Heterocyclic compound, preparation method therefor, and use thereof in preparation of VAV1 degradation agent

Abstract

Provided are a heterocyclic compound, a preparation method therefor, and a use thereof in the preparation of a VAV1 degradation agent, relating to the field of pharmaceutical chemistry. The compound can be used as a VAV1 degradation agent for preparing a drug for preventing and / or treating diseases such as autoimmune diseases, inflammation, and cancer. The compound has good degradation activity against VAV1, good oral pharmacokinetics, and good efficacy, and has broad application prospects.

Description

A heterocyclic compound, its preparation method, and its use in the preparation of VAV1 degrading agents. Technical Field

[0001] This invention provides a heterocyclic compound, its preparation method, and its use in the preparation of VAV1 degrading agents, belonging to the field of medicinal chemistry. Background Technology

[0002] The VAV family of proteins, including VAV1, VAV2, and VAV3, are guanine nucleotide exchange factors (GEFs) of Rho family GTPases. VAV1 is a 95 kDa protein and a positive regulator of T-cell and B-cell receptor signaling. VAV1 expression is typically highly restricted to hematopoietic cells. VAV1 is rapidly phosphorylated on tyrosine residues in response to various stimuli, including those of the T-cell receptor (TCR), B-cell receptor (BCR), and various cytokine receptors. VAV1 regulates multiple cellular functions and signaling pathways in hematopoietic-derived cells (e.g., T-cells and B-cells, natural killer cells, and osteoclasts) by activating certain GTPases. VAV1-mediated functions include gene transcription, development, and activation of immune cells (e.g., T-cells and B-cells).

[0003] Studies have found that reducing VAV1 can decrease immune cell activation, immune cell proliferation, and the production of various cytokines. VAV1 degraders show great promise in the treatment of autoimmune diseases and inflammation. Therefore, developing new drugs with excellent VAV1 degradation activity and favorable oral pharmacokinetic properties is of great significance. Summary of the Invention

[0004] The purpose of this invention is to provide a heterocyclic compound, a method for its preparation, and its use in the preparation of VAV1 degrading agents.

[0005] This invention provides compounds of Formula I, pharmaceutically acceptable salts thereof, isotopic compounds thereof, or stereoisomers thereof:

[0006] Among them, X 1 ,X 2 Selected independently from O and NR X ,CR X1 R X2 ;X 3 Selected from N,CR X1 ;where R X ,R X1 ,R X2 Each of the following is independently selected from alkyl groups: N, H, F, Cl, Br, I, and C1-C6 alkyl groups;

[0007] A X A YEach is independently selected from CH and N;

[0008] Ring A is R A1 ,R A2 ,R A3 The following groups are substituted: 6-10-membered aromatic ring, 5-10-membered aromatic heterocycle, 6-10-membered aromatic ring with 5-10-membered aromatic heterocycle, 5-10-membered aromatic heterocycle with 5-10-membered aromatic heterocycle, 6-10-membered aromatic ring with 6-10-membered aromatic ring;

[0009] R A1 Selected from none, H, F, Cl, Br, I, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl. Substituted C2-C6 alkynyl groups, halogen-substituted C1-C6 alkyl groups, groups obtained by replacing one or more methylene groups with heteroatoms in C1-C6 alkyl groups, C1-C6 alkoxy groups, C1-C6 alkylamine groups, NR e1 R e2 hydroxyl, cyano, mercapto, sulfone, carboxyl, CONR e1 R e2 Oxygen; R A4 ,R A5 ,R A6 Each alkyl group is independently selected from C1-C6 alkyl groups; R A2 ,R A3 Each group is independently selected from: none, H, F, Cl, Br, I, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen-substituted C1-C6 alkyl, C1-C6 alkyl groups obtained by replacing one or more methylene groups with heteroatoms, C1-C6 alkoxy, C1-C6 alkylamine, NR e1 R e2 hydroxyl, cyano, mercapto, sulfone, carboxyl, CONR e1 R e2 Or R A1 R A2 ,R A3 Any two or three of them can be connected to form a loop; R e1 Selected from hydrogen, C1-C6 alkyl, R e2 Selected from hydrogen, C1-C6 alkyl;

[0010] B is R B1 ,R B2 ,R B3 The following groups are substituted: 6-10 membered aromatic rings, 5-10 membered aromatic heterocycles, 6-10 membered aromatic rings with 6-10 membered aromatic rings, C2-C6 ynyl groups; wherein R B1 ,R B2 ,R B3Each group is independently selected from: none, H, F, Cl, Br, I, C1-C6 alkyl, halogen-substituted C1-C6 alkyl, C1-C6 alkyl groups obtained by replacing one or more methylene groups with heteroatoms, C1-C6 alkoxy, C1-C6 alkylamine, NR d1 R d2 hydroxyl, cyano, mercapto, sulfone, carboxyl, CONR d1 R d2 Or R B1 ,R B2 ,R B3 Any two or three of them can be connected to form a loop; R d1 Selected from hydrogen, C1-C6 alkyl, R d2 Selected from hydrogen, C1-C6 alkyl;

[0011] R is selected from halogens, C1-C6 alkyl groups, halogen-substituted C1-C6 alkyl groups, groups obtained by replacing one or more methylene groups with heteroatoms in C1-C6 alkyl groups, C1-C6 alkoxy groups, C1-C6 alkylamine groups, and L. 1 -NR 4 R 5 L 1 -hydroxyl group, L 1 -Cyano, L 1 -Thiol group, L 1 -sulfone group, L 1 -Carboxyl group, L 1 -CONR 4 R 5 L 2 -R 6 ;

[0012] R 4 Selected from hydrogen, C1-C6 alkyl, halogen-substituted C1-C6 alkyl, groups obtained by replacing one or more CH2 or CH atoms in a C1-C6 alkyl group with heteroatoms, L 3 -OH, L 3 -NH2;R 5 Selected from hydrogen, C1-C6 alkyl, halogen-substituted C1-C6 alkyl, or R 4 Connected with R5 to form an unsubstituted or R 4a Substituted groups include: 5-12 membered saturated heterocycles, 5-12 membered heteroaromatic rings; L 3 Selected from C1-C6 alkylene groups; R 4a Selected from C1-C6 alkyl groups and halogen-substituted C1-C6 alkyl groups;

[0013] L 1 Selected from C1-C6 alkylene groups;

[0014] L 2Selected from one bond, C1-C6 alkylene, (CH2) a O(CH2) b (CH2) a NR n (CH2) b ; a is 0, 1, 2, 3, or 4, b is 0, 1, 2, 3, or 4, R n Selected from hydrogen, C1-C6 alkyl;

[0015] R 6 For R 1 ,R 2 ,R 3 ,R 7 ,R 8 The following groups are substituted: 5-12-membered saturated heterocycles, 5-12-membered heteroaromatic rings, 5-12-membered heteroaromatic rings with 5-12-membered heteroaromatic rings, 5-12-membered heteroaromatic rings with 6-12-membered aromatic rings, 5-12-membered saturated heteroaromatic rings with 6-12-membered aromatic rings, 5-12-membered heteroaromatic rings with 5-12-membered saturated heterocycles, and 5-12-membered heteroaromatic rings with 5-12-membered saturated carbocyclic rings; wherein R 1 ,R 2 ,R 3 ,R 7 ,R 8 Each group is independently selected from: 0, hydrogen, halogen, C1-C6 alkyl, halogen-substituted C1-C6 alkyl, C1-C6 alkyl group obtained by replacing one or more methylene groups with heteroatoms, C1-C6 alkoxy group obtained by replacing one or more methylene groups with heteroatoms, C1-C6 alkoxy, C1-C6 alkylamine, NR m1 R m2 hydroxyl, cyano, mercapto, sulfone, carboxyl, CONR m1 R m2 Oxygen, halogen or deuterium or halogenated C1-C6 alkoxy groups, hydroxyl groups substituted with 3-6 saturated carbon rings, L 4 -3-6 saturated carbon rings, L 4 -4-6 saturated heterocyclic rings, L 4 - Halogenated or C1-C6 alkyl-substituted 3-6 membered saturated carbon rings, L 4 - Halogenated or C1-C6 alkyl or halo-C1-C6 alkyl or hydroxylated 4-6 membered saturated heterocycles, L 4 -6-12 Yuanfanghuan, L 4 - Halogenated or C1-C6 alkyl-substituted 6-12-membered aromatic ring, L 4 -5-12 polyaromatic rings, L 4 - Halogenated or C1-C6 alkyl or halo-C1-C6 alkyl-substituted 5-12-membered heteroaryl ring, L 4-5-6 membered saturated heterocyclic rings and 3-6 membered saturated carbon rings, L 4 -3-6 saturated heterocyclic spirocyclops, 3-6 saturated carbon ring, L 4 -3-6 quinary saturated carbon ring spirocyclops, 3-6 quinary saturated heterocyclic ring, L 4 -6-12 saturated carbon bridged rings, L 4 -6-12 saturated heterobridged ring; or R 1 ,R 2 ,R 3 ,R 7 ,R 8 Any two or three of them can be connected to form a loop; R m1 Selected from hydrogen, C1-C6 alkyl, halogen-substituted C1-C6 alkyl; R m2 Selected from hydrogen, C1-C6 alkyl; or R m1 and R m2 Linked into halogenated or non-halogenated 5-6 membered saturated heterocycles; L 4 Selected from one bond, C1-C6 alkylene, O, O-C1-C6 alkylene;

[0016] And when X 1 ,X 2 ,X 3 Both are C, ring A is a benzene ring, and R A1 When the methyl group is substituted with F, Cl, Br, methyl, methoxy, or halogen, and ring B is a benzene ring, R is limited to R. 1 ,R 2 ,R 3 ,R 7 ,R 8 Substituted 5-12 membered heteroaryl rings, R 1 ,R 2 ,R 3 ,R 7 ,R 8 Two adjacent substituents are linked to form a 7-8 membered ring, or R 1 ,R 2 ,R 3 ,R 7 ,R 8 At least one of them is selected from halogen-substituted C1-C6 alkyl or halogen-substituted C1-C6 alkoxy.

[0017] Furthermore, the structure of the compound is shown in Formula II:

[0018] Among them, X 3 R A1 R A2 R A3 A Y B and R are as described above.

[0019] Furthermore, ring A is a benzene ring, and the structure of the compound is shown in Formula III:

[0020] Among them, X 3 R A1 R A2 R A3 B and R are as described above;

[0021] And when X 3 For CH,R A1 When the molecule is H, F, Cl, Br, Me, CHF2, CF3, or OMe, and ring B is a benzene ring, R is limited to R. 1 ,R 2 ,R 3 ,R 7 ,R 8 Substituted 5-12 membered heteroaryl rings, R 1 ,R 2 ,R 3 ,R 7 ,R 8 Two adjacent substituents are linked to form a 7-8 membered ring, or R 1 ,R 2 ,R 3 ,R 7 ,R 8 At least one of them is selected from halogen-substituted C1-C6 alkyl or halogen-substituted C1-C6 alkoxy.

[0022] Furthermore, ring A is a benzene ring, and X 3 For CH, R A1 The compound is acetylene-based, and its structure is shown in Formula IV:

[0023] Among them, R A2 R A3 B and R are as described above.

[0024] Furthermore, B is a benzene ring, and the structure of the compound is shown in Formula V:

[0025] Among them, R A2 R A3 As mentioned above, R...

[0026] Furthermore, A is a benzene ring, X 3 The compound is N, and its structure is shown in Formula VI:

[0027] Among them, R A1 R A2 RA3 B and R are as described above.

[0028] Furthermore, B is a benzene ring, and the structure of the compound is shown in Formula VII:

[0029] Among them, R A1 R A2 R A3 As mentioned above, R...

[0030] Furthermore, ring A is an indazole, and the structure of the compound is shown in Formula VIII:

[0031] Among them, X 1 X 2 X 3 R A1 R A2 R A3 B and R are as described above.

[0032] Furthermore, X 1 X 2 The compound is C, and its structure is shown in Formula IX-1:

[0033] Among them, X 3 R A1 R A2 R A3 B and R are as described above.

[0034] Furthermore, B is R B1 Substituted benzene ring, R B1 Selected from H, F, Cl, Br, I, the structure of the compound is shown in Formula IX-2:

[0035] Among them, X 3 R A1 R A2 R A3 As mentioned above, R...

[0036] Furthermore, X 3 The compound is CH, and its structure is shown in Formula X:

[0037] Among them, R A1 R A2 R A3 , R, R B1 As mentioned above.

[0038] Furthermore, R is L 2 R 6 ,

[0039] Where L 2 Selected from one bond, C1-C6 alkylene, (CH2) a O(CH2) b (CH2) a NH(CH2) b ;a is 0, 1, 2, 3, or 4, b is 0, 1, 2, 3, or 4.

[0040] R 6 As mentioned above.

[0041] Furthermore, L 2 As a key, R is R 6 ,

[0042] R 6 For R 1 ,R 2 ,R 3 ,R 7 ,R 8 The following groups are substituted: 5-12-membered saturated heterocycles, 5-12-membered heteroaromatic rings, 5-12-membered heteroaromatic rings with 5-12-membered heteroaromatic rings, 5-12-membered heteroaromatic rings with 6-12-membered aromatic rings, 5-12-membered saturated heteroaromatic rings with 6-12-membered aromatic rings, 5-12-membered heteroaromatic rings with 5-12-membered saturated heterocycles, and 5-12-membered heteroaromatic rings with 5-12-membered saturated carbocyclic rings; wherein R 1 ,R 2 ,R 3 ,R 7 ,R 8 Each group is independently selected from the groups of no, H, halogen, cyano, hydroxyl, C1-C6 alkylamine, and NR. m1 R m2 CONR m1 R m2 C1-C6 alkyl, halogen-substituted C1-C6 alkyl, C1-C6 alkoxy, halogenated or deuterated or halogenated C1-C6 alkoxy-substituted C1-C6 alkoxy, a group obtained by replacing one or more methylene groups of a C1-C6 alkyl group with heteroatoms, a group obtained by replacing one or more methylene groups of a C1-C6 alkoxy group with heteroatoms, L 4 -3-6 saturated carbon rings, L 4 - Halogenated or C1-C6 alkyl-substituted 3-6 membered saturated carbon rings, L 4 -4-6 saturated heterocyclic rings, L 4 - Halogenated or C1-C6 alkyl or halo-C1-C6 alkyl or hydroxylated 4-6 membered saturated heterocycles, L 4 -Benzene ring, L 4 - Halogenated or C1-C6 alkyl-substituted benzene ring, L 4-5-6 cyclic aromatic rings, L 4 - A 5-6 membered heteroaryl ring substituted with a halogen or C1-C6 alkyl or halo-C1-C6 alkyl group, L 4 -5-6 membered saturated nitrogen heterocycles and 3-6 membered saturated carbon rings, L 4 -5-6 quinary saturated nitrogen heterocyclic spirocycloidens and 3-6 quinary saturated carbon rings, L 4 -4-6 quinary saturated carbon ring spirocyclohexane, L 4 -6-12 saturated carbon bridged rings, L 4 -7-membered saturated nitrogen-containing bridged ring; or, R 1 ,R 2 ,R 3 ,R 7 ,R 8 Any two of them are connected to form a ring, wherein the ring is selected from benzene ring, 3-6 member saturated carbon ring, 3-8 member unsaturated carbon ring, and 6-8 member unsaturated bridged ring;

[0043] R m1 Selected from hydrogen, C1-C6 alkyl, halogen-substituted C1-C6 alkyl; R m2 Selected from hydrogen, C1-C6 alkyl; or R m1 and R m2 Linked into 5-6 member saturated heterocycles or halogenated 5-6 member saturated heterocycles; L 4 It is selected from one bond, C1-C6 alkylene, O, O-C1-C6 alkylene.

[0044] Furthermore, R is a substituted pyridinone, and the structure of R is shown in XI:

[0045] U and V are independently selected from N and C, respectively, and are not both C at the same time;

[0046] R G1 ,R G2 ,R G3 ,R G4 Each group is independently selected from: ⇌ ⇌ H, halogen, cyano, hydroxyl, C1-C6 alkylamine, NR m1 R m2 CONR m1 R m2 C1-C6 alkyl, halogen-substituted C1-C6 alkyl, C1-C6 alkoxy, halogenated or deuterated or halogenated C1-C6 alkoxy, a group obtained by replacing one or more methylene groups of a C1-C6 alkyl group with O, S or NH, a group obtained by replacing one or more methylene groups of a C1-C6 alkoxy group with O, S or NH, L 4 -3-6 saturated carbon rings, L 4 - Halogenated or C1-C6 alkyl-substituted 3-6 membered saturated carbon rings, L4 -4-6 saturated heterocyclic rings, L 4 - Halogenated or C1-C6 alkyl or halo-C1-C6 alkyl or hydroxylated 4-6 membered saturated heterocycles, L 4 -Benzene ring, L 4 - Halogenated or C1-C6 alkyl-substituted benzene ring, L 4 -5-6 cyclic aromatic rings, L 4 - A 5-6 membered heteroaryl ring substituted with a halogen or C1-C6 alkyl or halo-C1-C6 alkyl group, L 4 -5-6 membered saturated nitrogen heterocycles and 3-6 membered saturated carbon rings, L 4 -5-6 quinary saturated nitrogen heterocyclic spirocycloidens and 3-6 quinary saturated carbon rings, L 4 -4-6 quinary saturated carbon ring spirocyclohexane, L 4 -6-12 saturated carbon bridged rings, L 4 -7-membered saturated nitrogen-containing bridged ring; or, R G1 ,R G2 ,R G3 ,R G4 Two adjacent rings are connected to form a ring, wherein the ring is selected from benzene rings, 6-8 membered unsaturated carbon rings, and 7-8 membered unsaturated carbon bridged rings; the heteroatom in the saturated heterocycle contains at least one N, O, or S; the heteroatom in the heteroaromatic ring contains at least one N, O, or S.

[0047] R m1 Selected from hydrogen, C1-C6 alkyl, halogen-substituted C1-C6 alkyl; R m2 Selected from hydrogen, C1-C6 alkyl; or R m1 and R m2 Connected to form a 5-6 member saturated nitrogen-containing heterocycle or a halogenated 5-6 member saturated nitrogen-containing heterocycle, wherein the nitrogen-containing heterocycle contains 0 or 1 O; L 4 It is selected from one bond, C1-C6 alkylene, O, O-C1-C6 alkylene.

[0048] Furthermore, the structure of the compound is shown in XII:

[0049] Among them, U, V, R G1 R G2 R G3 R G4 As mentioned above.

[0050] Furthermore, the structure of the compound is shown in XIII:

[0051] Among them, U, V, R G1 R G2 R G3 RG4 As mentioned above.

[0052] Furthermore, the structure of the compound is shown in XIV:

[0053] Among them, U, V, R G1 R G2 R G3 R G4 As mentioned above.

[0054] Furthermore, the structure of the compound is shown in XV:

[0055] U and V are as described above.

[0056] R G1 and R G2 The linkage forms a 7-8 quintile unsaturated monocyclic carbon ring or a 7-8 quintile unsaturated carbon bridge ring, R G3 and R G4 Each is independently selected from H, halogen-substituted C1-C6 alkoxy, halogen-substituted C1-C6 alkyl; or R G1 R G2 R G3 R G4 One of them is selected from a halogen-substituted C1-C6 alkyl group or a halogen-substituted C1-C6 alkoxy group, and the others are independently selected from H, a halogen-substituted C1-C6 alkoxy group, a halogen-substituted C1-C6 alkyl group, and L. 4 -3-6 saturated carbon rings; L 4 It is selected from one bond, C1-C6 alkylene, O, O-C1-C6 alkylene.

[0057] Furthermore, the structure of the compound is as shown in XVI-1 or XVI-2:

[0058] In formula XVI-1, R G1 and R G2 The linkage forms 7-8 quintile unsaturated monocyclic carbon rings and 7-8 quintile unsaturated carbon bridged rings, R G3 and R G4 Each is independently selected from H, halogen-substituted C1-C6 alkoxy, halogen-substituted C1-C6 alkyl; or R G1 R G2 R G3 R G4 One of them is selected from a halogen-substituted C1-C6 alkyl or a halogen-substituted C1-C6 alkoxy group, and the others are independently selected from H, a halogen-substituted C1-C6 alkoxy group, a halogen-substituted C1-C6 alkyl group, and L. 4 -3-6 saturated carbon rings; L4 Selected from one bond, C1-C6 alkylene, O, O-C1-C6 alkylene;

[0059] In formula XVI-2, R G1 R G2 R G3 R G4 One of them is selected from a halogen-substituted C1-C6 alkyl or a halogen-substituted C1-C6 alkoxy group, and the others are independently selected from H, a halogen-substituted C1-C6 alkoxy group, a halogen-substituted C1-C6 alkyl group, and L. 4 -3-6 saturated carbon rings; L 4 It is selected from one bond, C1-C6 alkylene, O, O-C1-C6 alkylene.

[0060] Furthermore, B is a naphthalene ring, and the structure of the compound is shown in XVI:

[0061] Among them, R 4 Selected from hydrogen, C1-C6 alkyl, halogen-substituted C1-C6 alkyl, C1-C6 alkyl groups obtained by replacing one or more CH2 or CH with O or N, L 3 -OH, L 3 -NH2;R 5 Selected from hydrogen, C1-C6 alkyl, halogen-substituted C1-C6 alkyl, or linked to form unsubstituted or R 4a The following groups are substituted: 5-6 membered saturated nitrogen-containing heterocycles, pyridinones; wherein the nitrogen-containing heterocycle contains 0 or 1 O;

[0062] L 3 Selected from C1-C6 alkylene groups;

[0063] R 4a Selected from C1-C6 alkyl groups and halogen-substituted C1-C6 alkyl groups.

[0064] Furthermore, the compound is selected from the following structures:

[0065] The present invention also provides a pharmaceutical composition, characterized in that it is a formulation prepared by adding pharmaceutically acceptable excipients to the aforementioned compound, its pharmaceutically acceptable salt, its isotopic compound or its stereoisomer as active ingredients.

[0066] The present invention also provides the use of the compounds described above, their pharmaceutically acceptable salts, their isotopic compounds or stereoisomers thereof in the preparation of VAV1 degrading agents.

[0067] Furthermore, the VAV1 degrading agent is a drug for the prevention and / or treatment of autoimmune diseases, inflammation, and cancer.

[0068] Furthermore, the autoimmune diseases or inflammations mentioned are rheumatoid arthritis, Crohn's disease, ulcerative colitis, psoriasis, multiple sclerosis, systemic lupus erythematosus, Hashimoto's thyroiditis, myasthenia gravis, type 1 or type 2 diabetes and related diseases, vasculitis, pernicious anemia, Sjögren's syndrome, uveitis, Graves' ophthalmopathy, alopecia areata, etc., allergic diseases (e.g., allergic asthma, atopic dermatitis, allergic rhinitis / conjunctivitis, allergic contact dermatitis), inflammatory diseases (which may be accompanied by underlying abnormal reactions, such as inflammatory bowel disease, Crohn's disease or ulcerative colitis, endogenous asthma, inflammatory lung injury, inflammatory liver injury, inflammatory glomerular injury), atherosclerosis, osteoarthritis, irritant contact dermatitis and further eczematous dermatitis, seborrheic dermatitis, skin manifestations of immune-mediated diseases, inflammatory eye diseases, keratoconjunctivitis, myocarditis, or hepatitis.

[0069] Furthermore, the cancer is a solid tumor and a hematologic malignancy (e.g., T-cell and B-cell malignancies).

