2 h. After the reaction was complete, methanol was added to quench the reaction, and the mixture was concentrated under reduced pressure to obtain the crude product. The residue was purified by column chromatography (PE:EA = 5:1) to give 1-((2-nitropyridine-3-yl)oxy)cyclopropane-1-carboxylic acid methyl ester (62-2, 3.0 g), with a yield of 88.2%.

[0411] LC-MS (m / z): 239.0 [M+H] + .

[0412] Step 2: Synthesis of spiro[cyclopropane-1,2'-pyrido[3,2-b][1,4]oxazine]-3'(4'H)-one (62-3)

[0413] Methyl 1-((2-nitropyridin-3-yl)oxy)cyclopropane-1-carboxylic acid (62-2, 3.0 g, 12.6 mmol) and iron powder (7.1 g, 126.0 mmol) were dissolved in acetic acid (20 mL). The mixture was heated to 90 °C and reacted for 16 h. After the reaction was completed, the mixture was filtered through diatomaceous earth. The pH of the filtrate was adjusted to 7-8 with saturated sodium bicarbonate solution. The filtrate was extracted with EA (30 mL × 3). The combined organic phases were washed with saturated NaCl (30 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give spiro[cyclopropane-1,2'-pyrido[3,2-b][1,4]oxazine]-3'(4'H)-one (62-3, 1.7 g), with a yield of 76.2%.

[0414] LC-MS (m / z): 177.0 [M+H] + .

[0415] Step 3: Synthesis of 4'-(4-bromophenyl)spiro[cyclopropane-1,2'-pyrido[3,2-b][1,4]oxazine]-3'(4'H)-one (62-4)

[0416] Spiro[cyclopropane-1,2'-pyrido[3,2-b][1,4]oxazine]-3'(4'H)-one (62-3, 1.7 g, 9.65 mmol), p-bromophenylboronic acid (2.3 g, 11.58 mmol), copper acetate (1.7 g, 9.65 mmol), and triethylamine (3.9 g, 28.95 mmol) were added to a DCE (30 mL), and the system was replaced with O2 atmosphere. The reaction was carried out at room temperature for 16 h. After the reaction was completed, the reaction solution was concentrated, and the residue was purified by column chromatography (PE:EA = 3:1) to give 4'-(4-bromophenyl)spiro[cyclopropane-1,2'-pyrido[3,2-b][1,4]oxazine]-3'(4'H)-one (62-4, 260 mg), with a yield of 8.1%.

[0417] LC-MS (m / z): 331.0, 333.0 [M+H] + .

[0418] Step 4: Synthesis of 4'-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)spiro[cyclopropane-1,2'-pyrido[3,2-b][1,4]oxazine]-3'(4'H)-one (62-5)

[0419] 4'-(4-bromophenyl)spiro[cyclopropane-1,2'-pyrido[3,2-b][1,4]oxazine]-3'(4'H)-one (62-4, 200 mg, 0.61 mmol) was dissolved in 1,4-dioxane (10 mL), and then pinacol diboronic acid ester (240 mg, 0.92 mmol), KOAc (180 mg, 1.83 mmol) and Pd(dppf)Cl2 (45 mg, 0.061 mmol) were added sequentially. The mixture was heated to 100 °C and reacted for 2 h under nitrogen protection. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (DCM:MeOH = 20:1) to give 4'-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)spiro[cyclopropane-1,2'-pyrido[3,2-b][1,4]oxazine]-3'(4'H)-one (62-5, 160 mg), yield 69.3%.

[0420] LC-MS (m / z): 379.0 [M+H] + .

[0421] Step 5: Synthesis of 3-(2-chloro-4'-(3'-oxospiro[cyclopropane-1,2'-pyrido[3,2-b][1,4]oxazine]-4'(3'H)-yl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (compound 62)

[0422] 4'-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)spiro[cyclopropane-1,2'-pyrido[3,2-b][1,4]oxazine]-3'(4'H)-one (62-5, 60 mg, 0.159 mmol) was dissolved in DMF (10 mL), and 3-(3-bromo-2-chlorophenyl)piperidin-2,6-dione (M1, 45 mg, 0.16 mmol), KOAc (50 mg, 0.48 mmol), and Pd(dppf)Cl2 (12 mg, 0.02 mmol) were added sequentially. The reaction was carried out at 100 °C for 3 h under nitrogen protection. After the reaction was completed, the mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by column chromatography (DCM:MeOH = 20:1) to give 3-(2-chloro-4'-(3'-oxospiro[cyclopropane-1,2'-pyrido[3,2-b][1,4]oxazine]-4'(3'H)-yl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione (62, 15 mg), yield 20.0%.

[0423] LC-MS (m / z): 474.0 [M+H] + .

[0424] 1H NMR (600MHz, DMSO-d6): δ10.94(s,1H),7.94(dd,J1=4.8Hz,J2=1.2Hz,1H),7.56(d,J=8.4Hz,2H),7.46-7.39(m,6H),7.10(dd,J1=7.8Hz,J2=4.8Hz,1H) ,4.40(dd,J1=12.0Hz,J2=4.8Hz,1H),2.84-2.78(m,1H),2.58-2.54(m,1H), 2.39-2.34(m,1H),2.09-2.06(m,1H),1.45-1.42(m,2H),1.40-1.37(m,2H).

[0425] Example 63: Synthesis of 3-(2-chloro-4'-(spiro[cyclopropane-1,2'-pyrido[3,2-b][1,4]oxazine]-4'(3'H)-yl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (compound 63)

[0426] Step 1: Synthesis of 4'-(4-bromophenyl)-3',4'-dihydrospiro[cyclopropane-1,2'-pyrido[3,2-b][1,4]oxazine] (63-1)

[0427] Compound 62-4 was prepared according to steps 1 to 3 of Example 62.

[0428] 4'-(4-bromophenyl)spiro[cyclopropane-1,2'-pyrido[3,2-b][1,4]oxazine]-3'(4'H)-one (62-5, 150 mg, 0.46 mmol) was dissolved in THF (10 mL), and borane-tetrahydrofuran solution (1 M, 2.3 mL, 2.27 mmol) was slowly added at 0 °C. The mixture was then heated to 60 °C and reacted for 2 h. After the reaction was completed, the temperature was lowered to 0 °C, and MeOH was slowly added to quench the reaction. The mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (DCM:MeOH = 40:1) to give 4'-(4-bromophenyl)-3',4'-dihydrospiro[cyclopropane-1,2'-pyrido[3,2-b][1,4]oxazine] (63-1, 120 mg), with a yield of 83.3%.

[0429] LC-MS (m / z): 317.0, 319.0 [M+H] + .

[0430] Step 2: Synthesis of 4'-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)-3',4'-dihydrospiro[cyclopropane-1,2'-pyrido[3,2-b][1,4]oxazine](63-2)

[0431] 4'-(4-bromophenyl)-3',4'-dihydrospiro[cyclopropane-1,2'-pyrido[3,2-b][1,4]oxazine] (63-1, 120 mg, 0.38 mmol) was dissolved in 1,4-dioxane (10 mL), and then pinacol diboronic acid ester (150 mg, 0.57 mmol), KOAc (120 mg, 1.14 mmol) and Pd(dppf)Cl2 (30 mg, 0.04 mmol) were added sequentially. The mixture was heated to 100 °C and reacted for 2 h under nitrogen protection. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (DCM:MeOH = 20:1) to give 4'-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)-3',4'-dihydrospiro[cyclopropane-1,2'-pyrido[3,2-b][1,4]oxazine] (63-2,70 mg), yield 50.7%.

[0432] LC-MS (m / z): 365.0 [M+H] + .

[0433] Step 3: Synthesis of 3-(2-chloro-4'-(spiro[cyclopropane-1,2'-pyrido[3,2-b][1,4]oxazine]-4'(3'H)-yl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (compound 63)

[0434] 4'-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)-3',4'-dihydrospiro[cyclopropane-1,2'-pyrido[3,2-b][1,4]oxazine] (63-2, 70 mg, 0.19 mmol) was dissolved in DMF (5 mL), and 3-(3-bromo-2-chlorophenyl)piperidin-2,6-dione (M1, 60 mg, 0.19 mmol), KOAc (56 mg, 0.57 mmol), and Pd(dppf)Cl2 (14 mg, 0.02 mmol) were added sequentially. The mixture was heated to 100 °C and reacted for 3 h under nitrogen protection. After the reaction was completed, the mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by column chromatography (DCM:MeOH = 20:1) to give 3-(2-chloro-4'-(spiro[cyclopropane-1,2'-pyrido[3,2-b][1,4]oxazine]-4'(3'H)-yl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione (63, 7.5 mg), yield 8.6%.

[0435] LC-MS (m / z): 460.0 [M+H] + .

[0436] 1H NMR (600MHz, DMSO-d6): δ10.93 (s, 1H), 7.71 (dd, J1 = 4.8Hz, J2 = 1.8Hz, 1H), 7.52 (d, J = 9.0Hz, 2H),7.41-7.39(m,3H),7.36-7.33(m,2H),7.10(dd,J1=7.8Hz,J2=1.8Hz,1H),6.75(dd,J1=7 .8Hz,J2=4.8Hz,1H),4.37(dd,J1=12.6Hz,J2=5.4Hz,1H),3.94(s,2H),2.82-2.77(m,1H),2. 57-2.54(m,1H),2.39-2.32(m,1H),2.08-2.04(m,1H),1.02-0.99(m,2H),0.89-0.86(m,2H).

[0437] Example 64: Synthesis of 3-(2-chloro-4'-(2'-oxospiro[cyclopropane-1,3'-pyrido[2,3-b][1,4]oxazine]-1'(2'H)-yl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (compound 64)

[0438] Step 1: Synthesis of methyl 1-((3-nitropyridin-2-yl)oxy)cyclopropane-1-carboxylate (64-2)

[0439] 1-Hydroxycyclopropane-1-carboxylic acid methyl ester (800 mg, 6.89 mmol) was dissolved in THF (10 mL), and sodium hydride (338 mg, 8.45 mmol) was slowly added under ice bath conditions with stirring for 30 min. Then, 2-fluoro-3-nitropyridine (64-1, 800 mg, 5.63 mmol) was added in portions, and the reaction was allowed to proceed to room temperature for 2 h. After the reaction was complete, methanol was added to quench the reaction, and the mixture was concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA = 5:1) to give 1-((3-nitropyridine-2-yl)oxy)cyclopropane-1-carboxylic acid methyl ester (64-2, 900 mg), with a yield of 66.9%.

[0440] LC-MS (m / z): 239.0 [M+H] + .

[0441] Step 2: Synthesis of spiro[cyclopropane-1,3'-pyrido[2,3-b][1,4]oxazine]-2'(1'H)-one (64-3)

[0442] Methyl 1-((3-nitropyridin-2-yl)oxy)cyclopropane-1-carboxylic acid (64-2, 900 mg, 3.77 mmol) and iron powder (2.1 g, 37.66 mmol) were dissolved in acetic acid (20 mL). The mixture was heated to 90 °C and reacted for 16 h. After the reaction was completed, the mixture was filtered through diatomaceous earth, and the pH was adjusted to 7-8 by adding saturated sodium bicarbonate. The mixture was extracted with EA (30 mL × 3). The combined organic phases were washed with saturated NaCl (30 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give spiro[cyclopropane-1,3'-pyrido[2,3-b][1,4]oxazine]-2'(1'H)-one (64-3, 400 mg), with a yield of 60.0%.

[0443] LC-MS (m / z): 177.0 [M+H] + .

[0444] Step 3: Synthesis of 4'-(4-bromophenyl)spiro[cyclopropane-1,3'-pyrido[3,2-b][1,4]oxazine]-2'(1'H)-one (64-4)

[0445] Spiro[cyclopropane-1,3'-pyrido[2,3-b][1,4]oxazine]-2'(1'H)-one (64-3, 400 mg, 2.27 mmol), p-bromophenylboronic acid (682 mg, 3.41 mmol), copper acetate (413 mg, 2.27 mmol), and triethylamine (687 mg, 6.81 mmol) were added to a DCE (30 mL), and the system was replaced with O2 atmosphere. The reaction was carried out at room temperature for 16 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography (PE:EA = 3:1) to give 4'-(4-bromophenyl)spiro[cyclopropane-1,3'-pyrido[3,2-b][1,4]oxazine]-2'(1'H)-one (64-4, 600 mg), with a yield of 88.1%.

[0446] LC-MS (m / z): 331.0, 333.0 [M+H] + .

[0447] Step 4: Synthesis of 1'-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)spiro[cyclopropane-1,3'-pyrido[2,3-b][1,4]oxazine]-2'(1'H)-one (64-5)

[0448] 4'-(4-bromophenyl)spiro[cyclopropane-1,3'-pyrido[3,2-b][1,4]oxazine]-2'(1'H)-one (64-4, 200 mg, 0.61 mmol) was dissolved in 1,4-dioxane (10 mL), and then pinacol diboronic acid ester (240 mg, 0.92 mmol), KOAc (180 mg, 1.83 mmol) and Pd(dppf)Cl2 (45 mg, 0.06 mmol) were added sequentially. The mixture was reacted at 100 °C for 2 h under nitrogen protection. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (DCM:MeOH = 20:1) to give 4'-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)spiro[cyclopropane-1,3'-pyrido[2,3-b][1,4]oxazine]-2'(1'H)-one (64-5, 250 mg), yield 99.0%.

[0449] LC-MS (m / z): 379.0 [M+H] + .

[0450] Step 5: Synthesis of 3-(2-chloro-4'-(2'-oxospiro[cyclopropane-1,3'-pyrido[2,3-b][1,4]oxazine]-1'(2'H)-yl)[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (compound 64)

[0451] 4'-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)spiro[cyclopropane-1,3'-pyrido[2,3-b][1,4]oxazine]-2'(1'H)-one (64-5, 220 mg, 0.58 mmol) was dissolved in DMF (10 mL), and 3-(3-bromo-2-chlorophenyl)piperidin-2,6-dione (M1, 176 mg, 0.58 mmol), KOAc (171 mg, 1.75 mmol), and Pd(dppf)Cl2 (42 mg, 0.06 mmol) were added sequentially. The reaction was carried out at 100 °C for 3 h under nitrogen protection. After the reaction was completed, the mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by column chromatography (DCM:MeOH = 20:1) to give 3-(2-chloro-4'-(2'-oxospiro[cyclopropane-1,3'-pyrido[2,3-b][1,4]oxazine]-1'(2'H)-yl)[1,1'-biphenyl]-3-yl)piperidin-2,6-dione (64,60 mg), yield 21.8%.

[0452] LC-MS (m / z): 474.0 [M+H] + .

[0453] 1H NMR (600MHz, DMSO-d6): δ10.95 (s, 1H), 7.90 (dd, J1 = 4.8Hz, J2 = 1.8Hz, 1H), 7.64 (d, J = 8.4Hz, 2H),7.52(dd,J1=6.6Hz,J2=2.4Hz,2H),7.45-7.41(m,3H),7.09(dd,J1=7.8Hz,J2=4.8Hz,1H) ,6.79(dd,J1=7.8Hz,J2=1.8Hz,1H),4.40(dd,J1=12.6Hz,J2=5.4Hz,1H),2.83-2.78(m,1H),2 .57-2.54(m,1H),2.37-2.34(m,1H),2.10-2.05(m,1H),1.47-1.45(m,2H),1.43-1.40(m,2H).

[0454] Example 67: Synthesis of 3-(2-chloro-4'-(7'-oxo-5'H-spiro[cyclopropane-1,6'-imidazo[1,2-a]pyrimidine]-8'(7'H)-yl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (compound 67)

[0455] Step 1: Synthesis of ethyl 1-(chloromethyl)cyclopropane-1-carboxylate (67-2)

[0456] Ethyl 1-(hydroxymethyl)cyclopropane-1-carboxylate (67-1, 5.0 g, 34.72 mmol) was dissolved in DCM (50 mL), and the mixture was cooled to 0 °C under nitrogen protection. Thionyl chloride (5.0 mL) was added to the system, and the mixture was slowly restored to room temperature. The reaction was allowed to proceed for 24 hours. After the reaction was complete, the mixture was concentrated under reduced pressure to give ethyl 1-(chloromethyl)cyclopropane-1-carboxylate (67-2, 5.0 g), with a yield of 88.9%.

[0457] LC-MS (m / z): 163.0, 165.0 [M+H] + .

[0458] Step 2: Synthesis of ethyl 1-((2-nitro-1H-imidazol-1-yl)methyl)cyclopropane-1-carboxylate (67-3)

[0459] Ethyl 1-(chloromethyl)cyclopropane-1-carboxylate (67-2, 1.5 g, 9.26 mmol) was dissolved in DMF (20 mL), and 2-nitro-1H-imidazole (1.26 g, 11.11 mmol) and potassium carbonate (2.56 g, 18.52 mmol) were added at room temperature. The mixture was heated to 70 °C and reacted for 24 h. After the reaction was complete, the mixture was diluted with water (20 mL), extracted with EA (20 mL × 3), and the organic phases were combined, washed with saturated NaCl (20 mL), dried over anhydrous Na₂SO₄, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA = 10:1) to give ethyl 1-((2-nitro-1H-imidazole-1-yl)methyl)cyclopropane-1-carboxylate (67-3, 600 mg), with a yield of 27.3%.

[0460] LC-MS (m / z): 240.0 [M+H] + .

[0461] Step 3: Synthesis of ethyl 1-((2-amino-1H-imidazol-1-yl)methyl)cyclopropane-1-carboxylate (67-4)

[0462] Ethyl 1-((2-nitro-1H-imidazol-1-yl)methyl)cyclopropane-1-carboxylate (67-3, 239 mg, 1.00 mmol) was dissolved in AcOH (10 mL), and iron powder (560 mg, 10.00 mmol) was added under ice bath conditions. The mixture was heated to 90 °C and reacted for 0.5 h. After the reaction was complete, the mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain crude ethyl 1-((2-amino-1H-imidazol-1-yl)methyl)cyclopropane-1-carboxylate (67-4, 210 mg).

[0463] LC-MS (m / z): 210.0 [M+H] + .

[0464] Step 4: Synthesis of 5'H-spiro[cyclopropane-1,6'-imidazo[1,2-a]pyrimidine]-7'(8'H)-one (67-5)

[0465] The crude ethyl 1-((2-amino-1H-imidazol-1-yl)methyl)cyclopropane-1-carboxylate (67-4) obtained in the previous step was dissolved in toluene (5 mL) and acetic acid (5 mL), and reacted at 120 °C for 16 hours under nitrogen protection. After the reaction was completed, the mixture was concentrated under reduced pressure, diluted with water (10 mL), and the pH was adjusted to 7 with saturated NaHCO3 aqueous solution. The mixture was extracted with EA (20 mL × 3), the organic phases were combined, washed with saturated NaCl (20 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to obtain crude 5'H-spiro[cyclopropane-1,6'-imidazo[1,2-a]pyrimidine]-7'(8'H)-one (67-5, 220 mg).

[0466] LC-MS (m / z): 164.0 [M+H] + .

[0467] Step 5: Synthesis of 8'-(4-bromophenyl)-5'H-spiro[cyclopropane-1,6'-imidazo[1,2-a]pyrimidine]-7'(8'H)-one (67-6)

[0468] The crude product (67-5) obtained in the previous step was dissolved in DMF (10 mL), and p-bromoiodobenzene (582 mg, 2.02 mmol), CuI (51 mg, 0.27 mmol), and DBU (410 mg, 2.70 mmol) were added sequentially. The mixture was heated to 120 °C and reacted for 16 hours under nitrogen protection. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (PE:EA = 3:1) to give 8'-(4-bromophenyl)-5'H-spiro[cyclopropane-1,6'-imidazo[1,2-a]pyrimidine]-7'(8'H)-one (67-6, 55 mg), with a three-step yield of 17.4%.

[0469] LC-MS (m / z): 318.0, 320.0 [M+H] + .

[0470] Step 6: Synthesis of 8'-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborphanecyclopentan-2-yl)phenyl)-5'H-spiro[cyclopropane-1,6'-imidazo[1,2-a]pyrimidine]-7'(8'H)-one (67-7)

[0471] 8'-(4-bromophenyl)-5'H-spiro[cyclopropane-1,6'-imidazo[1,2-a]pyrimidine]-7'(8'H)-one (67-6, 55 mg, 0.17 mmol), pinacol diboronic acid ester (88 mg, 0.34 mmol), KOAc (33 mg, 0.34 mmol) and Pd(dppf)Cl2 (12 mg, 0.02 mmol) were added to the flask in sequence, followed by dioxane (5 mL). The system was heated to 100 °C and reacted for 6 hours under nitrogen protection. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (PE:EA = 3:1) to give 8'-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborphanecyclopentan-2-yl)phenyl)-5'H-spiro[cyclopropane-1,6'-imidazo[1,2-a]pyrimidine]-7'(8'H)-one (67-7, 55 mg), yield 86.6%.

[0472] LC-MS (m / z): 366.0 [M+H] + .

[0473] Step 7: Synthesis of 3-(2-chloro-4'-(7'-oxo-5'H-spiro[cyclopropane-1,6'-imidazo[1,2-a]pyrimidine]-8'(7'H)-yl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (compound 67)

[0474] 8'-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborphanecyclopentan-2-yl)phenyl)-5'H-spiro[cyclopropane-1,6'-imidazo[1,2-a]pyrimidine]-7'(8'H)-one (67-7, 20 mg, 0.05 mmol) was dissolved in DMF (2 mL), and 3-(3-bromo-2-chlorophenyl)piperidin-2,6-dione (M1, 14 mg, 0.05 mmol), KOAc (10 mg, 0.10 mmol), and Pd(dppf)Cl2 (4 mg, 0.005 mmol) were added sequentially. The system was heated to 100 °C and reacted for 16 hours under nitrogen protection. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (DCM:MeOH = 20:1) to give 3-(2-chloro-4'-(7'-oxo-5'H-spiro[cyclopropane-1,6'-imidazo[1,2-a]pyrimidine]-8'(7'H)-yl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione (67.6 mg), yield 26.1%.

[0475] LC-MS (m / z): 461.0 [M+H] + .

[0476] 1 H NMR(600MHz,DMSO-d6):10.94(s,1H),7.66(d,J=1.8Hz,1H),7.50(d,J=8.4 Hz,2H),7.43(d,J=7.2Hz,1H),7.41-7.38(m,4H),6.91(d,J=1.8Hz,1H),4. 57(s,2H),4.37-4.35(m,1H),2.83-2.77(m,1H),2.62-2.56(m,1H),2.37-2 .31(m,1H),2.08-2.04(m,1H),1.05(t,J=7.2Hz,2H),0.76(t,J=6.0Hz,2H).

[0477] Example 69: Synthesis of 3-(2-chloro-4'-(4'-oxo-7'H-spiro[cyclopropane-1,6'-pyrazolo[1,5-a]pyrazine]-5'(4'H)-yl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (compound 69)

[0478] Step 1: Synthesis of methyl 1-((1-((tert-Butoxycarbonyl)amino)cyclopropyl)methyl)-1H-pyrazole-5-carboxylic acid (69-2)

[0479] 1H-pyrazole-5-carboxylic acid methyl ester (69-1, 3.0 g, 3.81 mmol) and tert-butyl(1-hydroxymethylcyclopropyl)carbamate (4.9 g, 26.19 mmol) pyridine were dissolved in THF (50 mL). Triphenylphosphine (15.6 g, 59.53 mmol) was added under nitrogen protection. The system was then protected with nitrogen, and DIAD (12.0 g, 59.53 mmol) was added dropwise in an ice bath. The mixture was slowly brought to room temperature and reacted for 16 hours. After the reaction was complete, the mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (PE:EA = 5:1) to give 1-((1-((tert-butyloxycarbonyl)amino)cyclopropyl)methyl)-1H-pyrazole-5-carboxylic acid methyl ester (69-2, 5.0 g), yield 71.0%.

[0480] LC-MS (m / z): 296.0 [M+H] + .

[0481] Step 2: Synthesis of methyl 1-((1-aminocyclopropyl)methyl)-1H-pyrazole-5-carboxylate (69-3)

[0482] Methyl 1-((1-((tert-Butoxycarbonyl)amino)cyclopropyl)methyl)-1H-pyrazole-5-carboxylic acid (69-2, 5.0 g, 16.89 mmol) was dissolved in DCM (25 mL), and TFA (5 mL) was added to the system. The reaction was carried out at room temperature for 16 hours. After the reaction was completed, the solution was concentrated under reduced pressure to obtain crude methyl 1-((1-aminocyclopropyl)methyl)-1H-pyrazole-5-carboxylic acid (69-3, 3.2 g).

[0483] LC-MS (m / z): 196.0 [M+H] + .

[0484] Step 3: Synthesis of 7'H-spiro[cyclopropane-1,6'-pyrazolo[1,5-a]pyrazine]-4'(5'H)-one (69-4)

[0485] The crude product (69-3, 1.9 g) obtained in the previous step was dissolved in methanol (20 mL), and triethylamine (4 mL) was added. The reaction was carried out at 80 °C for 16 hours under nitrogen protection. After the reaction was completed, the product was concentrated under reduced pressure, and the residue was purified by column chromatography (PE:EA = 5:1) to give 7'H-spiro[cyclopropane-1,6'-pyrazolo[1,5-a]pyrazine]-4'(5'H)-one (69-4, 1.0 g), with a two-step yield of 61.0%.

[0486] LC-MS (m / z): 164.0 [M+H] + .

[0487] Step 4: Synthesis of 5'-(4-bromophenyl)-7'H-spiro[cyclopropane-1,6'-pyrazolo[1,5-a]pyrazine]-4'(5'H)-one (69-5)

[0488] 7'H-spiro[cyclopropane-1,6'-pyrazolo[1,5-a]pyrazine]-4'(5'H)-one (69-4, 400 mg, 2.45 mmol) dissolved in DMF (10 mL) was added sequentially to a flask. Then, p-bromoiodobenzene (1.06 g, 3.68 mmol), CuI (90 mg, 0.49 mmol), and DBU (745 mg, 4.90 mmol) were added sequentially. The mixture was heated to 120 °C under nitrogen protection and reacted for 16 hours. After the reaction was complete, the mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (PE:EA = 5:1) to give 5'-(4-bromophenyl)-7'H-spiro[cyclopropane-1,6'-pyrazolo[1,5-a]pyrazine]-4'(5'H)-one (69-5, 180 mg), with a yield of 23.1%.

[0489] LC-MS (m / z): 318.0, 320.0 [M+H] + .

[0490] Step 5: Synthesis of 5'-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborphane-2-yl)phenyl)-7'H-spiro[cyclopropane-1,6'-pyrazolo[1,5-a]pyrazine]-4'(5'H)-one (69-6)

[0491] 5'-(4-bromophenyl)-7'H-spiro[cyclopropane-1,6'-pyrazolo[1,5-a]pyrazine]-4'(5'H)-one (69-5, 160 mg, 0.50 mmol), pinacol diboronic acid ester (254 mg, 1.00 mmol), KOAc (98 mg, 1.00 mmol) and Pd(dppf)Cl2 (37 mg, 0.05 mmol) were added sequentially to the flask, followed by dioxane (10 mL). The mixture was reacted at 100 °C for 6 hours under nitrogen protection. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (PE:EA = 3:1) to give 5'-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborphanecyclopentan-2-yl)phenyl)-7'H-spiro[cyclopropane-1,6'-pyrazolo[1,5-a]pyrazine]-4'(5'H)-one (69-6, 120 mg), yield 65.1%.

