VAV1 degrader

Abstract

Disclosed in the present invention are a VAV1 degrader represented by general formula (I), a pharmaceutical composition comprising same, a preparation method therefor and a use thereof in preparation of a drug for prevention and / or treatment of autoimmune diseases and inflammatory indications. The compound provided by the present invention has good VAV1 degradation activity, can enhance the degradation of a VAV1 protein by enhancing the interaction between the VAV1 protein and an E3 ligase, and can be used for treating and / or preventing various diseases related to VAV1, particularly autoimmune diseases and tumors.

Description

VAV1 degrading agent Technical Field

[0001] This invention belongs to the field of medicinal chemistry and relates to a VAV1 degrading agent, particularly to a drug that can degrade VAV1, its pharmaceutical composition, preparation method, and its use in the preparation, prevention, and / or treatment of autoimmune diseases and inflammatory indications. Background Technology

[0002] Molecular gluten is a small molecule compound that can synergistically bind at protein-protein interaction (PPI) interfaces, primarily regulating protein function and metabolism by inducing or stabilizing PPIs. Molecular gluten degraders (MGDs) are a type of MG that binds to E3 ubiquitin ligases. These E3 ligases transfer ubiquitin to substrate proteins, marking the target protein with a degradation signal. MGDs lead to E3 ubiquitination of the target protein, subsequently resulting in its recognition and degradation by the proteasome. Molecular gluten has been developed to treat various diseases, such as lenalidomide drugs, which are molecular gluten compounds of the E3 ligase cereblon and have been approved by the FDA for the treatment of hematologic malignancies such as multiple myeloma and myelodysplastic syndromes. Molecular gluten has significant application potential for druggable targets. VAV1, the target of this patent, has long been considered a "druggable target." Directly targeting the GEF domain of VAV1 is challenging because inhibiting GEF activity (catalytic activity) would still preserve its scaffold protein function, leading to insufficient inhibition of VAV1 activity and severely impacting efficacy. Molecular glue degraders targeting VAV1 may bring breakthrough progress in the treatment of VAV1-mediated diseases.

[0003] VAV1 (Vav guanine nucleotide exchange factor 1) belongs to the guanine nucleotide exchange factor (GEF) family and is an adaptor protein. In vertebrates, the VAV family consists of three members—VAV1, VAV2, and VAV3. VAV1 is highly specific for expression on hematopoietic cells, including T cells, B cells, dendritic cells, natural killer cells, and granulocytes, while VAV2 and VAV3 are expressed more universally.

[0004] Studies have found that VAV1 primarily exerts its functions through two pathways: GEF-dependent and GEF-independent. These pathways regulate T cell and B cell receptor signaling, T cell activation, T helper cell differentiation, cytokine production, actin polymerization, and cytoskeleton remodeling. The GEF-dependent function of VAV1 refers to its catalytic function; VAV1 can activate Rac / Rho family GTPases, leading to actin polymerization, integrin adhesion activation, immune synapse formation between T cells and APCs, and chemokine-mediated cell migration. The GEF-independent function of VAV1 refers to its "scaffolding" function. This function appears to depend on its involvement in the antigen receptor-neighbor signaling complex rather than GEF catalytic activity. It mediates signal transduction through the binding of its adaptor domain to other proteins. Studies have shown that in GEF-inactivated mice, it exhibits normal TCR-mediated calcium release and NFAT pathway activation. VAV1 plays a crucial role in T cell development due to its involvement in the regulation and transduction of multiple signaling pathways. VAV1 deficiency leads to severe T cell developmental defects. VAV1 also has an important impact on receptor signal transduction in T / B cells and is a positive regulator of T / B cell receptor signal transduction. It also affects the migration of hematopoietic lineage cells.

[0005] Multiple studies have shown that VAV1 may be associated with autoimmune diseases and inflammation. In diseases such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), inflammatory bowel disease (IBD), and multiple sclerosis (MS), VAV1 has been found to be closely related to the abnormal activation of T cells and B cells. Data indicate that the absence / inhibition of VAV1 can modulate autoimmunity and inflammation. Inhibition of VAV1 has also shown good pharmacodynamic responses in animals with T / B cell-mediated arthritis and colitis, supporting VAV1 as a potential therapeutic target for autoimmune diseases and inflammation. Summary of the Invention

[0006] In order to overcome the shortcomings of the prior art, the present invention aims to provide a VAV1 degrading agent, its pharmaceutical composition, preparation method and its use in the preparation, prevention and / or treatment of autoimmune diseases and inflammatory indications.

[0007] In one aspect, the present invention provides a compound of formula (I):

[0008] Or its deuterated derivatives, stereoisomers, or pharmaceutically acceptable salts, wherein:

[0009] R 1 Selected from:

[0010] 1) Choose 1-3 Rs dSubstitution; ring A is a 5- to 6-membered aromatic ring or a 5- to 6-membered heteroaromatic ring containing at most 4 heteroatoms selected from N, O, and S; X 1 X 2 Selected from C or N; q is an integer from 1 to 5; r is 0, 1, or 2;

[0011] 2) Choose 1-3 Rs d Substitution; ring B is a 5- to 6-membered aromatic ring or a 5- to 6-membered heteroaromatic ring containing at most 4 heteroatoms selected from N, O, and S; Z 1 Z 2 Selected from C or N; t is an integer from 1 to 5;

[0012] 3) Choose 1-3 Rs d replace;

[0013] 4) R a R b Each is independently selected from optionally substituted C1-C6 alkyl, C1-C6 alkoxy, optionally substituted C1-C6 alkoxy, optionally substituted 3-8 membered cycloalkyl, or R a R b It forms 3-8 membered heterocycles with the atoms it is attached to;

[0014] 5) R f Selected from optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 alkoxy, optionally substituted 3-8 membered cycloalkyl, optionally substituted 3-8 membered heterocycloalkyl containing 1-2 heteroatoms selected from N, O, S; L is a chemical bond, optionally substituted C1-C3 alkylene. R g Selected from 5-8 membered heterocyclic groups containing 1 to 3 heteroatoms selected from N, O, and S, which are substituted by choice;

[0015] 6) Choose 1-3 Rs d replace;

[0016] R 3 Selected from H, halogen, hydroxyl, cyano, amino, nitro, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted 3-6 membered cycloalkyl or optionally substituted 3-6 membered heterocycloalkyl.

[0017] n is an integer between 1 and 3;

[0018] R 2 R 4 R5 Each is independently selected from H, halogen, hydroxyl, cyano, amino, nitro, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted 3-6 membered cycloalkyl or optionally substituted 3-6 membered heterocycloalkyl.

[0019] Y 1 Y 2 For N or CR c ;

[0020] Y 3 For N or CR';

[0021] p is an integer between 0 and 3;

[0022] m is an integer between 1 and 3;

[0023] R 6 Each is independently selected from H, halogen, hydroxyl, cyano, amino, nitro, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted 3-6 membered cycloalkyl or optionally substituted 3-6 membered heterocycloalkyl, or two R 6 It forms 3-8 membered carbon rings or 3-8 membered heterocycles with the attached carbon atoms;

[0024] R c R d Each is selected from H, halogen, hydroxyl, cyano, amino, nitro, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkynyl, optionally substituted C1-C6 alkoxy, optionally substituted 3-8 membered cycloalkyl.

[0025] R' is selected from H, halogen, hydroxyl, cyano, amino, nitro, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted 3-8 membered cycloalkyl.

[0026] As a preferred option, R 3 It is selected from H, halogen, hydroxyl, cyano, amino, nitro, optional halogen-substituted C1-C3 alkyl, optional halogen-substituted C1-C3 alkoxy, optional halogen-substituted 3-6 membered cycloalkyl or optional halogen-substituted 3-6 membered heterocycloalkyl.

[0027] As a preferred embodiment, R is characterized by 3 Selected from H, F, Cl, Br, methyl, methoxy, trifluoromethyl, trifluoromethoxy, difluoromethyl, difluoromethoxy, and cyclopropyl.

[0028] As a preferred option, Y 1 For N or CR c ;

[0029] R cSelected from H, F, Cl, methyl, ethynyl, methoxy, trifluoromethyl, trifluoromethoxy, and cyclopropyl.

[0030] As a preferred option, Y 2 For N or CR c ;

[0031] R c Selected from H, F, Cl, cyano, methyl, ethynyl, methoxy, trifluoromethyl, trifluoromethoxy, and cyclopropyl.

[0032] Preferably, p is 1 or 2;

[0033] m is an integer between 1 and 3;

[0034] R 6 Each is independently selected from H, halogen, hydroxyl, cyano, amino, nitro, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted 3-6 membered cycloalkyl or optionally substituted 3-6 membered heterocycloalkyl.

[0035] When two R 6 When two R atoms are substituted for the same carbon atom or adjacent carbon atoms, the two R atoms are substituted for the same carbon atom or adjacent carbon atoms. 6 It can form 3-8 membered carbon rings or 3-8 membered heterocycles with the attached carbon atoms, preferably forming 3 membered carbon rings.

[0036] As a preferred option, R 2 R 4 R 5 Each is independently selected from H, F, Cl, Br, methyl, methoxy, trifluoromethyl, trifluoromethoxy, difluoromethyl, difluoromethoxy, and cyclopropyl.

[0037] As a preferred option, R 1 Selected from or

[0038] Choose 1-3 Rs d The following groups are substituted:

[0039] R a R b Selected from C that is arbitrarily substituted with halogen 1 -C 3 Alkyl groups, optionally halogenated 3-8 membered cycloalkyl groups, preferably methyl, trifluoromethyl, difluoromethyl, ethyl, propyl, cyclopropyl, cyclobutyl, or...

[0040] R a R b It forms 3-8 membered heterocycles with the atoms it is attached to;

[0041] Y 3 For N or CR';

[0042] R f The group is selected from C1-C3 alkyl, optionally halogenated C2-C6 alkenyl, optionally halogenated C2-C6 alkynyl, optionally halogenated C1-C3 alkoxy, optionally halogenated 3-6 membered cycloalkyl, optionally halogenated or C1-C3 alkyl, and optionally halogenated or C1-C3 alkyl containing 1-2 heterocyclic alkyl groups selected from N, O, and S heteroatoms, wherein the C1-C3 alkyl group is optionally substituted with 1-3 halogens, 3-6 membered cycloalkyl groups, C2-C3 alkenyl, C2-C6 alkynyl, or C1-C3 alkoxy groups, preferably trifluoromethyl, difluoromethyl, etc. Alternatively, the following groups may be optionally substituted with halogens or C1-C3 alkyl groups: Cyclopropyl, cyclobutyl,

[0043] L represents a chemical bond, and the C1-C3 alkylene group is optionally substituted with a halogen.

[0044] R h Selected from H, halogen, hydroxyl, cyano, amino, nitro, optional halogen-substituted C1-C3 alkyl, optional halogen-substituted C1-C3 alkoxy, optional halogen-substituted 3-8 membered cycloalkyl, or optional halogen-substituted or C1-C3 alkyl, preferably F, methyl, trifluoromethyl, difluoromethyl, methoxy, trifluoromethoxy, ethyl, propyl, cyclopropyl, cyclobutyl;

[0045] R d Selected from H, halogen, hydroxyl, cyano, amino, nitro, optional C1-C3 alkyl substituted with halogen, optional C1-C3 alkoxy substituted with halogen, optional 3-8 membered cycloalkyl substituted with halogen;

[0046] R e Selected from C1-C3 alkyl groups optionally substituted with halogens, and 3-8 membered cycloalkyl groups optionally substituted with halogens, preferably methyl, trifluoromethyl, difluoromethyl, ethyl, propyl, or cyclopropyl;

[0047] R' is selected from H, halogen, hydroxyl, cyano, amino, nitro, optional halogen-substituted C1-C3 alkyl, optional halogen-substituted C1-C3 alkoxy, optional halogen-substituted 3-8 membered cycloalkyl.

[0048] As a preferred option, R 1 Selected from

[0049] In some preferred embodiments, R 1 Selected from:

[0050] 1.1) Choose 1-3 Rs d Substitution; Ring A is a heteroaromatic ring; X 1 X 2 X 3 X 4 X 5 Selected from C and CR respectively d , N, NR e O, S, and at most 3 of them are heteroatoms; q is an integer selected from 1 to 5, preferably 1, 2 or 3;

[0051] 1.2) Choose 1-3 Rs d Replace; X 6 X 7 X 8 X 9 Selected from CR d , N, and at most 3 of them are N; q is an integer selected from 1 to 5, preferably 1, 2 or 3;

[0052] 2.1) Choose 1-3 Rs d Substitution; ring B is a heteroaromatic ring; Z 1 Z 2 Z 3 Z 4 Z 5 Selected from C and CR respectively d , N, NR e O, S, and at most 3 of them are heteroatoms; t is an integer selected from 1 to 5, preferably 1, 2 or 3;

[0053] 2.2) Choose 1-3 Rs d Replace; Z 6 Z 7 Z 8 Z 9 Selected from CR d , N, and at most 3 of them are N; t is an integer selected from 1 to 5, preferably 1, 2 or 3;

[0054] R d The groups are selected from H, halogen, hydroxyl, cyano, amino, nitro, C1-C3 alkyl groups optionally substituted with halogen, C1-C3 alkoxy groups optionally substituted with halogen, and 3-8 membered cycloalkyl groups optionally substituted with halogen.

[0055] R e It is selected from C1-C3 alkyl groups optionally substituted with halogens, and 3-8 membered cycloalkyl groups optionally substituted with halogens, preferably methyl, trifluoromethyl, difluoromethyl, ethyl, propyl, or cyclopropyl.

[0056] As a preferred option, R 1 Selected from 1-3 Rs d The following groups are substituted:

[0057] R d Selected from H, halogen, hydroxyl, cyano, amino, nitro, and C groups optionally substituted with halogens. 1 -C 3 Alkyl, C1-C3 alkoxy, optionally halogenated, 3-8 membered cycloalkyl;

[0058] R e It is selected from C1-C3 alkyl groups optionally substituted with halogens, and 3-8 membered cycloalkyl groups optionally substituted with halogens, preferably methyl, trifluoromethyl, difluoromethyl, ethyl, propyl, or cyclopropyl.

[0059] As a preferred option, R 1 Selected from

[0060] In some preferred embodiments, R 1 Selected from 1-3 Rs d The following groups are substituted:

[0061] R d The groups are selected from H, halogen, hydroxyl, cyano, amino, nitro, C1-C3 alkyl groups optionally substituted with halogen, C1-C3 alkoxy groups optionally substituted with halogen, and 3-8 membered cycloalkyl groups optionally substituted with halogen.

[0062] As a preferred option, R 1 Selected from

[0063] In some preferred embodiments, R 1 Selected from

[0064] Y 3 Let N be the number of people in the group.

[0065] Among them, R fThe group is selected from C1-C3 alkyl, optionally halogenated C2-C6 alkenyl, optionally halogenated C2-C6 alkynyl, optionally halogenated C1-C3 alkoxy, optionally halogenated 3-6 membered cycloalkyl, optionally halogenated or C1-C3 alkyl, and optionally halogenated or C1-C3 alkyl containing 1-2 heterocyclic alkyl groups selected from N, O, and S heteroatoms, wherein the C1-C3 alkyl group is optionally substituted with 1-3 halogens, 3-6 membered cycloalkyl groups, C2-C3 alkenyl, C2-C6 alkynyl, or C1-C3 alkoxy groups, preferably trifluoromethyl, difluoromethyl, etc. Alternatively, the following groups may be optionally substituted with halogens or C1-C3 alkyl groups: Cyclopropyl, cyclobutyl,

[0066] L represents a chemical bond, and the C1-C3 alkylene group is optionally substituted with a halogen.

[0067] R g Selected from R h Substituted with 1 to 3 5-6 membered heteroaryl groups selected from N, O, and S heteroatoms, optionally with R h The substituted alkyl group contains 1 to 3 5-6 membered heterocyclic alkyl groups selected from N, O, and S heteroatoms, preferably optionally R. h The following groups are substituted:

[0068] R h Selected from H, halogen, hydroxyl, cyano, amino, nitro, optional halogen-substituted C1-C3 alkyl, optional halogen-substituted C1-C3 alkoxy, optional halogen-substituted 3-8 membered cycloalkyl, or optional halogen-substituted or C1-C3 alkyl 3-6 membered heterocycloalkyl, preferably F, methyl, trifluoromethyl, difluoromethyl, Methoxy, trifluoromethoxy, ethyl, propyl, cyclopropyl, cyclobutyl.

[0069] In some preferred embodiments, R 1 Selected from

[0070] Y 3 For CR';

[0071] R' is selected from H, halogen, hydroxyl, cyano, amino, nitro, optional C1-C3 alkyl substituted with halogen, optional C1-C3 alkoxy substituted with halogen, optional 3-8 membered cycloalkyl substituted with halogen.

[0072] Among them, R fThe group is selected from C1-C3 alkyl groups, optionally halogenated C2-C6 alkenyl groups, optionally halogenated C2-C6 alkynyl groups, optionally halogenated 3-6 membered cycloalkyl groups substituted with halogen or C1-C3 alkyl groups, and optionally halogenated or C1-C3 alkyl groups containing 1 to 2 heterocyclic alkyl groups selected from N, O, and S heteroatoms, wherein the C1-C3 alkyl group is optionally substituted with a 3-6 membered cycloalkyl group, a C2-C3 alkenyl group, or a C2-C6 alkynyl group, preferably. Alternatively, the following groups may be optionally substituted with halogens or C1-C3 alkyl groups: Cyclopropyl, cyclobutyl,

[0073] L is selected from chemical bonds, optionally from C1-C3 alkylene groups substituted with halogens.

[0074] R g Selected from R h Substituted with 1 to 3 5-6 membered heteroaryl groups selected from N, O, and S heteroatoms, optionally with R h The substituted alkyl group contains 1 to 3 5-6 membered heterocyclic alkyl groups selected from N, O, and S heteroatoms, preferably optionally R. h The following groups are substituted:

[0075] R h Selected from H, halogen, hydroxyl, cyano, amino, nitro, optional halogen-substituted C1-C3 alkyl, optional halogen-substituted C1-C3 alkoxy, optional halogen-substituted 3-8 membered cycloalkyl, or optional halogen-substituted or C1-C3 alkyl 3-6 membered heterocycloalkyl, preferably F, methyl, trifluoromethyl, difluoromethyl, Methoxy, trifluoromethoxy, ethyl, propyl, cyclopropyl, cyclobutyl.

[0076] As a preferred option, R 1 Selected from

[0077] Better:

[0078] In some preferred embodiments, R 1 Selected from Choose 1-3 Rs d replace;

[0079] Y 1 Y 2 For N or CR c ;

[0080] p is an integer between 0 and 3;

[0081] m is an integer between 1 and 3;

[0082] R 6 Each is independently selected from H, halogen, hydroxyl, cyano, amino, nitro, optional halogen-substituted C1-C3 alkyl, optional halogen-substituted C1-C3 alkoxy, optional substituted 3-6 membered cycloalkyl, or optional substituted 3-6 membered heterocycloalkyl, or

[0083] When m is 2, the two R 6 It forms a 3-8 membered carbon ring or a 3-8 membered heterocycle with the attached carbon atom, preferably cyclopropyl;

[0084] R c R d Each is selected from H, halogen, hydroxyl, cyano, amino, nitro, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkynyl, optionally substituted C1-C6 alkoxy, optionally substituted 3-8 membered cycloalkyl.

[0085] In some preferred embodiments, R 1 Selected from

[0086] R a R b Each is independently selected from optionally substituted C1-C6 alkyl, C1-C6 alkoxy, optionally substituted C1-C6 alkoxy, optionally substituted 3-8 membered cycloalkyl, or R a R b It forms 3-8 membered heterocycles with the atoms it is attached to;

[0087] As a preferred option, R a R b Each is independently selected from C1-C3 alkyl groups optionally substituted with halogens, 3-8 membered cycloalkyl groups optionally substituted with halogens or C1-C3 alkyl groups, or R a R b It forms 3-8 membered heterocycles with the atoms it is attached to;

[0088] Further optimization, R a R b Each is independently selected from methyl, trifluoromethyl, difluoromethyl, ethyl, propyl, substituted with halogens, and cyclopropyl, cyclobutyl, substituted with halogens or C1-C3 alkyl groups.

[0089] or R a R b Forming with the attached atoms

[0090] Another aspect of the present invention provides a compound of formula (II):

[0091] Or its deuterated derivatives, stereoisomers, or pharmaceutically acceptable salts, wherein:

[0092] R 2 R 2 Each is independently selected from H, halogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted 3-6 membered cycloalkyl or optionally substituted 3-6 membered heterocycloalkyl;

[0093] R 4 R 5 Each is independently selected from H, halogen, hydroxyl, cyano, amino, nitro, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted 3-6 membered cycloalkyl or optionally substituted 3-6 membered heterocycloalkyl.

[0094] Y 1 Y 2 For N or CR c ;

[0095] m is an integer between 0 and 3;

[0096] R 6 Each is independently selected from H, halogen, hydroxyl, cyano, amino, nitro, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted 3-6 membered cycloalkyl or optionally substituted 3-6 membered heterocycloalkyl.

[0097] R c Each is selected from H, halogen, hydroxyl, cyano, amino, nitro, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkynyl, optionally substituted C1-C6 alkoxy, optionally substituted 3-8 membered cycloalkyl.

[0098] R f Selected from optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 alkoxy, optionally substituted 3-8 membered cycloalkyl, optionally substituted 3-8 membered heterocycloalkyl containing 1 to 2 heteroatoms selected from N, O, and S.

[0099] R g Selected from arbitrarily substituted 5-10 membered heterocyclic groups containing 1 to 3 heteroatoms selected from N, O, and S.

[0100] As a preferred option:

[0101] R 3 Selected from H, halogen, hydroxyl, cyano, C1-C3 alkyl, C1-C3 alkoxy, 3-6 membered cycloalkyl or 3-6 membered heterocycloalkyl, wherein the C1-C3 alkyl, C1-C3 alkoxy, 3-6 membered cycloalkyl or 3-6 membered heterocycloalkyl are optionally substituted with 1-3 halogens, C1-C3 alkyl, halogenated C1-C3 alkyl, C1-C3 alkoxy or halogenated C1-C3 alkoxy;

[0102] R 3 H, F, Cl, Br, methyl, methoxy, trifluoromethyl, trifluoromethoxy, difluoromethyl, difluoromethoxy, cyclopropyl are preferred, and Cl is even more preferred.

[0103] As a preferred option:

[0104] R 4 R 5 Each is independently selected from H, F, methyl, trifluoromethyl, methoxy, or trifluoromethoxy, with H being preferred.

[0105] As a preferred option:

[0106] Y 1 For CR c ;

[0107] R c The components are selected from H, F, Cl, methyl, methoxy, trifluoromethyl, and trifluoromethoxy, with H being preferred.

[0108] As a preferred option:

[0109] Y 2 For N or CR c ;

[0110] R c The components are selected from H, F, Cl, cyano, methyl, ethynyl, methoxy, trifluoromethyl, and trifluoromethoxy, with H being preferred.

[0111] As a preferred option:

[0112] m can be 0, 1, or 2, with 0 being preferred;

[0113] R 6 It is selected from H, halogen, hydroxyl, cyano, amino, nitro, methyl, trifluoromethyl, methoxy or trifluoromethoxy, with H being preferred.

[0114] As a preferred option:

[0115] R 2 R 2Each is independently selected from H, F, Cl, C1-C3 alkyl groups optionally substituted with 1-3 halogens, C1-C3 alkoxy groups optionally substituted with 1-3 halogens, 3-6 membered cycloalkyl groups or 3-6 membered heterocycloalkyl groups optionally substituted with 1-3 halogens or C1-C3 alkyl groups, preferably H, F, Cl, methyl, trifluoromethyl, difluoromethyl, methoxy, trifluoromethoxy, difluoromethoxy, cyclopropyl.

[0116] As a preferred option:

[0117] R f It is selected from C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, (C1-C3 alkylene)-(3-8 membered cycloalkyl), (C1-C3 alkylene)-(3-8 membered heterocycloalkyl), optionally substituted with 1-3 halogens, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C1-C3 alkylene, halo-C1-C3 alkyl, halo-C1-C3 alkylene, C1-C3 alkoxy, halo-C1-C3 alkoxy;

[0118] R f Selected from C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, 3-8 membered cycloalkyl, (C1-C3 alkylene)-(3-8 membered cycloalkyl), optionally substituted with 1-3 halogens, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C1-C3 alkylene, halo-C1-C3 alkyl, halo-C1-C3 alkylene;

[0119] R f Preferred compounds include C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, methylenecyclopropyl, methylenecyclobutyl, and methylenecyclopentyl. It may be optionally substituted with 1-3 Cl, F, methyl, ethyl, =CH2, difluoromethyl, trifluoromethyl, =CF2, vinyl, ethynyl, -CH=CH2, methoxy, difluoromethoxy, or trifluoromethoxy.

[0120] R f Preferred compounds include C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, methylenecyclopropyl, methylenecyclobutyl, and methylenecyclopentyl. It may be optionally substituted with 1-3 Cl, F, methyl, ethyl, =CH2, difluoromethyl, trifluoromethyl, =CF2, vinyl, ethynyl, or -CH=CH2;

[0121] R f More

[0122] R f More

[0123] In some preferred embodiments, the R f Not an unsubstituted C1-C3 alkyl group.

[0124] In some preferred embodiments, the R f It is selected from C2-C3 alkenyl, C2-C3 alkynyl, 3-8 membered cycloalkyl, (C1-C3 alkylene)-(3-8 membered cycloalkyl), optionally substituted with 1-3 halogens, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C1-C3 alkylene, halo-C1-C3 alkyl, halo-C1-C3 alkylene.

[0125] In some preferred embodiments, the R f It is selected from C1-C3 alkyl groups and is substituted by 1-3 halogens, C1-C3 alkyl groups, C2-C3 alkenyl groups, C2-C3 alkynyl groups, C1-C3 alkylene groups, halo-C1-C3 alkyl groups, or halo-C1-C3 alkylene groups.

[0126] As a preferred option:

[0127] R g Selected from 5-6 membered heterocyclic aryl groups containing 1-3 heteroatoms selected from N, O, and S, optionally substituted, and optionally substituted with 1-3 R atoms. h replace;

[0128] R g Selected from Preferred Choose 1-3 Rs h replace;

[0129] The R h The compounds are selected from halogens, C1-C3 alkyl groups, C1-C3 alkoxy groups, 3-6 membered cycloalkyl groups, 3-6 membered cycloalkyloxy groups, and (C1-C3 alkylene)-(3-6 membered cycloalkyl groups), wherein the C1-C3 alkyl groups, C1-C3 alkoxy groups, 3-6 membered cycloalkyl groups, 3-6 membered cycloalkyloxy groups, (C1-C3 alkylene)-(3-6 membered cycloalkyl groups), and C1-C3 alkylene groups are optionally substituted with 1-3 halogens, C1-C3 alkyl groups, C1-C3 alkoxy groups, halo-C1-C3 alkyl groups, and halo-C1-C3 alkoxy groups;

[0130] The R hPreferably, Cl, F, methyl, ethyl, propyl, cyclopropyl, methylenecyclopropyl, methoxy, cyclopropyloxy, cyclobutyl, and methylenecyclobutyl are used, wherein the methyl, ethyl, propyl, cyclopropyl, methylenecyclopropyl, methoxy, and cyclopropyloxy groups are optionally substituted by 1-3 Cl, F, methyl, trifluoromethyl, difluoromethyl, methoxy, trifluoromethoxy, and difluoromethoxy groups.

[0131] R h Preferably, Cl, F, methyl, ethyl, propyl, cyclopropyl, methylenecyclopropyl, methoxy, or cyclopropyloxy are used, wherein the methyl, ethyl, propyl, cyclopropyl, methylenecyclopropyl, methoxy, or cyclopropyloxy groups are optionally substituted by 1-3 Cl, F, methyl, trifluoromethyl, difluoromethyl, methoxy, trifluoromethoxy, or difluoromethoxy groups.

[0132] R h Preferably, Cl, F, methyl, ethyl, propyl, cyclopropyl, methylenecyclopropyl, methoxy, or cyclopropyloxy are used, wherein the methyl, ethyl, propyl, cyclopropyl, methylenecyclopropyl, methoxy, or cyclopropyloxy groups are optionally substituted by 1-3 Cl, F, methyl, methoxy, or trifluoromethoxy groups.

[0133] The R h More preferably Cl, F, methyl, propyl, difluoromethyl, trifluoromethyl, Cyclopropyl, methylenecyclopropyl, Methoxy, difluoromethoxy, trifluoromethoxy Cyclobutyl,

[0134] R h More preferably Cl, F, methyl, propyl, difluoromethyl, trifluoromethyl, Cyclopropyl, methylenecyclopropyl, Methoxy, difluoromethoxy, trifluoromethoxy

[0135] R h More preferably Cl, F, methyl, propyl, difluoromethyl, trifluoromethyl, Cyclopropyl, methylenecyclopropyl, Methoxy, difluoromethoxy, trifluoromethoxy

[0136] R h Further preferred compounds include Cl, F, methyl, propyl, difluoromethyl, and trifluoromethyl. Cyclopropyl, methylenecyclopropyl, Methoxy, difluoromethoxy, trifluoromethoxy

[0137] In some preferred embodiments, the deuteration site of the above-mentioned compound is preferably located on an alkyl group. In some more preferred embodiments, the deuteration site of the above-mentioned compound is preferably located on a methyl, difluoromethyl, methoxy, or difluoromethoxy group, where deuterium replaces the original H atom to form a deuterated compound. Preferably, the number of deuterations is 1, 2, or 3.

[0138] In some preferred embodiments of the present invention, the deuteration site of the above-mentioned deuterated compound is located at R h Alkyl groups, more preferably R h The methyl or methoxy group, preferably with 1, 2 or 3 deuterations. More preferably, R h for

[0139] The compound has the following structure:

[0140] Another aspect of the present invention provides a pharmaceutical composition for degrading VAV1 protein, comprising any of the compounds described above, their deuterated forms, stereoisomers or pharmaceutically acceptable salts, and pharmaceutically acceptable carriers thereof.

[0141] Preferably, the pharmaceutical composition mediates the interaction between VAV1 protein and E3 ligase, thereby increasing the degradation of VAV1 protein.

[0142] In another aspect, the present invention provides the use of any of the compounds, deuterated derivatives, stereoisomers or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, in the preparation of medicaments for treating and / or preventing diseases caused by or related to VAV1 polymorphism.

[0143] In another aspect, the present invention provides the use of any of the compounds, deuterated derivatives, stereoisomers, or pharmaceutically acceptable salts thereof, or any of the pharmaceutical compositions thereof, in the preparation of a medicament for treating and / or preventing diseases caused by or related to immune abnormalities in the body.

[0144] Preferably, the disease refers to an autoimmune disease or a tumor.

[0145] Preferably, the autoimmune diseases are selected from inflammatory bowel disease, rheumatoid arthritis, multiple sclerosis, lupus erythematosus, Hashimoto's thyroiditis, myasthenia gravis, Sjögren's syndrome, Graves' disease, type I diabetes and related diseases, vasculitis, urticaria, pulmonary hypertension, pemphigus, pernicious anemia and blood diseases mediated by autoimmune abnormalities, uveitis, psoriasis, Graves' ophthalmopathy, alopecia areata and other diseases, autoimmune nephritis, cutaneous manifestations of immune-mediated diseases, systemic sclerosis, morphine scleroderma, graft-versus-host disease, T-cell-mediated nephropathy, biliary sclerosis, sclerosing cholangitis, autoimmune liver disease, chronic inflammatory demyelinating diseases, ankylosing spondylitis, axial spondyloarthritis, and alopecia areata.

[0146] The inflammatory diseases mentioned include asthma, inflammatory lung injury, inflammatory liver injury, inflammatory glomerular injury, atherosclerosis, osteoarthritis, irritant contact dermatitis and eczematous dermatitis, seborrheic dermatitis, inflammatory eye disease, keratoconjunctivitis, pericarditis, myocarditis, hepatitis, pulmonary fibrosis, macular degeneration, generalized undulating hematoma, Alzheimer's disease, and amyloidosis.

[0147] The allergic diseases mentioned include allergic asthma, atopic dermatitis, allergic rhinitis / conjunctivitis, allergic contact dermatitis, and esophagitis.

[0148] Preferably, the disease is selected from inflammatory bowel disease, rheumatoid arthritis, multiple sclerosis, lupus erythematosus, psoriasis, type I diabetes, myasthenia gravis, chronic inflammatory demyelinating diseases, graft-versus-host disease, ankylosing spondylitis, and axial spondyloarthritis.

[0149] Preferably, the disease is selected from ulcerative colitis, Crohn's disease, rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, psoriasis, type I diabetes, myasthenia gravis, and graft-versus-host disease.

[0150] Preferably, the disease is selected from ulcerative colitis, rheumatoid arthritis, and multiple sclerosis.

[0151] Preferably, the tumor includes solid tumors and hematologic malignancies, especially hematologic malignancies; the hematologic malignancies include T-cell and B-cell malignancies.

[0152] Preferably, the hematologic malignancy is selected from leukemia and lymphoma.

[0153] The leukemia and lymphoma mentioned can specifically include: acute myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, early T-cell lymphoblastic leukemia, T-cell granulocytic leukemia, aggressive NK-cell leukemia, hairy cell leukemia, nasal NK / T-cell lymphoma, mycosis fungoides and Sezary syndrome, angioimmunoblastic T-cell lymphoma, peripheral T-cell lymphoma (not specifically mentioned), and adult T-cell lymphoma. Leukemia / lymphoma, anaplastic large cell lymphoma, primary cutaneous CD30-positive T-cell lymphoproliferative disorder, cutaneous T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, enteropathy-type T-cell lymphoma, hepatosplenic γ / δ T-cell lymphoma, Burkitt lymphoma, chronic lymphocytic leukemia / small lymphocytic lymphoma, diffuse large B-cell lymphoma, Waldenström macroglobulinemia, follicular lymphoma, mantle cell lymphoma, mucosa-associated lymphoid tissue lymphoma. Beneficial effects:

[0154] The compounds provided by this invention have strong efficacy, good pharmacokinetic properties, and low toxicity, making them ideal VAV1 degrading agents (also known as VAV1 molecular glue degrading agents). The compounds provided by this invention exhibit good VAV1 degradation activity and can enhance the degradation of VAV1 protein by strengthening the interaction between VAV1 protein and E3 ligase. Attached Figure Description

[0155] Figure 1 shows the arthritis scores in the CIA animal model in Test Example 2;

[0156] Figure 2 shows the DAI score in the IBD animal model in test example 3;

[0157] Figure 3 shows the incidence rate in the EAE animal model in test case 4;

[0158] Figure 4 shows the clinical scores in the EAE animal model in test case 4. Detailed Implementation

[0159] The present invention will be further described in detail below with reference to specific embodiments, but the present invention is not limited to the following embodiments.

[0160] definition

[0161] The terms "optional" or "optionally" used in this article mean that any optional option can be selected or not selected. For example, "group A is optionally replaced by 1-3 groups B" includes four cases: group A is not replaced by group B, group A is replaced by 1 group B, group A is replaced by 2 groups B, and group A is replaced by 3 groups B.

[0162] As used herein, "substitution" or "substituted" refers to the substitution of one or more hydrogen atoms on any atom of a group or segment by a substituent, which can include deuterium and hydrogen variants, provided that the valence state of the specific atom is normal and the substituted compound is stable. When the substituent is "oxo" (i.e., =O), it means that two hydrogen atoms are replaced by oxygen, and when the oxygen-substituted atom is a carbon atom, a carbonyl group (C=O) is formed. Oxygen substitution does not occur on aromatic groups. When the substituent is "=CH2", it means that two hydrogen atoms are replaced by a methylene group linked by a double bond.

[0163] As used in this article, "optionally substituted" means that it may or may not be substituted. Unless otherwise specified, the type and number of substituents can be arbitrary, provided that it is chemically feasible. For example, "optionally substituted 5-6 membered heterocyclic group" refers to a 5-6 membered heterocyclic group that is substituted or unsubstituted by any group. Another example is "optionally substituted with 1-3 R groups..." a Replacement C 1-6 "Alkyl" refers to an unsubstituted or alkyl group consisting of 1-3 R groups. a Replacement C 1-6 alkyl.

[0164] When any variable (e.g., R) appears more than once in the composition or structure of a compound, its definition is independent in each case. Thus, for example, if a group is substituted by 0-2 Rs, the group can optionally be substituted by at most two Rs, and the Rs in each case have independent options. Furthermore, combinations of substituents and / or their variants are only permitted if such combinations produce a stable compound.

[0165] The term "chemical bond" as used in this article generally refers to a covalent bond formed between two atoms in a compound molecule by sharing a pair of electrons.

[0166] When a substituent is vacant, it means that the substituent does not exist. For example, if X is vacant in AX, the structure is actually A. When the listed substituents do not specify which atom they are attached to the substituted group through, such substituents can be bonded to any of their atoms. For example, a pyridinium group as a substituent can be attached to the substituted group through any carbon atom on the pyridine ring.

[0167] Where the listed linking groups do not specify their connection direction, the connection direction is arbitrary. For example, in ring A-L1-R1, the linking group L1 is -MW-. In this case, -MW- can connect rings A and R1 in the same direction as the left-to-right reading order to form ring AMW-R1, or connect rings A and R1 in the opposite direction to the left-to-right reading order to form ring AWM-R1. Combinations of linking groups, substituents, and / or their variants are only permitted if such combinations produce a stable compound.

[0168] Unless otherwise specified, when a group has one or more connectable sites, any one or more sites of that group can be connected to other groups via chemical bonds. When the chemical bond connection is non-directional and the connectable site contains H atoms, the number of H atoms at that site will decrease accordingly with the number of chemical bonds connected, resulting in a group with the corresponding valence. The chemical bonds connecting the site to other groups can be straight solid line bonds. Dashed key For example, a straight solid line bond in -OCH3 indicates that the oxygen atom in that group is connected to other groups; The straight dashed bond in the diagram indicates that the group is connected to other groups through both ends of the carbon atom in the group; The dashed lines in the diagram indicate that the phenyl group is connected to other groups through the carbon atoms at positions 1 and 4 of the phenyl group. This indicates that any connectable site on the piperidinyl group can be linked to other groups via a single chemical bond, including at least... Even if H atoms are drawn on -N- in these four connection methods, Still includes In this type of linkage, when a chemical bond is attached, the number of hydrogen atoms at that site is reduced by one, resulting in a monovalent piperidinyl group.

[0169] Unless otherwise specified, in cyclic groups, the linkage site of the group or segment is located on the ring connected by the dashed line. For example, This indicates that any linking site on the benzene ring of this group can be connected to other groups by a single chemical bond, including at least... These are the four connection methods.

[0170] Generally, in aromatic or heteroaromatic rings, the use of double and single bonds is not significant. For example, Both refer to benzene rings or phenyl groups, where double bonds or Specifically refers to large π bonds delocalized on the plane of the benzene ring; In this context, when ring C is defined as a 5-membered aryl or heteroaryl, ring B and ring C form a conjugated cycloaryl or cycloheteroaryl group. Non-limiting embodiments include... even though The left-hand ring contains only two double bonds, but Still includes In this group, the double bond represents a large π bond delocalized on the fused aromatic ring.

[0171] The numerical ranges used in this article include the endpoints and any values ​​in between. For example, "0-3" can include 0, 1, 2, or 3, and "1-3" can include 1, 2, or 3.

[0172] The "C" used in this article 1-n "Including C" 1-2 C 1-3 ...C 1-n For example, "C" 1-6 A "group" refers to a part containing 1 to 6 carbon atoms; that is, a group may contain 1, 2, 3, 4, 5, or 6 carbon atoms. Therefore, for example, "C..." 1-4 "Alkyl" refers to an alkyl group containing 1 to 4 carbon atoms, specifically selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl. Numerical ranges, such as "1-6", refer to integers within a given range.

[0173] A linker atom refers to a non-hydrogen atom in a cyclic group that is used for ring formation. For example... The atom in the link consists of 3 carbon atoms; The middle element consists of three carbon atoms and one oxygen atom; The intermediate atom consists of 1 nitrogen atom and 5 carbon atoms; The middle element consists of 8 carbon atoms and 1 nitrogen atom.

[0174] As used herein, "nm-membered" refers to the number of link atoms in a cycloalkyl group. For example, a "3-8 membered" group means that the part has 3-8 link atoms, that is, the group contains 3, 4, 5, 6, 7, or 8 link atoms. Therefore, for example, "3-8 membered cycloalkyl" refers to a saturated cycloalkyl group containing 3-8 carbon atoms, that is, the alkyl group is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

[0175] The term "alkyl" as used alone or in combination herein refers to a saturated aliphatic hydrocarbon that is optionally substituted with a straight chain or optionally substituted with a branched chain. "alkyl" as used herein preferably has 1-6 carbon atoms, for example, 1-5 carbon atoms, 1-4 carbon atoms, or 1-3 carbon atoms. Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, hexyl, etc. When "alkyl" appears in a numerical range in the group defined herein, for example, "C..." 1-6 "Alkyl" refers to an alkyl group that can be composed of 1, 2, 3, 4, 5, or 6 carbon atoms, and also includes cases where no numerical range is specified. Alkyl groups can be optionally substituted or unsubstituted.

[0176] The term “alkyl” as used in this article refers to an alkyl group linked to other groups, such as an alkyl group in an alkoxy group, and is defined the same as when used alone.

[0177] The term "alkoxy" or "-O-alkyl" as used alone or in combination herein is meant as "alkyl-O-". Non-limiting examples of alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, etc. Alkoxy groups may be optionally substituted or unsubstituted.

[0178] The term "cycloalkyl" as used alone or in combination herein refers to a saturated monocyclic, bicyclic, or polycyclic carbon ring. Preferably, it is a 3-12 membered cycloalkyl, more preferably a 3-10 membered cycloalkyl, and most preferably a 3-8 membered cycloalkyl. Non-limiting examples of monocyclic cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and other cycloalkyl groups, which may be optionally substituted or unsubstituted.

[0179] The term "aryl" as used alone or in combination herein refers to an aromatic hydrocarbon ring. The term "aryl" includes monocyclic aromatic hydrocarbons and polycyclic fused-ring (fused-ring) aromatic hydrocarbons, wherein all fused-ring systems (excluding any ring system that is part of an optional substituent or formed by an optional substituent) are aromatic. Examples of aryl groups / parts include phenyl, naphthyl, anthraceneyl, and phenanthrene. Unless otherwise stated, the term "aryl" does not include "heteroaryl".

[0180] The term "heterocyclic group" as used alone or in combination herein includes alicyclic and heteroaryl groups, wherein one or more (such as one, two, three, or four) link atoms are heteroatoms, such as oxygen, nitrogen, sulfur, etc., including monocyclic, fused, bridged, and spirocyclic groups. Examples of heterocyclic groups include heterocyclic alkyl, heterocyclic alkenyl, and heteroaryl groups discussed below. Preferably, 3- to 10-membered monocyclic, bicyclic, or tricyclic heterocyclic groups are used herein, which may contain one, two, or three link atoms selected from nitrogen, oxygen, and / or sulfur. Non-limiting examples of "heterocyclic group" include azirrobutenyl, azirrobutyl, oxobutyl, thiobutyl, pyrrolyl, 2-oxo-pyrrolyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrazolyl, imidazoyl, dioxacyclopentyl, oxothiopentyl, piperidinyl, 2-oxo-piperidinyl, tetrahydropyranyl, thioalkyl, piperazinyl, piperazine-2-one, dioxacyclohexyl, morpholinyl and thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, etc. The heterocyclic group may be optionally substituted or unsubstituted.