[0070] Furthermore, the cancers mentioned include liver cancer, stomach cancer, colorectal cancer, leukemia, lymphoma, acute myeloid leukemia (AML), T-cell prolymphocytic leukemia, T-cell granulocytic lymphocytic leukemia, aggressive natural killer cell leukemia, hairy cell leukemia, nasal type and nasal NK / T-cell lymphoma, fungal granuloma and Cezari syndrome, angioimmune T-cell lymphoma, peripheral T-cell lymphoma nonspecific type (PTCL-NOS), and adult T-cell leukemia / lymphoma (HTL). V1), anaplastic large cell lymphoma, primary cutaneous CD30-positive T-cell proliferative disorders, cutaneous T-cell lymphoma, T-cell lymphoma resembling subcutaneous lipitis, enteropathy-associated lymphoma, hepatosplenic gamma / δ T-cell lymphoma, or non-Hodgkin lymphoma (e.g., B-cell non-Hodgkin lymphoma; e.g., Burkitt lymphoma, chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SLL), diffuse large B-cell lymphoma, follicular lymphoma, or covered cell lymphoma).

[0071] Peripheral T-cell lymphoma, not otherwise specified (PTCLNOS), is a type of peripheral T-cell lymphoma.

[0072] Enteropathy-associated lymphoma, also known as enteropathy-type intestinal T-cell lymphoma (ETCL), is intestinal T-cell lymphoma (+enteropathy).

[0073] Regarding the definition of terms used in this invention: Unless otherwise stated, the initial definitions provided for groups or terms herein apply to the groups or terms used throughout this specification; for terms not specifically defined herein, the meanings that a person skilled in the art would give them should be given based on the disclosure and context.

[0074] The minimum and maximum carbon atom content in hydrocarbon groups are indicated by prefixes. For example, the prefix Ca-Cb alkyl indicates any alkyl group containing "a" to "b" carbon atoms. For instance, C1-C6 alkyl refers to a straight-chain or branched alkyl group containing 1, 2, 3, 4, 5, or 6 carbon atoms, and C1-C6 alkylene refers to a straight-chain or branched alkylene containing 1, 2, 3, or 4 carbon atoms, and so on.

[0075] Unless otherwise stated, in this invention, "substitution" means that one, two or more hydrogen atoms in a molecule are replaced by other different atoms or molecules, including one, two or more substitutions on isotopes or ectopic atoms in the molecule.

[0076] In formula I, R A1 The substitution site can be any site in ring A.

[0077] An aromatic ring refers to a monocyclic group consisting entirely of carbon atoms with a conjugated π-electron system, such as a phenyl group. The aryl group must not contain heteroatoms, and the point of attachment to the parent compound must be on a carbon atom of a ring with a conjugated π-electron system.

[0078] Aromatic heterocycles refer to monocyclic heteroaromatic groups containing one or more heteroatoms and having a conjugated π-electron system. 5-12 membered heteroaromatic rings include pyridinones.

[0079] A fused ring is a polycyclic ring in which two rings share two adjacent carbon atoms. For example, a 6-membered aromatic heterocyclic fused to a 5-membered aromatic heterocyclic ring refers to a structure in which a 6-membered aromatic heterocyclic ring and a 5-membered aromatic heterocyclic ring share two adjacent carbon atoms, and so on.

[0080] A spirocycle is a polycyclic ring, and this polycyclic ring has two rings and one carbon atom.

[0081] A bridged ring is a polycyclic ring in which two rings share two non-adjacent carbon atoms.

[0082] Unless otherwise specified, carbon ring refers to monocyclic carbon ring, and heterocyclic refers to monocyclic heterocyclic ring.

[0083] Cyclic compounds composed of carbon atoms and heteroatoms are called heterocyclic compounds.

[0084] A saturated heterocycle is a heterocycle in which the bonds between the carbon atoms and heteroatoms in the ring are single bonds.

[0085] For the groups obtained by replacing one or more methylene groups of the C1-C6 alkyl group with heteroatoms, for example This represents the group obtained by replacing one methylene group in a propyl group with an oxygen atom.

[0086] Heteroatoms include, but are not limited to, oxygen, sulfur, and nitrogen.

[0087] Alkylamine group -NHR z R z It is an alkyl group. For example, C1-C6 alkylamine groups refer to -NHR. z1 R z1 It is a C1-C6 alkyl group.

[0088] The amino group refers to -NH2.

[0089] Amide groups refer to groups containing the -CONH- structure.

[0090] When L 2 When selected from a single key, it means that B and R6 are directly connected by a single key.

[0091] An isotopic compound is a compound obtained by replacing one or more atoms of a compound with their corresponding isotopes. For example, a compound obtained by replacing one or more hydrogen atoms (H) with deuterium (D) or tritium (T); or a compound obtained by replacing one or more carbon atoms with deuterium (D) or tritium (T). 12 Carbon 11 or carbon 13 The compound obtained after substitution.

[0092] Isotopic compounds include deuterated compounds, which are compounds obtained by replacing one or more hydrogen atoms on the carbon atom with deuterium.

[0093] The present invention achieves the following beneficial effects: the compounds provided by the present invention can be used as VAV1 degrading agents for the preparation of drugs for the prevention and / or treatment of autoimmune diseases, inflammation, cancer, and other diseases. The compounds of the present invention possess good VAV1 degrading activity, good oral pharmacokinetics, and good efficacy, and have broad application prospects.

[0094] Obviously, based on the above description of the present invention, and according to common technical knowledge and conventional methods in the field, various other modifications, substitutions or alterations can be made without departing from the basic technical concept of the present invention.

[0095] The following detailed embodiments further illustrate the above-described content of the present invention. However, this should not be construed as limiting the scope of the present invention to the following embodiments. All technologies implemented based on the above-described content of the present invention fall within the scope of the present invention. Attached Figure Description

[0096] Figure 1. Determination of the degradation activity of compound A and the compound obtained in Example 27 on VAV1 by WB method. Detailed Implementation

[0097] The raw materials and equipment used in this invention are all known products, obtained by purchasing commercially available products.

[0098] The following experiments, where no temperature is specified, are reactions conducted under normal temperature conditions, which is room temperature, or 25±5℃.

[0099] Example 1: 3-(1-(3-(2-oxopyridin-1(2H)-yl)phenyl)-1H-indazol-4-yl)piperidin-2,6-dione

[0100] Step 1: Synthesis of 4-(2,6-bis(benzyloxy)pyridin-3-yl)-1H-indazole

[0101] 2,6-bis(benzyloxy)-3-bromopyridine (740 mg, 2.0 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborin-2-yl)-1H-indazole (488 mg, 2.0 mmol) were dissolved in 10 mL of 1,4-dioxane, and 3 mL of water and potassium phosphate (849 mg, 4.0 mmol) were added. PddppfCl2 (37 mg, 0.1 mmol) was added, and the reaction was carried out at 100 °C for 8 hours under argon protection. The mixture was extracted with ethyl acetate, washed with water, and concentrated to dryness under reduced pressure. The product was purified by column chromatography to obtain 362 mg of 4-(2,6-bis(benzyloxy)pyridin-3-yl)-1H-indazole, yield: 45%. LC / MS (ESI+) calcd for C 26 H21 N3O2([M+H)) + )m / e 408.1, found 408.1.

[0102] Step 2: Synthesis of 3-(1H-indazol-4-yl)piperidine-2,6-dione

[0103] 4-(2,6-bis(benzyloxy)pyridin-3-yl)-1H-indazole (180 mg, 0.44 mmol) was dissolved in 35 mL of methanol, 70 mg of 10% palladium on carbon was added, the mixture was purged with hydrogen three times, and reacted at room temperature for 3 hours. The mixture was filtered, and the filtrate was concentrated to dryness under reduced pressure to give 101 mg of the product 3-(1H-indazole-4-yl)piperidine-2,6-dione, yield: 100%. LC / MS (ESI+) calcd for C 12 H 11 N3O2([M+H)) + )m / e 230.1, found 230.1.

[0104] Step 3: Synthesis of 3-(1-(3-(2-oxopyridin-1(2H)-yl)phenyl)-1H-indazol-4-yl)piperidin-2,6-dione

[0105] 3-(1H-indazol-4-yl)piperidin-2,6-dione (100 mg, 0.44 mmol) and 1-(3-iodophenyl)pyridin-2(1H)-one (156 mg, 0.52 mmol) were dissolved in 3 mL of dimethyl sulfoxide. Potassium carbonate (123 mg, 0.88 mmol), cuprous iodide (42 mg, 0.22 mmol), and 2-pyridinecarboxylic acid (28 mg, 0.22 mmol) were added. The mixture was reacted at 120 °C for 3 hours under argon protection. The mixture was extracted with ethyl acetate, washed with water, concentrated under pressure to dryness, and purified by thin-layer chromatography to obtain 20 mg of the product 3-(1-(3-(2-oxopyridin-1(2H)-yl)phenyl)-1H-indazol-4-yl)piperidin-2,6-dione (yield: 12%). LC / MS (ESI+) calcd for C 23 H 18 N4O3([M+H)) + )m / e 399.1, found 399.1; 1H NMR(400MHz, DMSO-d6)δ10.98(s,1H),8.46(d,J=0.9Hz,1H),7.90–7.84(m,3H),7.84–7.80(m, 1H),7.77–7.72(m,1H),7.55(ddd,J=8.9,6.5,2.0Hz,1H),7.52–7.43(m,2H),7.14(d,J=7.1Hz ,1H),6.54(dt,J=9.3,1.1Hz,1H),6.37(td,J=6.7,1.3Hz,1H),4.43(dd,J=12.2,4.8Hz,1H),2 .78(ddd,J=17.4,12.4,5.2Hz,1H),2.63–2.56(m,1H),2.49-2.44(m,,1H),2.16–2.09(m,1H).

[0106] Example 2: 3-(1-(3-(1,4-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)phenyl)-1H-indazol-4-yl)piperidin-2,6-dione

[0107] Step 1: Synthesis of 1,4-dimethylpyridin-2(1H)-one

[0108] 4-Methylpyridin-2(1H)-one (540 mg, 5.0 mmol) was dissolved in 10 mL of methanol, and potassium hydroxide (421 mg, 7.5 mmol) and methyl iodoform (2.13 g, 15 mmol) were added. The mixture was reacted overnight at room temperature. The solution was concentrated to dryness under reduced pressure and purified by column chromatography to give 540 mg of the product, yield: 88%.

[0109] Step 2: Synthesis of 3-(3-bromophenyl)-1,4-dimethylpyridin-2(1H)-one

[0110] 1,4-Dimethylpyridin-2(1H)-one (540 mg, 4.4 mmol) and (3-bromophenyl)hydrazine hydrochloride (1.18 g, 5.28 mmol) were dissolved in 15 mL of DMSO, and potassium carbonate (1.82 g, 13.2 mmol) was added. The mixture was reacted overnight in an open container. The mixture was extracted with ethyl acetate, washed with water, concentrated to dryness, and purified by column chromatography to give 50 mg of the product (yield: 4%). LC / MS (ESI+) calcd for C 13 H 13 BrNO([M+H] + )m / e 278.0, found 278.0.

[0111] Step 3: Synthesis of 3-(1-(3-(1,4-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)phenyl)-1H-indazol-4-yl)piperidin-2,6-dione

[0112] 3-(3-bromophenyl)-1,4-dimethylpyridin-2(1H)-one (46 mg, 0.17 mmol) and 3-(1H-indazol-4-yl)piperidin-2,6-dione (46 mg, 0.2 mmol) were dissolved in 4 mL of DMSO. Potassium phosphate (70 mg, 0.33 mmol), cuprous iodide (16 mg, 0.08 mmol), and 2-pyridinecarboxylic acid (10 mg, 0.08 mmol) were added. The mixture was reacted at 130 °C for 3 hours under argon protection. The mixture was extracted with ethyl acetate, washed with water, concentrated, and purified by thin-layer chromatography to obtain 10 mg of the product 3-(1-(3-(1,4-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)phenyl)-1H-indazol-4-yl)piperidin-2,6-dione (yield: 14%). LC / MS (ESI+) calcd for C 25 H 23 N4O3([M+H)) + )m / e 427.1, found 427.1; 1 H NMR (400MHz, DMSO-d6) δ10.97(s,1H),8.41(d,J=0.9Hz,1H),7.77(d,J=8.5Hz,1H),7.70(ddd,J=8.1,2 .2,1.1Hz,1H),7.65(d,J=6.9Hz,1H),7.63(d,J=7.8Hz,1H),7.60–7.58(m,1H),7.46(dd,J=8.5,7.1Hz, 1H),7.25(dt,J=7.6,1.3Hz,1H),7.11(d,J=7.1Hz,1H),6.25(dd,J=7.0,3.2Hz,1H),4.41(dd,J=12.1,4 .9Hz,1H),3.45(s,3H),2.80–2.73(m,1H),2.68–2.56(m,2H),2.13(dd,J=8.7,4.1Hz,1H),2.08(s,3H).

[0113] Example 3: 3-(1-(3-(6-(difluoromethyl)-2-oxopyridin-1(2H)-yl)phenyl)-1H-indazol-4-yl)piperidin-2,6-dione

[0114] Step 1: Synthesis of 1-(3-iodophenyl)-6-oxo-1,6-dihydropyridine-2-carboxaldehyde

[0115] 1-(3-iodophenyl)-6-methylpyridin-2(1H)-one (312 mg, 1.0 mmol) was dissolved in 8 mL of 1,4-dioxane, and selenium dioxide (222 mg, 2.0 mmol) was added. The mixture was incubated overnight at 100 °C under argon protection. The product was purified by column chromatography to obtain 275 mg of 1-(3-iodophenyl)-6-oxo-1,6-dihydropyridin-2-carboxaldehyde (yield: 85%).

[0116] LC / MS(ESI+)calcd for C 12 H9INO2([M+H) + )m / e 326.0, found 326.0.

[0117] Step 2: Synthesis of 6-(difluoromethyl)-1-(3-iodophenyl)pyridine-2(1H)-one

[0118] 1-(3-iodophenyl)-6-oxo-1,6-dihydropyridine-2-carboxaldehyde (195 mg, 0.6 mmol) was dissolved in 5 mL of dichloromethane. DAST (diethylaminotrifluoride, 387 mg, 2.4 mmol) was added dropwise under an ice-water bath. After the addition was complete, the reaction was allowed to proceed at room temperature for 3 hours. The reaction was quenched with sodium carbonate aqueous solution, extracted with dichloromethane, concentrated to dryness, and purified by thin-layer chromatography to obtain 160 mg of the product 6-(difluoromethyl)-1-(3-iodophenyl)pyridine-2(1H)-one (yield: 77%).

[0119] LC / MS(ESI+)calcd for C 12 H9IF2NO([M+H) + )m / e 348.0, found 348.0.

[0120] Step 3: Synthesis of 3-(1-(3-(6-(difluoromethyl)-2-oxopyridin-1(2H)-yl)phenyl)-1H-indazol-4-yl)piperidin-2,6-dione

[0121] The preparation method in step 2 of Example 33 is the same, except that 1-(3-iodophenyl)-6-methylpyridin-2(1H)-one is replaced with 6-(difluoromethyl)-1-(3-iodophenyl)pyridin-2(1H)-one, yielding the target compound 3-(1-(3-(6-(difluoromethyl)-2-oxopyridin-1(2H)-yl)phenyl)-1H-indazol-4-yl)piperidin-2,6-dione. LC / MS (ESI+) calcd for C 24 H 19 F2N4O3([M+H) + )m / e 449.1, found 449.1. 1H NMR(400MHz,DMSO-d6)δ10.97(s,1H),8.46(d,J=0.9Hz,1H),7.97–7.91(m,1H),7.78(dd,J =7.8,5.0Hz,2H),7.74(d,J=8.1Hz,1H),7.66(dd,J=9.3,6.9Hz,1H),7.48(dd,J=8.6,7.1H z,1H),7.35(dd,J=7.7,1.9Hz,1H),7.14(d,J=7.1Hz,1H),6.79–6.62(m,3H),4.42(dd,J=1 2.2, 4.8Hz, 1H), 2.78 (ddd, J=17.2, 12.4, 5.2Hz, 1H), 2.68–2.53 (m, 2H), 2.16–2.08 (m, 1H).

[0122] Example 4: 3-(1-(3-(5-fluoro-6-methyl-2-oxopyridin-1(2H)-yl)phenyl)-1H-indazol-4-yl)piperidin-2,6-dione

[0123] 3-(1-(3-(6-methyl-2-oxopyridin-1(2H)-yl)phenyl)-1H-indazol-4-yl)piperidine-2,6-dione (16 mg, 0.04 mmol) was dissolved in 5 mL of anhydrous acetonitrile, and Selectfluor (14 mg, 0.04 mmol of 1-chloromethyl-4-fluoro-1,4-diazabicyclo2,2,2-octanedi(tetrafluoroborate) salt) was added. The mixture was reacted overnight at room temperature, extracted with ethyl acetate, washed with water, concentrated to dryness, and purified by thin-layer chromatography to obtain 4 mg of the product 3-(1-(3-(5-fluoro-6-methyl-2-oxopyridin-1(2H)-yl)phenyl)-1H-indazol-4-yl)piperidine-2,6-dione, yield: 25%. LC / MS (ESI+) calcd for C 24 H 19 FN4O3([M+H) + )m / e 431.1, found 431.1. 1H NMR(400MHz,DMSO-d6)δ10.97(s,1H),8.46(s,1H),7.92(d,J=8.2Hz,1H),7.85– 7.73(m,3H),7.68(t,J=9.3Hz,1H),7.48(t,J=7.8Hz,1H),7.35(d,J=8.1Hz,1H), 7.14(d,J=7.2Hz,1H),6.42(dd,J=10.2,5.2Hz,1H),4.43(dd,J=12.1,4.7Hz,1H) ,2.82–2.73(m,1H),2.68–2.59(m,2H),2.16–2.08(m,1H),1.97(d,J=3.5Hz,3H).

[0124] Example 5: 3-(1-(3-(6-cyclopropyl-2-oxopyridin-1(2H)-yl)phenyl)-1H-indazol-4-yl)piperidin-2,6-dione

[0125] The target compound was prepared using a method similar to that in Example 33. LC / MS (ESI+) calcd for C 26 H 23 N4O3([M+H)) + )m / e 439.1, found439.1. 1 H NMR (400MHz, DMSO-d6) δ10.97(s,1H),8.45(s,1H),7.88(td,J=8.3,1.9Hz,1H),7.79(d,J=8.6Hz,1H),7.76(d,J=8.0Hz,1H),7 .74–7.72(m,1H),7.47(ddd,J=14.8,8.9,7.1Hz,2H),7.36(dd,J=8.0,2.0Hz,1H),7.14(d,J=7.1Hz,1H),6.38(dd,J=9.1,1.2Hz ,1H),6.10(d,J=7.0Hz,1H),4.43(dd,J=12.2,4.8Hz,1H),2.78(ddd,J=17.3,12.3,5.2Hz,1H),2.69–2.52(m,2H),2.13(dq,J=1 3.4,5.0Hz,1H),1.38(ddd,J=10.4,8.3,5.3Hz,1H),0.76(ddt,J=8.6,5.9,3.3Hz,2H),0.67(dtd,J=12.1,6.0,5.3,3.5Hz,2H).

[0126] Example 6: 3-(1-(3-(6-ethyl-2-oxopyridin-1(2H)-yl)phenyl)-1H-indazol-4-yl)piperidin-2,6-dione

[0127] The preparation method of Example 33 is the same, except that 6-methylpyridin-2(1H)-one in the first step is replaced with 6-ethylpyridin-2(1H)-one to obtain the target compound 3-(1-(3-(6-ethyl-2-oxopyridin-1(2H)-yl)phenyl)-1H-indazole-4-yl)piperidin-2,6-dione.

[0128] LC / MS(ESI+)calcd for C 25 H 23 N4O3([M+H)) + )m / e 427.1, found 427.1.

[0129] 1 H NMR (400MHz, DMSO-d6) δ10.97(s,1H),8.45(s,1H),7.91(d,J=8.2Hz,1H),7.83–7.71(m,2H),7. 69(t,J=2.2Hz,1H),7.49(dt,J=8.5,6.9Hz,2H),7.31(dd,J=7.9,1.7Hz,1H),7.14(d,J=7.1Hz,1 H),6.39(d,J=9.1Hz,1H),6.24(d,J=7.0Hz,1H),4.43(dd,J=12.1,4.9Hz,1H),2.78(t,J=12.3Hz ,1H),2.64(dd,J=25.5,2.6Hz,2H),2.36–2.28(m,2H),2.17–2.08(m,1H),1.03(t,J=7.4Hz,3H).

[0130] Example 7: 3-(3-fluoro-1-(3-(6-methyl-2-oxopyridin-1(2H)-yl)phenyl)-1H-indazol-4-yl)piperidin-2,6-dione

[0131] Step 1: Synthesis of 3-(3-fluoro-1H-indazol-4-yl)piperidine-2,6-dione

[0132] 3-(1H-indazol-4-yl)piperidine-2,6-dione (170 mg, 0.74 mmol) was dissolved in 10 mL of anhydrous acetonitrile, and Selectfluor (210 mg, 0.59 mmol) was added. The mixture was reacted overnight at 55 °C, extracted with ethyl acetate, washed with water, concentrated to dryness, and purified by thin-layer chromatography to obtain 25 mg of the product 3-(3-fluoro-1H-indazol-4-yl)piperidine-2,6-dione, yield: 13%.

[0133] LC / MS(ESI+)calcd for C 12 H 11 FN3O2([M+H) + )m / e 248.0, found 248.0.

[0134] Step 2: Synthesis of 3-(3-fluoro-1-(3-(6-methyl-2-oxopyridin-1(2H)-yl)phenyl)-1H-indazol-4-yl)piperidin-2,6-dione

[0135] The preparation method in step 2 of Example 33 is the same, except that 3-(1H-indazol-4-yl)piperidin-2,6-dione is replaced with 3-(3-fluoro-1H-indazol-4-yl)piperidin-2,6-dione, yielding the target compound 3-(3-fluoro-1-(3-(6-methyl-2-oxopyridin-1(2H)-yl)phenyl)-1H-indazol-4-yl)piperidin-2,6-dione. LC / MS (ESI+) calcd for C 24 H 20 FN4O3([M+H) + )m / e 431.1, found 431.1. 1 H NMR (400MHz, DMSO-d6) δ11.01(s,1H),7.84(dd,J=8.0,2.3Hz,1H),7.79(dd,J=8.6,2.2Hz,1H),7.7 3(t,J=8.0Hz,1H),7.69–7.65(m,1H),7.57(dd,J=8.7,7.2Hz,1H),7.44(dd,J=9.3,6.8Hz,1H),7.36 –7.29(m,1H),7.22(d,J=7.1Hz,1H),6.37(d,J=9.2Hz,1H),6.27(d,J=6.8Hz,1H),4.33(dd,J=12.7, 5.0Hz,1H),2.83(ddd,J=17.8,13.0,5.4Hz,1H),2.70–2.52(m,2H),2.20–2.11(m,1H),2.00(s,3H).

[0136] Example 8: 3-(1-(3-(6-cyclopropyl-4-methyl-2-oxopyridin-1(2H)-yl)phenyl)-1H-indazol-4-yl)piperidin-2,6-dione

[0137] The target compound was prepared using a method similar to that in Example 1.

[0138] The preparation method is the same as in Example 33, except that the 6-methylpyridin-2(1H)-one in the first step is replaced with 6-cyclopropylpyridin-2(1H)-one, yielding the target compound 3-(1-(3-(6-cyclopropyl-4-methyl-2-oxopyridin-1(2H)-yl)phenyl)-1H-indazole-4-yl)piperidin-2,6-dione. LC / MS (ESI+) calcd for C 27 H 25 N4O3([M+H)) + )m / e 453.1, found 453.1. 1 H NMR (400MHz, DMSO-d6) δ10.97(s,1H),8.45(s,1H),7.90–7.85(m,1H),7.78(d,J=8.5Hz,1H),7.73(t,J=8.0 Hz,1H),7.69(d,J=2.1Hz,1H),7.48(dd,J=8.5,7.1Hz,1H),7.35–7.31(m,1H),7.14(d,J=7.1Hz,1H),6.20( s,1H),5.98(d,J=1.8Hz,1H),4.42(dd,J=12.2,4.8Hz,1H),2.78(ddd,J=17.2,12.2,5.1Hz,2H),2.69–2.59 (m,2H),2.15(s,3H),2.12(dd,J=9.0,5.2Hz,1H),1.38–1.33(m,1H),0.80–0.73(m,2H),0.68–0.62(m,2H).