[0492] LC-MS (m / z): 366.0 [M+H] +.

[0493] Step 6: Synthesis of 3-(2-chloro-4'-(4'-oxo-7'H-spiro[cyclopropane-1,6'-pyrazolo[1,5-a]pyrazine]-5'(4'H)-yl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (69)

[0494] 5'-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborphanecyclopentan-2-yl)phenyl)-7'H-spiro[cyclopropane-1,6'-pyrazolo[1,5-a]pyrazine]-4'(5'H)-one (69-6, 120 mg, 0.33 mmol) was dissolved in DMF (5 mL), and 3-(3-bromo-2-chlorophenyl)piperidin-2,6-dione (M1, 93 mg, 0.30 mmol), KOAc (65 mg, 0.66 mmol), and Pd(dppf)Cl2 (24 mg, 0.03 mmol) were added sequentially. The reaction was carried out at 100 °C for 16 hours under nitrogen protection. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (DCM:MeOH = 20:1) to give 3-(2-chloro-4'-(4'-oxo-7'H-spiro[cyclopropane-1,6'-pyrazolo[1,5-a]pyrazine]-5'(4'H)-yl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione (69, 26 mg), yield 17.2%.

[0495] LC-MS (m / z): 461.0 [M+H] + .

[0496] 1 H NMR(600MHz,DMSO-d6):10.94(s,1H),7.66(d,J=1.8Hz,1H),7.50(d,J=8.4H z,2H),7.44-7.41(m,1H),7.40-7.36(m,4H),6.91(d,J=1.8Hz,1H),4.57(s,2 H),4.38(dd,J1=12.6Hz,J2=5.4Hz,1H),2.85-2.76(m,1H),2.62-2.53(m,1H) ,2.39-2.31(m,1H),2.08-2.04(m,1H),1.06-1.01(m,2H),0.78-0.71(m,2H).

[0497] Example 72: Synthesis of 4'-(2'-chloro-3'-(2,6-dioxopiperidin-3-yl)-[1,1'-biphenyl]-4-yl)-2'H,4'-spiro[cyclobutane-1,3'-pyrido[3,2-b][1,4]oxazine]-7'-nitrile (compound 72)

[0498] Step 1: Synthesis of (1-(((5-bromo-2-iodopyridin-3-yl)oxy)methyl)cyclobutyl)carbamate tert-butyl ester (72-2)

[0499] 5-Bromo-2-iodopyridin-3-ol (1.2 g, 4.00 mmol) was dissolved in toluene (12 mL), and tert-butyl (1-(hydroxymethyl)cyclobutyl)carbamate (72-1, 1210 mg, 6.00 mmol) and CMBP (1930 mg, 8.00 mmol) were added. The mixture was heated to 110 °C under N2 atmosphere for 48 h. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE / EA = 9:1) to give tert-butyl (1-(((5-bromo-2-iodopyridin-3-yl)oxy)methyl)cyclobutyl)carbamate (72-2, 366 mg), yield 18.6%.

[0500] LC-MS (m / z): 483.0, 485.0 [M+H] + .

[0501] Step 2: Synthesis of 7'-bromo-2'H,4'H-spiro[cyclobutane-1,3'-pyrido[3,2-b][1,4]oxazine]-4'-carboxylic acid tert-butyl ester (72-3)

[0502] (1-(((5-bromo-2-iodopyridin-3-yl)oxy)methyl)cyclobutyl)carbamate tert-butyl ester (72-2, 366 mg, 0.76 mmol) was dissolved in dioxane (5 mL), and cuprous iodide (15 mg, 0.08 mmol), L-proline (18 mg, 0.16 mmol), and sodium tert-butoxide (109 mg, 1.14 mmol) were added. The mixture was then microwaved at 100 °C for 1 h. After the reaction was complete, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE / EA = 10:1) to give 7'-bromo-2'H,4'H-spiro[cyclobutane-1,3'-pyrido[3,2-b][1,4]oxazine]-4'-carboxylic acid tert-butyl ester (72-3, 167 mg), with a yield of 62.1%.

[0503] LC-MS (m / z): 355.0, 357.0 [M+H] + .

[0504] Step 3: Synthesis of 2'H,4'H-spiro[cyclobutane-1,3'-pyrido[3,2-b][1,4]oxazine]-7'-nitrile (72-4)

[0505] 7'-bromo-2'H,4'H-spiro[cyclobutane-1,3'-pyrido[3,2-b][1,4]oxazine]-4'-carboxylic acid tert-butyl ester (72-3, 248 mg, 0.70 mmol) was dissolved in DMAC (3 mL), and zinc cyanide (49 mg, 0.42 mmol), zinc powder (5 mg, 0.08 mmol), Pd2(dba)3 (37 mg, 0.04 mmol) and dppf (46 mg, 0.08 mmol) were added. The mixture was heated to 150 °C under N2 environment and reacted for 8 h. After the reaction was complete, 10 mL of water was added, and the mixture was extracted with ethyl acetate (10 mL × 3), dried, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA = 2:1) to give 2'H,4'H-spiro[cyclobutane-1,3'-pyrido[3,2-b][1,4]oxazine]-7'-nitrile (72-4, 125 mg), with a yield of 89.0%.

[0506] LC-MS (m / z): 202.0 [M+H] + .

[0507] Step 4: Synthesis of 4-(4-bromophenyl)-2H,4H-spiro[benzo[b][1,4]oxazine-3,1'-cyclobutane]-7-nitrile (72-5)

[0508] 2'H,4'H-spiro[cyclobutane-1,3'-pyrido[3,2-b][1,4]oxazine]-7'-onitrile (72-4, 90 mg, 0.45 mmol) was dissolved in toluene (5 mL), and p-bromoiodobenzene (152 mg, 0.54 mmol), sodium tert-butoxide (86 mg, 0.89 mmol), Pd2(dba)3 (46 mg, 0.05 mmol), and Xantphos (58 mg, 0.10 mmol) were added. The mixture was heated to 100 °C for 12 h under N2 atmosphere. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE / EA = 9:1) to give 4-(4-bromophenyl)-2H,4H-spiro[benzo[b][1,4]oxazine-3,1'-cyclobutane]-7-onitrile (72-5, 100 mg), yield 62.7%.

[0509] LC-MS (m / z): 355.0 [M+H] + .

[0510] Step 5: Synthesis of 4'-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)-2'H,4'H-spiro[cyclobutane-1,3'-pyrido[3,2-b][1,4]oxazine]-7'-nitrile (72-6)

[0511] 4-(4-bromophenyl)-2H,4H-spiro[benzo[b][1,4]oxazine-3,1'-cyclobutane]-7-onitrile (72-5, 100 mg, 0.28 mmol) was dissolved in dioxane (5 mL), and pinacol diboronic acid ester (107 mg, 0.42 mmol), potassium acetate (55 mg, 0.56 mmol) and Pd(dppf)Cl2 (22 mg, 0.03 mmol) were added. The mixture was heated to 100 °C for 2 h under N2 atmosphere. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE / EA = 10:1) to give 4'-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)-2'H,4'H-spiro[cyclobutane-1,3'-pyrido[3,2-b][1,4]oxazine]-7'-nitrile (72-6,65 mg), yield 22.9%.

[0512] LC-MS (m / z): 404.0 [M+H] + .

[0513] Step 6: Synthesis of 4'-(2'-chloro-3'-(2,6-dioxopiperidin-3-yl)-[1,1'-biphenyl]-4-yl)-2'H,4'H-spiro[cyclobutane-1,3'-pyrido[3,2-b][1,4]oxazine]-7'-nitrile (compound 72)

[0514] 3-(3-bromo-2-chlorophenyl)piperidin-2,6-dione (M1, 17 mg, 0.06 mmol) was dissolved in DMF (2 mL), and 4'-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborin-2-yl)phenyl)-2'H,4'H-spiro[cyclobutane-1,3'-pyrido[3,2-b][1,4]oxazine]-7'-nitrile (72-6, 26 mg, 0.06 mmol), Pd(dppf)Cl2 (7 mg, 0.01 mmol) and potassium acetate (19 mg, 0.79 mmol) were added. The mixture was heated to 100 °C for 5 h under N2 atmosphere. After the reaction was completed, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (DCM / MeOH = 20:1) and preparative liquid chromatography to give 4'-(2'-chloro-3'-(2,6-dioxopiridine-3-yl)-[1,1'-biphenyl]-4-yl)-2'H,4'H-spiro[cyclobutane-1,3'-pyrido[3,2-b][1,4]oxazine]-7'-nitrile (72,18 mg), yield 55.9%.

[0515] LC-MS (m / z): 499.0 [M+H] + .

[0516] 1H NMR (600MHz, DMSO-d6): δ10.95 (s, 1H), 8.01 (d, J = 1.8Hz, 1H), 7.57-7.54 (m, 3H), 7 .45-7.41(m,2H),7.40-7.39(m,1H),7.33(d,J=8.4Hz,1H),4.40(s,2H),4.39-4.37 (m,1H),2.84-2.78(m,1H),2.62-2.53(m,1H),2.39-2.34(m,1H),2.21-2.16(m,2H ),2.09-2.06(m,1H),2.01-1.97(m,2H),1.84-1.79(m,1H),1.57(d,J=10.2Hz,1H).

[0517] Example 74: Synthesis of 3-(2-chloro-4'-(5'-methyl-6'-oxo-5',6'-dihydro-8'H-spiro[cyclopropane-1,7'-pteridine]-8'-yl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (compound 74)

[0518] Step 1: Synthesis of methyl 1-((tert-butoxycarbonyl)(4-methoxybenzyl)amino)cyclopropane-1-carboxylate (74-2)

[0519] Methyl 1-((tert-Butoxycarbonyl)amino)cyclopropane-1-carboxylate (74-1, 5 g, 23.23 mmol) was dissolved in DMF (120 mL), and NaH (1.39 g, 34.84 mmol) was added under ice bath conditions. After reacting for 0.5 h, PMBCl (5.46 g, 34.84 mmol) was added, and the reaction was carried out at room temperature for 16 h. After the reaction was completed, 400 mL of water was added, and the mixture was extracted with EA (50 mL × 3). The organic phases were combined, washed with saturated brine (50 mL × 3), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA = 9:1) to give methyl 1-((tert-Butoxycarbonyl)(4-methoxybenzyl)amino)cyclopropane-1-carboxylate (74-2, 13.1 g), with a yield of 84.1%.

[0520] LC-MS (m / z): 336.0 [M+H] + .

[0521] Step 2: Synthesis of methyl 1-((4-methoxybenzyl)amino)cyclopropane-1-carboxylate hydrochloride (74-3)

[0522] Methyl 1-((tert-butoxycarbonyl)(4-methoxybenzyl)amino)cyclopropane-1-carboxylate (74-2, 13.1 g, 39.06 mmol) was dissolved in EA (40 mL) saturated with hydrogen chloride and reacted at room temperature for 16 h. After the reaction was completed, the solution was concentrated under reduced pressure to give methyl 1-((4-methoxybenzyl)amino)cyclopropane-1-carboxylate hydrochloride (74-3, 10 g), in 87.5% yield.

[0523] LC-MS (m / z): 236.0 [M+H] + .

[0524] Step 3: Synthesis of methyl 1-((2-chloro-5-nitropyrimidin-4-yl)(4-methoxybenzyl)amino)cyclopropane-1-carboxylate (74-4)

[0525] 1-((4-methoxybenzyl)amino)cyclopropane-1-carboxylate hydrochloride (74-3, 2.71 g, 9.97 mmol) was dissolved in DCM (40 mL), and potassium bicarbonate (2 g, 19.95 mmol) and 2,4-dichloro-5-nitropyrimidine (1.93 g, 9.97 mmol) were added. The reaction was carried out at room temperature for 16 h. After the reaction was completed, the mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by pulping (PE:EA = 10:1) to give 1-((2-chloro-5-nitropyrimidine-4-yl)(4-methoxybenzyl)amino)cyclopropane-1-carboxylate (74-4, 3.5 g), with a yield of 89.3%.

[0526] LC-MS (m / z): 393.0, 395.0 [M+H] + .

[0527] Step 4: Synthesis of 2'-chloro-8'-(4-methoxybenzyl)-5',8'-dihydro-6'H-spiro[cyclopropane-1,7'-pteridine]-6'-one (74-5)

[0528] Methyl 1-((2-chloro-5-nitropyrimidin-4-yl)(4-methoxybenzyl)amino)cyclopropane-1-carboxylate (74-4, 1.7 g, 4.33 mmol) was dissolved in acetic acid (12 mL), and Fe powder (2.42 g, 43.28 mmol) was added. The mixture was heated to 90 °C and reacted for 1.5 h. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was extracted with 100 mL of water using EA (30 mL × 3). The organic phases were combined and concentrated under reduced pressure to give 2'-chloro-8'-(4-methoxybenzyl)-5',8'-dihydro-6'H-spiro[cyclopropane-1,7'-pteridine]-6'-one (74-5, 1.3 g), with a yield of 90.8%.

[0529] LC-MS (m / z): 331.0, 333.0 [M+H]+ .

[0530] Step 5: Synthesis of 2'-chloro-8'-(4-methoxybenzyl)-5'-methyl-5',8'-dihydro-6'H-spiro[cyclopropane-1,7'-pteridine]-6'-one (74-6)

[0531] 2'-Chloro-8'-(4-methoxybenzyl)-5',8'-dihydro-6'H-spiro[cyclopropane-1,7'-pteridine]-6'-one (74-5, 1.3 g, 3.93 mmol) was dissolved in DMF (13 mL), and Cs2CO3 (2.56 g, 7.86 mmol) and iodomethane (1.12 g, 7.86 mmol) were added. The mixture was reacted at room temperature for 3 h. After the reaction was complete, 50 mL of water was added, and the mixture was extracted with EA (15 mL × 3). The extract was dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA = 1:1) to give 2'-chloro-8'-(4-methoxybenzyl)-5'-methyl-5',8'-dihydro-6'H-spiro[cyclopropane-1,7'-pteridine]-6'-one (74-6, 1.0 g), with a yield of 73.8%.

[0532] LC-MS (m / z): 345.0, 347.0 [M+H] + .

[0533] Step 6: Synthesis of 8'-(4-methoxybenzyl)-5'-methyl-5',8'-dihydro-6'H-spiro[cyclopropane-1,7'-pteridine]-6'-one (74-7)

[0534] 2'-Chloro-8'-(4-methoxybenzyl)-5'-methyl-5',8'-dihydro-6'H-spiro[cyclopropane-1,7'-pteridine]-6'-one (74-6, 1 g, 2.90 mmol) was dissolved in EtOH (10 mL) and triethylamine (5 mL), and 10% Pd / C (500 mg) was added. The system was purged under a hydrogen atmosphere, and the reaction was carried out at room temperature for 16 h. After the reaction was completed, the mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (DCM:MeOH = 20:1) to give 8'-(4-methoxybenzyl)-5'-methyl-5',8'-dihydro-6'H-spiro[cyclopropane-1,7'-pteridine]-6'-one (74-7, 1.0 g), with a yield of 86.7%.

[0535] LC-MS (m / z): 311.0 [M+H] + .

[0536] Step 7: Synthesis of 5'-methyl-5',8'-dihydro-6'H-spiro[cyclopropane-1,7'-pteridine]-6'-one (74-8)

[0537] 8'-(4-methoxybenzyl)-5'-methyl-5',8'-dihydro-6'H-spiro[cyclopropane-1,7'-pterodin]-6'-one (74-7, 780 mg, 2.51 mmol) was dissolved in TFA (4 mL) and trifluoromethanesulfonic acid (1 mL) and reacted at 40 °C for 1 h. After the reaction was complete, the mixture was concentrated under reduced pressure, the residue was diluted with water, the pH was adjusted to neutral with saturated NaHCO3 solution, extracted with DCM (30 mL × 3), dried over anhydrous Na2SO4, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (DCM:MeOH = 20:1) to give 5'-methyl-5',8'-dihydro-6'H-spiro[cyclopropane-1,7'-pterodin]-6'-one (74-8, 300 mg), yield 62.8%.

[0538] LC-MS (m / z): 191.0 [M+H] + .

[0539] Step 8: Synthesis of 8'-(4-bromophenyl)-5'-methyl-5',8'-dihydro-6'H-spiro[cyclopropane-1,7'-pteridine]-6'-one (74-9)

[0540] 5'-Methyl-5',8'-dihydro-6'H-spiro[cyclopropane-1,7'-pteridine]-6'-one (74-8, 192 mg, 1.01 mmol) was dissolved in DMF (5 mL), and p-bromoiodobenzene (343 mg, 1.21 mmol), cuprous iodide (115 mg, 0.61 mmol), and DBU (456 mg, 3.03 mmol) were added. The system was purged with nitrogen, and the temperature was raised to 120 °C for 16 h. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (DCM:MeOH = 97:3) to give 8'-(4-bromophenyl)-5'-methyl-5',8'-dihydro-6'H-spiro[cyclopropane-1,7'-pteridine]-6'-one (74-9, 118 mg), with a yield of 33.9%.

[0541] LC-MS (m / z): 345.0, 347.0 [M+H] + .

[0542] Step 9: Synthesis of 5'-methyl-8'-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)phenyl)-5',8'-dihydro-6'H-spiro[cyclopropane-1,7'-pteridine]-6'-one (74-10)

[0543] 8'-(4-bromophenyl)-5'-methyl-5',8'-dihydro-6'H-spiro[cyclopropane-1,7'-pteridine]-6'-one (74-9, 118 mg, 0.34 mmol) was dissolved in dioxane (3 mL), and pinacol diboronate (130 mg, 0.51 mmol), potassium acetate (67 mg, 0.68 mmol), and Pd(dppf)Cl2 (22 mg, 0.03 mmol) were added. The system was heated to 100 °C and reacted for 2 h under N2 environment. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (DCM:MeOH = 97:3) to give 5'-methyl-8'-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)phenyl)-5',8'-dihydro-6'H-spiro[cyclopropane-1,7'-pteridine]-6'-one (74-10, 160 mg), yield 59.7%.

[0544] LC-MS (m / z): 393.0 [M+H] + .

[0545] Step 10: Synthesis of 3-(2-chloro-4'-(5'-methyl-6'-oxo-5',6'-dihydro-8'H-spiro[cyclopropane-1,7'-pteridine]-8'-yl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (compound 74)

[0546] 3-(3-bromo-2-chlorophenyl)piperidin-2,6-dione (M1, 60 mg, 0.20 mmol) was dissolved in DMF (2 mL), and 5'-methyl-8'-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)phenyl)-5',8'-dihydro-6'H-spiro[cyclopropane-1,7'-pteridine]-6'-one (74-10, 85 mg, 0.22 mmol), Pd(dppf)Cl2 (15 mg, 0.02 mmol) and potassium acetate (39 mg, 0.4 mmol) were added. The system was heated to 100 °C under N2 environment and reacted for 5 h. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (DCM:MeOH = 20:1) to give 3-(2-chloro-4'-(5'-methyl-6'-oxo-5',6'-dihydro-8'H-spiro[cyclopropane-1,7'-pteridine]-8'-yl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (74.6 mg), yield 6.2%.

[0547] LC-MS (m / z): 488.0 [M+H] + .

[0548] 1H NMR (600MHz, DMSO-d6): δ10.94(s,1H),8.17(d,J=5.4Hz,2H),7.53(dd,J1=6.6Hz,J2=2.4Hz,2H),7.45-7.41(m,1H),7.41-7.36(m,4H),4.39(dd,J1=1 2.0Hz, J2=4.8Hz,1H),3.35(s,3H),2.84-2.278(m,1H),2.57-2.52(m,1H), 2.39-2.33(m,1H),2.08-2.04(m,1H),1.37-1.35(m,2H),0.89-0.84(m,2H).

[0549] Example 75: Synthesis of 3-(2-chloro-4'-(1'-cyclopropyl-5'-oxo-1'H-spiro[cyclopropane-1,6'-pyrazolo[3,4-b][1,4]oxazine]-4'(5'H-yl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (compound 75)

[0550] Step 1: Synthesis of 1-cyclopropyl-4-nitro-1H-pyrazole (75-2)

[0551] 4-Nitroimidazole (75-1, 9.0 g, 79.65 mmol) was dissolved in DCE (100 mL), and cyclopropylboronic acid (13.7 g, 159.3 mmol), copper acetate (14.46 g, 79.65 mmol), sodium carbonate (16.9 g, 159.4 mmol), and bipyridine (12.6 g, 79.65 mmol) were added. The atmosphere was purged with oxygen, and the mixture was heated to 70 °C for 16 hours. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (PE:EA = 10:1) to give 1-cyclopropyl-4-nitro-1H-pyrazole (75-2, 4.5 g), with a yield of 36.9%.

[0552] LC-MS (m / z): 154.0 [M+H] + .

[0553] Step 2: Synthesis of 5-chloro-1-cyclopropyl-4-nitropyrazole (75-3)

[0554] 1-Cyclopropyl-4-nitro-1H-pyrazole (75-2, 4.59 g, 30.00 mmol) was dissolved in THF (50 mL), cooled to -60 °C under nitrogen protection, and a 1 M, 36 mL solution of LiHMDS in THF was added dropwise. The reaction was maintained at this temperature for 0.5 h, followed by the addition of hexachloroethane (8.57 g, 36.62 mmol) in portions. The reaction was then allowed to return to room temperature for 2 h. After the reaction was complete, methanol (5 mL) was added to quench the reaction. The mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (PE:EA = 10:1) to give 5-chloro-1-cyclopropyl-4-nitro-1H-pyrazole (75-3, 3.0 g), with a yield of 53.5%.

[0555] LC-MS (m / z): 188.0, 190.0 [M+H] + .

[0556] Step 3: Synthesis of 1-((1-cyclopropyl-4-nitro-1H-pyrazole-5-yl)oxy)cyclopropane-1-carboxylic acid methyl ester (75-4)

[0557] 1-Hydroxycyclopropane-1-carboxylic acid methyl ester (2.52 g, 21.72 mmol) was dissolved in THF (40 mL) under nitrogen protection. Sodium hydride (1.09 g, 27.25 mmol) was added in an ice bath, and the reaction was allowed to proceed for 0.5 h. Then, 5-chloro-1-cyclopropyl-4-nitro-1H-pyrazole (75-3, 3.4 g, 18.18 mmol) was added, and the mixture was slowly brought to room temperature and reacted for 2 h. After the reaction was complete, the mixture was concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA = 5:1) to give 1-((1-cyclopropyl-4-nitro-1H-pyrazole-5-yl)oxy)cyclopropane-1-carboxylic acid methyl ester (75-4, 2.5 g), yield 69.6%.

[0558] LC-MS (m / z): 268.0 [M+H] + .

[0559] Step 4: Synthesis of 1'-cyclopropyl-1',4'-dihydro-5'H-spiro[cyclopropane-1,6'-pyrazolo[3,4-b][1,4]oxazine]-5'-one (75-5) Methyl 1-((1-cyclopropyl-4-nitro-1H-pyrazol-5-yl)oxy)cyclopropane-1-carboxylic acid (75-4, 2.4 g, 9.00 mmol) was dissolved in AcOH (30 mL), and iron powder (5.04 g, 93.33 mmol) was added under ice bath conditions. The temperature was raised to 90 °C and the reaction was carried out for 16 h. After the reaction was completed, the mixture was concentrated under reduced pressure. Water (10 mL) was added to the system, and the pH was adjusted to 7 with saturated NaHCO3 aqueous solution (20 mL). The mixture was extracted with EA (20 mL × 3). The combined organic phases were washed with saturated NaCl (20 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give 1'-cyclopropyl-1',4'-dihydro-5'H-spiro[cyclopropane-1,6'-pyrazolo[3,4-b][1,4]oxazine]-5'-one (75-5, 1.4 g), yield 76.0%.

[0560] LC-MS (m / z): 206.0 [M+H] + .

[0561] Step 5: Synthesis of 4'-(4-bromophenyl)-1'-cyclopropyl-1',4'-dihydro-5'H-spiro[cyclopropane-1,6'-pyrazolo[3,4-b][1,4]oxazine]-5'-one (75-6)

[0562] 1'-Cyclopropyl-1',4'-dihydro-5'H-spiro[cyclopropane-1,6'-pyrazolo[3,4-b][1,4]oxazine]-5'-one (75-5, 1.1 g, 5.37 mmol) and p-bromoiodobenzene (3.05 g, 10.82 mmol) were dissolved in dioxane (20 mL), and Pd2(dba)3 (495.2 mg, 0.54 mmol), Xantphos (624.2 mg, 1.08 mmol) and sodium tert-butoxide (1.04 g, 10.8 mmol) were added sequentially. The system was heated to 105 °C and reacted for 16 hours under nitrogen protection. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (PE:EA = 3:1) to give 4'-(4-bromophenyl)-1'-cyclopropyl-1',4'-dihydro-5'H-spiro[cyclopropane-1,6'-pyrazolo[3,4-b][1,4]oxazine]-5'-one (75-6,450 mg), yield 23.7%.

[0563] LC-MS (m / z): 360.0 [M+H] + .

[0564] Step 6: Synthesis of 1'-cyclopropyl-4'-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)-1',4'-dihydro-5'H-spiro[cyclopropane-1,6'-pyrazolo[3,4-b][1,4]oxazine]-5'-one (75-7)

[0565] 4'-(4-bromophenyl)-1'-cyclopropyl-1',4'-dihydro-5'H-spiro[cyclopropane-1,6'-pyrazolo[3,4-b][1,4]oxazine]-5'-one (75-6, 450 mg, 1.25 mmol), pinacol diboronate (635 mg, 2.50 mmol), KOAc (245 mg, 2.50 mmol), and Pd(dppf)Cl2 (91 mg, 0.13 mmol) were added sequentially to the flask, followed by dioxane (10 mL). The mixture was heated to 100 °C under nitrogen protection and reacted for 6 hours. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (PE:EA = 3:1) to give 1'-cyclopropyl-4'-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)-1',4'-dihydro-5'H-spiro[cyclopropane-1,6'-pyrazolo[3,4-b][1,4]oxazine]-5'-one (75-7,360 mg), yield 70.59%.

[0566] LC-MS (m / z): 408.0 [M+H] + .

[0567] Step 7: Synthesis of 3-(2-chloro-4'-(1'-cyclopropyl-5'-oxo-1'H-spiro[cyclopropane-1,6'-pyrazolo[3,4-b][1,4]oxazine]-4'(5'H-yl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (compound 75)

[0568] 1'-Cyclopropyl-4'-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)-1',4'-dihydro-5'H-spiro[cyclopropane-1,6'-pyrazolo[3,4-b][1,4]oxazine]-5'-one (75-7, 360 mg, 0.88 mmol) was dissolved in DMF (10 mL), and 3-(3-bromo-2-chlorophenyl)piperidin-2,6-dione (M1, 241 mg, 0.80 mmol), KOAc (192 mg, 1.96 mmol), and Pd(dppf)Cl2 (64 mg, 0.09 mmol) were added sequentially. The mixture was heated to 100 °C and reacted for 16 hours under nitrogen protection. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (DCM:MeOH = 20:1) to give 3-(2-chloro-4'-(1'-cyclopropyl-5'-oxo-1'H-spiro[cyclopropane-1,6'-pyrazolo[3,4-b][1,4]oxazine]-4'(5'H-yl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (75, 80 mg), yield 18.0%.