[0181] In the definition of "heterocyclic group," "fused ring" refers to a polycyclic cyclic group containing two or more ring structures that share a pair of atoms. One or more rings may contain several unsaturated bonds, or it may be an aromatic system with one ring having fully conjugated π electrons. The ring atoms are selected from nitrogen, oxygen, or S(O). n (where n is selected from 0, 1, or 2) heteroatoms, and the remaining atoms are carbon. Preferably, they are 6-12 cyclic, more preferably 8-9 cyclic. Based on the number of rings, they can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic cyclic groups, preferably bicyclic or tricyclic, more preferably 5-membered / 5-membered or 5-membered / 6-membered bicyclic cyclic groups.

[0182] The term "heterocyclic alkyl" as used alone or in combination herein refers to a saturated heterocyclic group, which is a monocyclic, bicyclic, or polycyclic alkyl group in which one or more (such as one, two, three, or four) link atoms are heteroatoms, and may be spirocyclic or bridged. Preferably, it is a 3-12 membered cycloalkyl group, more preferably a 3-10 membered cycloalkyl group, and most preferably a 3-8 membered cycloalkyl group. Non-limiting examples of monocyclic heterocyclic alkyl groups include, but are not limited to, propylene oxide, thiocyclic propane, azirionic propane, azirionic butane, oxacyclobutane, thiocyclic butane, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, oxazolidine, thiazolylidine, imidazolylidine, tetrahydropyran, piperidine, dioxane, and azirionic heptane.

[0183] The term "heteroaryl" as used alone or in combination herein refers to a 5-12 member (preferably 5-10 member, more preferably 5-6 member) monocyclic, bicyclic, or tricyclic system, wherein at least one ring is aromatic and at least one ring contains one or more heteroatoms selected from nitrogen, oxygen, and sulfur, and the heteroaryl group has one or more attachment sites connected to the remainder of the molecule. Non-limiting examples of "heteroaryl" include furanyl, imidazolyl, isoxazolyl, oxazolyl, pyrroleyl, pyrazolyl, pyridinyl, pyrimidinyl, pyridazinyl, thiophene, thiazolyl, etc.; it also includes, but is not limited to, the following bicyclic groups: benzimidazolyl, benzofuranyl, benzothiophene, indolyl, oxoindolyl, dihydroindolyl, imidazopyridyl, pyrazolopyridyl, pyrazolopyrimidinyl, quinolinyl, isoquinolinyl, quinazolinyl, indazole, 1,8-naphthidine, benzo[d]isoxazole, benzo[ [d]Thiazole, pyrrolo[3,2-b]pyridine, furan[3,2-b]pyridine, pyrrolo[1,2-b]pyridazine, imidazo[1,2-b]pyridazine, pyrazolo[1,5-a]pyrimidine, thiazo[4,5-c]pyridine, thieno[3,2-b]pyridine, pyrrolo[1,2-b]pyridazine, 2,3-dihydrobenzofuran, benzo[c][1,2,5]oxadiazole, 1,3-dihydro-2H-benzo[d]imidazo-2-one, benzo[d]oxazol-2(3H)-one, etc. The heteroaryl group can be optionally substituted or unsubstituted.

[0184] The term “halogen” as used alone or in combination in this article refers to fluorine, chlorine, bromine or iodine.

[0185] The term "hydroxyl group" as used alone or in combination in this article refers to -OH.

[0186] The term "cyano" as used alone or in combination in this article refers to -CN.

[0187] As used herein, the terms “(substituted)” or “substituted with” refer to the substitution of one or more hydrogen atoms on a particular atom by a specified group (such as halogen, alkyl, etc.) where the substitution results in a stable compound if the normal valence of the specified atom is not exceeded under the present circumstances.

[0188] The term “pharmaceutically acceptable salt” as used herein is well known to those skilled in the art.

[0189] As used herein, the term "pharmaceutically acceptable" means a substance (such as a carrier or diluent) that does not affect the biological activity or properties of the compounds of the present invention and is relatively non-toxic, i.e., that the substance can be administered to an individual without causing an adverse biological reaction or interacting adversely with any component contained in the composition.

[0190] As used herein, the term "pharmaceutical composition" refers to a bioactive compound optionally mixed with at least one pharmaceutically acceptable chemical component, including but not limited to carriers, stabilizers, diluents, dispersants, suspending agents, thickeners, and / or excipients.

[0191] As used in this article, the term "carrier" refers to a relatively non-toxic chemical compound or reagent that facilitates the introduction of the compound into cells or tissues.

[0192] The term “stereoisomer” as used in this article includes, but is not limited to, enantiomers, cis-trans isomers, etc.

[0193] As used herein, the term "enantiomer" refers to isomerism in compounds with the same molecular formula, resulting from differences in the spatial arrangement of atoms or groups. Two enantiomers are mirror images of each other and cannot be superimposed. The term "cis-trans isomer" as used herein generally refers to stereoisomerism, a non-diasteretic phenomenon where the spatial arrangement of groups differs due to rotational constraints within the molecule. Organic molecules containing such isomers, such as alkenes, azo compounds, and alicyclic hydrocarbons, are considered cis-trans isomers. In this application, cis-trans isomerism is primarily manifested in alicyclic hydrocarbons. For example, in cyclohexane, cis-trans isomerism occurs when two substituents are substituted. When the two substituents are substituted on the same side of the ring, it is a "cis" isomer; when they are substituted on different sides, it is a "trans" isomer.

[0194] The compounds of this invention may contain asymmetric or chiral centers, and thus exist in different stereoisomer forms. It is contemplated that all stereoisomer forms of the compounds of this invention, including but not limited to diastereomers, enantiomers, sterically hindered isomers, and geometric (conformal) isomers and mixtures thereof, such as racemic mixtures, are within the scope of this invention.

[0195] Unless otherwise stated, the structures described in this invention also include all isomers of this structure (e.g., diastereomers, enantiomers, cis-trans isomers, sterically hindered isomers, geometric (conformal) isomers), for example, R and S configurations of each asymmetric center, (Z) and (E) double bond isomers, cis-trans isomers of aliphatic cyclic hydrocarbons, sterically hindered isomers of biphenyl structures (see *Basic Organic Chemistry* (Second Edition), Vol. 1, Xing Qiyi et al., pp. 104-105); PAC, 1996, 68, 2193. (*Basic terminology of stereochemistry* (IUPAC Recommendations 1996, on page 2201)), and (Z) and (E) conformational isomers. Therefore, individual stereoisomers of the compounds of this invention, as well as mixtures of enantiomers, mixtures of diastereomers, sterically hindered isomers, and mixtures of geometric (conformal) isomers, are all within the scope of this invention.

[0196] The present invention will be further described in detail below with reference to specific embodiments, but the present invention is not limited to the following embodiments.

[0197] The preparation conditions used in the examples are as follows:

[0198] Pre-HPLC preparation conditions: Instrument: GILSON-GX281; Wavelength: 220nm & 254nm; Column type: Waters X-bridge (30×100mm, 10μm) or Luna C18 (30×75mm, 3μm) or Luna C18 (30×75mm, 3μm); Mobile phase: A: 10mM ammonium bicarbonate or H2O (0.1% formic acid) or H2O (0.1% trifluoroacetic acid), B: acetonitrile; Run time: 15min; Flow rate: 25mL / min.

[0199] Reverse-phase column purification was performed using a C18 reverse-phase silica column (Spherical C18, 40-60 μm, 40 g-120 g) with water / acetonitrile (95 / 5~30 / 70) as the mobile phase.

[0200] Chiral separation conditions 1: Instrument: SFC 150; Column type: Daicel CHIRALPAK IB-N, 250mm×30mm inner diameter, 10μm; Mobile phase: CO2 / MeOH [0.2% NH3 (7M methanol solution)] = 50 / 50; Flow rate: 120g / min; Wavelength: UV 214nm; Temperature: 35℃.

[0201] Chiral separation conditions 2: Instrument: SFC 150; Column type: Daicel CHIRALCEL OD, 250mm×30mm inner diameter, 10μm; Mobile phase: CO2 / MeOH [0.2% NH3 (7M methanol solution)] = 60 / 40; Flow rate: 120g / min; Wavelength: UV 214nm; Temperature: 35℃.

[0202] The synthesis steps of some intermediates in this invention are as follows:

[0203] Intermediate 1: 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)phenyl)pyridine-2(1H)-one

[0204] (1) 1-(4-iodophenyl)pyridin-2(1H)-one

[0205] 1,4-Diiodobenzene (10 g, 30.3 mmol), pyridin-2(1H)-one (2.9 g, 30.3 mmol), cuprous iodide (0.58 g, 3 mmol), and potassium carbonate (10.47 g, 75.6 mmol) were dissolved in dimethyl sulfoxide (150 mL) and reacted at 120 °C under nitrogen protection for 16 hours with stirring. The reaction mixture was then extracted with water (500 mL), ethyl acetate (300 mL x 3), washed with saturated sodium chloride solution (1000 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 30 / 70) to give the title compound (3.58 g, white solid), yield: 40%. MS (ESI): m / z 298.0 [M+H] + .

[0206] (2) 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)pyridin-2(1H)-one

[0207] 1-(4-Iodophenyl)pyridin-2(1H)-one (400 mg, 1.3 mmol), pinacol diboronate (410.3 mg, 1.6 mmol),

[0208] [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (98.5 mg, 0.1 mmol) and potassium acetate (396.4 mg, 4.0 mmol) were dissolved in 1,4-dioxane (5 mL) and reacted at 80 °C under nitrogen protection with stirring for 16 hours. The reaction solution was cooled to give the title compound, which was used directly in the next reaction. MS (ESI): m / z 298.1 [M+H] + .

[0209] Intermediate 2: 3-(3-bromo-2-chlorophenyl)piperidine-2,6-dione

[0210] (1) 1-Bromo-3-(bromomethyl)-2-chlorobenzene

[0211] 1-Bromo-2-chloro-3-toluene (5 g, 24.3 mmol) and N-bromosuccinimide (4.8 g, 27.0 mmol) were dissolved in carbon tetrachloride (50 mL), and then benzoyl peroxide (0.3 g, 1.2 mmol) was added. The mixture was stirred at 90 °C under reflux for 16 hours. The reaction solution was filtered, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (100% petroleum ether) to give the title compound (3.8 g, colorless oil), yield: 55%. 1 H NMR (400MHz, CDCl3) δ7.60-7.55(m,1H),7.40-7.36(m,1H),7.13-7.06(m,1H),4.61-4.59(m,2H).

[0212] (2)2-(3-bromo-2-chlorophenyl)acetonitrile

[0213] 1-Bromo-3-(bromomethyl)-2-chlorobenzene (3.8 g, 13.4 mmol) was dissolved in dichloromethane (40 mL), and trimethylcyanosilane (1.99 g, 20.1 mmol) and tetrabutylammonium fluoride (20.1 mL, 20.1 mmol, 1 M in THF) were added at 0 °C, followed by stirring at room temperature for 4 hours. The reaction mixture was extracted with water (100 mL), ethyl acetate (50 x 3 mL), washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 90 / 10) to give the title compound (2.8 g, white solid), yield: 90%. 1 H NMR (400MHz, CDCl3) δ7.66-7.62(m,1H),7.50-7.47(m,1H),7.21-7.18(m,1H),3.89-3.87(m,2H).

[0214] (3) Tert-butyl 4-(3-bromo-2-chlorophenyl)-4-cyanobutyrate

[0215] 2-(3-bromo-2-chlorophenyl)acetonitrile (2.5 g, 10.8 mmol) was dissolved in tetrahydrofuran (25 mL), and potassium tert-butoxide (0.12 g, 2.2 mmol) and tert-butyl acrylate (1.38 g, 10.8 mmol) were added at 0 °C, followed by stirring at room temperature for 2 hours. The reaction mixture was extracted with water (100 mL), ethyl acetate (50 x 3 mL), washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by reverse-phase column chromatography to give the title compound (1.5 g, pale yellow oil), yield: 39%. MS (ESI): m / z 358.0 [M+H] + .

[0216] (4) 3-(3-bromo-2-chlorophenyl)piperidine-2,6-dione

[0217] 1.5 g (4.2 mmol) of tert-butyl 4-(3-bromo-2-chlorophenyl)-4-cyanobutyrate and 2.06 g (21 mmol) of concentrated sulfuric acid were dissolved in 15 mL of acetic acid and stirred at room temperature for 1 hour. The reaction mixture was then slowly added dropwise to 100 mL of ice water, resulting in the precipitation of a white solid. The precipitate was filtered to give the title compound (1.4 g, white solid), yield: 95%. MS (ESI): m / z 302.0 [M+H] + .

[0218] Intermediate 3: 3-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)phenyl)piperidin-2,6-dione

[0219] Intermediate 2 (300 mg, 1.0 mmol), pinacol diborate (330.2 mg, 1.3 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (36.6 mg, 0.05 mmol), and potassium acetate (294.4 mg, 3.0 mmol) were dissolved in 1,4-dioxane (5 mL), and the mixture was stirred at 80 °C under nitrogen protection for 3 hours. The reaction solution was cooled to give the title compound, which was used directly in the next reaction. MS (ESI): m / z 350.1 [M+H] + .

[0220] Intermediate 4: 3-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborphane-2-yl)phenyl)-3-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)piperidine-2,6-dione

[0221] (1) 3-(3-bromo-2-chlorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)piperidine-2,6-dione

[0222] Intermediate 2 (3 g, 9.9 mmol) was dissolved in tetrahydrofuran (30 mL), and 1,8-diazabispyrospirocyclic [5.4.0]undec-7-ene (3 g, 19.8 mmol) was added dropwise. At 0 °C, 2-(trimethylsilyl)ethoxymethyl chloride (3.3 g, 19.8 mmol) was added dropwise, and the reaction was carried out at room temperature for 2 hours. Water (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (10 mL x 3). The organic phases were combined, concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 50 / 50) to give the title compound (3.3 g, yellow solid), yield: 79%. MS (ESI): m / z 454.0 [M+Na] + .

[0223] (2) 3-(3-bromo-2-chlorophenyl)-3-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)piperidine-2,6-dione

[0224] 3-(3-bromo-2-chlorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)piperidine-2,6-dione (1 g, 2.3 mmol) was dissolved in tetrahydrofuran (15 mL). Bistrimethylsilylaminolithium (1 M, 3.4 mL, 3.4 mmol) was added dropwise at -60 °C, and the reaction was allowed to proceed at room temperature for half an hour. N-fluorobis(benzenesulfonamide) (1 g, 3.4 mmol) was then added dropwise, and the reaction was allowed to proceed overnight at room temperature. Water (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (10 mL x 3). The organic phases were combined, concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to give the title compound (180 mg, colorless oil), yield: 18%. 1 H NMR (400MHz, DMSO-d6) δ7.94-7.87(m,1H),7.68(d,J=8.0Hz,1H),7.46(t,J=8.0Hz,1H),5.28-5.0 4(m,2H),3.63-3.53(m,2H),3.06-2.76(m,3H),2.36-2.21(m,1H),0.88-0.81(m,2H),0.01(s,9H).

[0225] (3) 3-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)-3-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)piperidine-2,6-dione

[0226] 3-(3-bromo-2-chlorophenyl)-3-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)piperidine-2,6-dione (180 mg, 0.4 mmol), pinacol diboronate (153 mg, 0.6 mmol), PdCl2 (dppf) (29 mg, 0.04 mmol), and potassium acetate (78 mg, 0.8 mmol) were dissolved in 1,4-dioxane (5 mL). The reaction mixture was heated to 90 °C and stirred for 4 hours under nitrogen protection. The reaction solution was concentrated to give the title compound (199 mg), which was used directly in the next step. MS (ESI): m / z 520.2 [M+Na] + .

[0227] Intermediate 5: 1-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione

[0228] (1) 3-((3-bromo-2-chlorophenyl)amino)propionic acid

[0229] 3-Bromo-2-chloroaniline (500 mg, 2.4 mmol) and acrylic acid (223 mg, 3.1 mmol) were dissolved in toluene (10 mL), and the mixture was heated to 130 °C and reacted for 2 days. The reaction solution was concentrated to give the title compound (676 mg, crude product). MS (ESI): m / z 277.9 [M+H] + .

[0230] (2) 1-(3-bromo-2-chlorophenyl)dihydropyrimidine-2,4(1H,3H)-dione

[0231] 3-((3-bromo-2-chlorophenyl)amino)propionic acid (676 mg, 2.4 mmol) was dissolved in acetic acid (10 mL), and urea (432 mg, 7.2 mmol) was added. The mixture was reacted at 120 °C for 2 days. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to give the title compound (30 mg, white solid), yield: 4%. MS (ESI): m / z 303.0 [M+H] + .

[0232] (3) 1-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)dihydropyrimidin-2,4(1H,3H)-dione

[0233] 1-(3-bromo-2-chlorophenyl)dihydropyrimidine-2,4(1H,3H)-dione (200 mg, 0.66 mmol), pinacol diboronate (201 mg, 0.79 mmol), PdCl2 (dppf) (48 mg, 0.066 mmol), and potassium acetate (129 mg, 1.32 mmol) were dissolved in 1,4-dioxane (10 mL). The mixture was heated to 90 °C and stirred for 6 hours under nitrogen protection. The reaction solution was concentrated to give the title compound (232 mg, crude product). MS (ESI): m / z 351.1 [M+H] + .

[0234] Intermediate 6: 3-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborphane-2-yl)phenyl)-3-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)piperidine-2,6-dione

[0235] (1) 3-(3-bromo-2-chlorophenyl)-3-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)piperidine-2,6-dione

[0236] 3-(3-bromo-2-chlorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)piperidine-2,6-dione (3.4 g, 7.9 mmol, intermediate 4, step 1) was dissolved in tetrahydrofuran (50 mL). At -60 °C, lithium bis(trimethylsilyl)aminolithium (1 M, 11.8 mL, 11.8 mmol) was added dropwise, and the reaction was allowed to proceed at room temperature for half an hour. Iodomethane (1.7 g, 11.8 mmol) was then added dropwise, and the reaction was allowed to proceed overnight at room temperature. Water (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (10 mL x 3). The organic phases were combined, concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to give the title compound (1.2 g, colorless oil), yield: 34%. MS (ESI): m / z 468.1 [M + Na] + .

[0237] (2) 3-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)-3-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)piperidine-2,6-dione

[0238] 3-(3-bromo-2-chlorophenyl)-3-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)piperidine-2,6-dione (300 mg, 0.67 mmol), pinacol diboronate (254 mg, 1.0 mmol), PdCl2 (dppf) (49 mg, 0.067 mmol), and potassium acetate (127 mg, 1.3 mmol) were dissolved in 1,4-dioxane (5 mL). The reaction mixture was heated to 90 °C and stirred for 4 hours under nitrogen protection. The reaction solution was concentrated to give the title compound (330 mg), and the crude product was used directly in the next step of the reaction. MS (ESI): m / z 516.2 [M+Na] + .

[0239] Example 1

[0240] 3-(2-chloro-4'-((dimethyl(oxo)-λ) 6 -sulfonyl)amino)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0241] (1)((4-bromophenyl)imino)dimethyl-λ 6 -Sulfamethoxazole

[0242] 1-Bromo-4-iodobenzene (200 mg, 0.71 mmol), dimethylsulfinylimide (66 mg, 0.71 mmol), tris(dibenzylacetone)dipalladium (32 mg, 0.04 mmol), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (41 mg, 0.07 mmol), and cesium carbonate (576 mg, 1.77 mmol) were dissolved in 1,4-dioxane (20 mL), and the mixture was stirred at 95 °C under nitrogen protection for 16 hours. Water (50 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (50 mL x 3), washed with saturated sodium chloride solution (150 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 85 / 15) to give the title compound (90 mg, yellow solid), yield: 51%. MS (ESI): m / z 247.9 [M+H] + .

[0243] (2) dimethyl((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)imino)-λ 6 -Sulfamethoxazole

[0244] ((4-bromophenyl)imino)dimethyl-λ 6Sulfamethoxane (30 mg, 0.12 mmol), pinacol diborate (31 mg, 0.12 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (9 mg, 0.01 mmol), and potassium acetate (30 mg, 0.30 mmol) were dissolved in 1,4-dioxane (10 mL) and reacted at 95 °C under nitrogen protection with stirring for 16 hours. The reaction mixture was cooled to give the title compound, which was used directly in the next reaction. MS (ESI): m / z 296.1 [M+H] + .

[0245] (3) 3-(2-chloro-4'-((dimethyl(oxo)-λ) 6 -sulfonyl)amino)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0246] Dimethyl((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)phenyl)imino)-λ 6 Sulfamethoxane (35 mg, 0.12 mmol), intermediate 2 (36 mg, 0.12 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (9 mg, 0.01 mmol), and potassium carbonate (41 mg, 0.30 mmol) were dissolved in 1,4-dioxane / water (5 mL / 0.5 mL) and reacted at 95 °C under nitrogen protection for 16 hours with stirring. Water (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (10 mL x 3), washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 95 / 5) to obtain a crude product. Further purification by Prep-HPLC yielded the title compound (5.9 mg, white solid), yield: 13%. MS (ESI): m / z 391.0 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.90(s,1H),7.38-7.23(m,5H),6.99(d,J=8.4Hz,2H),5.76(dd,J=10.8,2 .4Hz,1H),3.26(s,6H),2.85-2.73(m,1H),2.59-2.55(m,1H),2.37-2.28(m,1H),2.09-1.98(m,1H).

[0247] Example 2

[0248] 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

[0249] (1) Ethyl 1-(1-((tert-butoxycarbonyl)amino)cyclopropyl)methyl)-1H-pyrazole-5-carboxylic acid ester

[0250] Ethyl 1H-pyrazole-3-carboxylate (500 mg, 3.6 mmol) and tert-butyl (1-(hydroxymethyl)cyclopropyl)carbamate (673 mg, 3.6 mmol) were dissolved in tetrahydrofuran (10 mL), followed by the addition of triphenylphosphine (1.4 g, 5.4 mmol) and diisopropyl azodicarbonate (1.09 g, 5.4 mmol). The reaction mixture was reacted overnight at 40 °C. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give the title compound (1 g, yellow oil), yield: 91%. MS (ESI): m / z 310.2 [M+H] + .

[0251] (2) Ethyl 1-((1-aminocyclopropyl)methyl)-1H-pyrazole-5-carboxylic acid ester

[0252] Ethyl 1-(1-((tert-Butoxycarbonyl)amino)cyclopropyl)methyl)-1H-pyrazole-5-carboxylic acid (1 g, 3.2 mmol) was dissolved in dichloromethane (10 mL), and trifluoroacetic acid (5 mL) was added. The reaction mixture was reacted at room temperature for 2 hours. The reaction solution was concentrated to give the title compound (676 mg, crude product). MS (ESI): m / z 210.2 [M+H] + .

[0253] (3) 7'-spiro[cyclopropane-1,6'-pyrazolo[1,5-a]pyrazine]-4'(5'H)-one

[0254] Ethyl 1-((1-aminocyclopropyl)methyl)-1H-pyrazole-5-carboxylate (676 mg, 3.2 mmol) and triethylamine (969 mg, 9.6 mmol) were dissolved in ethanol (10 mL) and reacted overnight at 90 °C. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to give the title compound (230 mg, yellow solid), yield: 44%. MS (ESI): m / z 164.1 [M+H] + .

[0255] (4) 5'-(4-bromophenyl)-7'H-spiro[cyclopropane-1,6'-pyrazolo[1,5-a]pyrazine]-4'(5'H)-one

[0256] 7'-spiro[cyclopropane-1,6'-pyrazolo[1,5-a]pyrazine]-4'(5'H)-one (130 mg, 0.80 mmol) and 1-bromo-4-iodobenzene (453 mg, 1.6 mmol) were dissolved in N,N-dimethylformamide (10 mL), and 8-hydroxyquinoline (46 mg, 0.32 mmol), cuprous iodide (30.4 mg, 0.16 mmol), and potassium carbonate (221 mg, 1.6 mmol) were added. The mixture was microwaved at 140 °C for 2 hours. The reaction solution was added to water (10 mL), and extracted with ethyl acetate (10 mL x 3). The organic phases were combined and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give the title compound (40 mg, yellow solid), yield: 16%. MS (ESI): m / z 318.0 [M+H] + .

[0257] (5) 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

[0258] 5'-(4-bromophenyl)-7'H-spiro[cyclopropane-1,6'-pyrazolo[1,5-a]pyrazine]-4'(5'H)-one (26 mg, 0.08 mmol), intermediate 3 (28 mg, 0.08 mmol), PdCl2 (dppf) (6 mg, 0.008 mmol), and potassium carbonate (22 mg, 0.16 mmol) were dissolved in 1,4-dioxane / water (10 mL / 2 mL). The reaction mixture was heated to 85 °C and stirred for 4 hours under nitrogen protection. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (100% ethyl acetate) to obtain a crude product, which was then purified by Prep-HPLC to obtain the title compound (6.5 mg, white solid), yield: 17%. MS (ESI): m / z 461.0 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.93(s,1H),7.65(d,J=1.6Hz,1H),7.50-7.48(m,2H),7.45-7.37(m,5H),6.90(d,J=1.6Hz,1H),4.57(s,2H),4.37 (dd,J=12.4,5.2Hz,1H),2.84-2.76(m,1H),2.57-2.53(m,1H),2.40-2.29(m,1H),2.10-2.03(m,1H),1.06-1.02(m,2H),0.76-0.73(m,2H).

[0259] Example 3

[0260] 3-(2-chloro-4'-(dimethylphosphoryl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0261] (1)(4-bromophenyl)dimethylphosphine oxide

[0262] 1-Bromo-4-iodobenzene (500 mg, 1.77 mmol), dimethylphosphine oxide (138 mg, 1.77 mmol), tris(dibenzylacetone)dipalladium (81 mg, 0.09 mmol), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (102 mg, 0.18 mmol), and cesium carbonate (1.44 g, 4.42 mmol) were dissolved in 1,4-dioxane (20 mL), and the mixture was stirred at 95 °C under nitrogen protection for 16 hours. Water (50 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (50 mL x 3), washed with saturated sodium chloride solution (150 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 80 / 20) to give the title compound (220 mg, white solid), yield: 53%. MS (ESI): m / z 233.0 [M+H] + .

[0263] (2) Dimethyl(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)phenyl)phosphine oxide

[0264] (4-Bromophenyl)dimethylphosphine oxide (50 mg, 0.21 mmol), pinacol diborate (65 mg, 0.26 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (16 mg, 0.02 mmol), and potassium acetate (53 mg, 0.54 mmol) were dissolved in 1,4-dioxane (10 mL), and the mixture was stirred at 95 °C under nitrogen protection for 16 hours. The reaction solution was cooled to give the title compound, the crude product, which was used directly in the next reaction. MS (ESI): m / z 281.2 [M+H] + .

[0265] (3) 3-(2-chloro-4'-(dimethylphosphoryl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0266] Dimethyl(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)phenyl)phosphine oxide (60 mg, 0.21 mmol), intermediate 2 (65 mg, 0.21 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (16 mg, 0.02 mmol), and potassium carbonate (74 mg, 0.54 mmol) were dissolved in 1,4-dioxane / water (5 mL / 0.5 mL) and stirred at 95 °C under nitrogen protection for 16 hours. Water (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (10 mL x 3), washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 95 / 5) to obtain a crude product. Further purification by Prep-HPLC yielded the title compound (9.3 mg, white solid), yield: 12%. MS(ESI): m / z 376.0 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.94(s,1H),7.86(dd,J=10.8,8.0Hz,2H),7.56(d,J=6.4Hz,2H),7.46-7.34(m,3H),4.36(dd, J=12.4,4.8Hz,1H),2.87-2.75(m,1H),2.65-2.57(m,1H),2.38-2.29(m,1H),2.11-2.01(m,1H),1.70(d,J=13.6Hz,6H).

[0267] Example 4

[0268] 1-(2-chloro-4'-(2-oxopyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)dihydropyrimidin-2,4(1H,3H)-dione

[0269] (1) 3-((3-bromo-2-chlorophenyl)amino)propionic acid

[0270] 3-Bromo-2-chloroaniline (500 mg, 2.4 mmol) and acrylic acid (223 mg, 3.1 mmol) were dissolved in toluene (10 mL), and the mixture was heated to 130 °C and reacted for 2 days. The reaction solution was concentrated to give the title compound (676 mg, crude product). MS (ESI): m / z 277.9 [M+H] + .

[0271] (2) 1-(3-bromo-2-chlorophenyl)dihydropyrimidine-2,4(1H,3H)-dione

[0272] 3-((3-bromo-2-chlorophenyl)amino)propionic acid (676 mg, 2.4 mmol) was dissolved in acetic acid (10 mL), and urea (432 mg, 7.2 mmol) was added. The mixture was reacted at 120 °C for 2 days. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to give the title compound (30 mg, white solid), yield: 4%. MS (ESI): m / z 303.0 [M+H] + .

[0273] (3) 1-(2-chloro-4'-(2-oxopyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)dihydropyrimidin-2,4(1H,3H)-dione

[0274] 1-(3-bromo-2-chlorophenyl)dihydropyrimidine-2,4(1H,3H)-dione (10 mg, 0.03 mmol), 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)phenyl)pyridin-2(1H)-one (9 mg, 0.03 mmol), PdCl2 (dppf) (2 mg, 0.003 mmol), and potassium carbonate (8 mg, 0.06 mmol) were dissolved in 1,4-dioxane / water (10 mL / 2 mL). The reaction mixture was heated to 90 °C and stirred for 4 hours under nitrogen protection. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (100% ethyl acetate) to obtain a crude product, which was then purified by Prep-HPLC to obtain the title compound (7.4 mg, white solid), yield: 57%. MS (ESI): m / z 394.0 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ10.50(s,1H),7.74(d,J=6.8Hz,1H),7.60-7.51(m,7H),7.46(d,J=7.2Hz,1H),6 .51(d,J=9.2Hz,1H),6.34(t,J=6.8Hz,1H),3.81-3.75(m,1H),3.70-3.64(m,1H),2.77(t,J=6.4Hz,2H).

[0275] Example 5

[0276] 7-(2-chloro-4'-(2-oxopyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)-5-azaspiro[2.5]octane-4,6-dione

[0277] (1) Ethyl 1-(2-(3-bromo-2-chlorophenyl)-2-cyanoethyl)cyclopropane-1-carboxylic acid ester

[0278] 2-(3-bromo-2-chlorophenyl)acetonitrile (160 mg, 0.7 mmol) was dissolved in tetrahydrofuran, and diisopropylaminolithium (0.7 mL, 1.4 mmol) was added dropwise at -78 °C, reacting at room temperature for half an hour. Then, 1-(bromomethyl)cyclopropane-1-carboxylic acid ethyl ester (145 mg, 0.7 mmol) was added dropwise at -78 °C, reacting overnight at room temperature. The reaction mixture was then added to water (20 mL), extracted with ethyl acetate (10 mL x 3), and the organic phase was washed with saturated sodium chloride solution (10 mL x 3), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give the title compound (150 mg, colorless oil), yield: 60%. MS (ESI): m / z 356.0 [M+H] + .

[0279] (2) 7-(3-bromo-2-chlorophenyl)-5-azaspiro[2.5]octane-4,6-dione

[0280] Ethyl 1-(2-(3-bromo-2-chlorophenyl)-2-cyanoethyl)cyclopropane-1-carboxylic acid (150 mg, 0.42 mmol) was dissolved in acetic acid (10 mL), and concentrated sulfuric acid (206 mg, 2.1 mmol) was added. The reaction mixture was reacted overnight at 90 °C. The reaction solution was neutralized with aqueous sodium bicarbonate solution, extracted with ethyl acetate (10 mL x 3), the organic phase was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give the title compound (130 mg, white solid), yield: 94%. MS (ESI): m / z 327.9 [M+H] + .

[0281] (3) 7-(2-chloro-4'-(2-oxopyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)-5-azaspiro[2.5]octane-4,6-dione

[0282] 7-(3-bromo-2-chlorophenyl)-5-azaspiro[2.5]octane-4,6-dione (40 mg, 0.12 mmol), intermediate 1 (25.8 mg, 0.12 mmol), PdCl2 (dppf) (9 mg, 0.012 mmol), and potassium carbonate (33 mg, 0.24 mmol) were dissolved in 1,4-dioxane / water (10 mL / 2 mL). The mixture was heated to 90 °C and stirred for 3 hours under nitrogen protection. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (100% ethyl acetate) to obtain a crude product, which was then purified by Prep-HPLC to obtain the title compound (8.8 mg, white solid), yield: 17%. MS (ESI): m / z 419.0 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ11.06(s,1H),7.74(d,J=6.8Hz,1H),7.56-7.50(m,5H),7.46-7.36(m,3H),6.52(d,J=9.2Hz,1H),6.34(t,J=6.4Hz,1H), 4.45(dd,J=12.4,5.2Hz,1H),2.76(t,J=13.2Hz,1H),1.63(dd,J=13.6,5.2Hz,1H),1.42-1.37(m,1H),1.02(t,J=8.0Hz,2H),0.83-0.78(m,1H).

[0283] Example 6

[0284] N-(2'-chloro-3'-(2,6-dioxopiperidin-3-yl)-[1,1'-biphenyl]-4-yl)-N-cyclopropyl-1-methyl-1H-imidazol-4-carboxamide

[0285] (1) N-Cyclopropyl-4-iodoaniline

[0286] 4-Iodoaniline (20 mg, 0.06 mmol) and 5-fluoropyrimidin-2-amine (1 g, 4.6 mmol) were dissolved in methanol (15 mL), and (1-ethoxycyclopropoxy)trimethylsilane (0.96 g, 5.5 mmol), acetic acid (3 mL), and sodium cyanoborohydride (1.16 g, 18.4 mmol) were added. The mixture was stirred at 70 °C under nitrogen protection for 16 hours. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20 / 1) to give the title compound (700 mg, pale yellow oil), yield: 58.7%. MS (ESI): m / z 260.0 [M+H] + .

[0287] (2) N-Cyclopropyl-N-(4-iodophenyl)-1-methyl-1H-imidazol-4-carboxamide

[0288] In a 50 mL three-necked flask, N-cyclopropyl-4-iodoaniline (300 mg, 1.16 mmol), pyridine (5 mL), 1-methyl-1H-imidazolium-4-carboxylic acid (175 mg, 1.39 mmol), and dichloromethane (5 mL) were added dropwise under nitrogen protection at 0 °C. Phosphorus oxychloride (355 mg, 2.32 mmol) was added dropwise. After reacting for 10 minutes, the reaction was quenched with water (30 mL), and the mixture was extracted with ethyl acetate (3 x 20 mL). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to give the title compound (220 mg, yellow solid), yield: 51.7%. MS (ESI): m / z 368.0 [M+H] + .

[0289] (3)N-(2'-chloro-3'-(2,6-dioxopiperidin-3-yl)-[1,1'-biphenyl]-4-yl)-N-cyclopropyl-1-methyl-1H-imidazol-4-carboxamide

[0290] Intermediate 3 (42 mg, 0.114 mmol) of 1,4-dioxane (5 mL) was mixed with N-cyclopropyl-N-(4-iodophenyl)-1-methyl-1H-imidazolium-4-carboxamide (40 mg, 0.114 mmol), 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride (8 mg, 0.011 mmol), potassium phosphate (48 mg, 0.23 mmol), and water (0.5 mL). The mixture was reacted overnight at 80 °C under nitrogen protection. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 8 / 1) to obtain a crude product, which was then purified by Prep-HPLC to obtain the title compound (4.3 mg, white solid), yield: 8%. MS (ESI): m / z 463.0 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.94(s,1H),7.54(s,1H),7.43-7.31(m,7H),7.21(s,1H),4.38-4.33(m,1H),3.60(s,3H),3.46-3. 40(m,1H),2.83-2.76(m,1H),2.57-2.56(m,1H),2.39-2.30(m,1H),2.08-2.04(m,1H),0.81-0.77(m,2H),0.51-0.44(m,2H).

[0291] Example 7

[0292] N-(2'-chloro-3'-(2,6-dioxopiperidin-3-yl)-[1,1'-biphenyl]-4-yl)-N-cyclopropylmorpholin-4-carboxamide

[0293] (1) N-Cyclopropyl-N-(4-iodophenyl)morpholine-4-carboxamide

[0294] In a 50 mL flask, N-cyclopropyl-4-iodoaniline (200 mg, 0.77 mmol), N,N-diisopropylethylamine (299 mg, 2.3 mmol), and 1,2-dichloroethane (5 mL) were added. Triphosgene (114 mg, 0.39 mmol) was added at 0 °C, and the mixture was stirred at room temperature for 30 minutes. Morpholine (135 mg, 1.54 mmol) was then added, and the reaction was continued at room temperature for 1 hour. The reaction was quenched with water (30 mL), and the mixture was extracted with ethyl acetate (3 x 20 mL). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give the title compound (100 mg, pale yellow oil), yield: 34.8%. MS (ESI): m / z 372.9 [M+H] + .

[0295] (2)N-(2'-chloro-3'-(2,6-dioxopiperidin-3-yl)-[1,1'-biphenyl]-4-yl)-N-cyclopropylmorpholin-4-carboxamide

[0296] Intermediate 3 (28 mg, 0.08 mmol) was dissolved in 1,4-dioxane (5 mL), and N-cyclopropyl-N-(4-iodophenyl)morpholine-4-carboxamide (30 mg, 0.08 mmol), 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride (6 mg, 0.008 mmol), potassium phosphate (34 mg, 0.16 mmol), and water (0.5 mL) were added. The reaction mixture was reacted overnight at 80 °C under nitrogen protection. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain a crude product, which was then purified by Prep-HPLC to obtain the title compound (6.7 mg, white solid), yield: 17.7%. MS (ESI): m / z 468.1 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ10.93 (s, 1H), 7.40-7.30 (m, 5H), 7.20 (d, J = 8.4Hz, 2H), 4.36-4.32 (m, 1H), 3.51-3.49 (m, 4H), 3.36-3.35 (m, 4H) ),2.83-2.75(m,1H),2.81-2.67(m,1H),2.59-2.54(m,1H),2.37-2.29(m,1H),2.08-2.02(m,1H),0.91-0.87(m,2H),0.67-0.63(m,2H).

[0297] Example 8

[0298] 3-(2-Cyclopropyl-4'-(2-oxopyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0299] (1) 2-Cyclopropyl-3-methylaniline

[0300] 2-Bromo-3-methylaniline (10.8 g, 58.2 mmol), cyclopropylboronic acid (5 g, 58.2 mmol), triphenylphosphine (1.5 g, 5.8 mmol), palladium acetate (1.3 g, 5.8 mmol), and potassium phosphate (30.9 g, 145.5 mmol) were dissolved in toluene / water (100 mL / 10 mL) and stirred at 100 °C under nitrogen protection and reflux for 16 hours. The reaction mixture was concentrated, extracted with water (200 mL), ethyl acetate (3 x 10 mL), washed with saturated sodium chloride solution (200 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 90 / 10) to give the title compound (5 g, yellow oil), yield: 58%. MS (ESI): m / z 148.5 [M+H] + .

[0301] (2) 1-Bromo-2-cyclopropyl-3-toluene

[0302] 2-Cyclopropyl-3-methylaniline (1 g, 6.8 mmol) and cuprous bromide (1.9 g, 13.6 mmol) were dissolved in acetonitrile (20 mL), and tert-butyl nitrite (1.4 g, 13.6 mmol) was added dropwise at 0 °C. The mixture was stirred at 60 °C for 1.5 hours. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (100% petroleum ether) to give the title compound (300 mg, colorless oil), yield: 21%. 1H NMR (400MHz, CDCl3) δ7.32(d,J=8.0Hz,1H),7.00(d,J=7.6Hz,1H),6.88(t,J=8. 0Hz,1H),2.37(s,3H),1.67-1.64(m,1H),1.06-1.01(m,2H),0.60-0.56(m,2H).

[0303] (3) 1-Bromo-3-(bromomethyl)-2-cyclopropylbenzene

[0304] 1-Bromo-2-cyclopropyl-3-toluene (300 mg, 1.4 mmol) and N-bromosuccinimide (302.6 mg, 1.7 mmol) were dissolved in carbon tetrachloride (10 mL), and then benzoyl peroxide (24.2 mg, 0.1 mmol) was added. The mixture was stirred at 90 °C under reflux for 16 hours. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (100% ethyl acetate) to give the title compound (165 mg, colorless oil), yield: 40%. 1 H NMR (400MHz, CDCl3) δ7.51 (d, J = 8.0 Hz, 1H), 7.32 (d, J = 7.6 Hz, 1H), 7.07 (t, J = 8. 0Hz,1H),4.80(s,2H),1.86-1.82(m,1H),1.23-1.18(m,2H),0.84-0.80(m,2H).

[0305] (4) 2-(3-bromo-2-cyclopropylphenyl)acetonitrile

[0306] 1-Bromo-3-(bromomethyl)-2-cyclopropylbenzene (165 mg, 0.6 mmol) was dissolved in dichloromethane (5 mL), and trimethylcyanosilane (89.3 mg, 0.9 mmol) and tetrabutylammonium fluoride (0.9 mL, 0.9 mmol, 1 M tetrahydrofuran solution) were added at 0 °C, followed by stirring at room temperature for 16 hours. The reaction mixture was then extracted with water (30 mL), followed by extraction with dichloromethane (3 x 15 mL), washing with saturated sodium chloride solution (30 mL), drying over anhydrous sodium sulfate, and concentrating. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 90 / 10) to give the title compound (130 mg, pale yellow oil), yield: 97%. MS (ESI): m / z 236.0 [M+H] + .

[0307] (5) Tert-butyl 4-(3-bromo-2-cyclopropylphenyl)-4-cyanobutyrate

[0308] 2-(3-bromo-2-cyclopropylphenyl)acetonitrile (130 mg, 0.6 mmol) was dissolved in tetrahydrofuran (5 mL), and tert-butyl acrylate (76.8 mg, 0.6 mmol) and sodium methoxide (5.4 mg, 0.1 mmol) were added at 0 °C. The mixture was then stirred at room temperature for 2 hours. The reaction solution was concentrated, and the residue was purified by reverse-phase column chromatography to give the title compound (100 mg, yellow oil), yield: 50%. MS (ESI): m / z 364.0 [M+H] + .

[0309] (6) 3-(3-bromo-2-cyclopropylphenyl)piperidine-2,6-dione

[0310] 100 mg (0.3 mmol) of tert-butyl 4-(3-bromo-2-cyclopropylphenyl)-4-cyanobutyrate and 147 mg (1.5 mmol) of concentrated sulfuric acid were dissolved in acetic acid (2 mL) and stirred at room temperature for 1 hour. The reaction mixture was slowly added dropwise to ice water (20 mL), extracted with dichloromethane (3 x 10 mL), washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, and concentrated to give the title compound (80 mg, white solid), yield: 95%. MS (ESI): m / z 308.0 [M+H] + .