[0139] Example 9: 3-(1-(3-(4-methyl-2-oxo-6-(trifluoromethyl)pyridin-1(2H)-yl)phenyl)-1H-indazol-4-yl)piperidin-2,6-dione

[0140] Step 1: Synthesis of 1-(3-iodophenyl)-4-methyl-6-(trifluoromethyl)pyridine-2(1H)-one

[0141] 4-Methyl-6-(trifluoromethyl)-2H-pyran-2-one (2.0 g, 11.2 mmol) and m-iodoaniline (2.47 g, 11.2 mmol) were dissolved in 10 mL of glacial acetic acid, and 5 mL of water were added. The mixture was reacted overnight at 100 °C under argon protection. Most of the glacial acetic acid was concentrated under reduced pressure, and the mixture was extracted with ethyl acetate, washed with water, concentrated to dryness under reduced pressure, and purified by column chromatography to give 120 mg of the product 1-(3-iodophenyl)-4-methyl-6-(trifluoromethyl)pyridin-2(1H)-one (yield: 3%).

[0142] LC / MS(ESI+)calcd for C 13 H 10 F3INO([M+H)) + )m / e 379.9, found 379.9.

[0143] Step 2: Synthesis of 3-(1-(3-(4-methyl-2-oxo-6-(trifluoromethyl)pyridin-1(2H)-yl)phenyl)-1H-indazol-4-yl)piperidin-2,6-dione

[0144] The preparation method in step 2 of Example 1 is the same, except that 1-(3-iodophenyl)-6-methylpyridin-2(1H)-one is replaced with 1-(3-iodophenyl)-4-methyl-6-(trifluoromethyl)pyridin-2(1H)-one, yielding the target compound 3-(1-(3-(4-methyl-2-oxo-6-(trifluoromethyl)pyridin-1(2H)-yl)phenyl)-1H-indazol-4-yl)piperidin-2,6-dione. LC / MS (ESI+) calcd for C 25 H 20 F3N4O3([M+H) + )m / e 481.1, found 481.1. 1 H NMR (400MHz, DMSO-d6) δ10.97 (s, 1H), 8.45 (s, 1H), 7.92 (dd, J = 8.1, 2.2Hz, 1H), 7.81 (d,J=2.2Hz,1H),7.77–7.70(m,2H),7.48(dd,J=8.6,7.1Hz,1H),7.36(d,J=7.9Hz,1H ),7.14(d,J=7.1Hz,1H),6.91(d,J=1.7Hz,1H),6.66(s,1H),4.42(dd,J=12.2,4.8Hz, 1H),2.77(td,J=12.3,6.1Hz,1H),2.70–2.52(m,2H),2.29(s,3H),2.16–2.09(m,1H).

[0145] Example 10: 3-(1-(3-(2-oxo-6-(trifluoromethyl)pyridin-1(2H)-yl)phenyl)-1H-indazol-4-yl)piperidin-2,6-dione

[0146] 3-(1-(3-(6-bromo-2-oxopyridin-1(2H)-yl)phenyl)-1H-indazole-4-yl)piperidin-2,6-dione (16 mg, 0.03 mmol) was dissolved in 2 mL of anhydrous DMF (N,N-dimethylformamide), and cuprous iodide (25 mg, 0.13 mmol) was added. The mixture was reacted at 130 °C for 1.5 h under argon protection. The mixture was extracted with ethyl acetate, washed with water, concentrated to dryness, and purified by thin-layer chromatography to obtain 5 mg of the product 3-(1-(3-(2-oxopyridin-1(2H)-yl)phenyl)-1H-indazole-4-yl)piperidin-2,6-dione, yield: 35%. LC / MS (ESI+) calcd for C 24 H 18 F3N4O3([M+H) + )m / e 467.1, found 467.1. 1 H NMR (400MHz, DMSO-d6) δ10.97 (s, 1H), 8.45 (s, 1H), 7.94 (dt, J = 8.0, 1.5Hz, 1H), 7.8 6(s,1H),7.78–7.63(m,3H),7.48(dd,J=8.6,7.1Hz,1H),7.40(d,J=7.6Hz,1H),7.14 (d,J=7.1Hz,1H),7.00(d,J=7.0Hz,1H),6.85(d,J=9.4Hz,1H),4.43(dd,J=12.2,4. 8Hz,1H),2.78(ddd,J=17.4,12.4,5.3Hz,1H),2.68–2.53(m,2H),2.16–2.09(m,1H).

[0147] Example 11: 3-(1-(2-fluoro-5-(4-methyl-2-oxo-6-(trifluoromethyl)pyridin-1(2H)-yl)phenyl)-1H-indazol-4-yl)piperidin-2,6-dione

[0148] The preparation method is the same as in Example 9, except that the m-iodoaniline in the first step is replaced with 3-bromo-4-fluoroaniline, yielding the target compound 3-(1-(2-fluoro-5-(4-methyl-2-oxo-6-(trifluoromethyl)pyridin-1(2H)-yl)phenyl)-1H-indazol-4-yl)piperidin-2,6-dione. LC / MS (ESI+) calcd for C25 H 19 F4N4O3([M+H) + )m / e 499.1, found 499.1. 1 H NMR (400MHz, DMSO-d6) δ10.98(s,1H),8.48(s,1H),7.82(d,J=6.8Hz,1H),7.72(t,J=9.6Hz,1H),7.60(s,1H),7.50–7.45(m,1H), 7.34–7.28(m,1H),7.14(d,J=7.1Hz,1H),6.91(s,1H),6.66(s,1H),2.82–2.75(m,1H),2.61-2.54(m,2H),2.13(d,J=14.1Hz,1H).

[0149] Example 12: 3-(2-ethynyl-4'-(6-methyl-2-oxopyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0150] Step 1: Synthesis of 1-(4-bromophenyl)-6-methylpyridin-2(1H)-one

[0151] 4-Bromophenylboronic acid (3.04 g, 15.0 mmol), 6-methylpyridin-2(1H)-one (1.1 g, 10.0 mmol), TMEDA (tetramethylethylenediamine, 465 mg, 4.0 mmol), copper trifluoromethanesulfonate (1.45 g, 4.0 mmol), and pyridine (2.38 g, 30.0 mmol) were added to dry DCE (dichloroethane) solvent. The reaction mixture was purged with oxygen three times, then heated to 50 °C and reacted for 4 hours. After cooling to room temperature, the mixture was extracted with dichloromethane, concentrated under reduced pressure, purified by silica gel column chromatography, and eluted with ethyl acetate / petroleum ether to give the target compound 1-(4-bromophenyl)-6-methylpyridin-2(1H)-one (586 mg, 2.22 mmol), yield: 22%. LC / MS (ESI+) calcd for C 12 H 11 BrNO([M+H] + )m / z 264; found 264.

[0152] Step 2: Synthesis of 6-methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)phenyl)pyridin-2(1H)-one

[0153] 1-(4-bromophenyl)-6-methylpyridin-2(1H)-one (586 mg, 2.22 mmol), pinacol diboronate (620 mg, 2.44 mmol), catalyst Pd(dppf)Cl2 (487 mg, 0.67 mmol), and potassium acetate (1.96 g, 20.0 mmol) were added to a dry dioxane solvent. The reaction mixture was purged three times with nitrogen and then heated to 80 °C for 4 hours. After cooling to room temperature, the mixture was extracted with ethyl acetate, concentrated under reduced pressure, purified by silica gel column chromatography, and eluted with ethyl acetate / petroleum ether to give the target compound 6-methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)pyridin-2(1H)-one (248 mg, 0.80 mmol), yield: 36%. LC / MS (ESI+) calcd for C 18 H 23 BNO3([M+H)) + )m / z 312.2; found 312.2.

[0154] Step 3: Synthesis of 3-(4'-(6-methyl-2-oxopyridin-1(2H)-yl)-2-((trimethylsilyl)ethynyl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0155] 3-(3-bromo-2-((trimethylsilyl)ethynyl)phenyl)piperidin-2,6-dione (36 mg, 0.10 mmol), 6-methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborin-2-yl)phenyl)pyridin-2(1H)-one (31 mg, 0.10 mmol), potassium phosphate (65 mg, 0.30 mmol), and catalyst Pd(dppf)Cl2 (8 mg, 0.01 mmol) were added to a mixed solvent of tetrahydrofuran and water (v / v of tetrahydrofuran and water was 10 / 1). The reaction mixture was purged with nitrogen three times and then heated to 35 °C for 1 hour. The solution was cooled to room temperature and concentrated under reduced pressure, then purified by silica gel column chromatography to obtain the target compound 3-(4'-(6-methyl-2-oxopyridin-1(2H)-yl)-2-((trimethylsilyl)ethynyl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione (19 mg, 0.04 mmol), yield: 40%. LC / MS (ESI+) calcd for C 28 H 29 N₂O₃Si([M+H)) + )m / z 469.2; found 469.2.

[0156] Step 4: Synthesis of 3-(2-ethynyl-4'-(6-methyl-2-oxopyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0157] Compound 3-(4'-(6-methyl-2-oxopyridin-1(2H)-yl)-2-((trimethylsilyl)ethynyl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione (19 mg, 0.04 mmol) was dissolved in 10 mL of dry tetrahydrofuran, and 0.5 mL of TBAF (tetrabutylammonium fluoride, 1 M) in tetrahydrofuran was added. The mixture was stirred at room temperature for 1 hour. When the reaction was determined to be complete based on TLC and LCMS analysis, the mixture was extracted with ethyl acetate, concentrated under reduced pressure, and then purified by silica gel column chromatography to obtain the target compound 3-(2-ethynyl-4'-(6-methyl-2-oxopyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione (10 mg, 0.025 mmol), yield: 63%. LC / MS (ESI+) calcd for C 25 H 21 N₂O₃([M+H)) + )m / z 397.2; found 397.2. 1 H NMR(400MHz, DMSO-d6)δ10.93(s,1H),7.72–7.65(m,2H),7.50(t,J=7.7Hz,1H), 7.44–7.38(m,2H),7.36–7.29(m,3H),6.37(d,J=9.2Hz,1H),6.26(dt,J=7.3,1. 4Hz,1H),4.41(s,1H),4.34(dd,J=12.1,5.0Hz,1H),2.77(ddd,J=17.5,12.7,5. 3Hz,1H),2.58-2.56(m,1H),2.40-2.36(m,1H),2.13–2.02(m,1H),1.95(s,3H).

[0158] Example 13: 3-(1-(3-((1,5-naphthid-2-yl)amino)phenyl)-1H-indazol-4-yl)piperidin-2,6-dione

[0159] Step 1: Synthesis of N-(3-iodophenyl)-1,5-naphthyl-2-amine

[0160] 2-Chloro-1,5-naphthylpyridine (165 mg, 1.0 mmol), 3-iodoaniline (329 mg, 1.5 mmol), and cesium carbonate (652 mg, 2.0 mmol) were added to dry DMSO solvent. The reaction mixture was purged three times with nitrogen and then heated to 130 °C for 12 h. After cooling to room temperature, the mixture was extracted with ethyl acetate, concentrated under reduced pressure, purified by silica gel column chromatography, and eluted with ethyl acetate / petroleum ether to give the target compound N-(3-iodophenyl)-1,5-naphthyl-2-amine (112 mg, 0.32 mmol), yield: 32%. LC / MS (ESI+) calcd for C 14 H 11 IN3([M+H) + )m / z 348; found 348.

[0161] Step 2: Synthesis of 3-(1-(3-((1,5-naphthid-2-yl)amino)phenyl)-1H-indazol-4-yl)piperidin-2,6-dione

[0162] N-(3-iodophenyl)-1,5-naphthidium-2-amine (69 mg, 0.2 mmol), 3-(1H-indazol-4-yl)piperidin-2,6-dione (46 mg, 0.2 mmol), cuprous iodide (15 mg, 0.08 mmol), 2-pyridinecarboxylic acid (10 mg, 0.08 mmol), and potassium carbonate (56 mg, 0.4 mmol) were added to dry DMSO solvent. The reaction mixture was purged with nitrogen three times and then heated to 110 °C for 1 hour. After cooling to room temperature, the mixture was extracted with ethyl acetate and concentrated under reduced pressure. The resulting product was purified by silica gel agar plate preparation and developed with dichloromethane / methanol to give the target compound 3-(1-(3-((1,5-naphthidium-2-yl)amino)phenyl)-1H-indazol-4-yl)piperidin-2,6-dione (12 mg, 0.03 mmol), yield: 13%. LC / MS (ESI+) calcd for C 26 H 21 N6O2([M+H)) + )m / z 449.2; found 449.2. 1H NMR (400MHz, DMSO-d6) δ10.98(s,1H),10.03(s,1H),8.87(t,J=2.1Hz,1H),8.68(dd,J=4.3,1.6H z,1H),8.44(s,1H),8.17(d,J=9.2Hz,1H),8.06(dd,J=8.3,4.6Hz,2H),7.75(d,J=8.1Hz,1H),7.6 5(dd,J=8.5,4.2Hz,1H),7.57(dt,J=11.6,7.6Hz,2H),7.43–7.35(m,2H),7.17(d,J=7.1Hz,1H),4 .45(dd,J=12.0,4.9Hz,1H),2.80(ddd,J=17.4,12.4,5.3Hz,1H),2.63(s,2H),2.22–2.10(m,1H).

[0163] Example 14: 3-(1-(3-(6-cyclopropyl-3-fluoro-2-oxopyridin-1(2H)-yl)phenyl)-1H-indazol-4-yl)piperidin-2,6-dione

[0164] Step 1: Synthesis of 2-(benzyloxy)-6-bromo-3-fluoropyridine

[0165] 6-Bromo-2-chloro-3-fluoropyridine (4.0 g, 19.0 mmol), benzyl alcohol (2.06 g, 19.0 mmol), and cesium carbonate (12.4 g, 38.0 mmol) were added to a dry acetonitrile solvent. The reaction mixture was purged three times with nitrogen and then heated to 60 °C for 12 h. After cooling to room temperature, the mixture was extracted with ethyl acetate, concentrated under reduced pressure, and purified by silica gel column chromatography, eluting with an ethyl acetate / petroleum ether system to give the target compound 2-(benzyloxy)-6-bromo-3-fluoropyridine (2.72 g, 9.64 mmol), yield: 51%. LC / MS (ESI+) calcd for C 12 H 10 B r FNO([M+H)) + )m / z 283; found 283.1.

[0166] Step 2: Synthesis of 2-(benzyloxy)-6-cyclopropyl-3-fluoropyridine

[0167] 2-(benzyloxy)-6-bromo-3-fluoropyridine (2.72 g, 9.64 mmol), pinacol cyclopropylborate (3.24 g, 19.3 mmol), potassium carbonate (2.66 g, 19.3 mmol), and catalyst Pd(dppf)Cl2 (352 mg, 0.5 mmol) were added to a mixed solvent of dioxane and water (dioxane to water v / v = 10 / 1). The reaction mixture was purged with nitrogen three times and then heated to 80 °C for 4 h. It was cooled to room temperature and concentrated under reduced pressure, then purified by silica gel column chromatography to give the target compound 2-(benzyloxy)-6-cyclopropyl-3-fluoropyridine (0.67 g, 2.76 mmol), yield: 29%. LC / MS (ESI+) calcd for C 15 H 15 FNO([M+H)) + )m / z 244.11; found 244.2.

[0168] Step 3: Synthesis of 6-cyclopropyl-3-fluoropyridine-2(1H)-one

[0169] 2-(benzyloxy)-6-cyclopropyl-3-fluoropyridine (0.67 g, 2.76 mmol) was dissolved in a mixture of methanol / tetrahydrofuran (v / v, 1 / 1), and palladium on carbon (70 mg, 10 wt%) was added. The reaction system was purged with hydrogen three times. When the reaction was determined to be complete based on TLC and LCMS analysis, the reaction vessel was rinsed with a mixture of dichloromethane / methanol (v / v, 10 / 1), filtered through diatomaceous earth, and the filtrate was concentrated to dryness. The filtrate was then purified by silica gel column chromatography, eluted with dichloromethane / methanol, to obtain the target compound 6-cyclopropyl-3-fluoropyridine-2(1H)-one (190 mg, 1.24 mmol), yield: 45%. LC / MS (ESI+) calcd for C8H9FNO([M+H) + )m / z 154.1; found 154.1.

[0170] Step 4: Synthesis of 6-cyclopropyl-3-fluoro-1-(3-iodophenyl)pyridine-2(1H)-one

[0171] 6-Cyclopropyl-3-fluoro-1-(3-iodophenyl)pyridin-2(1H)-one (190 mg, 1.24 mmol), m-iodophenylboronic acid (461 mg, 1.86 mmol), TMEDA (52 mg, 0.4 mmol), copper trifluoromethanesulfonate (133 mg, 0.4 mmol), and pyridine (295 mg, 3.73 mmol) were added to dry DCE solvent. The reaction mixture was purged with oxygen three times and then heated to 50 °C for 4 hours. After cooling to room temperature, the mixture was extracted with dichloromethane, concentrated under reduced pressure, purified by silica gel column chromatography, and eluted with ethyl acetate / petroleum ether to give the target compound 6-cyclopropyl-3-fluoro-1-(3-iodophenyl)pyridin-2(1H)-one (70 mg, 0.20 mmol), yield: 16%. LC / MS (ESI+) calcd for C 14 H 12 FINO([M+H] + )m / z 356; found 356.

[0172] Step 5: Synthesis of 3-(1-(3-(6-cyclopropyl-3-fluoro-2-oxopyridin-1(2H)-yl)phenyl)-1H-indazol-4-yl)piperidin-2,6-dione

[0173] 6-Cyclopropyl-3-fluoro-1-(3-iodophenyl)pyridin-2(1H)-one (54 mg, 0.152 mmol), 3-(1H-indazol-4-yl)piperidin-2,6-dione (35 mg, 0.152 mmol), cuprous iodide (12 mg, 0.06 mmol), 2-pyridinecarboxylic acid (8 mg, 0.06 mmol), and potassium carbonate (42 mg, 0.3 mmol) were added to 3 mL of dry DMSO solvent. The reaction mixture was purged with nitrogen three times, and then heated to 110 °C and reacted for 1 hour. The extract was cooled to room temperature, extracted with ethyl acetate, concentrated under reduced pressure, purified by silica gel plate preparation, and developed with a dichloromethane / methanol system to obtain the target compound 3-(1-(3-(6-cyclopropyl-3-fluoro-2-oxopyridin-1(2H)-yl)phenyl)-1H-indazol-4-yl)piperidin-2,6-dione (15 mg, 0.03 mmol), yield: 22%. LC / MS (ESI+) calcd for C 26 H 22 FN4O3([M+H) + )m / z 457.2; found 457.2.

[0174] 1H NMR (400MHz, DMSO-d6) δ10.96(s,1H),8.46(s,1H),7.95–7.89(m,1H),7.84(t,J=2.0Hz,1H),7.82–7.74(m, 2H),7.49(dd,J=8.6,7.1Hz,1H),7.42(dd,J=10.1,7.9Hz,2H),7.14(d,J=7.1Hz,1H),6.07(dd,J=7.9,4.4Hz ,1H),4.43(dd,J=12.2,4.9Hz,1H),2.80–2.72(m,1H),2.61(t,J=3.7Hz,1H),2.56(d,J=3.9Hz,1H),2.18–2 .07(m,1H),1.36(dd,J=13.4,6.4Hz,1H),0.75(qd,J=4.8,3.2,2.6Hz,2H),0.64(dq,J=8.7,3.4,2.6Hz,2H).

[0175] Example 15: 3-(1-(3-((1,6-naphthid-2-yl)amino)phenyl)-1H-indazol-4-yl)piperidin-2,6-dione

[0176] Step 1: Synthesis of N-(3-iodophenyl)-1,6-naphthyl-2-amine

[0177] 2-Chloro-1,6-naphthidine (100 mg, 0.61 mmol), 3-iodoaniline (200 mg, 0.92 mmol), and cesium carbonate (398 mg, 1.22 mmol) were added to dry DMSO solvent. The reaction mixture was purged three times with nitrogen, then heated to 130 °C and reacted for 12 hours. After cooling to room temperature, the mixture was extracted with ethyl acetate, concentrated under reduced pressure, purified by silica gel column chromatography, and eluted with ethyl acetate / petroleum ether to give the target compound N-(3-iodophenyl)-1,6-naphthidine-2-amine (23 mg, 0.06 mmol), yield: 11%.

[0178] LC / MS(ESI+)calcd for C 14 H 11 IN3([M+H) + )m / z 348; found 348.

[0179] Step 2: Synthesis of 3-(1-(3-((1,6-naphthid-2-yl)amino)phenyl)-1H-indazol-4-yl)piperidin-2,6-dione

[0180] N-(3-iodophenyl)-1,6-naphthyl-2-amine (23 mg, 0.06 mmol), 3-(1H-indazol-4-yl)piperidin-2,6-dione (15 mg, 0.06 mmol), cuprous iodide (5 mg, 0.03 mmol), 2-pyridinecarboxylic acid (5 mg, 0.03 mmol), and potassium carbonate (16 mg, 0.12 mmol) were added to dry DMSO solvent. The reaction mixture was purged three times with nitrogen and then heated to 110 °C for 1 hour. After cooling to room temperature, the mixture was extracted with ethyl acetate and concentrated under reduced pressure. The resulting product was purified by silica gel agar plate preparation and developed with a dichloromethane / methanol system to yield the target compound 3-(1-(3-((1,6-naphthyl-2-yl)amino)phenyl)-1H-indazol-4-yl)piperidin-2,6-dione (8 mg, 0.02 mmol), yield: 30%.

[0181] LC / MS(ESI+)calcd for C 26 H 21 N6O2([M+H)) + )m / z 449.2; found 449.2.

[0182] 1 H NMR (400MHz, DMSO-d6) δ10.99(s,1H),10.19(s,1H),9.03(s,1H),8.87(t,J=2.1Hz,1H),8. 56(d,J=5.9Hz,1H),8.45(s,1H),8.25(d,J=8.9Hz,1H),8.07(d,J=8.6Hz,1H),7.77–7.72( m,1H),7.62–7.56(m,2H),7.55–7.52(m,1H),7.46–7.41(m,1H),7.23–7.16(m,2H),4.45(d d,J=12.2,4.9Hz,1H),2.79(td,J=12.4,6.1Hz,1H),2.68–2.56(m,2H),2.20–2.12(m,1H).

[0183] Example 16: 3-(4'-(6-cyclopropyl-4-methyl-2-oxopyridin-1(2H)-yl)-2-ethynyl-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0184] Step 1: Synthesis of 2-(benzyloxy)-6-bromo-4-methylpyridine

[0185] 2-Bromo-6-chloro-4-methylpyridine (2.06 g, 10.0 mmol), benzyl alcohol (1.19 g, 11.0 mmol), potassium hydroxide (0.84 g, 15.0 mmol), and 18-crown-6 (264 mg, 1.0 mmol) were sequentially added to dry toluene solvent. The reaction mixture was purged three times with nitrogen, then heated to 80 °C and reacted for 3 h. The mixture was cooled to room temperature, extracted with ethyl acetate, concentrated under reduced pressure, purified by silica gel column chromatography, and eluted with ethyl acetate / petroleum ether to give the target compound 2-(benzyloxy)-6-bromo-4-methylpyridine (2.31 g, 8.30 mmol), yield: 83%.

[0186] LC / MS(ESI+)calcd for C 13 H 13 B r NO([M+H] + )m / z 278.01; found 278.1.