[0569] LC-MS (m / z): 503.0 [M+H] + .

[0570] 1 H NMR(600MHz,DMSO-d6):10.93(s,1H),7.55-7.52(m,4H),7.44-7.37(m,3H ),6.95(s,1H),4.38(dd,J1=12.0Hz,J1=4.8Hz,1H),3.42-3.39(m,1H),2.8 0-2.77(m,1H),2.57-2.54(m,1H),2.30-2.32(m,1H),2.08-2.05(m,1H),1 .47-1.45(m,2H),1.43-1.40(m,2H),1.01-0.98(m,2H),0.97-0.93(m,2H).

[0571] Example 76: Synthesis of 3-(2-chloro-4'-(1'-(difluoromethyl)-5'-oxo-1'H-spiro[cyclopropane-1,6'-pyrazolo[3,4-b][1,4]oxazine]-4'(5'H)-yl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (compound 76)

[0572] Step 1: Synthesis of 1-(4-methoxybenzyl)-4-nitro-1H-pyrazole (76-2)

[0573] 2-Nitroimidazole (76-1, 11.3 g, 0.1 mol) was dissolved in ACN (200 mL), followed by the sequential addition of 4-methoxybenzyl chloride (17.2 g, 0.11 mol) and potassium carbonate (17.25 g, 0.13 mol). The reaction was carried out under nitrogen protection at 55 °C for 8 hours. After the reaction was complete, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA = 10:1) to give 1-(4-methoxybenzyl)-4-nitro-1H-pyrazole (76-2, 19.0 g), in 81.2% yield.

[0574] LC-MS (m / z): 234.0 [M+H] + .

[0575] Step 2: Synthesis of 5-chloro-1-(4-methoxybenzyl)-4-nitro-1H-pyrazole (76-3)

[0576] 1-(4-methoxybenzyl)-4-nitro-1H-pyrazole (76-2, 18.0 g, 77.25 mmol) was added to the flask, followed by 20 mL of THF. The mixture was cooled to -60 °C under nitrogen protection, and a 1 M, 85 mL solution of LiHMDS in THF was added dropwise at this temperature. The reaction was maintained at this temperature for 0.5 h. Then, hexachloroethane (20.2 g, 86.32 mmol) was added in portions, and the mixture was allowed to return to room temperature for 2 h. After the reaction was complete, methanol (5 mL) was added to quench the reaction. The mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (PE:EA = 10:1) to give 5-chloro-1-(4-methoxybenzyl)-4-nitro-1H-pyrazole (76-3, 16.4 g), with a yield of 78.8%.

[0577] LC-MS (m / z): 268.0, 270.0 [M+H] + .

[0578] Step 3: Synthesis of methyl 1-((1-(4-methoxybenzyl)-4-nitro-1H-pyrazole-5-yl)oxy)cyclopropane-1-carboxylic acid (76-4)

[0579] 1-Hydroxycyclopropane-1-carboxylic acid methyl ester (7.35 g, 63.74 mmol) was dissolved in THF (150 mL), and the mixture was cooled to 0 °C under nitrogen protection. Sodium hydride (3.0 g, 75.00 mmol) was added to the system, and the reaction was carried out in an ice bath for 0.5 h. Then, 5-chloro-1-(4-methoxybenzyl)-4-nitro-1H-pyrazole (76-3, 15.4 g, 57.89 mmol) was added, and the mixture was slowly restored to room temperature for 2 h. After the reaction was completed, the mixture was concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA = 5:1) to give 1-((1-(4-methoxybenzyl)-4-nitro-1H-pyrazole-5-yl)oxy)cyclopropane-1-carboxylic acid methyl ester (76-4, 14.4 g), with a yield of 78%.

[0580] LC-MS (m / z): 348.0 [M+H] + .

[0581] Step 4: Synthesis of 1'-(4-methoxybenzyl)-1',4'-dihydro-5'H-spiro[cyclopropane-1,6'-pyrazolo[3,4-b][1,4]oxazine]-5'-one (76-5)

[0582] Methyl 1-((1-(4-methoxybenzyl)-4-nitro-1H-pyrazole-5-yl)oxy)cyclopropane-1-carboxylic acid (76-4, 13.4 g, 38.6 mmol) was dissolved in AcOH (100 mL), and reduced iron powder (21.6 g, 0.39 mol) was added under ice bath conditions. The mixture was heated to 90 °C and reacted for 16 h. After the reaction was completed, the mixture was concentrated under reduced pressure, and water (10 mL) was added. The pH was adjusted to 7 with saturated NaHCO3 aqueous solution (20 mL), and the mixture was extracted with EA (20 mL × 3). The combined organic phases were washed with saturated NaCl (20 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to give 1'-(4-methoxybenzyl)-1',4'-dihydro-5'H-spiro[cyclopropane-1,6'-pyrazolo[3,4-b][1,4]oxazine]-5'-one (76-5, 10.0 g), yield 90.9%.

[0583] LC-MS (m / z): 286.0 [M+H] + .

[0584] Step 5: Synthesis of 4'-(4-bromophenyl)-1'-(-4-methoxybenzyl)-1',4'-dihydro-5'H-spiro[cyclopropane-1,6'-pyrazolo[3,4-b][1,4]oxazine]-5'-one (76-6)

[0585] 1'-(4-methoxybenzyl)-1',4'-dihydro-5'H-spiro[cyclopropane-1,6'-pyrazolo[3,4-b][1,4]oxazine]-5'-one (76-5, 9.4 g, 33.0 mmol) and p-bromoiodobenzene (18.6 g, 66.0 mmol) were dissolved in dioxane (100 mL), and Pd2(dba)3 (6.05 g, 6.60 mmol), Xantphos (6.8 g, 13.20 mmol) and sodium tert-butoxide (6.3 g, 66.00 mmol) were added sequentially. The system was heated to 105 °C and reacted for 16 hours under nitrogen protection. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (PE:EA = 3:1) to give 4'-(4-bromophenyl)-1'-(-4-methoxybenzyl)-1',4'-dihydro-5'H-spiro[cyclopropane-1,6'-pyrazolo[3,4-b][1,4]oxazine]-5'-one (76-6, 1.4 g), yield 9.7%.

[0586] LC-MS (m / z): 440.0, 442.0 [M+H] + .

[0587] Step 6: Synthesis of 4'-(4-bromophenyl)-1',4'-dihydro-5'H-spiro[cyclopropane-1,6'-pyrazolo[3,4-b][1,4]oxazine]-5'-one (76-7)

[0588] 4'-(4-bromophenyl)-1'-(-4-methoxybenzyl)-1',4'-dihydro-5'H-spiro[cyclopropane-1,6'-pyrazolo[3,4-b][1,4]oxazine]-5'-one (76-6, 1.6 g, 3.65 mmol) was dissolved in TFA (10 mL), and trifluoromethanesulfonic anhydride (1 mL) was added to the system. The mixture was heated to 60 °C and reacted for 4 hours. After the reaction was complete, the mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (DCM:MeOH = 20:1) to give 4'-(4-bromophenyl)-1',4'-dihydro-5'H-spiro[cyclopropane-1,6'-pyrazolo[3,4-b][1,4]oxazine]-5'-one (76-7, 580 mg), yield 49.8%.

[0589] LC-MS (m / z): 320.0, 322.0 [M+H] + .

[0590] Step 7: Synthesis of 4'-(4-bromophenyl)-1'-(difluoromethyl)-1',4'-dihydro-5'H-spiro[cyclopropane-1,6'-pyrazolo[3,4-b][1,4]oxazine]-5'-one (76-8)

[0591] 4'-(4-bromophenyl)-1',4'-dihydro-5'H-spiro[cyclopropane-1,6'-pyrazolo[3,4-b][1,4]oxazine]-5'-one (76-7, 400 mg, 1.25 mmol) was dissolved in DMF (10 mL), and potassium fluoride (291 mg, 5.01 mmol) and sodium chlorodifluoroacetate (1.03 g, 3.76 mmol) were added at room temperature. The mixture was then heated to 70 °C and reacted for 16 h. After the reaction was completed, the mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (PE:EA = 5:1) to give 4'-(4-bromophenyl)-1'-(difluoromethyl)-1',4'-dihydro-5'H-spiro[cyclopropane-1,6'-pyrazolo[3,4-b][1,4]oxazine]-5'-one (76-8, 60 mg), yield 13.0%.

[0592] LC-MS (m / z): 370.0 [M+H] + .

[0593] Step 8: Synthesis of 1'-(difluoromethyl)-4'-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)-1',4'-dihydro-5'H-spiro[cyclopropane-1,6'-pyrazolo[3,4-b][1,4]oxazine]-5'-one (76-9)

[0594] Add 4'-(4-bromophenyl)-1'-(difluoromethyl)-1',4'-dihydro-5'H-spiro[cyclopropane-1,6'-pyrazolo[3,4-b][1,4]oxazine]-5'-one (76-8, 60 mg, 0.16 mmol), pinacol diboronate (83 mg, 0.33 mmol), KOAc (40 mg, 0.33 mmol), and Pd(dppf)Cl2 (12 mg, 0.02 mmol) to the flask in sequence, then add dioxane (5 mL), and heat to 100 °C for 6 hours under nitrogen protection. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (PE:EA = 3:1) to give 1'-(difluoromethyl)-4'-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)-1',4'-dihydro-5'H-spiro[cyclopropane-1,6'-pyrazolo[3,4-b][1,4]oxazine]-5'-one (76-9, 60 mg), yield 88.5%.

[0595] LC-MS (m / z): 418.0 [M+H] + .

[0596] Step 9: Synthesis of 3-(2-chloro-4'-(1'-(difluoromethyl)-5'-oxo-1'H-spiro[cyclopropane-1,6'-pyrazolo[3,4-b][1,4]oxazine]-4'(5'H)-yl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (compound 76)

[0597] 1'-(difluoromethyl)-4'-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)phenyl)-1',4'-dihydro-5'H-spiro[cyclopropane-1,6'-pyrazolo[3,4-b][1,4]oxazine]-5'-one (76-9, 50 mg, 0.12 mmol) was dissolved in DMF (2 mL), and 3-(3-bromo-2-chlorophenyl)piperidin-2,6-dione (M1, 36 mg, 0.11 mmol), KOAc (24 mg, 0.24 mmol), and Pd(dppf)Cl2 (9 mg, 0.01 mmol) were added sequentially. The mixture was heated to 100 °C and reacted for 16 hours under nitrogen protection. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (DCM:MeOH = 20:1) to give 3-(2-chloro-4'-(1'-(difluoromethyl)-5'-oxo-1'H-spiro[cyclopropane-1,6'-pyrazolo[3,4-b][1,4]oxazine]-4'(5'H)-yl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione (76.6 mg), yield 9.7%.

[0598] LC-MS (m / z): 513.0 [M+H] + .

[0599] 1 H NMR (600MHz, DMSO-d6): 10.94 (s, 1H), 7.81-7.61 (m, 1H), 7.59-7.55 (m, 4H), 7.46-7.36 (m, 4H), 4.39 (dd, J1=12.0Hz, J2=4. 8Hz,1H),2.84-2.78(m,1H),2.61-2.54(m,1H),2.39-2.29(m,1H),2.08-2.05(m,1H),1.52-1.46(m,2H),1.44-1.42(m,2H).

[0600] Example 77: Synthesis of 3-(2-chloro-4'-(2'H,4'H-spiro[cyclopropane-1,3'-pyrazino[2,3-b][1,4]oxazine]-4'-yl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (compound 77)

[0601] Step 1: Synthesis of tert-butyl (1-(((3-bromopyrazin-2-yl)oxy)methyl)cyclopropyl)carbamate (77-2)

[0602] 2,3-Dibromopyrazine (77-1, 4.52 g, 19.81 mmol) was dissolved in THF (100 mL), and tert-butyl (1-(hydroxymethyl)cyclopropyl)carbamate (5.34 g, 28.52 mmol) and cesium carbonate (12.39 g, 38.03 mmol) were added. The mixture was heated to 80 °C and reacted for 16 h. After the reaction was complete, the mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE / EA = 10:1) to give tert-butyl (1-(((3-bromopyrazin-2-yl)oxy)methyl)cyclopropyl)carbamate (77-2, 4 g), with a yield of 61.2%.

[0603] LC-MS (m / z): 344.0 [M+H] + .

[0604] Step 2: Synthesis of 2'H,4'H-spiro[cyclopropane-1,3'-pyrazino[2,3-b][1,4]oxazine]-4'-carboxylic acid tert-butyl ester (77-3)

[0605] (1-(((3-bromopyrazin-2-yl)oxy)methyl)cyclopropyl)tert-butyl carbamate (77-2, 2.8 g, 8.13 mmol) was dissolved in toluene (100 mL), and Pd2(dba)3 (741 mg, 0.81 mmol), Xantphos (936 mg, 1.62 mmol), and sodium tert-butoxide (1.56 mg, 16.27 mmol) were added. The system was heated to 105 °C for 16 h under nitrogen protection. After the reaction was completed, the mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE / EA = 10:1) to give 2'H,4'H-spiro[cyclopropane-1,3'-pyrazino[2,3-b][1,4]oxazine]-4'-carboxylic acid tert-butyl ester (77-3, 470 mg), yield 21.9%.

[0606] LC-MS (m / z): 264.0 [M+H] + .

[0607] Step 3: Synthesis of 2'H,4'H-spiro[cyclopropane-1,3'-pyrazino[2,3-b][1,4]oxazine] (77-4)

[0608] 2'H,4'H-spiro[cyclopropane-1,3'-pyrazino[2,3-b][1,4]oxazine]-4'-carboxylic acid tert-butyl ester (77-3, 470 mg, 1.79 mmol) was dissolved in HCl in EA solution (4 N, 5 mL) and reacted at room temperature for 5 h. After the reaction was completed, the solution was concentrated under reduced pressure to obtain crude 2'H,4'H-spiro[cyclopropane-1,3'-pyrazino[2,3-b][1,4]oxazine] (77-4), which was used directly in the next step.

[0609] LC-MS (m / z): 164.0 [M+H] + .

[0610] Step 4: Synthesis of 4'-(4-bromophenyl)-2'H,4'H-spiro[cyclopropane-1,3'-pyrazino[2,3-b][1,4]oxazine] (77-5)

[0611] The product (77-4) obtained in the previous step was dissolved in toluene (6 mL), and p-bromoiodobenzene (606 mg, 2.14 mmol), sodium tert-butoxide (514 mg, 5.36 mmol), Pd2(dba)3 (180 mg, 0.21 mmol), and Xantphos (231 mg, 0.41 mmol) were added. The system was heated to 105 °C under N2 environment and reacted for 12 h. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE / EA = 3:1) to give 4'-(4-bromophenyl)-2'H,4'H-spiro[cyclopropane-1,3'-pyrazino[2,3-b][1,4]oxazine] (77-5, 140 mg), with a two-step yield of 24.7%.

[0612] LC-MS (m / z): 318.0, 320.0 [M+H] + .

[0613] Step 5: Synthesis of 4'-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)-2'H,4'H-spiro[cyclopropane-1,3'-pyrazino[2,3-b][1,4]oxazine] (77-6)

[0614] 4'-(4-bromophenyl)-2'H,4'H-spiro[cyclopropane-1,3'-pyrazino[2,3-b][1,4]oxazine] (77-5, 140 mg, 0.44 mmol) was dissolved in dioxane (3 mL), and pinacol diboronate (166 mg, 0.66 mmol), potassium acetate (86 mg, 0.88 mmol), and Pd(dppf)Cl2 (38 mg, 0.04 mmol) were added. The system was heated to 100 °C under N2 environment and reacted for 2 h. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE / EA = 4:1) to give 4'-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)-2'H,4'H-spiro[cyclopropane-1,3'-pyrazino[2,3-b][1,4]oxazine] (77-6,92 mg), yield 57.3%.

[0615] LC-MS (m / z): 366.0 [M+H] + .

[0616] Step 6: Synthesis of 3-(2-chloro-4'-(2'H,4'H-spiro[cyclopropane-1,3'-pyrazino[2,3-b][1,4]oxazine]-4'-yl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (compound 77)

[0617] 3-(3-bromo-2-chlorophenyl)piperidin-2,6-dione (M1, 60 mg, 0.20 mmol) was dissolved in DMF (2 mL), and 4'-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborin-2-yl)phenyl)-2'H,4'H-spiro[cyclopropane-1,3'-pyrazino[2,3-b][1,4]oxazine] (77-6, 87 mg, 0.24 mmol), Pd(dppf)Cl2 (15 mg, 0.02 mmol) and potassium acetate (39 mg, 0.4 mmol) were added. The system was heated to 100 °C under N2 environment and reacted for 5 h. After the reaction was completed, the mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (DCM / MeOH = 20:1). Then, 3-(2-chloro-4'-(2'H,4'H-spiro[cyclopropane-1,3'-pyrazino[2,3-b][1,4]oxazine]-4'-yl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione (77, 20 mg) was prepared by liquid chromatography, with a yield of 21.9%.

[0618] LC-MS (m / z): 461.0 [M+H] + .

[0619] 1H NMR (600MHz, DMSO-d6): δ10.95(s,1H),7.65(d,J=3.0Hz,1H),7.54(d,J=3.0H z,1H),7.48-7.45(m,2H),7.44-7.39(m,1H),7.39-7.33(m,4H),4.40(s,2H),4 .38(dd,J1=12.0Hz,J2=4.8Hz,1H),2.83-2.77(m,1H),2.57-2.52(m,1H),2.39 -2.31(m,1H),2.08-2.03(m,1H),0.98(t,J=6.0Hz,2H),0.80(t,J=6.0Hz,2H).

[0620] Example 78: Synthesis of 3-(2-chloro-4'-(5'-oxo-1'H-spiro[cyclopropane-1,6'-pyrazolo[3,4-b][1,4]oxazine]-4'(5'H)-yl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (compound 78)

[0621] Step 1: Synthesis of 1'-(4-methoxybenzyl)-4'-(-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)-1',4'-dihydro-5'H-spiro[cyclopropane-1,6'-pyrazolo[3,4-b][1,4]oxazine]-5'-one (78-1)

[0622] Compound 76-6 was prepared according to steps 1 to 5 of Example 76.

[0623] 4'-(4-bromophenyl)-1'-(-4-methoxybenzyl)-1',4'-dihydro-5'H-spiro[cyclopropane-1,6'-pyrazolo[3,4-b][1,4]oxazine]-5'-one (76-6, 200 mg, 0.46 mmol), pinacol diboronate (234 mg, 0.92 mmol), KOAc (90 mg, 0.92 mmol), and Pd(dppf)Cl2 (33.6 mg, 0.05 mmol) were added sequentially to the flask, followed by dioxane (10 mL). The system was heated to 100 °C and reacted for 6 hours under nitrogen protection. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (PE:EA = 3:1) to give 1'-(4-methoxybenzyl)-4'-(-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)-1',4'-dihydro-5'H-spiro[cyclopropane-1,6'-pyrazolo[3,4-b][1,4]oxazine]-5'-one (78-1,110 mg), yield 49.6%.

[0624] LC-MS (m / z): 488.0 [M+H] + .

[0625] Step 2: Synthesis of 3-(2-chloro-4'-(1'-(4-methoxybenzyl)-5'-oxo-1'H-spiro[cyclopropane-1,6'-pyrazolo[3,4-b][1,4]oxazine]-4'(5'H)-yl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (78-2)

[0626] 1'-(4-methoxybenzyl)-4'-(-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)phenyl)-1',4'-dihydro-5'H-spiro[cyclopropane-1,6'-pyrazolo[3,4-b][1,4]oxazine]-5'-one (78-1, 90 mg, 0.18 mmol) was dissolved in DMF (5 mL), and 3-(3-bromo-2-chlorophenyl)piperidin-2,6-dione (M1, 50 mg, 0.16 mmol), KOAc (35 mg, 0.36 mmol), and Pd(dppf)Cl2 (13 mg, 0.02 mmol) were added sequentially. The system was heated to 100 °C and reacted for 16 hours under nitrogen protection. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (DCM:MeOH = 20:1) to give 3-(2-chloro-4'-(1'-(4-methoxybenzyl)-5'-oxo-1'H-spiro[cyclopropane-1,6'-pyrazolo[3,4-b][1,4]oxazine]-4'(5'H)-yl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione (78-2, 40 mg), yield 37.0%.

[0627] LC-MS (m / z): 583.0 [M+H] + .

[0628] Step 8: Synthesis of 3-(2-chloro-4'-(5'-oxo-1'H-spiro[cyclopropane-1,6'-pyrazolo[3,4-b][1,4]oxazine]-4'(5'H)-yl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (compound 78)

[0629] 3-(2-chloro-4'-(1'-(4-methoxybenzyl)-5'-oxo-1'H-spiro[cyclopropane-1,6'-pyrazolo[3,4-b][1,4]oxazine]-4'(5'H)-yl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione (78-2, 40 mg, 0.07 mmol) was dissolved in TFA (5 mL), and trifluoromethanesulfonic acid (1 mL) was added to the system. The reaction was carried out at room temperature for 4 hours. After the reaction was complete, the mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (DCM:MeOH = 20:1) to give 3-(2-chloro-4'-(5'-oxo-1'H-spiro[cyclopropane-1,6'-pyrazolo[3,4-b][1,4]oxazine]-4'(5'H)-yl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione (78.6 mg), yield 18.9%.

[0630] LC-MS (m / z): 463.0 [M+H] + .

[0631] 1 H NMR (600MHz, DMSO-d6): 10.94 (s, 1H), 7.81-7.61 (m, 1H), 7.59-7.55 (m, 4H), 7.49-7.36 (m, 4H), 4.39 (dd, J1=12.0Hz, J2=4. 8Hz,1H),2.84-2.78(m,1H),2.61-2.54(m,1H),2.39-2.32(m,1H),2.08-2.05(m,1H),1.52-1.46(m,2H),1.44-1.42(m,2H).

[0632] Example 80: Synthesis of 3-(2-chloro-4'-(8'-methyl-6'-oxo-6'H-spiro[cyclopropane-1,7'-pteridine]-5'(8'H)-yl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (compound 80)

[0633] Step 1: Synthesis of methyl 1-((tert-butoxycarbonyl)(methyl)amino)cyclopropane-1-carboxylate (80-2)

[0634] Methyl 1-((tert-Butoxycarbonyl)amino)cyclopropane-1-carboxylate (80-1, 5.36 g, 24.91 mmol) was dissolved in DMF (70 mL), and NaH (1.49 g, 37.37 mmol) was added at 0 °C. The reaction was allowed to proceed for 0.5 h, followed by the addition of iodomethane (5.3 g, 37.37 mmol) and the reaction continued at room temperature for 16 h. After the reaction was complete, 250 mL of water was added, and the mixture was extracted with EA (50 mL × 3), washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA = 9:1) to give methyl 1-((tert-Butoxycarbonyl)(Methyl)amino)cyclopropane-1-carboxylate (80-2, 6 g), with a yield of 89.3%.

[0635] LC-MS (m / z): 230.0 [M+H] + .

[0636] Step 2: Synthesis of methyl 1-(methylamino)cyclopropane-1-carboxylic acid ester hydrochloride (80-3)

[0637] Methyl 1-((tert-butoxycarbonyl)(methyl)amino)cyclopropane-1-carboxylate (80-2, 6 g, 26.17 mmol) was dissolved in HCl-saturated EA (20 mL), and the reaction was carried out at room temperature for 16 h. After the reaction was completed, the mixture was concentrated under reduced pressure to give methyl 1-(methylamino)cyclopropane-1-carboxylic acid hydrochloride (80-3, 4 g), with a yield of 92.3%.

[0638] LC-MS (m / z): 130.0 [M+H] + .

[0639] Step 3: Synthesis of methyl 1-((2-chloro-5-nitropyrimidin-4-yl)(methyl)amino)cyclopropane-1-carboxylate (80-4)

[0640] 1-(methylamino)cyclopropane-1-carboxylic acid methyl ester hydrochloride (80-3, 1.66 g, 10.02 mmol) was dissolved in DCM (30 mL), and potassium bicarbonate (2.01 g, 20.05 mmol) and 2,4-dichloro-5-nitropyrimidine (1.94 g, 10.02 mmol) were added. The reaction was carried out at room temperature for 16 h. After the reaction was completed, the mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by pulping (PE:EA = 10:1) to give 1-((2-chloro-5-nitropyrimidine-4-yl)(methyl)amino)cyclopropane-1-carboxylic acid methyl ester (80-4, 2.5 g), yield 87.0%.

[0641] LC-MS (m / z): 287.0, 289.0 [M+H] + .

[0642] Step 4: Synthesis of 2'-chloro-8'-methyl-5',8'-dihydro-6'H-spiro[cyclopropane-1,7'-pteridine]-6'-one (80-5)

[0643] Methyl 1-((2-chloro-5-nitropyrimidin-4-yl)(methyl)amino)cyclopropane-1-carboxylate (80-4, 2.3 g, 8.02 mmol) was dissolved in acetic acid (20 mL), and Fe powder (4.48 g, 80.23 mmol) was added. The mixture was heated to 90 °C and reacted for 1.5 h. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was extracted with 30 mL of water using EA (30 mL × 3). The residue was dried over anhydrous Na₂SO₄, filtered, and the filtrate was concentrated under reduced pressure to give 2'-chloro-8'-methyl-5',8'-dihydro-6'H-spiro[cyclopropane-1,7'-pteridine]-6'-one (80-5, 1.73 g), with a yield of 89.3%.

[0644] LC-MS (m / z): 225.0, 227.0 [M+H] + .

[0645] Step 5: Synthesis of 2'-chloro-5'-(4-methoxybenzyl)-8'-methyl-5',8'-dihydro-6'H-spiro[cyclopropane-1,7'-pteridine]-6'-one (80-6)

[0646] 2'-Chloro-8'-methyl-5',8'-dihydro-6'H-spiro[cyclopropane-1,7'-pterodin]-6'-one (80-5, 1.73 g, 7.7 mmol) was dissolved in DMF (20 mL), and Cs₂CO₃ (5.02 g, 15.4 mmol) and PMBCl (2.41 g, 15.4 mmol) were added. The reaction was carried out at room temperature for 12 h. After the reaction was completed, 80 mL of water was added, and the mixture was extracted with DCM (30 mL × 3). The extract was dried over anhydrous Na₂SO₄, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM:MeOH = 40:1) to give 2'-chloro-5'-(4-methoxybenzyl)-8'-methyl-5',8'-dihydro-6'H-spiro[cyclopropane-1,7'-pterodin]-6'-one (80-6, 2.0 g), with a yield of 75.3%.

[0647] LC-MS (m / z): 345.0, 347.0 [M+H] + .

[0648] Step 6: Synthesis of 5'-(4-methoxybenzyl)-8'-methyl-5',8'-dihydro-6'H-spiro[cyclopropane-1,7'-pteridine]-6'-one (80-7)

[0649] 2'-Chloro-5'-(4-methoxybenzyl)-8'-methyl-5',8'-dihydro-6'H-spiro[cyclopropane-1,7'-pteridine]-6'-one (80-6, 2 g, 5.8 mmol) was dissolved in EtOH (20 mL) and triethylamine (10 mL), and 10% palladium on carbon (1 g) was added. The system was replaced with a hydrogen atmosphere, and the reaction was carried out at room temperature for 16 h. After the reaction was completed, the mixture was filtered through diatomaceous earth, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (DCM:MeOH = 25:1) to give 5'-(4-methoxybenzyl)-8'-methyl-5',8'-dihydro-6'H-spiro[cyclopropane-1,7'-pteridine]-6'-one (80-7, 1.8 g), with a yield of 89.9%.