[0311] (7) 3-(2-Cyclopropyl-4'-(2-oxopyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0312] 3-(3-bromo-2-cyclopropylphenyl)piperidin-2,6-dione (20 mg, 0.06 mmol), intermediate 1 (19.29 mg, 0.06 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (4.75 mg, 0.06 mmol), and potassium carbonate (22.42 mg, 0.16 mmol) were dissolved in 1,4-dioxane / water (5 mL / 0.5 mL) and stirred at 90 °C under nitrogen protection for 16 hours. The reaction mixture was then extracted with water (20 mL), ethyl acetate (3 x 10 mL), washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 97 / 3) to obtain a crude product, which was then purified by Prep-HPLC to obtain the title compound (2.6 mg, white solid), yield: 10%. MS(ESI): m / z 399.1 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ10.89 (s, 1H), 7.72 (d, J = 6.4Hz, 1H), 7.55-7.51 (m, 3H), 7.47-7 .45(m,2H),7.31(t,J=7.6Hz,1H),7.20-7.17(m,2H),6.51(d,J=9.2Hz,1H),6.34(t,J= 6.8Hz,1H),4.72(dd,J=12.4,4.4Hz,1H),2.85-2.78(m,1H),2.62-2.59(m,1H),2.29-2 .23(m,1H),2.11-2.05(m,1H),2.02-1.98(m,1H),0.80-0.69(m,2H),0.13-0.02(m,2H).

[0313] Example 9

[0314] 3-(2-chloro-4'-(cyclopropyl(1-methyl-1H-pyrazol-3-yl)amino)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0315] (1) N-(4-bromophenyl)-1-methyl-1H-pyrazole-3-amine

[0316] 1-Bromo-4-iodobenzene (594 mg, 2.1 mmol), 1-methyl-1H-pyrazole-3-amine (200 mg, 2.1 mmol), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (231 mg, 0.4 mmol), tris(dibenzylacetone)dipalladium (183 mg, 0.2 mmol), and cesium carbonate (1.37 g, 4.2 mmol) were dissolved in 1,4-dioxane (10 mL), and the mixture was purged with nitrogen. The reaction mixture was stirred overnight at 90 °C under nitrogen protection. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give the title compound (380 mg, yellow solid), yield: 72%. MS (ESI): m / z 252.0 [M+H] + .

[0317] (2) N-(4-bromophenyl)-N-cyclopropyl-1-methyl-1H-pyrazole-3-amine

[0318] N-(4-bromophenyl)-1-methyl-1H-pyrazole-3-amine (50 mg, 0.2 mmol) and cyclopropylboronic acid (34.4 mg, 0.4 mmol) were dissolved in dichloromethane (5 mL), and 2,2'-bipyridine (31 mg, 0.2 mmol), copper acetate (36 mg, 0.2 mmol), and potassium carbonate (55 mg, 0.4 mmol) were added. The mixture was stirred overnight at 70 °C under an oxygen bulb. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give the title compound (20 mg, yellow oil), yield: 34%. MS (ESI): m / z 292.0 [M+H] + .

[0319] (3) 3-(2-chloro-4'-(cyclopropyl(1-methyl-1H-pyrazol-3-yl)amino)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0320] N-(4-bromophenyl)-N-cyclopropyl-1-methyl-1H-pyrazole-3-amine (20 mg, 0.07 mmol), intermediate 3 (24 mg, 0.07 mmol), PdCl2 (dppf) (5 mg, 0.007 mmol), and potassium carbonate (19 mg, 0.14 mmol) were dissolved in 1,4-dioxane / water (5 mL / 1 mL). The mixture was heated to 85 °C and stirred for 4 hours under nitrogen protection. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (100% ethyl acetate) to obtain a crude product, which was then purified by Prep-HPLC to obtain the title compound (1.7 mg, white solid), yield: 6%. MS (ESI): m / z 435.1 [M+H]+. 1 H NMR (400MHz, DMSO-d6) δ10.90(s,1H),7.66(s,1H),7.37-7.14(m,7H),6.06(s,1H),4.33(dd,J=10.8,3.6Hz,1H) ,3.79(s,3H),2.82-2.74(m,3H),2.37-2.31(m,1H),2.05-2.03(m,1H),0.89(d,J=6.0Hz,2H),0.58-0.54(m,2H).

[0321] Example 10

[0322] N-(2'-chloro-3'-(2,6-dioxopiperidin-3-yl)-[1,1'-biphenyl]-4-yl)-N-cyclopropyl-1-methyl-1H-pyrazole-3-sulfonamide

[0323] (1) N-Cyclopropyl-4-iodoaniline

[0324] 4-Iodoaniline (500 mg, 2.28 mmol) was dissolved in methanol (10 mL), and 1-ethoxy-1-trimethoxycyclopropane (478 mg, 2.74 mmol), acetic acid (2 mL), and sodium cyanoborohydride (574 mg, 9.13 mmol) were added. The reaction mixture was reacted overnight at 70 °C under nitrogen protection. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20 / 1) to give the title compound (420 mg, pale yellow oil), yield: 71%. MS (ESI): m / z 260.0 [M+H] + .

[0325] (2) N-Cyclopropyl-N-(4-iodophenyl)-1-methyl-1H-pyrazole-3-sulfonamide

[0326] N-cyclopropyl-4-iodoaniline (100 mg, 0.39 mmol) was dissolved in dichloromethane (4 mL), and triethylamine (117 mg, 1.16 mmol) and 1-methyl-1H-pyrazole-3-sulfonyl chloride (105 mg, 0.58 mmol) were added. The reaction mixture was reacted overnight at room temperature under nitrogen protection. The reaction solution was diluted with dichloromethane (20 mL), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to give the title compound (39 mg, pale yellow oil), yield: 25%. MS (ESI): m / z 403.9 [M+H] + .

[0327] (3)N-(2'-chloro-3'-(2,6-dioxopiridine-3-yl)-[1,1'-biphenyl]-4-yl)-N-cyclopropyl-1-methyl-1H-pyrazole-3-sulfonamide

[0328] N-cyclopropyl-N-(4-iodophenyl)-1-methyl-1H-pyrazole-3-sulfonamide (30 mg, 0.074 mmol) was dissolved in 1,4-dioxane (4 mL), and intermediate 3 (26 mg, 0.074 mmol), potassium phosphate (47 mg, 0.22 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (5 mg, 0.007 mmol), and water (0.5 mL) were added. The reaction mixture was reacted overnight at 90 °C under nitrogen protection. The reaction solution was concentrated, and the residue was purified by Prep-TLC (100% ethyl acetate) to obtain a crude, pale yellow oil, which was then purified by Prep-HPLC to obtain the title compound (2.2 mg, white solid), yield: 5.8%. MS (ESI): m / z 499.1 [M+H]+. 1H NMR (400MHz, DMSO-d6) δ10.92(s,1H),7.93(d,J=2.0Hz,1H),7.42-7.31(m,5H),7.26-7.24(m,2H),6.53(d,J=2.4Hz,1H),4.37-4.33(m,1H),3. 96(s,3H),3.02-2.97(m,1H),2.83-2.75(m,1H),2.59-2.56(m,1H),2.3 5-2.34(m,1H),2.07-2.03(m,1H),0.85-0.80(m,2H),0.69-0.66(m,2H).

[0329] Example 11

[0330] 3-(2-chloro-4'-((cyclopropyl(methyl)(oxo)-λ) 6 -sulfonyl)amino)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0331] (1)((4-bromophenyl)imino)(cyclopropyl)(methyl)-λ 6 -Sulfamethoxazole

[0332] 1-Bromo-4-iodobenzene (70 mg, 0.25 mmol), cyclopropyl(imino)(methyl)-λ 6 Sulfamethoxane (30 mg, 0.25 mmol), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (29 mg, 0.05 mmol), tris(dibenzylacetone)palladium (23 mg, 0.025 mmol), and cesium carbonate (163 g, 0.5 mmol) were dissolved in 1,4-dioxane (10 mL), and the mixture was purged with nitrogen. The mixture was stirred overnight at 90 °C under nitrogen protection. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give the title compound (39 mg, yellow solid), yield: 58%. MS (ESI): m / z 274.0 [M+H] + .

[0333] (2) 3-(2-chloro-4'-((cyclopropyl(methyl)(oxo)-λ) 6 -sulfonyl)amino)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0334] ((4-bromophenyl)imino)(cyclopropyl)(methyl)-λ 6Sulfamethoxazole (39 mg, 0.14 mmol), intermediate 3 (49 mg, 0.14 mmol), PdCl2 (dppf) (10 mg, 0.014 mmol), and potassium carbonate (38 mg, 0.28 mmol) were dissolved in 1,4-dioxane / water (5 mL / 1 mL). The mixture was heated to 85 °C and stirred for 4 hours under nitrogen protection. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (100% ethyl acetate) to obtain a crude product, which was then purified by Prep-HPLC to obtain the title compound (2.0 mg, white solid), yield: 3%. MS (ESI): m / z 417.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.90(s,1H),7.38-7.34(m,1H),7.30-7.26(m,2H),7.23-7.21(m,2H),7.00-6.98(m,2H),4.33(dd,J=12.4,5.2 Hz,1H),3.22(s,3H),2.87-2.75(m,2H),2.56-2.55(m,1H),2.38-2.27(m,1H),2.07-2.01(m,1H),1.24-1.18(m,2H),1.10-1.01(m,2H).

[0335] Example 12

[0336] 3-(2-chloro-4'-(cyclopropyl((1-methyl-1H-pyrazol-3-yl)methyl)amino)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0337] (1) 4-Iodo-N-((1-methyl-1H-pyrazol-3-yl)methyl)aniline

[0338] 4-Iodoaniline (990 mg, 4.5 mmol) was dissolved in methanol (15 mL), and 1-methyl-1H-pyrazole-3-carboxaldehyde (500 mg, 4.5 mmol), acetic acid (3 mL), and sodium cyanoborohydride (850 mg, 13.5 mmol) were added. The reaction mixture was reacted overnight at 40 °C under nitrogen protection. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to give the title compound (900 mg, gray oil), yield: 64.4%. MS (ESI): m / z 314.0 [M+H] + .

[0339] (2) N-Cyclopropyl-4-iodo-N-(1-methyl-1H-pyrazole-3-yl)methyl)aniline

[0340] 4-Iodo-N-((1-methyl-1H-pyrazol-3-yl)methyl)aniline (200 mg, 0.64 mmol) was dissolved in methanol (50 mL), and 1-ethoxy-1-trimethoxycyclopropane (134 mg, 0.77 mmol), acetic acid (1 mL), and sodium cyanoborohydride (161 mg, 2.56 mmol) were added. The reaction mixture was reacted overnight at 70 °C under nitrogen protection. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4 / 1) to give the title compound (130 mg, pale yellow oil), yield: 57.6%. MS (ESI): m / z 354.0 [M+H] + .

[0341] (3) 3-(2-chloro-4'-(cyclopropyl((1-methyl-1H-pyrazol-3-yl)methyl)amino)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0342] N-cyclopropyl-4-iodo-N-(1-methyl-1H-pyrazole-3-yl)methyl)aniline (80 mg, 0.23 mmol) was dissolved in 1,4-dioxane (4 mL), and intermediate 3 (79 mg, 0.227 mmol), potassium phosphate (144 mg, 0.68 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (17 mg, 0.023 mmol), and water (0.5 mL) were added. The reaction mixture was reacted overnight at 90 °C under nitrogen protection. The reaction solution was concentrated, and the residue was purified by Prep-TLC (petroleum ether / ethyl acetate = 2 / 1) to give a crude, pale yellow oil. This crude oil was then purified by Prep-HPLC to give the title compound (4.4 mg, white solid), yield: 4.2%. MS (ESI): m / z 449.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.90 (s, 1H), 7.54 (d, J = 2.0Hz, 1H), 7.35-7.32 (m, 1H),7.27-7.21(m,4H),7.05-7.03(m,2H),5.99(d,J=2.4Hz,1H),4.52(s,2 H),4.34-4.30(m,1H),3.77(s,3H),2.82-2.74(m,1H),2.64-2.54(m,2H),2 .36-2.29(m,1H),2.06-2.02(m,1H),0.92-0.87(m,2H),0.68-0.65(m,2H).

[0343] Example 13

[0344] 3-(2-chloro-4'-((1-tetrahydro-1λ) 6-thiophene-1-yl)amino)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0345] (1) 1-((4-iodophenyl)imino)tetrahydro-1H-1λ 6 -Thiophene 1-oxide

[0346] 1-Bromo-4-iodobenzene (100 mg, 0.30 mmol), 1-imino-1-oxothiacyclopentane (36.12 mg, 0.30 mmol), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (35.01 mg, 0.06 mmol), tris(dibenzylacetone)dipalladium (27.27 mg, 0.03 mmol), and cesium carbonate (296.26 mg, 0.91 mmol) were dissolved in 1,4-dioxane (5 mL), and the mixture was purged with nitrogen. The reaction mixture was stirred overnight at 90 °C under nitrogen protection. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 9 / 1) to give the title compound (40 mg, brown oil), yield: 41%. MS (ESI): m / z 321.9 [M+H] + .

[0347] (2)3-(2-chloro-4'-((1-tetrahydro-1λ) 6 -thiophene-1-yl)amino)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0348] 1-((4-iodophenyl)imino)tetrahydro-1H-1λ 6 Thiophene 1-oxide (30 mg, 0.09 mmol), intermediate 3 (31 mg, 0.09 mmol), PdCl2 (dppf) (6.6 mg, 0.009 mmol), and potassium phosphate (38 mg, 0.18 mmol) were dissolved in 1,4-dioxane / water (5 mL / 1 mL). The reaction mixture was heated to 90 °C and stirred for 4 hours under nitrogen protection. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (100% ethyl acetate) to obtain a crude product, which was then purified by Prep-HPLC to obtain the title compound (2.8 mg, white solid), yield: 8%. MS (ESI): m / z 417.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.90 (s, 1H), 7.36-7.24 (m, 5H), 6.98 (d, J = 8.0Hz, 2H), 4.3 3(dd,J=12.4,5.2Hz,1H),3.43-3.35(m,2H),2.83-2.74(m,2H),2.37-2.05(m,8H).

[0349] Example 14

[0350] 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

[0351] (1) Ethyl 1-((1-((tert-butoxycarbonyl)amino)cyclobutyl)methyl)-1H-pyrazole-5-carboxylic acid ester

[0352] Ethyl 1H-pyrazole-3-carboxylate (600 mg, 4.3 mmol) and tert-butyl (1-(hydroxymethyl)cyclobutyl)carbamate (864 mg, 4.3 mmol) were dissolved in tetrahydrofuran (15 mL), followed by the addition of triphenylphosphine (1.7 g, 6.5 mmol) and diisopropyl azodicarbonate (1.3 g, 6.5 mmol). The reaction mixture was reacted overnight at 60 °C. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to give the title compound (230 mg, colorless oil), yield: 17%. MS (ESI): m / z 324.2 [M+H] + .

[0353] (2) Ethyl 1-((1-aminocyclobutyl)methyl)-1H-pyrazole-5-carboxylic acid ester

[0354] Ethyl 1-((1-((tert-Butoxycarbonyl)amino)cyclobutyl)methyl)-1H-pyrazole-5-carboxylic acid (230 mg, 0.71 mmol) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (3 mL) was added. The reaction mixture was reacted at room temperature for 2 hours. The reaction solution was concentrated to give the title compound (158 mg, crude product). MS (ESI): m / z 224.2 [M+H] + .

[0355] (3) 7'H-spiro[cyclobutane-1,6'-pyrazolo[1,5-a]pyrazine]-4'(5'H)-one

[0356] Ethyl 1-((1-aminocyclobutyl)methyl)-1H-pyrazole-5-carboxylate (158 mg, 0.71 mmol) and sodium hydroxide (85 mg, 2.13 mmol) were dissolved in methanol / water (5 mL / 1 mL) and reacted overnight at room temperature. The reaction mixture was then extracted with water (10 mL) and precipitated with dichloromethane (10 mL x 3). The organic phase was concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 9) to give the title compound (90 mg, white solid), yield: 72%. MS (ESI): m / z 178.2 [M+H] +.

[0357] (4) 5'-(4-bromophenyl)-7'H-spiro[cyclobutane-1,6'-pyrazolo[1,5-a]pyrazine]-4'(5'H)-one

[0358] 7'H-spiro[cyclobutane-1,6'-pyrazolo[1,5-a]pyrazine]-4'(5'H)-one (90 mg, 0.51 mmol) and 1-bromo-4-iodobenzene (283 mg, 1.0 mmol) were dissolved in N,N-dimethylformamide (5 mL), and 8-hydroxyquinoline (29 mg, 0.2 mmol), cuprous iodide (19 mg, 0.1 mmol), and potassium carbonate (138 mg, 1.0 mmol) were added. The mixture was microwaved at 140 °C for 6 hours. Water (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (10 mL x 3). The organic phase was concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give the title compound (32 mg, white solid), yield: 19%. MS (ESI): m / z 332.0 [M+H] + .

[0359] (5) 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

[0360] 5'-(4-bromophenyl)-7'H-spiro[cyclobutane-1,6'-pyrazolo[1,5-a]pyrazine]-4'(5'H)-one (10 mg, 0.03 mmol), intermediate 3 (10 mg, 0.03 mmol), PdCl2 (dppf) (2 mg, 0.003 mmol), and potassium carbonate (8 mg, 0.06 mmol) were dissolved in 1,4-dioxane / water (5 mL / 1 mL). The reaction mixture was heated to 85 °C and stirred for 4 hours under nitrogen protection. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (100% ethyl acetate) to obtain a crude product, which was then purified by Prep-HPLC to obtain the title compound (1.2 mg, white solid), yield: 8.5%. MS (ESI): m / z 475.1 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ10.93(s,1H),7.66(d,J=1.6Hz,1H),7.55(d,J=8.4Hz,2H),7.46-7.39(m,5H),6.84(d,J=2.0Hz,1 H), 4.76 (s, 2H), 4.38 (dd, J = 12.0, 4.8Hz, 1H), 2.84-2.77 (m, 1H), 2.58-2.57 (m, 2H), 2.38-2.33 (m, 1H), 2.17-1.90 (m, 6H).

[0361] Example 15

[0362] 3-(2-chloro-4'-(1'-oxo-1',4'-dihydro-2'H-spiro[cyclopropane-1,3'-isoquinoline]-2'-yl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0363] (1) 1-(2-bromobenzyl)cyclopropane-1-amine

[0364] 2-(2-bromophenyl)acetonitrile (5 g, 25.6 mmol) and tetraisopropyl titanate (8 g, 28.2 mmol) were dissolved in tetrahydrofuran (50 mL). A solution of 2M ethyl magnesium bromide (25.6 mL, 51.2 mmol) in tetrahydrofuran was added dropwise at 0 °C, and the reaction was allowed to proceed at room temperature for 2 hours. Boron trifluoride diethyl ether (7.3 g, 51.2 mmol) was added dropwise at 0 °C, and the reaction was allowed to proceed overnight at room temperature. Sodium bicarbonate aqueous solution (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (10 mL x 3). The organic phases were combined and concentrated to give the title compound (5.7 g, crude). MS (ESI): m / z 226.0 [M+H] + .

[0365] (2) (1-(2-bromobenzyl)cyclopropyl)tert-butyl carbamate

[0366] 1-(2-bromobenzyl)cyclopropane-1-amine (3 g, 13.3 mmol) and di-tert-butyl dicarbonate (4.3 g, 20 mmol) were dissolved in dichloromethane (30 mL), and triethylamine (4 g, 40 mmol) was added. The reaction mixture was reacted at room temperature for 3 hours. The reaction solution was concentrated, and the residue was purified by reverse-phase column chromatography to give the title compound (1 g, yellow solid), yield: 23%. MS (ESI): m / z 248.0 [M+Na] + .

[0367] (3) 2-((1-((tert-butoxycarbonyl)amino)cyclopropyl)methyl)benzoate

[0368] (1-(2-bromobenzyl)cyclopropyl)carbamate tert-butyl ester (650 mg, 2 mmol) and 1,3-bis(diphenylphosphine)propane (165 mg, 0.4 mmol) were dissolved in methanol / acetonitrile (10 mL / 5 mL), and palladium acetate (45 mg, 0.2 mmol) and potassium carbonate (552 mg, 4 mmol) were added. The mixture was reacted in an autoclave at 5 MPa and 140 °C for 48 hours under a carbon monoxide atmosphere. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give the title compound (480 mg, colorless oil), yield: 79%. MS (ESI): m / z 328.1 [M+Na] + .

[0369] (4) Methyl 2-((1-aminocyclopropyl)methyl)benzoate

[0370] Methyl 2-((1-((tert-Butoxycarbonyl)amino)cyclopropyl)methyl)benzoate (200 mg, 0.66 mmol) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (3 mL) was added. The reaction mixture was reacted at room temperature for 2 hours. The reaction solution was concentrated to give the title compound (134 mg, crude product). MS (ESI): m / z 206.1 [M+H] + .

[0371] (5) 2'H-spiro[cyclopropane-1,3'-isoquinoline]-1'(4'H)-one

[0372] Methyl 2-((1-aminocyclopropyl)methyl)benzoate (134 mg, 0.65 mmol) and sodium hydroxide (52 mg, 1.3 mmol) were dissolved in methanol / water (5 mL / 1 mL) and reacted overnight at room temperature. The reaction mixture was then extracted with water (10 mL) and dichloromethane (10 mL x 3). The organic phases were combined and concentrated. The residue was purified by silica gel column chromatography (100% ethyl acetate) to give the title compound (120 mg, white solid), yield: 96%. MS (ESI): m / z 174.1 [M+H] + .

[0373] (6) 2'-(4-bromophenyl)-2'H-spiro[cyclopropane-1,3'-isoquinoline]-1'(4'H)-one

[0374] 2'H-spiro[cyclopropane-1,3'-isoquinoline]-1'(4'H)-one (80 mg, 0.46 mmol) and 1-bromo-4-iodobenzene (260 mg, 0.92 mmol) were dissolved in N,N-dimethylformamide (5 mL), and 8-hydroxyquinoline (27 mg, 0.18 mmol), cuprous iodide (17 mg, 0.09 mmol), and potassium carbonate (127 mg, 0.92 mmol) were added. The mixture was microwaved at 140 °C for 6 hours. Water (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (10 mL x 3). The organic phases were combined and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to give the title compound (20 mg, yellow solid), yield: 13%. MS (ESI): m / z 328.0 [M+H] + .

[0375] (7) 3-(2-chloro-4'-(1'-oxo-1',4'-dihydro-2'H-spiro[cyclopropane-1,3'-isoquinoline]-2'-yl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0376] 2'-(4-bromophenyl)-2'H-spiro[cyclopropane-1,3'-isoquinoline]-1'(4'H)-one (20 mg, 0.06 mmol), intermediate 3 (21 mg, 0.06 mmol), PdCl2 (dppf) (4.4 mg, 0.006 mmol), and potassium phosphate (25 mg, 0.12 mmol) were dissolved in 1,4-dioxane / water (5 mL / 1 mL). The mixture was heated to 90 °C and stirred for 4 hours under nitrogen protection. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain a crude product, which was then purified by Prep-HPLC to obtain the title compound (2.2 mg, white solid), yield: 8%. MS (ESI): m / z 471.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.93(s,1H),7.95(dd,J=7.6,0.8Hz,1H),7.58(t,J=1.2Hz,1H),7.56-7.32(m,9H),4.37(dd,J=12.4,5.2Hz ,1H),3.17(s,2H),2.85-2.76(m,1H),2.58-2.57(m,1H),2.37-2.33(m,1H),2.09-1.99(m,1H),0.81-0.77(m,2H),0.63-0.60(m,2H).

[0377] Example 16

[0378] N-(2'-chloro-3'-(2,6-dioxopiperidin-3-yl)-[1,1'-biphenyl]-4-yl)-N-cyclopropyl-1-methyl-1H-pyrazole-3-carboxamide

[0379] (1) N-Cyclopropyl-N-(4-iodophenyl)-1-methyl-1H-pyrazole-3-carboxamide

[0380] In a 50 mL three-necked flask, N-cyclopropyl-4-iodoaniline (120 mg, 0.46 mmol), pyridine (4 mL), 1-methyl-1H-pyrazole-3-carboxylic acid (88 mg, 0.7 mmol), and dichloromethane (4 mL) were added. Under nitrogen protection, phosphorus oxychloride (213 mg, 1.4 mmol) was added dropwise at 0 °C, and the reaction was maintained in an ice bath for 30 min. The reaction mixture was quenched with water (30 mL), extracted with ethyl acetate (3 x 20 mL), and the combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 3) to give the title compound (54 mg, white solid), yield: 31.8%. MS (ESI): m / z 368.0 [M+H] + .

[0381] (2)N-(2'-chloro-3'-(2,6-dioxopiperidin-3-yl)-[1,1'-biphenyl]-4-yl)-N-cyclopropyl-1-methyl-1H-pyrazole-3-carboxamide

[0382] Intermediate 3 (57 mg, 0.16 mmol) was dissolved in 1,4-dioxane (5 mL), and N-cyclopropyl-N-(4-iodophenyl)-1-methyl-1H-pyrazole-3-carboxamide (50 mg, 0.136 mmol), 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (10 mg, 0.014 mmol), potassium phosphate (87 mg, 0.41 mmol), and water (0.5 mL) were added. The mixture was heated to 90 °C for 3 hours under nitrogen protection. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 8 / 1) to obtain a crude product, which was then purified by Prep-HPLC to obtain the title compound (17.1 mg, white solid), yield: 27.1%. MS (ESI): m / z 463.1 [M+H] + . 1¹H NMR (400MHz, DMSO-d⁶) δ 10.92 (s, 1H), 7.62-7.61 (m, 1H), 7.37-7.29 (m, 7H), 6.24 (d, J = 2.4Hz, 1H), 4.35 (dd, J = 12.0, 4.8Hz, 1H), 3.78 (s, 3H), 3.38-3.34 (m, 1H), 2.84-2.75 (m, 1H), 2.57-2.56 (m, 1H), 2.39-2.32 (m, 1H), 2.07-2.03 (m, 1H), 0.81-0.76 (m, 2H), 0.51-0.48 (m, 2H). Example 17

[0383] 3-(2-chloro-4'-(cyclopropyl(pyrimidin-2-yl)amino)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0384] (1) N-(4-bromophenyl)pyrimidin-2-amine

[0385] 1-Bromo-4-iodobenzene (300 mg, 1.06 mmol), pyrimidin-2-amine (101 mg, 1.06 mmol), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (123 mg, 0.21 mmol), tris(dibenzylacetone)dipalladium (97 mg, 0.11 mmol), and cesium carbonate (864 mg, 2.65 mmol) were dissolved in 1,4-dioxane (10 mL), and the mixture was purged with nitrogen. The reaction mixture was stirred overnight at 90 °C under nitrogen protection. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 90 / 10) to give the title compound (230 mg, yellow solid), yield: 87%. MS (ESI): m / z 250.0 [M+H] + .

[0386] (2) N-(4-bromophenyl)-N-cyclopropylpyrimidin-2-amine

[0387] N-(4-bromophenyl)pyrimidin-2-amine (230 mg, 0.92 mmol) and cyclopropylboronic acid (158 mg, 1.84 mmol) were dissolved in dichloroethane (5 mL). 2,2'-bipyridine (144 mg, 0.92 mmol), copper acetate (167 mg, 0.92 mmol), and potassium carbonate (254 mg, 1.84 mmol) were added, and the mixture was stirred at 80 °C under oxygen bulb conditions for 22 hours. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 80 / 20) to give the title compound (100 mg, white solid), yield: 37%. MS (ESI): m / z 290.0 [M+H] + .

[0388] (3) 3-(2-chloro-4'-(cyclopropyl(pyrimidin-2-yl)amino)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0389] N-(4-bromophenyl)-N-cyclopropylpyrimidin-2-amine (50 mg, 0.17 mmol), intermediate 3 (60 mg, 0.17 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (13 mg, 0.02 mmol), and potassium carbonate (60 mg, 0.43 mmol) were dissolved in 1,4-dioxane / water (5 mL / 0.5 mL) and reacted at 80 °C under nitrogen protection for 16 hours with stirring. Water (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (10 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 40 / 60) to obtain a crude product, which was then purified by Prep-HPLC to give the title compound (7 mg, white solid), yield: 9%. MS(ESI): m / z 433.2 [M+H] + . 1 ¹H NMR (400MHz, DMSO-d⁶) δ 10.93 (s, 1H), 8.43 (d, J = 4.4Hz, 2H), 7.44–7.33 (m, 7H), 6.83 (t, J = 4.4Hz, 1H), 4.37 (dd, J = 12.0, 4.8Hz, 1H), 3.20–3.16 (m, 1H), 2.84–2.76 (m, 1H), 2.61–2.57 (m, 1H), 2.37–2.33 (m, 1H), 2.09–2.05 (m, 1H), 0.92–0.90 (m, 2H), 0.51–0.47 (m, 2H). Example 18

[0390] 3-(2-chloro-4'-(cyclobutyl((1-methyl-1H-pyrazol-3-yl)methyl)amino)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0391] (1) N-cyclobutyl-4-iodo-N-(1-methyl-1H-pyrazole-3-yl)methyl)aniline

[0392] Acetic acid (1 mL), cyclobutanone (67 mg, 0.96 mmol), and sodium cyanoborohydride (90 mg, 1.44 mmol) were added to a methanol (10 mL) solution of 4-iodo-N-((1-methyl-1H-pyrazol-3-yl)methyl)aniline (150 mg, 0.48 mmol), and the mixture was reacted overnight at 40 °C. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to give the title compound (140 mg, pale yellow oil), yield: 79.6%. MS (ESI): m / z 368.0 [M+H] + .

[0393] (2) 3-(2-chloro-4'-(cyclobutyl((1-methyl-1H-pyrazol-3-yl)methyl)amino)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0394] Intermediate 3 (57 mg, 0.16 mmol) was dissolved in 1,4-dioxane (5 mL), and N-cyclobutyl-4-iodo-N-(1-methyl-1H-pyrazole-3-yl)methyl)aniline (60 mg, 0.16 mmol), 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (12 mg, 0.016 mmol), potassium phosphate (104 mg, 0.49 mmol), and water (0.5 mL) were added. The reaction mixture was reacted at 90 °C for 3 hours under nitrogen protection. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 8 / 1) to obtain a crude product, which was then purified by Prep-HPLC to obtain the title compound (4.4 mg, white solid), yield: 5.7%. MS (ESI): m / z 463.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.90(s,1H),7.54(d,J=2.0Hz,1H),7.35-7.18(m,5H),6.81-6.79(m,2H),5.98(d,J=2.0Hz,1H),4.45(s,2H),4.31(dd,J =12.0,4.8Hz,1H),4.20-4.10(m,1H),3.78(s,3H),2.85-2.71(m,1H),2. 56-2.54(m,1H),2.35-2.26(m,3H),2.16-1.98(m,3H),1.71-1.63(m,2H).

[0395] Example 19

[0396] 3-(2-chloro-4'-(2,2-difluoroethyl)(1-methyl-1H-pyrazol-3-yl)amino)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0397] (1) N-(4-bromophenyl)-N-(2,2-difluoroethyl)-1-methyl-1H-pyrazole-3-amine

[0398] N-(4-bromophenyl)-1-methyl-1H-pyrazole-3-amine (150 mg, 0.6 mmol) and cesium carbonate (391 mg, 1.2 mmol) were dissolved in N,N-dimethylformamide (10 mL), and 1,1-difluoro-2-iodoethane (172 mg, 0.9 mmol) was added. The mixture was stirred overnight at 130 °C. The reaction solution was added to water (10 mL), and extracted with ethyl acetate (10 mL x 3). The organic phases were combined and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to give the title compound (20 mg, yellow oil), yield: 11%. MS (ESI): m / z 316.0 [M+H] + .

[0399] (2) 3-(2-chloro-4'-(2,2-difluoroethyl)(1-methyl-1H-pyrazol-3-yl)amino)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0400] N-(4-bromophenyl)-N-(2,2-difluoroethyl)-1-methyl-1H-pyrazole-3-amine (20 mg, 0.06 mmol), intermediate 3 (42 mg, 0.12 mmol), PdCl2 (dppf) (5 mg, 0.006 mmol), and potassium phosphate (25 mg, 0.12 mmol) were dissolved in 1,4-dioxane / water (5 mL / 1 mL). The mixture was heated to 90 °C and stirred for 4 hours under nitrogen protection. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain a crude product, which was then purified by Prep-HPLC to obtain the title compound (8.2 mg, white solid), yield: 30%. MS (ESI): m / z 459.1 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ10.91 (s, 1H), 7.62 (d, J = 2.4Hz, 1H), 7.39-7.35 (m, 1 H),7.32-7.28(m,4H),7.17-7.15(m,2H),6.46-6.16(m,1H),5.93(d,J=2.4Hz ,1H),4.34(dd,J=12.0,4.8Hz,1H),4.18(td,J=14.8,4.4Hz,2H),3.77(s,3H) ,2.83-2.74(m,1H),2.56-2.55(m,1H),2.38-2.27(m,1H),2.07-2.01(m,1H).

[0401] Example 20

[0402] 3-(2-chloro-4'-(cyclobutyl(1-methyl-1H-pyrazol-3-yl)amino)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0403] (1) N-cyclobutyl-1-methyl-1H-pyrazole-3-amine

[0404] 1-Methyl-1H-pyrazole-3-amine (1.5 g, 15.4 mmol) and cyclobutanone (1.1 g, 15.4 mmol) were dissolved in methanol / acetic acid (20 mL / 1 mL) and stirred at 40 °C for 0.5 h. Sodium cyanoborohydride (2.9 g, 46.2 mmol) was then added, and the reaction mixture was stirred at 40 °C for 6 h. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 50 / 50) to give the title compound (1 g, colorless oil), yield: 43%. MS (ESI): m / z 152.2 [M+H] + .

[0405] (2) N-(4-bromophenyl)-N-cyclobutyl-1-methyl-1H-pyrazole-3-amine

[0406] N-cyclobutyl-1-methyl-1H-pyrazole-3-amine (200 mg, 1.3 mmol), 1-bromo-4-iodobenzene (374 mg, 1.3 mmol), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (116 mg, 0.2 mmol), tris(dibenzylacetone)dipalladium (92 mg, 0.1 mmol), and cesium carbonate (1.1 g, 3.3 mmol) were dissolved in 1,4-dioxane (10 mL), and the mixture was purged with nitrogen. The reaction mixture was stirred overnight at 90 °C under nitrogen protection. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 70 / 30) to give the title compound (120 mg, brown oil), yield: 39%. MS (ESI): m / z 306.1 [M+H] + .

[0407] (3) 3-(2-chloro-4'-(cyclobutyl(1-methyl-1H-pyrazol-3-yl)amino)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0408] N-(4-bromophenyl)-N-cyclobutyl-1-methyl-1H-pyrazole-3-amine (40 mg, 0.13 mmol), intermediate 3 (46 mg, 0.13 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (7 mg, 0.01 mmol), and potassium carbonate (45 mg, 0.33 mmol) were dissolved in 1,4-dioxane / water (5 mL / 0.5 mL) and reacted at 80 °C under nitrogen protection for 16 hours with stirring. Water (20 mL) was added to the reaction mixture, and the aqueous phase was extracted with ethyl acetate (10 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 40 / 60) to obtain a crude product, which was then purified by Prep-HPLC to give the title compound (1.7 mg, white solid), yield: 9%. MS(ESI): m / z 449.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.90(s,1H),7.71(d,J=2.4Hz,1H),7.36-7.19(m,5H),6.72(d,J=8.8Hz,2H),6.00(d,J=2.4Hz,1H),4.37-4.29 (m,2H),3.82(s,3H),2.82-2.72(m,1H),2.55-2.54(m,1H),2.37-2.20(m,3H),2.05-1.99(m,1H),1.91-1.81(m,2H),1.69-1.57(m,2H).

[0409] Example 21

[0410] 3-(2-chloro-4'-(8'-oxo-5'H-spiro[cyclopropane-1,6'-[1,2,4]triazolo[1,5-a]pyrazine]-7'(8'H)-yl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0411] (1) methyl 1-((1-((tert-butoxycarbonyl)amino)cyclopropyl)methyl)-1H-1,2,4-triazole-5-carboxylic acid ester

[0412] Methyl 1H-1,2,4-triazol-5-carboxylic acid (1 g, 7.9 mmol) and tert-butyl (1.4 g, 7.9 mmol) carbamate (1.4 g, 7.9 mmol) were dissolved in tetrahydrofuran (15 mL), and triphenylphosphine (3.1 g, 11.8 mmol) and diisopropyl azodicarbonate (2.4 g, 11.8 mmol) were added. The mixture was reacted overnight at 40 °C. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give the title compound (1.1 g, white solid), yield: 48%. MS (ESI): m / z 297.2 [M+H] + .

[0413] (2) Methyl 1-((1-aminocyclopropyl)methyl)-1H-1,2,4-triazole-5-carboxylic acid ester

[0414] Methyl 1-((1-((tert-Butoxycarbonyl)amino)cyclopropyl)methyl)-1H-1,2,4-triazol-5-carboxylic acid (400 mg, 1.35 mmol) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (3 mL) was added. The reaction mixture was reacted at room temperature for 2 hours. The reaction solution was concentrated to give the title compound (265 mg, crude product). MS (ESI): m / z 197.2 [M+H] + .

[0415] (3) 5'-spiro[cyclopropane-1,6'-[1,2,4]triazolo[1,5-a]pyrazine]-8'(7'H)-one

[0416] Methyl 1-((1-aminocyclopropyl)methyl)-1H-1,2,4-triazol-5-carboxylic acid (463 mg, 2.4 mmol) and sodium hydroxide (288 mg, 7.2 mmol) were dissolved in methanol / water (5 mL / 1 mL) and reacted overnight at room temperature. The reaction mixture was added to water (10 mL) and extracted with dichloromethane (10 mL x 3). The organic phases were combined, concentrated, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to give the title compound (220 mg, white solid), yield: 56%. MS (ESI): m / z 165.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.11 (s, 2H), 4.35 (s, 2H), 1.19 (t, J = 7.2Hz, 2H), 1.03 (t, J = 6.0Hz, 2H).

[0417] (4) 7'-(4-bromophenyl)-5'H-spiro[cyclopropane-1,6'-[1,2,4]triazolo[1,5-a]pyrazine]-8'(7'H)-one

[0418] 5'-spiro[cyclopropane-1,6'-[1,2,4]triazolo[1,5-a]pyrazine]-8'(7'H)-one (220 mg, 1.34 mmol) and 1-bromo-4-iodobenzene (759 mg, 2.68 mmol) were dissolved in N,N-dimethylformamide (5 mL), and 8-hydroxyquinoline (78 mg, 0.53 mmol), cuprous iodide (51 mg, 0.27 mmol), and potassium carbonate (386 mg, 2.8 mmol) were added. The mixture was microwaved at 140 °C for 6 hours. The reaction solution was added to water (10 mL) and extracted with ethyl acetate (10 mL x 3). The organic phases were combined, concentrated, and the residue was purified by silica gel column chromatography (100% ethyl acetate) to give the title compound (200 mg, white solid), yield: 47%. MS (ESI): m / z 319.0 [M+H] + .

[0419] (5) 3-(2-chloro-4'-(8'-oxo-5'H-spiro[cyclopropane-1,6'-[1,2,4]triazolo[1,5-a]pyrazine]-7'(8'H)-yl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0420] 7'-(4-bromophenyl)-5'H-spiro[cyclopropane-1,6'-[1,2,4]triazolo[1,5-a]pyrazine]-8'(7'H)-one (80 mg, 0.25 mmol), intermediate 3 (150 mg, 0.25 mmol), PdCl2 (dppf) (18 mg, 0.025 mmol), and potassium phosphate (106 mg, 0.5 mmol) were dissolved in 1,4-dioxane / water (5 mL / 1 mL). The reaction mixture was heated to 90 °C and stirred for 4 hours under nitrogen protection. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (100% ethyl acetate) to obtain a crude product, which was then purified by Prep-HPLC to obtain the title compound (9.2 mg, white solid), yield: 8%. MS (ESI): m / z 462.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.93(s,1H),8.28(s,1H),7.52-7.50(m,2H),7.45-7.37(m,5H),4.71(s,2H),4.37(dd,J=12.4,4.8Hz ,1H),2.89-2.73(m,1H),2.57-2.65(m,1H),2.40-2.31(m,1H),2.07-2.05(m,1H),1.08(t,J=6.8Hz,2H),0.80(t,J=6.0Hz,2H).

[0421] Example 22

[0422] 3-(2-chloro-4'-(cyclopropyl(1-methyl-1H-1,2,4-triazol-3-yl)amino)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0423] (1) N-(4-bromophenyl)-1-methyl-1H-1,2,4-triazol-3-amine

[0424] 1-Bromo-4-iodobenzene (2 g, 7.1 mmol), 1-methyl-1H-1,2,4-triazol-3-amine (0.7 g, 7.1 mmol), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (0.8 g, 1.4 mmol), tris(dibenzylacetone)dipalladium (0.6 g, 0.7 mmol), and cesium carbonate (5.78 g, 17.8 mmol) were dissolved in 1,4-dioxane (30 mL), and the mixture was purged with nitrogen. The reaction mixture was stirred overnight at 90 °C under nitrogen protection. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 98 / 2) to give the title compound (230 mg, yellow solid), yield: 87%. MS (ESI): m / z 253.0 [M+H]+ .

[0425] (2) N-(4-bromophenyl)-N-cyclopropyl-1-methyl-1H-1,2,4-triazol-3-amine

[0426] N-(4-bromophenyl)-1-methyl-1H-1,2,4-triazol-3-amine (400 mg, 1.58 mmol) and cyclopropylboronic acid (272 mg, 3.16 mmol) were dissolved in N,N-dimethylformamide (10 mL), and 2,2'-bipyridine (247 mg, 1.58 mmol), copper acetate (287 mg, 1.58 mmol), and potassium carbonate (437 mg, 3.16 mmol) were added. The mixture was stirred at 120 °C for 22 hours under oxygen bulb conditions. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 95 / 5) to give the title compound (100 mg, yellow oil), yield: 22%. MS (ESI): m / z 293.0 [M+H] + .

[0427] (3) 3-(2-chloro-4'-(cyclopropyl(1-methyl-1H-1,2,4-triazol-3-yl)amino)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0428] N-(4-bromophenyl)-N-cyclopropyl-1-methyl-1H-1,2,4-triazol-3-amine (50 mg, 0.17 mmol), intermediate 3 (60 mg, 0.17 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (13 mg, 0.02 mmol), and potassium carbonate (60 mg, 0.43 mmol) were dissolved in 1,4-dioxane / water (5 mL / 0.5 mL) and reacted at 80 °C under nitrogen protection for 16 hours with stirring. Water (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (10 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was subjected to silica gel column chromatography (dichloromethane / methanol = 98 / 2) to give a crude product, which was then purified by Prep-HPLC to give the title compound (11.5 mg, white solid), yield: 15%. MS(ESI): m / z 436.1 [M+H] + . 1¹H NMR (400MHz, DMSO-d⁶) δ 10.91 (s, 1H), 8.30 (s, 1H), 7.37-7.29 (m, 7H), 4.34 (dd, J = 11.6, 4.0Hz, 1H), 3.81 (s, 3H), 2.94-2.89 (m, 1H), 2.83-2.75 (m, 1H), 2.61-2.56 (m, 1H), 2.37-2.28 (m, 1H), 2.07-2.03 (m, 1H), 0.94-0.93 (m, 2H), 0.60-0.51 (m, 2H). Example 23

[0429] 3-(2-chloro-4'-((cyclobutyl(methyl)(oxo)-λ) 6 -sulfonyl)amino)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0430] (1) Cyclobutyl(methyl)thion

[0431] Bromocyclobutane (1.26 g, 9.4 mmol) and 20% sodium methanethiol aqueous solution (4.9 g, 14 mmol) were dissolved in ethanol (20 mL) and reacted overnight at 70 °C with stirring. The reaction solution was added to water (10 mL) and extracted with ethyl acetate (5 mL x 3) to give the title compound (959 mg, crude product), which was used directly in the next step.