[0187] Step 2: Synthesis of 2-(benzyloxy)-6-cyclopropyl-4-methylpyridine

[0188] 2-(benzyloxy)-6-bromo-4-methylpyridine (2.21 g, 7.94 mmol), cyclopropylboronic acid (1.37 g, 15.9 mmol), potassium phosphate (5.06 g, 23.8 mmol), and catalyst Pd(dppf)Cl2 (290 mg, 0.04 mmol) were added to a dry toluene solution. The reaction mixture was purged three times with nitrogen and then heated to 100 °C for 12 h. The mixture was cooled to room temperature and concentrated under reduced pressure, then purified by silica gel column chromatography to give the target compound 2-(benzyloxy)-6-cyclopropyl-4-methylpyridine (1.84 g, 7.69 mmol), yield: 97%.

[0189] LC / MS(ESI+)calcd for C 16 H 18 NO([M+H] + )m / z 240.13; found 240.2.

[0190] Step 3: Synthesis of 6-cyclopropyl-4-methylpyridine-2(1H)-one

[0191] 2-(benzyloxy)-6-cyclopropyl-4-methylpyridine (1.84 g, 7.69 mmol) was dissolved in a mixture of methanol / tetrahydrofuran (v / v, 1 / 1), and palladium on carbon (190 mg, 10% by mass) was added. The reaction system was then purged with hydrogen three times. When the reaction was determined to be complete based on TLC and LCMS analysis, the reaction vessel was rinsed with a mixture of dichloromethane / methanol (v / v, 10 / 1), filtered through diatomaceous earth, and the filtrate was concentrated to dryness. The filtrate was then purified by silica gel column chromatography and eluted with a dichloromethane / methanol system to obtain the target compound 6-cyclopropyl-4-methylpyridine-2(1H)-one (780 mg, 5.23 mmol), yield: 68%.

[0192] LC / MS(ESI+)calcd for C9H 12 NO([M+H] + )m / z 150.1; found 150.1.

[0193] Step 4: Synthesis of 1-(4-bromophenyl)-6-cyclopropyl-4-methylpyridin-2(1H)-one

[0194] 6-Cyclopropyl-4-methylpyridin-2(1H)-one (300 mg, 2.0 mmol), p-bromophenylboronic acid (606 mg, 3.0 mmol), TMEDA (93 mg, 0.8 mmol), copper trifluoromethanesulfonate (290 mg, 0.8 mmol), and pyridine (474 ​​mg, 6.0 mmol) were added to dry DCE solvent. The reaction mixture was purged with oxygen three times, then heated to 50 °C and reacted for 4 hours. The mixture was cooled to room temperature, extracted with dichloromethane, concentrated under reduced pressure, purified by silica gel column chromatography, and eluted with ethyl acetate / petroleum ether to give the target compound 1-(4-bromophenyl)-6-cyclopropyl-4-methylpyridin-2(1H)-one (233 mg, 0.77 mmol), yield: 39%.

[0195] LC / MS(ESI+)calcd for C 15 H 15 BrNO([M+H] + )m / z 304.03; found 304.1.

[0196] Step 5: Synthesis of 6-cyclopropyl-4-methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)pyridin-2(1H)-one

[0197] 1-(4-bromophenyl)-6-cyclopropyl-4-methylpyridin-2(1H)-one (233 mg, 0.77 mmol), pinacol diboronate (215 mg, 0.84 mmol), catalyst Pd(dppf)Cl2 (60 mg, 0.08 mmol), and potassium acetate (228 mg, 2.31 mmol) were added to a dry dioxane solvent. The reaction mixture was purged three times with nitrogen and then heated to 80 °C for 4 hours. After cooling to room temperature, the mixture was extracted with ethyl acetate, concentrated under reduced pressure, purified by silica gel column chromatography, and eluted with ethyl acetate / petroleum ether to give the target compound 6-cyclopropyl-4-methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)pyridin-2(1H)-one (146 mg, 0.42 mmol), yield: 54%. LC / MS(ESI+)calcd for C 21 H 27 BNO3([M+H)) + )m / z 352.2; found 352.2.

[0198] Step 6: Synthesis of 3-(4'-(6-cyclopropyl-4-methyl-2-oxopyridin-1(2H)-yl)-2-((trimethylsilyl)ethynyl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0199] 3-(3-bromo-2-((trimethylsilyl)ethynyl)phenyl)piperidin-2,6-dione (36 mg, 0.10 mmol), 6-cyclopropyl-4-methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborin-2-yl)phenyl)pyridin-2(1H)-one (36 mg, 0.10 mmol), potassium phosphate (65 mg, 0.30 mmol), and catalyst Xphos-Pd-G3 (8 mg, 0.01 mmol) were added to a mixed solvent of tetrahydrofuran and water (v / v, 10 / 1). The reaction mixture was purged with nitrogen three times and then heated to 35 °C for 1 hour. The compound was cooled to room temperature and concentrated under reduced pressure, then purified by silica gel column chromatography to obtain the target compound 3-(4'-(6-cyclopropyl-4-methyl-2-oxopyridin-1(2H)-yl)-2-((trimethylsilyl)ethynyl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione (19 mg, 0.04 mmol), yield: 40%. LC / MS (ESI+) calcd for C 31 H 33 N₂O₃Si([M+H)) + )m / z 509.2; found 509.2.

[0200] Step 7: Synthesis of 3-(4'-(6-cyclopropyl-4-methyl-2-oxopyridin-1(2H)-yl)-2-ethynyl-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0201] The compound 3-(4'-(6-cyclopropyl-4-methyl-2-oxopyridin-1(2H)-yl)-2-((trimethylsilyl)ethynyl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione (19 mg, 0.04 mmol) was dissolved in 10 mL of dry tetrahydrofuran, and 0.5 mL of TBAF (1 M) tetrahydrofuran solution was added. The mixture was stirred at room temperature for 1 hour. When the reaction was determined to be complete based on TLC and LCMS analysis, the mixture was extracted with ethyl acetate, concentrated under reduced pressure, and then purified by silica gel column chromatography to obtain the target compound 3-(4'-(6-cyclopropyl-4-methyl-2-oxopyridin-1(2H)-yl)-2-ethynyl-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione (10 mg, 0.025 mmol), yield: 63%. LC / MS(ESI+)calcd for C 28 H 25 N₂O₃([M+H)) + )m / z 437.2; found 437.2. 1 H NMR (400MHz, DMSO-d6) δ10.93(s,1H),7.72–7.60(m,2H),7.49(t,J=7.7Hz,1H),7.40(d,J=7.5 Hz,1H),7.36–7.28(m,3H),6.18(s,1H),5.96(d,J=1.8Hz,1H),4.40(s,1H),4.33(dd,J=12.1, 5.0Hz,1H),2.76(ddd,J=17.4,12.5,5.2Hz,1H),2.56(m,1H),2.38(d,J=13.1Hz,1H),2.14(s, 3H),2.10–2.03(m,1H),1.24(d,J=3.1Hz,1H),0.78–0.69(m,2H),0.64(dt,J=8.4,3.2Hz,2H).

[0202] Example 17: 3-(4'-(6-cyclopropyl-2-oxopyridin-1(2H)-yl)-2-ethynyl-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0203] 3-(4'-(6-cyclopropyl-2-oxopyridin-1(2H)-yl)-2-ethynyl-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione, i.e., HC-12699, was prepared using a synthetic procedure similar to that in Example 16. LC / MS (ESI+) calcd for C 27 H 23 N₂O₃([M+H)) + )m / z 423.16; found 423.2. 1 H NMR (400MHz, DMSO-d6) δ10.93(s,1H),7.71–7.63(m,2H),7.49(t,J=7.7Hz,1H),7.42(dt,J=7.8,6 .7Hz,2H),7.38–7.31(m,3H),6.40–6.34(m,1H),6.08(d,J=7.0Hz,1H),4.40(s,1H),4.33(dd,J=1 2.1,5.1Hz,1H),2.76(ddd,J=17.6,12.6,5.3Hz,1H),2.56(t,J=3.9Hz,1H),2.38(d,J=12.3Hz,1H ),2.12–2.02(m,1H),1.26–1.22(m,1H),0.73(tt,J=5.4,3.0Hz,2H),0.66(dt,J=8.3,3.0Hz,2H).

[0204] Example 18: 3-(1-(3-((6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)oxy)phenyl)-1H-indazol-4-yl)piperidin-2,6-dione

[0205] In the first step of the reaction, the products 2-(3-iodophenoxy)-6,7-dihydro-5H-cyclopenta[b]pyridine and 1-(3-iodophenyl)-1,5,6,7-tetrahydro-2H-cyclopenta[b]pyridine-2-one were isolated.

[0206] The preparation method in step 2 of Example 1 is the same, except that 1-(3-iodophenyl)-6-methylpyridin-2(1H)-one is replaced with 2-(3-iodophenoxy)-6,7-dihydro-5H-cyclopenta[b]pyridine, yielding the target compound 3-(1-(3-((6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)oxy)phenyl)-1H-indazol-4-yl)piperidin-2,6-dione. LC / MS (ESI+) calcd for C 26 H 23 N4O3(M+H + )m / z,439.2;found,439.2.1 H NMR (400MHz, DMSO-d6) δ10.97(s,1H),8.41(s,1H),7.78(d,J=8.5Hz,1H),7.72(d,J=8.1Hz,1H),7.65–7.56(m,2H),7.50– 7.43(m,2H),7.16–7.10(m,2H),6.87(d,J=8.1Hz,1H),4.41(dd,J=12.2,4.9Hz,1H),2.91–2.71(m,6H),2.16–2.00(m,4H).

[0207] Example 19: 3-(1-(3-(2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridin-1-yl)phenyl)-1H-indazol-4-yl)piperidin-2,6-dione

[0208] In the first step of the reaction, the products 2-(3-iodophenoxy)-6,7-dihydro-5H-cyclopenta[b]pyridine and 1-(3-iodophenyl)-1,5,6,7-tetrahydro-2H-cyclopenta[b]pyridine-2-one were isolated.

[0209] The preparation method in step 2 of Example 33 is the same, except that 1-(3-iodophenyl)-6-methylpyridin-2(1H)-one is replaced with 1-(3-iodophenyl)-1,5,6,7-tetrahydro-2H-cyclopentan[b]pyridin-2-one, yielding the target compound 3-(1-(3-(2-oxo-2,5,6,7-tetrahydro-1H-cyclopentan[b]pyridin-1-yl)phenyl)-1H-indazol-4-yl)piperidin-2,6-dione. LC / MS (ESI+) calcd for C 26 H 23 N4O3(M+H + )m / z,439.2;found,439.2. 1 H NMR(400MHz,DMSO-d6)δ10.98(s,1H),8.45(d,J=0.9Hz,1H),7.91–7.86(m,1H) ,7.80(d,J=8.5Hz,1H),7.76–7.70(m,2H),7.49(dt,J=8.6,3.3Hz,2H),7.36(d t,J=8.1,1.2Hz,1H),7.14(d,J=7.1Hz,1H),6.35(d,J=9.1Hz,1H),4.43(dd,J= 12.3, 4.8Hz, 1H), 2.83–2.65 (m, 4H), 2.57 (t, J = 3.8Hz, 2H), 2.17–1.97 (m, 4H).

[0210] Example 20: 3-(1-(3-(quinazolin-2-yloxy)phenyl)-1H-indazol-4-yl)piperidine-2,6-dione

[0211] Step 1: Synthesis of 2-(3-iodophenoxy)quinazoline

[0212] Compound 2-chloroquinazoline (328 mg, 2.00 mmol), m-iodophenol (440 mg, 2.00 mmol), and Cs₂CO₃ (1300 mg, 4.00 mmol) were added to 12 mL of DMSO and stirred at 120 °C for 4 h. Water was added, and the mixture was extracted three times by EA extraction. The combined organic phases were washed with saturated NaCl solution, dried over anhydrous sodium sulfate, and subjected to rotary evaporation and column chromatography to obtain the target compound (300 mg, 33% yield).

[0213] LC / MS(ESI+)calcd for C 14 H 10 IN2O(M+H + )m / z,348.9;found,348.9.

[0214] Step 2: Synthesis of 3-(1-(3-(quinazolin-2-yloxy)phenyl)-1H-indazol-4-yl)piperidine-2,6-dione

[0215] The preparation method in step 2 of Example 33 is the same, except that 1-(3-iodophenyl)-6-methylpyridin-2(1H)-one is replaced with 2-(3-iodophenoxy)quinazoline to obtain the target compound 3-(1-(3-(quinazoline-2-yloxy)phenyl)-1H-indazol-4-yl)piperidin-2,6-dione. LC / MS (ESI+) calcd for C 26 H 20 N5O3(M+H + )m / z,450.1;found,450.1. 1H NMR (400MHz, DMSO-d6) δ10.97(s,1H),9.61(s,1H),8.43(d,J=0.9Hz,1H),8.17(dd,J=8.1,1.4H z,1H),7.97(ddd,J=8.5,6.9,1.4Hz,1H),7.86(d,J=8.6Hz,1H),7.82–7.74(m,2H),7.72–7.61( m,3H),7.46(dd,J=8.6,7.1Hz,1H),7.35(dt,J=6.7,2.2Hz,1H),7.13(d,J=7.1Hz,1H),4.42(dd ,J=12.2,4.8Hz,1H),2.78(ddd,J=17.4,12.3,5.2Hz,1H),2.72–2.54(m,2H),2.17–2.07(m,1H).

[0216] Example 21: 3-(1-(3-(2-methyl-6-oxopyrimidin-1(6H)-yl)phenyl)-1H-indazol-4-yl)piperidin-2,6-dione

[0217] Step 1: Synthesis of intermediate 3-(3-iodophenyl)-2-methylpyrimidin-4(3H)-one

[0218] Compound 2-methylpyrimidin-4-ol (220 mg, 2.0 mmol), 3-iodophenylboronic acid (744 mg, 3.0 mmol), copper trifluoromethanesulfonate (145 mg, 0.4 mmol), TMEDA (47 mg, 0.4 mmol), and pyridine (474 ​​mg, 6.0 mmol) were dissolved in dichloroethane (10 mL) and reacted overnight at 50 °C in an oxygen atmosphere. The reaction was monitored by TLC until the starting material was completely consumed. The solution was filtered through diatomaceous earth, concentrated, and column chromatography was performed to give 118 mg of the compound, with a yield of 19%.

[0219] Step 2: Synthesis of the target compound

[0220] The preparation method in step 2 of Example 33 is the same, except that 1-(3-iodophenyl)-6-methylpyridin-2(1H)-one is replaced with 3-(3-iodophenyl)-2-methylpyrimidin-4(3H)-one to obtain the target compound 3-(1-(3-(2-methyl-6-oxopyrimidin-1(6H)-yl)phenyl)-1H-indazole-4-yl)piperidin-2,6-dione. 1H NMR (400MHz, DMSO-d6) δ10.97(s,1H),8.46(s,1H),7.98-7.86(m,3H),7.84-7.72(m,2H),7.54-7.36(m,2H),7.14(d,J=7.1Hz,1H),6.43(d ,J=6.7Hz,1H),4.43(dd,J=12.2,4.8Hz,1H),2.78(ddd,J=17.3,12.3,5.1Hz,1H),2.59(d,J=17.2Hz,2H),2.18(s,3H),2.16-2.09(m,1H).

[0221] LC / MS(ESI+)calcd for C 23 H 20 N5O3([M+H)) + )m / z:414.2; found 413.9.

[0222] Example 22: 3-(1-(3-(6-methyl-2-oxopyrazin-1(2H)-yl)phenyl)-1H-indazol-4-yl)piperidine-2,6-dione

[0223] The preparation method of Example 21 was used, except that 2-methylpyrimidin-4-ol was replaced with 6-methylpyrazine-2-ol to obtain the target compound 3-(1-(3-(6-methyl-2-oxopyrazine-1(2H)-yl)phenyl)-1H-indazole-4-yl)piperidine-2,6-dione. 1 H NMR(400MHz,DMSO-d6)δ10.97(s,1H),8.46(s,1H),8.02(s,1H),7.97-7.90(m,1H),7 .87(t,J=2.0Hz,1H),7.79(q,J=8.4,8.0Hz,2H),7.49(t,J=7.9Hz,1H),7.41(d,J=6. 4Hz, 2H), 7.14 (d, J = 7.1Hz, 1H), 4.43 (dd, J = 12.2, 4.8Hz, 1H), 2.78 (ddd, J = 17.2, 12. 1,5.0Hz,1H),2.68-2.53(m,2H),2.19-2.07(m,1H),2.01(s,3H).LC / MS(ESI+)calcd for C 23 H 20 N5O3([M+H)) + )m / z:414.2; found 413.9.

[0224] Example 23: 3-(1-(3-(2-methyl-6-oxopiridin-1-yl)phenyl)-1H-indazol-4-yl)piperidin-2,6-dione

[0225] Step 1: Synthesis of intermediate 1-(3-iodophenyl)-6-methylpiperidin-2-one

[0226] Compound 6-methylpiperidin-2-one (220 mg, 2.0 mmol), 3-iodophenylboronic acid (744 mg, 3.0 mmol), copper trifluoromethanesulfonate (145 mg, 0.4 mmol), TMEDA (47 mg, 0.4 mmol), and pyridine (474 ​​mg, 6.0 mmol) were dissolved in dichloroethane (10 mL) and reacted overnight at 50 °C in an oxygen atmosphere. The reaction was monitored by TLC until the starting material was completely consumed. The solution was filtered through diatomaceous earth, concentrated, and column chromatography to give 118 mg of compound 1-(3-iodophenyl)-6-methylpiperidin-2-one, in 19% yield.

[0227] Step 2: Synthesis of the target compound

[0228] The preparation method in step 2 of Example 33 is the same, except that 1-(3-iodophenyl)-6-methylpyridin-2(1H)-one is replaced with 1-(3-iodophenyl)-6-methylpiperidin-2-one to obtain the target compound 3-(1-(3-(2-methyl-6-oxoperidin-1-yl)phenyl)-1H-indazole-4-yl)piperidin-2,6-dione.

[0229] 1 H NMR (400MHz, DMSO-d6) δ10.97(s,1H),8.42(s,1H),7.78-7.43(m,5H),7.19(dd,J=50.0,7.2Hz,2H),4.42(d,J=12.1Hz,1 H),4.07(s,1H),3.09-2.55(m,4H),2.11(d,J=14.8Hz,2H),2.02-1.66(m,4H),1.04(d,J=6.3Hz,3H).LC / MS(ESI+)calcd for C 24 H 25 N4O3([M+H)) + )m / z:417.2; found 417.1.

[0230] Example 24: 3-(1-(3-(5-oxo-4-azaspiro[2.5]oct-4-yl)phenyl)-1H-indazol-4-yl)piperidine-2,6-dione

[0231] The preparation method of Example 23 was followed, except that 6-methylpiperidin-2-one was replaced with 5-oxo-4-azaspiro[2.5]octane to obtain the target compound 3-(1-(3-(5-oxo-4-azaspiro[2.5]oct-4-yl)phenyl)-1H-indazol-4-yl)piperidin-2,6-dione. 1 H NMR(400MHz,DMSO-d6)δ10.97(s,1H),8.42(s,1H),7.74(d,J=8.5Hz,1H),7.70-7.64 (m,1H),7.59(t,J=8.0Hz,1H),7.52-7.40(m,2H),7.18-7.09(m,2H),4.42(dd,J=12.2 ,4.9Hz,1H),2.78(ddd,J=17.5,12.3,5.2Hz,1H),2.64-2.52(m,4H),2.21-2.04(m,1H ),2.03-1.84(m,4H),0.77(t,J=3.4Hz,2H),0.64(d,J=5.6Hz,2H).LC / MS(ESI+)calcd for C 25 H 24 N4O3([M+H)) + )m / z:428.2; found 428.1.

[0232] Example 25: 3-(1-(3-(6-methoxy-2-oxopyridin-1(2H)-yl)phenyl)-1H-indazol-4-yl)piperidin-2,6-dione

[0233] Step 1: Synthesis of intermediate 2-(benzyloxy)-6-methoxypyridine

[0234] 2-Chloro-6-methoxypyridine (1.43 g, 10 mmol), benzyl alcohol (1.4 g, 13 mmol), 18-crown-6 (132 mg, 0.5 mmol), and potassium hydroxide (1.85 g, 33 mmol) were dissolved in toluene (30 mL) and reacted overnight at 100 °C. The reaction was monitored by TLC until the starting material was completely consumed. The solution was filtered through diatomaceous earth, concentrated, and subjected to column chromatography to give 1.42 g of 2-(benzyloxy)-6-methoxypyridine, in 66% yield.

[0235] Step 2: Synthesis of intermediate 6-methoxypyridine-2-ol

[0236] 1.07 g (5 mmol) of compound 2-(benzyloxy)-6-methoxypyridine was dissolved in methanol (40 mL), and 100 mg (10% by mass) of palladium on carbon was added. The reaction system was replaced with hydrogen gas, and the reaction was carried out overnight at room temperature. The reaction was monitored by TLC until the starting material was completely consumed. The solution was filtered through diatomaceous earth, concentrated, and column chromatography was performed to give 524 mg of compound 6-methoxypyridine-2-ol, with a yield of 84%.

[0237] Step 3: Synthesizing the target compound

[0238] The preparation method of Example 1 is the same, except that 6-methylpyridin-2(1H)-one is replaced with 6-methoxypyridin-2-ol to obtain the target compound 3-(1-(3-(6-methoxy-2-oxopyridin-1(2H)-yl)phenyl)-1H-indazole-4-yl)piperidin-2,6-dione. 1 H NMR (400MHz, DMSO-d6) δ10.97(s,1H),8.49-8.40(m,1H),7.92-7.82(m,1H),7.77(d,J=8.5Hz,1H),7. 70(t,J=8.0Hz,1H),7.63(t,J=2.0Hz,1H),7.51(ddd,J=22.9,8.8,7.4Hz,3H),7.30-7.22(m,1H),7.13 (d,J=7.1Hz,1H),6.12(dd,J=9.2,1.0Hz,1H),5.91-5.84(m,1H),4.43(dd,J=12.2,4.8Hz,1H),3.77(s ,4H),2.77(ddd,J=21.5,10.9,4.7Hz,1H),2.59(dt,J=16.9,3.8Hz,2H),2.12(dd,J=12.9,4.0Hz,1H).

[0239] LC / MS(ESI+)calcd for C 24 H 21 N4O4([M+H)) + )m / z:429.2; found 429.1.

[0240] Example 26: 3-(1-(3-(6-(dimethylamino)-2-oxopyridin-1(2H)-yl)phenyl)-1H-indazol-4-yl)piperidin-2,6-dione

[0241] Step 1: Synthesis of intermediate 6-(dimethylamino)-1-(3-iodophenyl)pyridine-2(1H)-one

[0242] The compound 6-fluoro-1-(3-iodophenyl)pyridin-2(1H)-one (157 mg, 0.5 mmol), dimethylamine hydrochloride (244 mg, 3.0 mmol), and potassium carbonate (414 mg, 3.0 mmol) were dissolved in DMF (5 mL) and the reaction was carried out at 80 °C. The reaction was monitored by TLC until the starting material was completely consumed. The mixture was filtered through diatomaceous earth, concentrated, and column chromatography was performed to give 140 mg of the compound 6-(dimethylamino)-1-(3-iodophenyl)pyridin-2(1H)-one, in 82% yield.

[0243] Step 2: Synthesis of the target compound

[0244] The preparation method in step 2 of Example 1 is the same, except that 1-(3-iodophenyl)-6-methylpyridin-2(1H)-one is replaced with 6-(dimethylamino)-1-(3-iodophenyl)pyridin-2(1H)-one to obtain the target compound 3-(1-(3-(6-(dimethylamino)-2-oxopyridin-1(2H)-yl)phenyl)-1H-indazole-4-yl)piperidin-2,6-dione. 1 H NMR (400MHz, DMSO-d6) δ10.97(s,1H),8.44(s,1H),7.83-7.75(m,2H),7.74(t,J=2.1Hz ,1H),7.68(t,J=7.9Hz,1H),7.51-7.40(m,2H),7.32(d,J=8.2Hz,1H),7.13(d,J=7.1Hz ,1H),6.12(d,J=9.1Hz,1H),5.89(d,J=7.4Hz,1H),4.42(dd,J=12.3,4.8Hz,1H),2.95( d,J=7.8Hz,1H),2.84-2.64(m,2H),2.48(s,6H),2.20-2.08(m,1H).LC / MS(ESI+)calcd for C 25 H 24 N5O3([M+H)) + )m / z:442.2; found 442.0.