[0650] LC-MS (m / z): 311.0 [M+H] + .

[0651] Step 7: Synthesis of 8'-methyl-5',8'-dihydro-6'H-spiro[cyclopropane-1,7'-pteridine]-6'-one (80-8)

[0652] 5'-(4-methoxybenzyl)-8'-methyl-5',8'-dihydro-6'H-spiro[cyclopropane-1,7'-pterodin]-6'-one (80-7, 1.8 g, 5.80 mmol) was dissolved in TFA (8 mL) and trifluoromethanesulfonic acid (2 mL) and reacted at 40 °C for 5 h. After the reaction was complete, the mixture was concentrated under reduced pressure, the residue was diluted with water, the pH was adjusted to neutral with saturated NaHCO3 solution, extracted with DCM (30 mL × 3), dried over anhydrous Na2SO4, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (DCM:MeOH = 20:1) to give 8'-methyl-5',8'-dihydro-6'H-spiro[cyclopropane-1,7'-pterodin]-6'-one (80-8, 740 mg), yield 67.1%.

[0653] LC-MS (m / z): 191.0 [M+H] + .

[0654] Step 8: Synthesis of 5'-(4-bromophenyl)-8'-methyl-5',8'-dihydro-6'H-spiro[cyclopropane-1,7'-pteridine]-6'-one (80-9)

[0655] 8'-Methyl-5',8'-dihydro-6'H-spiro[cyclopropane-1,7'-pterodin]-6'-one (80-8, 750 mg, 3.94 mmol) was dissolved in DCE (20 mL), and p-bromophenylboronic acid (2.38 g, 11.83 mmol), copper acetate (716 mg, 3.94 mmol), and triethylamine (1.2 g, 11.83 mmol) were added. The system was replaced with an oxygen atmosphere, and the reaction was carried out at room temperature for 16 h. After the reaction was completed, the mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (DCM:MeOH = 20:1) to give 5'-(4-bromophenyl)-8'-methyl-5',8'-dihydro-6'H-spiro[cyclopropane-1,7'-pterodin]-6'-one (80-9, 900 mg), with a yield of 66.1%.

[0656] LC-MS (m / z): 345.0, 347.0 [M+H] + .

[0657] Step 9: Synthesis of 8'-methyl-5'-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)phenyl)-5',8'-dihydro-6'H-spiro[cyclopropane-1,7'-pteridine]-6'-one (80-10)

[0658] 5'-(4-bromophenyl)-8'-methyl-5',8'-dihydro-6'H-spiro[cyclopropane-1,7'-pteridine]-6'-one (80-9, 600 mg, 1.74 mmol) was dissolved in dioxane (5 mL), and pinacol diboronate (662 mg, 2.61 mmol), potassium acetate (341 mg, 3.48 mmol), and Pd(dppf)Cl2 (127 mg, 0.17 mmol) were added. The system was replaced with N2 environment, and the temperature was raised to 100 °C for 2 h. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (DCM:MeOH = 97:3) to give 8'-methyl-5'-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)phenyl)-5',8'-dihydro-6'H-spiro[cyclopropane-1,7'-pteridine]-6'-one (80-10, 820 mg), yield 92.2%.

[0659] LC-MS (m / z): 393.0 [M+H] + .

[0660] Step 10: Synthesis of 3-(2-chloro-4'-(8'-methyl-6'-oxo-6'H-spiro[cyclopropane-1,7'-pteridine]-5'(8'H)-yl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (80)

[0661] 3-(3-bromo-2-chlorophenyl)piperidin-2,6-dione (M1, 480 mg, 1.59 mmol) was dissolved in DMF (5 mL), and 8'-methyl-5'-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)phenyl)-5',8'-dihydro-6'H-spiro[cyclopropane-1,7'-pteridine]-6'-one (80-10, 622 mg, 1.59 mmol), Pd(dppf)Cl2 (117 mg, 0.16 mmol) and potassium acetate (311 mg, 3.17 mmol) were added. The system was replaced with N2 environment, and the temperature was raised to 100 °C and reacted for 5 h. After the reaction was completed, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (DCM:MeOH = 20:1) to give 3-(2-chloro-4'-(8'-methyl-6'-oxo-6'H-spiro[cyclopropane-1,7'-pteridine]-5'(8'H)-yl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (80, 60 mg), yield 7.8%.

[0662] LC-MS (m / z): 488.0 [M+H] + .

[0663] 1 H NMR (600MHz, DMSO-d6): δ10.95(s,1H),8.27(s,1H),7.62(d,J=8.4Hz,2H),7.47-7.40(m,5H),7.08(s,1H),4.39(dd,J1=12.6,J2=5.4H z,1H),2.93(s,3H),2.84-2.78(m,1H),2.58-2.54(m,1H),2.40-2.31(m,1H),2.09-2.05(m,1H),1.58-1.55(m,2H),1.37-1.35(m,2H).

[0664] Example 81: Synthesis of 3-(2-chloro-4'-(3'-methyl-5'-oxo-1'H-spiro[cyclopropane-1,6'-pyrazolo[3,4-b][1,4]oxazine]-4'(5'H)-yl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (compound 81)

[0665] Step 1: Synthesis of 1-(4-methoxybenzyl)-3-methyl-4-nitro-1H-pyrazole (81-2)

[0666] 3-Methyl-4-nitro-1H-pyrazole (81-1, 8.0 g, 63.00 mmol) was dissolved in ACN (200 mL), and 4-methoxybenzyl chloride (10.9 g, 69.30 mmol) and potassium carbonate (10.9 g, 78.80 mmol) were added sequentially. The mixture was heated to 55 °C for 8 hours under nitrogen protection. After the reaction was complete, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA = 10:1) to give 1-(4-methoxybenzyl)-3-methyl-4-nitro-1H-pyrazole (81-2, 12.0 g), with a yield of 77.1%.

[0667] LC-MS (m / z): 248.0 [M+H] + .

[0668] Step 2: Synthesis of 5-chloro-1-(4-methoxybenzyl)-3-methyl-4-nitro-1H-pyrazole (81-3)

[0669] 1-(4-methoxybenzyl)-3-methyl-4-nitro-1H-pyrazole (81-2, 12.0 g, 48.58 mmol) was added to a flask, followed by the addition of THF (100 mL). The mixture was cooled to -60 °C under nitrogen protection, and a LiHMDS THF solution (1 N, 56.6 mL) was slowly added dropwise. After reacting for 30 min, hexachloroethane (13.5 g, 56.58 mmol) was added in portions, and the mixture was allowed to return to room temperature for 2 h. After the reaction was complete, methanol (5 mL) was added to quench the reaction, and the mixture was concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA = 10:1) to give 5-chloro-1-(4-methoxybenzyl)-3-methyl-4-nitro-1H-pyrazole (81-3, 6.5 g), with a yield of 47.4%.

[0670] LC-MS (m / z): 282.0, 284.0 [M+H] + .

[0671] Step 3: Synthesis of methyl 1-((1-(4-methoxybenzyl)-3-methyl-4-nitro-1H-pyrazol-5-yl)oxy)cyclopropane-1-carboxylate (81-4)

[0672] Methyl 1-hydroxycyclopropane-1-carboxylic acid (2.68 g, 23.13 mmol) was dissolved in THF (50 mL), and the mixture was cooled to 0 °C under nitrogen protection. Sodium hydride (1.4 g, 34.70 mmol) was added to the system, and the reaction was allowed to proceed for 0.5 h. Then, 5-chloro-1-(4-methoxybenzyl)-3-methyl-4-nitro-1H-pyrazole (81-3, 6.5 g, 23.13 mmol) was added, and the mixture was slowly restored to room temperature for 2 h. After the reaction was complete, the mixture was concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA = 5:1) to give methyl 1-((1-(4-methoxybenzyl)-3-methyl-4-nitro-1H-pyrazole-5-yl)oxy)cyclopropane-1-carboxylic acid (81-4, 4.0 g), with a yield of 47.9%.

[0673] LC-MS (m / z): 362.0 [M+H] + .

[0674] Step 4: Synthesis of 1'-(4-methoxybenzyl)-3'-methyl-1',4'-dihydro-5'H-spiro[cyclopropane-1,6'-pyrazolo[3,4-b][1,4]oxazine]-5'-one (81-5)

[0675] 1-((1-(4-methoxybenzyl)-3-methyl-4-nitro-1H-pyrazol-5-yl)oxy)cyclopropane-1-carboxylic acid methyl ester (81-4, 4.0 g, 11.08 mmol) was dissolved in AcOH (50 mL), and iron powder (3.7 g, 66.48 mmol) was added under ice bath conditions. The mixture was then heated to 90 °C and reacted for 16 h. After the reaction was completed, the mixture was concentrated under reduced pressure. Water (10 mL) was added to the system, the pH was adjusted to 7 with saturated NaHCO3 aqueous solution, and the mixture was extracted with EA (20 mL × 3). The organic phases were combined, washed with saturated NaCl (20 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to obtain crude 1'-(4-methoxybenzyl)-3'-methyl-1',4'-dihydro-5'H-spiro[cyclopropane-1,6'-pyrazolo[3,4-b][1,4]oxazine]-5'-one (81-5, 2.0 g).

[0676] LC-MS (m / z): 300.0 [M+H] + .

[0677] Step 5: Synthesis of 4'-(4-bromophenyl)-1'-(4-methoxybenzyl)-3'-methyl-1',4'-dihydro-5'H-spiro[cyclopropane-1,6'-pyrazolo[3,4-b][1,4]oxazine]-5'-one (81-6)

[0678] The crude product obtained in the previous step (81-5, 1.0 g) and p-bromoiodobenzene (1.4 g, 5.00 mmol) were dissolved in DMF (30 mL), and CuI (187 mg, 1.00 mmol) and DBU (1.0 g, 6.69 mmol) were added sequentially. The mixture was heated to 120 °C and reacted for 16 hours under nitrogen protection. After the reaction was completed, the mixture was concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA = 3:1) to give 4'-(4-bromophenyl)-1'-(4-methoxybenzyl)-3'-methyl-1',4'-dihydro-5'H-spiro[cyclopropane-1,6'-pyrazolo[3,4-b][1,4]oxazine]-5'-one (81-6, 320 mg), with a two-step yield of 12.75%.

[0679] LC-MS (m / z): 454.0, 456.0 [M+H] + .

[0680] Step 6: Synthesis of 1'-(4-methoxybenzyl)-3'-methyl-4'-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)phenyl)-1',4'-dihydro-5'H-spiro[cyclopropane-1,6'-pyrazolo[3,4-b][1,4]oxazine]-5'-one (81-7)

[0681] 4'-(4-bromophenyl)-1'-(4-methoxybenzyl)-3'-methyl-1',4'-dihydro-5'H-spiro[cyclopropane-1,6'-pyrazolo[3,4-b][1,4]oxazine]-5'-one (81-6, 320 mg, 0.71 mmol), pinacol diboronate (362 mg, 1.42 mmol), KOAc (139 mg, 1.42 mmol), and Pd(dppf)Cl2 (52 mg, 0.07 mmol) were added sequentially to the flask, followed by dioxane (10 mL). The mixture was heated to 100 °C under nitrogen protection and reacted for 6 hours. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (PE:EA = 3:1) to give 1'-(4-methoxybenzyl)-3'-methyl-4'-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)phenyl)-1',4'-dihydro-5'H-spiro[cyclopropane-1,6'-pyrazolo[3,4-b][1,4]oxazine]-5'-one (81-7, 350 mg), yield 99.2%.

[0682] LC-MS (m / z): 502.0 [M+H] + .

[0683] Step 7: Synthesis of 3-(2-chloro-4'-(1'-(4-methoxybenzyl)-3'-methyl-5'-oxo-1'H-spiro[cyclopropane-1,6'-pyrazolo[3,4-b][1,4]oxazine]-4'(5'H)-yl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (81-8)

[0684] 1'-(4-methoxybenzyl)-3'-methyl-4'-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborphane-2-yl)phenyl)-1',4'-dihydro-5'H-spiro[cyclopropane-1,6'-pyrazolo[3,4-b][1,4]oxazine]-5'-one (81-7, 350 mg, 0.77 mmol) was dissolved in DMF (5 mL), and 3-(3-bromo-2-chlorophenyl)piperidin-2,6-dione (M1, 209 mg, 0.69 mmol), KOAc (151 mg, 1.54 mmol), and Pd(dppf)Cl2 (56 mg, 0.08 mmol) were added sequentially. The mixture was heated to 100 °C and reacted for 16 hours under nitrogen protection. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (DCM:MeOH = 20:1) to give 3-(2-chloro-4'-(1'-(4-methoxybenzyl)-3'-methyl-5'-oxo-1'H-spiro[cyclopropane-1,6'-pyrazolo[3,4-b][1,4]oxazine]-4'(5'H)-yl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione (81-8, 300 mg), yield 70.1%.

[0685] LC-MS (m / z): 597.0 [M+H] + .

[0686] Step 8: Synthesis of 3-(2-chloro-4'-(3'-methyl-5'-oxo-1'H-spiro[cyclopropane-1,6'-pyrazolo[3,4-b][1,4]oxazine]-4'(5'H)-yl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (81)

[0687] 3-(2-chloro-4'-(1'-(4-methoxybenzyl)-3'-methyl-5'-oxo-1'H-spiro[cyclopropane-1,6'-pyrazolo[3,4-b][1,4]oxazine]-4'(5'H)-yl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (81-8, 200 mg, 0.36 mmol) was dissolved in TFA (5 mL), and trifluoromethanesulfonic acid (1 mL) was added to the system. The reaction was carried out at room temperature for 4 hours. After the reaction was complete, the mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (DCM:MeOH = 20:1) to give 3-(2-chloro-4'-(3'-methyl-5'-oxo-1'H-spiro[cyclopropane-1,6'-pyrazolo[3,4-b][1,4]oxazine]-4'(5'H)-yl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione (81,36 mg), yield 22.5%.

[0688] LC-MS (m / z): 477.0 [M+H] + .

[0689] 1 H NMR(600MHz,DMSO-d6):11.76(s,1H),10.93(s,1H),7.55-7.52(m,2H),7 .49-7.48(m,2H),7.45-7.42(m,1H),7.41-7.37(m,2H),4.37(dd,J1=12.6 Hz,J2=5.4Hz,1H),2.83-2.77(m,1H),2.57-2.53(m,1H),2.41-2.31(m,1 H),2.08-2.04(m,1H),1.55(s,3H),1.40-1.34(m,2H),1.30-1.25(m,2H).

[0690] Example 82: Synthesis of 3-(2-chloro-4'-(3'-oxospiro[cyclopropane-1,2'-pyrazino[2,3-b][1,4]oxazine]-4'(3'H)-yl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (Compound 82)

[0691] Step 1: Synthesis of methyl 1-((3-chloropyrazin-2-yl)oxy)cyclopropane-1-carboxylate (82-2)

[0692] 2,3-Dichloropyrazine (82-1, 500 mg, 3.38 mmol), methyl 1-hydroxycyclopropane-1-carboxylate (588 mg, 5.07 mmol), and cesium carbonate (2.2 g, 6.76 mmol) were dissolved in THF (5 mL), and the mixture was heated to 50 °C and reacted for 6 h. After the reaction was complete, the mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (PE:EA = 5:1) to give methyl 1-((3-chloropyrazine-2-yl)oxy)cyclopropane-1-carboxylate (82-2, 400 mg), in 51.9% yield.

[0693] LC-MS (m / z): 229.0 [M+H] + .

[0694] Step 2: Synthesis of 4'-(4-bromophenyl)spiro[cyclopropane-1,2'-pyrazino[2,3-b][1,4]oxazine]-3'(4'H)-one (82-3)

[0695] 1-((3-chloropyrazin-2-yl)oxy)cyclopropane-1-carboxylate methyl ester (82-2, 400 mg, 1.75 mmol), 4-bromoaniline (898 mg, 5.25 mmol), Pd2(dba)3 (165 mg, 0.18 mmol), Xantphos (203 mg, 0.35 mmol), and cesium carbonate (1.1 g, 3.38 mmol) were added to a flask, followed by dioxane (4 mL). The system was heated to 100 °C under nitrogen protection and reacted for 4 h. After the reaction was complete, the mixture was concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA = 3:1) to give 4'-(4-bromophenyl)spiro[cyclopropane-1,2'-pyrazino[2,3-b][1,4]oxazine]-3'(4'H)-one (82-3, 130 mg), in 20.5% yield.

[0696] LC-MS (m / z): 332.0, 334.0 [M+H] + .

[0697] Step 3: Synthesis of 4'-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborphane-2-yl)phenyl)spiro[cyclopropane-1,2'-pyrazino[2,3-b][1,4]oxazine]-3'(4'H)-one (82-4)

[0698] 4'-(4-bromophenyl)spiro[cyclopropane-1,2'-pyrazino[2,3-b][1,4]oxazine]-3'(4'H)-one (82-3, 130 mg, 0.39 mmol), pinacol diboronate (396 mg, 1.56 mmol), KOAc (153 mg, 1.56 mmol), and Pd(dppf)Cl2 (29 mg, 0.04 mmol) were added sequentially to the flask, followed by dioxane (3 mL). The system was heated to 100 °C and reacted for 4 h under nitrogen protection. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (PE:EA = 3:1) to give 4'-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborphane-2-yl)phenyl)spiro[cyclopropane-1,2'-pyrazino[2,3-b][1,4]oxazine]-3'(4'H)-one (82-4, 140 mg), yield 94.6%.

[0699] LC-MS (m / z): 380.0 [M+H] + .

[0700] Step 4: Synthesis of 3-(2-chloro-4'-(3'-oxospiro[cyclopropane-1,2'-pyrazino[2,3-b][1,4]oxazine]-4'(3'H)-yl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (82)

[0701] 4'-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborphane-2-yl)phenyl)spiro[cyclopropane-1,2'-pyrazino[2,3-b][1,4]oxazine]-3'(4'H)-one (82-4, 140 mg, 0.37 mmol), 3-(3-bromo-2-chlorophenyl)piperidin-2,6-dione (M1, 100 mg, 0.33 mmol), KOAc (109 mg, 1.11 mmol) and Pd(dppf)Cl2 (29 mg, 0.04 mmol) were dissolved in DMF (2 mL), and the system was heated to 100 °C for 6 h under nitrogen protection. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (DCM:MeOH = 20:1) to give 3-(2-chloro-4'-(3'-oxospiro[cyclopropane-1,2'-pyrazino[2,3-b][1,4]oxazine]-4'(3'H)-yl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione (82,70 mg), yield 39.8%.

[0702] LC-MS (m / z): 475.0 [M+H] + .

[0703] 1H NMR (400MHz, DMSO-d6): δ10.95(s,1H),7.96(d,J=2.8Hz,1H),7.92(d,J=2.8Hz,1H),7.58-7.54(m,2H),7.49-7.47(m,2H),7.45-7.39(m, 3H),4.40(dd,J1=12.0Hz,J2=4.8Hz,1H),2.85-2.77(m,1H),2.58-2.52(m,1H),2.41-2.30(m,1H),2.11-2.05(m,1H),1.55-1.47(m,4H).

[0704] Example 85: Synthesis of 3-(2-chloro-4'-(2'H,4'H-spiro[cyclobutane-1,3'-pyrazino[2,3-b][1,4]oxazine]-4'-yl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (Compound 85)

[0705] Step 1: Synthesis of tert-butyl (1-(((3-bromopyrazin-2-yl)oxy)methyl)cyclobutyl)carbamate (85-2)

[0706] 2,3-Dibromopyrazine (85-1, 2.7 g, 11.35 mmol) was dissolved in THF (40 mL), and tert-butyl (1-hydroxymethylcyclobutyl)carbamate (3.4 g, 17.03 mmol) and cesium carbonate (7.4 g, 22.7 mmol) were added. The mixture was heated to 80 °C and reacted for 16 h. After the reaction was complete, the mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (PE / EA = 9:1) to give tert-butyl (1-(((3-bromopyrazin-2-yl)oxy)methyl)cyclobutyl)carbamate (85-2, 2.3 g), yield 56.6%.

[0707] LC-MS (m / z): 358.0 [M+H] + .

[0708] Step 2: Synthesis of 2'H,4'H-spiro[cyclobutane-1,3'-pyrazino[2,3-b][1,4]oxazine]-4'-carboxylic acid tert-butyl ester (85-3)

[0709] (1-(((3-bromopyrazin-2-yl)oxy)methyl)cyclobutyl)carbamate tert-butyl ester (85-2, 1.8 g, 5.02 mmol) was dissolved in DMF (60 mL), and cuprous iodide (574 mg, 3.12 mmol) and DBU (2.29 g, 15.06 mmol) were added. The system was heated to 120 °C for 16 h under nitrogen protection. After the reaction was completed, water (300 mL) was added, and the mixture was extracted with EA (50 mL × 3). The organic phases were combined, 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 (PE / EA = 10:1) to give 2'H,4'H-spiro[cyclobutane-1,3'-pyrazino[2,3-b][1,4]oxazine]-4'-carboxylic acid tert-butyl ester (85-3, 1 g), yield 71.8%.

[0710] LC-MS (m / z): 278.0 [M+H] + .

[0711] Step 3: Synthesis of 2'H,4'H-spiro[cyclobutane-1,3'-pyrazino[2,3-b][1,4]oxazine] (85-4)

[0712] 2'H,4'H-spiro[cyclobutane-1,3'-pyrazino[2,3-b][1,4]oxazine]-4'-carboxylic acid tert-butyl ester (85-3, 600 mg, 2.16 mmol) was dissolved in HCl-saturated EA (10 mL) and reacted at room temperature for 3 h. After the reaction was completed, the solution was concentrated under reduced pressure, the pH was adjusted to 8 with saturated sodium bicarbonate aqueous solution, and extracted with DCM (10 mL x 3). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 2'H,4'H-spiro[cyclobutane-1,3'-pyrazino[2,3-b][1,4]oxazine] (85-4, 350 mg), yield 75.7%.

[0713] LC-MS (m / z): 178.0 [M+H] + .

[0714] Step 4: Synthesis of 4'-(4-bromophenyl)-2'H,4'H-spiro[cyclobutane-1,3'-pyrazino[2,3-b][1,4]oxazine] (85-5)

[0715] 2'H,4'H-spiro[cyclobutane-1,3'-pyrazino[2,3-b][1,4]oxazine] (85-4, 550 mg, 3.1 mmol) was dissolved in DMF (5 mL), and p-bromoiodobenzene (1.05 g, 3.72 mmol), cuprous iodide (355 mg, 1.86 mmol), and DBU (1.41 g, 9.3 mmol) were added. The system was purged under nitrogen atmosphere and the temperature was raised to 120 °C for 16 h. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE / EA = 3:1) to give 4'-(4-bromophenyl)-2'H,4'H-spiro[cyclobutane-1,3'-pyrazino[2,3-b][1,4]oxazine] (85-5, 497 mg), with a yield of 48.2%.

[0716] LC-MS (m / z): 332.0, 334.0 [M+H] + .

[0717] Step 5: Synthesis of 4'-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)phenyl)-2'H,4'H-spiro[cyclobutane-1,3'-pyrazino[2,3-b][1,4]oxazine] (85-6)

[0718] 4'-(4-bromophenyl)-2'H,4'H-spiro[cyclobutane-1,3'-pyrazino[2,3-b][1,4]oxazine] (85-5, 497 mg, 1.5 mmol) was dissolved in dioxane (5 mL), and pinacol diboronate (570 mg, 2.24 mmol), Pd(dppf)Cl2 (110 mg, 0.15 mmol) and potassium acetate (294 mg, 2.99 mmol) were added. The system was purged under a nitrogen atmosphere and heated to 100 °C for 2 h. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (PE / EA = 3:1) to give 4'-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborphane-2-yl)phenyl)-2'H,4'H-spiro[cyclobutane-1,3'-pyrazino[2,3-b][1,4]oxazine] (85-6, 180 mg), yield 31.7%.

[0719] LC-MS (m / z): 380.0 [M+H] + .

[0720] Step 6: Synthesis of 3-(2-chloro-4'-(2'H,4'H-spiro[cyclobutane-1,3'-pyrazino[2,3-b][1,4]oxazine]-4'-yl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (85)

[0721] 3-(3-bromo-2-chlorophenyl)piperidin-2,6-dione (M1, 120 mg, 0.4 mmol) was dissolved in DMF (3 mL), and 4'-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborphane-2-yl)phenyl)-2'H,4'H-spiro[cyclobutane-1,3'-pyrazino[2,3-b][1,4]oxazine] (85-6, 165 mg, 0.44 mmol), Pd(dppf)Cl2 (29 mg, 0.04 mmol) and potassium acetate (78 mg, 0.80 mmol) were added. The system was purged under a nitrogen atmosphere and heated to 100 °C for 5 h. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (DCM / MeOH = 20:1) to give 3-(2-chloro-4'-(2'H,4'H-spiro[cyclobutane-1,3'-pyrazino[2,3-b][1,4]oxazine]-4'-yl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione (85,62 mg), yield 32.9%.

[0722] LC-MS (m / z): 475.0 [M+H] + .

[0723] 1 H NMR (600MHz, DMSO-d6): δ10.94 (s, 1H), 7.57 (d, J = 4.8Hz, 1H), 7.55-7.54 (m, 2H), 7.4 5-7.41(m,3H),7.40-7.38(m,1H),7.32-7.31(m,2H),4.53(s,2H),4.39(dd,J1=12.0H z,J2=4.8Hz,1H),2.83-2.78(m,1H),2.58-2.54(m,1H),2.39-2.32(m,1H),2.21-2.1 5(m,2H),2.09-2.06(m,1H),2.03-1.99(m,2H),1.86-1.78(m,1H),1.60-1.54(m,1H).

[0724] Example 87: Synthesis of 3-(2-chloro-4'-(4'-oxo-7'H-spiro[cyclobutane-1,6'-pyrazolo[1,5-a]pyrazine]-5'(4'H)-yl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (Compound 87)

[0725] Step 1: Synthesis of methyl 1-((1-((tert-Butoxycarbonyl)amino)cyclobutyl)methyl)-1H-pyrazole-5-carboxylic acid (87-2)

[0726] 1H-pyrazole-5-carboxylic acid methyl ester (87-1, 3.06 g, 24.26 mmol) was dissolved in THF (100 mL), and tert-butyl(1-hydroxymethylcyclobutyl)carbamate (7.33 g, 36.29 mmol), triphenylphosphine (9.55 g, 36.29 mmol), and DIAD (7.35 g, 36.29 mmol) were added. The system was purged under nitrogen atmosphere and stirred at room temperature for 24 h. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE / EA = 4:1) to give 1-((1-((tert-butyloxycarbonyl)amino)cyclobutyl)methyl)-1H-pyrazole-5-carboxylic acid methyl ester (87-2, 2 g), yield 26.6%.

[0727] LC-MS (m / z): 310.0 [M+H] + .