[0432] (2) Cyclobutyl(imino)(methyl)-λ 6 -Sulfamethoxazole

[0433] The reaction mixture from the previous step, consisting of cyclobutyl(methyl)thione (500 mg, 4.9 mmol) and ammonium carbamate (573 mg, 7.3 mmol), was dissolved in ethanol (10 mL). Iodobenzene acetate (3.9 g, 12 mmol) was added at 0 °C, and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to give the title compound (200 mg, yellow oil), yield: 31%. MS (ESI): m / z 134.2 [M+H] + .

[0434] (3)((4-bromophenyl)imino)(cyclobutyl)(methyl)-λ 6 -Sulfamethoxazole

[0435] 1-Bromo-4-iodobenzene (106 mg, 0.37 mmol), cyclobutyl(imino)(methyl)-λ 6Sulfamethoxane (100 mg, 0.75 mmol), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (43 mg, 0.07 mmol), tris(dibenzylacetone)palladium (34 mg, 0.037 mmol), and cesium carbonate (241 mg, 0.74 mmol) were dissolved in 1,4-dioxane (10 mL), and the mixture was purged with nitrogen. The reaction mixture was stirred overnight at 90 °C under nitrogen protection. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give the title compound (20 mg, yellow oil), yield: 19%. MS (ESI): m / z 288.0 [M+H] + .

[0436] (4) 3-(2-chloro-4'-((cyclobutyl(methyl)(oxo)-λ) 6 -sulfonyl)amino)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0437] ((4-bromophenyl)imino)(cyclobutyl)(methyl)-λ 6 Sulfamethoxazole (20 mg, 0.07 mmol), intermediate 3 (24 mg, 0.07 mmol), PdCl2 (dppf) (5 mg, 0.007 mmol), and potassium phosphate (30 mg, 0.14 mmol) were dissolved in 1,4-dioxane / water (5 mL / 1 mL). The reaction mixture was heated to 90 °C and stirred for 4 hours under nitrogen protection. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (100% ethyl acetate) to obtain a crude product, which was then purified by Prep-HPLC to obtain the title compound (1.3 mg, white solid), yield: 4.3%. MS (ESI): m / z 431.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ10.90(s,1H),7.38-7.21(m,5H),7.02-7.00(m,2H),4.33(dd,J=12.0,4.8Hz,1H),4.25-4.17 (m,1H),3.05(s,3H),2.83-2.74(m,1H),2.57-2.52(m,1H),2.46-2.42(m,2H),2.38-2.22(m,3H),2.07-1.89(m,3H).

[0438] Example 24

[0439] 3-(2-chloro-4'-(7'-oxo-4'H-spiro[cyclopropane-1,5'-pyrazolo[1,5-c]pyrimidine]-6'(7'H)-yl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0440] (1) 2-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5-yl)acetonitrile

[0441] At 0 °C, 2-(1H-pyrazol-5-yl)acetonitrile (1 g, 9.3 mmol) was dissolved in tetrahydrofuran (15 mL), sodium hydride (60%, 744 mg, 18.6 mmol) was added, and the mixture was stirred for 5 minutes. Then, 2-(trimethylsilyl)ethoxymethyl chloride (3.1 g, 18.6 mmol) was added dropwise, and the mixture was reacted overnight at room temperature. Water (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (10 mL x 3). The organic phases were combined, filtered, concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to give the title compound (1.9 g, yellow oil), yield: 86%.

[0442] (2) 1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)methylcyclopropane-1-amine

[0443] 2-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)acetonitrile (1 g, 4.2 mmol) and tetraisopropyl titanate (1.9 g, 16.8 mmol) were dissolved in tetrahydrofuran (15 mL). A solution of 2M ethyl magnesium bromide (12.6 mL, 25.2 mmol) in tetrahydrofuran was added dropwise at 0 °C, and the reaction was allowed to proceed at room temperature for 2 hours. Boron trifluoride diethyl ether (3.6 g, 25.2 mmol) was added dropwise at 0 °C, and the reaction was allowed to proceed overnight at room temperature. Sodium bicarbonate aqueous solution (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (10 mL x 3). The organic phases were combined, filtered, concentrated, and the residue was purified by reverse-phase column chromatography to give the title compound (500 mg, yellow solid), yield: 45%. MS (ESI): m / z 268.2 [M+H] + .

[0444] (3)(1-(1-(((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5-yl)methyl ester)cyclopropyl)tert-butyl carbamate

[0445] 1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)methylcyclopropane-1-amine (500 mg, 1.9 mmol) and di-tert-butyl dicarbonate (610 mg, 2.8 mmol) were dissolved in dichloromethane (10 mL), and triethylamine (384 mg, 3.8 mmol) was added. The reaction mixture was reacted at room temperature for 3 hours. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to give the title compound (180 mg, yellow oil), yield: 26%. MS (ESI): m / z 368.2 [M+H] + .

[0446] (4) 1-((1H-pyrazol-5-yl)methyl)cyclopropane-1-amine

[0447] (1-(1-(1-(((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5-yl)methyl ester)cyclopropyl)tert-butyl carbamate (160 mg, 0.44 mmol) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (3 mL) was added. The reaction mixture was reacted at room temperature for 3 hours. The reaction solution was concentrated to give the title compound (60 mg, crude product). MS (ESI): m / z 138.2 [M+H] + .

[0448] (5) 4'-spiro[cyclopropane-1,5'-pyrazolo[1,5-c]pyrimidine]-7'(6'H)-one

[0449] 1-((1H-pyrazol-5-yl)methyl)cyclopropane-1-amine (60 mg, 0.44 mmol) and 1,8-diazabispyrocyclo[5.4.0]undecyl-7-ene (133 mg, 0.88 mmol) were dissolved in acetonitrile (5 mL), and N,N'-carbonyldiimidazole (142 mg, 0.88 mmol) was added. The reaction mixture was reacted overnight at room temperature. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to give the title compound (30 mg, yellow oil), yield: 42%. MS (ESI): m / z 164.1 [M+H] + .

[0450] (6) 6'-(4-bromophenyl)-4'H-spiro[cyclopropane-1,5'-pyrazolo[1,5-c]pyrimidine]-7'(6'H)-one

[0451] 4'-spiro[cyclopropane-1,5'-pyrazolo[1,5-c]pyrimidine]-7'(6'H)-one (30 mg, 0.18 mmol) and 1-bromo-4-iodobenzene (102 mg, 0.36 mmol) were dissolved in N,N-dimethylformamide (5 mL), and 8-hydroxyquinoline (10 mg, 0.07 mmol), cuprous iodide (7 mg, 0.035 mmol), and potassium carbonate (50 mg, 0.36 mmol) were added. The mixture was microwaved at 140 °C for 6 hours. Water (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (10 mL x 3). The organic phases were combined, filtered, concentrated, and the residue was purified by silica gel column chromatography (100% ethyl acetate) to give the title compound (8 mg, yellow solid), yield: 14%. MS (ESI): m / z 318.0 [M+H] + .

[0452] (7) 3-(2-chloro-4'-(7'-oxo-4'H-spiro[cyclopropane-1,5'-pyrazolo[1,5-c]pyrimidin]-6'(7'H)-yl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0453] 6'-(4-bromophenyl)-4'H-spiro[cyclopropane-1,5'-pyrazolo[1,5-c]pyrimidine]-7'(6'H)-one (8 mg, 0.025 mmol), intermediate 3 (17 mg, 0.05 mmol), PdCl2 (dppf) (2 mg, 0.0025 mmol), and potassium phosphate (11 mg, 0.05 mmol) were dissolved in 1,4-dioxane / water (5 mL / 1 mL). The reaction mixture was heated to 90 °C and stirred for 4 hours under nitrogen protection. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (100% ethyl acetate) to obtain a crude product, which was then purified by Prep-HPLC to obtain the title compound (1.2 mg, white solid), yield: 11%. MS (ESI): m / z 461.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.93(s,1H),7.78(d,J=1.2Hz,1H),7.51-7.36(m,8H),4.37(dd,J=12.0,4.8Hz,1H),3.27(s,2H) ,2.85-2.76(m,1H),2.54-2.51(m,1H),2.39-2.31(m,1H),2.03-1.97(m,1H),0.85(t,J=6.4Hz,2H),0.69(t,J=6.0Hz,2H).

[0454] Example 25

[0455] 3-(2-chloro-3'-fluoro-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

[0456] (1) 5'-(4-chloro-2-fluorophenyl)-7',7a'-dihydrospiro[cyclopropane-1,6'-pyrrolo[3,2-c]pyridine]-4'(5'H)-one

[0457] 7'-spiro[cyclopropane-1,6'-pyrazolo[1,5-a]pyrazine]-4'(5'H)-one (200 mg, 1.23 mmol, Step 3 of Example 2) and 4-chloro-2-fluoro-1-iodobenzene (629 mg, 2.45 mmol) were dissolved in N,N-dimethylformamide (5 mL), and 8-hydroxyquinoline (71 mg, 0.49 mmol), cuprous iodide (47 mg, 0.25 mmol), and potassium carbonate (339 mg, 2.45 mmol) were added. The mixture was microwaved at 140 °C for 6 hours. Water (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 3) to give the title compound (140 mg, gray solid), yield: 39.1%. MS(ESI): m / z 292.1 [M+H] + .

[0458] (2) 3-(2-chloro-3'-fluoro-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

[0459] 5'-(4-chloro-2-fluorophenyl)-7',7a'-dihydrospiro[cyclopropane-1,6'-pyrrolo[3,2-c]pyridine]-4'(5'H)-one (60 mg, 0.21 mmol), cyclopropylboronic acid (3 mg, 0.035 mmol), tricyclohexylphosphine (23 mg, 0.08 mmol), tris(dibenzylacetone)dipalladium (38 mg, 0.04 mmol), and potassium phosphate (109 mg, 41 mmol) were dissolved in 1,4-dioxane / water (5 mL / 0.5 mL). The mixture was reacted at 110 °C for 1 hour under nitrogen protection. Intermediate 3 (86 mg, 0.25 mmol) was then added, and the reaction continued for 48 hours. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (100% ethyl acetate) to obtain a crude product. This crude product was then purified by Prep-HPLC to obtain the title compound (4.9 mg, white solid), yield: 5%. MS(ESI): m / z 479.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.94(s,1H),7.68(d,J=2.0Hz,1H),7.56-7.31(m,7H),6.95(d,J=2.0Hz,1H),4.66-4.45(m,2H),4.41- 4.30(m,1H),2.86-2.76(m,1H),2.59-2.56(m,1H),2.39-2.34(m,1H),2.09-2.01(m,1H),1.16-1.00(m,2H),0.92-0.59(m,2H).

[0460] Example 26

[0461] 1-(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)dihydropyrimidine-2,4(1H,3H)-dione

[0462] (1) 1-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)dihydropyrimidin-2,4(1H,3H)-dione

[0463] 1-(3-bromo-2-chlorophenyl)dihydropyrimidine-2,4(1H,3H)-dione (200 mg, 0.66 mmol, Step 2 of Example 4), pinacol diboronate (201 mg, 0.79 mmol), PdCl2 (dppf) (48 mg, 0.066 mmol), and potassium acetate (129 mg, 1.32 mmol) were dissolved in 1,4-dioxane (10 mL). The reaction mixture was heated to 90 °C and stirred for 6 hours under nitrogen protection. The reaction solution was concentrated to give the title compound (232 mg, crude product). MS (ESI): m / z 351.1 [M+H] + .

[0464] (2) 1-(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)dihydropyrimidin-2,4(1H,3H)-dione

[0465] 1-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione (66 mg, 0.19 mmol), 5'-(4-bromophenyl)-7'H-spiro[cyclopropane-1,6'-pyrazolo[1,5-a]pyrazine]-4'(5'H)-one (50 mg, 0.16 mmol, Step 4 of Example 2), PdCl2 (dppf) (12 mg, 0.016 mmol), and potassium phosphate (68 mg, 0.32 mmol) were dissolved in 1,4-dioxane / water (5 mL / 1 mL). The mixture was heated to 90 °C and stirred for 4 hours under nitrogen protection. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (100% ethyl acetate) to obtain a crude product, which was then purified by Prep-HPLC to give the title compound (25.2 mg, white solid), yield: 35%. MS (ESI): m / z 462.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.49(s,1H),7.65(d,J=2.0Hz,1H),7.56-7.45(m,5H),7.41-7.39(m,2H),6.90(d,J=2.0Hz,1 H),4.57(s,2H),3.80-3.74(m,1H),3.69-3.32(m,1H),2.78-2.74(m,2H),1.04(t,J=6.4Hz,2H),0.75(t,J=6.4Hz,2H).

[0466] Example 27

[0467] 1-(2-chloro-4'-(cyclopropyl(pyrimidin-2-yl)amino)-[1,1'-biphenyl]-3-yl)dihydropyrimidin-2,4(1H,3H)-dione

[0468] N-(4-bromophenyl)-N-cyclopropylpyrimidin-2-amine (50 mg, 0.17 mmol, Step 2 of Example 17), 1-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)phenyl)dihydropyrimidin-2,4(1H,3H)-dione (60 mg, 0.17 mmol, Step 1 of Example 26), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (13 mg, 0.02 mmol), and potassium carbonate (60 mg, 0.43 mmol) were dissolved in 1,4-dioxane / water (5 mL / 0.5 mL), and the mixture was stirred at 80 °C under nitrogen protection for 16 hours. Water (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (10 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 40 / 60) to give a crude product, which was then purified by Prep-HPLC to give the title compound (7.6 mg, white solid), yield: 10%. MS (ESI): m / z 434.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.49(s,1H),8.43(d,J=4.8Hz,2H),7.54-7.45(m,5H),7.38-7.36(m,2H),6.83(t,J=4.8Hz,1 H),3.77-3.74(m,1H),3.68-3.65(m,1H),3.21-3.17(m,1H),2.78-2.75(m,2H),0.92-0.90(m,2H),0.51-0.49(m,2H).

[0469] Example 28

[0470] 1-(2-chloro-4'-((cyclopropyl(methyl)(oxo)-λ) 6 -sulfonyl)amino)-[1,1'-biphenyl]-3-yl)dihydropyrimidin-2,4(1H,3H)-dione

[0471] 1-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione (50 mg, 0.14 mmol, Example 26, Step 1), ((4-bromophenyl)imino)(cyclopropyl)(methyl)-λ 6 Sulfamethoxazole (38 mg, 0.14 mmol, Example 11, Step 1), PdCl2 (dppf) (10 mg, 0.014 mmol), and potassium phosphate (59 mg, 0.28 mmol) were dissolved in 1,4-dioxane / water (5 mL / 1 mL). The mixture was heated to 90 °C and stirred for 4 hours under nitrogen protection. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (100% ethyl acetate) to obtain a crude product, which was then purified by Prep-HPLC to obtain the title compound (20 mg, white solid), yield: 34%. MS (ESI): m / z 418.0 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ10.46(s,1H),7.47-7.42(m,2H),7.38-7.35(m,1H),7.27-7.24(m,2H),7.02-7.00(m,2 H),3.77-3.71(m,1H),3.67-3.61(m,1H),3.23(s,3H),2.89-2.83(m,1H),2.76-2.73(m,2H),1.23-1.00(m,4H).

[0472] Example 29

[0473] 3-(2-chloro-4'-(cyclopropyl(5-methylpyrimidin-2-yl)amino)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0474] (1) N-(4-bromophenyl)-5-methylpyrimidin-2-amine

[0475] 1-Bromo-4-iodobenzene (300 mg, 1.06 mmol) and 5-methylpyrimidin-2-amine (116 mg, 1.06 mmol) were dissolved in 1,4-dioxane (10 mL), and 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (123 mg, 0.21 mmol), tris(dibenzylacetone)dipalladium (97 mg, 0.11 mmol), and cesium carbonate (864 mg, 2.65 mmol) were added. The mixture was stirred overnight at 90 °C under nitrogen protection. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 70 / 30) to give the title compound (220 mg, yellow solid), yield: 78.6%. MS (ESI): m / z 264.0 [M+H] + .

[0476] (2) N-(4-bromophenyl)-N-cyclopropyl-5-methylpyrimidin-2-amine

[0477] N-(4-bromophenyl)-5-methylpyrimidin-2-amine (220 mg, 0.83 mmol) and cyclopropylboronic acid (143 mg, 1.67 mmol) were dissolved in dichloroethane (5 mL). 2,2'-bipyridine (130 mg, 0.83 mmol), copper acetate (151 mg, 0.83 mmol), and potassium carbonate (230 mg, 1.67 mmol) were added, and the mixture was stirred overnight at 80 °C under an oxygen bulb. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 80 / 20) to give the title compound (110 mg, pale yellow solid), yield: 21.7%. MS (ESI): m / z 304.1 [M+H] + .

[0478] (3) 3-(2-chloro-4'-(cyclopropyl(5-methylpyrimidin-2-yl)amino)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0479] N-(4-bromophenyl)-N-cyclopropyl-5-methylpyrimidin-2-amine (110 mg, 0.36 mmol), intermediate 3 (126 mg, 0.36 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (26 mg, 0.036 mmol), and potassium phosphate (190 mg, 0.9 mmol) were dissolved in 1,4-dioxane / water (5 mL / 0.5 mL) and reacted overnight at 90 °C under nitrogen protection. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 40 / 60) to obtain a crude product, which was then purified by Prep-HPLC to give the title compound (17.8 mg, white solid), yield: 22%. MS (ESI): m / z 447.1 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ10.93(s,1H),8.29(s,2H),7.45-7.30(m,7H),4.36(dd,J=12.0,4.8Hz,1H),3.19-3.09(m,1H),2.8 6-2.74(m,1H),2.62-2.55(m,1H),2.41-2.29(m,1H),2.13(s,3H),2.09-2.01(m,1H),0.98-0.83(m,2H),0.55-0.42(m,2H).

[0480] Example 30

[0481] 3-(2-chloro-4'-(cyclopropyl(5-methoxypyrimidin-2-yl)amino)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0482] (1) N-(4-bromophenyl)-5-methoxypyrimidine-2-amine

[0483] 1-Bromo-4-iodobenzene (300 mg, 1.06 mmol) and 5-methoxypyrimidin-2-amine (133 mg, 1.06 mmol) were dissolved in 1,4-dioxane (10 mL), and 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (123 mg, 0.21 mmol), tris(dibenzylacetone)dipalladium (97 mg, 0.11 mmol), and cesium carbonate (864 mg, 2.65 mmol) were added. The mixture was stirred overnight at 90 °C under nitrogen protection. The reaction solution was concentrated, and the residue was purified by column chromatography (petroleum ether / ethyl acetate = 70 / 30) to give the title compound (210 mg, yellow solid), yield: 70.7%. MS (ESI): m / z 280.0 [M+H] + .

[0484] (2) N-(4-bromophenyl)-N-cyclopropyl-5-methoxypyrimidin-2-amine

[0485] N-(4-bromophenyl)-5-methoxypyrimidin-2-amine (210 mg, 0.75 mmol) and cyclopropylboronic acid (129 mg, 1.5 mmol) were dissolved in N,N-dimethylformamide (5 mL), and 2,2'-bipyridine (117 mg, 0.75 mmol), copper acetate (136 mg, 0.75 mmol), and potassium carbonate (207 mg, 1.5 mmol) were added. The mixture was stirred overnight at 120 °C under an oxygen bulb. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 80 / 20) to give the title compound (120 mg, pale yellow solid), yield: 20%. MS (ESI): m / z 320.0 [M+H] + .

[0486] (3) 3-(2-chloro-4'-(cyclopropyl(5-methoxypyrimidin-2-yl)amino)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0487] N-(4-bromophenyl)-N-cyclopropyl-5-methoxypyrimidin-2-amine (120 mg, 0.37 mmol), intermediate 3 (131 mg, 0.37 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (27 mg, 0.037 mmol), and potassium phosphate (199 mg, 0.94 mmol) were dissolved in 1,4-dioxane / water (5 mL / 0.5 mL) and reacted overnight at 90 °C under nitrogen protection. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 40 / 60) to obtain a crude product, which was then purified by Prep-HPLC to give the title compound (29.1 mg, white solid), yield: 42%. MS (ESI): m / z 463.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.93(s,1H),8.29(s,2H),7.50-7.27(m,7H),4.36(dd,J=12.0,4.8Hz,1H),3.80(s,3H),3.16-3.0 6(m,1H),2.85-2.75(m,1H),2.62-2.55(m,1H),2.41-2.29(m,1H),2.10-2.02(m,1H),0.98-0.85(m,2H),0.60-0.44(m,2H).

[0488] Example 31

[0489] 3-(2-chloro-4'-(cyclopropyl(pyrimidin-2-yl)amino)-3'-fluoro-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0490] (1) N-(4-bromo-2-fluorophenyl)pyrimidin-2-amine

[0491] 4-Bromo-2-fluoro-1-iodobenzene (300 mg, 1 mmol), pyrimidin-2-amine (95 mg, 1 mmol), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (116 mg, 0.2 mmol), tris(dibenzylacetone)dipalladium (92 mg, 0.1 mmol), and cesium carbonate (815 mg, 2.5 mmol) were dissolved in 1,4-dioxane (10 mL), and the mixture was purged with nitrogen and stirred overnight at 90 °C under nitrogen protection. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 95 / 5) to give the title compound (210 mg, yellow solid), yield: 78%. MS (ESI): m / z 268.0 [M+H] + .

[0492] (2) N-(4-bromo-2-fluorophenyl)-N-cyclopropylpyrimidin-2-amine

[0493] N-(4-bromo-2-fluorophenyl)pyrimidin-2-amine (210 mg, 0.78 mmol) and cyclopropylboronic acid (135 mg, 1.57 mmol) were dissolved in 1,2-dichloroethane (5 mL). 2,2'-bipyridine (122 mg, 0.78 mmol), copper acetate (142 mg, 0.78 mmol), and potassium carbonate (217 mg, 1.57 mmol) were added, and the mixture was stirred at 80 °C for 22 hours under oxygen bulb conditions. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 95 / 5) to give the title compound (60 mg, white solid), yield: 25%. MS (ESI): m / z 308.0 [M+H] + .

[0494] (3) 3-(2-chloro-4'-(cyclopropyl(pyrimidin-2-yl)amino)-3'-fluoro-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0495] N-(4-bromo-2-fluorophenyl)-N-cyclopropylpyrimidin-2-amine (60 mg, 0.19 mmol), intermediate 3 (68 mg, 0.19 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (14 mg, 0.02 mmol), and potassium carbonate (67 mg, 0.49 mmol) were dissolved in 1,4-dioxane / water (5 mL / 0.5 mL). The mixture was stirred at 80 °C under nitrogen protection for 16 hours. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20 / 80) to obtain a crude product, which was then purified by Prep-HPLC to give the title compound (44.5 mg, white solid), yield: 51%. MS (ESI): m / z 451.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.94 (s, 1H), 8.45 (d, J = 4.8Hz, 2H), 7.46-7.39 (m, 4H ),7.35(d,J=11.2Hz,1H),7.29(d,J=8.0Hz,1H),6.85(t,J=4.4Hz,1H),4.38(d d,J=12.0,4.8Hz,1H),3.22-3.19(m,1H),2.84-2.77(m,1H),2.58-2.54(m,1H ),2.37-2.29(m,1H),2.09-2.05(m,1H),0.91-0.86(m,2H),0.54-0.50(m,2H).

[0496] Example 32

[0497] 3-(2-chloro-3'-methyl-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

[0498] Following the synthetic method of Example 25, the first step involved replacing 4-chloro-2-fluoro-1-iodobenzene with 4-chloro-1-iodo-2-methylbenzene, and a similar synthetic procedure yielded the title compound (6.5 mg, white solid). MS (ESI): m / z 475.1 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ10.92(s,1H),7.66(s,1H),7.42-7.23(m,6H),6.91(s,1H),4.78(d,J=13.6Hz,1H),4.38-4.35(m,2H),2.82-2.7 7(m,1H),2.61-2.57(m,1H),2.36-2.33(m,1H),2.26(s,3H),2.11-2.04(m,1H),1.03-0.99(m,2H),0.88-0.85(m,1H),0.51-0.48(m,1H).

[0499] Example 33

[0500] 3-(2-chloro-4'-((2,2-difluoroethyl)(1-methyl-1H-1,2,4-triazol-3-yl)amino)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0501] Following the synthetic method of Example 19, in the first step, N-(4-bromophenyl)-1-methyl-1H-1,2,4-triazol-3-amine was replaced with N-(4-bromophenyl)-1-methyl-1H-pyrazole-3-amine (step 1 of Example 22). A similar synthetic procedure yielded the title compound (29.0 mg, white solid). MS (ESI): m / z 460.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.92(s,1H),8.25(s,1H),7.50-7.48(m,2H),7.41-7.31(m,5H),6.34(tt,J=56.0,4.4Hz ,1H),4.37-4.28(m,3H),3.77(s,3H),2.84-2.75(m,1H),2.58-2.56(m,1H),2.36-2.30(m,1H),2.10-2.02(m,1H).

[0502] Example 34

[0503] 3-(2-chloro-4'-((2,2-difluoroethyl)(pyrimidin-2-yl)amino)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0504] (1) N-(4-bromophenyl)-N-(2,2-difluoroethyl)pyrimidin-2-amine

[0505] N-(4-bromophenyl)pyrimidin-2-amine (200 mg, 0.8 mmol, Step 1, Example 17) and 1,1-difluoro-2-iodoethane (307 mg, 1.6 mmol) were dissolved in N,N-dimethylformamide (8 mL), and cesium carbonate (521 mg, 1.6 mmol) was added. The mixture was reacted in a sealed tube at 130 °C for 16 hours. The reaction mixture was poured into water (50 mL) and extracted with ethyl acetate (2 x 20 mL). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 80 / 20) to give the title compound (75 mg, pale yellow solid), yield: 30%. MS (ESI): m / z 314.0 [M+H] + .

[0506] (2) 3-(2-chloro-4'-((2,2-difluoroethyl)(pyrimidin-2-yl)amino)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0507] N-(4-bromophenyl)-N-(2,2-difluoroethyl)pyrimidin-2-amine (75 mg, 0.24 mmol), intermediate 3 (84 mg, 0.24 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (18 mg, 0.024 mmol), and potassium phosphate (127 mg, 0.6 mmol) were dissolved in 1,4-dioxane / water (5 mL / 0.5 mL), and the reaction was carried out at 90 °C for 5 hours under nitrogen protection. The reaction solution was concentrated, and the residue was subjected to silica gel column chromatography (petroleum ether / ethyl acetate = 40 / 60) to obtain a crude product, which was then purified by Prep-HPLC to give the title compound (36.6 mg, white solid), yield: 33.54%. MS (ESI): m / z 457.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.93(s,1H),8.45(d,J=4.8Hz,2H),7.57-7.32(m,7H),6.87(t,J=4.8Hz,1H),6.38(tt,J =56.4,4.0Hz,1H),4.52-4.27(m,3H),2.87-2.74(m,1H),2.61-2.56(m,1H),2.38-2.26(m,1H),2.17-1.97(m,1H).

[0508] Example 35

[0509] 3-(2-chloro-4'-(cyclobutyl(1-methyl-1H-1,2,4-triazol-3-yl)amino)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0510] (1) N-(4-bromophenyl)-N-cyclobutyl-1-methyl-1H-1,2,4-triazol-3-amine

[0511] N-(4-bromophenyl)-1-methyl-1H-1,2,4-triazol-3-amine (100 mg, 0.40 mmol, Step 1 of Example 22) was dissolved in N,N-dimethylformamide (5 mL). Sodium hydride (32 mg, 0.79 mmol) was added at 0 °C and the mixture was stirred for 0.5 h. Then, bromocyclobutane (107 mg, 0.79 mmol) was added, and the mixture was stirred at 70 °C for 16 h. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (30 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 95 / 5) to give the title compound (90 mg, colorless oil), yield: 74%. MS (ESI): m / z 307.0 [M+H] + .

[0512] (2) 3-(2-chloro-4'-(cyclobutyl(1-methyl-1H-1,2,4-triazol-3-yl)amino)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0513] N-(4-bromophenyl)-N-cyclobutyl-1-methyl-1H-1,2,4-triazol-3-amine (50 mg, 0.16 mmol), intermediate 3 (57 mg, 0.16 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (15 mg, 0.02 mmol), and potassium carbonate (57 mg, 0.41 mmol) were dissolved in 1,4-dioxane / water (5 mL / 0.5 mL). The mixture was stirred at 90 °C under nitrogen protection for 16 hours. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 92 / 8) to obtain a crude product, which was then purified by Prep-HPLC to obtain the title compound (25.4 mg, white solid), yield: 35%. MS (ESI): m / z 450.1 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ10.91(s,1H),8.24(s,1H),7.42-7.28(m,5H),7.02(d,J=8.4Hz,2H),4.49-4.43(m,1H),4.34(dd,J=1 2.1,4.9Hz,1H),3.77(s,3H),2.84-2.73(m,1H),2.56-2.53(m,1H),2.39-2.21(m,3H),2.10-1.87(m,3H),1.70-1.55(m,2H).

[0514] Example 36

[0515] 3-(2-chloro-3',5'-dimethyl-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

[0516] (1) 5'-(2,6-dimethyl-4-nitrophenyl)-7'H-spiro[cyclopropane-1,6'-pyrazolo[1,5-a]pyrazine]-4'(5'H)-one

[0517] 7'-spiro[cyclopropane-1,6'-pyrazolo[1,5-a]pyrazine]-4'(5'H)-one (800 mg, 4.9 mmol, Step 3 of Example 2) and 2-fluoro-1,3-dimethyl-5-nitrobenzene (1.66 g, 9.8 mmol) were dissolved in N,N-dimethylformamide (10 mL), and cesium carbonate (3.19 g, 9.8 mmol) was added. The mixture was stirred at 120 °C for 3 days. Water (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (15 mL x 3). The organic phases were combined and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 50 / 50) to give the title compound (800 mg, yellow solid), yield: 52%. MS (ESI): m / z 313.1 [M+H] + .

[0518] (2) 5'-(4-amino-2,6-dimethylphenyl)-7'H-spiro[cyclopropane-1,6'-pyrazolo[1,5-a]pyrazine]-4'(5'H)-one

[0519] 5'-(2,6-dimethyl-4-nitrophenyl)-7'H-spiro[cyclopropane-1,6'-pyrazolo[1,5-a]pyrazine]-4'(5'H)-one (400 mg, 1.28 mmol) and iron powder (286 mg, 5.1 mmol) were dissolved in ethanol / water (10 mL / 2 mL), and ammonium chloride (275 mg, 5.1 mmol) was added. The mixture was stirred at 80 °C for 1 hour. The reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to give the title compound (280 mg, yellow solid), yield: 78%. MS (ESI): m / z 283.2 [M+H] + .

[0520] (3) 5'-(4-bromo-2,6-dimethylphenyl)-7'H-spiro[cyclopropane-1,6'-pyrazolo[1,5-a]pyrazine]-4'(5'H)-one

[0521] 5'-(4-amino-2,6-dimethylphenyl)-7'H-spiro[cyclopropane-1,6'-pyrazolo[1,5-a]pyrazine]-4'(5'H)-one (280 mg, 1 mmol) and cuprous bromide (143 mg, 1 mmol) were dissolved in acetonitrile (10 mL), and tert-butyl nitrite (103 mg, 1 mmol) was added dropwise at 0 °C. The mixture was stirred at room temperature for 5 hours. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 50 / 50) to give the title compound (80 mg, yellow solid), yield: 23%. MS (ESI): m / z 346.0 [M+H] + .

[0522] (4) 3-(2-chloro-3',5'-dimethyl-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

[0523] 5'-(4-bromo-2,6-dimethylphenyl)-7'H-spiro[cyclopropane-1,6'-pyrazolo[1,5-a]pyrazine]-4'(5'H)-one (30 mg, 0.08 mmol), intermediate 3 (56 mg, 0.16 mmol), PdCl2 (dppf) (6 mg, 0.008 mmol), and potassium phosphate (34 mg, 0.16 mmol) were dissolved in 1,4-dioxane / water (5 mL / 1 mL). The reaction mixture was heated to 90 °C and stirred for 4 hours under nitrogen protection. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (100% ethyl acetate) to obtain a crude product, which was then purified by Prep-HPLC to obtain the title compound (7.8 mg, white solid), yield: 20%. MS (ESI): m / z 489.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.92 (s, 1H), 7.67 (d, J = 2.0Hz, 1H), 7.44-7.29 (m, 3H),7.20(s,2H),6.94(d,J=2.0Hz,1H),4.58(s,2H),4.35(dd,J=12.2,5.0H z,1H),2.79(dd,J=10.8,6.4Hz,1H),2.57-2.56(m,1H),2.40-2.30(m,1H),2 .21(s,6H),2.12-2.01(m,1H),1.05(t,J=6.4Hz,2H),0.64(t,J=6.4Hz,2H).

[0524] Example 37

[0525] 3-(2-chloro-3',5'-difluoro-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

[0526] Following the synthetic method of Example 36, the first step involved replacing 2-fluoro-1,3-dimethyl-5-nitrobenzene with 1,2,3-trifluoro-5-nitrobenzene, and a similar synthetic procedure yielded the title compound (20.9 mg, white solid). MS (ESI): m / z 497.1 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ10.94(s,1H),7.70(d,J=2.0Hz,1H),7.53-7.35(m,5H),7.00(d,J=2.0Hz,1H),4.58(s,2H),4.38(dd,J=12 .0,4.8Hz,1H),2.89-2.72(m,1H),2.60-2.54(m,1H),2.40-2.29(m,1H),2.12-1.99(m,1H),1.19-1.09(m,2H),0.82-0.69(m,2H).

[0527] Example 38

[0528] 3-(2-chloro-4'-(cyclobutyl(pyrimidin-2-yl)amino)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0529] (1) 4-Bromo-N-cyclobutylaniline

[0530] p-Bromoaniline (1 g, 5.8 mmol) was dissolved in methanol (20 mL), and glacial acetic acid (2 mL), cyclobutanone (0.81 g, 11.6 mmol), and sodium cyanoborohydride (0.73 g, 11.6 mmol) were added. The mixture was reacted overnight at room temperature. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 95 / 5) to give the title compound (600 mg, pale yellow oil), yield: 46.55%. MS (ESI): m / z 226.0 [M+H] + .

[0531] (2) N-(4-bromophenyl)-N-cyclobutylpyrimidin-2-amine

[0532] 4-Bromo-N-cyclobutylaniline (592 mg, 2.62 mmol) was dissolved in 1,4-dioxane (6 mL), and glacial acetic acid (2 mL) and 2-chloropyrimidine (200 mg, 1.75 mmol) were added. The mixture was refluxed at 110 °C for 16 hours. The reaction solution was poured into water (50 mL) and extracted with ethyl acetate (2 x 20 mL). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 90 / 10) to give the title compound (200 mg, white solid), yield: 37.65%. MS (ESI): m / z 304.1 [M+H] + .

[0533] (3) 3-(2-chloro-4'-(cyclobutyl(pyrimidin-2-yl)amino)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0534] N-(4-bromophenyl)-N-cyclobutylpyrimidin-2-amine (50 mg, 0.164 mmol), intermediate 3 (69 mg, 0.2 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (12 mg, 0.016 mmol), and potassium phosphate (70 mg, 0.33 mmol) were dissolved in 1,4-dioxane / water (5 mL / 0.5 mL), and the reaction was carried out at 90 °C for 5 hours under nitrogen protection. The reaction solution was concentrated, and the residue was subjected to silica gel column chromatography (petroleum ether / ethyl acetate = 40 / 60) to obtain a crude product, which was then purified by Prep-HPLC to give the title compound (25.7 mg, white solid), yield: 34.7%. MS (ESI): m / z 447.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.94(s,1H),8.35(d,J=4.8Hz,2H),7.49(d,J=8.4Hz,2H) ,7.47-7.35(m,3H),7.22(d,J=8.4Hz,2H),6.71(t,J=4.8Hz,1H),5.11-5.00(m,1H ),4.38(dd,J=12.0,4.8Hz,1H),2.87-2.75(m,1H),2.61-2.55(m,1H),2.41-2.30( m,1H),2.26-2.16(m,2H),2.14-2.03(m,1H),1.88-1.74(m,2H),1.70-1.48(m,2H).

[0535] Example 39

[0536] 3-(2-chloro-4'-(((3,3-difluorocyclobutyl)(methyl)(oxo)-λ 6 -sulfonyl)amino)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0537] Following the synthetic method of Example 23, the first step involved replacing bromocyclobutane with 3-bromo-1,1-difluorocyclobutane, and a similar synthetic procedure yielded the title compound (11.4 mg, white solid). MS (ESI): m / z 467.1 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ10.91(s,1H),7.39-7.24(m,5H),7.03(d,J=8.2Hz,2H),4.33(d,J=7.6Hz,1H),4.26-4.17( m,1H),3.19(s,3H),3.09-3.02(m,4H),2.83-2.75(m,1H),2.59-2.56(m,1H),2.37-2.28(m,1H),2.06-1.99(m,1H).

[0538] Example 40

[0539] 3-(2-chloro-4'-(3,3-difluoro-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

[0540] (1) methyl methanesulfonate (1-((tert-butoxycarbonyl)amino)-3,3-difluorocyclobutyl)methanesulfonate

[0541] (3,3-Difluoro-1-(hydroxymethyl)cyclobutyl)carbamate tert-butyl ester (600 mg, 4.3 mmol) and triethylamine (864 mg, 4.3 mmol) were dissolved in dichloromethane (15 mL), and methanesulfonyl chloride (1.3 g, 6.5 mmol) was added. The mixture was reacted at room temperature for 3 hours. Water (10 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (10 mL x 3). The organic phases were combined and concentrated to give the title compound (797 mg, white solid). MS (ESI): m / z 338.1 [M+Na] + .

[0542] (2) Ethyl 1-((1-((tert-butoxycarbonyl)amino)-3,3-difluorocyclobutyl)methyl)-1H-pyrazole-5-carboxylic acid ester

[0543] Methyl (1-((tert-Butoxycarbonyl)amino)-3,3-difluorocyclobutyl)methanesulfonate (800 mg, 2.5 mmol) and ethyl 1H-pyrazole-3-carboxylate (420 mg, 3 mmol) were dissolved in N,N-dimethylformamide (15 mL), and cesium carbonate (1.2 g, 3.7 mmol) was added. The mixture was reacted at 50 °C for 5 hours. Water (10 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (10 mL x 3). The organic phases were combined, concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to give the title compound (600 mg, white solid), yield: 67%. MS (ESI): m / z 360.1 [M+H] + .

[0544] (3) Ethyl 1-((1-amino-3,3-difluorocyclobutyl)methyl)-1H-pyrazole-5-carboxylic acid ester

[0545] Ethyl 1-((1-((tert-Butoxycarbonyl)amino)-3,3-difluorocyclobutyl)methyl)-1H-pyrazole-5-carboxylic acid (600 mg, 1.67 mmol) was dissolved in dichloromethane (10 mL), and trifluoroacetic acid (5 mL) was added. The reaction was carried out at room temperature for 2 hours. The reaction solution was concentrated to give the title compound (433 mg, crude product).

[0546] (4) 3,3-Difluoro-7'H-spiro[cyclobutane-1,6'-pyrazolo[1,5-a]pyrazine]-4'(5'H)-one

[0547] Ethyl 1-((1-amino-3,3-difluorocyclobutyl)methyl)-1H-pyrazole-5-carboxylate (430 mg, 1.66 mmol) and sodium hydroxide (266 mg, 6.6 mmol) were dissolved in methanol / water (10 mL / 2 mL) and reacted overnight at room temperature. Water (10 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (10 mL x 3). The organic phases were combined, concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 9) to give the title compound (340 mg, white solid), yield: 96%. MS (ESI): m / z 214.2 [M+H] + .

[0548] (5) 5'-(4-bromophenyl)-3,3-difluoro-7'H-spiro[cyclobutane-1,6'-pyrazolo[1,5-a]pyrazine]-4'(5'H)-one

[0549] 3,3-Difluoro-7'H-spiro[cyclobutane-1,6'-pyrazolo[1,5-a]pyrazine]-4'(5'H)-one (150 mg, 0.7 mmol) and 1-bromo-4-iodobenzene (398 mg, 1.4 mmol) were dissolved in N,N-dimethylformamide (5 mL), and 8-hydroxyquinoline (40 mg, 0.28 mmol), cuprous iodide (27 mg, 0.14 mmol), and potassium carbonate (193 mg, 1.4 mmol) were added. The mixture was microwaved at 140 °C for 6 hours. Water (10 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (10 mL x 3). The organic phases were combined, concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give the title compound (50 mg, yellow solid), yield: 19%. MS (ESI): m / z 368.1 [M+H] + .

[0550] (6) 3-(2-chloro-4'-(3,3-difluoro-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

[0551] 5'-(4-bromophenyl)-3,3-difluoro-7'H-spiro[cyclobutane-1,6'-pyrazolo[1,5-a]pyrazine]-4'(5'H)-one (50 mg, 0.13 mmol), intermediate 3 (45 mg, 0.13 mmol), PdCl2 (dppf) (10 mg, 0.013 mmol), and potassium phosphate (55 mg, 0.26 mmol) were dissolved in 1,4-dioxane / water (5 mL / 1 mL). The reaction mixture was heated to 90 °C and stirred for 4 hours under nitrogen protection. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (100% ethyl acetate) to obtain a crude product, which was then purified by Prep-HPLC to obtain the title compound (23.2 mg, white solid), yield: 35%. MS (ESI): m / z 511.2 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ10.93(s,1H),7.71(s,1H),7.59-7.57(m,2H),7.49-7.45(m,2H),7.43-7.40(m,3H),6.91(s,1H) ,4.74(s,2H),4.37(dd,J=12.2,4.8Hz,1H),2.92-2.81(m,5H),2.58-2.57(m,1H),2.38-2.33(m,1H),2.08-2.01(m,1H).

[0552] Example 41

[0553] 3-(2-chloro-4'-(cyclopropyl(1-(difluoromethyl)-1H-1,2,4-triazol-3-yl)amino)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0554] (1) 1-(difluoromethyl)-3-nitro-1H-1,2,4-triazole

[0555] 3-Nitro-1H-1,2,4-triazole (300 mg, 2.6 mmol) and sodium 2-chloro-2,2-difluoroacetate (400 mg, 9.8 mmol) were dissolved in N,N-dimethylformamide (5 mL), and potassium carbonate (718 mg, 5.2 mmol) was added. The mixture was stirred in a microwave at 120 °C for 3 hours. Water (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (15 mL x 3). The organic phases were combined, concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give the title compound (280 mg, yellow oil), yield: 65%. MS (ESI): m / z 165.0 [M+H] + .

[0556] (2) 1-(difluoromethyl)-1H-1,2,4-triazol-3-amine

[0557] 1-(difluoromethyl)-3-nitro-1H-1,2,4-triazole (200 mg, 1.2 mmol) and iron powder (269 mg, 4.8 mmol) were dissolved in ethanol / water (10 mL / 2 mL), and ammonium chloride (254 mg, 4.8 mmol) was added. The mixture was stirred at 80 °C for 1 hour. The reaction solution was filtered through diatomaceous earth, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give the title compound (100 mg, yellow solid), yield: 63%. MS (ESI): m / z 135.2 [M+H] + .