[0245] Example 27: 3-(1-(3-(2-oxo-6-(pyrrolidone-1-yl)pyridin-1(2H)-yl)phenyl)-1H-indazol-4-yl)piperidin-2,6-dione

[0246] The preparation method of Example 26 was used, except that dimethylamine hydrochloride was replaced with cyclobutimine to obtain the target compound 3-(1-(3-(6-(dimethylamino)-2-oxopyridin-1(2H)-yl)phenyl)-1H-indazole-4-yl)piperidine-2,6-dione.1 HNMR (400MHz, DMSO-d6) δ10.97(s,1H),8.44(s,1H),7.77(dd,J=16.4,7.9Hz,3H),7.67(t,J=8.0 Hz,1H),7.48(t,J=7.8Hz,1H),7.36(t,J=8.3Hz,1H),7.28(d,J=7.8Hz,1H),7.13(d,J=7.2Hz,1H) ,5.86(d,J=8.9Hz,1H),5.70(d,J=7.9Hz,1H),4.42(dd,J=12.2,4.8Hz,1H),2.89-2.88(m,1H),2. 85-2.68(m,4H),2.60-2.58(m,2H),2.17-2.05(m,1H),1.65(d,J=14.2Hz,4H).LC / MS(ESI+)calcd for C 27 H 26 N5O3([M+H)) + )m / z:468.2; found 468.1.

[0247] Example 28: 3-(1-(3-(6-cyclopropoxy-2-oxopyridin-1(2H)-yl)phenyl)-1H-indazol-4-yl)piperidin-2,6-dione

[0248] Step 1: Synthesis of intermediate 2-chloro-6-cyclopropoxypyridine

[0249] Cyclopropanol (1.16 g, 20 mmol) was dissolved in dry DMF (20 mL), and sodium hydroxide (880 mg, 22 mmol) was added. The mixture was stirred at room temperature for half an hour. Then, 2-chloro-6-fluoropyridine (2.6 g, 20 mmol) was added, and the reaction was carried out overnight at 100 °C. The reaction was quenched with saturated ammonium chloride aqueous solution, extracted with ethyl acetate, washed with water, washed with saturated brine, dried, concentrated, and subjected to column chromatography to give 2.72 g of compound 2-chloro-6-cyclopropoxypyridine, in 80% yield.

[0250] Step 2: Synthesis of intermediate 2-benzyloxy-6-cyclopropoxypyridine

[0251] Benzyl alcohol (1.08 g, 10 mmol) was dissolved in dry DMF (5 mL), and sodium hydroxide (440 mg, 11 mmol) was added. The mixture was stirred at room temperature for 10 minutes. Then, 2-chloro-6-cyclopropoxypyridine (1.69 g, 10 mmol) was added, and the reaction was allowed to proceed overnight at room temperature. The reaction was quenched with saturated ammonium chloride solution, extracted with ethyl acetate, washed with water and saturated brine, dried, concentrated, and subjected to column chromatography to give 890 mg of compound 2-benzyloxy-6-cyclopropoxypyridine, in 37% yield.

[0252] Step 3: Synthesizing the target compound

[0253] Subsequent steps involved synthesis using a method similar to that of Example 33. 1 H NMR (400MHz, DMSO-d6) δ10.97(s,1H),8.44(s,1H),7.88-7.79(m,1H),7.74(d,J=8.5Hz,1H),7.67(t,J=8.0Hz ,1H),7.62(t,J=2.1Hz,1H),7.59-7.53(m,1H),7.47(dd,J=8.5,7.1Hz,1H),7.23(dd,J=7.7,2.0Hz,1H),7.13 (d,J=7.1Hz,1H),6.15-6.09(m,2H),4.42(dd,J=12.2,4.9Hz,1H),3.98(td,J=6.1,3.0Hz,1H),2.78(td,J=12 .2,6.3Hz,1H),2.65-2.55(m,2H),2.18-2.05(m,1H),0.76-0.70(m,2H),0.66-0.60(m,2H).LC / MS(ESI+)calcd for C 26 H 23 N4O4([M+H)) + m / z:455.2; found455.1.

[0254] Example 29: 3-(4'-(6-cyclopropyl-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-2-ethynyl-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0255] Step 1: Synthesis of intermediate 2-chloro-6-cyclopropyl-4-(trifluoromethyl)pyridine

[0256] Compound 2,6-dichloro-4-(trifluoromethyl)pyridine (4.28 g, 20 mmol), 2-cyclopropyl-4,4,5,5-tetramethyl-1,3,2-dioxaborane (3.19 g, 19 mmol), Pd(dppf)Cl2 (731 mg, 1.0 mmol), and potassium phosphate (8.48 g, 40 mmol) were dissolved in dioxane (60 mL) and water (20 mL), and reacted overnight at 90 °C under a nitrogen atmosphere. The mixture was filtered through diatomaceous earth, concentrated, and subjected to column chromatography to give 2.1 g of compound 2-chloro-6-cyclopropyl-4-(trifluoromethyl)pyridine, in 47% yield.

[0257] Step 2: Synthesis of intermediate 6-cyclopropyl-4-(trifluoromethyl)pyridine-2-ol

[0258] 1.77 g (8 mmol) of 2-chloro-6-cyclopropyl-4-(trifluoromethyl)pyridine and 1.85 g (33 mmol) of potassium hydroxide were dissolved in 10 mL of DMSO and reacted overnight at 120 °C. The reaction was monitored by TLC until the starting material was completely consumed. The pH was adjusted to weakly acidic with dilute hydrochloric acid, extracted with ethyl acetate, washed with saturated brine, concentrated, and subjected to column chromatography to give 876 mg of 6-cyclopropyl-4-(trifluoromethyl)pyridine-2-ol, in 54% yield.

[0259] Step 3: Synthesis of intermediate 1-(4-bromophenyl)-6-cyclopropyl-4-(trifluoromethyl)pyridine-2(1H)-one

[0260] Compound 6-cyclopropyl-4-(trifluoromethyl)pyridin-2-ol (609 mg, 3.0 mmol), 4-bromophenylboronic acid (660 mg, 3.3 mmol), copper trifluoromethanesulfonate (434 mg, 1.2 mmol), TMEDA (140 mg, 1.2 mmol), and pyridine (720 mg, 9.0 mmol) were dissolved in dichloroethane (10 mL) and reacted overnight at 60 °C in an oxygen atmosphere. The reaction was monitored by TLC until the starting material was completely consumed. The mixture was filtered through diatomaceous earth, concentrated, and column chromatography to give 408 mg of compound 1-(4-bromophenyl)-6-cyclopropyl-4-(trifluoromethyl)pyridin-2(1H)-one, in 38% yield.

[0261] Step 4: Synthesis of intermediate 6-cyclopropyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)-4-(trifluoromethyl)pyridine-2(1H)-one

[0262] Compound 1-(4-bromophenyl)-6-cyclopropyl-4-(trifluoromethyl)pyridin-2(1H)-one (357 mg, 1.0 mmol), pinacol diboronate (280 mg, 1.1 mmol), Pd(dppf)Cl2 (74 mg, 0.1 mmol), and potassium acetate (294 mg, 3.0 mmol) were dissolved in dry dioxane (6 mL). The reaction was carried out overnight at 80 °C under a nitrogen atmosphere. The reaction was monitored by TLC until the starting material was completely consumed. After diatomaceous earth filtration, concentration, and column chromatography, 267 mg of compound 6-cyclopropyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)-4-(trifluoromethyl)pyridin-2(1H)-one was obtained, with a yield of 66%.

[0263] Step 5: Synthesize intermediate 3-(4'-(6-cyclopropyl-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-2-((trimethylsilyl)ethynyl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0264] Compounds 6-cyclopropyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)-4-(trifluoromethyl)pyridin-2(1H)-one (40 mg, 0.1 mmol), 3-(3-bromo-2-((trimethylsilyl)ethynyl)phenyl)piperidin-2,6-dione (37 mg, 0.1 mmol), Xphos Pd G3 (9 mg, 0.01 mmol) and potassium phosphate (63 mg, 0.3 mmol) were dissolved in tetrahydrofuran (3 mL) and distilled water (1 mL), and reacted at 35 °C for 1 hour under a nitrogen atmosphere. The compound was filtered through diatomaceous earth, concentrated, and subjected to column chromatography to yield 10 mg of 3-(4'-(6-cyclopropyl-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-2-((trimethylsilyl)ethynyl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione, in 18% yield. Step 6: 3-(4'-(6-cyclopropyl-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-2-ethynyl-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0265] Compound 3-(4'-(6-cyclopropyl-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-2-((trimethylsilyl)ethynyl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione (10 mg, 0.018 mmol) was dissolved in tetrahydrofuran (3 mL), and TBAF (5 mg, 0.018 mmol) was added. The mixture was reacted under nitrogen at room temperature for 1 hour. After concentration, column chromatography yielded 5 mg of compound 3-(4'-(6-cyclopropyl-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-2-ethynyl-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione, in 57% yield. 1 H NMR (400MHz, DMSO-d6) δ10.92(s,1H),7.70(d,J=8.0Hz,2H),7.46(ddt,J=21.7,13.4,6.7Hz,4H),7.34(d,J=7.8Hz,1H),6.78(s,1H),6.27(s,1H) ,4.40(s,1H),4.38-4.29(m,1H),2.88-2.55(m,3H),2.12-2.03(m,1H),1 .32(q,J=6.3Hz,1H),0.88(q,J=11.1,8.9Hz,2H),0.71(d,J=7.9Hz,2H).

[0266] LC / MS(ESI+)calcd for C 28 H 22 F3N2O3([M+H) + )m / z:491.2; found 491.1.

[0267] Example 30: 1-(2-chloro-4'-(2-oxopyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

[0268] Step 1: Synthesis of 3-((3-bromo-2-chlorophenyl)amino)propionic acid

[0269] 3-Bromo-2-chloroaniline (2 g, 10 mmol) was added to 20 mL of toluene, followed by allyl propionic acid (2.1 g, 29 mmol). The mixture was heated to reflux and stirred for 16 h. After cooling to room temperature, the solvent was evaporated to dryness. 10 mL of dichloromethane was added, and the mixture was stirred. The solid was filtered and dried to give 3-((3-bromo-2-chlorophenyl)amino)propionic acid (1.6 g, 5.7 mmol), in 60% yield.

[0270] Step 2: Synthesis of 1-(3-bromo-2-chlorophenyl)dihydropyrimidine-2,4(1H,3H)-dione

[0271] Under nitrogen protection, 3-((3-bromo-2-chlorophenyl)amino)propionic acid (400 mg, 1.4 mmol) was dissolved in 8 mL of acetic acid, and urea (862 mg, 14 mmol) was added. The mixture was heated to reflux and stirred for 48 h, then cooled to room temperature. The mixture was extracted with ethyl acetate and water. The ethyl acetate was dried over anhydrous sodium sulfate, evaporated to dryness at low temperature, and purified by silica gel column chromatography to give 1-(3-bromo-2-chlorophenyl)dihydropyrimidine-2,4(1H,3H)-dione (260 mg, 0.8 mmol), yield 59%.

[0272] Step 3: Synthesis of 1-(2-chloro-4'-(2-oxopyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)dihydropyrimidin-2,4(1H,3H)-dione

[0273] Under nitrogen protection, 1-(3-bromo-2-chlorophenyl)dihydropyrimidine-2,4(1H,3H)-dione (60 mg, 0.2 mmol), 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)pyridine-2(1H)-one (64 mg, 1.1 mmol), sodium carbonate (63 mg, 0.6 mmol), and Pd(dppf)Cl2 were added to 3 mL of dioxane and 0.5 mL of water, and the mixture was purged with nitrogen three times. Heating to 90°C and stirring for 2 hours, then cooling to room temperature, followed by extraction with ethyl acetate and water. The ethyl acetate was dried over anhydrous sodium sulfate, evaporated to dryness, and purified using silica gel stencils to yield 1-(2-chloro-4'-(2-oxopyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (30 mg, 0.07 mmol), yield: 39%. LC / MS (ESI+) calcd for C 21 H 16 ClN3O3 + ([M+H)) + )m / z:394.1; found 394.1. 1 H NMR(400MHz,DMSO-d6)δ10.52(s,1H),7.77–7.71(m,1H),7.63–7.50(m,7H),7.46(dd,J=7.4,2.0Hz,1H), 6.56–6.50(m,1H),6.34(td,J=6.7,1.4Hz,1H),3.83–3.74(m,1H),3.73–3.63(m,1H),2.83–2.72(m,2H).

[0274] Example 31: 1-(2-chloro-4'-(6-methyl-2-oxopyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

[0275] It was prepared using a method similar to that of Example 30. LC / MS (ESI+) calcd for C 22 H 19 ClN3O3 + ([M+H)) + )m / z:408.1; found 408.1. 1 H NMR (400MHz, DMSO-d6) δ10.52(s,1H),7.60(d,J=8.1Hz,2H),7.57–7.42(m,4H),7.37(d,J=7.9Hz,2H) ,6.37(d,J=9.2Hz,1H),6.28(d,J=6.9Hz,1H),3.79–3.64(m,2H),2.77(t,J=6.6Hz,2H),1.96(s,3H).

[0276] Example 32: 1-(2-chloro-4'-(6-ethyl-2-oxopyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

[0277] 1. Synthesis of 1-(4-bromophenyl)-6-ethylpyridin-2(1H)-one

[0278] 6-Ethylpyridin-2-ol (250 mg, 2 mmol), 4-bromophenylboronic acid (611 mg, 3 mmol), bis(((trifluoromethyl)sulfonyl)oxy)copper (367 mg, 1 mmol), TMEDA (117 mg, 1 mmol), and pyridine (481 mg, 6 mmol) were added to 10 mL of 1,2-dichloroethane and purged with an oxygen bulb. The mixture was heated to 60 °C and stirred for 16 h. After cooling to room temperature, dichloromethane and 1N hydrochloric acid were added, and the mixture was extracted. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, evaporated to dryness, and purified by silica gel column chromatography. 1-(4-bromophenyl)-6-ethylpyridin-2(1H)-one (50 mg, 0.2 mmol) was given in 9% yield; 2-(4-bromophenoxy)-6-ethylpyridine (210 mg, 0.8 mmol) was given in 37% yield. LC / MS (ESI+) calcd for C 13 H 13 BrNO + ([M+H)) +)m / z:278.0; found 278.0.

[0279] 2. Synthesis of 6-ethyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)pyridine-2(1H)-one

[0280] Under nitrogen protection, 1-(4-bromophenyl)-6-ethylpyridin-2(1H)-one (16 mg, 0.06 mmol), bipinacol borate (16 mg, 0.06 mmol), potassium acetate (17 mg, 0.17 mmol), and Pd(dppf)Cl2 (10 mg, 0.006 mmol) were added to 1 mL of anhydrous dioxane. The mixture was heated to 90 °C and stirred for 16 h. After cooling to room temperature, the solution was evaporated to dryness and purified by silica gel column chromatography. The result was 6-ethyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)pyridin-2(1H)-one (10 mg, 0.03 mmol), in 53% yield. LC / MS (ESI+) calcd for C 13 H 25 BNO3 + ([M+H)) + )m / z:326.2; found 326.2.

[0281] 3. Synthesis of 1-(2-chloro-4'-(6-ethyl-2-oxopyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

[0282] Under nitrogen protection, 6-ethyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborin-2-yl)phenyl)pyridin-2(1H)-one (10 mg, 0.03 mmol), 3-bromo-2-chlorophenyl)dihydropyrimidine-2,4(1H,3H)-dione (10 mg, 0.03 mmol), sodium bicarbonate (8 mg, 0.09 mmol), and Pd(dppf)Cl2 (5 mg, 0.003 mmol) were added to 1 mL of anhydrous dioxane and 0.2 mL of water. The mixture was heated to 90 °C and stirred for 3 h. After cooling to room temperature, ethyl acetate and water were added, and the mixture was extracted. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness to prepare purified saturated plates. 1-(2-chloro-4'-(6-ethyl-2-oxopyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)dihydropyrimidin-2,4(1H,3H)-dione (5 mg, 0.01 mmol), yield 40%. LC / MS (ESI+) calcd for C 23 H 21 ClN3O3 + ([M+H))+ )m / z:422.1; found 422.1. 1 H NMR (400MHz, DMSO-d6) δ10.52 (s, 1H), 7.59 (dd, J = 7.1, 5.3Hz, 2H), 7.57–7. 54(m,1H),7.54–7.45(m,3H),7.37(d,J=8.3Hz,2H),6.38(d,J=9.2Hz,1H), 6.24(d,J=6.9Hz,1H),3.78(dt,J=13.9,7.1Hz,1H),3.67(dt,J=12.4,6.3H z,1H),2.77(t,J=6.3Hz,2H),2.22(q,J=7.4Hz,2H),1.01(t,J=7.4Hz,3H).

[0283] Example 33: 3-(1-(3-(6-methyl-2-oxopyridin-1(2H)-yl)phenyl)-1H-indazol-4-yl)piperidin-2,6-dione

[0284] Step 1: Synthesis of 1-(3-iodophenyl)-6-methylpyridin-2(1H)-one

[0285] 6-Methylpyridin-2(1H)-one (218 mg, 2.0 mmol) and 3-iodophenylboronic acid (991 mg, 4.0 mmol) were dissolved in 10 mL of 1,2-dichloroethane. Cu(OTf)₂ (289 mg, 0.8 mmol), tetramethylethylenediamine (93 mg, 0.8 mmol), and pyridine (475 mg, 6.0 mmol) were added. The mixture was purged with oxygen three times and reacted at 50 °C for 3 hours. The solution was concentrated to dryness under reduced pressure and purified by column chromatography to obtain 150 mg of the product 1-(3-iodophenyl)-6-methylpyridin-2(1H)-one, yield: 24%.

[0286] LC / MS(ESI+)calcd for C 12 H 11 INO([M+H)) + )m / e 311.9, found 311.9.

[0287] Step 2: Synthesis of 3-(1-(3-(6-methyl-2-oxopyridin-1(2H)-yl)phenyl)-1H-indazol-4-yl)piperidin-2,6-dione

[0288] 3-(1H-indazol-4-yl)piperidin-2,6-dione (81 mg, 0.35 mmol) and 1-(3-iodophenyl)-6-methylpyridin-2(1H)-one (100 mg, 0.32 mmol) were dissolved in 3 mL of dimethyl sulfoxide (DMSO). Potassium phosphate (136 mg, 0.64 mmol), cuprous iodide (30 mg, 0.16 mmol), and 2-pyridinecarboxylic acid (20 mg, 0.16 mmol) were added. The mixture was reacted at 120 °C for 2 hours under argon protection. The mixture was extracted with ethyl acetate, washed with water, concentrated under pressure to dryness, and purified by thin-layer chromatography to give 35 mg of the product 3-(1-(3-(6-methyl-2-oxopyridin-1(2H)-yl)phenyl)-1H-indazol-4-yl)piperidin-2,6-dione (yield: 27%). LC / MS (ESI+) calcd for C 24 H 21 N4O3([M+H)) + )m / e413.1, found 413.1. 1 H NMR (400MHz, DMSO-d6) δ10.97(s,1H),8.45(s,1H),7.90(dd,J=8.3,2.0Hz,1H),7.82–7.77(m,1 H),7.74(d,J=8.0Hz,1H),7.70(t,J=2.1Hz,1H),7.47(ddd,J=15.7,8.9,7.0Hz,2H),7.34–7.29( m,1H),7.14(d,J=7.1Hz,1H),6.38(d,J=9.1Hz,1H),6.28(d,J=6.8Hz,1H),4.43(dd,J=12.2,4.9 Hz,1H),2.78(ddd,J=17.3,12.3,5.2Hz,1H),2.70–2.55(m,2H),2.18–2.08(m,1H),2.02(s,3H).

[0289] Example 34: 3-(1-(3-(5-methyl-2-oxopyridin-1(2H)-yl)phenyl)-1H-indazol-4-yl)piperidin-2,6-dione

[0290] The target compound was prepared using a method similar to that in Example 1. LC / MS (ESI+) calcd for C 24 H 21 N4O3([M+H)) + )m / e 413.1, found 413.1. 1H NMR (400MHz, DMSO-d6) δ10.97(s,1H),8.45(s,1H),7.89–7.80(m,3H),7.73(t,J=7. 9Hz,1H),7.62(d,J=2.5Hz,1H),7.49(dd,J=8.6,7.1Hz,1H),7.43(ddd,J=9.4,5.9, 2.1Hz,2H),7.14(d,J=7.1Hz,1H),6.48(d,J=9.3Hz,1H),4.43(dd,J=12.3,4.8Hz,1 H),2.77(td,J=12.4,6.1Hz,1H),2.68–2.55(m,2H),2.17–2.10(m,1H),2.08(s,3H).

[0291] Example 35: 3-(1-(4-(pyridin-2-yloxy)phenyl)-1H-indazol-4-yl)piperidin-2,6-dione

[0292] Step 1: Synthesis of 2-(4-bromophenoxy)pyridine

[0293] 2-Fluoropyridine (970 mg, 10.00 mmol), 4-bromophenol (1730 mg, 10.00 mmol), and K3CO3 (3450 mg, 25.00 mmol) were added to 15 mL of DMAc and stirred overnight at 90 °C. Water was added, and the mixture was extracted three times with EA. The organic phases were combined, washed with saturated NaCl solution, dried over anhydrous sodium sulfate, and subjected to rotary evaporation and column chromatography to obtain the target compound (1625 mg, 65% yield). LC / MS (ESI+) calcd for C 11 H9BrNO([M+H)) + )m / z 251.9; found 251.9.

[0294] Step 2: Synthesis of 3-(1-(4-(pyridin-2-yloxy)phenyl)-1H-indazol-4-yl)piperidine-2,6-dione

[0295] Compounds 2-(4-bromophenoxy)pyridine (66 mg, 0.26 mmol), 3-(1H-indazol-4-yl)piperidin-2,6-dione (50 mg, 0.22 mmol), CuI (42 mg, 0.22 mmol), 2-pyridinecarboxylic acid (54 mg, 0.44 mmol), and K3PO4 (93 mg, 0.44 mmol) were added to 4 mL of DMSO and stirred at 120 °C for 2.5 h. After cooling to room temperature, the reaction solution was added to 15 mL of saturated ammonium chloride solution, resulting in the precipitation of a large amount of solid. The solid was filtered, and the filter cake was dissolved in DCM / MeOH = 10 / 1, then filtered again. The filtrate was dried over anhydrous sodium sulfate, and the solution was stirred under evaporation. Column chromatography yielded the target compound (15 mg, 17% yield). LC / MS (ESI+) calcd for C 23 H 19 N4O3([M+H)) + )m / z 399.1, found 399.1. 1 H NMR (400MHz, DMSO-d6) δ10.98(s,1H),8.43–8.38(m,1H),8.20(dd,J=5.1,2.0Hz,1H),7.90(d dd,J=8.3,7.2,2.0Hz,1H),7.82–7.77(m,2H),7.75(d,J=8.5Hz,1H),7.46(dd,J=8.5,7.1Hz, 1H),7.38–7.33(m,2H),7.20–7.15(m,1H),7.13(dd,J=7.7,5.0Hz,2H),4.42(dd,J=12.2,4.9 Hz,1H),2.78(ddd,J=17.2,12.3,5.2Hz,1H),2.59(dt,J=17.1,3.9Hz,1H),2.20–1.93(m,2H).