[0728] Step 2: Synthesis of 1-((1-aminocyclobutyl)methyl)-1H-pyrazole-5-carboxylic acid methyl ester hydrochloride (87-3)

[0729] Methyl 1-((1-((tert-Butoxycarbonyl)amino)cyclobutyl)methyl)-1H-pyrazole-5-carboxylic acid (87-2, 2 g, 6.46 mmol) was dissolved in 15 mL of HCl-saturated EA and stirred at room temperature for 2 h. After the reaction was completed, the solution was concentrated under reduced pressure to give methyl 1-((1-aminocyclobutyl)methyl)-1H-pyrazole-5-carboxylic acid hydrochloride (87-3, 1.59 g), which was used directly in the next step.

[0730] LC-MS (m / z): 210.0 [M+H] + .

[0731] Step 3: Synthesis of 7'H-spiro[cyclobutane-1,6'-pyrazolo[1,5-a]pyrazine]-4'(5'H)-one (87-4)

[0732] The methyl 1-((1-aminocyclobutyl)methyl)-1H-pyrazole-5-carboxylic acid hydrochloride (87-3) obtained in the previous step was dissolved in MeOH (20 mL), and triethylamine (4 mL) was added. The system was heated to 80 °C and reacted for 8 h. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE / EA = 3:2) to give 7'H-spiro[cyclobutane-1,6'-pyrazolo[1,5-a]pyrazine]-4'(5'H)-one (87-4, 1 g), with a two-step yield of 87.2%.

[0733] LC-MS (m / z): 178.0 [M+H] + .

[0734] Step 4: Synthesis of 5'-(4-bromophenyl)-7'H-spiro[cyclobutane-1,6'-pyrazolo[1,5-a]pyrazine]-4'(5'H)-one (87-5)

[0735] 7'H-spiro[cyclobutane-1,6'-pyrazolo[1,5-a]pyrazine]-4'(5'H)-one (87-4, 720 mg, 4.06 mmol) was dissolved in DMF (12 mL), and p-bromoiodobenzene (1.38 g, 4.88 mmol), cuprous iodide (464 mg, 2.44 mmol), and DBU (1.85 g, 12.18 mmol) were added. The system was purged under nitrogen atmosphere and the temperature was raised to 120 °C for 16 h. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE / EA = 3:2) to give 5'-(4-bromophenyl)-7'H-spiro[cyclobutane-1,6'-pyrazolo[1,5-a]pyrazine]-4'(5'H)-one (87-5, 300 mg), yield 22.2%.

[0736] LC-MS (m / z): 332.0, 334.0 [M+H] + .

[0737] Step 5: Synthesis of 5'-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborphane-2-yl)phenyl)-7'H-spiro[cyclobutane-1,6'-pyrazolo[1,5-a]pyrazine]-4'(5'H)-one (87-6)

[0738] 5'-(4-bromophenyl)-7'H-spiro[cyclobutane-1,6'-pyrazolo[1,5-a]pyrazine]-4'(5'H)-one (87-5, 290 mg, 0.87 mmol) was dissolved in dioxane (5 mL), and pinacol diboronic acid ester (332 mg, 1.31 mmol), Pd(dppf)Cl2 (64 mg, 0.09 mmol) and potassium acetate (171 mg, 1.75 mmol) were added. The system was purged under a nitrogen atmosphere and heated to 100 °C for 2 h. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE / EA = 3:2) to give 5'-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborphane-2-yl)phenyl)-7'H-spiro[cyclobutane-1,6'-pyrazolo[1,5-a]pyrazine]-4'(5'H)-one (87-6, 230 mg), yield 69.5%.

[0739] LC-MS (m / z): 380.0 [M+H] + .

[0740] Step 6: Synthesis of 3-(2-chloro-4'-(4'-oxo-7'H-spiro[cyclobutane-1,6'-pyrazolo[1,5-a]pyrazine]-5'(4'H)-yl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (87)

[0741] 3-(3-bromo-2-chlorophenyl)piperidin-2,6-dione (M1, 100 mg, 0.33 mmol) was dissolved in DMF (5 mL), and 5'-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborphanecyclopentan-2-yl)phenyl)-7'H-spiro[cyclobutane-1,6'-pyrazolo[1,5-a]pyrazine]-4'(5'H)-one (87-6, 150 mg, 0.40 mmol), Pd(dppf)Cl2 (24 mg, 0.03 mmol) and potassium acetate (65 mg, 0.66 mmol) were added. The system was purged under a nitrogen atmosphere and the temperature was raised to 100 °C for 4 h. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (DCM / MeOH = 20:1) to give 3-(2-chloro-4'-(4'-oxo-7'H-spiro[cyclobutane-1,6'-pyrazolo[1,5-a]pyrazine]-5'(4'H)-yl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione (87, 10 mg), yield 6.4%.

[0742] LC-MS (m / z): 475.0 [M+H] + .

[0743] 1 H NMR (600MHz, DMSO-d6): δ10.94(s,1H),7.66(d,J=1.8Hz,1H),7.56(d,J=8.4Hz,2H),7. 45-7.43(m,1H),7.42-7.39(m,4H),6.84(d,J=1.8Hz,1H),4.76(s,2H),4.39(dd,J1=12 .6Hz, J2=5.4Hz,1H),2.86-2.78(m,1H),2.58-2.54(m,1H),2.37-2.32(m,1H),2.16-2. 11(m,2H),2.09-2.05(m,1H),2.00-1.95(m,2H),1.93-1.87(m,1H),1.63-1.58(m,1H).

[0744] Example 90: Synthesis of 3-(2-chloro-4'-(7'H-spiro[cyclopropane-1,6'-pyrazino[2,3-e][1,4]oxazapyrrol]-5'(9'H)-yl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (compound 90)

[0745] Step 1: Synthesis of (3-bromopyrazin-2-yl)methanol (90-2)

[0746] Methyl 3-bromopyrazine-2-carboxylic acid (90-1, 8.0 g, 37.04 mmol) and lithium chloride (3.4 g, 81.49 mmol) were dissolved in THF (50 mL) and ethanol (20 mL). The system was protected with nitrogen, and sodium borohydride (5.6 g, 148.16 mmol) was added at 0 °C. The mixture was stirred overnight at room temperature. After the reaction was complete, the mixture was quenched with water (40 mL), extracted with ethyl acetate (20 mL × 3), and the organic phases were combined. The mixture was washed with saturated NaCl (20 mL), dried over anhydrous Na₂SO₄, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA = 3:1) to give (3-bromopyrazine-2-yl)methanol (90-2, 2.8 g), with a yield of 40.6%.

[0747] LC-MS (m / z): 189.0, 191.0 [M+H] + .

[0748] Step 2: Synthesis of 2-bromo-3-(bromomethyl)pyrazine (90-3)

[0749] (3-bromopyrazin-2-yl)methanol (90-2, 2.8 g, 14.89 mmol) was dissolved in THF (30 mL), and phosphine tribromide (6.1 g, 22.34 mmol) was added under ice bath conditions. The reaction was stirred at room temperature for 2 h. After the reaction was completed, the mixture was quenched with saturated sodium thiosulfate solution (20 mL) and extracted with EA (20 mL × 3). The organic phases were combined, washed with saturated NaCl (20 mL), dried over anhydrous Na₂SO₄, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA = 3:1) to give 2-bromo-3-(bromomethyl)pyrazine (90-3, 2.8 g), with a yield of 75.7%.

[0750] LC-MS(m / z):251.0,253.0,255.0[M+H] + .

[0751] Step 3: Synthesis of (1-(((3-bromopyrazin-2-yl)methoxy)methyl)cyclopropyl)tert-butyl carbamate (90-4)

[0752] 2-Bromo-3-(bromomethyl)pyrazine (90-3, 2.8 g, 11.20 mmol), tert-butyl (1-hydroxymethylcyclopropyl)carbamate (3.1 g, 16.80 mmol), and cesium carbonate (10.9 g, 33.60 mmol) were dissolved in acetonitrile (30 mL), and the mixture was heated to 50 °C and reacted for 1 h. After the reaction was complete, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA = 3:1) to give tert-butyl (1-(((3-bromopyrazin-2-yl)methoxy)methyl)cyclopropyl)carbamate (90-4, 1.2 g), in 30.8% yield.

[0753] LC-MS (m / z): 358.0, 360.0 [M+H] + .

[0754] Step 4: Synthesis of 7'H-spiro[cyclopropane-1,6'-pyrazino[2,3-e][1,4]oxazono]-5'(9'H)-tert-butyl carboxylate (90-5)

[0755] (1-(((3-bromopyrazin-2-yl)methoxy)methyl)cyclopropyl)tert-butyl carbamate (90-4, 1.2 g, 3.36 mmol), cuprous iodide (659 mg, 3.36 mmol), and DBU (1.5 g, 10.08 mmol) were dissolved in DMF (10 mL), and the mixture was heated to 120 °C overnight under nitrogen protection. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (PE:EA = 3:1) to give 7'H-spiro[cyclopropane-1,6'-pyrazino[2,3-e][1,4]oxazapyridine]-5'(9'H)-tert-butyl carboxylate (90-5, 450 mg), yield 48.4%.

[0756] LC-MS (m / z): 278.0 [M+H] + .

[0757] Step 5: Synthesis of 5',9'-dihydro-7'H-spiro[cyclopropane-1,6'-pyrazinyl[2,3-e][1,4]oxazonyl](90-6)

[0758] 7'H-spiro[cyclopropane-1,6'-pyrazino[2,3-e][1,4]oxazazole]-5'(9'H)-carboxylic acid tert-butyl ester (90-5, 450 mg, 1.62 mmol) was added to a reaction flask, and HCl-saturated EA (3 mL) was added dropwise. The reaction was carried out at room temperature for 2 h. After the reaction was completed, the pH of the system was adjusted to weakly alkaline with saturated sodium bicarbonate solution, and the mixture was extracted with EA (5 mL × 3). The organic phases were combined, washed with saturated NaCl (10 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA = 3:1) to give 5',9'-dihydro-7'H-spiro[cyclopropane-1,6'-pyrazino[2,3-e][1,4]oxazazole] (90-6, 80 mg), with a yield of 27.8%.

[0759] LC-MS (m / z): 178.0 [M+H] + .

[0760] Step 6: Synthesis of 5'-(4-bromophenyl)-5',9'-dihydro-7'H-spiro[cyclopropane-1,6'-pyrazino[2,3-e][1,4]oxazapine](90-7)

[0761] 5',9'-dihydro-7'H-spiro[cyclopropane-1,6'-pyrazino[2,3-e][1,4]oxazazepine] (90-6, 80 mg, 0.45 mmol), cuprous iodide (86 mg, 0.45 mmol), p-bromoiodobenzene (254 mg, 0.90 mmol), and DBU (205 mg, 1.35 mmol) were dissolved in DMF (1 mL), and the mixture was heated to 120 °C overnight under nitrogen protection. After the reaction was complete, the mixture was concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA = 3:1) to give 5'-(4-bromophenyl)-5',9'-dihydro-7'H-spiro[cyclopropane-1,6'-pyrazino[2,3-e][1,4]oxazazepine] (90-7, 45 mg), in 30.2% yield.

[0762] LC-MS (m / z): 332.0, 334.0 [M+H] + .

[0763] Step 7: Synthesis of 5'-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborphane-2-yl)phenyl)-5',9'-dihydro-7'H-spiro[cyclopropane-1,6'-pyrazino[2,3-e][1,4]oxazono](90-8)

[0764] 5'-(4-bromophenyl)-5',9'-dihydro-7'H-spiro[cyclopropane-1,6'-pyrazino[2,3-e][1,4]oxazono] (90-7, 45 mg, 0.14 mmol), pinacol diboronic acid ester (276 mg, 1.12 mmol), KOAc (110 mg, 1.12 mmol), and Pd(dppf)Cl2 (30 mg, 0.04 mmol) were added sequentially to the flask, followed by dioxane (1 mL). The system was heated to 100 °C and reacted for 4 h under nitrogen protection. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (PE:EA = 3:1) to give crude product of 5'-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborphane-2-yl)phenyl)-5',9'-dihydro-7'H-spiro[cyclopropane-1,6'-pyrazino[2,3-e][1,4]oxazazepine] (90-8,60 mg).

[0765] LC-MS (m / z): 380.0 [M+H] + .

[0766] Step 8: Synthesis of 3-(2-chloro-4'-(7'H-spiro[cyclopropane-1,6'-pyrazino[2,3-e][1,4]oxazapyrrol]-5'(9'H)-yl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (90)

[0767] The crude product (90-1) obtained in the previous step was dissolved in DMF (1 mL), and 3-(3-bromo-2-chlorophenyl)piperidin-2,6-dione (43 mg, 0.14 mmol), KOAc (47 mg, 0.48 mmol), and Pd(dppf)Cl2 (12 mg, 0.02 mmol) were added sequentially. The system was heated to 100 °C for 3 h under nitrogen protection. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (DCM:MeOH = 20:1) to give 3-(2-chloro-4'-(7'H-spiro[cyclopropane-1,6'-pyrazino[2,3-e][1,4]oxazapyrrol]-5'(9'H)-yl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione (90, 8 mg), with a two-step yield of 12.4%.

[0768] LC-MS (m / z): 475.0 [M+H] + .

[0769] 1H NMR (400MHz, DMSO-d6): δ10.92(s,1H),8.34-8.32(m,2H),7.40-7.36(m,1H),7.34-7.27(m,6H),4.90(s,2H),4.36(dd,J1=12.4Hz,J2= 5.2Hz,1H),3.88(s,2H),2.83-2.75(m,1H),2.57-2.55(m,1H),2.38-2.28(m,1H),2.07-2.01(m,1H),1.09--1.08(m,2H),0.92(s,2H).

[0770] Example 94: Synthesis of 3-(2-chloro-4'-(5a,6,7,7a-tetrahydro-8H-cyclobutano[b]pyrazino[2,3-e][1,4]oxazin-8-yl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (compound 94)

[0771] Step 1: Synthesis of (2-((3-bromopyrazin-2-yl)oxy)cyclobutyl)carbamate (94-2)

[0772] 2,3-Dibromopyrazine (94-1, 1.3 g, 5.43 mmol) was dissolved in THF (40 mL), and benzyl (2-hydroxycyclobutyl)carbamate (1.0 g, 4.52 mmol) and cesium carbonate (3.0 g, 9.04 mmol) were added sequentially. The mixture was heated to 70 °C and reacted for 16 hours. After the reaction was complete, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA = 4:1) to give benzyl (2-((3-bromopyrazin-2-yl)oxy)cyclobutyl)carbamate (94-2, 1.5 g), with a yield of 73.5%.

[0773] LC-MS (m / z): 378.0 [M+H] + .

[0774] Step 2: Synthesis of 5a,6,7,7a-tetrahydro-8H-cyclobutano[b]pyrazino[2,3-e][1,4]oxazine-8-carboxylic acid benzyl ester (94-3)

[0775] (2-((3-bromopyrazin-2-yl)oxy)cyclobutyl)carbamate (94-2, 1.5 g, 3.98 mmol) was dissolved in DMF (30 mL), and CuI (372 mg, 1.99 mmol) and DBU (1.2 g, 7.96 mmol) were added. The mixture was heated to 120 °C for 16 hours under nitrogen protection. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (PE:EA = 3:1) to give 5a,6,7,7a-tetrahydro-8H-cyclobutano[b]pyrazino[2,3-e][1,4]oxazine-8-carboxylic acid benzyl ester (94-3, 320 mg), yield 27.1%.

[0776] LC-MS (m / z): 298.0 [M+H] + .

[0777] Step 3: Synthesis of 5a,6,7a,8-tetrahydro-7H-cyclobutane[b]pyrazino[2,3-e][1,4]oxazine (94-4)

[0778] 5a,6,7,7a-tetrahydro-8H-cyclobutan[b]pyrazino[2,3-e][1,4]oxazine-8-carboxylic acid benzyl ester (94-3, 300 mg, 1.01 mmol) was dissolved in THF (10 mL), and 10% Pd / C (60 mg) was added. The system was replaced with a hydrogen atmosphere, and the reaction was carried out at room temperature for 24 hours. After the reaction was completed, the mixture was filtered through diatomaceous earth, and the filter cake was washed with EA (30 mL). The filtrates were combined and concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA = 3:1) to give 5a,6,7a,8-tetrahydro-7H-cyclobutan[b]pyrazino[2,3-e][1,4]oxazine (94-4, 80 mg), with a yield of 48.8%.

[0779] LC-MS (m / z): 164.0 [M+H] + .

[0780] Step 4: Synthesis of 8-(4-bromophenyl)-5a,6,7a,8-tetrahydro-7H-cyclobutanorhexano[b]pyrazino[2,3-e][1,4]oxazine (94-5)

[0781] 5a,6,7a,8-tetrahydro-7H-cyclobutan[b]pyrazino[2,3-e][1,4]oxazine (94-4, 68 mg, 0.42 mmol) and p-bromoiodobenzene (156 mg, 0.54 mmol) were dissolved in DMF (5 mL), and CuI (39 mg, 0.21 mmol) and DBU (125 mg, 0.82 mmol) were added. The system was heated to 120 °C for 16 hours under nitrogen protection. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (PE:EA = 3:1) to give 8-(4-bromophenyl)-5a,6,7a,8-tetrahydro-7H-cyclobutan[b]pyrazino[2,3-e][1,4]oxazine (94-5, 70 mg), yield 53.0%.

[0782] LC-MS (m / z): 318.0, 320.0 [M+H] + .

[0783] Step 5: Synthesis of 8-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)phenyl)-5a,6,7a,8-tetrahydro-7H-cyclobutano[b]pyrazino[2,3-e][1,4]oxazine (94-6)

[0784] 8-(4-bromophenyl)-5a,6,7a,8-tetrahydro-7H-cyclobutanorhexano[b]pyrazino[2,3-e][1,4]oxazine (94-5, 63 mg, 0.20 mmol), pinacol diboronate (102 mg, 0.40 mmol), KOAc (39 mg, 0.40 mmol), and Pd(dppf)Cl2 (15 mg, 0.02 mmol) were added sequentially to a flask, followed by dioxane (5 mL). The system was heated to 100 °C under nitrogen protection and reacted for 6 hours. After the reaction was completed, the mixture was concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA = 3:1) to give 8-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborphanecyclopentan-2-yl)phenyl)-5a,6,7a,8-tetrahydro-7H-cyclobutano[b]pyrazino[2,3-e][1,4]oxazine (94-6,70 mg) in 95.8% yield.

[0785] LC-MS (m / z): 366.0 [M+H] + .

[0786] Step 6: Synthesis of 3-(2-chloro-4'-(5a,6,7,7a-tetrahydro-8H-cyclobutano[b]pyrazino[2,3-e][1,4]oxazin-8-yl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (compound 94)

[0787] 8-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborphanecyclopentan-2-yl)phenyl)-5a,6,7a,8-tetrahydro-7H-cyclobutan[b]pyrazino[2,3-e][1,4]oxazine (94-6, 45 mg, 0.12 mmol) was dissolved in DMF (5 mL), followed by the addition of 3-(3-bromo-2-chlorophenyl)piperidin-2,6-dione (M1, 33 mg, 0.11 mmol), KOAc (24 mg, 0.25 mmol), and Pd(dppf)Cl2 (9 mg, 0.01 mmol). The mixture was heated to 100 °C and reacted for 16 hours under nitrogen protection. After the reaction was completed, the mixture was concentrated under reduced pressure. The residue was purified by column chromatography (DCM:MeOH = 20:1) to give 3-(2-chloro-4'-(5a,6,7,7a-tetrahydro-8H-cyclobutano[b]pyrazino[2,3-e][1,4]oxazin-8-yl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione (94,26 mg), yield 45.9%.

[0788] LC-MS (m / z): 461.0 [M+H] + .

[0789] 1 H NMR(600MHz,DMSO-d6):10.93(s,1H),7.82(s,1H),7.69(s,1H),7.50(d,J=8.4 Hz,2H),7.41-7.38(m,3H),7.35-7.32(m,2H),4.36(dd,J1=12.0Hz,J2=4.8Hz,1 H),4.25-4.21(m,1H),3.85(q,J=8.4Hz,1H),2.82-2.76(m,1H),2.57-2.50(m,2 H),2.38-2.30(m,2H),2.16-2.10(m,1H),2.07-2.03(m,1H),1.73-1.67(m,1H).

[0790] Example 95: Synthesis of 3-(2-chloro-4'-(8'-oxo-5'H-spiro[cyclobutane-1,6'-imidazo[1,2-a]pyrazine]-7'(8'H)-yl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (Compound 95)

[0791] Step 1: Synthesis of ethyl 1-((1-((tert-Butoxycarbonyl)amino)cyclobutyl)methyl)-1H-imidazolium-2-carboxylate (95-2)

[0792] Ethyl 1H-imidazolium-2-carboxylate (95-1, 4.18 g, 29.61 mmol) was dissolved in toluene (100 mL), and tert-butyl(1-hydroxymethylcyclobutyl)carbamate (7.15 g, 35.54 mmol) and cyanomethylenetri-n-butylphosphine (7.92 g, 32.84 mmol) were added. The system was heated to 100 °C for 2 h under nitrogen protection. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (DCM / MeOH = 30:1) to give ethyl 1-((1-((tert-butyloxycarbonyl)amino)cyclobutyl)methyl)-1H-imidazolium-2-carboxylate (95-2, 8 g), yield 82.9%.

[0793] LC-MS (m / z): 324.0 [M+H] + .

[0794] Step 2: Synthesis of 1-((1-aminocyclobutyl)methyl)-1H-imidazolium-2-carboxylic acid ethyl ester hydrochloride (95-3)

[0795] Ethyl 1-((1-((tert-Butoxycarbonyl)amino)cyclobutyl)methyl)-1H-imidazolium-2-carboxylate (95-2, 8 g, 24.74 mmol) was dissolved in HCl-saturated EA (30 mL), and the mixture was stirred at room temperature for 3 h. After the reaction was completed, the solution was concentrated under reduced pressure to obtain crude ethyl hydrochloride of 1-((1-aminocyclobutyl)methyl)-1H-imidazolium-2-carboxylate (95-3, 6.43 g), which was used directly in the next step.

[0796] LC-MS (m / z): 224.0 [M+H] + .

[0797] Step 3: Synthesis of 5'H-spiro[cyclobutane-1,6'-imidazo[1,2-a]pyrazine]-8'(7'H)-one (95-4)

[0798] The crude 1-((1-aminocyclobutyl)methyl)-1H-imidazolium-2-carboxylic acid ethyl ester hydrochloride (95-3) obtained in the previous step was dissolved in MeOH (30 mL) and triethylamine (10 mL), and the system was heated to 80 °C and reacted for 4 h. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (DCM / MeOH = 20:1) to give 5'H-spiro[cyclobutane-1,6'-imidazo[1,2-a]pyrazine]-8'(7'H)-one (95-4, 3 g), with a two-step yield of 68.4%.

[0799] LC-MS (m / z): 178.0 [M+H] + .

[0800] Step 4: Synthesis of 7'-(4-bromophenyl)-5'H-spiro[cyclobutane-1,6'-imidazo[1,2-a]pyrazine]-8'(7'H)-one (95-5)

[0801] 5'H-spiro[cyclobutane-1,6'-imidazo[1,2-a]pyrazine]-8'(7'H)-one (95-4, 2 g, 11.29 mmol) was dissolved in DCE (40 mL), and (4-bromophenyl)boronic acid (6.8 g, 33.86 mmol), copper acetate (2.05 g, 11.29 mmol), and triethylamine (4.57 g, 45.14 mmol) were added. The system was replaced with an oxygen atmosphere, and the reaction was carried out at room temperature for 16 h. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (DCM / MeOH = 30:1) to give 7'-(4-bromophenyl)-5'H-spiro[cyclobutane-1,6'-imidazo[1,2-a]pyrazine]-8'(7'H)-one (95-5, 700 mg), yield 18.7%.

[0802] LC-MS (m / z): 332.0, 334.0 [M+H] + .

[0803] Step 5: Synthesis of 3-(2-chloro-4'-(8'-oxo-5'H-spiro[cyclobutane-1,6'-imidazo[1,2-a]pyrazine]-7'(8'H)-yl)-[1,1'-biphenyl]-3-yl)-1-(4-methoxybenzyl)piperidine-2,6-dione (95-6)

[0804] 7'-(4-bromophenyl)-5'H-spiro[cyclobutane-1,6'-imidazo[1,2-a]pyrazine]-8'(7'H)-one (95-5, 690 mg, 2.08 mmol) was dissolved in DMF (20 mL), and 3-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)phenyl)-1-(4-methoxybenzyl)piperidin-2,6-dione (M3, 1.46 g, 2.49 mmol), Pd(dppf)Cl2 (150 mg, 0.21 mmol) and potassium acetate (408 mg, 4.15 mmol) were added. The system was replaced with a nitrogen atmosphere, and the temperature was raised to 100 °C and reacted for 12 h. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (DCM / MeOH = 97:3) to give 3-(2-chloro-4'-(8'-oxo-5'H-spiro[cyclobutane-1,6'-imidazo[1,2-a]pyrazine]-7'(8'H)-yl)-[1,1'-biphenyl]-3-yl)-1-(4-methoxybenzyl)piperidine-2,6-dione (95-6, 1 g), yield 40.5%.

[0805] LC-MS (m / z): 595.0 [M+H] + .

[0806] Step 6: Synthesis of 3-(2-chloro-4'-(8'-oxo-5'H-spiro[cyclobutane-1,6'-imidazo[1,2-a]pyrazine]-7'(8'H)-yl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (95)

[0807] 3-(2-chloro-4'-(8'-oxo-5'H-spiro[cyclobutane-1,6'-imidazo[1,2-a]pyrazine]-7'(8'H)-yl)-[1,1'-biphenyl]-3-yl)-1-(4-methoxybenzyl)piperidine-2,6-dione (95-6, 540 mg, 0.91 mmol) was dissolved in TFA (4 mL) and trifluoromethanesulfonic acid (0.8 mL) and reacted at room temperature for 24 h. After the reaction was complete, the mixture was concentrated under reduced pressure, then neutralized with saturated sodium bicarbonate aqueous solution, extracted with EA (15 mL × 3), the organic phases were combined, washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (DCM / MeOH = 20:1) to give 3-(2-chloro-4'-(8'-oxo-5'H-spiro[cyclobutane-1,6'-imidazo[1,2-a]pyrazine]-7'(8'H)-yl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione (95, 60 mg), yield 13.9%.

[0808] LC-MS (m / z): 475.0 [M+H] + .

[0809] 1 H NMR (600MHz, DMSO-d6): δ10.94(s,1H),7.55-7.54(m,2H),7.48(s,1H),7.44 -7.41(m,1H),7.41-7.37(m,4H),7.21(s,1H),4.66(s,2H),4.39(dd,J1=12. 0Hz, J2=4.8Hz,1H),2.84-2.78(m,1H),2.58-2.52(m,1H),2.39-2.33(m,1H) ,2.14-2.05(m,3H),1.98-1.94(m,2H),1.84-1.79(m,1H),1.65-1.60(m,1H).