[0558] (3) N-(4-bromophenyl)-1-(difluoromethyl)-1H-1,2,4-triazol-3-amine

[0559] 1-Bromo-4-iodobenzene (200 mg, 0.72 mmol), 1-(difluoromethyl)-1H-1,2,4-triazol-3-amine (100 mg, 0.72 mmol), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (80 mg, 0.14 mmol), tris(dibenzylacetone)dipalladium (64 mg, 0.07 mmol), and cesium carbonate (456 mg, 1.4 mmol) were dissolved in 1,4-dioxane (10 mL), and the mixture was purged with nitrogen. The reaction mixture was stirred overnight at 90 °C under nitrogen protection. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give the title compound (150 mg, yellow solid), yield: 72%. MS (ESI): m / z 289.1 [M+H] + .

[0560] (4) N-(4-bromophenyl)-N-cyclopropyl-1-(difluoromethyl)-1H-1,2,4-triazol-3-amine

[0561] N-(4-bromophenyl)-1-(difluoromethyl)-1H-1,2,4-triazol-3-amine (70 mg, 0.24 mmol) and cyclopropylboronic acid (41 mg, 0.48 mmol) were dissolved in N,N-dimethylformamide (5 mL). 2,2'-bipyridine (37 mg, 0.24 mmol), copper acetate (44 mg, 0.24 mmol), and potassium carbonate (66 mg, 0.48 mmol) were added. The mixture was heated to 120 °C and stirred overnight under oxygen bulb conditions. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give the title compound (50 mg, yellow oil), yield: 63%. MS (ESI): m / z 329.0 [M+H] + .

[0562] (5) 3-(2-chloro-4'-(cyclopropyl(1-(difluoromethyl)-1H-1,2,4-triazol-3-yl)amino)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0563] N-(4-bromophenyl)-N-cyclopropyl-1-(difluoromethyl)-1H-1,2,4-triazol-3-amine (50 mg, 0.15 mmol), intermediate 3 (80 mg, 0.23 mmol), PdCl2 (dppf) (11 mg, 0.015 mmol), and potassium phosphate (64 mg, 0.3 mmol) were dissolved in 1,4-dioxane / water (5 mL / 1 mL). The mixture was heated to 85 °C and stirred for 4 hours under nitrogen protection. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (100% ethyl acetate) to obtain a crude product, which was then purified by Prep-HPLC to obtain the title compound (4.3 mg, white solid), yield: 6%. MS (ESI): m / z 472.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.92(s,1H),8.84(s,1H),7.83(t,J=58.3Hz,1H),7.51-7.33(m,7H),4.35(dd,J=12.3,4.9Hz,1H),3.09 -3.08(m,1H),2.83-2.75(m,1H),2.57-2.56(m,1H),2.36-2.33(m,1H),2.07-2.03(m,1H),1.01-0.97(m,2H),0.61-0.57(m,2H).

[0564] Example 42

[0565] 3-(2-chloro-4'-(cyclopropyl(1-(2,2-difluoroethyl)-1H-1,2,4-triazol-3-yl)amino)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0566] (1) 1-(2,2-difluoroethyl)-3-nitro-1H-1,2,4-triazole

[0567] 3-Nitro-1H-1,2,4-triazole (800 mg, 7.0 mmol) and 1,1-difluoro-2-iodoethane (1.3 g, 7.0 mmol) were dissolved in N,N-dimethylformamide (5 mL), and cesium carbonate (4.6 g, 14 mmol) was added. The mixture was stirred overnight at 100 °C. Water (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (15 mL x 3). The organic phases were combined, concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give the title compound (400 mg, yellow oil), yield: 33%. MS (ESI): m / z 179.1 [M+H] + .

[0568] (2) 1-(2,2-difluoroethyl)-1H-1,2,4-triazol-3-amine

[0569] 1-(2,2-difluoroethyl)-3-nitro-1H-1,2,4-triazole (600 mg, 3.4 mmol) and iron powder (755 mg, 13 mmol) were dissolved in ethanol / water (10 mL / 2 mL), and ammonium chloride (689 mg, 13 mmol) was added. The mixture was stirred overnight at 80 °C. The reaction solution was filtered through diatomaceous earth, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (100% ethyl acetate) to give the title compound (140 mg, white solid), yield: 28%. MS (ESI): m / z 149.1 [M+H] + .

[0570] (3) N-(4-bromophenyl)-1-(2,2-difluoroethyl)-1H-1,2,4-triazol-3-amine

[0571] 1-Bromo-4-iodobenzene (268 mg, 0.94 mmol), 1-(2,2-difluoroethyl)-1H-1,2,4-triazol-3-amine (140 mg, 0.94 mmol), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (108 mg, 0.19 mmol), tris(dibenzylacetone)dipalladium (86 mg, 0.094 mmol), and cesium carbonate (613 mg, 1.89 mmol) were dissolved in 1,4-dioxane (10 mL), and the mixture was purged with nitrogen. The reaction mixture was stirred overnight at 90 °C under nitrogen protection. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give the title compound (250 mg, yellow solid), yield: 88%. MS (ESI): m / z 303.0 [M+H] + .

[0572] (4) N-(4-bromophenyl)-N-cyclopropyl-1-(2,2-difluoroethyl)-1H-1,2,4-triazol-3-amine

[0573] N-(4-bromophenyl)-1-(2,2-difluoroethyl)-1H-1,2,4-triazol-3-amine (200 mg, 0.66 mmol) and cyclopropylboronic acid (114 mg, 1.32 mmol) were dissolved in N,N-dimethylformamide (5 mL). 2,2'-bipyridine (103 mg, 0.66 mmol), copper acetate (120 mg, 0.66 mmol), and potassium carbonate (182 mg, 1.32 mmol) were added. The mixture was heated to 120 °C and stirred overnight under oxygen bulb conditions. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give a crude product (50 mg, yellow oil), yield: 22%. MS (ESI): m / z 343.0 [M+H] + .

[0574] (5) 3-(2-chloro-4'-(cyclopropyl(1-(2,2-difluoroethyl)-1H-1,2,4-triazol-3-yl)amino)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0575] N-(4-bromophenyl)-N-cyclopropyl-1-(2,2-difluoroethyl)-1H-1,2,4-triazol-3-amine (20 mg, 0.06 mmol), intermediate 3 (42 mg, 0.12 mmol), PdCl2 (dppf) (4.4 mg, 0.006 mmol), and potassium phosphate (25 mg, 0.12 mmol) were dissolved in 1,4-dioxane / water (5 mL / 1 mL). The mixture was heated to 85 °C and stirred for 4 hours under nitrogen protection. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (100% ethyl acetate) to obtain a crude product, which was then purified by Prep-HPLC to obtain the title compound (15.1 mg, white solid), yield: 52%. MS (ESI): m / z 486.1 [M+H] + . 1 ¹H NMR (400MHz, DMSO-d⁶) δ 10.91 (s, 1H), 8.42 (s, 1H), 7.42–7.29 (m, 7H), 6.41 (tt, J = 54.7, 3.6Hz, 1H), 4.68 (td, J = 15.1, 3.6Hz, 2H), 4.34 (dd, J = 12.2, 5.1Hz, 1H), 2.99–2.96 (m, 1H), 2.84–2.75 (m, 1H), 2.56–2.55 (m, 1H), 2.37–2.29 (m, 1H), 2.07–2.03 (m, 1H), 0.98–0.93 (m, 2H), 0.58–0.55 (m, 2H). Example 43

[0576] 3-(2-chloro-4'-(cyclopropyl(1-methyl-1H-1,2,4-triazol-3-yl)amino)-3'-fluoro-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0577] (1) N-(4-bromo-2-fluorophenyl)-1-methyl-1H-1,2,4-triazol-3-amine

[0578] 4-Bromo-2-fluoro-1-iodobenzene (600 mg, 2.0 mmol), 1-methyl-1H-1,2,4-triazol-3-amine (196 mg, 2.0 mmol), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (231 mg, 0.4 mmol), tris(dibenzylacetone)dipalladium (183 mg, 0.2 mmol), and cesium carbonate (1.3 g, 4.0 mmol) were dissolved in 1,4-dioxane (10 mL), and the mixture was purged with nitrogen. The reaction mixture was stirred overnight at 90 °C under nitrogen protection. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (100% ethyl acetate) to give the title compound (500 mg, yellow solid), yield: 93%. MS (ESI): m / z 271.1 [M+H] + .

[0579] (2) N-(4-bromo-2-fluorophenyl)-N-cyclopropyl-1-methyl-1H-1,2,4-triazol-3-amine

[0580] N-(4-bromo-2-fluorophenyl)-1-methyl-1H-1,2,4-triazol-3-amine (250 mg, 0.93 mmol) and cyclopropylboronic acid (159 mg, 1.85 mmol) were dissolved in N,N-dimethylformamide (5 mL). 2,2'-bipyridine (145 mg, 0.93 mmol), copper acetate (169 mg, 0.93 mmol), and potassium carbonate (255 mg, 1.85 mmol) were added. The mixture was heated to 120 °C and stirred overnight under oxygen bulb conditions. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (100% ethyl acetate) to give the title compound (150 mg, yellow oil), yield: 52%. MS (ESI): m / z 311.0 [M+H] + .

[0581] (3) 3-(2-chloro-4'-(cyclopropyl(1-methyl-1H-1,2,4-triazol-3-yl)amino)-3'-fluoro-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0582] N-(4-bromo-2-fluorophenyl)-N-cyclopropyl-1-methyl-1H-1,2,4-triazol-3-amine (60 mg, 0.19 mmol), intermediate 3 (100 mg, 0.29 mmol), PdCl2 (dppf) (14 mg, 0.019 mmol), and potassium phosphate (85 mg, 0.4 mmol) were dissolved in 1,4-dioxane / water (5 mL / 1 mL). The mixture was heated to 85 °C and stirred for 4 hours under nitrogen protection. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (100% ethyl acetate) to obtain a crude product, which was then purified by Prep-HPLC to obtain the title compound (26.9 mg, white solid), yield: 31%. MS (ESI): m / z 454.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.93(s,1H),8.09(s,1H),7.46-7.36(m,4H),7.28-7.22(m,2H),4.36(dd,J=12.1,4.9Hz,1H),3.72(s,3H), 3.03-3.02(m,1H),2.85-2.76(m,1H),2.57-2.56(m,1H),2.36-2.30(m,1H),2.07-2.06(m,1H),0.83-0.79(m,2H),0.62-0.58(m,2H).

[0583] Example 44

[0584] 3-(2-chloro-4'-((5-chloropyrimidin-2-yl)(cyclopropyl)amino)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0585] Following the synthetic method of Example 30, the first step involved replacing 5-methoxypyrimidine-2-amine with 5-chloropyrimidine-2-amine, and a similar synthetic procedure yielded the title compound (28.7 mg, white solid). MS (ESI): m / z 467.0 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.93(s,1H),8.51(s,2H),7.46-7.33(m,7H),4.37(dd,J=12.0,4.8Hz,1H),3.25-3.10(m,1H) ),2.91-2.71(m,1H),2.63-2.53(m,1H),2.35-2.31(m,1H),2.13-2.02(m,1H),0.93-0.89(m,2H),0.54-0.48(m,2H).

[0586] Example 45

[0587] 3-(2-chloro-4'-(cyclopropyl(5-methylpyrimidin-2-yl)amino)-3'-methyl-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0588] (1) N-(4-bromo-2-methylphenyl)-5-methylpyrimidin-2-amine

[0589] 4-Bromo-1-iodo-2-methylbenzene (300 mg, 1.0 mmol) and 5-methylpyrimidin-2-amine (110 mg, 1.0 mmol) were dissolved in 1,4-dioxane (10 mL), and 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (88 mg, 0.15 mmol), tris(dibenzylacetone)dipalladium (69 mg, 0.076 mmol), and cesium carbonate (823 mg, 2.5 mmol) were added. The mixture was stirred overnight at 90 °C under nitrogen protection. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 70 / 30) to give the title compound (240 mg, pale yellow solid), yield: 85.4%. MS (ESI): m / z 278.0 [M+H] + .

[0590] (2) N-(4-bromo-2-methylphenyl)-N-cyclopropyl-5-methylpyrimidin-2-amine

[0591] N-(4-bromo-2-methylphenyl)-5-methylpyrimidin-2-amine (240 mg, 0.86 mmol) and cyclopropylboronic acid (148 mg, 1.73 mmol) were dissolved in N,N-dimethylformamide (10 mL), and 2,2'-bipyridine (135 mg, 0.86 mmol), copper acetate (157 mg, 0.86 mmol), and potassium carbonate (239 mg, 1.73 mmol) were added. The mixture was heated to 120 °C and stirred overnight under an oxygen atmosphere. The reaction mixture was poured into saturated brine (50 mL) and extracted with ethyl acetate (2 x 30 mL). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 75 / 25) to give the title compound (115 mg, pale yellow oil), yield: 41.9%. MS(ESI): m / z 318.1 [M+H] + .

[0592] (3) 3-(2-chloro-4'-(cyclopropyl(5-methylpyrimidin-2-yl)amino)-3'-methyl-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0593] N-(4-bromo-2-methylphenyl)-N-cyclopropyl-5-methylpyrimidin-2-amine (100 mg, 0.314 mmol), intermediate 3 (110 mg, 0.314 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (23 mg, 0.031 mmol), and potassium phosphate (167 mg, 0.79 mmol) were dissolved in 1,4-dioxane / water (5 mL / 0.5 mL), and the reaction was carried out at 90 °C for 6 hours under nitrogen protection. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 40 / 60) to obtain a crude product, which was then purified by Prep-HPLC to obtain the title compound (23.1 mg, white solid), yield: 15.7%. MS (ESI): m / z 461.0 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.93(s,1H),8.26(s,2H),7.43-7.25(m,5H),7.15(d,J=8.0Hz,1H),4.36(dd,J=12.0,4.8Hz,1H),3.22-3.14(m,1H) ,2.85-2.75(m,1H),2.59-2.55(m,1H),2.38-2.30(m,1H),2.11(s,3H) ,2.10-2.06(m,1H),2.04(s,3H),0.86-0.77(m,2H),0.49-0.38(m,2H).

[0594] Example 46

[0595] 3-(2-chloro-4'-(cyclopropyl(5-methoxypyrimidin-2-yl)amino)-3'-methyl-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0596] Following the synthetic method of Example 45, the first step involved replacing 5-methylpyrimidin-2-amine with 5-methoxypyrimidin-2-amine, and a similar synthetic procedure yielded the title compound (15.8 mg, white solid). MS (ESI): m / z 477.1 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ10.93(s,1H),8.24(s,2H),7.43-7.25(m,5H),7.16(d,J=8.0Hz,1H),4.36(dd,J=12.0,4.8Hz,1H),3.78(s,3H),3.20 -3.11(m,1H),2.88-2.74(m,1H),2.59-2.54(m,1H),2.40-2.30(m,1H) ,2.10-2.06(m,1H),2.05(s,3H),0.86-0.77(m,2H),0.50-0.39(m,2H).

[0597] Example 47

[0598] 1-(2-chloro-4'-(cyclopropyl(5-methylpyrimidin-2-yl)amino)-[1,1'-biphenyl]-3-yl)dihydropyrimidin-2,4(1H,3H)-dione

[0599] N-(4-bromophenyl)-N-cyclopropyl-5-methylpyrimidin-2-amine (50 mg, 0.16 mmol, Step 2 of Example 29), 1-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)phenyl)dihydropyrimidin-2,4(1H,3H)-dione (70 mg, 0.2 mmol, Step 1 of Example 26), PdCl2 (dppf) (12 mg, 0.016 mmol), and potassium phosphate (68 mg, 0.32 mmol) were dissolved in 1,4-dioxane / water (5 mL / 1 mL). The mixture was heated to 85 °C and stirred for 4 hours under nitrogen protection. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (100% ethyl acetate) to obtain a crude product, which was then purified by Prep-HPLC to obtain the title compound (23.1 mg, white solid), yield: 32%. MS(ESI): m / z 448.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ10.49(s,1H),8.30(s,2H),7.54-7.35(m,7H),3.80-3.73(m,1H),3.70-3.6 3(m,1H),3.17-3.12(m,1H),2.78-2.74(m,2H),2.13(s,3H),0.94-0.89(m,2H),0.50-0.46(m,2H).

[0600] Example 48

[0601] 1-(2-chloro-4'-(cyclopropyl(5-methoxypyrimidin-2-yl)amino)-[1,1'-biphenyl]-3-yl)dihydropyrimidin-2,4(1H,3H)-dione

[0602] Following the synthetic method of Example 47, N-(4-bromophenyl)-N-cyclopropyl-5-methoxypyrimidin-2-amine was replaced with N-(4-bromophenyl)-N-cyclopropyl-5-methylpyrimidin-2-amine (step 2 of Example 30), and the title compound (31.2 mg, white solid) was obtained through similar synthetic steps. MS (ESI): m / z 464.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ10.49(s,1H),8.29(s,2H),7.53-7.36(m,7H),3.80(s,3H),3.77-3.73(m,1 H),3.69-3.63(m,1H),3.14-3.08(m,1H),2.78-2.74(m,2H),0.94-0.89(m,2H),0.51-0.47(m,2H).

[0603] Example 49

[0604] 1-(2-chloro-4'-(cyclopropyl(1-methyl-1H-1,2,4-triazol-3-yl)amino)-[1,1'-biphenyl]-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

[0605] Following the synthetic method of Example 47, N-(4-bromophenyl)-N-cyclopropyl-1-methyl-1H-1,2,4-triazol-3-amine was substituted with N-(4-bromophenyl)-N-cyclopropyl-5-methylpyrimidin-2-amine (step 2 of Example 22), and the title compound (31.2 mg, white solid) was obtained through similar synthetic steps. MS (ESI): m / z 437.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.47(s,1H),8.31(s,1H),7.48-7.32(m,7H),3.82(s,3H),3.78-3.72(m,1 H),3.68-3.62(m,1H),2.96-2.91(m,1H),2.78-2.72(m,2H),0.97-0.91(m,2H),0.58-0.54(m,2H).

[0606] Example 50

[0607] 3-(2-chloro-4'-(cyclobutyl(5-fluoropyrimidin-2-yl)amino)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0608] (1) N-(4-bromophenyl)-5-fluoropyrimidine-2-amine

[0609] 1-Bromo-4-iodobenzene (500 mg, 1.77 mmol), 5-fluoropyrimidin-2-amine (200 mg, 1.77 mmol), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (197 mg, 0.34 mmol), tris(dibenzylacetone)dipalladium (156 mg, 0.17 mmol), and cesium carbonate (1.44 g, 4.42 mmol) were dissolved in 1,4-dioxane (10 mL), and the mixture was stirred overnight at 90 °C under nitrogen protection. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 95 / 5) to give the title compound (320 mg, pale yellow solid), yield: 68%. MS (ESI): m / z 267.9 [M+H] + .

[0610] (2) N-(4-bromophenyl)-N-cyclobutyl-5-fluoropyrimidine-2-amine

[0611] N-(4-bromophenyl)-5-fluoropyrimidine-2-amine (100 mg, 0.37 mmol) was dissolved in N,N-dimethylformamide (10 mL), and sodium hydride (30 mg, 0.75 mmol) was added at 0 °C and stirred for 0.5 h. Then, bromocyclobutane (101 mg, 0.75 mol) was added, and the reaction mixture was stirred at 70 °C for 16 h. Water (50 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 95 / 5) to give the title compound (40 mg, colorless oil), yield: 33%. MS (ESI): m / z 322.0 [M+H] + .

[0612] (3) 3-(2-chloro-4'-(cyclobutyl(5-fluoropyrimidin-2-yl)amino)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0613] N-(4-bromophenyl)-N-cyclobutyl-5-fluoropyrimidin-2-amine (40 mg, 0.12 mmol), intermediate 3 (43 mg, 0.12 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (7 mg, 0.01 mmol), and potassium carbonate (43 mg, 0.31 mmol) were dissolved in 1,4-dioxane / water (5 mL / 0.5 mL). The mixture was stirred at 90 °C under nitrogen protection for 16 hours. The reaction solution was concentrated, and the residue was subjected to silica gel column chromatography (dichloromethane / ethyl acetate = 92 / 8) to obtain a crude product, which was then purified by Prep-HPLC to give the title compound (12.2 mg, pale yellow solid), yield: 21%. MS (ESI): m / z 465.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.94(s,1H),8.44(s,2H),7.59-7.10(m,7H),5.04-4.83(m,1H),4.48-4.28(m,1H),2.86-2.76( m,1H),2.61-2.56(m,1H),2.38-2.31(m,1H),2.26-2.17(m,2H),2.12-2.02(m,1H),1.89-1.75(m,2H),1.70-1.51(m,2H).

[0614] Example 51

[0615] 3-(2-chloro-4'-(cyclopropyl(1-isopropyl-1H-1,2,4-triazol-3-yl)amino)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0616] Following the synthetic method of Example 42, in step 1, 1,1-difluoro-2-iodoethane was replaced with 2-bromopropane, and a similar synthetic procedure was performed to obtain the title compound (6.3 mg, white solid). MS (ESI): m / z 464.1 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ10.91(s,1H),8.39(s,1H),7.49-7.19(m,7H),4.60-4.46(m,1H),4.34(dd,J=12.1,4.9Hz,1H),2.97-2.90(m,1H) ,2.84-2.72(m,1H),2.59-2.55(m,1H),2.37-2.27(m,1H),2.08-2.01(m,1H),1.46(d,J=6.8Hz,6H),0.97-0.90(m,2H),0.61-0.53(m,2H).

[0617] Example 52

[0618] 3-(2-chloro-4'-(cyclopropyl(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)amino)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0619] Following the synthetic method of Example 42, in step 1, 1-difluoro-2-iodoethane was replaced with deuterated iodomethane, and similar synthetic steps were performed to obtain the title compound (31 mg, white solid). MS (ESI): m / z 439.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.91(s,1H),8.30(s,1H),7.39-7.29(m,7H),4.35-4.26(m,1H),2.94-2.91(m,1H),2. 83-2.73(m,1H),2.56-2.54(m,1H),2.38-2.27(m,1H),2.10-2.00(m,1H),0.94-0.93(m,2H),0.56-0.52(m,2H).

[0620] Example 53

[0621] 3-(2-chloro-4'-(cyclopropyl(5-methylpyrimidin-2-yl)amino)-3'-fluoro-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0622] Following the synthetic method of Example 45, the first step involved replacing 4-bromo-1-iodo-2-methylbenzene with 4-bromo-2-fluoro-1-iodobenzene, and a similar synthetic procedure yielded the title compound (34.7 mg, white solid). MS (ESI): m / z 465.1 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ10.94(s,1H),8.29(s,2H),7.46-7.37(m,4H),7.35-7.26(m,2H),4.37(dd,J=12.0,4.8Hz,1H),3.20-3.12(m ,1H),2.86-2.76(m,1H),2.61-2.54(m,1H),2.40-2.30(m,1H),2.13(s,3H),2.10-2.03(m,1H),0.92-0.83(m,2H),0.56-0.45(m,2H).

[0623] Example 54

[0624] 3-(2-chloro-4'-(cyclopropyl(5-methoxypyrimidin-2-yl)amino)-3'-fluoro-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0625] Following the synthetic method of Example 45, in the first step, 4-bromo-1-iodo-2-methylbenzene and 5-methylpyrimidin-2-amine were replaced with 4-bromo-2-fluoro-1-iodobenzene and 5-methoxypyrimidin-2-amine, respectively. A similar synthetic procedure yielded the title compound (54.5 mg, white solid). MS (ESI): m / z 481.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.94(s,1H),8.28(s,2H),7.46-7.37(m,4H),7.35-7.25(m,2H),4.37(dd,J=12.0,4.8Hz,1H),3.81(s,3H), 3.18-3.09(m,1H),2.86-2.75(m,1H),2.59-2.54(m,1H),2.37-2.28(m,1H),2.11-2.02(m,1H),0.93-0.81(m,2H),0.61-0.47(m,2H).

[0626] Example 55

[0627] 3-(2-chloro-4'-(cyclopropyl(1-methyl-1H-1,2,4-triazol-3-yl)amino)-3'-methyl-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0628] Following the synthetic method of Example 43, the first step involved replacing 4-bromo-2-fluoro-1-iodobenzene with 4-bromo-1-iodo-2-methylbenzene, and a similar synthetic procedure yielded the title compound (11.6 mg, white solid). MS (ESI): m / z 450.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.92(s,1H),8.03(s,1H),7.41-7.33(m,3H),7.25-7.24(m,3H),4.35(dd,J=12.1,5.0Hz,1H),3.70(s,3H), 3.08-3.03(m,1H),2.83-2.76(m,1H),2.57-2.56(m,1H),2.36-2.30(m,1H),2.09-2.04(m,4H),0.78-0.73(m,2H),0.51-0.47(m,2H).

[0629] Example 56

[0630] 3-(2-chloro-4'-((2,2-difluoroethyl)(5-methylpyrimidin-2-yl)amino)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0631] Following the synthetic method of Example 34, the first step involved replacing N-(4-bromophenyl)pyrimidin-2-amine with N-(4-bromophenyl)-5-methylpyrimidin-2-amine (step 1 of Example 29), and a similar synthetic procedure yielded the title compound (12 mg, white solid). MS (ESI): m / z 471.0 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ10.93(s,1H),8.31(s,2H),7.47-7.35(m,7H),6.54-6.14(m,1H),4.41-4.2 9(m,3H),2.86-2.75(m,1H),2.60-2.54(m,1H),2.37-2.31(m,1H),2.14(s,3H),2.10-2.02(m,1H).

[0632] Example 57

[0633] 3-(2-chloro-4'-((2,2-difluoroethyl)(5-methoxypyrimidin-2-yl)amino)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0634] Following the synthetic method of Example 34, in the first step, N-(4-bromophenyl)pyrimidine-2-amine was replaced with N-(4-bromophenyl)-5-methoxypyrimidine-2-amine (step 1 of Example 30), and the title compound (13.4 mg, white solid) was obtained through similar synthetic steps. MS (ESI): m / z 487.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ10.93(s,1H),8.29(s,2H),7.46-7.34(m,7H),6.57-6.16(m,1H),4.42-4.2 7(m,3H),3.81(s,3H),2.86-2.75(m,1H),2.59-2.55(m,1H),2.38-2.31(m,1H),2.10-2.02(m,1H).

[0635] Example 58

[0636] (S)-3-(2-chloro-4'-((cyclopropyl(methyl)(oxo)-λ) 6 -sulfonyl)amino)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione and (R)-3-(2-chloro-4'-((cyclopropyl(methyl)(oxo)-λ) 6 -sulfonyl)amino)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0637] (1)(S)-((4-bromophenyl)imino)(cyclopropyl)(methyl)-λ 6 -Sulfamethoxane (01) and (R)-((4-bromophenyl)imino)(cyclopropyl)(methyl)-λ 6 -Sulfamethoxazole (02)

[0638] 1-Bromo-4-iodobenzene (1 g, 3.5 mmol), cyclopropyl(imino)(methyl)-λ 6 Sulfamethoxane (420 mg, 3.5 mmol), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (405 mg, 0.7 mmol), tris(dibenzylideneacetone)palladium (320 mg, 0.35 mmol), and cesium carbonate (2.28 g, 7.0 mmol) were dissolved in 1,4-dioxane (20 mL), and the mixture was purged with nitrogen and stirred overnight at 90 °C under nitrogen protection. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give the racemic mixture ((4-bromophenyl)imino)(cyclopropyl)(methyl)-λ 6- Sulfamethoxazole (900 mg, yellow solid), yield: 94%. Take 250 mg of the racemic mixture ((4-bromophenyl)imino)(cyclopropyl)(methyl)-λ 6 Sulfamethoxazole was chirally resolved by chiral IG column chromatography, yielding title compound O1 (90 mg) and title compound O2 (120 mg), with absolute configurations undetermined. MS (ESI): m / z 274.0 [M+H] + .

[0639] (2)(S)-3-(2-chloro-4'-((cyclopropyl(methyl)(oxo)-λ) 6 -sulfonyl)amino)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione (03) and (R)-3-(2-chloro-4'-((cyclopropyl(methyl)(oxo)-λ) 6 -sulfonyl)amino)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione (04)

[0640] (S)-((4-bromophenyl)imino)(cyclopropyl)(methyl)-λ 6 Sulfamethoxazole (60 mg, 0.22 mmol), intermediate 3 (90 mg, 0.33 mmol), PdCl2 (dppf) (16 mg, 0.022 mmol), and potassium phosphate (93 mg, 0.44 mmol) were dissolved in 1,4-dioxane / water (5 mL / 1 mL). The mixture was heated to 85 °C and stirred for 4 hours under nitrogen protection. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (100% ethyl acetate) to obtain a crude product, which was then purified by Prep-HPLC to give the title compound O3 (29.5 mg, white solid), the absolute configuration of which was undetermined. MS (ESI): m / z 417.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ10.91(s,1H),7.40-7.21(m,5H),7.00-6.98(m,2H),4.33(dd,J=12.1,5.0Hz,1H),3 .04(s,3H),2.88-2.74(m,2H),2.56-2.55(m,1H),2.38-2.27(m,1H),2.07-2.02(m,1H),1.24-1.00(m,4H).

[0641] Referring to the above method, (R)-((4-bromophenyl)imino)(cyclopropyl)(methyl)-λ 6Using sulfamethoxazole (60 mg, 0.22 mmol) as a starting material, the same procedure was followed to obtain the title compound O4 (16.1 mg, white solid), the absolute configuration of which was undetermined. MS (ESI): m / z 417.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ10.91(s,1H),7.40-7.21(m,5H),7.00-6.98(m,2H),4.33(dd,J=12.1,5.0Hz,1H),3 .22(s,3H),2.88-2.74(m,2H),2.56-2.54(m,1H),2.37-2.28(m,1H),2.07-2.02(m,1H),1.24-1.00(m,4H).

[0642] Example 59

[0643] 3-(2-chloro-4'-(cyclopropyl(5-cyclopropylpyrimidin-2-yl)amino)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0644] (1) N-(4-bromophenyl)-5-cyclopropylpyrimidin-2-amine

[0645] p-Bromoaniline (200 mg, 1.16 mmol), 5-cyclopropylpyrimidine-2-amine (157 mg, 1.16 mmol), and cesium carbonate (1.14 g, 3.49 mmol) were dissolved in N,N-dimethylformamide (5 mL), and the mixture was stirred at 130 °C for 16 hours. Water (50 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 80 / 20) to give the title compound (305 mg, pale yellow solid), yield: 30%. MS (ESI): m / z 290.0 [M+H] + .

[0646] (2) N-(4-bromophenyl)-N,5-dicyclopropylpyrimidin-2-amine

[0647] N-(4-bromophenyl)-5-cyclopropylpyrimidine-2-amine (100 mg, 0.34 mmol) and cyclopropylboronic acid (59 mg, 0.69 mmol) were dissolved in N,N-dimethylformamide (10 mL), and 2,2'-bipyridine (53 mg, 0.34 mmol), copper acetate (62 mg, 0.34 mmol), and potassium carbonate (95 mg, 0.69 mmol) were added. The mixture was heated to 120 °C and stirred for 30 hours under oxygen bulb conditions. Water (50 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 92 / 8) to give the title compound (60 mg, white solid), yield: 53%. MS (ESI): m / z 330.1 [M+H] + .

[0648] (3) 3-(2-chloro-4'-(cyclopropyl(5-cyclopropylpyrimidin-2-yl)amino)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0649] N-(4-bromophenyl)-N,5-dicyclopropylpyrimidin-2-amine (60 mg, 0.18 mmol), intermediate 3 (64 mg, 0.18 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (15 mg, 0.02 mmol), and potassium carbonate (62 mg, 0.45 mmol) were dissolved in 1,4-dioxane / water (5 mL / 0.5 mL). The mixture was stirred at 85 °C under nitrogen protection for 16 hours. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 97 / 3) to obtain a crude product, which was then purified by Prep-HPLC to obtain the title compound (28.7 mg, white solid), yield: 23%. MS (ESI): m / z 473.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.93(s,1H),8.24(s,2H),7.51-7.21(m,7H),4.36(dd,J=12.1,4.9Hz,1H),3.19-3.07(m,1H),2.91-2.69(m,1H) ),2.66-2.53(m,1H),2.39-2.21(m,1H),2.13-1.99(m,1H),1.88-1.70(m,1H),0.96-0.83(m,4H),0.72-0.64(m,2H),0.53-0.42(m,2H).

[0650] Example 60

[0651] 3-(2-chloro-4'-(cyclopropyl(5-(difluoromethyl)pyrimidin-2-yl)amino)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0652] (1) N-(4-bromophenyl)-5-(difluoromethyl)pyrimidin-2-amine

[0653] p-Bromoaniline (50 mg, 0.29 mmol) and 2-chloro-5-(difluoromethyl)pyrimidine (48 mg, 0.29 mmol) were dissolved in 1,4-dioxane / acetic acid (3 mL / 1 mL) and reacted with stirring at 110 °C for 16 hours. Water (30 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 85 / 15) to give the title compound (65 mg, pale yellow solid), yield: 67%. MS (ESI): m / z 300.0 [M+H] + .

[0654] (2) N-(4-bromophenyl)-N-cyclopropyl-5-(difluoromethyl)pyrimidin-2-amine

[0655] N-(4-bromophenyl)-5-(difluoromethyl)pyrimidin-2-amine (65 mg, 0.22 mmol) and cyclopropylboronic acid (37 mg, 0.43 mmol) were dissolved in N,N-dimethylformamide (10 mL), and 2,2'-bipyridine (34 mg, 0.22 mmol), copper acetate (39 mg, 0.22 mmol), and potassium carbonate (60 mg, 0.43 mmol) were added. The mixture was heated to 120 °C and stirred for 48 hours under oxygen bulb conditions. Water (50 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 92 / 8) to give the title compound (58 mg, white solid), yield: 79%. MS (ESI): m / z 340.0 [M+H] + .

[0656] (3) 3-(2-chloro-4'-(cyclopropyl(5-(difluoromethyl)pyrimidin-2-yl)amino)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0657] N-(4-bromophenyl)-N-cyclopropyl-5-(difluoromethyl)pyrimidin-2-amine (58 mg, 0.17 mmol), intermediate 3 (60 mg, 0.17 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (15 mg, 0.02 mmol), and potassium carbonate (59 mg, 0.43 mmol) were dissolved in 1,4-dioxane / water (5 mL / 0.5 mL). The mixture was stirred at 85 °C under nitrogen protection for 10 hours. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 92 / 8) to obtain a crude product, which was then purified by Prep-HPLC to obtain the title compound (4.4 mg, white solid), yield: 5%. MS (ESI): m / z 483.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.93(s,1H),8.63(s,2H),7.48-7.32(m,7H),7.17-6.87(m,1H),4.37(dd,J=12.1,5.0Hz,1H),3.29-3 .25(m,1H),2.83-2.77(m,1H),2.58-2.56(m,1H),2.39-2.29(m,1H),2.10-2.03(m,1H),0.96-0.90(m,2H),0.56-0.48(m,2H).

[0658] Example 61

[0659] 3-(2-chloro-4'-(cyclobutyl(5-methylpyrimidin-2-yl)amino)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0660] (1) N-(4-bromophenyl)-N-cyclobutyl-5-methylpyrimidin-2-amine

[0661] N-(4-bromophenyl)-5-methylpyrimidin-2-amine (220 mg, 0.83 mmol, Step 1 of Example 29) was dissolved in N,N-dimethylformamide (5 mL), sodium hydride (100 mg, 2.5 mmol) was added, followed by bromocyclobutane (225 mg, 1.67 mmol). The mixture was stirred overnight at 70 °C under nitrogen protection. The reaction solution was poured into saturated brine (50 mL) and extracted with ethyl acetate (2 x 30 mL). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 80 / 20) to give the title compound (90 mg, pale yellow solid), yield: 34%. MS (ESI): m / z 318.0 [M+H] + .

[0662] (2) 3-(2-chloro-4'-(cyclobutyl(5-methylpyrimidin-2-yl)amino)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0663] N-(4-bromophenyl)-N-cyclobutyl-5-methylpyrimidin-2-amine (90 mg, 0.28 mmol), intermediate 3 (119 mg, 0.34 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (21 mg, 0.03 mmol), and potassium phosphate (180 mg, 0.85 mmol) were dissolved in 1,4-dioxane / water (5 mL / 0.5 mL), and the reaction was carried out at 90 °C for 6 hours under nitrogen protection. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 40 / 60) to obtain a crude product, which was then purified by Prep-HPLC to obtain the title compound (9.5 mg, white solid), yield: 7.3%. MS (ESI): m / z 461.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.94(s,1H),8.20(s,2H),7.50-7.36(m,5H),7.23-7.15(m,2H),5.11-4.91(m,1H),4.37(dd,J=12.0,4.8Hz,1H),2.8 5-2.76(m,1H),2.59-2.56(m,1H),2.39-2.31(m,1H),2.24-2.16(m,2H) ,2.08(s,3H),2.08-1.99(m,1H),1.85-1.75(m,2H),1.65-1.49(m,2H).

[0664] Example 62

[0665] 3-(2-chloro-4'-(cyclobutyl(5-methoxypyrimidin-2-yl)amino)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0666] Following the synthetic method of Example 61, in the first step, N-(4-bromophenyl)-5-methoxypyrimidin-2-amine was replaced with N-(4-bromophenyl)-5-methylpyrimidin-2-amine (step 1 of Example 30), and the title compound (13 mg, white solid) was obtained through similar synthetic steps. MS (ESI): m / z 477.1 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ10.94(s,1H),8.19(s,2H),7.49-7.34(m,5H),7.23-7.13(m,2H),5.04-4.80(m,1H),4.37(dd,J=12.0,4.8Hz,1H),3.7 6(s,3H),2.85-2.76(m,1H),2.60-2.54(m,1H),2.38-2.32(m,1H),2.25 -2.17(m,2H),2.10-2.03(m,1H),1.86-1.76(m,2H),1.65-1.51(m,2H).

[0667] Example 63

[0668] 3-(2-chloro-4'-((2,2-difluoroethyl)(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)amino)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0669] (1) N-(4-bromophenyl)-N-(2,2-difluoroethyl)-1-(methyl-d3)-1H-1,2,4-triazol-3-amine

[0670] N-(4-bromophenyl)-1-(methyl-d3)-1H-1,2,4-triazol-3-amine (100 mg, 0.39 mmol, Example 52) and 1,1-difluoro-2-iodoethane (150 mg, 0.78 mmol) were dissolved in N,N-dimethylformamide (5 mL), and cesium carbonate (254 mg, 0.78 mmol) was added. The mixture was stirred at 130 °C for 16 hours. Water (50 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 50 / 50) to give the title compound (26 mg, colorless oil), yield: 21%. MS (ESI): m / z 320.0 [M+H] + .

[0671] (2) 3-(2-chloro-4'-((2,2-difluoroethyl)(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)amino)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0672] N-(4-bromophenyl)-N-(2,2-difluoroethyl)-1-(methyl-d3)-1H-1,2,4-triazol-3-amine (26 mg, 0.08 mmol), intermediate 3 (35 mg, 0.10 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (7 mg, 0.01 mmol), and potassium carbonate (28 mg, 0.20 mmol) were dissolved in 1,4-dioxane / water (5 mL / 0.5 mL) and the mixture was stirred at 85 °C under nitrogen protection for 16 hours. Water (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (10 x 3 mL). The organic phases were combined, washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (100% ethyl acetate) to obtain a crude product, which was then purified by Prep-HPLC to give the title compound (7.2 mg, white solid), yield: 19%. MS(ESI): m / z 463.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.91(s,1H),8.25(s,1H),7.52-7.47(m,2H),7.42-7.31(m,5H),6.50-6.18( m,1H),4.40-4.27(m,3H),2.84-2.75(m,1H),2.62-2.54(m,1H),2.39-2.27(m,1H),2.09-2.02(m,1H).

[0673] Example 64

[0674] 3-(2-chloro-4'-(cyclobutyl(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)amino)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0675] (1) N-(4-bromophenyl)-N-cyclobutyl-1-(methyl-d3)-1H-1,2,4-triazol-3-amine

[0676] N-(4-bromophenyl)-1-(methyl-d3)-1H-1,2,4-triazol-3-amine (70 mg, 0.27 mmol, Example 52) was dissolved in N,N-dimethylformamide (5 mL), and sodium hydride (22 mg, 0.54 mol) was added at 0 °C and stirred for 0.5 h. Then, bromocyclobutane (73 mg, 0.54 mol) was added, and the reaction mixture was stirred at 70 °C for 16 h. Water (50 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 95 / 5) to give the title compound (65 mg, colorless oil), yield: 76%. MS (ESI): m / z 310.1 [M+H] + .

[0677] (2) 3-(2-chloro-4'-(cyclobutyl(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)amino)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0678] N-(4-bromophenyl)-N-cyclobutyl-1-(methyl-d3)-1H-1,2,4-triazol-3-amine (65 mg, 0.21 mmol), intermediate 3 (73 mg, 0.21 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (15 mg, 0.02 mmol), and potassium carbonate (72 mg, 0.52 mmol) were dissolved in 1,4-dioxane / water (5 mL / 0.5 mL). The mixture was stirred at 90 °C under nitrogen protection for 16 hours. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 92 / 8) to obtain a crude product, which was then purified by Prep-HPLC to obtain the title compound (22.7 mg, white solid), yield: 24%. MS (ESI): m / z 453.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.92(s,1H),8.24(s,1H),7.41-7.29(m,5H),7.04-7.00(m,2H),4.52-4.42(m,1H),4.34(dd,J=12.1, 5.0Hz,1H),2.83-2.74(m,1H),2.59-2.52(m,1H),2.35-2.22(m,3H),2.07-2.04(m,1H),1.97-1.89(m,2H),1.68-1.56(m,2H).

[0679] Example 65

[0680] 3-(4'-(bicyclo[1.1.1]pentan-1-yl(5-methylpyrimidin-2-yl)amino)-2-chloro-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0681] (1) N-(bicyclo[1.1.1]pent-1-yl)-5-methylpyrimidin-2-amine

[0682] 2-Bromo-5-methylpyrimidine (500 mg, 2.9 mmol), bicyclo[1.1.1]pentane-1-amine hydrochloride (346 mg, 2.9 mmol), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (335 mg, 0.58 mmol), tris(dibenzylacetone)dipalladium (265 mg, 0.29 mmol), and cesium carbonate (1.9 g, 6 mmol) were dissolved in 1,4-dioxane (10 mL), and the mixture was purged with nitrogen. The mixture was stirred overnight at 90 °C under nitrogen protection. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 70 / 30) to give the title compound (100 mg, yellow solid), yield: 20%. MS (ESI): m / z 176.3 [M+H] + .

[0683] (2) N-(bicyclo[1.1.1]pent-1-yl)-N-(4-bromophenyl)-5-methylpyrimidin-2-amine

[0684] N-(bicyclo[1.1.1]pent-1-yl)-5-methylpyrimidin-2-amine (50 mg, 0.28 mmol) and (4-bromophenyl)boronic acid (114 mg, 0.57 mmol) were dissolved in N,N-dimethylformamide (5 mL), and 2,2'-bipyridine (44 mg, 0.28 mmol), copper acetate (51 mg, 0.28 mmol), and potassium carbonate (78 mg, 0.57 mmol) were added. The mixture was heated to 120 °C and stirred overnight under oxygen bulb conditions. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 80 / 20) to give the title compound (10 mg, white solid), yield: 11%. MS (ESI): m / z 330.0 [M+H] + .