[0296] Example 36: 3-(1-(3-(quinolin-2-yloxy)phenyl)-1H-indazol-4-yl)piperidine-2,6-dione

[0297] 1. Synthesis of compound 2-(3-iodophenoxy)quinoline

[0298] Weigh quinoline-2(1H)-one (500 mg, 3.44 mmol), m-diiodobenzene (2273 mg, 6.88 mmol), iodide ketone (328 mg, 1.72 mmol), and anhydrous potassium carbonate (951 mg, 6.88 mmol) into a round-bottom flask. Add 25 mL of dry DMSO and purge the system under vacuum with argon gas five times. After the purging is complete, heat the system in an oil bath at 120 °C for 3 hours. Stop the reaction and allow the system to cool to room temperature. Filter the system using diatomaceous earth. Wash the filter cake repeatedly with ethyl acetate. Combine the filtrates and extract with water and ethyl acetate. Wash the organic phase successively with water and saturated brine, dry with anhydrous sodium sulfate, and remove the solvent by rotary evaporation to obtain the crude product. Purify the crude product by column chromatography to obtain the target compound 2-(3-iodophenoxy)quinoline (100 mg). Yield: 8%. LC / MS (ESI) + calcd for C 15 H 10 INO([M+H)) + )m / z,348.0; found,347.9. 1 H NMR (400MHz, DMSO-d6) δ8.41(t,J=8.1Hz,1H),7.99–7.90(m,1H),7.68–7.61(m,3H),7.54–7.42(m,2H),7.27(ddd,J=12.2,7.1,2.8Hz,3H).

[0299] 2. Synthesis of compound 3-(1-(3-(quinolin-2-yloxy)phenyl)-1H-indazol-4-yl)piperidine-2,6-dione

[0300] Weigh 66 mg (0.29 mmol) of 3-(1H-indazol-4-yl)piperidin-2,6-dione, 100 mg (0.29 mmol) of 2-(3-iodophenoxy)quinoline, 29 mg (0.15 mmol) of iodide ketone, 19 mg (0.15 mmol) of 2-pyridinecarboxylic acid, and 80 mg (0.58 mmol) of anhydrous potassium carbonate into a round-bottom flask. After purging with argon gas three times under vacuum, add 3 mL of dry DMSO. Purge with argon gas five times while stirring, then transfer the flask to an oil bath at 110 °C and heat to react. After 1 h, LC-MS monitoring showed the starting material had disappeared. After the system cooled to room temperature, filter using diatomaceous earth. Wash the filter cake several times with ethyl acetate. The filtrates were combined, and water and ethyl acetate were added to complete the extraction. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation to obtain the crude product. Prep-TLC purification yielded the target compound 3-(1-(3-(quinolin-2-yloxy)phenyl)-1H-indazol-4-yl)piperidine-2,6-dione (24 mg). Yield: 19%. LC / MS (ESI) + calcd for C 27 H 20 N4O3([M+H)) + )m / z,449.2; found,449.1. 1 H NMR (400MHz, DMSO-d6) δ10.97(s,1H),8.47(d,J=8.8Hz,1H),8.43(s,1H),7.99(d,J=7.9Hz,1H),7. 88(d,J=8.5Hz,1H),7.80–7.60(m,5H),7.57–7.49(m,1H),7.46(t,J=7.8Hz,1H),7.36(d,J=8.8Hz,1 H),7.32(dt,J=6.7,3.4Hz,1H),7.13(d,J=7.1Hz,1H),4.42(dd,J=12.1,4.7Hz,1H),2.77(ddd,J=1 7.1,12.6,5.1Hz,1H),2.67–2.53(m,1H),2.12(dd,J=8.8,4.0Hz,1H),1.99(dt,J=14.1,6.9Hz,1H).

[0301] Example 37: 1-(2-chloro-4'-(4-methyl-2-oxo-6-(trifluoromethyl)pyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

[0302] It was prepared using a method similar to that of Example 30. LC / MS (ESI+) calcd for C 23 H 18 F3ClN3O3 + ([M+H)) + )m / z:476.1; found 476.1. 1 H NMR (400MHz, DMSO-d6) δ10.51(s,1H),7.62–7.55(m,3H),7.52(t,J=7.6Hz,1H),7.50–7.46(m,1H),7.42(d,J=8.0Hz,2H),6.90(d,J =1.7Hz,1H),6.66(s,1H),3.77(dt,J=13.6,6.9Hz,1H),3.67(dt,J=12.4,6.3Hz,1H),2.76(t,J=6.7Hz,2H),2.29(d,J=1.2Hz,3H).

[0303] Example 38: 3-(1-(3-(2-oxoquinoline-1(2H)-yl)phenyl)-1H-indazol-4-yl)piperidine-2,6-dione

[0304] 1. Synthesis of compound 1-(3-iodophenyl)quinoline-2(1H)-one

[0305] Weigh quinoline-2(1H)-one (500 mg, 3.44 mmol), m-diiodobenzene (2273 mg, 6.88 mmol), iodide ketone (328 mg, 1.72 mmol), and anhydrous potassium carbonate (951 mg, 6.88 mmol) into a round-bottom flask. Add 25 mL of dry DMSO and purge the system under vacuum with argon gas five times. After purging, heat the system in an oil bath at 120 °C for 3 hours. Stop the reaction and allow the system to cool to room temperature. Filter the system using diatomaceous earth. Wash the filter cake repeatedly with ethyl acetate. Combine the filtrates and extract with water and ethyl acetate. Wash the organic phase successively with water and saturated brine, dry with anhydrous sodium sulfate, and remove the solvent by rotary evaporation to obtain the crude product. Purify the crude product by column chromatography to obtain the target compound 1-(3-iodophenyl)quinoline-2(1H)-one (234 mg). Yield: 20%. LC / MS (ESI) + calcd for C 15 H 10 INO([M+H)) + )m / z,348.0; found,347.9. 1H NMR (400MHz, DMSO-d6) δ8.04(d,J=9.6Hz,1H),7.93(dt,J=7.6,1.4Hz,1H),7.77(dd,J=8.3,1 .3Hz,2H),7.47–7.35(m,3H),7.28–7.21(m,1H),6.67(d,J=9.6Hz,1H),6.53(d,J=8.5Hz,1H).

[0306] 2. Synthesis of compound 3-(1-(3-(2-oxoquinoline-1(2H)-yl)phenyl)-1H-indazol-4-yl)piperidine-2,6-dione

[0307] Weigh 59 mg (0.26 mmol) of 3-(1H-indazol-4-yl)piperidin-2,6-dione, 90 mg (0.26 mmol) of 1-(3-iodophenyl)quinoline-2(1H)-one, 25 mg (0.13 mmol) of iodide ionone, 16 mg (0.13 mmol) of 2-pyridinecarboxylic acid, and 72 mg (0.52 mmol) of anhydrous potassium carbonate into a round-bottom flask. After purging with argon gas three times under vacuum, add 3 mL of dry DMSO. Purge with argon gas five times while stirring, then transfer the flask to an oil bath at 110 °C and heat to react. After 1 h, LCMS monitoring showed the starting material had disappeared. After the system cooled to room temperature, filtration was performed using diatomaceous earth, and the filter cake was washed multiple times with ethyl acetate. The filtrates were combined, and water and ethyl acetate were added to complete the extraction. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation to obtain the crude product. Prep-TLC purification yielded the target compound 3-(1-(3-(2-oxoquinoline-1(2H)-yl)phenyl)-1H-indazol-4-yl)piperidine-2,6-dione (3 mg). Yield: 3%. LC / MS (ESI) + calcd for C 27 H 20 N4O3([M+H)) + )m / z,449.2; found,449.1. 1H NMR(400MHz,DMSO-d6)δ10.97(s,1H),8.45(s,1H),8.08(d,J=9.6Hz,1H),8.04–7.96(m,1H),7 .89–7.74(m,4H),7.52–7.42(m,2H),7.42–7.35(m,1H),7.31–7.24(m,1H),7.14(d,J=7.1Hz,1H ),6.72(dd,J=9.0,5.6Hz,2H),4.42(dd,J=12.2,4.7Hz,1H),2.77(ddd,J=17.2,12.3,5.1Hz,1 H), 2.58 (dt, J=17.0, 3.4Hz, 1H), 2.12 (dp, J=12.8, 4.8, 4.1Hz, 1H), 1.99 (p, J=6.8, 6.2Hz, 1H).

[0308] Example 39: 3-(1-(2-fluoro-5-(quinolin-2-ylamino)phenyl)-1H-indazol-4-yl)piperidine-2,6-dione

[0309] 1. Synthesis of compound N-(3-bromo-4-fluorophenyl)quinoline-2-amine

[0310] 2-Chloroquinoline (327 mg, 2.00 mmol), 3-bromo-4-fluoroaniline (418 mg, 2.20 mmol), and cesium carbonate (1303 mg, 4.00 mmol) were weighed and placed in a round-bottom flask. After purging with argon three times, 10 mL of dry DMSO was added, and the system was purged with argon five times. The mixture was then heated in an oil bath at 100 °C. The next day, LC / MS showed that the starting materials were consumed. After the system cooled to room temperature, diatomaceous earth was used for filtration, and the filter cake was washed repeatedly with ethyl acetate. The filtrates were combined, and ethyl acetate and water were added for extraction. The organic phase was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation to obtain the crude product. The crude product was purified by Prep-TLC to obtain the target compound N-(3-bromo-4-fluorophenyl)quinoline-2-amine (107 mg). Yield: 17%. LC / MS (ESI) + calcd for C 15 H 10 BrFN2([M+H] + )m / z 317.0; found 316.8.

[0311] 2. Synthesis of compound 3-(1-(2-fluoro-5-(quinolin-2-ylamino)phenyl)-1H-indazol-4-yl)piperidine-2,6-dione

[0312] Weigh 60 mg (0.26 mmol) of 3-(1H-indazol-4-yl)piperidin-2,6-dione, 84 mg (0.26 mmol) of 2-chloro-6-(3-iodophenoxy)pyridine, 25 mg (0.13 mmol) of iodide ionone, 16 mg (0.13 mmol) of 2-pyridinecarboxylic acid, and 110 mg (0.52 mmol) of anhydrous potassium phosphate into a round-bottom flask. After purging with argon gas three times under vacuum, add 3 mL of dry DMSO. Purge with argon gas five times while stirring, then transfer the flask to an oil bath at 130 °C and heat to react. After 3 h, LCMS monitoring showed the starting material had disappeared. After the system cooled to room temperature, filter using diatomaceous earth. Wash the filter cake several times with ethyl acetate. The filtrates were combined, and water and ethyl acetate were added to complete the extraction. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation to obtain the crude product. Prep-TLC purification yielded the target compound 3-(1-(2-fluoro-5-(quinolin-2-ylamino)phenyl)-1H-indazol-4-yl)piperidine-2,6-dione (5 mg). Yield: 4%. LC / MS (ESI) + calcd for C 27 H 20 FN5O2([M+H) + )m / z,466.2; found,465.9. 1 H NMR (400MHz, DMSO-d6) δ10.99(s,1H),9.76(s,1H),8.60(dd,J=6.9,2.6Hz,1H),8.48(s,1H),8.11(d,J=8.9Hz, 1H),7.95(dq,J=9.0,2.9Hz,1H),7.76(d,J=7.9Hz,1H),7.63–7.55(m,2H),7.55–7.47(m,3H),7.31(ddd,J=8.0, 6.2,2.0Hz,1H),7.16(dd,J=6.1,1.5Hz,1H),7.07(d,J=8.9Hz,1H),4.45(dd,J=12.2,4.8Hz,1H),2.80(ddd,J=1 7.2,12.4,5.2Hz,1H),2.61(dt,J=17.0,3.5Hz,1H),2.17(dq,J=12.7,4.8Hz,1H),1.99(dt,J=13.9,6.9Hz,1H).

[0313] Example 40: 3-(1-(2-fluoro-5-(quinoxalo-2-ylamino)phenyl)-1H-indazol-4-yl)piperidine-2,6-dione

[0314] It was prepared using a method similar to that of Example 39. LC / MS (ESI) + calcd for C 26 H 19 FN6O2([M+H) + )m / z,467.2; found,466.9. 1 H NMR (400MHz, DMSO-d6) δ10.99(s,1H),10.29(s,1H),8.67–8.36(m,3H),7.98(s,1H),7.88(d,J=6.7Hz,1H),7.66(s,2H),7.62–7. 42(m,4H),7.19–7.07(m,1H),4.53–4.35(m,1H),2.88–2.72(m,1H),2.72–2.61(m,1H),2.24–2.11(m,1H),1.97(t,J=15.7Hz,1H).

[0315] Example 41: 3-(1-(3-(quinazolin-2-ylamino)phenyl)-1H-indazol-4-yl)piperidine-2,6-dione

[0316] It was prepared using a method similar to that of Example 39. LC / MS (ESI) + calcd for C 26 H 20 N5O2([M+H) + )m / z,448.2; found,449.0. 1 H NMR (400MHz, DMSO-d6) δ10.98(s,1H),10.24(s,1H),9.38(s,1H),8.77(s,1H),8.43(s,1H),8.05(d,J=8.5H z,1H),7.97(d,J=7.5Hz,1H),7.91–7.80(m,2H),7.69(d,J=8.4Hz,1H),7.55(dt,J=12.2,7.7Hz,2H),7.44( t,J=7.4Hz,1H),7.41–7.36(m,1H),7.17(d,J=7.1Hz,1H),4.44(dd,J=12.2,4.8Hz,1H),2.80(ddd,J=17.4, 12.6,5.4Hz,1H),2.61(dt,J=17.2,3.5Hz,1H),2.16(dq,J=13.1,4.5Hz,1H),1.99(dt,J=12.1,6.7Hz,1H).

[0317] Example 42: 3-(1-(2-fluoro-5-(quinazolin-2-ylamino)phenyl)-1H-indazol-4-yl)piperidine-2,6-dione

[0318] It was prepared using a method similar to that of Example 39. LC / MS (ESI) + calcd for C 26 H 19 FN6O2([M+H) + )m / z,467.2; found,466.9. 1 H NMR (400MHz, DMSO-d6) δ10.99(s,1H),10.22(s,1H),9.36(s,1H),8.47(s,1H),8.45(dd,J=6.7,2.6Hz ,1H),8.09–8.03(m,1H),7.95(d,J=8.2Hz,1H),7.83(t,J=7.7Hz,1H),7.61(d,J=8.4Hz,1H),7.56–7. 50(m,1H),7.49(d,J=4.5Hz,2H),7.42(t,J=7.3Hz,1H),7.17–7.13(m,1H),4.44(dd,J=12.2,4.9Hz,1 H),2.80(ddd,J=16.6,12.0,5.0Hz,1H),2.65–2.57(m,1H),2.21–2.12(m,1H),1.99(p,J=7.0Hz,1H).

[0319] Example 43: 3-(1-(5-((1,5-naphthid-2-yl)amino)-2-fluorophenyl)-1H-indazol-4-yl)piperidin-2,6-dione

[0320] It was prepared using a method similar to that of Example 39. LC / MS (ESI) + calcd for C 26 H 19 FN6O2([M+H) + )m / z,467.2; found,467.1. 1H NMR(400MHz,DMSO-d6)δ10.99(s,1H),9.98(s,1H),8.66(d,J=3.6Hz,1H),8.58–8.50(m,1H), 8.48(s,1H),8.15(d,J=9.1Hz,1H),8.03–7.92(m,2H),7.60(dd,J=8.4,4.1Hz,1H),7.57–7.4 6(m,3H),7.31(d,J=9.1Hz,1H),7.19–7.11(m,1H),4.44(dd,J=12.1,4.7Hz,1H),2.80(ddd,J =17.3,12.2,4.9Hz,1H),2.65–2.57(m,1H),2.22–2.11(m,1H),1.99(dt,J=12.5,6.9Hz,1H).

[0321] Example 44: 3-(1-(3-(3-(3-2-dimethyl-2-oxopyridin-1(2H)-yl)phenyl)-1H-indazol-4-yl)piperidin-2,6-dione

[0322] Preparation of 1,3,6-dimethylpyridin-2(1H)-one:

[0323] 3-Bromo-2-hydroxy-6-methylpyridine (1.88 g, 13.6 mmol, 1.0 eq), trimethylcyclotriboroxane (3.5 min THF, 13.6 mL, 47.6 mmol, 3.5 eq), palladium acetate (152 mg, 0.68 mmol, 0.05 eq), and DPEphos (366 mg, 0.68 mmol, 0.05 eq) were weighed into a dry reaction flask. DME (23 mL) and an aqueous solution of sodium bicarbonate (2.86 g, 35.0 mmol, 2.5 eq) (23 mL) were added. The reaction mixture was incubated at 85 °C for 12 hours under argon protection. The reaction solution was cooled to room temperature, filtered through diatomaceous earth, quenched with a saturated ammonium chloride solution, extracted with DCM, and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (DCM-MeOH = 50:1) to obtain 3,6-dimethylpyridin-2(1H)-one (gray solid, 700 mg, 42%). LC-MS (ESI) + ): calcdfor C7H 10 NO([M+H] + )m / z 124.1, found 124.1.

[0324] 2.1-(3-Iodophenyl)-3,6-dimethylpyridin-2(1H)-one:

[0325] 3,6-Dimethylpyridin-2(1H)-one (500 mg, 4.06 mmol, 1.0 eq), 3-iodophenylboronic acid (1.51 g, 6.09 mmol, 1.5 eq), TMEDA (0.24 mL, 1.62 mmol, 0.4 eq), pyridine (0.98 mL, 12.2 mmol, 3.0 eq), and copper trifluoromethanesulfonate (586 mg, 1.62 mmol, 0.4 eq) were weighed into a dry reaction flask. DCE solution (10 mL) was added, and the mixture was purged three times with oxygen. The reaction mixture was then reacted at 50 °C in an oxygen atmosphere for 4 hours. The reaction solution was cooled to room temperature, quenched with saturated ammonium chloride aqueous solution, extracted with DCM, and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (PE-EA = 1:2) to give 1-(3-iodophenyl)-3,6-dimethylpyridin-2(1H)-one (light yellow solid, 108 mg, 8%). LC-MS (ESI) + ): calcd for C 13 H 13 INO([M+H)) + )m / z 326.0, found 325.8.

[0326] 3. Preparation of 3-(1-(3-(3-(3-2-dimethyl-2-oxopyridin-1(2H)-yl)phenyl)-1H-indazol-4-yl)piperidine-2,6-dione:

[0327] The following were administered: 3-(1H-indazol-4-yl)piperidin-2,6-dione (50.0 mg, 0.22 mmol, 1.0 eq), 1-(3-iodophenyl)-3,6-dimethylpyridin-2(1H)-one (78.0 mg, 0.24 mmol, 1.1 eq), 2-pyridinecarboxylic acid (13.5 mg, 0.11 mmol, 0.5 eq), and cuprous iodide (21.0 mg, 0.11 mmol).

[0328] 0.5 eq) and potassium carbonate (60.7 mg, 0.44 mmol, 2.0 eq) were weighed into a dry reaction flask. After purging with argon three times, 2 mL of dry DMSO was added, and the mixture was reacted in an oil bath at 110 °C for 1 hour. The reaction solution was cooled, filtered through diatomaceous earth, quenched with saturated ammonium chloride aqueous solution, extracted with ethyl acetate, and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by PTLC (DCM-MeOH = 15:1) to give 3-(1-(3-(3-(3-2-dimethyl-2-oxopyridin-1(2H)-yl)phenyl)-1H-indazol-4-yl)piperidin-2,6-dione (pale yellow solid, 20 mg, 21.3%). LC / MS (ESI) + ): calcd for C25 H 23 N4O3([M+H)) + )m / z 427.2, found 427.0. 1 H NMR (400MHz, DMSO-d6) δ10.96(s,1H),8.45(s,1H),7.89(dd,J=7.5,2.1Hz,1H),7.78(d,J =8.5Hz,1H),7.74(t,J=8.0Hz,1H),7.70–7.66(m,1H),7.52–7.43(m,1H),7.37–7.32(m,1H ),7.31–7.27(m,1H),7.14(d,J=7.1Hz,1H),6.19(d,J=6.9Hz,1H),4.42(dd,J=12.3,4.9H z,1H),2.84–2.72(m,1H),2.69–2.55(m,2H),2.18–2.08(m,1H),2.01(s,3H),1.98(s,3H).

[0329] Example 45: 3-(1-(3-(6-cyclopropyl-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)phenyl)-1H-indazol-4-yl)piperidin-2,6-dione

[0330] Step 1: Preparation of 6-cyclopropyl-1-(3-iodophenyl)-4-(trifluoromethyl)pyridine-2(1H)-one:

[0331] 6-Cyclopropyl-4-(trifluoromethyl)pyridin-2-ol (mg, 4.06 mmol, 1.0 eq), 3-iodophenylboronic acid (1.51 g, 6.09 mmol, 1.5 eq), TMEDA (0.24 mL, 1.62 mmol, 0.4 eq), pyridine (0.98 mL, 12.2 mmol, 3.0 eq), and copper trifluoromethanesulfonate (586 mg, 1.62 mmol, 0.4 eq) were weighed into a dry reaction flask. DCE solution (10 mL) was added, and the mixture was purged three times with oxygen. The reaction mixture was then reacted at 50 °C in an oxygen atmosphere for 4 hours. The reaction solution was cooled to room temperature, quenched with saturated ammonium chloride aqueous solution, extracted with DCM, and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (PE-EA = 80:1 to 1:2) to give 6-cyclopropyl-1-(3-iodophenyl)-4-(trifluoromethyl)pyridin-2(1H)-one (PE-EA = 1:1, pale yellow solid, 130 mg, 7%). LC-MS (ESI) + ): calcd for C 15 H 12F3INO([M+H)) + )m / z 406.0, found 405.8.

[0332] Step 2: Preparation of 3-(1-(3-(6-cyclopropyl-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)phenyl)-1H-indazol-4-yl)piperidine-2,6-dione:

[0333] 3-(1H-indazol-4-yl)piperidin-2,6-dione (50.0 mg, 0.22 mmol, 1.0 eq), 6-cyclopropyl-1-(3-iodophenyl)-4-(trifluoromethyl)pyridin-2(1H)-one (97.0 mg, 0.24 mmol, 1.1 eq), 2-pyridinecarboxylic acid (13.5 mg, 0.11 mmol, 0.5 eq), cuprous iodide (21.0 mg, 0.11 mmol, 0.5 eq), and potassium carbonate (60.7 mg, 0.44 mmol, 2.0 eq) were weighed into a dry reaction flask. After purging with argon three times, 2 mL of dry DMSO was added, and the reaction was carried out in an oil bath at 110 °C for 1 hour. After cooling, the reaction solution was filtered through diatomaceous earth, quenched with saturated ammonium chloride aqueous solution, extracted with ethyl acetate, and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by PTLC (DCM-MeOH = 18:1) to give 3-(1-(3-(6-cyclopropyl-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)phenyl)-1H-indazol-4-yl)piperidin-2,6-dione (pale yellow solid, 22.0 mg, 20%). LC / MS (ESI) + ): calcd for C 27 H 22 F3N4O3([M+H) + )m / z 507.2, found 506.9. 1H NMR (400MHz, DMSO-d6) δ10.96(s,1H),8.46(s,1H),7.94–7.90(m,1H),7.88(t,J=2.1Hz,1H),7. 81(d,J=8.6Hz,1H),7.77(t,J=8.0Hz,1H),7.53–7.44(m,1H),7.43(d,J=8.4Hz,1H),7.14(d,J= 7.1Hz,1H),6.79(s,1H),6.29(d,J=1.9Hz,1H),4.42(dd,J=12.2,4.8Hz,1H),2.85–2.73(m,1H) ,2.70–2.54(m,2H),2.20–2.07(m,1H),1.50–1.41(m,1H),0.95–0.87(m,2H),0.79–0.68(m,2H).