[0810] Example 96: 3-(2-chloro-4'-(3'-methyl-8'-oxo-5'H-spiro[cyclopropane-1,6'-imidazo[1,5-a]pyrazine]-7'(8'H)-yl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione (96)

[0811] Step 1: Synthesis of methyl 2-methyl-1H-imidazolium-5-carboxylate (96-2)

[0812] 2-Methyl-1H-imidazolium-5-carboxylic acid (96-1, 5.0 g, 39.68 mmol) was dissolved in methanol (30 mL), and concentrated hydrochloric acid (15 mL) was slowly added dropwise. The system was heated to 80 °C and reacted for 4 h. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was adjusted to neutral with saturated NaHCO3 solution (30 mL) and extracted with DCM (30 mL × 3). The organic phases were combined, washed with saturated NaCl (30 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (DCM:MeOH = 20:1) to give methyl 2-methyl-1H-imidazolium-5-carboxylic acid (96-2, 3.5 g), yield 63.6%.

[0813] LC-MS (m / z): 141.0 [M+H] + .

[0814] Step 2: Synthesis of methyl 2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazolium-5-carboxylate (96-3)

[0815] 2-Methyl-1H-imidazolium-5-carboxylate (96-2, 5.0 g, 35.71 mmol), cesium carbonate (8.9 g, 53.57 mmol), and THF (50 mL) were added to a flask, followed by 2-(trimethylsilyl)ethoxymethyl chloride (23.3 g, 71.42 mmol). The reaction was carried out at room temperature for 2 h. After the reaction was complete, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA = 1:1) to give 2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazolium-5-carboxylate (96-3, 4.8 g), in 49.8% yield.

[0816] LC-MS (m / z): 271.0 [M+H] + .

[0817] Step 3: Synthesis of 2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-carboxylic acid (96-4)

[0818] Methyl 2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazolium-5-carboxylic acid (96-3, 4.8 g, 17.80 mmol) was dissolved in methanol (40 mL), and an aqueous solution of lithium hydroxide (1.3 g, 53.40 mmol) (10 mL) was added dropwise to the system. The reaction was carried out at room temperature for 2 h. After the reaction was completed, the reaction mixture was concentrated under reduced pressure. The residue was adjusted to pH 3 with 2N hydrochloric acid and extracted with DCM (20 mL × 3). The organic phases were combined, washed with saturated NaCl (20 mL), dried over anhydrous Na2SO4, and concentrated to give crude 2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazolium-5-carboxylic acid (96-4, 4.6 g).

[0819] LC-MS (m / z): 257.0 [M+H] + .

[0820] Step 4: Synthesis of methyl 1-(2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-carbamate)cyclopropane-1-carboxylate (96-5)

[0821] 2-Methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-carboxylic acid (96-4, 4.6 g, 17.97 mmol), methyl 1-aminocyclopropane-1-carboxylate (2.5 g, 21.56 mmol), DIPEA (7.0 g, 53.91 mmol), and DMF (50 mL) were added to the flask, followed by HATU (8.2 g, 21.56 mmol). The reaction was carried out at room temperature for 2 h. After the reaction was completed, the mixture was concentrated under reduced pressure. The residue was washed with EA (30 mL) and saturated NaCl (30 mL × 3). The organic phases were combined, dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (DCM:MeOH = 20:1) to give methyl 1-(2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-carbamate)cyclopropane-1-carboxylate (96-5, 6.0 g), with a two-step yield of 95.7%.

[0822] LC-MS (m / z): 354.0 [M+H] + .

[0823] Step 5: Synthesis of N-(1-(hydroxymethyl)cyclopropyl)-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazolium-5-carboxamide (96-6)

[0824] Methyl 1-(2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-carbamate)cyclopropane-1-carboxylate (96-5, 5.0 g, 14.15 mmol), lithium chloride (11.9 g, 280 mmol), and THF (15 mL) were added to a flask. Under nitrogen protection, sodium borohydride (10.7 g, 280 mmol) was added in an ice bath, followed by ethanol (5 mL). The reaction was then carried out at room temperature for 48 h. After the reaction was completed, water (10 mL) was added in an ice bath, the pH was adjusted to neutral with dilute hydrochloric acid, and the mixture was extracted with DCM (20 mL × 3). The organic phases were combined, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The residue was purified by column chromatography (DCM:MeOH = 10:1) to give N-(1-(hydroxymethyl)cyclopropyl)-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-carboxamide (96-6, 2.6 g), yield 56.5%.

[0825] LC-MS (m / z): 326.0 [M+H] + .

[0826] Step 6: Synthesis of N-(1-(hydroxymethyl)cyclopropyl)-2-methyl-1H-imidazol-5-carboxamide (96-7)

[0827] N-(1-(hydroxymethyl)cyclopropyl)-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-carboxamide (96-6, 2.6 g, 8.0 mmol), trifluoroacetic acid (5 mL), and trifluoromethanesulfonic acid (1 mL) were added sequentially to a flask, and the reaction was carried out at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure, and methanol (20 mL) and potassium carbonate (4.0 g) were added to the residue, and the mixture was stirred at room temperature for 6 h. After the reaction was completed, the mixture was filtered, the filtrate was concentrated, and the residue was purified by column chromatography (DCM:MeOH = 10:1) to give N-(1-(hydroxymethyl)cyclopropyl)-2-methyl-1H-imidazol-5-carboxamide (96-7, 800 mg), with a yield of 51.3%.

[0828] LC-MS (m / z): 196.0 [M+H] + .

[0829] Step 7: Synthesis of 3'-methyl-5'H-spiro[cyclopropane-1,6'-imidazo[1,5-a]pyrazine]-8'(7'H)-one (96-8)

[0830] N-(1-(hydroxymethyl)cyclopropyl)-2-methyl-1H-imidazol-5-carboxamide (96-7, 400 mg, 2.05 mmol) was dissolved in toluene (100 mL), and CMBP (750 mg, 3.08 mmol) was added. The reaction was carried out overnight at 110 °C under nitrogen protection. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (DCM:MeOH = 20:1) to give 3'-methyl-5'H-spiro[cyclopropane-1,6'-imidazo[1,5-a]pyrazine]-8'(7'H)-one (96-8, 140 mg), in 38.6% yield.

[0831] LC-MS (m / z): 178.0 [M+H] + .

[0832] Step 8: Synthesis of 7'-(4-bromophenyl)-3'-methyl-5'H-spiro[cyclopropane-1,6'-imidazo[1,5-a]pyrazine]-8'(7'H)-one (96-9)

[0833] 3'-Methyl-5'H-spiro[cyclopropane-1,6'-imidazo[1,5-a]pyrazine]-8'(7'H)-one (96-8, 140 mg, 0.79 mmol), p-bromoiodobenzene (446 mg, 150 mmol), cuprous iodide (150 mg, 0.79 mmol), and DBU (360 mg, 2.37 mmol) were dissolved in DMF (4 mL). The system was protected under nitrogen, and the temperature was raised to 120 °C and reacted overnight. After the reaction was complete, the mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (DCM:MeOH = 20:1) to give 7'-(4-bromophenyl)-3'-methyl-5'H-spiro[cyclopropane-1,6'-imidazo[1,5-a]pyrazine]-8'(7'H)-one (96-9, 100 mg), with a yield of 38.3%.

[0834] LC-MS (m / z): 332.0, 334.0 [M+H] + .

[0835] Step 9: Synthesis of 3-(2-chloro-4'-(3'-methyl-8'-oxo-5'H-spirocyclic [cyclopropane-1,6'-imidazo[1,5-a]pyrazine]-7'(8'H)-yl)-[1,1'-biphenyl]-3-yl)-1-(4-methoxybenzyl)piperidine-2,6-dione (96-10)

[0836] 7'-(4-bromophenyl)-3'-methyl-5'H-spiro[cyclopropane-1,6'-imidazo[1,5-a]pyrazine]-8'(7'H)-one (96-9, 100 mg, 0.31 mmol), 3-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)phenyl)-1-(4-methoxybenzyl)piperidin-2,6-dione (M3, 144 mg, 0.31 mmol), KOAc (88 mg, 0.85 mmol), and Pd(dppf)Cl2 (22 mg, 0.03 mmol) were added sequentially to the flask, followed by DMF (2 mL). The mixture was heated to 100 °C under nitrogen protection and reacted for 4 h. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (DCM:MeOH = 20:1) to give 3-(2-chloro-4'-(1'-(4-methoxybenzyl)-5'-oxo-3'-(trifluoromethyl)-1'H-spiro[cyclopropane-1,6'-pyrazolo[3,4-b][1,4]oxazine]-4'(5'H)-yl)-[1,1'-biphenyl]-3-yl)-1-(4-methoxybenzyl)piperidine-2,6-dione (96-10, 130 mg), yield 73.0%.

[0837] LC-MS (m / z): 595.0 [M+H] + .

[0838] Step 10: Synthesis of 3-(2-chloro-4'-(3'-methyl-8'-oxo-5'H-spiro[cyclopropane-1,6'-imidazo[1,5-a]pyrazine]-7'(8'H)-yl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (96)

[0839] 3-(2-chloro-4'-(1'-(4-methoxybenzyl)-5'-oxo-3'-(trifluoromethyl)-1'H-spiro[cyclopropane-1,6'-pyrazolo[3,4-b][1,4]oxazine]-4'(5'H)-yl)-[1,1'-biphenyl]-3-yl)-1-(4-methoxybenzyl)piperidine-2,6-dione (96-10, 60 mg, 0.10 mmol) was dissolved in TFA (2 mL), and trifluoromethanesulfonic acid (0.5 mL) was added to the system. The reaction was carried out at 40 °C for 4 hours. After the reaction was complete, the mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (DCM:MeOH = 20:1) to give 3-(2-chloro-4'-(3'-methyl-8'-oxo-5'H-spiro[cyclopropane-1,6'-imidazo[1,5-a]pyrazine]-7'(8'H)-yl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione (96, 15 mg), yield 31.9%.

[0840] LC-MS (m / z): 475.0 [M+H] + .

[0841] 1 H NMR (400MHz, DMSO-d6): δ10.92(s,1H),7.52(s,1H),7.49-7.44(m,2H),7.43-7.31(m,5H),4.39(dd,J1=12.4Hz,J2=5.2Hz,1H),4.29( s,2H),2.85-2.76(m,1H),2.59-2.53(m,1H),2.37(s,3H),2.33-2.29(m,1H),2.12-2.01(m,1H),1.05-0.98(m,2H),0.73-0.66(m,2H).

[0842] Example 97: Synthesis of 3-(2-chloro-4'-(3'-methyl-5'-oxo-7'H-spiro[cyclopropane-1,6'-pyrazolo[1,5-a]pyrimidine]-4'(5'H)-yl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (Compound 97)

[0843] Step 1: Synthesis of ethyl 1-((4-methyl-5-nitro-1H-pyrazol-1-yl)methyl)cyclopropane-1-carboxylate (97-2)

[0844] 4-Methyl-5-nitro-1H-pyrazole (97-1, 3.56 g, 27.98 mmol) was dissolved in toluene (60 mL), and ethyl 1-(hydroxymethyl)cyclopropane-1-carboxylate (4.84 g, 33.57 mmol) and CMBP (8.1 g, 33.57 mmol) were added. The system was heated to 105 °C for 1.5 h under nitrogen protection. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE / EA = 4:1) to give ethyl 1-((4-methyl-5-nitro-1H-pyrazole-1-yl)methyl)cyclopropane-1-carboxylate (97-2, 1.88 g), with a yield of 26.5%.

[0845] LC-MS (m / z): 254.0 [M+H] + .

[0846] Step 2: Synthesis of 3'-methyl-7'H-spiro[cyclopropane-1,6'-pyrazolo[1,5-a]pyrimidine]-5'(4'H)-one (97-3)

[0847] Ethyl 1-((4-methyl-5-nitro-1H-pyrazol-1-yl)methyl)cyclopropane-1-carboxylate (97-2, 1.88 g, 7.42 mmol) was dissolved in acetic acid (16 mL), and iron powder (4.15 g, 74.2 mmol) was added. The system was heated to 90 °C and reacted for 1.5 h. After the reaction was completed, the mixture was concentrated under reduced pressure, and water (50 mL) was added to precipitate the solid. The solid was filtered, and the filter cake was washed with a mixed solvent of DCM and MeOH. The filtrate was extracted with EA (50 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 3'-methyl-7'H-spiro[cyclopropane-1,6'-pyrazolo[1,5-a]pyrimidine]-5'(4'H)-one (97-3, 1.7 g), with a yield of 93.9%.

[0848] LC-MS (m / z): 178.0 [M+H] + .

[0849] Step 3: Synthesis of 4'-(4-bromophenyl)-3'-methyl-7'H-spiro[cyclopropane-1,6'-pyrazolo[1,5-a]pyrimidine]-5'(4'H)-one (97-4)

[0850] 3'-Methyl-7'H-spiro[cyclopropane-1,6'-pyrazolo[1,5-a]pyrimidine]-5'(4'H)-one (97-3, 1.64 g, 9.23 mmol) was dissolved in DCE (30 mL), and p-bromophenylboronic acid (5.56 g, 27.68 mmol), copper acetate (1.68 g, 9.23 mmol), and triethylamine (2.8 g, 27.68 mmol) were added. The system was purged under an oxygen atmosphere and reacted at room temperature for 16 h. After the reaction was complete, the mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE / EA = 4:1) to give 4'-(4-bromophenyl)-3'-methyl-7'H-spiro[cyclopropane-1,6'-pyrazolo[1,5-a]pyrimidine]-5'(4'H)-one (97-4, 240 mg), yield 7.8%.

[0851] LC-MS (m / z): 332.0 [M+H] + .

[0852] Step 4: Synthesis of 3'-methyl-4'-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborphanecyclopentan-2-yl)phenyl)-7'H-spiro[cyclopropane-1,6'-pyrazolo[1,5-a]pyrimidine]-5'(4'H)-one (97-5)

[0853] 4'-(4-bromophenyl)-3'-methyl-7'H-spiro[cyclopropane-1,6'-pyrazolo[1,5-a]pyrimidine]-5'(4'H)-one (97-4, 240 mg, 0.72 mmol) was dissolved in dioxane (5 mL), and pinacol diboronic acid ester (275 mg, 1.08 mmol), Pd(dppf)Cl2 (52 mg, 0.07 mmol) and potassium acetate (142 mg, 1.44 mmol) were added. The system was purged under a nitrogen atmosphere and heated to 100 °C for 2 h. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE / EA = 4:1) to give 3'-methyl-4'-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborphanecyclopentan-2-yl)phenyl)-7'H-spiro[cyclopropane-1,6'-pyrazolo[1,5-a]pyrimidine]-5'(4'H)-one (97-5, 239 mg), yield 87.2%.

[0854] LC-MS (m / z): 380.0 [M+H] + .

[0855] Step 5: Synthesis of 3-(2-chloro-4'-(3'-methyl-5'-oxo-7'H-spiro[cyclopropane-1,6'-pyrazolo[1,5-a]pyrimidine]-4'(5'H)-yl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (97)

[0856] 3-(3-bromo-2-chlorophenyl)piperidin-2,6-dione (M1, 191 mg, 0.63 mmol) was dissolved in DMF (2 mL), and 3'-methyl-4'-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborphane-2-yl)phenyl)-7'H-spiro[cyclopropane-1,6'-pyrazolo[1,5-a]pyrimidine]-5'(4'H)-one (97-5, 239 mg, 0.63 mmol), Pd(dppf)Cl2 (44 mg, 0.06 mmol) and potassium acetate (124 mg, 1.26 mmol) were added. The system was purged under a nitrogen atmosphere and the temperature was raised to 100 °C for 2 h. After the reaction was completed, the mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (DCM / MeOH = 20:1) to give 3-(2-chloro-4'-(3'-methyl-5'-oxo-7'H-spiro[cyclopropane-1,6'-pyrazolo[1,5-a]pyrimidine]-4'(5'H)-yl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione (97,60 mg), yield 20.0%.

[0857] LC-MS (m / z): 475.0 [M+H] + .

[0858] 1 H NMR (400MHz, DMSO-d6): δ10.93(s,1H),7.53(d,J=8.0Hz,2H),7.49-7.35(m,5H),7.16(s,1H),4.39-4.28(m,3H),2.85-2 .74(m,1H),2.57-2.53(m,1H),2.39-2.29(m,1H),2.07-2.04(m,1H),1.31-1.28(m,2H),1.19(s,3H),1.08-1.05(m,2H).

[0859] Example 98: Synthesis of 3-(2-chloro-4'-(5'-oxo-3'-(trifluoromethyl)-1'H-spiro[cyclopropane-1,6'-pyrazolo[3,4-b][1,4]oxazine]-4'(5'H)-yl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (compound 98)

[0860] Step 1: Synthesis of 1-(4-methoxybenzyl)-4-nitro-3-(trifluoromethyl)-1H-pyrazole (98-2)

[0861] 4-Nitro-3-(trifluoromethyl)-1H-pyrazole (98-1, 4.0 g, 22.10 mmol) was dissolved in acetonitrile (60 mL), and 4-methoxybenzyl chloride (3.8 g, 24.31 mmol) and potassium carbonate (9.2 g, 66.30 mmol) were added sequentially. The mixture was stirred at room temperature for 8 h. After the reaction was complete, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA = 3:1) to give 1-(4-methoxybenzyl)-4-nitro-3-(trifluoromethyl)-1H-pyrazole (98-2, 4.6 g), in 69.7% yield.

[0862] LC-MS (m / z): 302.0 [M+H] + .

[0863] Step 2: Synthesis of 5-chloro-1-(4-methoxybenzyl)-4-nitro-3-(trifluoromethyl)-1H-pyrazole (98-3)

[0864] Add 1-(4-methoxybenzyl)-4-nitro-3-(trifluoromethyl)-1H-pyrazole (98-2, 4.6 g, 16.61 mmol) to the flask, add THF (20 mL), and protect the system under nitrogen atmosphere. Cool to -60 °C, and at this temperature, add a 1 M, 20 mL solution of LiHMDS in THF dropwise. Maintain the temperature and stir for 30 min. Then, add hexachloroethane (4.7 g, 19.92 mmol) in portions, and allow the reaction to return to room temperature for 2 h. After the reaction is complete, quench the reaction with saturated ammonium chloride solution (10 mL) and extract with EA (20 mL × 3). Combine the organic phases, wash with saturated NaCl (20 mL), dry with anhydrous Na2SO4, filter, and concentrate the filtrate under reduced pressure. The residue was purified by column chromatography (PE:EA = 3:1) to give 5-chloro-1-(4-methoxybenzyl)-4-nitro-3-(trifluoromethyl)-1H-pyrazole (98-3, 2.2 g), yield 39.3%.

[0865] LC-MS (m / z): 336.0, 338.0 [M+H] + .

[0866] Step 3: Synthesis of methyl 1-((1-(4-methoxybenzyl)-4-nitro-3-(trifluoromethyl)-1H-pyrazol-5-yl)oxy)cyclopropane-1-carboxylate (98-4)

[0867] 5-Chloro-1-(4-methoxybenzyl)-4-nitro-3-(trifluoromethyl)-1H-pyrazole (98-3, 2.2 g, 6.57 mmol), methyl 1-hydroxycyclopropane-1-carboxylate (1.2 g, 9.85 mmol), and cesium carbonate (6.4 g, 19.71 mmol) were dissolved in THF (30 mL), and the mixture was heated to 80 °C and reacted overnight. After the reaction was complete, the mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (PE:EA = 5:1) to give methyl 1-((1-(4-methoxybenzyl)-4-nitro-3-(trifluoromethyl)-1H-pyrazole-5-yl)oxy)cyclopropane-1-carboxylate (98-4, 600 mg), yield 22.2%.

[0868] LC-MS (m / z): 416.0 [M+H] + .

[0869] Step 4: Synthesis of 1'-(4-methoxybenzyl)-3'-(trifluoromethyl)-1',4'-dihydro-5'H-spiro[cyclopropane-1,6'-pyrazolo[3,4-b][1,4]oxazine]-5'-one (98-5)

[0870] Methyl 1-((1-(4-methoxybenzyl)-4-nitro-3-(trifluoromethyl)-1H-pyrazol-5-yl)oxy)cyclopropane-1-carboxylate (98-4, 600 mg, 1.44 mmol) was dissolved in AcOH (10 mL), and iron powder (806 mg, 14.4 mmol) was added under ice bath conditions. The mixture was then heated to 90 °C and reacted for 4 h. After the reaction was completed, the mixture was concentrated under reduced pressure, water (10 mL) was added, the pH was adjusted to 7 with saturated NaHCO3 aqueous solution (20 mL), and EA extraction (20 mL × 3) was performed. The organic phases were combined, washed with saturated NaCl (20 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give 1'-(4-methoxybenzyl)-3'-(trifluoromethyl)-1',4'-dihydro-5'H-spiro[cyclopropane-1,6'-pyrazolo[3,4-b][1,4]oxazine]-5'-one (98-5, 400 mg), yield 78.7%.

[0871] LC-MS (m / z): 354.0 [M+H] + .

[0872] Step 5: Synthesis of 4'-(4-bromophenyl)-1'-(4-methoxybenzyl)-3'-(trifluoromethyl)-1',4'-dihydro-5'H-spiro[cyclopropane-1,6'-pyrazolo[3,4-b][1,4]oxazine]-5'-one (98-6)

[0873] 1'-(4-methoxybenzyl)-3'-(trifluoromethyl)-1',4'-dihydro-5'H-spiro[cyclopropane-1,6'-pyrazolo[3,4-b][1,4]oxazine]-5'-one (98-5, 400 mg, 1.13 mmol), p-bromophenylboronic acid (452 ​​mg, 2.26 mmol), copper acetate (206 mg, 1.13 mmol), and triethylamine (343 mg, 3.39 mmol) were dissolved in DCE (5 mL), and the system was reacted overnight at room temperature under oxygen protection. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (PE:EA = 5:1) to give 4'-(4-bromophenyl)-1'-(4-methoxybenzyl)-3'-(trifluoromethyl)-1',4'-dihydro-5'H-spiro[cyclopropane-1,6'-pyrazolo[3,4-b][1,4]oxazine]-5'-one (98-6, 300 mg), yield 52.4%.

[0874] LC-MS (m / z): 508.0, 510.0 [M+H] + .

[0875] Step 6: Synthesis of 3-(2-chloro-4'-(1'-(4-methoxybenzyl)-5'-oxo-3'-(trifluoromethyl)-1'H-spiro[cyclopropane-1,6'-pyrazolo[3,4-b][1,4]oxazine]-4'(5'H)-yl)-[1,1'-biphenyl]-3-yl)-1-(4-methoxybenzyl)piperidine-2,6-dione (98-7)

[0876] 4'-(4-bromophenyl)-1'-(4-methoxybenzyl)-3'-(trifluoromethyl)-1',4'-dihydro-5'H-spiro[cyclopropane-1,6'-pyrazolo[3,4-b][1,4]oxazine]-5'-one (98-6, 150 mg, 0.29 mmol), 3-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)phenyl)-1-(4-methoxybenzyl)piperidine-2,6-dione (M3, 155 mg, 0.33 mmol), KOAc (89 mg, 0.87 mmol), and Pd(dppf)Cl2 (22 mg, 0.03 mmol) were added sequentially to the flask, followed by DMF (2 mL). The system was heated to 100 °C and reacted for 4 h under nitrogen protection. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (PE:EA = 1:1) to give 3-(2-chloro-4'-(1'-(4-methoxybenzyl)-5'-oxo-3'-(trifluoromethyl)-1'H-spiro[cyclopropane-1,6'-pyrazolo[3,4-b][1,4]oxazine]-4'(5'H)-yl)-[1,1'-biphenyl]-3-yl)-1-(4-methoxybenzyl)piperidine-2,6-dione (98-7, 120 mg), yield 53.8%.

[0877] LC-MS (m / z): 771.0 [M+H] + .

[0878] Step 7: Synthesis of 3-(2-chloro-4'-(5'-oxo-3'-(trifluoromethyl)-1'H-spiro[cyclopropane-1,6'-pyrazolo[3,4-b][1,4]oxazine]-4'(5'H)-yl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (98)

[0879] 3-(2-chloro-4'-(1'-(4-methoxybenzyl)-5'-oxo-3'-(trifluoromethyl)-1'H-spiro[cyclopropane-1,6'-pyrazolo[3,4-b][1,4]oxazine]-4'(5'H)-yl)-[1,1'-biphenyl]-3-yl)-1-(4-methoxybenzyl)piperidine-2,6-dione (98-7, 120 mg, 0.16 mmol) was dissolved in TFA (2 mL), and trifluoromethanesulfonic acid (0.5 mL) was added. The mixture was reacted at 40 °C for 4 hours. After the reaction was complete, the mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (DCM:MeOH = 20:1) to give 3-(2-chloro-4'-(5'-oxo-3'-(trifluoromethyl)-1'H-spiro[cyclopropane-1,6'-pyrazolo[3,4-b][1,4]oxazine]-4'(5'H)-yl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione (98, 32 mg), with a purity of 37.6%.

[0880] LC-MS (m / z): 531.0 [M+H] + .

[0881] Example 99: Synthesis of 3-(2-chloro-4'-(1'-cyclopropyl-3'-methyl-5'-oxo-1'H-spiro[cyclopropane-1,6'-pyrazolo[3,4-b][1,4]oxazine]-4'(5'H)-yl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (compound 99)

[0882] Step 1: Synthesis of 1-cyclopropyl-3-methyl-4-nitro-1H-pyrazole (99-2)

[0883] 3-Methyl-4-nitro-1H-pyrazole (99-1, 9.0 g, 70.86 mmol) was dissolved in DCE (100 mL), and cyclopropylboronic acid (12.2 g, 141.72 mmol), copper acetate (12.9 g, 70.86 mmol), sodium bicarbonate (11.9 g, 141.72 mmol), and bipyridine (11.1 g, 70.86 mmol) were added. The system was replaced with an oxygen atmosphere, and the temperature was raised to 70 °C for 16 hours. After the reaction was completed, the mixture was concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA = 10:1) to give 1-cyclopropyl-3-methyl-4-nitro-1H-pyrazole (99-2, 4.5 g), in 38.0% yield.

[0884] LC-MS (m / z): 168.0 [M+H] + .

[0885] Step 2: Synthesis of 5-chloro-1-cyclopropyl-3-methyl-4-nitro-1H-pyrazole (99-3)

[0886] 1-Cyclopropyl-3-methyl-4-nitro-1H-pyrazole (99-2, 4.5 g, 26.95 mmol) was dissolved in ultradry THF (50 mL), and the mixture was cooled to -60 °C under nitrogen protection. At this temperature, a LiHMDS THF solution (1 M, 32 mL) was added dropwise, and the reaction was maintained for 30 min. Then, hexachloroethane (7.6 g, 32.3 mmol) was added in portions, and the reaction was allowed to return to room temperature for 2 h. After the reaction was complete, methanol (5 mL) was added to quench the reaction, and the mixture was concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA = 10:1) to give 5-chloro-1-cyclopropyl-3-methyl-4-nitro-1H-pyrazole (99-3, 2.1 g), in 38.8% yield.

[0887] LC-MS (m / z): 202.0 [M+H] + .