[0685] (3) 3-(4'-(bicyclo[1.1.1]pent-1-yl(5-methylpyrimidin-2-yl)amino)-2-chloro-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0686] N-(bicyclo[1.1.1]pent-1-yl)-N-(4-bromophenyl)-5-methylpyrimidin-2-amine (10 mg, 0.03 mmol), intermediate 3 (16 mg, 0.045 mmol), PdCl2 (dppf) (2 mg, 0.003 mmol), and potassium phosphate (8 mg, 0.04 mmol) were dissolved in 1,4-dioxane / water (5 mL / 1 mL). The mixture was heated to 85 °C and stirred for 4 hours under nitrogen protection. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 50 / 50) to obtain a crude product, which was then purified by Prep-HPLC to obtain the title compound (1.1 mg, white solid), yield: 8%. MS (ESI): m / z 473.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.93(s,1H),8.23(s,2H),7.45-7.36(m,5H),7.23-7.21(m,2H),4.37(dd,J=12.2,4.9Hz,1H ),2.85-2.73(m,1H),2.57-2.56(m,1H),2.47(s,1H)2.37-2.33(m,1H),2.12(s,6H),2.10(s,3H),2.03-1.97(m,1H).

[0687] Example 66

[0688] 3-(4'-(bicyclo[1.1.1]pent-1-yl(5-methoxypyrimidin-2-yl)amino)-2-chloro-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0689] Following the synthetic method of Example 65, the first step involved replacing 2-bromo-5-methylpyrimidine with 2-bromo-5-methoxypyrimidine, and a similar synthetic procedure yielded the title compound (2.4 mg, white solid). MS (ESI): m / z 489.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.92(s,1H),8.21(s,2H),7.44-7.35(m,5H),7.22(d,J=8.4Hz,2H),4.36(dd,J=12.1,5.0Hz,1 H),3.78(s,3H),2.85-2.76(m,1H),2.58-2.53(m,1H),2.47(s,1H),2.40-2.29(m,1H),2.12(s,6H),2.09-1.97(m,1H).

[0690] Example 67

[0691] 3-(2-chloro-4'-(cyclopropyl(1-(2-methoxyethyl)-1H-1,2,4-triazol-3-yl)amino)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0692] Following the synthetic method of Example 42, the first step involved replacing 1,1-difluoro-2-iodoethane with 1-bromo-2-methoxyethane, and a similar synthetic procedure yielded the title compound (4.5 mg, white solid). MS (ESI): m / z 480.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.91(s,1H),8.32(s,1H),7.39-7.29(m,7H),4.34(dd,J=12.1,5.0Hz,1H),4.27(t,J=5.2Hz,2H),3.70(t,J=5.2Hz,2H), 3.25(s,3H),2.97-2.92(m,1H),2.83-2.75(m,1H),2.57-2.55(m,1H),2. 38-2.28(m,1H),2.07-1.97(m,1H),0.97-0.92(m,2H),0.58-0.54(m,2H).

[0693] Example 68

[0694] 3-(2-chloro-4'-((1-cyclopropyl-1H-1,2,4-triazol-3-yl)(2,2-difluoroethyl)amino)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0695] (1) 3-Bromo-1-cyclopropyl-1H-1,2,4-triazole

[0696] 3-Bromo-1H-1,2,4-triazole (1 g, 6.8 mmol) was dissolved in 1,2-dichloroethane (30 mL), along with 2,2-bipyridine (1.06 g, 6.8 mmol), cyclopropylboronic acid (1.17 g, 13.6 mmol), acetone (1.24 g, 6.8 mmol), and potassium carbonate (1.88 g, 13.6 mmol). The reaction mixture was stirred overnight at 80 °C under an oxygen atmosphere. The reaction solution was diluted with dichloromethane (50 mL), filtered, and the filtrate was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 80 / 20) to give the title compound (700 mg, pale yellow oil), yield: 54.4%. MS (ESI): m / z 188.0 [M+H] + .

[0697] (2) N-(4-chlorophenyl)-1-cyclopropyl-1H-1,2,4-triazol-3-amine

[0698] 3-Bromo-1-cyclopropyl-1H-1,2,4-triazole (590 mg, 31.4 mmol), p-chloroaniline (600 mg, 4.7 mmol), tris(dibenzylacetone)dipalladium (287 mg, 0.31 mmol), 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (299 mg, 0.63 mmol), and sodium tert-butoxide (603 mg, 6.3 mmol) were dissolved in 1,4-dioxane (15 mL), and the reaction was carried out at 110 °C for 6 hours under nitrogen protection. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 40 / 60) to give a colorless oil, which was then purified by Prep-HPLC to give the title compound (310 mg, white solid), yield: 42%. MS (ESI): m / z 235.1 [M+H] + .

[0699] (3) N-(4-chlorophenyl)-1-cyclopropyl-N-(2,2-difluoroethyl)-1H-1,2,4-triazol-3-amine

[0700] N-(4-chlorophenyl)-1-cyclopropyl-1H-1,2,4-triazol-3-amine (260 mg, 1.1 mmol) and 1,1-difluoro-2-iodoethane (425 mg, 2.2 mmol) were added to a 20 mL sealed tube, followed by N,N-dimethylformamide (10 mL) and cesium carbonate (1.08 g, 3.33 mmol). The mixture was stirred overnight at 130 °C under nitrogen protection. The reaction mixture was poured into saturated brine (50 mL) and extracted with ethyl acetate (2 x 30 mL). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 70 / 30) to give the title compound (75 mg, yellow oil), yield: 22.7%. MS (ESI): m / z 299.1 [M+H] + .

[0701] (4) 3-(2-chloro-4'-((1-cyclopropyl-1H-1,2,4-triazol-3-yl)(2,2-difluoroethyl)amino)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0702] N-(4-chlorophenyl)-1-cyclopropyl-N-(2,2-difluoroethyl)-1H-1,2,4-triazol-3-amine (25 mg, 0.084 mmol), intermediate 3 (110 mg, 0.126 mmol), methanesulfonic acid (2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (7 mg, 0.009 mmol), and potassium phosphate (36 mg, 0.17 mmol) were dissolved in toluene / water (4 mL / 0.5 mL) and reacted overnight at 80 °C under nitrogen protection. The reaction solution was diluted with ethyl acetate (20 mL). The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by preparative thin-layer chromatography (100% ethyl acetate) to obtain a crude product, which was then purified by Prep-HPLC to give the title compound (1.9 mg, white solid), yield: 4.7%. MS (ESI): m / z 486.1 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ10.92(s,1H),8.36(s,1H),7.51-7.46(m,2H),7.41-7.31(m,5H),6.51-6.17(m,1H),4.37-4.27( m,3H),3.62-3.61(m,1H),2.83-2.76(m,1H),2.57-2.56(m,1H),2.40-2.33(m,1H),2.09-2.01(m,1H),1.09-0.94(m,4H).

[0703] Example 69

[0704] 3-(2-chloro-4'-(cyclobutyl(1-cyclopropyl-1H-1,2,4-triazol-3-yl)amino)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0705] (1) N-(4-chlorophenyl)-N-cyclobutyl-1-cyclopropyl-1H-1,2,4-triazol-3-amine

[0706] N-(4-chlorophenyl)-1-cyclopropyl-1H-1,2,4-triazol-3-amine (170 mg, 0.72 mmol) was dissolved in N,N-dimethylformamide (4 mL), sodium hydride (87 mg, 2.17 mmol) was added, followed by bromocyclobutane (196 mg, 1.45 mmol). The mixture was stirred overnight at 70 °C under nitrogen protection. The reaction solution was poured into saturated brine (50 mL) and extracted with ethyl acetate (2 x 30 mL). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 60 / 40) to give the title compound (100 mg, white solid), yield: 47.8%. MS (ESI): m / z 289.1 [M+H] + .

[0707] (2) 3-(2-chloro-4'-(cyclobutyl(1-cyclopropyl-1H-1,2,4-triazol-3-yl)amino)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0708] N-(4-chlorophenyl)-N-cyclobutyl-1-cyclopropyl-1H-1,2,4-triazol-3-amine (30 mg, 0.104 mmol), intermediate 3 (136 mg, 0.156 mmol), methanesulfonic acid (2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (8 mg, 0.01 mmol), and potassium phosphate (44 mg, 0.1 mmol) were dissolved in toluene / water (4 mL / 0.5 mL) and reacted overnight at 80 °C under nitrogen protection. The reaction solution was diluted with ethyl acetate (20 mL), the organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by preparative thin-layer chromatography (100% ethyl acetate) to obtain a crude product, which was then purified by Prep-HPLC to give the title compound (2.9 mg, white solid), yield: 5.9%. MS (ESI): m / z 476.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.92(s,1H),8.33(s,1H),7.42-7.29(m,5H),7.10-7.01(m,2H),4.52-4.41(m,1H),4.34(dd,J=12.0,4.8Hz,1H ),3.68-3.60(m,1H),2.83-2.77(m,1H),2.57-2.56(m,1H),2.30-2.22(m,2H),2.08-1.86(m,4H),1.70-1.56(m,2H),1.09-0.93(m,4H).

[0709] Example 70

[0710] 3-(2-chloro-4'-(cyclopropyl(1-(cyclopropylmethyl)-1H-1,2,4-triazol-3-yl)amino)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0711] Following the synthetic method of Example 42, the first step involved replacing 1,1-difluoro-2-iodoethane with (iodomethyl)cyclopropane, and a similar synthetic procedure yielded the title compound (19.8 mg, white solid). MS (ESI): m / z 476.2 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ10.91(s,1H),8.38(s,1H),7.39-7.29(m,7H),4.34(dd,J=12.2,5.0Hz,1H),3.98(d,J=7.2Hz,2H),2.97-2.92(m,1H),2.83 -2.75(m,1H),2.56-2.55(m,1H),2.38-2.28(m,1H),2.07-2.03(m,1H),1. 31-1.25(m,1H),0.97-0.92(m,2H),0.59-0.54(m,4H),0.41-0.37(m,2H).

[0712] Example 71

[0713] 3-(2-chloro-4'-(cyclopropyl(5-(difluoromethoxy)pyrimidin-2-yl)amino)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0714] (1) N-(4-bromophenyl)-5-(difluoromethoxy)pyrimidin-2-amine

[0715] 4-Bromoaniline (400 mg, 2.33 mmol), 2-chloro-5-(difluoromethoxy)pyrimidine (420 mg, 2.33 mmol), and cesium carbonate (1.52 mg, 4.66 mmol) were dissolved in N,N-dimethylformamide (10 mL), and the mixture was stirred at 130 °C for 16 hours. Water (50 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by reverse-phase column chromatography (acetonitrile / water = 70 / 30) to give the title compound (230 mg, brown solid), yield: 31%. MS (ESI): m / z 316.0 [M+H] + .

[0716] (2) N-(4-bromophenyl)-N-cyclopropyl-5-(difluoromethoxy)pyrimidin-2-amine

[0717] N-(4-bromophenyl)-5-(difluoromethoxy)pyrimidine-2-amine (230 mg, 0.73 mmol) and cyclopropylboronic acid (125 mg, 1.46 mmol) were dissolved in N,N-dimethylformamide (10 mL), and 2,2'-bipyridine (114 mg, 0.73 mmol), copper acetate (132 mg, 0.73 mmol), and potassium carbonate (201 mg, 1.46 mmol) were added. The mixture was stirred at 120 °C under an oxygen bulb for 24 hours. Water (50 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 93 / 7) to give the title compound (100 mg, pale yellow oil), yield: 39%. MS(ESI): m / z 356.0 [M+H] + .

[0718] (3) 3-(2-chloro-4'-(cyclopropyl(5-(difluoromethoxy)pyrimidin-2-yl)amino)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0719] N-(4-bromophenyl)-N-cyclopropyl-5-(difluoromethoxy)pyrimidin-2-amine (100 mg, 0.28 mmol), intermediate 3 (147 mg, 0.42 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (15 mg, 0.02 mmol), and potassium phosphate (148 mg, 0.70 mmol) were dissolved in 1,4-dioxane / water (5 mL / 0.5 mL). The mixture was stirred at 85 °C under nitrogen protection for 16 hours. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (dichloromethane / ethyl acetate = 92 / 8) to obtain a crude product, which was then purified by Prep-HPLC to obtain the title compound (39 mg, white solid), yield: 28%. MS (ESI): m / z 499.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.93(s,1H),8.41(d,J=3.0Hz,2H),7.44-7.34(m,7H),7.30-6.93(m,1H),4.36(d,J=11.3Hz,1H),3.27 -3.12(m,1H),2.87-2.69(m,1H),2.60-2.51(m,1H),2.40-2.26(m,1H),2.14-1.98(m,1H),1.02-0.83(m,2H),0.59-0.42(m,2H).

[0720] Example 72

[0721] 3-(2-chloro-4'-((5-cyclopropoxypyrimidin-2-yl)(cyclopropyl)amino)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0722] (1) 2-Bromo-5-cyclopropoxypyrimidine

[0723] 2-Bromo-5-fluoropyrimidine (3 g, 17 mmol) was dissolved in tetrahydrofuran (15 mL), sodium hydride (1.3 g, 34 mmol) was added at 0 °C, followed by dropwise addition of cyclopropanol (988 mg, 17 mmol). The mixture was stirred at 0 °C for 2 hours. Water (20 mL) was added to the reaction mixture, and the solution was extracted with ethyl acetate (15 mL x 3). The organic phases were combined, concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give the title compound (130 mg, colorless oil), yield: 3.6%. MS (ESI): m / z 215.1 [M+H] + .

[0724] (2) N-(4-chlorophenyl)-5-cyclopropoxypyrimidin-2-amine

[0725] 2-Bromo-5-cyclopropoxypyrimidine (120 mg, 0.56 mmol), 4-chloroaniline (72 mg, 0.56 mmol), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (64 mg, 0.11 mmol), tris(dibenzylacetone)dipalladium (48 mg, 0.06 mmol), and cesium carbonate (270 mg, 1.12 mmol) were dissolved in 1,4-dioxane (10 mL), and the mixture was purged with nitrogen. The mixture was stirred overnight at 100 °C under nitrogen protection. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give the title compound (90 mg, yellow solid), yield: 62%. MS (ESI): m / z 262.1 [M+H] + .

[0726] (3) N-(4-chlorophenyl)-5-cyclopropoxy-N-cyclopropylpyrimidine-2-amine

[0727] N-(4-chlorophenyl)-5-cyclopropoxypyrimidin-2-amine (140 mg, 0.54 mmol) and cyclopropylboronic acid (138 mg, 1.6 mmol) were dissolved in N,N-dimethylformamide (5 mL), and 2,2'-bipyridine (84 mg, 0.54 mmol), copper acetate (98 mg, 0.54 mmol), and potassium carbonate (138 mg, 1 mmol) were added. The mixture was stirred overnight at 120 °C under an oxygen bulb. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give the title compound (50 mg, colorless oil), yield: 31%. MS (ESI): m / z 302.2 [M+H] + .

[0728] (4) 3-(2-chloro-4'-((5-cyclopropoxypyrimidin-2-yl)(cyclopropyl)amino)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0729] N-(4-chlorophenyl)-5-cyclopropoxy-N-cyclopropylpyrimidin-2-amine (50 mg, 0.17 mmol), intermediate 3 (87 mg, 0.25 mmol), tBuXPhos Pd G3 (13 mg, 0.017 mmol), and potassium phosphate (72 mg, 0.34 mmol) were dissolved in toluene / water (10 mL / 2 mL). The mixture was heated to 90 °C and stirred overnight under nitrogen protection. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give a crude product, which was then purified by Prep-HPLC to give the title compound (1.2 mg, white solid), yield: 1.5%. MS (ESI): m / z 489.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.92(s,1H),8.35(s,2H),7.43-7.35(m,7H),4.36(dd,J=12.1,5.0Hz,1H),3.95-3.90(m,1H),3.14-3.09(m,1H),2.85-2 .76(m,1H),2.57-2.56(m,1H),2.40-2.30(m,1H),2.08-2.03(m,1H),0.9 4-0.89(m,2H),0.78-0.74(m,2H),0.72-0.67(m,2H),0.51-0.47(m,2H).

[0730] Example 73

[0731] 3-(2-chloro-4'-((cyclopropylmethyl)(1-methyl-1H-1,2,4-triazol-3-yl)amino)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0732] (1) N-(4-bromophenyl)-N-(cyclopropylmethyl)-1-methyl-1H-1,2,4-triazol-3-amine

[0733] N-(4-bromophenyl)-1-methyl-1H-1,2,4-triazol-3-amine (100 mg, 0.40 mmol, Step 1 of Example 22) was dissolved in N,N-dimethylformamide (5 mL). Sodium hydride (32 mg, 0.79 mol) was added at 0 °C and the mixture was stirred for 0.5 h. Then (bromomethyl)cyclopropane (53 mg, 0.40 mmol) was added, and the mixture was stirred at 70 °C for 16 h. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (30 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 50 / 50) to give the title compound (100 mg, pale yellow oil), yield: 82%. MS (ESI): m / z 307.1 [M+H] + .

[0734] (2) 3-(2-chloro-4'-((cyclopropylmethyl)(1-methyl-1H-1,2,4-triazol-3-yl)amino)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0735] N-(4-bromophenyl)-N-(cyclopropylmethyl)-1-methyl-1H-1,2,4-triazol-3-amine (100 mg, 0.33 mmol), intermediate 3 (114 mg, 0.33 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (14 mg, 0.02 mmol), and potassium phosphate (173 mg, 0.81 mmol) were dissolved in 1,4-dioxane / water (5 mL / 0.5 mL). The mixture was stirred at 85 °C under nitrogen protection for 16 hours. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 95 / 5) to obtain a crude product, which was then purified by Prep-HPLC to obtain the title compound (62.2 mg, white solid), yield: 42%. MS (ESI): m / z 450.1 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ10.92(s,1H),8.19(s,1H),7.47(d,J=8.7Hz,2H),7.41-7.29(m,5H),4.35(dd,J=12.1,5.0Hz,1H),3.84(d,J=6.6Hz,2H), 3.76(s,3H),2.85-2.73(m,1H),2.60-2.53(m,1H),2.40-2.29(m,1H),2. 06-2.00(m,1H),1.26-1.14(m,1H),0.46-0.38(m,2H),0.33-0.22(m,2H).

[0736] Example 74

[0737] 3-(2-chloro-4'-(((1-fluorocyclopropyl)methyl)(1-methyl-1H-1,2,4-triazol-3-yl)amino)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0738] (1) Methyl (1-fluorocyclopropyl)methanesulfonate

[0739] (1-Fluorocyclopropyl)methanol (200 mg, 2.66 mmol) and triethylamine (674 mg, 6.66 mol) were dissolved in dichloromethane (5 mL). Methylsulfonyl chloride (303 mg, 2.66 mol) was added at 0 °C, and the mixture was stirred at room temperature for 0.5 h. The reaction solution was concentrated to give the title compound (373 mg, white solid), yield: 100%. 1 H NMR (400MHz, CDCl3) δ4.48 (d, J = 22.0Hz, 1H), 3.11 (s, 3H), 1.30-1.16 (m, 2H), 0.93-0.79 (m, 2H).

[0740] (2) N-(4-bromophenyl)-N-((1-fluorocyclopropyl)methyl)-1-methyl-1H-1,2,4-triazol-3-amine

[0741] N-(4-bromophenyl)-1-methyl-1H-1,2,4-triazol-3-amine (250 mg, 0.99 mmol, Step 1 of Example 22) was dissolved in N,N-dimethylformamide (5 mL). Sodium hydride (79 mg, 1.98 mmol) was added at 0 °C and the mixture was stirred for 0.5 h. Then, methyl (1-fluorocyclopropyl) methanesulfonate (166 mg, 0.99 mmol) was added, and the mixture was stirred at 70 °C for 16 h. The reaction mixture was then diluted with water (50 mL) and extracted with ethyl acetate (30 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 50 / 50) to give the title compound (50 mg, pale yellow oil), yield: 16%. MS (ESI): m / z 325.0 [M+H] + .

[0742] (3) 3-(2-chloro-4'-(((cyclopropylmethyl)(1-methyl-1H-1,2,4-triazol-3-yl)amino)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0743] N-(4-bromophenyl)-N-((1-fluorocyclopropyl)methyl)-1-methyl-1H-1,2,4-triazol-3-amine (50 mg, 0.15 mmol), intermediate 3 (54 mg, 0.15 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (7 mg, 0.01 mmol), and potassium phosphate (82 mg, 0.38 mmol) were dissolved in 1,4-dioxane / water (5 mL / 0.5 mL), and the mixture was stirred at 85 °C under nitrogen protection for 16 hours. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 95 / 5) to obtain a crude product, which was then purified by Prep-HPLC to obtain the title compound (11.2 mg, white solid), yield: 16%. MS (ESI): m / z 468.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.92(s,1H),8.20(s,1H),7.47(d,J=8.7Hz,2H),7.42-7.25(m,5H),4.47-4.30(m,3H),3.75(s ,3H),2.81-2.75(m,1H),2.59-2.55(m,1H),2.37-2.28(m,1H),2.11-1.98(m,1H),1.00-0.90(m,2H),0.82-0.72(m,2H).

[0744] Example 75

[0745] 3-(2-chloro-4'-((cyclopropylmethyl)(5-methoxypyrimidin-2-yl)amino)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0746] (1) N-(4-bromophenyl)-N-(cyclopropylmethyl)-5-methoxypyrimidin-2-amine

[0747] N-(4-bromophenyl)-5-methoxypyrimidine-2-amine (100 mg, 0.35 mmol, Step 1 of Example 30) was dissolved in N,N-dimethylformamide (3 mL). Sodium hydride (17.14 mg, 0.71 mmol) was added under nitrogen protection at 0 °C, followed by bromomethylcyclopropane (100 mg, 0.35 mmol). The reaction mixture was stirred at room temperature for 16 hours under nitrogen protection. The reaction mixture was poured into saturated brine (50 mL) and extracted with ethyl acetate (2 x 30 mL). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by reversed-phase column chromatography (acetonitrile / water = 20 / 80) to give the title compound (91 mg, yellow solid), yield: 68%. MS (ESI): m / z 334.1 [M+H]+.

[0748] (2) 3-(2-chloro-4'-((cyclopropylmethyl)(5-methoxypyrimidin-2-yl)amino)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0749] N-(4-bromophenyl)-N-(cyclopropylmethyl)-5-methoxypyrimidin-2-amine (91 mg, 0.27 mmol), intermediate 3 (95 mg, 0.27 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (20 mg, 0.02 mmol), and potassium phosphate (115 mg, 0.54 mmol) were dissolved in 1,4-dioxane / water (5 mL / 0.5 mL). The mixture was stirred at 90 °C under nitrogen protection for 2 hours. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 50 / 50) to obtain a crude product, which was then purified by Prep-HPLC to obtain the title compound (37.2 mg, white solid), yield: 28%. MS (ESI): m / z 477.2 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ10.93(s,1H),8.22(s,2H),7.43-7.34(m,7H),4.41-4.32(m,1H),3.86(d,J=4.0Hz,2H),3.79(s,3H),2.8 6-2.74(m,1H),2.61-2.53(m,1H),2.39-2.29(m,1H),2.12-2.01(m,1H),1.21-1.11(m,1H),0.45-0.37(m,2H),0.19-0.14(m,2H).

[0750] Example 76

[0751] 3-(2-chloro-4'-((1-(difluoromethyl)cyclopropyl)(5-methoxypyrimidin-2-yl)amino)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0752] (1) N-(1-(difluoromethyl)cyclopropyl)-5-methoxypyrimidin-2-amine

[0753] 2-Bromo-5-methoxypyrimidine (2.6 g, 13.8 mmol), 1-(difluoromethyl)cyclopropane-1-amine hydrochloride (1 g, 6.9 mmol),

[0754] 4,5-Bisdiphenylphosphine-9,9-dimethyloxanthracene (797 mg, 1.4 mmol), tris(dibenzylacetone)dipalladium (631 mg, 0.69 mmol), and cesium carbonate (4.5 g, 13.8 mmol) were dissolved in 1,4-dioxane (10 mL) and reacted overnight at 90 °C under nitrogen protection with stirring. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give the title compound (120 mg, yellow solid), yield: 8%. MS (ESI): m / z 216.2 [M+H] + .

[0755] (2) N-(4-bromophenyl)-N-(1-(difluoromethyl)cyclopropyl)-5-methoxypyrimidin-2-amine

[0756] N-(1-(difluoromethyl)cyclopropyl)-5-methoxypyrimidine-2-amine (120 mg, 0.56 mmol) and (4-bromophenyl)boronic acid (211 mg, 1.1 mmol) were dissolved in N,N-dimethylformamide (5 mL), and 2,2'-bipyridine (87 mg, 0.56 mmol), copper acetate (102 mg, 0.56 mmol), and potassium carbonate (152 mg, 1.1 mmol) were added. The mixture was stirred overnight at 100 °C under an oxygen bulb. The reaction mixture was added to water (10 mL) and extracted with ethyl acetate (10 mL x 3). The organic phases were combined, concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to give the title compound (8 mg, yellow oil), yield: 4%. MS (ESI): m / z 370.1 [M+H] + .

[0757] (3) 3-(2-chloro-4'-((1-(difluoromethyl)cyclopropyl)(5-methoxypyrimidin-2-yl)amino)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0758] N-(4-bromophenyl)-N-(1-(difluoromethyl)cyclopropyl)-5-methoxypyrimidin-2-amine (8 mg, 0.02 mmol), intermediate 3 (10 mg, 0.03 mmol), PdCl2 (dppf) (1.5 mg, 0.002 mmol), and potassium phosphate (8 mg, 0.04 mmol) were dissolved in dioxane / water (10 mL / 2 mL). The mixture was heated to 90 °C and stirred for 1 hour under nitrogen protection. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (100% ethyl acetate) to obtain a crude product, which was then purified by Prep-HPLC to obtain the title compound (2 mg, white solid), yield: 20%. MS (ESI): m / z 513.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.93(s,1H),8.29(s,2H),7.44-7.28(m,7H),6.50(t,J=58.1Hz,1H),4.36(dd,J=12.1,5.0Hz,1H),3.81(s,3H ),2.85-2.73(m,1H),2.57-2.56(m,1H),2.36-2.35(m,1H),2.09-2.03(m,1H),1.47-1.45(m,1H),1.33-1.29(m,2H),1.00-0.92(m,1H).

[0759] Example 77

[0760] 3-(2-chloro-4'-(((1-fluorocyclopropyl)methyl)(5-methoxypyrimidin-2-yl)amino)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0761] (1) N-(4-bromophenyl)-N-((1-fluorocyclopropyl)methyl)-5-methoxypyrimidin-2-amine

[0762] N-(4-bromophenyl)-5-methoxypyrimidine-2-amine (100 mg, 0.35 mmol, Example 30, Step 1) was dissolved in N,N-dimethylformamide (3 mL). Sodium hydride (17.14 mg, 0.71 mmol) was added under nitrogen protection at 0 °C, followed by methyl (1-fluorocyclopropyl) methanesulfonate (60 mg, 0.35 mmol, Example 74, Step 1). The mixture was heated to 70 °C and stirred under nitrogen protection for 16 hours. The reaction mixture was poured into saturated brine (50 mL) and extracted with ethyl acetate (2 x 30 mL). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by reverse-phase column chromatography (acetonitrile / water = 20 / 80) to give the title compound (30 mg, yellow oil), yield: 22%. MS (ESI): m / z 352.1 [M+H] + .

[0763] (2) 3-(2-chloro-4'-(((1-fluorocyclopropyl)methyl)(5-methoxypyrimidin-2-yl)amino)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0764] N-(4-bromophenyl)-N-((1-fluorocyclopropyl)methyl)-5-methoxypyrimidin-2-amine (30 mg, 0.08 mmol), intermediate 3 (35 mg, 0.1 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (6 mg, 0.008 mmol), and potassium phosphate (36 mg, 0.17 mmol) were dissolved in 1,4-dioxane / water (3 mL / 0.5 mL). The mixture was stirred at 90 °C under nitrogen protection for 3 hours. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 50 / 50) to obtain a crude product, which was then purified by Prep-HPLC to obtain the title compound (4.0 mg, white solid), yield: 9%. MS (ESI): m / z 495.2 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ10.93(s,1H),8.22(s,2H),7.43-7.35(m,7H),4.48(d,J=20.0Hz,2H),4.41-4.33(m,1H),3.79(s ,3H),2.85-2.74(m,1H),2.61-2.57(m,1H),2.38-2.29(m,1H),2.11-2.02(m,1H),0.97-0.88(m,2H),0.75-0.66(m,2H).

[0765] Example 78

[0766] 3-(2-chloro-4'-((1-(cyclopropylmethyl)-1H-1,2,4-triazol-3-yl)(2,2-difluoroethyl)amino)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0767] (1) N-(4-bromophenyl)-1-(cyclopropylmethyl)-N-(2,2-difluoroethyl)-1H-1,2,4-triazol-3-amine

[0768] N-(4-bromophenyl)-1-(cyclopropylmethyl)-1H-1,2,4-triazol-3-amine (50 mg, 0.17 mmol, Example 70) and 1,1-difluoro-2-iodoethane (66 mg, 0.34 mmol) were dissolved in N,N-dimethylformamide (5 mL), and sodium hydride (20 mg, 0.51 mmol) was added. The mixture was stirred overnight at 70 °C. Water (10 mL) was added to the reaction mixture, and the solution was extracted with ethyl acetate (10 mL x 3). The organic phases were combined, concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give the title compound (40 mg, colorless oil), yield: 67%. MS (ESI): m / z 357.0 [M+H] + .

[0769] (2) 3-(2-chloro-4'-((1-(cyclopropylmethyl)-1H-1,2,4-triazol-3-yl)(2,2-difluoroethyl)amino)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0770] N-(4-bromophenyl)-1-(cyclopropylmethyl)-N-(2,2-difluoroethyl)-1H-1,2,4-triazol-3-amine (50 mg, 0.14 mmol), intermediate 3 (98 mg, 0.28 mmol), PdCl2 (dppf) (10 mg, 0.014 mmol), and potassium phosphate (59 mg, 0.28 mmol) were dissolved in 1,4-dioxane / water (10 mL / 2 mL). The mixture was heated to 90 °C and stirred for 4 hours under nitrogen protection. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain a crude product, which was then purified by Prep-HPLC to obtain the title compound (21.3 mg, white solid), yield: 30%. MS (ESI): m / z 500.2 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ10.92(s,1H),8.33(s,1H),7.52-7.50(m,2H),7. 41-7.31(m,5H),6.35(tt,J=56.2,4.3Hz,1H),4.37-4.29(m,3H),3.93(d, J=7.2Hz,2H),2.84-2.75(m,1H),2.57-2.56(m,1H),2.38-2.29(m,1H),2. 07-2.04(m,1H),1.30-1.24(m,1H),0.58-0.53(m,2H),0.39-0.36(m,2H).

[0771] Example 79

[0772] 3-(2-chloro-4'-((3,3-difluorocyclobutyl)(1-methyl-1H-1,2,4-triazol-3-yl)amino)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0773] (1) N-(3,3-difluorocyclobutyl)-1-methyl-1H-1,2,4-triazol-3-amine

[0774] 3-Bromo-1-methyl-1H-1,2,4-triazole (1 g, 6.2 mmol), 3,3-difluorocyclobutane-1-amine (1.3 g, 12.4 mmol), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (720 mg, 1.2 mmol), tris(dibenzylacetone)dipalladium (550 mg, 0.6 mmol), and cesium carbonate (4 g, 12 mmol) were dissolved in 1,4-dioxane (10 mL), and the mixture was purged with nitrogen. The reaction mixture was stirred overnight at 120 °C under nitrogen protection. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (100% ethyl acetate) to give the title compound (260 mg, yellow oil), yield: 22%. MS (ESI): m / z 189.2 [M+H] + .

[0775] (2) N-(4-bromophenyl)-N-(3,3-difluorocyclobutyl)-1-methyl-1H-1,2,4-triazol-3-amine

[0776] N-(3,3-difluorocyclobutyl)-1-methyl-1H-1,2,4-triazol-3-amine (100 mg, 0.53 mmol) and (4-bromophenyl)boronic acid (213 mg, 1 mmol) were dissolved in N,N-dimethylformamide (5 mL), and 2,2'-bipyridine (83 mg, 0.53 mmol), copper acetate (96 mg, 0.53 mmol), and potassium carbonate (146 mg, 1 mmol) were added. The mixture was stirred overnight at 120 °C under an oxygen bulb. Water (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (10 mL x 3). The organic phases were combined, concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give the title compound (10 mg, yellow oil), yield: 6%. MS (ESI): m / z 343.0 [M+H] + .

[0777] (3) 3-(2-chloro-4'-((3,3-difluorocyclobutyl)(1-methyl-1H-1,2,4-triazol-3-yl)amino)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0778] N-(4-bromophenyl)-N-(3,3-difluorocyclobutyl)-1-methyl-1H-1,2,4-triazol-3-amine (10 mg, 0.03 mmol), intermediate 3 (21 mg, 0.06 mmol), PdCl2 (dppf) (2 mg, 0.003 mmol), and potassium phosphate (13 mg, 0.06 mmol) were dissolved in 1,4-dioxane / water (10 mL / 2 mL). The mixture was heated to 90 °C and stirred for 4 hours under nitrogen protection. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (100% ethyl acetate) to obtain a crude product, which was then purified by Prep-HPLC to obtain the title compound (3.2 mg, white solid), yield: 23%. MS (ESI): m / z 486.2 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ10.92(s,1H),8.27(s,1H),7.41-7.30(m,5H),7.18-7.16(m,2H),4.45-4.32(m,2H), 3.78(s,3H),3.06-2.96(m,2H),2.84-2.75(m,1H),2.67-2.59(m,3H),2.39-2.29(m,1H),2.07-1.99(m,1H).

[0779] Example 80

[0780] 3-(2-chloro-4'-((2,2-difluoroethyl)(5-(difluoromethyl)pyrimidin-2-yl)amino)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0781] (1) N-(4-bromophenyl)-N-(2,2-difluoroethyl)-5-(difluoromethyl)pyrimidin-2-amine

[0782] N-(4-bromophenyl)-5-(difluoromethyl)pyrimidin-2-amine (55 mg, 0.18 mmol, Example 60, Step 1) was dissolved in N,N-dimethylformamide (5 mL), and sodium hydride (22 mg, 0.55 mmol) was added at 0 °C and stirred for 0.5 h. Then, 1,1-difluoro-2-iodoethane (70 mg, 0.37 mmol) was added, and the reaction was stirred at 70 °C for 16 h. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (30 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 95 / 5) to give the title compound (40 mg, white solid), yield: 60%. MS (ESI): m / z 364.0 [M+H] +.

[0783] (2) 3-(2-chloro-4'-((2,2-difluoroethyl)(5-(difluoromethyl)pyrimidin-2-yl)amino)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0784] N-(4-bromophenyl)-N-(2,2-difluoroethyl)-5-(difluoromethyl)pyrimidin-2-amine (40 mg, 0.11 mmol), intermediate 3 (38 mg, 0.11 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (7 mg, 0.01 mmol), and potassium phosphate (58 mg, 0.27 mmol) were dissolved in 1,4-dioxane / water (5 mL / 0.5 mL), and the mixture was stirred at 85 °C under nitrogen protection for 16 hours. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 95 / 5) to obtain a crude product, which was then purified by Prep-HPLC to obtain the title compound (14 mg, white solid), yield: 25%. MS (ESI): m / z 507.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.93(s,1H),8.66(s,2H),7.56-7.31(m,7H),7.05(t,J=55.3Hz,1H),6.40(tt,J=56. 0,4.1Hz,1H),4.51-4.32(m,3H),2.88-2.73(m,1H),2.60-2.52(m,1H),2.42-2.32(m,1H),2.17-2.02(m,1H).

[0785] Example 81

[0786] 3-(2-chloro-4'-((1-difluoromethylcyclopropyl)(5-methylpyrimidin-2-yl)amino)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0787] Following the synthetic method of Example 76, the first step involved replacing 2-bromo-5-methoxypyrimidine with 2-bromo-5-methylpyrimidine, and a similar synthetic procedure yielded the title compound (2.9 mg, white solid). MS (ESI): m / z 497.2 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ10.93(s,1H),8.31(s,2H),7.45-7.28(m,7H),6.53(t,J=58.2Hz,1H),4.37(dd,J=12.1,4.9Hz,1H),2 .85-2.76(m,1H),2.57-2.53(m,1H),2.39-2.29(m,1H),2.14(s,3H),2.09-1.97(m,1H),1.35-1.29(m,2H),1.02-0.90(m,2H).

[0788] Example 82

[0789] 3-(2-chloro-4'-((3,3-difluorocyclobutyl)(5-methoxypyrimidin-2-yl)amino)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0790] (1) N-(3,3-difluorocyclobutyl)-5-methoxypyrimidin-2-amine

[0791] 2-Chloro-5-methoxypyrimidine (400 mg, 2.76 mmol), 3,3-difluorocyclobutyl-1-amine (592.7 mg, 5.53 mmol), and N,N-diisopropylethylamine (1072.8 mg, 8.3 mmol) were dissolved in N-methylpyrrolidone (6 mL), and the mixture was stirred at 130 °C for 48 hours under sealed conditions. The reaction mixture was poured into saturated brine (50 mL) and extracted with ethyl acetate (2 x 30 mL). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by reverse-phase column chromatography (acetonitrile / water = 20 / 80) to give the title compound (300 mg, yellow solid), yield: 31%. MS (ESI): m / z 216.2 [M+H] + .

[0792] (2) N-(4-bromophenyl)-N-(3,3-difluorocyclobutyl)-5-methoxypyrimidin-2-amine

[0793] N-(3,3-difluorocyclobutyl)-5-methoxypyrimidin-2-amine (100 mg, 0.46 mmol), 1-bromo-4-iodobenzene (197.2 mg, 0.69 mmol), tris(dibenzylacetone)dipalladium (42.5 mg, 0.046 mmol), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (53.7 mg, 0.092 mmol), and cesium carbonate (302.8 mg, 0.92 mmol) were dissolved in 1,4-dioxane (6 mL), and the mixture was stirred at 100 °C under nitrogen protection for 6 hours. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 50 / 50) to give the title compound (39 mg, yellow oil), yield: 21%. MS (ESI): m / z 370.1 [M+H] + .

[0794] (3) 3-(2-chloro-4'-((3,3-difluorocyclobutyl)(5-methoxypyrimidin-2-yl)amino)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0795] N-(4-bromophenyl)-N-(3,3-difluorocyclobutyl)-5-methoxypyrimidin-2-amine (39 mg, 0.1 mmol), intermediate 3 (44.22 mg, 0.12 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (7.71 mg, 0.01 mmol), and potassium phosphate (44.75 mg, 0.21 mmol) were dissolved in 1,4-dioxane / water (3 mL / 0.5 mL), and the mixture was stirred at 90 °C under nitrogen protection for 2 hours. The reaction solution was concentrated, and the residue was subjected to silica gel column chromatography (petroleum ether / ethyl acetate = 50 / 50) to obtain a crude product, which was then purified by Prep-HPLC to give the title compound (12.8 mg, white solid), yield: 23%. MS (ESI): m / z 513.2 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ10.93(s,1H),8.25(s,2H),7.51-7.46(m,2H),7.45-7.36(m,3H),7.33-7.28(m,2H),4.78-4.69(m,1H), 4.39-4.34(m,1H),3.78(s,3H),2.98-2.93(m,2H),2.86-2.75(m,1H),2.61-2.52(m,2H),2.48-2.27(m,2H),2.13-2.01(m,1H).

[0796] Example 83

[0797] 3-(2-chloro-4'-(cyclopropyl(1-((1-fluorocyclopropyl)methyl)-1H-1,2,4-triazol-3-yl)amino)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0798] Following the synthetic method of Example 42, the first step involved replacing 1,1-difluoro-2-iodoethane with methyl (1-fluorocyclopropyl) methanesulfonate (step 1 of Example 74), and a similar synthetic procedure yielded the title compound (19.8 mg, white solid). MS (ESI): m / z 494.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.90(s,1H),8.43(s,1H),7.52-7.25(m,7H),4.56(d,J=21.9Hz,2H),4.35-4.28(m,1H),2.97-2.89(m,1H), 2.79-2.74(m,1H),2.58-2.54(m,1H),2.39-2.32(m,1H),2.07-1.96(m,1H),1.15-1.05(m,2H),1.00-0.92(m,4H),0.61-0.49(m,2H).

[0799] Example 84

[0800] 3-(2-chloro-4'-(cyclopropyl(1-cyclopropyl-1H-1,2,4-triazol-3-yl)amino)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0801] (1) 3-(3-bromo-2-chlorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)piperidine-2,6-dione

[0802] Intermediate 2 (1 g, 3.3 mmol) and 1,8-diazabispyrocyclo[5.4.0]undec-7-ene (1.1 g, 6.6 mmol) were dissolved in tetrahydrofuran (5 mL), and 2-(trimethylsilyl)ethoxymethyl chloride (1 g, 6.6 mmol) was added dropwise. The mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give the title compound (1.1 g, yellow oil), yield: 78%. MS (ESI): m / z 454.0 [M+Na] + .

[0803] (2) 3-(4'-amino-2-chloro-[1,1'-biphenyl]-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)piperidin-2,6-dione

[0804] 3-(3-bromo-2-chlorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)piperidin-2,6-dione (1.1 g, 2.5 mmol), pinacol 4-aminophenylboronic acid (657 mg, 3.0 mmol), PdCl2 (dppf) (183 mg, 0.25 mmol), and potassium phosphate (1.06 g, 5 mmol) were dissolved in 1,4-dioxane / water (10 mL / 2 mL). The mixture was heated to 90 °C and stirred overnight under nitrogen protection. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to give the title compound (1.0 g, yellow oil), yield: 90%. MS (ESI): m / z 445.2 [M+H] + .

[0805] (3) 3-(2-chloro-4'-((1-cyclopropyl-1H-1,2,4-triazol-3-yl)amino)-[1,1'-biphenyl]-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)piperidin-2,6-dione

[0806] 3-(4'-amino-2-chloro-[1,1'-biphenyl]-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)piperidin-2,6-dione (100 mg, 0.23 mmol), 3-bromo-1-cyclopropyl-1H-1,2,4-triazole (42 mg, 0.23 mmol), 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthracene (26 mg, 0.046 mmol), tris(dibenzylideneacetone)dipalladium (21 mg, 0.023 mmol), and cesium carbonate (150 mg, 0.46 mmol) were dissolved in 1,4-dioxane (5 mL), and the mixture was purged with nitrogen. The reaction mixture was stirred overnight at 120 °C under nitrogen protection. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to give the title compound (30 mg, yellow solid), yield: 24%. MS(ESI): m / z 552.2 [M+H] + .