[0334] Example 46: 3-(1-(3-(4-chloro-6-cyclopropyl-2-oxopyridin-1(2H)-yl)phenyl)-1H-indazol-4-yl)piperidin-2,6-dione

[0335] Step 1: Preparation of 6-bromo-4-chloropyridin-2-ol:

[0336] Potassium tert-butoxide (18.5 g, 165 mmol, 10.0 eq) was slowly added to a tert-butanol solution (40 mL) of 2,6-dibromo-4-chloropyridine (4.50 g, 16.6 mmol, 1.0 eq), and the mixture was refluxed for 12 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure to remove the solvent, and 4 M hydrochloric acid aqueous solution (50 mL) was added. The mixture was stirred at room temperature for 2 hours, extracted with DCM, and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (PE-EA = 10:1) to obtain 6-bromo-4-chloropyridine-2-ol (white solid, 1.10 g, 32%). LC-MS (ESI) was then performed. + ):calcd for C5H4BrClNO([M+H] + )m / z 207.9, found 207.8.

[0337] Step 2: Preparation of 4-chloro-6-cyclopropylpyridine-2-ol:

[0338] 6-Bromo-4-chloropyridin-2-ol (1.00 g, 4.80 mmol, 1.0 eq), pinacol cyclopropylborate (2.63 mL, 14.4 mmol, 3.5 eq), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (391 mg, 0.48 mmol, 0.10 eq) were weighed into a flask, and 23 mL of 1,4-dioxane solution and 23 mL of potassium phosphate (2.54 g, 12.0 mmol, 2.5 eq) aqueous solution were added. The reaction mixture was incubated at 80 °C for 12 hours under argon protection. The reaction solution was cooled to room temperature, filtered through diatomaceous earth, quenched with saturated ammonium chloride aqueous solution, extracted with DCM, and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (DCM-MeOH = 30:1) to give 4-chloro-6-cyclopropylpyridine-2-ol (pale yellow solid, 300 mg, 37%). LC / MS (ESI) + ): calcd for C8H9ClNO([M+H] + )m / z 170.0, found 169.9.

[0339] Step 3: Preparation of 4-chloro-6-cyclopropyl-1-(3-iodophenyl)pyridine-2(1H)-one:

[0340] 4-Chloro-6-cyclopropylpyridin-2-ol (300 mg, 1.76 mmol, 1.0 eq), 3-iodophenylboronic acid (735 mg, 2.11 mmol, 1.2 eq), TMEDA (82.3 mg, 0.71 mmol, 0.4 eq), pyridine (356 μL, 4.40 mmol, 2.5 eq), and copper trifluoromethanesulfonate (222 mg, 0.71 mmol, 0.4 eq) were weighed into a dry reaction flask. DCE solution (5 mL) was added, and the mixture was purged three times with oxygen. The reaction mixture was then reacted at 50 °C in an oxygen atmosphere for 10 hours. The reaction solution was cooled to room temperature, quenched with saturated ammonium chloride aqueous solution, extracted with DCM, and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (PE-EA = 1:2) to give 4-chloro-6-cyclopropyl-1-(3-iodophenyl)pyridin-2(1H)-one (pale yellow solid, 56.0 mg, 9%). LC / MS (ESI) + ): calcd for C 14 H 12 ClNO([M+H)) + )m / z 371.9, found 371.8.

[0341] Step 4: Preparation of 3-(1-(3-(4-chloro-6-cyclopropyl-2-oxopyridin-1(2H)-yl)phenyl)-1H-indazol-4-yl)piperidine-2,6-dione:

[0342] 3-(1H-indazol-4-yl)piperidin-2,6-dione (34.7 mg, 0.15 mmol, 1.0 eq), 1-(3-iodophenyl)-5,6-dimethylpyridin-2(1H)-one (56.0 mg, 0.15 mmol, 1.1 eq), 2-pyridinecarboxylic acid (9.2 mg, 0.075 mmol, 0.5 eq), cuprous iodide (14.3 mg, 0.075 mmol, 0.5 eq), and potassium carbonate (60.7 mg, 0.44 mmol, 2.0 eq) were weighed into a dry reaction flask. After purging with argon three times, dry DMSO (2 mL) was added, and the reaction was carried out in an oil bath at 110 °C for 1 hour. After cooling, the reaction solution was filtered through diatomaceous earth, washed with ethyl acetate (50 mL), quenched with saturated ammonium chloride aqueous solution, extracted with ethyl acetate, and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by PTLC (DCM-MeOH = 15:1) to give a pale yellow solid, 8.0 mg, 11%. LC / MS (ESI) + ): calcd for C 26 H 22 ClN4O3([M+H) + )m / z 473.1, found 473.1. 1 H NMR(400MHz,DMSO-d6)δ10.97(s,1H),8.45(s,1H),7.97–7.86(m,1H),7.84–7.78(m,2H),7.75(t, J=8.0Hz,1H),7.48(dd,J=8.5,7.2Hz,1H),7.39(d,J=7.9Hz,1H),7.14(d,J=7.1Hz,1H),6.55(d,J= 2.2Hz,1H),6.22(d,J=2.2Hz,1H),4.42(dd,J=12.3,4.8Hz,1H),2.78(ddd,J=17.5,12.6,5.4Hz,1 H),2.69–2.56(m,2H),2.18–2.08(m,1H),1.42–1.37(m,1H),0.89–0.86(m,2H),0.77–0.58(m,2H).

[0343] Example 47: 3-(1-(2-fluoro-5-(6-methyl-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)phenyl)-1H-indazol-4-yl)piperidin-2,6-dione

[0344] Step 1: Preparation of 1-(3-bromo-4-fluorophenyl)-6-methyl-4-(trifluoromethyl)pyridin-2(1H)-one:

[0345] 6-Methyl-4-(trifluoromethyl)pyridin-2-ol (814 mg, 4.06 mmol, 1.0 eq), 3-bromo-4-fluorophenylboronic acid (1.33 g, 6.09 mmol, 1.5 eq), TMEDA (0.24 mL, 1.62 mmol, 0.4 eq), pyridine (0.98 mL, 12.2 mmol, 3.0 eq), and copper trifluoromethanesulfonate (586 mg, 1.62 mmol, 0.4 eq) were weighed into a dry reaction flask. DCE solution (10 mL) was added, and the mixture was purged three times with oxygen. The reaction mixture was then reacted at 50 °C in an oxygen atmosphere for 4 hours. The reaction solution was cooled to room temperature, quenched with saturated ammonium chloride aqueous solution, extracted with DCM, and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (PE-EA = 1:2) to obtain 1-(3-bromo-4-fluorophenyl)-6-methyl-4-(trifluoromethyl)pyridin-2(1H)-one (pale yellow solid, 242 mg, 17%). LC-MS (ESI) + ): calcd for C 13 H9BrF4NO([M+H) + )m / z 350.0, found 350.0.

[0346] Step 2: Preparation of 3-(1-(2-fluoro-5-(6-methyl-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)phenyl)-1H-indazol-4-yl)piperidine-2,6-dione:

[0347] 3-(1H-indazol-4-yl)piperidin-2,6-dione (50.0 mg, 0.22 mmol, 1.0 eq), 1-(3-bromo-4-fluorophenyl)-6-methyl-4-(trifluoromethyl)pyridin-2(1H)-one (84.0 mg, 0.24 mmol, 1.1 eq), 2-pyridinecarboxylic acid (13.5 mg, 0.11 mmol, 0.5 eq), cuprous iodide (21.0 mg, 0.11 mmol, 0.5 eq), and potassium phosphate (93.3 mg, 0.44 mmol, 2.0 eq) were weighed into a dry reaction flask. After purging with argon three times, 2 mL of dry DMSO was added, and the reaction was carried out in an oil bath at 125 °C for 3 hours. After cooling, the reaction solution was filtered through diatomaceous earth, quenched with saturated ammonium chloride aqueous solution, extracted with ethyl acetate, and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by PTLC (DCM-MeOH = 18:1) to give 3-(1-(2-fluoro-5-(6-methyl-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)phenyl)-1H-indazol-4-yl)piperidin-2,6-dione (pale yellow solid, 5.0 mg, 5%). LC / MS (ESI) + ): calcd for C 25 H 19 F4N4O3([M+H) + )m / z 499.1, found m 498.9. 1 H NMR(400MHz,DMSO-d6)δ10.97(s,1H),8.48(s,1H),7.83(dd,J=6.8,2.6Hz,1H ),7.76(dd,J=10.3,8.9Hz,1H),7.60(dd,J=7.6,4.5Hz,1H),7.51–7.44(m,1H) ,7.42–7.36(m,1H),7.14(d,J=7.0Hz,1H),6.79(s,1H),6.60(s,1H),4.42(d,J =12.0Hz,1H),2.88–2.72(m,1H),2.70–2.55(m,2H),2.14(s,1H),2.11(s,3H).

[0348] Example 48: 3-(1-(5-(4,6-dimethyl-2-oxopyridin-1(2H)-yl)-2-fluorophenyl)-1H-indazol-4-yl)piperidin-2,6-dione

[0349] Step 1: Preparation of 1-(3-bromo-4-fluorophenyl)-4,6-dimethylpyridin-2(1H)-one:

[0350] 4,6-Dimethyl-2-hydroxypyridine (499 mg, 4.06 mmol, 1.0 eq), 3-bromo-4-fluorophenylboronic acid (1.33 g, 6.09 mmol, 1.5 eq), TMEDA (0.24 mL, 1.62 mmol, 0.4 eq), pyridine (0.98 mL, 12.2 mmol, 3.0 eq), and copper trifluoromethanesulfonate (586 mg, 1.62 mmol, 0.4 eq) were weighed into a dry reaction flask. DCE solution (10 mL) was added, and the mixture was purged three times with oxygen. The reaction mixture was then reacted at 50 °C in an oxygen atmosphere for 4 hours. The reaction solution was cooled to room temperature, quenched with saturated ammonium chloride aqueous solution, extracted with DCM, and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (PE-EA = 1:1) to give 1-(3-bromo-4-fluorophenyl)-4,6-dimethylpyridin-2(1H)-one (pale yellow solid, 95.8 mg, 8%). LC-MS (ESI) + ): calcd for C 13 H 12 BrFNO([M+H] + )m / z 296.0, found 295.8.

[0351] Step 2: Preparation of 3-(1-(5-(4,6-dimethyl-2-oxopyridin-1(2H)-yl)-2-fluorophenyl)-1H-indazol-4-yl)piperidine-2,6-dione:

[0352] 3-(1H-indazol-4-yl)piperidin-2,6-dione (50.0 mg, 0.22 mmol, 1.0 eq), 1-(3-bromo-4-fluorophenyl)-4,6-dimethylpyridin-2(1H)-one (70.8 mg, 0.24 mmol, 1.1 eq), 2-pyridinecarboxylic acid (13.5 mg, 0.11 mmol, 0.5 eq), cuprous iodide (21.0 mg, 0.11 mmol, 0.5 eq), and potassium phosphate (93.3 mg, 0.44 mmol, 2.0 eq) were weighed into a dry reaction flask. After purging with argon three times, 2 mL of dry DMSO was added, and the reaction was carried out in an oil bath at 125 °C for 3 hours. After cooling, the reaction solution was filtered through diatomaceous earth, quenched with saturated ammonium chloride aqueous solution, extracted with ethyl acetate, and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by PTLC (DCM-MeOH = 18:1) to give 3-(1-(5-(4,6-dimethyl-2-oxopyridin-1(2H)-yl)-2-fluorophenyl)-1H-indazol-4-yl)piperidin-2,6-dione (pale yellow solid, 5.0 mg, 5%). LC / MS (ESI) + ): calcd for C 25 H 22FN4O3([M+H) + )m / z 445.2, found 445.1. 1 H NMR (400MHz, DMSO-d6) δ10.97(s,1H),8.47(s,1H),7.79–7.70(m,1H),7.69–7.63(m,1H),7.54–7.42(m,2H),7.41–7.33(m,1H),7.14(d,J=7 .1Hz,1H),6.19(s,1H),6.14(s,1H),4.48–4.33(m,1H),2.88–2.73(m ,1H),2.70–2.64(m,2H),2.14(s,3H),2.04–2.00(m,1H),1.99(s,3H).

[0353] Example 49: 3-(1-(2-fluoro-5-(6-methyl-2-oxopyridin-1(2H)-yl)phenyl)-1H-indazol-4-yl)piperidin-2,6-dione

[0354] The target compound was prepared using a method similar to that in Example 48. LC / MS (ESI+) calcd for C 24 H 19 FN4O3([M+H) + )m / z 431.1; found 430.9. 1 H NMR (400MHz, DMSO-d6) δ10.97(s,1H),8.48(s,1H),7.75–7.67(m,2H),7.53–7.36(m,4H),7.14(d,J=7.1Hz,1H),6.37(d,J=9.1Hz,1H ),6.26(d,J=6.8Hz,1H),4.41(dd,J=9.6,6.2Hz,1H),2.76(d,J=12.0Hz,1H),2.59(d,J=17.4Hz,2H),2.16–2.09(m,1H),2.02(s,3H).

[0355] Example 50: 3-(1-(3-fluoro-5-(6-methyl-2-oxopyridin-1(2H)-yl)phenyl)-1H-indazol-4-yl)piperidin-2,6-dione

[0356] The target compound was prepared using a method similar to that in Example 48. LC / MS (ESI+) calcd for C 24 H 19 FN4O3([M+H) +)m / z 431.1; found 430.9. 1 H NMR (400MHz, DMSO-d6) δ10.97(s,1H),8.49(s,1H),7.85(d,J=8.6Hz,1H),7.80(dt,J=9 .9,2.2Hz,1H),7.63(s,1H),7.48(ddd,J=20.9,8.9,7.0Hz,2H),7.36(dt,J=9.0,2.1Hz ,1H),7.17(d,J=7.2Hz,1H),6.39(d,J=9.1Hz,1H),6.29(d,J=6.8Hz,1H),4.43(dd,J=1 2.3,4.9Hz,1H),2.81–2.73(m,1H),2.69–2.55(m,2H),2.16–2.09(m,1H),2.06(s,3H).

[0357] Example 51: 3-(1-(2-fluoro-5-(2-oxoquinoline-1(2H)-yl)phenyl)-1H-indazol-4-yl)piperidin-2,6-dione

[0358] The target compound was prepared using a method similar to that in Example 48. LC / MS (ESI+) calcd for C 27 H 19 FN4O3([M+H) + )m / z 467.1; found 466.9. 1 H NMR(400MHz,DMSO-d6)δ10.96(s,1H),8.48(s,1H),8.06(d,J=9.6Hz,1H),7.85–7.75 (m,3H),7.58(ddd,J=8.8,4.3,2.6Hz,1H),7.51–7.42(m,3H),7.28(t,J=7.2Hz,1H),7 .14(d,J=6.7Hz,1H),6.76(d,J=8.5Hz,1H),6.71(d,J=9.6Hz,1H),4.42(dd,J=12.2,4 .9Hz,1H),2.77(ddd,J=17.4,12.4,5.2Hz,1H),2.66–2.52(m,2H),2.17–2.08(m,1H).

[0359] Example 52: 3-(1-(3-(2-oxoquinoxalo-1(2H)-yl)phenyl)-1H-indazol-4-yl)piperidine-2,6-dione

[0360] The target compound was prepared using a method similar to that in Example 48. LC / MS (ESI+) calcd for C 26 H 19 N5O3([M+H)) + )m / z 450.1; found 449.9. 1 H NMR (400MHz, DMSO-d6) δ10.97(s,1H),8.47(s,1H),8.37(s,1H),8.04(ddd,J=8.2,2.2, 1.0Hz,1H),7.95–7.80(m,4H),7.54–7.45(m,3H),7.40(ddd,J=8.2,7.3,1.3Hz,1H),7. 14(d,J=7.1Hz,1H),6.80(dd,J=8.4,1.2Hz,1H),4.43(dd,J=12.2,4.8Hz,1H),2.78(dd d,J=17.4,12.4,5.3Hz,1H),2.59(dt,J=17.1,3.8Hz,2H),2.13(dt,J=13.0,3.9Hz,1H).

[0361] Example 53: 3-(1-(2-fluoro-5-(quinolin-2-yloxy)phenyl)-1H-indazol-4-yl)piperidine-2,6-dione

[0362] Step 1: Synthesis of 2-(3-bromo-4-fluorophenoxy)quinoline

[0363] 3-Bromo-4-fluorophenol (400 mg, 2.10 mmol) and 2-chloroquinoline (343 mg, 2.10 mmol) were dissolved in DMSO (5 mL) and reacted at 100 °C for 2 h. After the reaction was complete as monitored by TLC, it was cooled to room temperature, quenched with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, evaporated to dryness, and separated by column chromatography to obtain 412 mg of the target analyte, yield: 62%. LC / MS (ESI+) calcd for C 15 H9BrFNO([M+H) + )m / z 317.9; found 317.8.

[0364] Step 2: Synthesis of 3-(1-(2-fluoro-5-(quinolin-2-yloxy)phenyl)-1H-indazol-4-yl)piperidine-2,6-dione

[0365] 4-Hydroxy-1-(3-iodophenyl)-6-methylpyridin-2(1H)-one (63 mg, 0.20 mmol) was dissolved in dry DMSO (5 mL), and 3-(1H-indazol-4-yl)piperidin-2,6-dione (46 mg, 0.20 mmol), CuI (15 mg, 0.08 mmol), 2-pyridinecarboxylic acid (10 mg, 0.08 mmol), potassium phosphate (84 mg, 0.40 mmol) were added. The mixture was substituted with Ar three times, and the reaction was carried out at 130 °C for 3 h. After the reaction was complete as monitored by TLC, the mixture was cooled and filtered. The filtrate was quenched with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and evaporated to dryness. The crude product was separated by prep-TLC to obtain 13 mg of the target compound, yield: 14%. LC / MS (ESI+) calcd for C 27 H 19 FN4O3([M+H) + )m / z 467.1; found 466.9.

[0366] 1 H NMR (400MHz, DMSO-d6) δ10.96(s,1H),8.46(t,J=4.4Hz,2H),7.98(d,J=8.1Hz,1H),7.73–7.63(m,4H),7.54–7.43(m,4H),7.35 (d,J=8.8Hz,1H),7.13(dd,J=6.1,1.9Hz,1H),4.42(dd,J=12.2,4.9Hz,1H),2.82–2.74(m,1H),2.60(s,2H),2.16–2.08(m,1H).

[0367] Example 54: 3-(1-(3-(quinoxalo-2-yloxy)phenyl)-1H-indazol-4-yl)piperidine-2,6-dione

[0368] The target compound was prepared using a method similar to that in Example 53. LC / MS (ESI+) calcd for C 26 H 19 N5O3([M+H)) + )m / z 450.1; found 449.9. 1H NMR (400MHz, DMSO-d6) δ10.96(s,1H),8.94(s,1H),8.44(d,J=0.9Hz,1H),8.10(dd,J=7.6, 1.5Hz,1H),7.88(d,J=8.5Hz,1H),7.85(d,J=2.2Hz,1H),7.82–7.77(m,2H),7.75–7.72(m, 3H),7.47(dd,J=8.5,7.1Hz,1H),7.40(dt,J=7.1,2.1Hz,1H),7.13(d,J=7.2Hz,1H),4.42( dd,J=12.2,4.9Hz,1H),2.77(td,J=12.3,6.1Hz,1H),2.67–2.55(m,2H),2.17–2.08(m,1H).

[0369] Example 55: 3-(1-(3-(4-methoxy-6-methyl-2-oxopyridin-1(2H)-yl)phenyl)-1H-indazol-4-yl)piperidin-2,6-dione

[0370] Step 1: Synthesis of 1-(3-iodophenyl)-4-methoxy-6-methylpyridin-2(1H)-one

[0371] 250 mg (0.76 mmol) of 4-hydroxy-1-(3-iodophenyl)-6-methylpyridin-2(1H)-one was dissolved in acetone (10 mL), and KOH (86 mg, 1.53 mmol) was added. Dimethyl sulfate (193 mg, 1.53 mmol) was added dropwise at room temperature, and the reaction was carried out overnight at 50 °C. After the reaction was completed by TLC monitoring, it was cooled to room temperature, adjusted to weak acidity with dilute HCl, extracted with ethyl acetate, dried over anhydrous sodium sulfate, the solvent was removed by rotary evaporation, and the target analyte was separated by column chromatography to obtain 220 mg of the target analyte, yield: 82%. LC / MS (ESI+) calcd for C 13 H 12 INO2([M+H)) + )m / z 341.9; found 342.0.

[0372] Step 2: Synthesis of 3-(1-(3-(4-methoxy-6-methyl-2-oxopyridin-1(2H)-yl)phenyl)-1H-indazol-4-yl)piperidin-2,6-dione

[0373] 1-(3-iodophenyl)-4-methoxy-6-methylpyridin-2(1H)-one (68 mg, 0.20 mmol) was dissolved in dry DMSO (5 mL), and 3-(1H-indazol-4-yl)piperidin-2,6-dione (46 mg, 0.20 mmol), CuI (15 mg, 0.08 mmol), 2-pyridinecarboxylic acid (10 mg, 0.08 mmol), potassium carbonate (55 mg, 0.40 mmol) were added. The mixture was substituted with Ar three times, and the reaction was carried out at 110 °C for 1 h. After the reaction was complete as monitored by TLC, the mixture was cooled and filtered. The filtrate was quenched with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and evaporated to dryness. The crude product was separated by prep-TLC to obtain 20 mg of the target compound, yield: 22%. LC / MS (ESI+) calcd for C 25 H 22 N4O4([M+H)) + )m / z 443.2; found 443.1. 1 H NMR (400MHz, DMSO-d6) δ10.96(s,1H),8.45(s,1H),7.93–7.85(m,1H),7.78(d,J=8.5Hz,1H),7.72 (t,J=8.0Hz,1H),7.66(t,J=2.1Hz,1H),7.48(dd,J=8.5,7.1Hz,1H),7.28(dt,J=8.1,1.2Hz,1H),7 .14(d,J=7.1Hz,1H),6.07–6.01(m,1H),5.82(d,J=2.7Hz,1H),4.42(dd,J=12.3,4.8Hz,1H),3.78( s,3H),2.77(td,J=12.3,6.1Hz,1H),2.59(dt,J=17.0,3.8Hz,2H),2.17–2.08(m,1H),1.97(s,3H).

[0374] Example 56: 3-(1-(3-(quinoxalo-2-ylamino)phenyl)-1H-indazol-4-yl)piperidine-2,6-dione

[0375] The target compound was prepared using a method similar to that in Example 53. LC / MS (ESI+) calcd for C 26 H 20 N6O2([M+H)) + )m / z 449.1; found 449.1. 1H NMR (400MHz, DMSO-d6) δ10.99(s,1H),10.31(s,1H),8.84(t,J=2.1Hz,1H),8.62(s,1H),8.50–8.44( m,1H),8.07(d,J=8.5Hz,1H),7.90(dd,J=8.2,1.4Hz,1H),7.74(ddt,J=13.0,8.4,2.0Hz,3H),7.59( td,J=7.8,7.4,1.8Hz,2H),7.52(ddd,J=8.3,6.6,1.8Hz,1H),7.49–7.44(m,1H),7.18(d,J=7.1Hz,1 H),4.45(dd,J=12.2,4.9Hz,1H),2.84–2.76(m,1H),2.61(dt,J=17.0,3.7Hz,2H),2.19–2.13(m,1H).

[0376] Example 57: 3-(1-(3-(6-(cyclopropylmethyl)-2-oxopyridin-1(2H)-yl)phenyl)-1H-indazol-4-yl)piperidin-2,6-dione

[0377] Step 1: Synthesis of 1-(3-iodophenyl)-6-oxo-1,6-dihydropyridine-2-carboxaldehyde

[0378] 1-(3-Iodophenyl)-6-methylpyridin-2(1H)-one (500 mg, 1.60 mmol) was dissolved in 15 mL of dry 1,4-dioxane, and SeO2 (356 mg, 3.20 mmol) was added. The mixture was purged three times with Ar gas and stirred overnight at 100 °C. After the reaction was complete as monitored by TLC, the sample was directly mixed with silica gel and separated by column chromatography to obtain 500 mg of the target analyte, yield: 96%. LC / MS (ESI+) calcd for C 12 H8INO2([M+H) + )m / z 325.9; found 325.9.