[0888] Step 3: Synthesis of methyl 1-((1-cyclopropyl-3-methyl-4-nitro-1H-pyrazol-5-yl)oxy)cyclopropane-1-carboxylate (99-4)

[0889] 1-Hydroxycyclopropane-1-carboxylic acid methyl ester (1.4 g, 11.88 mmol) was dissolved in THF (40 mL), and the mixture was replaced with nitrogen for protection. Sodium hydride (648 mg, 16.20 mmol) was added under ice bath conditions, and the reaction was maintained at this temperature for 0.5 h. Then, 5-chloro-1-cyclopropyl-3-methyl-4-nitro-1H-pyrazole (99-3, 2.2 g, 10.80 mmol) was added, and the mixture was slowly restored to room temperature. The reaction was continued for 2 h. After the reaction was completed, saturated ammonium chloride solution (20 mL) was added to quench the reaction, and the mixture was extracted with EA (20 mL × 3). The combined organic phases were washed with saturated NaCl (20 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA = 5:1) to give methyl 1-((1-cyclopropyl-3-methyl-4-nitro-1H-pyrazol-5-yl)oxy)cyclopropane-1-carboxylate (99-4, 1.4 g), with a yield of 47.8%.

[0890] LC-MS (m / z): 282.0 [M+H] + .

[0891] Step 4: Synthesis of 1'-cyclopropyl-3'-methyl-1',4'-dihydro-5'H-spiro[cyclopropane-1,6'-pyrazolo[3,4-b][1,4]oxazine]-5'-one (99-5)

[0892] Methyl 1-((1-cyclopropyl-3-methyl-4-nitro-1H-pyrazol-5-yl)oxy)cyclopropane-1-carboxylate (99-4, 1.4 g, 4.98 mmol) was dissolved in AcOH (30 mL), and iron powder (2.8 g, 49.82 mmol) was added under ice bath conditions. The mixture was heated to 90 °C and reacted for 16 h. After the reaction was completed, the solution was concentrated under reduced pressure. Add water (10 mL), then adjust the pH to 7 with saturated sodium bicarbonate solution, and extract with EA (20 mL × 3). Combine the organic phases, wash with saturated NaCl (20 mL), dry with anhydrous Na2SO4, filter, and concentrate the filtrate under reduced pressure to give 1'-cyclopropyl-3'-methyl-1',4'-dihydro-5'H-spiro[cyclopropane-1,6'-pyrazolo[3,4-b][1,4]oxazine]-5'-one (99-5, 800 mg), yield 73.4%.

[0893] LC-MS (m / z): 220.0 [M+H] + .

[0894] Step 5: Synthesis of 4'-(4-bromophenyl)-1'-cyclopropyl-3'-methyl-1',4'-dihydro-5'H-spiro[cyclopropane-1,6'-pyrazolo[3,4-b][1,4]oxazine]-5'-one (99-6)

[0895] 1'-Cyclopropyl-3'-methyl-1',4'-dihydro-5'H-spiro[cyclopropane-1,6'-pyrazolo[3,4-b][1,4]oxazine]-5'-one (99-5, 800 mg, 3.65 mmol) and p-bromophenylboronic acid (1.1 g, 5.48 mmol) were dissolved in DCE (20 mL), and copper acetate (683 mg, 3.65 mmol) and triethylamine (1.5 g, 14.6 mmol) were added sequentially. The system was heated to 105 °C and reacted for 16 hours under an oxygen atmosphere. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (PE:EA = 3:1) to give 4'-(4-bromophenyl)-1'-cyclopropyl-3'-methyl-1',4'-dihydro-5'H-spiro[cyclopropane-1,6'-pyrazolo[3,4-b][1,4]oxazine]-5'-one (99-6,650 mg), yield 47.4%.

[0896] LC-MS (m / z): 374.0 [M+H] + .

[0897] Step 6: Synthesis of 1'-cyclopropyl-3'-methyl-4'-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)phenyl)-1',4'-dihydro-5'H-spiro[cyclopropane-1,6'-pyrazolo[3,4-b][1,4]oxazine]-5'-one (99-7)

[0898] 4'-(4-bromophenyl)-1'-cyclopropyl-3'-methyl-1',4'-dihydro-5'H-spiro[cyclopropane-1,6'-pyrazolo[3,4-b][1,4]oxazine]-5'-one (99-6, 650 mg, 1.74 mmol), pinacol diboronate (885 mg, 3.49 mmol), KOAc (342 mg, 3.49 mmol), and Pd(dppf)Cl2 (127 mg, 0.17 mmol) were added sequentially to the flask, followed by dioxane (10 mL). The system was heated to 100 °C and reacted for 6 hours under nitrogen protection. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (PE:EA = 3:1) to give 1'-cyclopropyl-3'-methyl-4'-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)phenyl)-1',4'-dihydro-5'H-spiro[cyclopropane-1,6'-pyrazolo[3,4-b][1,4]oxazine]-5'-one (99-7,600 mg), yield 81.9%.

[0899] LC-MS (m / z): 422.0 [M+H] + .

[0900] Step 7: Synthesis of 3-(2-chloro-4'-(1'-cyclopropyl-3'-methyl-5'-oxo-1'H-spiro[cyclopropane-1,6'-pyrazolo[3,4-b][1,4]oxazine]-4'(5'H)-yl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (99)

[0901] 1'-Cyclopropyl-3'-methyl-4'-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)phenyl)-1',4'-dihydro-5'H-spiro[cyclopropane-1,6'-pyrazolo[3,4-b][1,4]oxazine]-5'-one (99-7, 600 mg, 1.43 mmol) was dissolved in DMF (10 mL), and 3-(3-bromo-2-chlorophenyl)piperidin-2,6-dione (M1, 430 mg, 1.43 mmol), KOAc (280 mg, 2.86 mmol), and Pd(dppf)Cl2 (102 mg, 0.14 mmol) were added sequentially. The system was heated to 100 °C and reacted for 16 hours under nitrogen protection. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (DCM:MeOH = 20:1) to give 3-(2-chloro-4'-(1'-cyclopropyl-3'-methyl-5'-oxo-1'H-spiro[cyclopropane-1,6'-pyrazolo[3,4-b][1,4]oxazine]-4'(5'H)-yl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione (99,350 mg), yield 47.6%.

[0902] LC-MS (m / z): 517.0 [M+H] + .

[0903] 1 H NMR (600MHz, DMSO-d6): δ10.94(s,1H),7.54-7.52(m,2H),7.48-7.46(m,2H),7.4 3-7.37(m,3H),4.38(dd,J1=18.0Hz,J2=7.2Hz,1H),3.30-3.29(m,1H),2.85-2.7 5(m,1H),2.58-2.56(m,1H),2.40-2.33(m,1H),2.07-2.03(m,1H),1.47(s,3H),1 .43(t,J=3.6Hz,2H),1.40(t,J=4.2Hz,2H),0.97-0.94(m,2H),0.93-0.90(m,2H).

[0904] Example 101: 3-(2-chloro-4'-(2'-oxospiro[cyclopropane-1,3'-pyrrolo[2,3-b]pyridine]-1'(2'H)-yl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione (101)

[0905] Step 1: Synthesis of spiro[cyclopropane-1,3'-pyrrolo[2,3-b]pyridine]-2'(1'H)-one (101-2)

[0906] 1,3-Dihydro-2H-pyrrolo[2,3-b]pyridin-2-one (101-1, 804 mg, 6.0 mmol) was dissolved in DMF (10 mL), followed by the addition of (2-bromoethyl)diphenylsulfonium (3.2 g, 7.2 mmol) and zinc trifluoromethanesulfonate (4.4 g, 12.0 mmol). Triethylamine (2.5 mL, 18.0 mmol) was slowly added dropwise under ice bath conditions, and the reaction was carried out at room temperature for 4 hours. After the reaction was completed, the mixture was diluted with ethyl acetate (50 mL), extracted with saturated brine (20 mL × 3), dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography (PE:EA = 2:1) to give spiro[cyclopropane-1,3'-pyrrolo[2,3-b]pyridin]-2'(1'H)-one (101-2, 400 mg), yield 41.4%.

[0907] LC-MS (m / z): 161.0 [M+H] + .

[0908] Step 2: Synthesis of 1'-(4-bromophenyl)spiro[cyclopropane-1,3'-pyrrolo[2,3-b]pyridine]-2'(1'H)-one (101-3)

[0909] Spiro[cyclopropane-1,3'-pyrrolo[2,3-b]pyridine]-2'(1'H)-one (101-2, 400 mg, 2.5 mmol) and p-bromophenylboronic acid (750 mg, 3.8 mmol) were dissolved in DCE (10 mL), and copper acetate (468 mg, 2.5 mmol) and triethylamine (505 mg, 5.0 mmol) were added sequentially. The system was reacted at room temperature under oxygen protection for 16 hours. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (PE:EA = 3:1) to give 1'-(4-bromophenyl)spiro[cyclopropane-1,3'-pyrrolo[2,3-b]pyridine]-2'(1'H)-one (101-3, 120 mg), with a yield of 15.2%.

[0910] LC-MS (m / z): 315.0 [M+H] + .

[0911] Step 3: Synthesis of 1'-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborphanecyclopentan-2-yl)phenyl)spiro[cyclopropane-1,3'-pyrrolo[2,3-b]pyridine]-2'(1'H)-one (101-4)

[0912] 1'-(4-bromophenyl)spiro[cyclopropane-1,3'-pyrrolo[2,3-b]pyridine]-2'(1'H)-one (101-3, 120 mg, 0.38 mmol), pinacol diborate (192 mg, 0.76 mmol), KOAc (75 mg, 0.76 mmol), and Pd(dppf)Cl2 (28 mg, 0.04 mmol) were added sequentially to the flask, followed by dioxane (10 mL). The system was heated to 100 °C and reacted for 6 hours under nitrogen protection. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (PE:EA = 3:1) to give 1'-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborphanecyclopentan-2-yl)phenyl)spiro[cyclopropane-1,3'-pyrrolo[2,3-b]pyridine]-2'(1'H)-one (101-4, 80 mg), yield 58.0%.

[0913] LC-MS (m / z): 363.0 [M+H] + .

[0914] Step 4: Synthesis of 3-(2-chloro-4'-(2'-oxospiro[cyclopropane-1,3'-pyrrolo[2,3-b]pyridine]-1'(2'H)-yl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (101)

[0915] 1'-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborphanecyclopentan-2-yl)phenyl)spiro[cyclopropane-1,3'-pyrrolo[2,3-b]pyridine]-2'(1'H)-one (101-4, 80 mg, 0.22 mmol) was dissolved in DMF (5 mL), and 3-(3-bromo-2-chlorophenyl)piperidin-2,6-dione (M1, 67 mg, 0.22 mmol), KOAc (63 mg, 0.64 mmol), and Pd(dppf)Cl2 (16 mg, 0.02 mmol) were added sequentially. The system was heated to 100 °C and reacted for 16 hours under nitrogen protection. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (DCM:MeOH = 20:1) to give 3-(2-chloro-4'-(2'-oxospiro[cyclopropane-1,3'-pyrrolo[2,3-b]pyridin]-1'(2'H)-yl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione (101,26 mg), yield 25.7%.

[0916] LC-MS (m / z): 458.0 [M+H] + .

[0917] 1H NMR (400MHz, DMSO-d6): δ10.94 (s, 1H), 8.14 (dd, J1=5.2Hz, J1=1.6Hz, 1H), 7.66-7.63(m,2H),7.58-7.55(m,3H),7.45-7.36(m,3H),7.14-7.10(m,1H), 4.40(dd,J1=12.4Hz,J1=4.8Hz,1H),2.86-2.77(m,1H),2.58-2.51(m,1H), 2.41-2.31(m,1H),2.09-2.05(m,1H),1.86-1.83(m,2H),1.74-1.71(m,2H).

[0918] Example 102: Synthesis of 3-(2-chloro-4'-(spiro[cyclopropane-1,3'-pyrrolo[2,3-b]pyridine]-1'(2'H)-yl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (compound 102)

[0919] Step 1: Synthesis of spiro[cyclopropane-1,3'-pyrrolo[2,3-b]pyridine]-2'(1'H)-one (102-2)

[0920] 1,3-Dihydro-2H-pyrrolo[2,3-b]pyridin-2-one (102-1, 804.0 mg, 6.0 mmol) was dissolved in DMF (10 mL), and (2-bromoethyl)diphenylsulfonium trifluoromethanesulfonate (3.2 g, 7.2 mmol) and zinc trifluoromethanesulfonate (4.4 g, 12.0 mmol) were added sequentially. Triethylamine (2.5 mL, 18.0 mmol) was slowly added dropwise under ice bath, and the reaction was carried out at room temperature for 4 h. The mixture was diluted with ethyl acetate (50 mL), extracted with saturated brine (20 mL × 3), dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography (PE:EA = 2:1) to give spiro[cyclopropane-1,3'-pyrrolo[2,3-b]pyridin]-2'(1'H)-one (102-2, 400.0 mg), yield 41.4%.

[0921] LC-MS (m / z): 161.0 [M+H] + .

[0922] Step 2: Synthesis of 1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[2,3-b]pyridine](102-3)

[0923] Spiro[cyclopropane-1,3'-pyrrolo[2,3-b]pyridine]-2'(1'H)-one (102-2, 200.0 mg, 1.25 mmol) was dissolved in THF (5 mL), and then LiAlH4 (100.0 mg, 2.5 mmol) was added. The reaction was carried out at 60 °C for 3 h under nitrogen protection. After cooling to room temperature, the system was added dropwise to a saturated ammonium chloride aqueous solution and extracted with EA (50 mL). The organic phase was dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA = 1:1) to give 1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[2,3-b]pyridine] (102-3, 100.0 mg), with a yield of 54.4%.

[0924] LC-MS (m / z): 147.0 [M+H] + .

[0925] Step 3: Synthesis of 1'-(4-bromophenyl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[2,3-b]pyridine](102-4)

[0926] 1',2'-Dihydrospiro[cyclopropane-1,3'-pyrrolo[2,3-b]pyridine] (102-3, 80.0 mg, 0.55 mmol) was dissolved in DCE (5 mL) with p-bromophenylboronic acid (220.0 mg, 1.1 mmol), followed by the addition of copper acetate (100.0 mg, 0.55 mmol) and triethylamine (175.0 mg, 1.65 mmol). The reaction was carried out at room temperature under an oxygen atmosphere for 16 h. The mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (PE:EA = 3:1) to give 1'-(4-bromophenyl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[2,3-b]pyridine] (102-4, 60.0 mg), in 36.5% yield.

[0927] LC-MS (m / z): 301.0 [M+H] + .

[0928] Step 4: Synthesis of 1'-(4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)phenyl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[2,3-b]pyridine](102-5)

[0929] 1'-(4-bromophenyl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[2,3-b]pyridine] (102-4, 60.0 mg, 0.17 mmol), pinacol diborate (84.0 mg, 0.34 mmol), KOAc (33.0 mg, 0.34 mmol), and Pd(dppf)Cl2 (67.0 mg, 0.09 mmol) were added sequentially to the flask, followed by dioxane (10 mL). The mixture was reacted at 100 °C for 4 h under nitrogen protection. The reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography (PE:EA = 3:1) to give 1'-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)phenyl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[2,3-b]pyridine] (102-5, 50.0 mg), yield 86.5%.

[0930] LC-MS (m / z): 349.0 [M+H] + .

[0931] Step 5: Synthesis of 3-(2-chloro-4'-(spiro[cyclopropane-1,3'-pyrrolo[2,3-b]pyridine]-1'(2'H)-yl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (102)

[0932] 1'-(4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)phenyl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[2,3-b]pyridine] (102-5, 40.0 mg, 0.12 mmol) was dissolved in DMF (5 mL), and 3-(3-bromo-2-chlorophenyl)piperidine-2,6-dione (M1, 33.0 mg, 0.12 mmol), KOAc (24.0 mg, 0.24 mmol), and Pd(dppf)Cl2 (8.0 mg, 0.01 mmol) were added sequentially. The reaction was carried out at 100 °C for 4 h under nitrogen protection. The residue was concentrated under reduced pressure and purified by column chromatography (DCM:MeOH = 20:1) to give 3-(2-chloro-4'-(spiro[cyclopropane-1,3'-pyrrolo[2,3-b]pyridin]-1'(2'H)-yl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione (102, 6.0 mg), yield 11.8%.

[0933] LC-MS (m / z): 444.0 [M+H] + .

[0934] 1H NMR (600MHz, DMSO-d6) δ10.91(s,1H),7.97(m,3H),7.40(dd,J1=18Hz,J2=6Hz,3H),7.33(d,J=6Hz,2H),7.10(d,J=6Hz,1H),6.71(dd, J1=12Hz, J2=6Hz,1H),4.36(d,J=6Hz,1H),4.10(s,2H),2.80(m,1H),2.56(m,1H),2.34(m,1H),2.06(m,1H),1.17(s,2H),1.15(s,2H).

[0935] Example 103: Synthesis of 3-(2-chloro-4'-(8'-oxo-5'H-spiro[cyclopropane-1,6'-imidazo[1,2-a]pyrazine]-7'(8'H)-yl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (103)

[0936] Step 1: Synthesis of ethyl 1-((1-((tert-Butoxycarbonyl)amino)cyclopropyl)methyl)-1H-imidazolium-2-carboxylate (103-2)

[0937] Ethyl 1H-imidazolium-2-carboxylate (10³⁻¹, 5.0 g, 35.68 mmol) was dissolved in toluene (100 mL), and tert-butyl(1-hydroxymethylcyclopropyl)carbamate (10.0 g, 53.53 mmol) and CMBP (12.9 g, 53.52 mmol) were added. The system was heated to 100 °C and reacted for 24 h. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (DCM / MeOH = 97:3) to give ethyl 1-((1-((tert-butyloxycarbonyl)amino)cyclopropyl)methyl)-1H-imidazolium-2-carboxylate (10³⁻², 5 g), with a yield of 45.3%.

[0938] LC-MS (m / z): 310.0 [M+H] + .

[0939] Step 2: Synthesis of 1-((1-aminocyclopropyl)methyl)-1H-imidazolium-2-carboxylic acid ethyl ester hydrochloride (103-3)

[0940] Ethyl 1-((1-((tert-Butoxycarbonyl)amino)cyclopropyl)methyl)-1H-imidazolium-2-carboxylate (103-2, 2.0 g, 6.47 mmol) was dissolved in 10 mL of HCl-saturated EA, and the reaction was carried out at room temperature for 2 h. After the reaction was completed, the solution was concentrated under reduced pressure to obtain ethyl hydrochloride of 1-((1-aminocyclopropyl)methyl)-1H-imidazolium-2-carboxylate (103-3, crude product), which was directly used in the next step of the reaction.

[0941] LC-MS (m / z): 210.0 [M+H] + .

[0942] Step 3: Synthesis of 5'H-spiro[cyclopropane-1,6'-imidazo[1,2-a]pyrazine]-8'(7'H)-one (103-4)

[0943] The crude product (103-3) obtained in the previous step was dissolved in MeOH (10 mL), and triethylamine (3 mL) was added. The system was heated to 70 °C and reacted for 3 h. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (DCM / MeOH = 97:3) to give 5'H-spiro[cyclopropane-1,6'-imidazo[1,2-a]pyrazine]-8'(7'H)-one (103-4, 420 mg), with a two-step yield of 39.8%.

[0944] LC-MS (m / z): 164.0 [M+H] + .

[0945] Step 4: Synthesis of 7'-(4-bromophenyl)-5'H-spiro[cyclopropane-1,6'-imidazo[1,2-a]pyrazine]-8'(7'H)-one (103-5)

[0946] 5'H-spiro[cyclopropane-1,6'-imidazo[1,2-a]pyrazine]-8'(7'H)-one (103-5, 210 mg, 1.29 mmol) was dissolved in DCE (5 mL), and p-bromophenylboronic acid (775 mg, 3.86 mmol), copper acetate (233 mg, 1.29 mmol), and triethylamine (390 mg, 3.86 mmol) were added. The system was replaced with an oxygen atmosphere, and the reaction was carried out at room temperature for 16 h. After the reaction was completed, the mixture was filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (DCM / MeOH = 20:1) to give 7'-(4-bromophenyl)-5'H-spiro[cyclopropane-1,6'-imidazo[1,2-a]pyrazine]-8'(7'H)-one (103-5, 129 mg), with a yield of 31.5%.

[0947] LC-MS (m / z): 318.0 [M+H] + .

[0948] Step 5: Synthesis of 3-(2-chloro-4'-(8'-oxo-5'H-spiro[cyclopropane-1,6'-imidazo[1,2-a]pyrazine]-7'(8'H)-yl)-[1,1'-biphenyl]-3-yl)-1-(4-methoxybenzyl)piperidine-2,6-dione (103-6)

[0949] 7'-(4-bromophenyl)-5'H-spiro[cyclopropane-1,6'-imidazo[1,2-a]pyrazine]-8'(7'H)-one (103-5, 129 mg, 0.41 mmol) was dissolved in DMF (5 mL), and 3-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)phenyl)-1-(4-methoxybenzyl)piperidin-2,6-dione (M3, 286 mg, 0.61 mmol), Pd(dppf)Cl2 (29 mg, 0.04 mmol) and potassium acetate (119 mg, 1.22 mmol) were added. The system was purged with nitrogen and the temperature was raised to 100 °C for 3 h. After the reaction was completed, the residue was concentrated and purified by silica gel column chromatography (DCM / MeOH = 97:3) to give 3-(2-chloro-4'-(8'-oxo-5'H-spiro[cyclopropane-1,6'-imidazo[1,2-a]pyrazine]-7'(8'H)-yl)-[1,1'-biphenyl]-3-yl)-1-(4-methoxybenzyl)piperidine-2,6-dione (103-6, 140 mg), yield 59.4%.

[0950] LC-MS (m / z): 581.0 [M+H] + .

[0951] Step 6: Synthesis of 3-(2-chloro-4'-(8'-oxo-5'H-spiro[cyclopropane-1,6'-imidazo[1,2-a]pyrazine]-7'(8'H)-yl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (103)

[0952] 3-(2-chloro-4'-(8'-oxo-5'H-spiro[cyclopropane-1,6'-imidazo[1,2-a]pyrazine]-7'(8'H)-yl)-[1,1'-biphenyl]-3-yl)-1-(4-methoxybenzyl)piperidine-2,6-dione (103-6, 140 mg, 0.24 mmol) was dissolved in TFA (1 mL) and trifluoromethanesulfonic acid (0.5 mL), and the system was reacted at room temperature for 24 h. After the reaction was completed, the filtrate was concentrated under reduced pressure, the residue was neutralized with saturated sodium bicarbonate solution, extracted with DCM (15 mL × 3), the organic phases were combined, dried, concentrated, and the residue was purified by silica gel column chromatography (DCM / MeOH = 20:1) to give 3-(2-chloro-4'-(8'-oxo-5'H-spiro[cyclopropane-1,6'-imidazo[1,2-a]pyrazine]-7'(8'H)-yl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione (103, 60 mg), yield 54.3%.

[0953] LC-MS (m / z): 461.0 [M+H] + .

[0954] 1 H NMR (400MHz, DMSO-d6): δ10.93(s,1H),7.50-7.47(m,2H),7.45-7.36(m,6H),7.22(s,1H),4.44(s,2H),4.39(dd,J1=12.4Hz,J2 =5.2Hz,1H),2.85-2.76(m,1H),2.60-2.52(m,1H),2.40-2.30(m,1H),2.12-2.01(m,1H),1.04-0.97(m,2H),0.76-0.69(m,2H).

[0955] Example 104: 3-(2-chloro-4'-(1'-oxo-4'H-spiro[cyclopropane-1,3'-pyrrolo[1,2-a]pyrazine]-2'(1'H)-yl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (104)

[0956] Step 1: Synthesis of methyl 1-((1-((tert-butoxycarbonyl)amino)cyclopropyl)methyl)-1H-pyrrole-2-carboxylate (104-2)

[0957] Methyl 1H-pyrrole-2-carboxylate (104-1, 2.0 g, 16.00 mmol) and tert-butyl (1-(bromomethyl)cyclopropyl)carbamate (3.9 g, 16.00 mmol) were dissolved in DMF (20 mL), and cesium carbonate (10.4 g, 32.00 mmol) was added. The mixture was heated to 100 °C and reacted overnight. After the reaction was complete, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA = 5:1) to give methyl 1-((1-((tert-butoxycarbonyl)amino)cyclopropyl)methyl)-1H-pyrrole-2-carboxylate (104-2, 1.6 g), in 34.0% yield.

[0958] LC-MS (m / z): 295.0 [M+H] + .

[0959] Step 2: Synthesis of methyl 1-((1-aminocyclopropyl)methyl)-1H-pyrrole-2-carboxylate (104-3)

[0960] Methyl 1-((1-((tert-butoxycarbonyl)amino)cyclopropyl)methyl)-1H-pyrrole-2-carboxylate (104-2, 1.6 g, 5.44 mmol) was dissolved in DCM (25 mL), and 20 mL of ethyl acetate saturated with HCl was added to the system. The reaction was carried out at room temperature for 2 h. After the reaction was completed, the solution was concentrated under reduced pressure to obtain crude methyl 1-((1-aminocyclopropyl)methyl)-1H-pyrrole-2-carboxylate (104-3, 2.0 g), which was used directly in the next step.

[0961] LC-MS (m / z): 195.0 [M+H] + .

[0962] Step 3: Synthesis of 4'H-spiro[cyclopropane-1,3'-pyrrolo[1,2-a]pyrazine]-1'(2'H)-one (104-4)

[0963] The crude product (104-3) obtained in the previous step was dissolved in methanol (20 mL), and triethylamine (5 mL) was added. The mixture was heated to 80 °C and reacted for 16 hours. After the reaction was completed, the mixture was concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA = 1:1) to give 4'H-spiro[cyclopropane-1,3'-pyrrolo[1,2-a]pyrazine]-1'(2'H)-one (104-4, 200 mg), with a two-step yield of 22.7%.

[0964] LC-MS (m / z): 163.0 [M+H] + .

[0965] Step 4: Synthesis of 2'-(4-bromophenyl)-4'H-spiro[cyclopropane-1,3'-pyrrolo[1,2-a]pyrazine]-1'(2'H)-one (104-5)

[0966] 4'H-spiro[cyclopropane-1,3'-pyrrolo[1,2-a]pyrazine]-1'(2'H)-one (104-4, 200 mg, 1.23 mmol) dissolved in DCE (5 mL) was added sequentially to a flask. Then, p-bromophenylboronic acid (492 mg, 2.46 mmol), copper acetate (224 mg, 1.23 mmol), and TEA (373 mg, 3.69 mmol) were added sequentially. The system was reacted at room temperature under an oxygen atmosphere for 16 hours. After the reaction was complete, the mixture was concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA = 1:1) to give 2'-(4-bromophenyl)-4'H-spiro[cyclopropane-1,3'-pyrrolo[1,2-a]pyrazine]-1'(2'H)-one (104-5, 150 mg), yield 44.3%.

[0967] LC-MS (m / z): 317.0, 319.0 [M+H] + .

[0968] Step 5: Synthesis of 2'-(4-(4,4,5,5-tetramethyl-1,3,2-dioxoboron-2-yl)phenyl)-4'H-spiro[cyclopropane-1,3'-pyrrolo[1,2-a]pyrazine]-1'(2'H)-one (104-6)

[0969] 2'-(4-bromophenyl)-4'H-spiro[cyclopropane-1,3'-pyrrolo[1,2-a]pyrazine]-1'(2'H)-one (104-5, 80 mg, 0.25 mmol), pinacol diboronic acid ester (127 mg, 0.50 mmol), KOAc (74 mg, 0.75 mmol) and Pd(dppf)Cl2 (19 mg, 0.025 mmol) were added to the flask in sequence, followed by dioxane (4 mL). The system was heated to 100 °C and reacted for 3 h under nitrogen protection. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (PE:EA = 1:1) to give 2'-(4-(4,4,5,5-tetramethyl-1,3,2-dioxoboron-2-yl)phenyl)-4'H-spiro[cyclopropane-1,3'-pyrrolo[1,2-a]pyrazine]-1'(2'H)-one (104-6, 80 mg), yield 87.9%.