[0807] (4) 3-(2-chloro-4'-(cyclopropyl(1-cyclopropyl-1H-1,2,4-triazol-3-yl)amino)-[1,1'-biphenyl]-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)piperidin-2,6-dione

[0808] 3-(2-chloro-4'-((1-cyclopropyl-1H-1,2,4-triazol-3-yl)amino)-[1,1'-biphenyl]-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)piperidin-2,6-dione (30 mg, 0.054 mmol) and cyclopropylboronic acid (9.3 mg, 0.108 mmol) were dissolved in N,N-dimethylformamide (2 mL), and 2,2'-bipyridine (8.4 mg, 0.054 mmol), copper acetate (9.8 mg, 0.054 mmol), and potassium carbonate (14.9 mg, 0.108 mmol) were added. The mixture was stirred overnight at 120 °C under an oxygen bulb. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give the title compound (10 mg, yellow oil), yield: 31%. MS(ESI): m / z 592.1 [M+H] + .

[0809] (5) 3-(2-chloro-4'-(cyclopropyl(1-cyclopropyl-1H-1,2,4-triazol-3-yl)amino)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0810] 10 mg (0.017 mmol) of 3-(2-chloro-4'-(cyclopropyl(1-cyclopropyl-1H-1,2,4-triazol-3-yl)amino)-[1,1'-biphenyl]-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)piperidine-2,6-dione) was dissolved in dichloromethane (2 mL), and 0.2 mL of trifluoroacetic acid was added. The mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated, and the residue was dissolved in acetonitrile (2 mL). 0.1 mL of ammonia was added, and the mixture was stirred at room temperature for 1 hour. The pH of the reaction solution was adjusted to 4 with 2 M hydrochloric acid aqueous solution, and the solution was concentrated. The residue was purified by Prep-HPLC to give the title compound (3.6 mg, white solid), yield: 46%. MS (ESI): m / z 462.1 [M+H] + .

[0811] The compound in Example 84 can also be prepared by the following method:

[0812] (1) 3-Iodo-1-cyclopropyl-1H-1,2,4-triazole

[0813] 3-Iodo-1H-1,2,4-triazole (900 mg, 4.6 mmol) was dissolved in 1,2-dichloroethane (20 mL), and 2,2-bipyridine (721 mg, 4.6 mmol), cyclopropylboronic acid (793 mg, 9.2 mmol), acetone (838 mg, 4.6 mmol), and potassium carbonate (1.28 g, 9.2 mmol) were added. The reaction mixture was stirred overnight at 80 °C under an oxygen atmosphere. The reaction solution was diluted with dichloromethane (50 mL) and filtered. The filtrate was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 80 / 20) to give the title compound (237 mg, pale yellow oil), yield: 21.8%. MS (ESI): m / z 236.0 [M+H] + .

[0814] (2) N-(4-bromophenyl)-1-cyclopropyl-1H-1,2,4-triazol-3-amine

[0815] 3-Iodo-1-cyclopropyl-1H-1,2,4-triazole (200 mg, 0.85 mmol) was dissolved in 1,4-dioxane (10 mL), and tris(dibenzylacetone)dipalladium (39 mg, 0.043 mmol), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (49 mg, 0.085 mmol), p-bromoaniline (176 mg, 1 mmol), and cesium carbonate (832 mg, 2.55 mmol) were added. The mixture was stirred overnight at 90 °C under nitrogen protection. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 50 / 50) to give the title compound (140 mg, pale yellow solid), yield: 58.9%. MS (ESI): m / z 279.1 [M+H] + .

[0816] (3) N-(4-bromophenyl)-N,1-dicyclopropyl-1H-1,2,4-triazol-3-amine

[0817] N-(4-bromophenyl)-1-cyclopropyl-1H-1,2,4-triazol-3-amine (140 mg, 0.5 mmol) was dissolved in N,N-dimethylformamide (5 mL), and cyclopropylboronic acid (86 mg, 1 mmol), acetone (91 mg, 0.5 mmol), 2,2'-bipyridine (78 mg, 0.5 mmol), and potassium carbonate (139 mg, 1 mmol) were added. The mixture was stirred overnight at 120 °C under an oxygen atmosphere. The reaction solution was diluted with ethyl acetate (30 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 60 / 40) to give the title compound (25 mg, pale yellow oil), yield: 15.6%. MS (ESI): m / z 319.1 [M+H] + .

[0818] (4) 3-(2-chloro-4'-(cyclopropyl(1-cyclopropyl-1H-1,2,4-triazol-3-yl)amino)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0819] N-(4-bromophenyl)-N,1-dicyclopropyl-1H-1,2,4-triazol-3-amine (20 mg, 0.063 mmol), intermediate 3 (82 mg, 0.094 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (5 mg, 0.007 mmol), and potassium phosphate (40 mg, 0.188 mmol) were dissolved in 1,4-dioxane / water (4 mL / 0.5 mL), and the reaction was carried out at 90 °C for 6 hours under nitrogen protection. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20 / 80) to obtain a crude product, which was then purified by Prep-HPLC to obtain the title compound (8.4 mg, white solid), yield: 29%. MS (ESI): m / z 462.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.91(s,1H),8.41(s,1H),7.39-7.29(m,7H),4.34(dd,J=12.0,4.8Hz,1H),3.74-3.64(m,1H),2.97-2.90(m,1H),2.83-2 .75(m,1H),2.56-2.55(m,1H),2.35-2.30(m,1H),2.08-2.01(m,1H),1.1 1-1.06(m,2H),1.02-0.97(m,2H),0.97-0.90(m,2H),0.59-0.52(m,2H).

[0820] Example 85

[0821] 3-(2-chloro-4'-((5-methoxypyrimidin-2-yl)(2,2,2-trifluoroethyl)amino)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0822] (1) N-(4-bromophenyl)-5-methoxy-N-(2,2,2-trifluoroethyl)pyrimidin-2-amine

[0823] N-(4-bromophenyl)-5-methoxypyrimidine-2-amine (700 mg, 2.5 mmol, Example 30, Step 1), N,N-dimethylformamide (10 mL), cesium carbonate (1.63 g, 5 mmol), and 2,2,2-trifluoroethyltrifluoromethanesulfonate (870 mg, 3.75 mmol) were added to a 20 mL sealed tube and stirred overnight at 100 °C under nitrogen protection. The reaction mixture was poured into saturated brine (50 mL) and extracted with ethyl acetate (2 x 30 mL). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 80 / 20) to give the title compound (60 mg, pale yellow solid), yield: 6.6%. MS (ESI): m / z 362.0 [M+H] + .

[0824] (2) 3-(2-chloro-4'-((5-methoxypyrimidin-2-yl)(2,2,2-trifluoroethyl)amino)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0825] N-(4-bromophenyl)-5-methoxy-N-(2,2,2-trifluoroethyl)pyrimidin-2-amine (60 mg, 0.166 mmol), intermediate 3 (174 mg, 0.2 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (12 mg, 0.0166 mmol), and potassium phosphate (106 mg, 0.5 mmol) were dissolved in 1,4-dioxane / water (4 mL / 0.5 mL), and the reaction was carried out at 90 °C for 6 hours under nitrogen protection. The reaction solution was concentrated, and the residue was subjected to silica gel column chromatography (petroleum ether / ethyl acetate = 40 / 60) to obtain a crude product, which was then purified by Prep-HPLC to give the title compound (32.6 mg, white solid), yield: 39%. MS (ESI): m / z 505.1 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ10.93(s,1H),8.30(s,2H),7.49-7.34(m,7H),4.89(q,J=9.2Hz,2H),4.37(dd,J=1 2.0,4.8Hz,1H),3.81(s,3H),2.87-2.76(m,1H),2.59-2.55(m,1H),2.38-2.29(m,1H),2.10-2.02(m,1H).

[0826] Example 86

[0827] 3-(2-chloro-4'-(cyclopropyl(5-(difluoromethyl)pyrimidin-2-yl)amino)-3'-methyl-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0828] (1) N-(4-bromo-2-methylphenyl)-5-(difluoromethyl)pyrimidin-2-amine

[0829] 2-Chloro-5-(difluoromethyl)pyrimidine (100 mg, 0.61 mmol), 4-bromo-2-methylaniline (226 mg, 1.22 mmol), glacial acetic acid (0.5 mL), and 1,4-dioxane (1.5 mL) were added to a 10 mL sealed tube and reacted overnight at 100 °C under nitrogen protection with stirring. The reaction mixture was diluted with ethyl acetate (30 mL), the organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by reverse-phase column chromatography (acetonitrile / water = 50 / 50) to give the title compound (80 mg, pale yellow solid), yield: 42%. MS (ESI): m / z 314.0 [M+H] + .

[0830] (2) N-(4-bromo-2-methylphenyl)-N-cyclopropyl-5-(difluoromethyl)pyrimidin-2-amine

[0831] N-(4-bromo-2-methylphenyl)-5-(difluoromethyl)pyrimidin-2-amine (30 mg, 0.1 mmol) was dissolved in N,N-dimethylformamide (5 mL), and cyclopropylboronic acid (16.4 mg, 0.19 mmol), acetone (17 mg, 0.1 mmol), 2,2'-bipyridine (15 mg, 0.1 mmol), and potassium carbonate (26.4 mg, 0.19 mmol) were added. The mixture was stirred overnight at 120 °C under an oxygen atmosphere. The reaction solution was diluted with ethyl acetate (30 mL). The organic phase was washed with 1N dilute hydrochloric acid (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 60 / 40) to give the title compound (20 mg, pale yellow oil), yield: 59.2%. MS (ESI): m / z 354.0 [M+H] + .

[0832] (3) 3-(2-chloro-4'-(cyclopropyl(5-(difluoromethyl)pyrimidin-2-yl)amino)-3'-methyl-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0833] N-(4-bromo-2-methylphenyl)-N-cyclopropyl-5-(difluoromethyl)pyrimidin-2-amine (20 mg, 0.057 mmol), intermediate 3 (74 mg, 0.085 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (4 mg, 0.006 mmol), and potassium phosphate (24 mg, 0.11 mmol) were dissolved in 1,4-dioxane / water (4 mL / 0.5 mL), and the reaction was carried out at 90 °C for 6 hours under nitrogen protection. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 40 / 60) to obtain a crude product, which was then purified by Prep-HPLC to obtain the title compound (8.8 mg, white solid), yield: 31.3%. MS (ESI): m / z 497.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ10.93(s,1H),8.62(s,2H),7.44-7.32(m,4H),7.30 (dd,J=8.0,2.0Hz,1H),7.20(d,J=8.0Hz,1H),7.01(t,J=55.2Hz,1H),4.36( dd,J=12.0,4.8Hz,1H),2.83-2.76(m,1H),2.57-2.55(m,2H),2.37-2.31(m ,1H),2.07(s,3H),2.06-1.99(m,1H),0.92-0.79(m,2H),0.57-0.40(m,2H).

[0834] Example 87

[0835] 3-(2-chloro-4'-((1-cyclopropyl-1H-1,2,4-triazol-3-yl)(cyclopropylmethyl)amino)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0836] (1) N-(4-chlorophenyl)-1-cyclopropyl-N-(cyclopropylmethyl)-1H-1,2,4-triazol-3-amine

[0837] N-(4-chlorophenyl)-1-cyclopropyl-1H-1,2,4-triazol-3-amine (88 mg, 0.375 mmol, Step 2 of Example 68), N,N-dimethylformamide (4 mL), (bromomethyl)cyclopropane (101 mg, 0.75 mmol), and sodium hydride (45 mg, 1.13 mmol) were added to a 20 mL sealed tube and the mixture was stirred overnight at 70 °C under nitrogen protection. The reaction mixture was poured into saturated brine (50 mL) and extracted with ethyl acetate (2 x 30 mL). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 60 / 40) to give the title compound (72 mg, pale yellow oil), yield: 66.5%. MS (ESI): m / z 289.2 [M+H] + .

[0838] (2) 3-(2-chloro-4'-((1-cyclopropyl-1H-1,2,4-triazol-3-yl)(cyclopropylmethyl)amino)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0839] N-(4-chlorophenyl)-1-cyclopropyl-N-(cyclopropylmethyl)-1H-1,2,4-triazol-3-amine (72 mg, 0.25 mmol), intermediate 3 (357 mg, 0.37 mmol), methanesulfonic acid (2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (20 mg, 0.025 mmol), and potassium phosphate (159 mg, 0.75 mmol) were dissolved in toluene / water (4 mL / 0.5 mL) and reacted overnight at 90 °C under nitrogen protection. The reaction solution was concentrated, and the residue was purified by thin-layer chromatography (100% ethyl acetate) to obtain a crude product, which was then purified by Prep-HPLC to obtain the title compound (1.2 mg, white solid), yield: 1%. MS (ESI): m / z 476.2 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ10.78(s,1H),8.29(s,1H),7.56-7.25(m,7H),4.37-4.31(m,1H),3.83(d,J=6.4Hz,2H),3.64-3.61(m,1H),2.82-2.76 (m,1H),2.57-2.56(m,1H),2.37-2.28(m,1H),2.06-1.97(m,2H),1.08 -1.02(m,2H),1.02-0.93(m,2H),0.48-0.38(m,2H),0.36-0.22(m,2H).

[0840] Example 88

[0841] 3-(2-chloro-4'-((3,3-difluorocyclobutyl)(5-(difluoromethyl)pyrimidin-2-yl)amino)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0842] (1) N-(3,3-difluorocyclobutyl)-5-(difluoromethyl)pyrimidin-2-amine

[0843] 2-Chloro-5-(difluoromethyl)pyrimidine (50 mg, 0.30 mmol) and 3,3-difluorocyclobutane-1-amine (32 mg, 0.30 mmol) were dissolved in N-methylpyrrolidone (5 mL), and N,N-diisopropylethylamine (77 mg, 0.60 mmol) was added. The mixture was stirred at 130 °C for 16 hours. The reaction mixture was then extracted with water (30 mL) and ethyl acetate (20 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 99 / 1) to give the title compound (50 mg, pale yellow solid), yield: 70%. MS (ESI): m / z 236.1 [M+H] + .

[0844] (2) N-(4-bromophenyl)-N-(3,3-difluorocyclobutyl)-5-(difluoromethyl)pyrimidin-2-amine

[0845] N-(3,3-difluorocyclobutyl)-5-(difluoromethyl)pyrimidin-2-amine (20 mg, 0.09 mmol) and 4-bromophenylboronic acid (34 mg, 0.17 mmol) were dissolved in N,N-dimethylformamide (5 mL), and 2,2'-bipyridine (13 mg, 0.09 mmol), copper acetate (15 mg, 0.09 mmol), and potassium carbonate (23 mg, 0.17 mmol) were added. The mixture was stirred at 120 °C for 20 hours under oxygen bulb conditions. The reaction mixture was then diluted with water (50 mL) and extracted with ethyl acetate (30 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 92 / 8) to give the title compound (10 mg, white solid), yield: 30%. MS (ESI): m / z 390.0 [M+H] + .

[0846] (3) 3-(2-chloro-4'-((3,3-difluorocyclobutyl)(5-(difluoromethyl)pyrimidin-2-yl)amino)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0847] N-(4-bromophenyl)-N-(3,3-difluorocyclobutyl)-5-(difluoromethyl)pyrimidin-2-amine (10 mg, 0.026 mmol), intermediate 3 (11 mg, 0.031 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (2 mg, 0.003 mmol), and potassium phosphate (11 mg, 0.052 mmol) were dissolved in 1,4-dioxane / water (5 mL / 0.5 mL). The mixture was stirred at 85 °C under nitrogen protection for 16 hours. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 92 / 8) to obtain a crude product, which was then purified by Prep-HPLC to obtain the title compound (2 mg, white solid), yield: 15%. MS (ESI): m / z 533.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.93(s,1H),8.62(s,2H),7.55-7.32(m,7H),7.02(t,J=55.2Hz,1H),4.92-4.88(m,1H), 4.40-4.34(m,1H),3.06-2.93(m,2H),2.85-2.74(m,1H),2.63-2.55(m,2H),2.45-2.27(m,2H),2.11-1.98(m,1H).

[0848] Example 89

[0849] 3-(2-chloro-4'-((3-(difluoromethylene)cyclobutyl)(5-methoxypyrimidin-2-yl)amino)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0850] (1)(3-(difluoro(pyridin-2-ylsulfonyl)methyl)-3-hydroxycyclobutyl)carbamate tert-butyl ester

[0851] Potassium tert-butoxide (1.2 g, 10.8 mmol) was dissolved in N,N-dimethylformamide (10 mL), and tert-butyl (3-oxocyclobutyl)carbamate (1 g, 5.4 mmol) and 2-((difluoromethyl)sulfonyl)pyridine (1 g, 5.4 mmol) were dissolved in N,N-dimethylformamide (10 mL). These solutions were added dropwise to the reaction mixture at -50 °C. The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was directly purified by reverse-phase column chromatography to give the title compound (500 mg, yellow solid), yield: 25%. MS (ESI): m / z 379.1 [M+H] + .

[0852] (2) 3-(difluoromethylene)cyclobutane-1-amine hydrochloride

[0853] (400 mg, 1.06 mmol) tert-butyl (3-(difluoro(pyridin-2-ylsulfonyl)methyl)-3-hydroxycyclobutyl)carbamate was dissolved in 10 mL of 4 M dioxane hydrochloride solution and stirred at room temperature for 4 hours. The reaction solution was concentrated to give the title compound (125 mg, colorless oil), which was used directly in the next step. MS (ESI): m / z 120.2 [M+H] + .

[0854] (3) N-(3-(difluoromethylene)cyclobutyl)-5-methoxypyrimidin-2-amine

[0855] 3-(difluoromethylene)cyclobutane-1-amine hydrochloride (120 mg, 1 mmol), 2-bromo-5-methoxypyrimidine (189 mg, 1 mmol), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (116 mg, 0.2 mmol), tris(dibenzylacetone)dipalladium (91.5 mg, 0.1 mmol), and cesium carbonate (652 mg, 2 mmol) were dissolved in 1,4-dioxane (10 mL), and the mixture was purged with nitrogen. The reaction mixture was stirred overnight at 100 °C under nitrogen protection. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to give the title compound (70 mg, yellow solid), yield: 30.7%. MS (ESI): m / z 228.1 [M+H] + .

[0856] (4) N-(4-bromophenyl)-N-(3-(difluoromethylene)cyclobutyl)-5-methoxypyrimidin-2-amine

[0857] N-(3-(difluoromethylene)cyclobutyl)-5-methoxypyrimidin-2-amine (70 mg, 0.3 mmol) and 4-bromophenylboronic acid (120 mg, 0.6 mmol) were dissolved in N,N-dimethylformamide (5 mL), and 2,2'-bipyridine (47 mg, 0.3 mmol), copper acetate (55 mg, 0.3 mmol), and potassium carbonate (83 mg, 0.6 mmol) were added. The mixture was stirred overnight at 120 °C under an oxygen bulb. Water (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (10 mL x 3). The organic phase was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to give the title compound (8 mg, yellow oil), yield: 7%. MS (ESI): m / z 382.0 [M+H] + .

[0858] (5) 3-(2-chloro-4'-((3-(difluoromethylene)cyclobutyl)(5-methoxypyrimidin-2-yl)amino)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0859] N-(4-bromophenyl)-N-(3-(difluoromethylene)cyclobutyl)-5-methoxypyrimidin-2-amine (8 mg, 0.02 mmol) and intermediate 3 (14 mg, 0.04 mmol) were dissolved in 1,4-dioxane / water (5 mL / 1 mL), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (2 mg, 0.002 mmol) and potassium phosphate (8 mg, 0.04 mmol) were added. The reaction mixture was heated to 90 °C and stirred for 4 hours under nitrogen protection. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain a crude product, which was then purified by Prep-HPLC to obtain the title compound (1.8 mg, white solid), yield: 17%. MS (ESI): m / z 525.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.94(s,1H),8.24(s,2H),7.49-7.27(m,7H),5.04-4.96(m,1H),4.37(dd,J=12.0,4.8Hz,1H),3.7 8(s,3H),3.06-2.99(m,2H),2.85-2.76(m,1H),2.74-2.67(m,2H),2.57-2.56(m,1H),2.39-2.31(m,1H),2.09-2.03(m,1H).

[0860] Example 90

[0861] 3-(2-chloro-4'-(cyclopropyl(5-(1-fluorocyclopropyl)pyrimidin-2-yl)amino)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0862] (1) Methyl 2-(cyclopropyl(4-methoxybenzyl)amino)pyrimidine-5-carboxylic acid

[0863] 2-Chloroprene-5-carboxylic acid methyl ester (1 g, 5.8 mmol) and N-(4-methoxybenzyl)cyclopropylamine (1 g, 5.8 mmol) were dissolved in acetonitrile (10 mL), and potassium carbonate (1.6 g, 11.6 mmol) was added. The mixture was stirred at 60 °C for 3 hours. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to give the title compound (1.7 g, colorless oil), yield: 93%. MS (ESI): m / z 314.2 [M+H] + .

[0864] (2) 1-(2-(cyclopropyl(4-methoxybenzyl)amino)pyrimidin-5-yl)cyclopropyl-1-ol

[0865] Methyl 2-(cyclopropyl(4-methoxybenzyl)amino)pyrimidine-5-carboxylic acid (1.7 g, 5.4 mmol) was dissolved in tetrahydrofuran (10 mL). Tetraisopropyl titanate (3 g, 10.8 mmol) and magnesium ethyl bromide (3.4 M, 6.3 mL, 21.6 mmol) were added dropwise to the reaction mixture at 0 °C. The reaction mixture was stirred overnight at room temperature. A saturated ammonium chloride aqueous solution (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (10 mL x 3). The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give the title compound (460 mg, colorless oil), yield: 27%. MS (ESI): m / z 312.2 [M+H] + .

[0866] (3) N-Cyclopropyl-5-(1-Fluorocyclopropyl)-N-(4-Methoxybenzyl)pyrimidin-2-amine

[0867] 1-(2-(cyclopropyl(4-methoxybenzyl)amino)pyrimidin-5-yl)cycloprop-1-ol (460 mg, 1.5 mmol) was dissolved in dichloromethane (10 mL), and diethylaminosulfur trifluoride (DAST) (1.2 g, 7.5 mmol) was added at -50 °C. The mixture was stirred for half an hour. The reaction solution was quenched with methanol (20 mL), concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to give the title compound (180 mg, colorless oil), yield: 39%. MS (ESI): m / z 314.2 [M+H] + .

[0868] (4) N-Cyclopropyl-5-(1-Fluorocyclopropyl)pyrimidin-2-amine

[0869] N-cyclopropyl-5-(1-fluorocyclopropyl)-N-(4-methoxybenzyl)pyrimidine-2-amine (180 mg, 0.58 mmol) was dissolved in trifluoroacetic acid (5 mL), and the reaction mixture was heated to 70 °C and stirred for 5 hours. The reaction mixture was concentrated to give the title compound (110 mg, colorless oil). MS (ESI): m / z 194.2 [M+H] + .

[0870] (5) N-(4-bromophenyl)-N-cyclopropyl-5-(1-fluorocyclopropyl)pyrimidin-2-amine

[0871] N-cyclopropyl-5-(1-fluorocyclopropyl)pyrimidin-2-amine (110 mg, 0.57 mmol) and 4-bromophenylboronic acid (228 mg, 1.14 mmol) were dissolved in N,N-dimethylformamide (5 mL), and 2,2'-bipyridine (89 mg, 0.57 mmol), copper acetate (104 mg, 0.57 mmol), and potassium carbonate (157 mg, 1.14 mmol) were added. The mixture was stirred overnight at 120 °C under an oxygen bulb. Water (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (10 mL x 3). The organic phase was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to give the title compound (24 mg, yellow oil), yield: 12%. MS (ESI): m / z 348.2 [M+H] + .

[0872] (6) 3-(2-chloro-4'-(cyclopropyl(5-(1-fluorocyclopropyl)pyrimidin-2-yl)amino)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0873] N-(4-bromophenyl)-N-cyclopropyl-5-(1-fluorocyclopropyl)pyrimidin-2-amine (24 mg, 0.07 mmol) and intermediate 3 (49 mg, 0.14 mmol) were dissolved in 1,4-dioxane / water (5 mL / 1 mL), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (5 mg, 0.007 mmol) and potassium phosphate (30 mg, 0.14 mmol) were added. The reaction mixture was heated to 90 °C and stirred for 4 hours under nitrogen protection. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain a crude product, which was then purified by Prep-HPLC to obtain the title compound (2.5 mg, white solid), yield: 7.3%. MS (ESI): m / z 491.2 [M+H] + . 1 ¹H NMR (400MHz, DMSO-d⁶) δ 10.93 (s, 1H), 8.49 (s, 2H), 7.45-7.33 (m, 7H), 4.37 (dd, J = 12.0, 4.8Hz, 1H), 3.25-3.19 (m, 1H), 2.85-2.73 (m, 1H), 2.57-2.56 (m, 1H), 2.40-2.29 (m, 1H), 2.09-2.05 (m, 1H), 1.43-1.35 (m, 2H), 1.13-1.07 (m, 2H), 0.94-0.90 (m, 2H), 0.53-0.49 (m, 2H). Example 91

[0874] 3-(2-chloro-4'-(cyclopropyl(5-(difluoromethyl)pyrimidin-2-yl)amino)-3'-fluoro-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0875] (1) N-(4-bromo-2-fluorophenyl)-5-(difluoromethyl)pyrimidin-2-amine

[0876] 4-Bromo-2-fluoroaniline (50 mg, 0.26 mmol) and 2-chloro-5-(difluoromethyl)pyrimidine (43 mg, 0.26 mmol) were dissolved in 1,4-dioxane / acetic acid (3 mL / 1 mL), and the mixture was heated to 110 °C and stirred for 16 hours. Water (30 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 85 / 15) to give the title compound (40 mg, pale yellow solid), yield: 48%. MS (ESI): m / z 318.0 [M+H] + .

[0877] (2) N-(4-bromo-2-fluorophenyl)-N-cyclopropyl-5-(difluoromethyl)pyrimidin-2-amine

[0878] N-(4-bromo-2-fluorophenyl)-5-(difluoromethyl)pyrimidin-2-amine (40 mg, 0.13 mmol) and cyclopropylboronic acid (22 mg, 0.26 mmol) were dissolved in N,N-dimethylformamide (10 mL), and 2,2'-bipyridine (20 mg, 0.13 mmol), copper acetate (24 mg, 0.13 mmol), and potassium carbonate (36 mg, 0.26 mmol) were added. The mixture was stirred at 120 °C under oxygen bulb conditions for 20 hours. Water (50 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 90 / 10) to give the title compound (40 mg, white solid), yield: 86%. MS (ESI): m / z 358.0 [M+H] + .

[0879] (3) 3-(2-chloro-4'-(cyclopropyl(5-(difluoromethyl)pyrimidin-2-yl)amino)-6-fluoro-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0880] N-(4-bromo-2-fluorophenyl)-N-cyclopropyl-5-(difluoromethyl)pyrimidin-2-amine (40 mg, 0.11 mmol) and intermediate 3 (56 mg, 0.16 mmol) were dissolved in 1,4-dioxane / water (5 mL / 0.5 mL), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (7 mg, 0.01 mmol) and potassium phosphate (47 mg, 0.22 mmol) were added. The mixture was heated to 85 °C and stirred for 10 hours under nitrogen protection. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 92 / 8) to obtain a crude product, which was then purified by Prep-HPLC to obtain the title compound (11.5 mg, white solid), yield: 21%. MS (ESI): m / z 501.2 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ10.94(s,1H),8.66(s,2H),7.48-7.31(m,6H),7.03(t,J=55.4Hz,1H),4.38(dd,J=12.0,4.8Hz,1H),3.30 -3.23(m,1H),2.83-2.77(m,1H),2.58-2.56(m,1H),2.39-2.28(m,1H),2.11-2.01(m,1H),0.97-0.88(m,2H),0.60-0.49(m,2H).

[0881] Example 92

[0882] 3-(2-chloro-4'-((1-methyl-1H-1,2,4-triazol-3-yl)(oxetane-3-yl)amino)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0883] (1) N-(4-bromophenyl)-1-methyl-N-(oxetane-3-yl)-1H-1,2,4-triazol-3-amine

[0884] N-(4-bromophenyl)-1-methyl-1H-1,2,4-triazol-3-amine (100 mg, 0.39 mmol, Step 1 of Example 22) and 3-iodooxetine (144 mg, 0.78 mmol) were dissolved in N,N-dimethylformamide (5 mL), and sodium hydride (48 mg, 1.2 mmol) was added. The mixture was stirred overnight at 70 °C. Water (10 mL) was added to the reaction mixture, and the solution was extracted with ethyl acetate (10 mL x 3). The organic phases were combined, concentrated, and the residue was purified by silica gel column chromatography (100% ethyl acetate) to give the title compound (60 mg, white solid), yield: 49.8%. MS (ESI): m / z 309.0 [M+H] + .

[0885] (2) 3-(2-chloro-4'-((1-methyl-1H-1,2,4-triazol-3-yl)(oxetane-3-yl)amino)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0886] N-(4-bromophenyl)-1-methyl-N-(oxetane-3-yl)-1H-1,2,4-triazol-3-amine (60 mg, 0.19 mmol) and intermediate 3 (99 mg, 0.28 mmol) were dissolved in 1,4-dioxane / water (5 mL / 1 mL), and PdCl2 (dppf) (14 mg, 0.019 mmol) and potassium phosphate (80 mg, 0.38 mmol) were added. The mixture was heated to 90 °C and stirred for 4 hours under nitrogen protection. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to obtain a crude product, which was then purified by Prep-HPLC to obtain the title compound (19.9 mg, white solid), yield: 23%. MS (ESI): m / z 452.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.92(s,1H),8.23(s,1H),7.41-7.30(m,5H),7.24-7.21(m,2H),5.16-5.10(m,1H),4.78(t,J=6.8Hz,2H),4.42 (t,J=6.8Hz,2H),4.35(dd,J=12.0,4.8Hz,1H),3.75(s,3H),2.84-2.75(m,1H),2.56-2.54(m,1H),2.38-2.29(m,1H),2.07-2.03(m,1H).

[0887] Example 93

[0888] 3-(2-chloro-4'-((1-cyclopropyl-1H-1,2,4-triazol-3-yl)(oxetane-3-yl)amino)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0889] (1) N-(4-bromophenyl)-1-cyclopropyl-N-(oxetane-3-yl)-1H-1,2,4-triazol-3-amine

[0890] N-(4-bromophenyl)-1-cyclopropyl-1H-1,2,4-triazol-3-amine (50 mg, 0.18 mmol), N,N-dimethylformamide (4 mL), 3-iodooxetine (66 mg, 0.36 mmol), and sodium hydride (22 mg, 0.54 mmol, 60%) were added to a 20 mL sealed tube and the mixture was stirred overnight at 100 °C under nitrogen protection. The reaction mixture was poured into saturated brine (50 mL) and extracted with ethyl acetate (2 x 30 mL). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 40 / 60) to give the title compound (32 mg, pale yellow oil), yield: 53%. MS (ESI): m / z 335.1 [M+H] + .

[0891] (2) 3-(2-chloro-4'-((1-cyclopropyl-1H-1,2,4-triazol-3-yl)(oxetane-3-yl)amino)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0892] N-(4-bromophenyl)-1-cyclopropyl-N-(oxetane-3-yl)-1H-1,2,4-triazol-3-amine (30 mg, 0.09 mmol) and intermediate 3 (117 mg, 0.13 mmol) were dissolved in dioxane / water (4 mL / 0.5 mL). [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (7 mg, 0.01 mmol) and potassium phosphate (57 mg, 0.27 mmol) were added, and the mixture was heated to 90 °C for 3 hours under nitrogen protection. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (100% ethyl acetate) to obtain a crude product, which was then purified by Prep-HPLC to give the title compound (8.6 mg, white solid), yield: 20.1%. MS (ESI): m / z 478.2 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ10.91(s,1H),8.33(s,1H),7.44-7.30(m,5H),7.23 (d,J=8.4Hz,2H),5.19-5.04(m,1H),4.78(t,J=6.8Hz,2H),4.41(t,J=6.8H z,2H),4.34(dd,J=12.0,4.8Hz,1H),3.68-3.58(m,1H),2.85-2.73(m,1H), 2.58-2.55(m,1H),2.39-2.31(m,1H),2.09-2.00(m,1H),1.07-0.93(m,4H).

[0893] Example 94

[0894] 3-(2-chloro-4'-(cyclopropyl(5-methoxypyrimidin-2-yl)amino)-[1,1'-biphenyl]-3-yl)-3-fluoropiperidine-2,6-dione

[0895] (1) 3-(2-chloro-4'-(cyclopropyl(5-methoxypyrimidin-2-yl)amino)-[1,1'-biphenyl]-3-yl)-3-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)piperidin-2,6-dione

[0896] Intermediate 4 (200 mg, 0.4 mmol), N-(4-bromophenyl)-N-cyclopropyl-5-methoxypyrimidin-2-amine (128 mg, 0.4 mmol, Step 2 of Example 30), PdCl2 (dppf) (29 mg, 0.04 mmol), and potassium phosphate (170 mg, 0.8 mmol) were dissolved in 1,4-dioxane / water (5 mL / 1 mL). The mixture was heated to 90 °C and stirred overnight under nitrogen protection. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 85 / 15) to give the title compound (190 mg, yellow oil), yield: 78%. MS (ESI): m / z 611.2 [M+H] + .

[0897] (2) 3-(2-chloro-4'-(cyclopropyl(5-methoxypyrimidin-2-yl)amino)-[1,1'-biphenyl]-3-yl)-3-fluoropiperidin-2,6-dione

[0898] 3-(2-chloro-4'-(cyclopropyl(5-methoxypyrimidin-2-yl)amino)-[1,1'-biphenyl]-3-yl)-3-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)piperidin-2,6-dione (90 mg, 0.15 mmol) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (3 mL) was added. The reaction mixture was reacted at room temperature for 2 hours. The reaction mixture was concentrated, and acetonitrile (5 mL) was added, followed by ammonia (26%, 0.2 mL). The reaction mixture was reacted at room temperature for 2 hours. The reaction mixture was concentrated, and the residue was purified by Prep-HPLC to give the title compound (24 mg, white solid), yield: 34%. MS (ESI): m / z 481.1 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ11.50(s,1H),8.29(s,2H),7.67-7.50(m,3H),7.39-7.36(m,4H),3.80(s,3H),3.13- 3.08(m,1H),3.03-2.84(m,2H),2.67-2.60(m,1H),2.35-2.28(m,1H),0.93-0.89(m,2H),0.50-0.46(m,2H).

[0899] Example 95

[0900] 1-(2-chloro-4'-(cyclopropyl(5-(difluoromethyl)pyrimidin-2-yl)amino)-[1,1'-biphenyl]-3-yl)dihydropyrimidin-2,4(1H,3H)-dione

[0901] N-(4-bromophenyl)-N-cyclopropyl-5-(difluoromethyl)pyrimidin-2-amine (25 mg, 0.07 mmol, Step 2 of Example 60), intermediate 5 (28 mg, 0.08 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (7 mg, 0.01 mmol), and potassium phosphate (25 mg, 0.18 mmol) were dissolved in 1,4-dioxane / water (5 mL / 0.5 mL), and the mixture was stirred at 85 °C under nitrogen protection for 10 hours. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 92 / 8) to obtain a crude product, which was then purified by Prep-HPLC to obtain the title compound (5.1 mg, white solid), yield: 14%. MS (ESI): m / z 484.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.49(s,1H),8.63(s,2H),7.57-7.45(m,5H),7.37(d,J=8.3Hz,2H),7.02(t,J=55 .4Hz,1H),3.83-3.62(m,2H),3.28-3.24(m,1H),2.83-2.73(m,2H),0.98-0.90(m,2H),0.56-0.48(m,2H).

[0902] Example 96

[0903] 3-(2-chloro-4'-(cyclopropyl(1-methyl-1H-1,2,4-triazol-3-yl)amino)-[1,1'-biphenyl]-3-yl)-3-fluoropiperidine-2,6-dione

[0904] (1) 3-(2-chloro-4'-(cyclopropyl(1-methyl-1H-1,2,4-triazol-3-yl)amino)-[1,1'-biphenyl]-3-yl)-3-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)piperidin-2,6-dione

[0905] Intermediate 4 (338 mg, 0.68 mmol), N-(4-bromophenyl)-N-cyclopropyl-1-methyl-1H-1,2,4-triazol-3-amine (200 mg, 0.68 mmol, Step 2 of Example 22), PdCl2 (dppf) (50 mg, 0.068 mmol), and potassium phosphate (288 mg, 1.36 mmol) were dissolved in 1,4-dioxane / water (10 mL / 2 mL). The mixture was heated to 90 °C and stirred overnight under nitrogen protection. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20 / 80) to give the title compound (237 mg, yellow oil), yield: 60%. MS (ESI): m / z 584.3 [M+H] + .

[0906] (2) 3-(2-chloro-4'-(cyclopropyl(1-methyl-1H-1,2,4-triazol-3-yl)amino)-[1,1'-biphenyl]-3-yl)-3-fluoropiperidin-2,6-dione

[0907] 3-(2-chloro-4'-(cyclopropyl(1-methyl-1H-1,2,4-triazol-3-yl)amino)-[1,1'-biphenyl]-3-yl)-3-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)piperidin-2,6-dione (237 mg, 0.4 mmol) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (5 mL) was added. The reaction mixture was reacted at room temperature for 2 hours. The reaction mixture was concentrated, and acetonitrile (5 mL) was added, followed by ammonia (26%, 0.5 mL). The reaction mixture was reacted at room temperature for 2 hours. The reaction mixture was concentrated, and the residue was purified by Prep-HPLC to give the title compound (52.1 mg, white solid), yield: 28%. MS (ESI): m / z 454.1 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ11.47(s,1H),8.31(s,1H),7.64-7.62(m,1H),7.54(t,J=7.7Hz,1H),7.46-7.44(m,1H),7.36-7.34(m,2H ),7.29-7.27(m,2H),3.81(s,3H),2.98-2.86(m,3H),2.67-2.60(m,1H),2.33-2.26(m,1H),0.96-0.91(m,2H),0.57-0.53(m,2H).

[0908] Example 97

[0909] 1-(2-chloro-4'-(cyclopropyl(5-(difluoromethoxy)pyrimidin-2-yl)amino)-[1,1'-biphenyl]-3-yl)dihydropyrimidin-2,4(1H,3H)-dione

[0910] N-(4-bromophenyl)-N-cyclopropyl-5-(difluoromethoxy)pyrimidin-2-amine (15 mg, 0.04 mmol, Step 2 of Example 71), intermediate 5 (18 mg, 0.05 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (7 mg, 0.01 mmol), and potassium phosphate (14 mg, 0.10 mmol) were dissolved in 1,4-dioxane / water (5 mL / 0.5 mL), and the mixture was stirred at 85 °C under nitrogen protection for 10 hours. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 92 / 8) to obtain a crude product, which was then purified by Prep-HPLC to obtain the title compound (2.0 mg, white solid), yield: 10%. MS (ESI): m / z 500.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.49(s,1H),8.42(s,2H),7.54-7.43(m,5H),7.37(d,J=8.5Hz,2H),7.13(t,J=73.6Hz,1H) ,3.81-3.73(m,1H),3.70-3.63(m,1H),3.23-3.16(m,1H),2.80-2.74(m,2H),0.97-0.80(m,2H),0.64-0.41(m,2H).

[0911] Examples 98 and 99

[0912] (R)-3-(2-chloro-4'-(cyclopropyl(1-methyl-1H-1,2,4-triazol-3-yl)amino)-[1,1'-biphenyl]-3-yl)-3-fluoropiperidine-2,6-dione and (S)-3-(2-chloro-4'-(cyclopropyl(1-methyl-1H-1,2,4-triazol-3-yl)amino)-[1,1'-biphenyl]-3-yl)-3-fluoropiperidine-2,6-dione

[0913] Compound 96 (70 mg) was prepared by chiral separation (chiral separation condition 1) to obtain compound 98 (23.8 mg, white solid) and compound 99 (29 mg, white solid). Absolute configuration was not determined.

[0914] Compound of Example 98 (corresponding to compounds with shorter retention times): MS (ESI): m / z 454.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ11.50(s,1H),8.31(s,1H),7.64-7.62(m,1H),7.54(t,J=7.7Hz,1H),7.46-7.44(m,1H),7.36-7.34(m,2H ),7.29-7.27(m,2H),3.81(s,3H),2.98-2.86(m,3H),2.67-2.60(m,1H),2.33-2.28(m,1H),0.96-0.91(m,2H),0.57-0.53(m,2H).

[0915] Compound of Example 99 (corresponding to the compound with longer retention time): MS (ESI): m / z 454.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ11.50(s,1H),8.31(s,1H),7.64-7.62(m,1H),7.54(t,J=7.7Hz,1H),7.46-7.44(m,1H),7.36-7.34(m,2H ),7.29-7.27(m,2H),3.81(s,3H),2.98-2.86(m,3H),2.67-2.60(m,1H),2.33-2.27(m,1H),0.96-0.91(m,2H),0.57-0.53(m,2H).

[0916] Examples 100 and 101

[0917] (R)-3-(2-chloro-4'-(cyclopropyl(5-methoxypyrimidin-2-yl)amino)-[1,1'-biphenyl]-3-yl)-3-fluoropiperidine-2,6-dione and (S)-3-(2-chloro-4'-(cyclopropyl(5-methoxypyrimidin-2-yl)amino)-[1,1'-biphenyl]-3-yl)-3-fluoropiperidine-2,6-dione

[0918] Compound 94 (20 mg) was prepared by chiral separation (chiral separation condition 2) to obtain compound 100 (6 mg, white solid) and compound 101 (5.1 mg, white solid). Absolute configuration was not determined.

[0919] Compound of Example 100 (corresponding to compounds with shorter retention times): MS (ESI): m / z 481.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ11.49(s,1H),8.29(s,2H),7.67-7.50(m,3H),7.39-7.36(m,4H),3.80(s,3H),3.13- 3.08(m,1H),3.02-2.84(m,2H),2.67-2.61(m,1H),2.33-2.27(m,1H),0.93-0.89(m,2H),0.50-0.46(m,2H).

[0920] Example 101 Compound (corresponding to the compound with longer retention time): MS (ESI): m / z 481.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ11.50(s,1H),8.29(s,2H),7.67-7.52(m,3H),7.39-7.36(m,4H),3.80(s,3H),3.15- 3.06(m,1H),2.98-2.87(m,2H),2.64-2.61(m,1H),2.33-2.27(m,1H),0.92-0.90(m,2H),0.50-0.44(m,2H).

[0921] Example 102

[0922] 3-(2-chloro-4'-(cyclopropyl(1-methyl-1H-1,2,4-triazol-3-yl)amino)-[1,1'-biphenyl]-3-yl)-3-methylpiperidin-2,6-dione

[0923] (1) 3-(2-chloro-4'-(cyclopropyl(1-methyl-1H-1,2,4-triazol-3-yl)amino)-[1,1'-biphenyl]-3-yl)-3-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)piperidin-2,6-dione

[0924] Intermediate 6 (220 mg, 0.45 mmol), N-(4-bromophenyl)-N-cyclopropyl-1-methyl-1H-1,2,4-triazol-3-amine (131 mg, 0.45 mmol, Step 2 of Example 22), PdCl2 (dppf) (33 mg, 0.045 mmol), and potassium phosphate (190 mg, 0.9 mmol) were dissolved in 1,4-dioxane / water (10 mL / 2 mL). The mixture was heated to 90 °C and stirred overnight under nitrogen protection. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (100% ethyl acetate) to give the title compound (80 mg, yellow oil), yield: 31%. MS (ESI): m / z 580.3 [M+H] + .