[0970] LC-MS (m / z): 365.0 [M+H] + .

[0971] Step 6: Synthesis of 3-(2-chloro-4'-(1'-oxo-4'H-spiro[cyclopropane-1,3'-pyrrolo[1,2-a]pyrazine]-2'(1'H)-yl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (104)

[0972] 2'-(4-(4,4,5,5-tetramethyl-1,3,2-dioxoboron-2-yl)phenyl)-4'H-spiro[cyclopropane-1,3'-pyrrolo[1,2-a]pyrazine]-1'(2'H)-one (104-6, 80 mg, 0.22 mmol) was dissolved in DMF (4 mL), and 3-(3-bromo-2-chlorophenyl)piperidin-2,6-dione (66 mg, 0.22 mmol), KOAc (65 mg, 0.66 mmol), and Pd(dppf)Cl2 (24 mg, 0.03 mmol) were added sequentially. The system was heated to 100 °C and reacted for 3 h under nitrogen protection. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (DCM:MeOH = 20:1) to give 3-(2-chloro-4'-(1'-oxo-4'H-spiro[cyclopropane-1,3'-pyrrolo[1,2-a]pyrazine]-2'(1'H)-yl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione (104, 26 mg), yield 17.2%.

[0973] LC-MS (m / z): 460.0 [M+H] + .

[0974] 1 H NMR(600MHz,DMSO-d6)δ10.93(s,1H),7.47–7.44(m,2H),7.43–7.40(m,1H) ,7.37(m,2H),7.34–7.31(m,2H),7.04(m,1H),6.78(m,1H),6.23(m,1H),4. 36(dd,J1=12.0Hz,J2=4.8Hz,1H),4.31(s,2H),2.80(m,1H),2.59–2.52(m, 1H),2.35(m,1H),2.10–2.04(m,1H),0.99–0.93(m,2H),0.72–0.67(m,2H).

[0975] Example 109: 3-(2-fluoro-4'-(3'-oxospiro[cyclopropane-1,2'-pyrido[3,2-b][1,4]oxazine]-4'(3'H)-yl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione (109)

[0976] Step 1: Synthesis of tert-butyl 4-(3-bromo-2-fluorophenyl)-4-cyanobutyrate (109-2)

[0977] 2-(3-bromo-2-fluorophenyl)acetonitrile (109-1, 2.1 g, 10.0 mmol) was dissolved in ACN (40 mL), and tert-butyl acrylate (1.3 g, 10.0 mmol) and cesium carbonate (6.5 g, 20.0 mmol) were added sequentially. The mixture was reacted at room temperature for 4 hours. After the reaction was complete, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA = 10:1) to give tert-butyl 4-(3-bromo-2-fluorophenyl)-4-cyanobutyrate (109-2, 2.0 g), with a yield of 58.6%.

[0978] LC-MS (m / z): 342.0, 344.0 [M+H] + .

[0979] Step 2: Synthesis of 3-(3-bromo-2-fluorophenyl)piperidine-2,6-dione (109-3)

[0980] 4-(3-bromo-2-fluorophenyl)-4-cyanobutyrate tert-butyl ester (109-2, 500 mg, 1.47 mmol) was dissolved in AcOH (20 mL), and then sulfuric acid (2 mL) was added. The system was heated to 90 °C and reacted for 3 hours. After the reaction was completed, the mixture was cooled to room temperature, and ice water was added dropwise until no solid precipitated. The mixture was filtered, the filter cake was washed with water, and dried to give 3-(3-bromo-2-fluorophenyl)piperidin-2,6-dione (109-3, 200 mg), with a yield of 47.9%.

[0981] LC-MS (m / z): 286.0, 288.0 [M+H] + .

[0982] Step 3: Synthesis of 3-(2-fluoro-4'-(3'-oxospiro[cyclopropane-1,2'-pyrido[3,2-b][1,4]oxazine]-4'(3'H)-yl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (109)

[0983] Compound 62-5 was prepared according to steps 1 to 4 of Example 62.

[0984] 4'-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborphanecyclopentan-2-yl)phenyl)spiro[cyclopropane-1,2'-pyrido[3,2-b][1,4]oxazine]-3'(4'H)-one (62-5, 355 mg, 1.02 mmol) was dissolved in DMF (10 mL), and 3-(3-bromo-2-fluorophenyl)piperidin-2,6-dione (109-3, 290 mg, 1.02 mmol), KOAc (200 mg, 2.04 mmol), and Pd(dppf)Cl2 (74 mg, 0.10 mmol) were added sequentially. The system was heated to 100 °C and reacted for 16 hours under nitrogen protection. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (DCM:MeOH = 20:1) to give 3-(2-fluoro-4'-(3'-oxospiro[cyclopropane-1,2'-pyrido[3,2-b][1,4]oxazine]-4'(3'H)-yl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione (109, 26 mg), yield 5.6%.

[0985] LC-MS (m / z): 458.0 [M+H] + .

[0986] 1 H NMR (400MHz, DMSO-d6): δ10.93 (s, 1H), 7.93 (dd, J1=4.8Hz, J1=1.6Hz, 1H), 7.67-7.6 4(m,2H),7.57-7.53(m,1H),7.47-7.43(m,3H),7.40-7.36(m,1H),7.34-7.30(m,1H) ,7.12-7.09(m,1H),4.20(dd,J1=12.4Hz,J1=4.8Hz,1H),2.84-2.75(m1H),2.61-2.5 5(m,1H),2.35-2.24(m,1H),2.13-2.07(m,1H),1.46-1.43(m,2H),1.40-1.36(m,2H).

[0987] Example 116: Synthesis of 3-(2-chloro-4'-(2'-methyl-4'-oxo-7'H-spirocyclic[cyclopropane-1,6'-pyrazolo[1,5-a]pyrazine]-5'(4'H)-yl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (116)

[0988] Step 1: Synthesis of ethyl 1-((1-((tert-butoxycarbonyl)amino)cyclopropyl)methyl)-3-methyl-1H-pyrazole-5-carboxylate (116-2)

[0989] Ethyl 3-methyl-1H-pyrazole-5-carboxylate (116-1, 200 mg, 1.30 mmol) and tert-butyl (1-(hydroxymethyl)cyclopropyl)carbamate (365 mg, 1.95 mmol) were dissolved in toluene (10 mL), and then CMBP (470 mg, 1.95 mmol) was added. The mixture was heated to 100 °C and reacted overnight. After the reaction was complete, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA = 3:1) to give ethyl 1-((1-((tert-butoxycarbonyl)amino)cyclopropyl)methyl)-3-methyl-1H-pyrazole-5-carboxylate (116-2, 300 mg), in 47.7% yield.

[0990] LC-MS (m / z): 324.0 [M+H] + .

[0991] Step 2: Synthesis of ethyl 1-((1-aminocyclopropyl)methyl)-3-methyl-1H-pyrazole-5-carboxylate (116-3)

[0992] Ethyl 1-((1-((tert-butoxycarbonyl)amino)cyclopropyl)methyl)-3-methyl-1H-pyrazole-5-carboxylate (116-2, 300 mg, 0.93 mmol) was added to a flask, followed by 5 mL of ethyl acetate saturated with HCl. The reaction was carried out at room temperature for 2 h. After the reaction was complete, the solution was concentrated under reduced pressure to obtain crude ethyl 1-((1-aminocyclopropyl)methyl)-3-methyl-1H-pyrazole-5-carboxylate (116-3, 200 mg), which was used directly in the next step.

[0993] LC-MS (m / z): 224.0 [M+H] + .

[0994] Step 3: Synthesis of 2'-methyl-7'H-spiro[cyclopropane-1,6'-pyrazolo[1,5-a]pyrazine]-4'(5'H)-one (116-4)

[0995] The crude product (116-3) obtained in the previous step was dissolved in methanol (5 mL), and triethylamine (1 mL) was added. The mixture was heated to 80 °C and reacted for 12 hours. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (PE:EA = 1:1) to give 2'-methyl-7'H-spiro[cyclopropane-1,6'-pyrazolo[1,5-a]pyrazine]-4'(5'H)-one (116-4, 150 mg), with a two-step yield of 91.2%.

[0996] LC-MS (m / z): 178.0 [M+H] + .

[0997] Step 4: Synthesis of 5'-(4-bromophenyl)-2'-methyl-7'H-spiro[cyclopropane-1,6'-pyrazolo[1,5-a]pyrazine]-4'(5'H)-one (116-5)

[0998] 2'-Methyl-7'H-spiro[cyclopropane-1,6'-pyrazolo[1,5-a]pyrazine]-4'(5'H)-one (116-4, 150 mg, 0.84 mmol) dissolved in DCE (5 mL) was added sequentially to a flask. Then, p-bromophenylboronic acid (504 mg, 2.52 mmol), copper acetate (153 mg, 0.84 mmol), and TEA (254 mg, 2.52 mmol) were added sequentially. The system was reacted at room temperature under an oxygen atmosphere for 16 hours. After the reaction was complete, the mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (PE:EA = 1:1) to give 5'-(4-bromophenyl)-2'-methyl-7'H-spiro[cyclopropane-1,6'-pyrazolo[1,5-a]pyrazine]-4'(5'H)-one (116-5, 130 mg), with a yield of 47.4%.

[0999] LC-MS (m / z): 332.0, 334.0 [M+H] + .

[1000] Step 5: Synthesis of 2'-methyl-5'-(4-(4,4,5,5-tetramethyl-1,3,2-dioxoboron-2-yl)phenyl)-7'H-spiro[cyclopropane-1,6'-pyrazolo[1,5-a]pyrazine]-4'(5'H)-one (116-6)

[1001] 5'-(4-bromophenyl)-2'-methyl-7'H-spiro[cyclopropane-1,6'-pyrazolo[1,5-a]pyrazine]-...

Claims

1. A heterocyclic compound having a structure represented by Formula (I) or a pharmaceutically acceptable salt, isotopic derivative, solvate, or stereoisomer, geometric isomer, tautomer, or prodrug molecule, metabolite thereof: in, X is selected from CR a or N; R a selected from hydrogen, deuterium, fluorine or methyl; R1 is selected from hydrogen, deuterium, halogen, cyano, methyl, difluoromethyl, trifluoromethyl, or methoxy; R2, R3, R4are each independently selected from the group consisting of hydrogen, deuterium, halogen, cyano, C 1-6 alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl, C 3-6 alkynyl or C 1-4 alkoxy; W and Y are each independently selected from N or CR e ; Each R e R5 is independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 1-6 Alkyl sulfone group, C 1-6 Alkylthio, C 1-6 alkylamine group, C 1-6 alkyl ester group, C 1-6 Alkyl acyl, C 1-6 Alkylamide group, C 1-6 alkylsulfonyl, C 1-6 alkylsulfonamide group, 3-8 membered heterocyclic group, 5-14 membered heteroaryl group or C 6-12 Aryl; the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 1-6 Alkyl sulfone group, C 1-6 Alkylthio, C 1-6 alkylamine group, C 1-6 alkyl ester group, C 1-6 Alkyl acyl, C 1-6 Alkylamide group, C 1-6 alkylsulfonyl, C 1-6 alkylsulfonamide group, 3-8 membered heterocyclic group, 5-14 membered heteroaryl group or C 6-12 The aryl group may optionally be affected by one or more R groups. b replace; n is selected from 0, 1, or 2; Ring A is selected from 9-14 membered heteroaryl or heterocyclic groups; R6 and R7 can be attached to the same carbon atom, or to different carbon atoms or heteroatoms. R6, R7, and the atoms directly attached to them together form C. 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-8 Aryl or 5-8 quinone heteroaryl, wherein C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-8 Aryl or 5-8 heteroaryl groups may optionally be replaced by one or more R groups. c replace; Each R8 group is independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, oxo, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 1-6 Alkyl sulfone group, C 1-6 Alkylthio, C 1-6 alkylamine group, C 1-6 alkyl ester group, C 1-6 Alkyl acyl, C 1-6 Alkylamide group, C 1-6 alkylsulfonyl, C 1-6 alkylsulfonamide group, 3-8 membered heterocyclic group, 5-14 membered heteroaryl group or C 6-12 Aryl; the C 1-6 Alkyl, C 2- 6-olefin, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 1-6 Alkyl sulfone group, C 1-6 Alkylthio, C 1-6 alkylamine group, C 1-6 alkyl ester group, C 1-6 Alkyl acyl, C 1-6 Alkylamide group, C 1-6 alkylsulfonyl, C 1-6 alkylsulfonamide group, 3-8 membered heterocyclic group, 5-14 membered heteroaryl group or C 6-12 The aryl group may optionally be affected by one or more R groups. d replace; m is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12; Each R b R d Each is independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, mercapto, oxo, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 1-6 Alkyl sulfone group, C 1-6 Alkylthio, C 1-6 alkylamine group, C 1-6 alkyl ester group, C 1-6 Alkyl acyl, C 1-6 Alkylamide group, C 1-6 alkylsulfonyl, C 1-6 alkylsulfonamide group, C 1-6 Phosphoryl group, 3-8 membered heterocyclic group, 5-14 membered heteroaryl group or C 6-12 Aryl; the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 1-6 Alkyl sulfone group, C 1-6 Alkylthio, C 1-6 alkylamine group, C 1-6 alkyl ester group, C 1-6 Alkyl acyl, C 1-6 Alkylamide group, C 1-6 alkylsulfonyl, C 1-6 alkylsulfonamide group, C 1-6 Phosphoryl group, 3-8 membered heterocyclic group, 5-14 membered heteroaryl group or C 6-12 The aryl group may optionally be further reacted with one or more hydrogens, deuteriums, halogens, cyano groups, hydroxyl groups, amino groups, mercapto groups, oxo groups, or C groups. 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 1-6 Alkyl sulfone group, C 1-6 Alkylthio, C 1-6 alkylamine group, C 1-6 Alkyl acyl, 4-10 membered heterocyclic, 5-14 membered heteroaryl or C 6-12 Aryl groups are replaced; Each R c Each is independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, oxo group, C 1-6 Alkyl, C 2-6 alkenyl, C 3-6 alkynyl group, C 1-6 Alkoxy, C 3-6 cycloalkyl or C 1-6 Halogenated alkyl groups.

2. The compound of claim 1, or a pharmaceutically acceptable salt, isotopic derivative, solvate, or a stereoisomer, geometric isomer, tautomer thereof, or a prodrug molecule, metabolite thereof, wherein, R6 and R7 can be attached to the same carbon atom, or to different carbon atoms or heteroatoms. R6, R7, and the atoms directly attached to them together form C. 3-8 Cycloalkyl, 3-8 membered heterocyclic or 5-8 membered heteroaryl, wherein C 3-8 Cycloalkyl, 3-8 membered heterocyclic or 5-8 membered heteroaryl groups may optionally be coupled with one or more R groups. c replace; Each R c Each is independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C 1-6 Alkyl, C 2-6 alkenyl, C 3-6 alkynyl group, C 1-6 Alkoxy, C 3-6 cycloalkyl or C 1-6 Halogenated alkyl groups.

3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt, isotopic derivative, solvate, or a stereoisomer, geometric isomer, tautomer thereof, or a prodrug molecule, metabolite thereof, characterized in that, The compounds have the following formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Im), (In), (Io), (Ip), (Iq), (Ir), (Is), (It), (Iu), (Iv), or (Iw): in, It can be a single bond or a double bond; Ring B is selected from phenyl, 5-8 membered heteroaryl, or 5-8 membered heterocyclic group; Ring C is C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-8 Aryl or 5-8 quinone heteroaryl, wherein C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-8 Aryl or 5-8 heteroaryl groups may optionally be replaced by one or more R groups. c Substitution; preferably, ring C is C 3-8 Cycloalkyl, 3-8 membered heterocyclic or 5-8 membered heteroaryl, wherein C 3-8 Cycloalkyl, 3-8 membered heterocyclic or 5-8 membered heteroaryl groups may optionally be coupled with one or more R groups. c replace; J2 is selected from C, CH, or N; J3 is selected from C, CH, or N; J1, J4, J5are each independently selected from the group consisting of -(C=0)-, -SO2-, -0-, -CR 81 R 82 - or -NR 83 -; Each R 81 R 82 R 83 Each is independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 1-6 Alkyl sulfone group, C 1-6 Alkylthio, C 1-6 alkylamine group, C 1-6 alkyl ester group, C 1-6 Alkyl acyl, C 1-6 Alkylamide group, C 1-6 alkylsulfonyl, C 1-6 alkylsulfonamide group, 3-8 membered heterocyclic group, 5-14 membered heteroaryl group or C 6-12 Aryl; the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 1-6 Alkyl sulfone group, C 1-6 Alkylthio, C 1-6 alkylamine group, C 1-6 alkyl ester group, C 1-6 Alkyl acyl, C 1-6 Alkylamide group, C 1-6 alkylsulfonyl, C 1-6 alkylsulfonamide group, 3-8 membered heterocyclic group, 5-14 membered heteroaryl group or C 6- 12 The aryl group may optionally be affected by one or more R groups. d replace; m1 and m2 are each independently selected from 0, 1, 2, 3, 4, 5 or 6; X, Y, W, R1, R2, R3, R4, R5, R8, R c , n are as defined in claim 1 or 2. d , n are as defined in claim 1 or 2.

4. The compound of claim 3, or a pharmaceutically acceptable salt, isotopic derivative, solvate, or a stereoisomer, geometric isomer, tautomer thereof, or a prodrug molecule, metabolite thereof, wherein, The compound has the following formula (I-1)、(I-2)、(I-3)、(I-4)、(I-5)、(I-6)、(I-7)、(I-8)、(I-9)、(I-10)、(I-11)、( I-12)、(I-13)、(I-14)、(I-15)、(I-16)、(I-17)、(I-18)、(I-19)、(I-20)、(I-21)、(I-22)、(I- 23)、(I-24)、(I-25)、(I-26)、(I-27)、(I-28)、(I-29)、(I-30)、(I-31)、(I-32)、(I-33)、(I-34 )、(I-35)、(I-36)、(I-37)、(I-38)、(I-39)、(I-40)、(I-41)、(I-42)、(I-43)、(I-44)、(I-45)、( I-46)、(I-47)、(I-48)、(I-49)、(I-50)、(I-51)、(I-52)、(I-53)、(I-54)、(I-55)、(I-56)、(I- 57)、(I-58)、(I-59)、(I-60)、(I-61)、(I-62)、(I-63)、(I-64)、(I-65)、(I-66)、(I-67)、(I-68) 、(I-69)、(I-70)、(I-71)、(I-72)、(I-73)、(I-74)、(I-75)、(I-76)、(I-77)、(I-78)、(I-79)、( I-80)、(I-81)、(I-82)、(I-83)、(I-84)、(I-85)、(I-86)、(I-87)、(I-88)、(I-89) or (I-90) shown structure: wherein X, Y, W, R1, R2, R3, R4, R5, R8, R 81 , R 82 , R 83 , R c , n are as defined in claim 3.

5. The compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt, isotopic derivative, solvate, or a stereoisomer, geometric isomer, tautomer thereof, or a prodrug molecule, metabolite thereof, wherein, X is CH.

6. The compound of any one of claims 1 to 5, or a pharmaceutically acceptable salt, isotopic derivative, solvate, or a stereoisomer, geometric isomer, tautomer thereof, or a prodrug molecule, metabolite thereof, wherein, Y is CH.

7. The compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt, isotopic derivative, solvate, or a stereoisomer, geometric isomer, tautomer thereof, or a prodrug molecule, metabolite thereof, wherein, The W is CH.

8. The compound of any one of claims 1 to 7, or a pharmaceutically acceptable salt, isotopic derivative, solvate, or a stereoisomer, geometric isomer, tautomer thereof, or a prodrug molecule, metabolite thereof, wherein, R1 is a halogen.

9. The compound of claim 8, or a pharmaceutically acceptable salt, isotopic derivative, solvate, or a stereoisomer, geometric isomer, tautomer thereof, or a prodrug molecule, metabolite thereof, wherein, R1 is chlorine or fluorine; preferably, R1 is chlorine.

10. The compound of any one of claims 1 to 9, or a pharmaceutically acceptable salt, isotopic derivative, solvate, or a stereoisomer, geometric isomer, tautomer thereof, or a prodrug molecule, metabolite thereof, wherein, R2 is hydrogen.

11. The compound of any one of claims 1 to 10, or a pharmaceutically acceptable salt, isotopic derivative, solvate, or a stereoisomer, geometric isomer, tautomer thereof, or a prodrug molecule, metabolite thereof, wherein, R3 is hydrogen.

12. The compound of any one of claims 1 to 11, or a pharmaceutically acceptable salt, isotopic derivative, solvate, or a stereoisomer, geometric isomer, tautomer thereof, or a prodrug molecule, metabolite thereof, wherein, R4 is hydrogen.

13. The compound of any one of claims 1 to 12, or a pharmaceutically acceptable salt, isotopic derivative, solvate, or a stereoisomer, geometric isomer, tautomer thereof, or a prodrug molecule, metabolite thereof, wherein, R5 is hydrogen.

14. The compound of any one of claims 1 to 13, or a pharmaceutically acceptable salt, isotopic derivative, solvate, or a stereoisomer, geometric isomer, tautomer thereof, or a prodrug molecule, metabolite thereof, wherein, Each of the R8 groups is independently selected from hydrogen, halogen, cyano, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-8 membered heterocyclic or C 1-6 alkylamine group, the C 1-6 Alkyl groups may optionally be C 1-6 Alkylamine substitution.

15. The compound of claim 14, or a pharmaceutically acceptable salt, isotopic derivative, solvate, or a stereoisomer, geometric isomer, tautomer thereof, or a prodrug molecule, metabolite thereof, wherein, each of said R8is independently selected from hydrogen, fluoro, methoxy, methyl, trifluoromethyl, difluoromethyl, cyclopropyl, cyano, 16. The compound of any one of claims 1 to 15, or a pharmaceutically acceptable salt, isotopic derivative, solvate, or a stereoisomer, geometric isomer, tautomer thereof, or a prodrug molecule, metabolite thereof, wherein, said R 81 selected from hydrogen, R 82 selected from hydrogen.

17. The compound of any one of claims 1 to 16, or a pharmaceutically acceptable salt, isotopic derivative, solvate, or a stereoisomer, geometric isomer, tautomer thereof, or a prodrug molecule, metabolite thereof, wherein, said R 83 selected from hydrogen, C 1-6 alkyl, C 1-6 alkylacyl or C 1-6 alkylsulfonyl, said C 1-6 alkyl is optionally substituted with one or more R d each R d is each independently selected from hydrogen, hydroxyl or C 1-6 alkoxy.

18. The compound of claim 17, or a pharmaceutically acceptable salt, isotopic derivative, solvate, or a stereoisomer, geometric isomer, tautomer thereof, or a prodrug molecule, metabolite thereof, wherein, said R 83 each independently selected from hydrogen, methyl, 19. The compound of any one of claims 1 to 18, or a pharmaceutically acceptable salt, isotopic derivative, solvate, or a stereoisomer, geometric isomer, tautomer thereof, or a prodrug molecule, metabolite thereof, wherein, The R c It is hydrogen.

20. The compound of any one of claims 1 to 19, or a pharmaceutically acceptable salt, isotopic derivative, solvate, or a stereoisomer, geometric isomer, tautomer thereof, or a prodrug molecule, metabolite thereof, wherein, The compound is selected from the following structural compounds:

21. A pharmaceutical composition comprising, The pharmaceutical composition contains a therapeutically effective amount of any one of the compounds of claims 1-20 or a pharmaceutically acceptable salt, isotope derivative, solvate thereof, or a stereoisomer, geometric isomer, tautomer thereof, or a prodrug molecule or metabolite thereof.

22. Use of any compound of claims 1 to 20 or a pharmaceutically acceptable salt, isotope derivative, solvate thereof, or a stereoisomer, geometric isomer, tautomer thereof, or a prodrug molecule, metabolite thereof, or pharmaceutical composition of claim 21 in the preparation of a medicament for treating VAV1-related diseases or conditions and related diseases or conditions.

23. Use of any compound of claims 1 to 20 or a pharmaceutically acceptable salt, isotope derivative, solvate thereof, or a stereoisomer, geometric isomer, tautomer thereof, or a prodrug molecule, metabolite thereof, or pharmaceutical composition of claim 21 for the treatment of VAV1-related diseases or conditions and related diseases or conditions.

24. A method of treating and / or preventing a disease, comprising administering to a subject a therapeutically effective amount of any one of claims 1 to 20, or a pharmaceutically acceptable salt, isotope derivative, solvate thereof, or a stereoisomer, geometric isomer, tautomer thereof, or a prodrug molecule, metabolite thereof, or pharmaceutical composition of claim 21 thereof.

25. The method of claim 24, wherein, The diseases to be treated and / or prevented are VAV1-related diseases or conditions and related diseases or conditions.

26. The use according to claim 22 or 23, or the method according to claim 25, wherein, The VAV1-related diseases or conditions and related diseases or conditions are diseases caused by abnormalities in the T cell signaling pathway (TCR) or B cell signaling pathway (BCR), including autoimmune diseases, inflammatory diseases and hematologic malignancies.

27. Use or method according to claim 26, characterized in that, The autoimmune diseases include multiple sclerosis, arthritis, systemic lupus erythematosus, chronic autoimmune thyroiditis, myasthenia gravis, type I / II diabetes and its complications, vasculitis, pernicious anemia, Sjögren's syndrome, uveitis, psoriasis, Graves' ophthalmopathy, alopecia areata, allergic asthma, atopic dermatitis, allergic rhinitis, allergic conjunctivitis, etc.; the inflammatory diseases include inflammatory bowel disease, Crohn's disease, endogenous asthma, inflammatory lung injury, inflammatory liver injury, inflammatory kidney injury, atherosclerosis, etc. The list includes conditions such as osteoarthritis, irritant dermatitis, eczema, seborrheic dermatitis, keratitis, myocarditis, and hepatitis; the hematologic malignancies include leukemia, lymphoma, acute myeloid leukemia (AML), T-lymphoblastic lymphoma, T-chronic lymphocytic leukemia, aggressive NK-cell leukemia, hairy cell leukemia, extranodal NK / T-cell lymphoma, mycosis fungoides, Sézary syndrome, angioimmunoblastic T-cell lymphoma, peripheral T-cell lymphoma, and adult T-cell leukemia (HTLV1). + ), anaplastic large cell lymphoma, cutaneous T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, intestinal T-cell lymphoma, hepatosplenic T-cell lymphoma, non-Hodgkin lymphoma (e.g., B-cell non-Hodgkin lymphoma, Burkitt lymphoma, chronic lymphocytic leukemia / small lymphocytic lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, and mantle cell lymphoma).

28. An intermediate compound M3-1, M3, or a pharmaceutically acceptable salt, isotopic derivative, solvate thereof, or a stereoisomer, geometric isomer, tautomer thereof, or a prodrug molecule thereof:

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