[0925] (2) 3-(2-chloro-4'-(cyclopropyl(1-methyl-1H-1,2,4-triazol-3-yl)amino)-[1,1'-biphenyl]-3-yl)-3-methylpiperidin-2,6-dione

[0926] 3-(2-chloro-4'-(cyclopropyl(1-methyl-1H-1,2,4-triazol-3-yl)amino)-[1,1'-biphenyl]-3-yl)-3-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)piperidin-2,6-dione (80 mg, 0.14 mmol) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (5 mL) was added. The reaction mixture was reacted at room temperature for 2 hours. The reaction mixture was concentrated, and acetonitrile (5 mL) and ammonia (26%, 0.5 mL) were added. The reaction mixture was reacted at room temperature for 2 hours. The reaction mixture was concentrated, and the residue was purified by Prep-HPLC to give the title compound (9.2 mg, white solid), yield: 15%. MS (ESI): m / z 450.2 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ10.85(s,1H),8.31(s,1H),7.37-7.30(m,7H),3.82(s,3H),2.96-2.83(m,2H ),2.59-2.55(m,2H),2.12-2.03(m,1H),1.16(d,J=6.8Hz,3H),0.96-0.91(m,2H),0.58-0.54(m,2H).

[0927] Example 103

[0928] 3-(2-chloro-4'-(cyclopropyl(5-methoxypyrimidin-2-yl)amino)-[1,1'-biphenyl]-3-yl)-3-methylpiperidin-2,6-dione

[0929] (1) 3-(2-chloro-4'-(cyclopropyl(5-methoxypyrimidin-2-yl)amino)-[1,1'-biphenyl]-3-yl)-3-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)piperidin-2,6-dione

[0930] Intermediate 6 (330 mg, 0.67 mmol), N-(4-bromophenyl)-N-cyclopropyl-5-methoxypyrimidin-2-amine (214 mg, 0.67 mmol, Step 2 of Example 30), PdCl2 (dppf) (49 mg, 0.067 mmol), and potassium phosphate (284 mg, 1.34 mmol) were dissolved in 1,4-dioxane / water (5 mL / 1 mL). The mixture was heated to 90 °C and stirred overnight under nitrogen protection. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 85 / 15) to give the title compound (300 mg, yellow oil), yield: 74%. MS (ESI): m / z 607.3 [M+H] + .

[0931] (2) 3-(2-chloro-4'-(cyclopropyl(5-methoxypyrimidin-2-yl)amino)-[1,1'-biphenyl]-3-yl)-3-methylpiperidin-2,6-dione

[0932] 3-(2-chloro-4'-(cyclopropyl(5-methoxypyrimidin-2-yl)amino)-[1,1'-biphenyl]-3-yl)-3-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)piperidin-2,6-dione (300 mg, 0.5 mmol) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (3 mL) was added. The reaction mixture was reacted at room temperature for 2 hours. The reaction mixture was concentrated, and acetonitrile (5 mL) was added, followed by ammonia (26%, 0.5 mL). The reaction mixture was reacted at room temperature for 2 hours. The reaction mixture was concentrated, and the residue was purified by Prep-HPLC to give the title compound (42.7 mg, white solid), yield: 18%. MS (ESI): m / z 477.2 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ10.87(s,1H),8.29(s,2H),7.40-7.33(m,7H),3.80(s,3H),3.32-3.29(m,1H),3.13-3.08(m,1H ),2.95-2.84(m,1H),2.60-2.53(m,1H),2.11-2.06(m,1H),1.17(d,J=6.8Hz,3H),0.94-0.89(m,2H),0.51-0.47(m,2H).

[0933] Examples 104 and 105

[0934] (R)-3-(2-chloro-4'-(cyclopropyl(1-methyl-1H-1,2,4-triazol-3-yl)amino)-[1,1'-biphenyl]-3-yl)-3-methylpiperidin-2,6-dione and (S)-3-(2-chloro-4'-(cyclopropyl(1-methyl-1H-1,2,4-triazol-3-yl)amino)-[1,1'-biphenyl]-3-yl)-3-methylpiperidin-2,6-dione

[0935] Compound 40 mg from Example 102 was prepared by chiral separation (chiral separation condition 1) to obtain compound 104 (15.6 mg, white solid) and compound 105 (17.8 mg, white solid). Absolute configuration was not determined.

[0936] Compound 104 (corresponding to compounds with shorter retention times): MS (ESI): m / z 450.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ10.85(s,1H),8.31(s,1H),7.36-7.30(m,7H),3.82(s,3H),2.96-2.84(m,2H ),2.59-2.55(m,2H),2.13-2.03(m,1H),1.16(d,J=6.8Hz,3H),0.96-0.91(m,2H),0.58-0.54(m,2H).

[0937] Compound 105 (corresponding to compounds with longer retention times): MS (ESI): m / z 450.1 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ10.85(s,1H),8.31(s,1H),7.36-7.30(m,7H),3.82(s,3H),2.96-2.85(m,2H ),2.59-2.54(m,2H),2.13-2.03(m,1H),1.16(d,J=6.8Hz,3H),0.96-0.91(m,2H),0.58-0.54(m,2H).

[0938] Examples 106 and 107

[0939] (R)-3-(2-chloro-4'-(cyclopropyl(5-methoxypyrimidin-2-yl)amino)-[1,1'-biphenyl]-3-yl)-3-methylpiperidin-2,6-dione and (S)-3-(2-chloro-4'-(cyclopropyl(5-methoxypyrimidin-2-yl)amino)-[1,1'-biphenyl]-3-yl)-3-methylpiperidin-2,6-dione

[0940] Compound 40 mg of Example 103 was prepared by chiral separation (chiral separation condition 2) to obtain compound 106 (19.1 mg, white solid) and compound 107 (18.8 mg, white solid). The absolute configuration was not determined.

[0941] Compound 106 (corresponding to compounds with shorter retention times): MS (ESI): m / z 477.2 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ10.87(s,1H),8.29(s,2H),7.40-7.33(m,7H),3.80(s,3H),3.32-3.29(m,1H),3.13-3.09(m,1H ),2.95-2.84(m,1H),2.60-2.53(m,1H),2.11-2.05(m,1H),1.17(d,J=6.8Hz,3H),0.94-0.89(m,2H),0.51-0.47(m,2H).

[0942] Compound 107 (corresponding to the compound with the longer retention time): MS (ESI): m / z 477.2 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ10.87(s,1H),8.29(s,2H),7.41-7.33(m,7H),3.80(s,3H),3.32-3.29(m,1H),3.14-3.08(m,1H ),2.95-2.84(m,1H),2.60-2.53(m,1H),2.11-2.06(m,1H),1.17(d,J=6.8Hz,3H),0.94-0.89(m,2H),0.51-0.47(m,2H).

[0943] Example 108

[0944] 3-(2-chloro-4'-(cyclopropyl(1-((1-methoxycyclopropyl)methyl)-1H-1,2,4-triazol-3-yl)amino)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0945] Following the synthetic method of Example 42, the first step involved replacing 1,1-difluoro-2-iodoethane with methyl methanesulfonate (1-methoxycyclopropyl) and proceeding with similar synthetic steps to obtain the title compound (1.9 mg, white solid). MS (ESI): m / z 506.1 [M+H] + .

[0946] Example 109

[0947] 3-(2-chloro-4'-((1-methyl-1H-1,2,4-triazol-3-yl)(2,2,2-trifluoroethyl)amino)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0948] Following the synthetic method of Example 33, the first step involved replacing 1,1-difluoro-2-iodoethane with 2,2,2-trifluoroethyltrifluoromethanesulfonate, and a similar synthetic procedure yielded the title compound (1.8 mg, white solid). MS (ESI): m / z 478.1 [M+H] + .

[0949] Example 110

[0950] 3-(2-chloro-4'-((1-cyclopropyl-1H-1,2,4-triazol-3-yl)(3,3-difluorocyclobutyl)amino)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0951] Following the synthetic method of Example 79, in the first step, 3-bromo-1-methyl-1H-1,2,4-triazole was replaced with 3-iodo-1-cyclopropyl-1H-1,2,4-triazole (Step 1 of Method 2 in Example 84). Similar synthetic steps yielded the title compound (1.6 mg, white solid). MS (ESI): m / z 512.1 [M+H] + .

[0952] Example 111

[0953] 3-(2-chloro-4'-((3-(difluoromethylene)cyclobutyl)(1-methyl-1H-1,2,4-triazol-3-yl)amino)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0954] Following the synthetic method of Example 79, the first step involved replacing 3,3-difluorocyclobutane-1-amine with 3-(difluoromethylene)cyclobutane-1-amine hydrochloride (step 2 of Example 89), and a similar synthetic procedure yielded the title compound (1.3 mg, white solid). MS (ESI): m / z 498.1 [M+H] + .

[0955] Example 112

[0956] 3-(2-chloro-4'-((5-methoxypyrimidin-2-yl)(oxetane-3-yl)amino)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0957] Following the synthetic method of Example 92, in the first step, N-(4-bromophenyl)-5-methoxypyrimidin-2-amine was replaced with N-(4-bromophenyl)-1-methyl-1H-1,2,4-triazol-3-amine (step 1 of Example 30). A similar synthetic procedure yielded the title compound (1.1 mg, white solid). MS (ESI): m / z 479.1 [M+H] + .

[0958] Example 113

[0959] 3-(2-chloro-4'-((5-(difluoromethyl)pyrimidin-2-yl)(oxetane-3-yl)amino)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0960] Following the synthetic method of Example 92, in the first step, N-(4-bromophenyl)-5-(difluoromethyl)pyrimidin-2-amine was replaced with N-(4-bromophenyl)-1-methyl-1H-1,2,4-triazol-3-amine (step 1 of Example 60). Similar synthetic steps yielded the title compound (1.0 mg, white solid). MS (ESI): m / z 499.1 [M+H] + .

[0961] Example 114

[0962] 3-(2-chloro-4'-((1-methyl-1H-1,2,4-triazol-3-yl)(prop-2-yn-1-yl)amino)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0963] Following the synthetic method of Example 33, the first step involved replacing 1,1-difluoro-2-iodoethane with 3-bromopropyne, and a similar synthetic procedure yielded the title compound (1.5 mg, white solid). MS (ESI): m / z 434.1 [M+H] + .

[0964] Example 115

[0965] 3-(2-chloro-4'-((5-methoxypyrimidin-2-yl)(prop-2-yn-1-yl)amino)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0966] Following the synthetic method of Example 85, the first step involved replacing 2,2,2-trifluoroethyltrifluoromethanesulfonate with 3-bromopropyne, and a similar synthetic procedure yielded the title compound (1.6 mg, white solid). MS (ESI): m / z 461.1 [M+H] + .

[0967] Example 116

[0968] 3-(2-chloro-4'-((5-(difluoromethyl)pyrimidin-2-yl)(prop-2-yn-1-yl)amino)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0969] Following the synthetic method of Example 80, the first step involved replacing 1,1-difluoro-2-iodoethane with 3-bromopropyne, and a similar synthetic procedure yielded the title compound (1.2 mg, white solid). MS (ESI): m / z 481.1 [M+H] + .

[0970] Examples 117 to 139

[0971] The compounds of Examples 117-139 were synthesized (see Table 1) by following the synthesis methods of Examples 48 and 49, using intermediate 5 and the corresponding halogenated product as starting materials, and through similar synthesis steps to obtain the corresponding example compounds.

[0972] Table 1

[0973] Examples 140 to 165

[0974] The compounds of Examples 140-165 were synthesized (see Table 2) by following the synthesis methods of Examples 94 and 96, using intermediate 4 and the corresponding halogenated product as starting materials, and through similar synthesis steps to obtain the corresponding example compounds.

[0975] Table 2

[0976] The compounds in the following examples were obtained by resolving the compounds of Examples 140-165 under either chiral separation condition one or chiral separation condition two to obtain the corresponding single chiral isomer 1 or chiral isomer 2 (see Table 3).

[0977] Table 3

[0978] Test Example 1: VAV1 Degradation Activity

[0979] The degradation activity of compounds on VAV1 was detected in the constructed Jurkat-VAV1-HiBiT-Knock in Cells. 40 μL / well of cells were seeded into 384-well plates in RPMI 1640, 10% FBS, and 1% Penicilin / Streptomycin. Different concentration gradients of the compounds were added to the cells, and the cells were cultured at 37°C and 5% CO2 for 24 h. The cell culture plates were equilibrated at room temperature for 10 min. LgBiT protein and... HiBiT lysing substrate was diluted to appropriate volumes at dilutions of 1:100 and 1:50, respectively. Mix thoroughly by inverting the plate in HiBiT lysis buffer. Add 20 μL of Nano-Glo HiBiT lysis reagent to the plate and shake at 300 rpm for 3 minutes in the dark. Incubate the cell culture plate at 25°C for 15 minutes. Read the fluorescence parameters using a microplate reader.

[0980] The compound DC was fitted based on a nonlinear regression equation. 50 :Y=Bottom+(Top-Bottom) / (1+10^((LogDC 50 -X)*HillSlope)), X: compound concentration; Y: Degradation%; Top and Bottom: Plateaus in same units as Y; logDC 50 :same log units as X;HillSlope:Slope factor or Hill slope.

[0981] The compound detection results are shown in Table 4, where A++ indicates <1 nM, A+ indicates 1-5 nM, A indicates 5-10 nM, B indicates 10-100 nM, C indicates 100-1000 nM, and D indicates >1000 nM.

[0982] The positive control drug MRT-6160 was prepared according to the method of compound 185 in Example 24 of WO2024 / 151547.

[0983] Table 4

[0984] Test Example 2: Drug Efficacy Experiment in a Mouse Model of Rheumatoid Arthritis (CIA)

[0985] The purpose of this experiment was to evaluate the efficacy of the test substance in a type II bovine collagen adjuvant-induced DBA / 1 mouse model of arthritis.

[0986] 1. Collagen emulsion formulation

[0987] Collagen dissolution: Collagen was dissolved in 0.1M acetic acid and incubated overnight at 2-8°C to achieve a collagen concentration of 8 mg / mL.

[0988] Emulsification: Add an equal volume of CFA to the collagen solution and emulsify the collagen using a high-speed homogenizer to form an emulsion. This process is carried out on ice.

[0989] 2. Animal modeling

[0990] On Day 0, six animals were randomly selected as Group G1. The other animals were anesthetized with 1-4% isoflurane and injected with collagen / C...

Claims

1. A compound of formula (I): Or its deuterated derivatives, stereoisomers, or pharmaceutically acceptable salts, wherein: R 1 selected from the group consisting of: 1) Choose 1-3 Rs d Substitution; ring A is a 5- to 6-membered aromatic ring or a 5- to 6-membered heteroaromatic ring containing at most 4 heteroatoms selected from N, O, and S; X 1 X 2 Selected from C or N; q is an integer from 1 to 5; r is 0, 1, or 2; 2) Choose 1-3 Rs d Substitution; ring B is a 5- to 6-membered aromatic ring or a 5- to 6-membered heteroaromatic ring containing at most 4 heteroatoms selected from N, O, and S; Z 1 Z 2 Selected from C or N; t is an integer from 1 to 5; 3) optionally substituted with 1-3 R d substituents; 4) R a R b Each is independently selected from optionally substituted C1-C6 alkyl, C1-C6 alkoxy, optionally substituted C1-C6 alkoxy, optionally substituted 3-8 membered cycloalkyl, or R a R b It forms 3-8 membered heterocycles with the atoms it is attached to; 5) R f Selected from optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 alkoxy, optionally substituted 3-8 membered cycloalkyl, optionally substituted 3-8 membered heterocycloalkyl containing 1-2 heteroatoms selected from N, O, S; L is a chemical bond, optionally substituted C1-C3 alkylene. R g selected from the group consisting of optionally substituted 5-8 membered heterocyclyl containing 1-3 heteroatoms selected from N, O, S; 6) optionally substituted with 1-3 R d substituents; R 3 Selected from H, halogen, hydroxyl, cyano, amino, nitro, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted 3-6 membered cycloalkyl or optionally substituted 3-6 membered heterocycloalkyl. n is an integer between 1 and 3; R 2 R 4 R 5 Each is independently selected from H, halogen, hydroxyl, cyano, amino, nitro, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted 3-6 membered cycloalkyl or optionally substituted 3-6 membered heterocycloalkyl. Y 1 Y 2 For N or CR c ; Y 3 For N or CR'; p is an integer between 0 and 3; m is an integer between 1 and 3; R 6 Each is independently selected from H, halogen, hydroxyl, cyano, amino, nitro, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted 3-6 membered cycloalkyl or optionally substituted 3-6 membered heterocycloalkyl, or two R 6 It forms 3-8 membered carbon rings or 3-8 membered heterocycles with the attached carbon atoms; R c R d Each is selected from H, halogen, hydroxyl, cyano, amino, nitro, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkynyl, optionally substituted C1-C6 alkoxy, optionally substituted 3-8 membered cycloalkyl. R' is selected from H, halogen, hydroxyl, cyano, amino, nitro, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted 3-8 membered cycloalkyl.

2. The compound according to claim 1, or its deuterated derivatives, stereoisomers, or pharmaceutically acceptable salts thereof, characterized in that, R 3 It is selected from H, halogen, hydroxyl, cyano, amino, nitro, optional halogen-substituted C1-C3 alkyl, optional halogen-substituted C1-C3 alkoxy, optional halogen-substituted 3-6 membered cycloalkyl or optional halogen-substituted 3-6 membered heterocycloalkyl.

3. The compound or its deuterated derivatives, stereoisomers, or pharmaceutically acceptable salts according to claim 2, characterized in that, R 3 Selected from H, F, Cl, Br, methyl, methoxy, trifluoromethyl, trifluoromethoxy, difluoromethyl, difluoromethoxy, and cyclopropyl.

4. The compound according to claim 1, or its deuterated derivatives, stereoisomers, or pharmaceutically acceptable salts thereof, characterized in that: Y 1 For N or CR c ; R c Selected from H, F, Cl, methyl, ethynyl, methoxy, trifluoromethyl, trifluoromethoxy, and cyclopropyl.

5. The compound according to claim 1, or its deuterated derivatives, stereoisomers, or pharmaceutically acceptable salts thereof, characterized in that: Y 2 For N or CR c ; R c Selected from H, F, Cl, cyano, methyl, ethynyl, methoxy, trifluoromethyl, trifluoromethoxy, and cyclopropyl.

6. The compound according to claim 1, or its deuterated derivative, stereoisomer, or pharmaceutically acceptable salt thereof, characterized in that: p is 1 or 2; m is an integer between 1 and 3; R 6 Each is independently selected from H, halogen, hydroxyl, cyano, amino, nitro, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted 3-6 membered cycloalkyl or optionally substituted 3-6 membered heterocycloalkyl. When two R 6 When two R atoms are substituted for the same carbon atom or adjacent carbon atoms, the two R atoms are substituted for the same carbon atom or adjacent carbon atoms. 6 It can form 3-8 membered carbon rings or 3-8 membered heterocycles with the attached carbon atoms, preferably forming 3 membered carbon rings.

7. The compound according to claim 1, or its deuterated derivative, stereoisomer, or pharmaceutically acceptable salt thereof, characterized in that: R 2 R 4 R 5 Each is independently selected from H, F, Cl, Br, methyl, methoxy, trifluoromethyl, trifluoromethoxy, difluoromethyl, difluoromethoxy, and cyclopropyl.

8. The compound according to claim 1, or its deuterated derivative, stereoisomer, or pharmaceutically acceptable salt thereof, characterized in that: R 1 Selected from or Choose 1-3 Rs d The following groups are substituted: R a R b Selected from C1-C3 alkyl groups optionally substituted with halogens, or 3-8 membered cycloalkyl groups optionally substituted with halogens, preferably methyl, trifluoromethyl, difluoromethyl, ethyl, propyl, cyclopropyl, or cyclobutyl. R a R b It forms 3-8 membered heterocycles with the atoms it is attached to; Y 3 For N or CR'; R f The group is selected from C1-C3 alkyl, optionally halogenated C2-C6 alkenyl, optionally halogenated C2-C6 alkynyl, optionally halogenated C1-C3 alkoxy, optionally halogenated 3-6 membered cycloalkyl, optionally halogenated or C1-C3 alkyl, and optionally halogenated or C1-C3 alkyl containing 1-2 heterocyclic alkyl groups selected from N, O, and S heteroatoms, wherein the C1-C3 alkyl group is optionally substituted with 1-3 halogens, 3-6 membered cycloalkyl groups, C2-C3 alkenyl, C2-C6 alkynyl, or C1-C3 alkoxy groups, preferably trifluoromethyl, difluoromethyl, etc. Alternatively, the following groups may be optionally substituted with halogens or C1-C3 alkyl groups: Cyclopropyl, cyclobutyl, L represents a chemical bond, and the C1-C3 alkylene group is optionally substituted with a halogen. R h Selected from H, halogen, hydroxyl, cyano, amino, nitro, optional halogen-substituted C1-C3 alkyl, optional halogen-substituted C1-C3 alkoxy, optional halogen-substituted 3-8 membered cycloalkyl, or optional halogen-substituted or C1-C3 alkyl, preferably F, methyl, trifluoromethyl, difluoromethyl, methoxy, trifluoromethoxy, ethyl, propyl, cyclopropyl, cyclobutyl; R d Selected from H, halogen, hydroxyl, cyano, amino, nitro, optional C1-C3 alkyl substituted with halogen, optional C1-C3 alkoxy substituted with halogen, optional 3-8 membered cycloalkyl substituted with halogen; R e Selected from C1-C3 alkyl groups optionally substituted with halogens, and 3-8 membered cycloalkyl groups optionally substituted with halogens, preferably methyl, trifluoromethyl, difluoromethyl, ethyl, propyl, or cyclopropyl; R' is selected from H, halogen, hydroxyl, cyano, amino, nitro, optional halogen-substituted C1-C3 alkyl, optional halogen-substituted C1-C3 alkoxy, optional halogen-substituted 3-8 membered cycloalkyl.

9. The compound according to claim 8, or its deuterated derivative, stereoisomer, or pharmaceutically acceptable salt thereof, characterized in that: R 1 Selected from 10. The compound according to any one of claims 1-7, or its deuterated form, stereoisomer, or pharmaceutically acceptable salt, characterized in that: R 1 Selected from: 1.1) Choose 1-3 Rs d Substitution; Ring A is a heteroaromatic ring; X 1 X 2 X 3 X 4 X 5 Selected from C and CR respectively d , N, NR e O, S, and at most 3 of them are heteroatoms; q is an integer selected from 1 to 5, preferably 1, 2 or 3; 1.2) Choose 1-3 Rs d Replace; X 6 X 7 X 8 X 9 Selected from CR d , N, and at most 3 of them are N; q is an integer selected from 1 to 5, preferably 1, 2 or 3; 2.1) Choose 1-3 Rs d Substitution; ring B is a heteroaromatic ring; Z 1 Z 2 Z 3 Z 4 Z 5 Selected from C and CR respectively d , N, NR e O, S, and at most 3 of them are heteroatoms; t is an integer selected from 1 to 5, preferably 1, 2 or 3; 2.2) Choose 1-3 Rs d Replace; Z 6 Z 7 Z 8 Z 9 Selected from CR d , N, and at most 3 of them are N; t is an integer selected from 1 to 5, preferably 1, 2 or 3; R d The groups are selected from H, halogen, hydroxyl, cyano, amino, nitro, C1-C3 alkyl groups optionally substituted with halogen, C1-C3 alkoxy groups optionally substituted with halogen, and 3-8 membered cycloalkyl groups optionally substituted with halogen. R e It is selected from C1-C3 alkyl groups optionally substituted with halogens, and 3-8 membered cycloalkyl groups optionally substituted with halogens, preferably methyl, trifluoromethyl, difluoromethyl, ethyl, propyl, or cyclopropyl.

11. The compound according to claim 10, or its deuterated derivative, stereoisomer, or pharmaceutically acceptable salt thereof, characterized in that: R 1 Selected from 1-3 Rs d The following groups are substituted: R d The groups are selected from H, halogen, hydroxyl, cyano, amino, nitro, C1-C3 alkyl groups optionally substituted with halogen, C1-C3 alkoxy groups optionally substituted with halogen, and 3-8 membered cycloalkyl groups optionally substituted with halogen. R e It is selected from C1-C3 alkyl groups optionally substituted with halogens, and 3-8 membered cycloalkyl groups optionally substituted with halogens, preferably methyl, trifluoromethyl, difluoromethyl, ethyl, propyl, or cyclopropyl.

12. The compound according to claim 11, or its deuterated derivatives, stereoisomers, or pharmaceutically acceptable salts thereof, characterized in that: R 1 Selected from 13. The compound according to claim 10, or its deuterated form, stereoisomer, or pharmaceutically acceptable salt thereof, characterized in that: R 1 Selected from 1-3 Rs d The following groups are substituted: R d The groups are selected from H, halogen, hydroxyl, cyano, amino, nitro, C1-C3 alkyl groups optionally substituted with halogen, C1-C3 alkoxy groups optionally substituted with halogen, and 3-8 membered cycloalkyl groups optionally substituted with halogen.

14. The compound according to claim 13, or its deuterated derivative, stereoisomer, or pharmaceutically acceptable salt thereof, characterized in that: R 1 Selected from 15. The compound or its deuterated derivative, stereoisomer, or pharmaceutically acceptable salt according to any one of claims 1-7, characterized in that: R 1 Selected from Y 3 Let N be the number of people in the group. Among them, R f The group is selected from C1-C3 alkyl, optionally halogenated C2-C6 alkenyl, optionally halogenated C2-C6 alkynyl, optionally halogenated C1-C3 alkoxy, optionally halogenated 3-6 membered cycloalkyl, optionally halogenated or C1-C3 alkyl, and optionally halogenated or C1-C3 alkyl containing 1-2 heterocyclic alkyl groups selected from N, O, and S heteroatoms, wherein the C1-C3 alkyl group is optionally substituted with 1-3 halogens, 3-6 membered cycloalkyl groups, C2-C3 alkenyl, C2-C6 alkynyl, or C1-C3 alkoxy groups, preferably trifluoromethyl, difluoromethyl, etc. Alternatively, the following groups may be optionally substituted with halogens or C1-C3 alkyl groups: Cyclopropyl, cyclobutyl, L represents a chemical bond, and the C1-C3 alkylene group is optionally substituted with a halogen. R g Selected from R h Substituted with 1 to 3 5-6 membered heteroaryl groups selected from N, O, and S heteroatoms, optionally with R h The substituted alkyl group contains 1 to 3 5-6 membered heterocyclic alkyl groups selected from N, O, and S heteroatoms, preferably optionally R. h The following groups are substituted: R h Selected from H, halogen, hydroxyl, cyano, amino, nitro, optional halogen-substituted C1-C3 alkyl, optional halogen-substituted C1-C3 alkoxy, optional halogen-substituted 3-8 membered cycloalkyl, or optional halogen-substituted or C1-C3 alkyl 3-6 membered heterocycloalkyl, preferably F, methyl, trifluoromethyl, difluoromethyl, Methoxy, trifluoromethoxy, ethyl, propyl, cyclopropyl, cyclobutyl.

16. The compound according to any one of claims 1-7, or its deuterated form, stereoisomer, or pharmaceutically acceptable salt, characterized in that: R 1 Selected from Y 3 For CR'; R' is selected from H, halogen, hydroxyl, cyano, amino, nitro, optional C1-C3 alkyl substituted with halogen, optional C1-C3 alkoxy substituted with halogen, optional 3-8 membered cycloalkyl substituted with halogen. Among them, R f Selected from C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 ynyl, optionally substituted 3-6 membered cycloalkyl, optionally substituted with halogen or C1-C3 alkyl, containing 1 to 2 atoms selected from N, The C1-C3 alkyl group is a 3-6 membered heterocyclic alkyl group with O or S heteroatoms, wherein the C1-C3 alkyl group is optionally substituted with a 3-6 membered cycloalkyl group, a C2-C3 alkenyl group, or a C2-C6 alkynyl group, preferably a 3-6 membered cycloalkyl group, a C2-C3 alkenyl group, or a C2-C6 alkynyl group. Alternatively, the following groups may be optionally substituted with halogens or C1-C3 alkyl groups: Cyclopropyl, cyclobutyl, L is selected from chemical bonds, optionally from C1-C3 alkylene groups substituted with halogens. R g Selected from R h Substituted with 1 to 3 5-6 membered heteroaryl groups selected from N, O, and S heteroatoms, optionally with R h The substituted alkyl group contains 1 to 3 5-6 membered heterocyclic alkyl groups selected from N, O, and S heteroatoms, preferably optionally R. h The following groups are substituted: R h Selected from H, halogen, hydroxyl, cyano, amino, nitro, optional halogen-substituted C1-C3 alkyl, optional halogen-substituted C1-C3 alkoxy, optional halogen-substituted 3-8 membered cycloalkyl, or optional halogen-substituted or C1-C3 alkyl 3-6 membered heterocycloalkyl, preferably F, methyl, trifluoromethyl, difluoromethyl, Methoxy, trifluoromethoxy, ethyl, propyl, cyclopropyl, cyclobutyl.

17. The compound according to claim 15 or 16, or its deuterated form, stereoisomer, or pharmaceutically acceptable salt thereof, characterized in that: R 1 Selected from Better:

18. The compound according to claim 1, or its deuterated derivatives, stereoisomers, or pharmaceutically acceptable salts thereof, characterized in that: R 1 Selected from Choose 1-3 Rs d replace; Y 1 Y 2 For N or CR c ; p is an integer between 0 and 3; m is an integer between 1 and 3; R 6 Each is independently selected from H, halogen, hydroxyl, cyano, amino, nitro, optional halogen-substituted C1-C3 alkyl, optional halogen-substituted C1-C3 alkoxy, optional substituted 3-6 membered cycloalkyl, or optional substituted 3-6 membered heterocycloalkyl, or When m is 2, the two R 6 It forms a 3-8 membered carbon ring or a 3-8 membered heterocycle with the attached carbon atom, preferably cyclopropyl; R c R d Each is selected from H, halogen, hydroxyl, cyano, amino, nitro, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkynyl, optionally substituted C1-C6 alkoxy, optionally substituted 3-8 membered cycloalkyl.

19. The compound according to claim 1, or its deuterated derivative, stereoisomer, or pharmaceutically acceptable salt thereof, characterized in that: R 1 Selected from R a R b Each is independently selected from optionally substituted C1-C6 alkyl, C1-C6 alkoxy, optionally substituted C1-C6 alkoxy, optionally substituted 3-8 membered cycloalkyl, or R a R b It forms 3-8 membered heterocycles with the atoms it is attached to; As a preferred option, R a R b Each is independently selected from C1-C3 alkyl groups optionally substituted with halogens, 3-8 membered cycloalkyl groups optionally substituted with halogens or C1-C3 alkyl groups, or R a R b It forms 3-8 membered heterocycles with the atoms it is attached to; Further optimization, R a R b Each is independently selected from methyl, trifluoromethyl, difluoromethyl, ethyl, propyl, substituted with halogens, and cyclopropyl, cyclobutyl, substituted with halogens or C1-C3 alkyl groups. or R a R b Forming with the attached atoms 20. A compound of formula (II): Or its deuterated derivatives, stereoisomers, or pharmaceutically acceptable salts, wherein: R 2 R 2 Each is independently selected from H, halogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted 3-6 membered cycloalkyl or optionally substituted 3-6 membered heterocycloalkyl; R 3 Selected from H, halogen, hydroxyl, cyano, amino, nitro, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted 3-6 membered cycloalkyl or optionally substituted 3-6 membered heterocycloalkyl. R 4 R 5 Each is independently selected from H, halogen, hydroxyl, cyano, amino, nitro, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted 3-6 membered cycloalkyl, or optionally substituted 3-6 membered heterocycloalkyl; Y 1 Y 2 For N or CR c ; m is an integer between 0 and 3; R 6 Each is independently selected from H, halogen, hydroxyl, cyano, amino, nitro, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted 3-6 membered cycloalkyl or optionally substituted 3-6 membered heterocycloalkyl. R c Each is selected from H, halogen, hydroxyl, cyano, amino, nitro, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkynyl, optionally substituted C1-C6 alkoxy, optionally substituted 3-8 membered cycloalkyl. R f Selected from optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 alkoxy, optionally substituted 3-8 membered cycloalkyl, optionally substituted 3-8 membered heterocycloalkyl containing 1 to 2 heteroatoms selected from N, O, and S. R g Selected from arbitrarily substituted 5-10 membered heterocyclic groups containing 1 to 3 heteroatoms selected from N, O, and S.

21. The compound or its deuterated derivative, stereoisomer, or pharmaceutically acceptable salt according to claim 20, characterized in that: R 3 Selected from H, halogen, hydroxyl, cyano, C1-C3 alkyl, C1-C3 alkoxy, 3-6 membered cycloalkyl or 3-6 membered heterocycloalkyl, wherein the C1-C3 alkyl, C1-C3 alkoxy, 3-6 membered cycloalkyl or 3-6 membered heterocycloalkyl are optionally substituted with 1-3 halogens, C1-C3 alkyl, halogenated C1-C3 alkyl, C1-C3 alkoxy or halogenated C1-C3 alkoxy; R 3 H, F, Cl, Br, methyl, methoxy, trifluoromethyl, trifluoromethoxy, difluoromethyl, difluoromethoxy, cyclopropyl are preferred, and Cl is even more preferred.

22. The compound according to claim 20, or its deuterated form, stereoisomer, or pharmaceutically acceptable salt thereof, characterized in that: R 4 R 5 Each is independently selected from H, F, methyl, trifluoromethyl, methoxy, or trifluoromethoxy, with H being preferred.

23. The compound according to claim 20, or its deuterated derivative, stereoisomer, or pharmaceutically acceptable salt thereof, characterized in that: Y 1 For CR c ; R c The components are selected from H, F, Cl, methyl, methoxy, trifluoromethyl, and trifluoromethoxy, with H being preferred.

24. The compound according to claim 20, or its deuterated derivative, stereoisomer, or pharmaceutically acceptable salt thereof, characterized in that: Y 2 For N or CR c ; R c The components are selected from H, F, Cl, cyano, methyl, ethynyl, methoxy, trifluoromethyl, and trifluoromethoxy, with H being preferred.

25. The compound according to claim 20, or its deuterated derivative, stereoisomer, or pharmaceutically acceptable salt thereof, characterized in that: m can be 0, 1, or 2, with 0 being preferred; R 6 It is selected from H, halogen, hydroxyl, cyano, amino, nitro, methyl, trifluoromethyl, methoxy or trifluoromethoxy, with H being preferred.

26. The compound according to claim 20, or its deuterated derivative, stereoisomer, or pharmaceutically acceptable salt thereof, characterized in that: R 2 R 2 Each is independently selected from H, F, Cl, C1-C3 alkyl groups optionally substituted with 1-3 halogens, C1-C3 alkoxy groups optionally substituted with 1-3 halogens, 3-6 membered cycloalkyl groups or 3-6 membered heterocycloalkyl groups optionally substituted with 1-3 halogens or C1-C3 alkyl groups, preferably H, F, Cl, methyl, trifluoromethyl, difluoromethyl, methoxy, trifluoromethoxy, difluoromethoxy, cyclopropyl.

27. The compound according to claim 20, or its deuterated form, stereoisomer, or pharmaceutically acceptable salt thereof, characterized in that: R f It is selected from C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, (C1-C3 alkylene)-(3-8 membered cycloalkyl), (C1-C3 alkylene)-(3-8 membered heterocycloalkyl), optionally substituted with 1-3 halogens, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C1-C3 alkylene, halo-C1-C3 alkyl, halo-C1-C3 alkylene, C1-C3 alkoxy, halo-C1-C3 alkoxy; R f Preferably, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, 3-8 membered cycloalkyl, (C1-C3 alkylene)-(3-8 membered cycloalkyl) are substituted, and optionally replaced by 1-3 halogens, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C1-C3 alkylene, halo-C1-C3 alkyl, or halo-C1-C3 alkylene; R f Preferred compounds include C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, methylenecyclopropyl, methylenecyclobutyl, and methylenecyclopentyl. It may be optionally substituted with 1-3 Cl, F, methyl, ethyl, =CH2, difluoromethyl, trifluoromethyl, =CF2, vinyl, ethynyl, -CH=CH2, methoxy, difluoromethoxy, or trifluoromethoxy. R f Preferred compounds include C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, methylenecyclopropyl, methylenecyclobutyl, and methylenecyclopentyl. It may be optionally substituted with 1-3 Cl, F, methyl, ethyl, =CH2, difluoromethyl, trifluoromethyl, =CF2, vinyl, ethynyl, or -CH=CH2; R f More R f More 28. The compound according to claim 20, or its deuterated derivative, stereoisomer, or pharmaceutically acceptable salt thereof, characterized in that: R g Selected from 5-6 membered heterocyclic aryl groups containing 1-3 heteroatoms selected from N, O, and S, optionally substituted, and optionally substituted with 1-3 R atoms. h replace; R g Selected from Preferred Choose 1-3 Rs h replace; The R h The compounds are selected from halogens, C1-C3 alkyl groups, C1-C3 alkoxy groups, 3-6 membered cycloalkyl groups, 3-6 membered cycloalkyloxy groups, and (C1-C3 alkylene)-(3-6 membered cycloalkyl groups), wherein the C1-C3 alkyl groups, C1-C3 alkoxy groups, 3-6 membered cycloalkyl groups, 3-6 membered cycloalkyloxy groups, (C1-C3 alkylene)-(3-6 membered cycloalkyl groups), and C1-C3 alkylene groups are optionally substituted with 1-3 halogens, C1-C3 alkyl groups, C1-C3 alkoxy groups, halo-C1-C3 alkyl groups, and halo-C1-C3 alkoxy groups; The R h Preferably, Cl, F, methyl, ethyl, propyl, cyclopropyl, methylenecyclopropyl, methoxy, cyclopropyloxy, cyclobutyl, and methylenecyclobutyl are used, wherein the methyl, ethyl, propyl, cyclopropyl, methylenecyclopropyl, methoxy, and cyclopropyloxy groups are optionally substituted by 1-3 Cl, F, methyl, trifluoromethyl, difluoromethyl, methoxy, trifluoromethoxy, and difluoromethoxy groups. R h Preferably, Cl, F, methyl, ethyl, propyl, cyclopropyl, methylenecyclopropyl, methoxy, or cyclopropyloxy are used, wherein the methyl, ethyl, propyl, cyclopropyl, methylenecyclopropyl, methoxy, or cyclopropyloxy groups are optionally substituted by 1-3 Cl, F, methyl, trifluoromethyl, difluoromethyl, methoxy, trifluoromethoxy, or difluoromethoxy groups. R h Preferably, Cl, F, methyl, ethyl, propyl, cyclopropyl, methylenecyclopropyl, methoxy, or cyclopropyloxy are used, wherein the methyl, ethyl, propyl, cyclopropyl, methylenecyclopropyl, methoxy, or cyclopropyloxy groups are optionally substituted by 1-3 Cl, F, methyl, methoxy, or trifluoromethoxy groups. The R h More preferably Cl, F, methyl, propyl, difluoromethyl, trifluoromethyl, Cyclopropyl, methylenecyclopropyl, Methoxy, difluoromethoxy, trifluoromethoxy Cyclobutyl, R h More preferably Cl, F, methyl, propyl, difluoromethyl, trifluoromethyl, Cyclopropyl, methylenecyclopropyl, Methoxy, difluoromethoxy, trifluoromethoxy R h More preferably Cl, F, methyl, propyl, difluoromethyl, trifluoromethyl, Cyclopropyl, methylenecyclopropyl, Methoxy, difluoromethoxy, trifluoromethoxy R h Further preferred compounds include Cl, F, methyl, propyl, difluoromethyl, and trifluoromethyl. Cyclopropyl, methylenecyclopropyl, Methoxy, difluoromethoxy, trifluoromethoxy 29. The compound or its deuterated derivative, stereoisomer, or pharmaceutically acceptable salt according to claim 1, characterized in that, Selected from the following compounds:

30. A pharmaceutical composition for degrading VAV1 protein, comprising the compound, a deuterated form thereof, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable carrier thereof, according to any one of claims 1-29.

31. The pharmaceutical composition according to claim 30, characterized in that, The pharmaceutical composition mediates the interaction between VAV1 protein and E3 ligase, thereby increasing the degradation of VAV1 protein.

32. Use of the compound, its deuterated form, stereoisomer, or pharmaceutically acceptable salt according to any one of claims 1-29, or the pharmaceutical composition according to claim 30 or 31, in the preparation of a medicament for treating and / or preventing diseases caused by or related to VAV1 polymorphism.

33. The use of the compound, its deuterated form, stereoisomer, or pharmaceutically acceptable salt according to any one of claims 1-29, or the pharmaceutical composition according to claim 30 or 31, in the preparation of a medicament for treating and / or preventing diseases caused by or related to immune abnormalities.

34. The use according to claim 32 or 33, characterized in that, The diseases referred to are autoimmune diseases, inflammatory diseases, allergic diseases, and tumors.

35. The use according to claim 34, characterized in that, The autoimmune diseases mentioned are selected from inflammatory bowel disease, rheumatoid arthritis, multiple sclerosis, lupus erythematosus, Hashimoto's thyroiditis, myasthenia gravis, Sjögren's syndrome, Graves' disease, type I diabetes and related diseases, vasculitis, urticaria, pulmonary hypertension, pemphigus, pernicious anemia and blood diseases mediated by autoimmune abnormalities, uveitis, psoriasis, Graves' ophthalmopathy, alopecia areata and other diseases, autoimmune nephritis, cutaneous manifestations of immune-mediated diseases, systemic sclerosis, morphine scleroderma, graft-versus-host disease, T-cell mediated nephropathy, biliary sclerosis, sclerosing cholangitis, autoimmune liver disease, chronic inflammatory demyelinating diseases, ankylosing spondylitis, axial spondyloarthritis, and alopecia areata. The inflammatory diseases mentioned include asthma, inflammatory lung injury, inflammatory liver injury, inflammatory glomerular injury, atherosclerosis, osteoarthritis, irritant contact dermatitis and eczematous dermatitis, seborrheic dermatitis, inflammatory eye disease, keratoconjunctivitis, pericarditis, myocarditis, hepatitis, pulmonary fibrosis, macular degeneration, generalized undulating hematoma, Alzheimer's disease, and amyloidosis. The allergic diseases mentioned include allergic asthma, atopic dermatitis, allergic rhinitis / conjunctivitis, allergic contact dermatitis, and esophagitis.

36. The use according to claim 35, characterized in that, The diseases mentioned are selected from inflammatory bowel disease, rheumatoid arthritis, multiple sclerosis, lupus erythematosus, psoriasis, type I diabetes, myasthenia gravis, chronic inflammatory demyelinating diseases, graft-versus-host disease, ankylosing spondylitis, and axial spondyloarthritis.

37. The use according to claim 36, characterized in that, The diseases mentioned are selected from ulcerative colitis, Crohn's disease, rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, psoriasis, type I diabetes, myasthenia gravis, and graft-versus-host disease.

38. The use according to claim 37, characterized in that, The diseases mentioned are selected from ulcerative colitis, rheumatoid arthritis, and multiple sclerosis.

39. The use according to claim 34, characterized in that, The tumors include solid tumors and hematologic malignancies, especially hematologic malignancies; the hematologic malignancies include T-cell and B-cell malignancies.

40. The use according to claim 39, characterized in that, The malignant tumors of the hematologic system are selected from: leukemia and lymphoma.

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