[0379] Step 2: Synthesis of 6-(cyclopropyl(hydroxy)methyl)-1-(3-iodophenyl)pyridine-2(1H)-one

[0380] 1-(3-iodophenyl)-6-oxo-1,6-dihydropyridine-2-carboxaldehyde (250 mg, 0.77 mmol) was dissolved in 15 mL of dry THF. Under Ar protection, 1 M cyclopropylmagnesium bromide (1.15 mL, 1.15 mmol) was added dropwise at 0 °C, and the mixture was slowly heated to room temperature for 1 h. After the reaction was complete as monitored by TLC, the mixture was quenched with saturated NH4Cl solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and evaporated to dryness. The crude product was separated by column chromatography to obtain 180 mg of the target compound, yield: 64%. LC / MS (ESI+) calcd for C 15 H 14 INO2([M+H)) + )m / z 368.0; found 368.0.

[0381] Step 3: Synthesis of 6-(cyclopropylmethyl)-1-(3-iodophenyl)pyridine-2(1H)-one

[0382] 180 mg (0.49 mmol) of 6-(cyclopropyl(hydroxy)methyl)-1-(3-iodophenyl)pyridin-2(1H)-one was dissolved in 5 mL of TFA, and 1 mL of Et3SiH was added at 0 °C. The mixture was reacted overnight at 50 °C. After the reaction was complete, the solution was directly evaporated to dryness, mixed with silica gel, and separated by column chromatography to obtain 30 mg of the target compound, yield: 18%. LC / MS (ESI+) calcd for C 15 H 14 INO([M+H)) + )m / z 352.0; found 352.0.

[0383] Step 4: Synthesis of 3-(1-(3-(6-(cyclopropylmethyl)-2-oxopyridin-1(2H)-yl)phenyl)-1H-indazol-4-yl)piperidin-2,6-dione

[0384] 6-(cyclopropylmethyl)-1-(3-iodophenyl)pyridin-2(1H)-one (30 mg, 0.08 mmol) was dissolved in dry DMSO (3 mL), and 3-(1H-indazol-4-yl)piperidin-2,6-dione (20 mg, 0.08 mmol), CuI (8 mg, 0.04 mmol), 2-pyridinecarboxylic acid (5 mg, 0.04 mmol), potassium carbonate (23 mg, 0.17 mmol), and Ar was added three times for displacement. The reaction was carried out at 110 °C for 1 h. After the reaction was completed by TLC monitoring, the mixture was cooled and filtered. The filtrate was quenched with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and evaporated to dryness. The crude product was separated by prep-TLC to obtain 4 mg of the target compound, yield: 10%. LC / MS (ESI+) calcd for C 27 H 24N4O3([M+H)) + )m / z 453.2; found 453.0.

[0385] 1 H NMR(400MHz, DMSO-d6)δ10.95(s,1H),8.45(d,J=2.0Hz,1H),7.90(d,J=8.2Hz,1H),7.79–7.74(m,1H), 7.66(d,J=14.1Hz,1H),7.50(dt,J=15.9,9.1Hz,2H),7.32–7.21(m,2H),7.14(d,J=7.2Hz,1H),6.51–6. 37(m,2H),4.42(dd,J=12.2,4.8Hz,1H),2.79(td,J=12.1,6.1Hz,1H),2.58(d,J=20.9Hz,2H),2.45(d, J=6.6Hz,2H),2.16–2.09(m,1H),2.02(d,J=8.6Hz,1H),1.75–1.69(m,2H),1.65(dt,J=6.1,3.0Hz,2H).

[0386] Example 58: 3-(2-ethynyl-4'-(4-methyl-2-oxo-6-(trifluoromethyl)pyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0387] The target compound was prepared using a method similar to that of Example 29. LC / MS (ESI+) calcd for C 26 H 19 F3N2O3([M+H) + )m / z 465.1; found 465.1. 1 H NMR (400MHz, DMSO-d6) δ10.92(s,1H),7.66(d,J=8.0Hz,2H),7.49(t,J=7.7Hz,1H),7.39(d,J=8.9Hz,2H),7.37–7.33(m,2H),6.88(s,1H),6. 65(s,1H),4.39(s,1H),4.34(dd,J=11.3,4.8Hz,1H),2.80–2.73(m,1H ),2.57(s,1H),2.38(d,J=12.7Hz,1H),2.29(s,3H),2.10–2.05(m,1H).

[0388] Example 59: 3-(1-(2-fluoro-5-(4-methoxy-6-methyl-2-oxopyridin-1(2H)-yl)phenyl)-1H-indazol-4-yl)piperidin-2,6-dione

[0389] The target compound was prepared using a method similar to that in Example 48. LC / MS (ESI+) calcd for C 25 H 21 FN4O4([M+H) + )m / z 461.1; found 461.1. 1 H NMR(400MHz,DMSO-d6)δ10.96(s,1H),8.47(s,1H),7.71(d,J=9.4Hz,1H),7.67–7.64 (m,1H),7.47(dd,J=9.6,5.5Hz,2H),7.37(dd,J=8.8,3.0Hz,1H),7.14(d,J=7.0Hz,1H ),6.02(d,J=2.6Hz,1H),5.81(d,J=2.7Hz,1H),4.46–4.39(m,1H),3.76(s,3H),2.77( td,J=12.5,6.3Hz,1H),2.66–2.54(m,2H),2.14(dt,J=13.1,4.5Hz,1H),1.98(s,3H).

[0390] Example 60: 3-(1-(3-(4-methoxy-2-oxo-6-(trifluoromethyl)pyridin-1(2H)-yl)phenyl)-1H-indazol-4-yl)piperidin-2,6-dione

[0391] Step 1: Synthesis of 4-hydroxy-1-(3-iodophenyl)-6-(trifluoromethyl)pyridine-2(1H)-one

[0392] 2,2-Dimethyl-6-(3,3,3-trifluoro-2-oxopropyl)-4H-1,3-dioxin-4-one (4.76 g, 20.00 mmol) and 3-iodoaniline (5.26 g, 24.00 mmol) were dissolved in 1,4-dioxane (60 mL) and reacted at 90 °C for 3.5 h. The reaction solution was cooled to room temperature, and concentrated H₂SO₄ (2.94 g, 30.00 mmol) was slowly added dropwise with stirring. After the addition was complete, the reaction was continued at 90 °C for 2 h. After the reaction was complete, it was cooled to room temperature, quenched with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, the solvent was removed by rotary evaporation, and the target analyte was separated by column chromatography to obtain 764 mg of the target analyte, yield: 10%. LC / MS (ESI+) calcd for C 12H7F3INO2([M+H) + )m / z381.9; found 382.0.

[0393] Step 2: Synthesis of 1-(3-iodophenyl)-4-methoxy-6-(trifluoromethyl)pyridine-2(1H)-one

[0394] 300 mg (0.79 mmol) of 4-hydroxy-1-(3-iodophenyl)-6-(trifluoromethyl)pyridin-2(1H)-one was dissolved in 10 mL of acetone, and 88 mg (1.57 mmol) of KOH was added. Dimethyl sulfate (198 mg, 1.57 mmol) was added dropwise at room temperature, and the reaction was carried out at 50 °C for 2 h. After the reaction was completed by TLC monitoring, it was cooled to room temperature, adjusted to weak acidity with dilute HCl, extracted with ethyl acetate, dried over anhydrous sodium sulfate, the solvent was removed by rotary evaporation, and the target analyte was separated by column chromatography to obtain 193 mg of the target analyte, yield: 62%. LC / MS (ESI+) calcd for C 13 H9F3INO2([M+H) + )m / z 395.9; found 395.9.

[0395] Step 3: Synthesis of 3-(1-(3-(4-methoxy-2-oxo-6-(trifluoromethyl)pyridin-1(2H)-yl)phenyl)-1H-indazol-4-yl)piperidin-2,6-dione

[0396] 1-(3-iodophenyl)-4-methoxy-6-(trifluoromethyl)pyridin-2(1H)-one (79 mg, 0.20 mmol) was dissolved in dry DMSO (5 mL), and 3-(1H-indazol-4-yl)piperidin-2,6-dione (46 mg, 0.20 mmol), CuI (15 mg, 0.08 mmol), 2-pyridinecarboxylic acid (10 mg, 0.08 mmol), potassium carbonate (55 mg, 0.40 mmol) were added. The mixture was substituted with Ar three times, and the reaction was carried out at 110 °C for 1 h. After the reaction was complete as monitored by TLC, the mixture was cooled and filtered. The filtrate was quenched with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and evaporated to dryness. The crude product was separated by prep-TLC to obtain 17 mg of the target compound, yield: 17%. LC / MS (ESI+) calcd for C 25 H 19 F3N4O4([M+H) + )m / z 497.1; found 497.1. 1H NMR (400MHz, DMSO-d6) δ10.96(s,1H),8.45(s,1H),7.92(dd,J=8.0,2.2Hz,1H),7.81(d,J= 2.2Hz,1H),7.72(t,J=8.1Hz,2H),7.48(dd,J=8.6,7.1Hz,1H),7.36(d,J=7.8Hz,1H),7.14( d,J=7.1Hz,1H),6.72(d,J=2.6Hz,1H),6.23(d,J=2.6Hz,1H),4.43(dd,J=12.2,4.8Hz,1H), 3.87(s,3H),2.82–2.74(m,1H),2.58(dt,J=21.6,4.8Hz,2H),2.13(dt,J=13.3,4.4Hz,1H).

[0397] Example 61: 3-(1-(3-(2-oxo-1,8-naphthopyridin-1(2H)-yl)phenyl)-1H-indazol-4-yl)piperidin-2,6-dione

[0398] Step 1: Synthesis of intermediate 1-(3-iodophenyl)-1,8-naphthidium-2(1H)-one

[0399] Compound 1,8-naphthid-2(1H)-one (282 mg, 2.0 mmol), 3-iodophenylboronic acid (744 mg, 3.0 mmol), anhydrous copper acetate (145 mg, 0.8 mmol), and triethylamine (606 mg, 6.0 mmol) were dissolved in dichloromethane and reacted overnight at room temperature under an oxygen atmosphere. The reaction was monitored by TLC until the starting material was completely consumed. The mixture was filtered through diatomaceous earth, concentrated, and column chromatography to give 173 mg of the compound, in 25% yield.

[0400] Step 2: Synthesis of the target compound

[0401] Compounds 1-(3-iodophenyl)-1,8-naphthidium-2(1H)-one (70 mg, 0.2 mmol), 3-(1H-indazol-4-yl)piperidin-2,6-dione (46 mg, 0.2 mmol), cuprous iodide (15.2 mg, 0.08 mmol), 2-pyridinecarboxylic acid (10 mg, 0.08 mmol), and potassium carbonate (83 mg, 0.6 mmol) were dissolved in dimethyl sulfoxide and reacted at 110 °C for 1 hour under a nitrogen atmosphere. The mixture was filtered through diatomaceous earth, concentrated, and column chromatography was performed to give 12 mg of the target compound, in 13% yield. 1H NMR (400MHz, DMSO-d6) δ10.97 (s, 1H), 8.49-8.40 (m, 2H), 8.25 (dd, J=7.7, 1.9Hz, 1H), 8.10 (dd, J= 9.6,3.2Hz,1H),7.88(ddd,J=8.1,2.2,1.1Hz,1H),7.80-7.67(m,3H),7.46(dd,J=8.5,7.1Hz,1H) ,7.36-7.30(m,2H),7.12(dd,J=7.5,4.2Hz,1H),6.85-6.79(m,1H),4.42(dd,J=12.2,4.9Hz,1H), 2.92(dd,J=17.3,7.7Hz,1H),2.58(dd,J=16.9,4.0Hz,2H),2.17-2.07(m,1H).LC / MS(ESI+)calcd for C 26 H 20 N5O3([M+H)) + )m / z:450.2; found 450.1.

[0402] Example 62: 3-(7-fluoro-1-(3-(6-methyl-2-oxopyridin-1(2H)-yl)phenyl)-1H-indazol-4-yl)piperidin-2,6-dione

[0403] It was prepared using a method similar to that of Example 33. LC / MS (ESI+) calcd for C 24 H 19 FN4O3 + ([M+H)) + )m / z:431.1;found 431.1. 1 H NMR (400MHz, DMSO-d6) δ10.97(s,1H),8.53(d,J=2.2Hz,1H),7.78(dd,J=8.6,4.7Hz,1H),7. 72(q,J=8.4,7.9Hz,1H),7.60(q,J=3.1,2.5Hz,1H),7.43(dd,J=8.0,5.5Hz,1H),7.37–7.27( m,2H),7.08(dt,J=6.1,2.8Hz,1H),6.36(d,J=9.1Hz,1H),6.27(d,J=7.0Hz,1H),4.42(dd,J =12.6,4.7Hz,1H),2.87–2.66(m,2H),2.61(d,J=3.7Hz,1H),2.14–2.06(m,1H),2.00(s,3H).

[0404] Example 63: 3-(1-(3-(6-chloro-2-oxopyridin-1(2H)-yl)phenyl)-1H-indazol-4-yl)piperidin-2,6-dione

[0405] 1. Synthesis of compound 6-chloro-1-(3-iodophenyl)pyridin-2(1H)-one

[0406] Weigh 500 mg (3.86 mmol) of 6-chloropyridin-2(1H)-one, 1435 mg (5.79 mmol) of m-iodophenylboronic acid, 558 mg (1.54 mmol) of trifluoromethanesulfonate one, 179 mg (1.54 mmol) of TMEDA, and 904 mg (11.58 mmol) of pyridine into a round-bottom flask. Add 10 mL of 1,2-dichloroethane and perform a vacuum purging and oxygen purging operation three times. Heat the mixture in an oil bath at 50 °C. After 5 h, LC / MS showed that the starting materials were consumed. After the system cooled to room temperature, filter the mixture using diatomaceous earth. Wash the filter cake several times with dichloromethane. Combine the filtrates, remove the solvent by rotary evaporation to obtain the crude product, and purify by column chromatography to obtain the target compound 6-chloro-1-(3-iodophenyl)pyridin-2(1H)-one (35 mg), yield: 3%. LC / MS (ESI) + calcd for C 11 H7ClNO([M+H) + )m / z,331.9;found,331.9.

[0407] 2. Synthesis of compound 3-(1-(3-(6-chloro-2-oxopyridin-1(2H)-yl)phenyl)-1H-indazol-4-yl)piperidine-2,6-dione

[0408] Weigh 24 mg (0.11 mmol) of 3-(1H-indazol-4-yl)piperidin-2,6-dione, 35 mg (0.11 mmol) of 6-chloro-1-(3-iodophenyl)pyridin-2(1H)-one, 10 mg (0.05 mmol) of iodide ionone, 7 mg (0.05 mmol) of 2-pyridinecarboxylic acid, and 29 mg (0.21 mmol) of anhydrous potassium carbonate into a round-bottom flask. After purging with argon gas three times under vacuum, add 3 mL of dry DMSO. Purge with argon gas five times while stirring, then transfer the flask to an oil bath at 110 °C and heat to react. After 1 h, LCMS monitoring showed the starting material had disappeared. After the system cooled to room temperature, filter using diatomaceous earth. Wash the filter cake several times with ethyl acetate. The filtrates were combined, and water and ethyl acetate were added to complete the extraction. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation to obtain the crude product. Prep-TLC purification yielded the target compound 3-(1-(3-(6-chloro-2-oxopyridin-1(2H)-yl)phenyl)-1H-indazol-4-yl)piperidin-2,6-dione (9 mg). Yield: 20%. LC / MS (ESI) + calcd for C 23 H 17 ClN4O3([M+H) + )m / z,433.1;found,433.0. 1 H NMR (400MHz, DMSO-d6) δ10.97(s,1H),8.46(s,1H),7.92(d,J=8.0Hz,1H),7.78(dt,J=1 6.5,8.1Hz,3H),7.52(dt,J=22.3,8.2Hz,2H),7.38(d,J=7.7Hz,1H),7.14(d,J=7.0Hz, 1H),6.64(d,J=7.2Hz,1H),6.54(d,J=9.3Hz,1H),4.43(dd,J=12.0,4.4Hz,1H),2.78(d dd,J=17.0,11.9,4.2Hz,1H),2.65–2.55(m,1H),2.17–2.07(m,1H),2.04–1.93(m,1H).

[0409] Example 64: 1-(2-chloro-4'-(6-cyclopropyl-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)dihydropyrimidin-2,4(1H,3H)-dione

[0410] 1. Preparation of 1-(4-bromophenyl)-6-cyclopropyl-4-(trifluoromethyl)pyridine-2(1H)-one

[0411] 6-Cyclopropyl-4-(trifluoromethyl)pyridin-2(1H)-one (500 mg, 2.46 mmol) and 4-bromophenylboronic acid (542 mg, 2.71 mmol) were dissolved in 20 mL of DCE. Trifluoromethanesulfonate ketone (445 mg, 1.23 mmol) and pyridine (292 mg, 3.69 mmol) were added, followed by the addition of TMEDA (142 mg, 1.23 mmol). After oxygen replacement, the mixture was heated to 60 °C and reacted overnight. The mixture was filtered, extracted with 1 M dilute hydrochloric acid and DCM, and the organic phase was dried over anhydrous sodium sulfate. The solution was purified by silica gel column chromatography to obtain 350 mg of 1-(4-bromophenyl)-6-cyclopropyl-4-(trifluoromethyl)pyridin-2(1H)-one. LC / MS (ESI+) Calcd for C 15 H 11 BrF3NO(M+H + )m / z,358.0;found 358.0.

[0412] 2. Preparation of 6-cyclopropyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)-4-(trifluoromethyl)pyridin-2(1H)-one

[0413] 1-(4-bromophenyl)-6-cyclopropyl-4-(trifluoromethyl)pyridin-2(1H)-one (320 mg, 0.90 mmol) and pinacol diboronate (229 mg, 0.90 mmol) were dissolved in 5 mL of 1,4-dioxane, Pd(dppf)Cl2 (73 mg, 0.1 mmol) was added, followed by anhydrous potassium acetate (132 mg, 1.35 mmol). After purging with argon, the mixture was heated to 85 °C and reacted overnight. The mixture was extracted with water and EA, and the organic phase was dried over anhydrous sodium sulfate. The solution was purified by TLC to give 58 mg of 6-cyclopropyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)-4-(trifluoromethyl)pyridin-2(1H)-one. LC / MS (ESI+) Calcd for C 21 H 23 BF3NO3(M+H + )m / z,406.2;found 406.2.

[0414] 3. Preparation of 1-(2-chloro-4'-(6-cyclopropyl-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

[0415] It was prepared using a method similar to that in Example 63. After purification, 15 mg of 1-(2-chloro-4'-(6-cyclopropyl-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)dihydropyrimidin-2,4(1H,3H)-dione was obtained. LC / MS (ESI+) Calcd for C 25 H 19 ClF3N3O3(M+H + )m / z,502.1;found 502.1. 1 H NMR (400MHz, DMSO-d6) δ10.51(s,1H),7.66–7.45(m,7H),6.78(d,J=1.8Hz,1H),6.28(d,J=1.9Hz,1H),3.82–3.71(m,1H),3 .67(dt,J=12.4,6.3Hz,1H),2.80–2.72(m,2H),1.33(td,J=8.6,4.3Hz,1H),0.89(dt,J=6.1,3.1Hz,2H),0.75–0.67(m,2H).

[0416] Example 65: 1-(2-chloro-4'-(6-cyclopropyl-2-oxopyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

[0417] 1. Preparation of 2-cyclopropyl-6-methoxypyridine

[0418] 2-Bromo-6-methoxypyridine (5 g, 26.7 mmol) and cyclopropylboronic acid (2.5 g, 29.4 mmol) were dissolved in 50 mL of dioxane. XPos-Pd-G3 (2.5 g, 2.7 mmol) and potassium phosphate (11 g, 53.4 mmol) were added. After purging with argon, the mixture was heated to 100 °C and reacted overnight. The mixture was filtered, extracted with water and EA, and the organic phase was dried over anhydrous sodium sulfate. The solution was purified by silica gel column chromatography to obtain 850 mg of 2-cyclopropyl-6-methoxypyridine. LC / MS (ESI+) Calcd for C9H 11 NO(M+H + )m / z,150.1;found 150.1.

[0419] 2. Preparation of 6-cyclopropylpyridine-2(1H)-one

[0420] 2-Cyclopropyl-6-methoxypyridine (300 mg, 2.0 mmol) and sodium iodide (300 mg, 2.0 mmol) were dissolved in 5 mL of acetonitrile, and TMSCl (216 mg, 2.0 mmol) was added. The mixture was heated to reflux for 5 h. The reaction was quenched with saturated sodium thiosulfate aqueous solution, extracted with EA, and the organic phase was dried over anhydrous sodium sulfate. The solution was purified by TLC to give 168 mg of 6-cyclopropylpyridine-2(1H)-one. LC / MS (ESI+) Calcd for C8H9NO(M+H + )m / z,136.1;found 136.1.

[0421] The remaining steps are as described in Example 64. Purification yielded 22 mg of 1-(2-chloro-4'-(6-cyclopropyl-2-oxopyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)dihydropyrimidine-2,4(1H,3H)-dione. LC / MS (ESI+) Calcd for C 24 H 20 ClN3O3(M+H + )m / z,434.1;found 434.1. 1 H NMR (400MHz, DMSO-d6) δ10.51(s,1H),7.63–7.36(m,8H),6.40–6.32(m,1H),6.08(d,J=7.0Hz,1H),3.78(ddd,J=12.2,7.9,6.3Hz, 1H),3.67(dt,J=12.4,6.3Hz,1H),2.80–2.73(m,2H),1.28–1.22(m,1H),0.73(dt,J=5.5,2.7Hz,2H),0.66(dt,J=8.3,3.0Hz,2H).

[0422] Example 66: 1-(2-chloro-4'-(6-cyclopropyl-4-methyl-2-oxopyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

[0423] Prepared using a method similar to that of Example 63. LC / MS (ESI+) Calcd for C 25 H 22 ClN3O3(M+H + )m / z,448.1;found 448.1. 1H NMR(400MHz,DMSO-d6)δ10.51(s,1H),7.62–7.44(m,5H),7.40–7.33(m,2H), 6.19(t,J=1.5Hz,1H),5.97(d,J=1.7Hz,1H),3.78(ddd,J=12.2,7.8,6.3Hz, 1H),3.67(dt,J=12.4,6.3Hz,1H),2.80–2.72(m,2H),2.18–2.11(m,3H),1.2 8–1.21(m,1H),0.73(td,J=6.3,5.5,4.3Hz,2H),0.65(dt,J=8.6,3.2Hz,2H).

[0424] Example 67: 1-(2-chloro-4'-(4-methoxy-2-oxo-6-(trifluoromethyl)pyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

[0425] Prepared using a method similar to that of Example 63. LC / MS (ESI+) Calcd for C 23 H 17 ClF3N3O4(M+H + )m / z,492.1;found 492.1. 1 H NMR (400MHz, DMSO-d6) δ10.51(s,1H),7.64–7.45(m,5H),7.42(t,J=6.8Hz,2H),6.71(d,J=2.6Hz,1H),6.22(d, J=2.4Hz,1H),3.87(s,3H),3.77(ddd,J=12.3,7.7,6.5Hz,1H),3.67(dt,J=12.4,6.3Hz,1H),2.81–2.72(m,2H).

[0426] Example 68: 3-(2-ethynyl-4'-(4-methoxy-2-oxo-6-(trifluoromethyl)pyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0427] Step 1: Synthesis of 2,2-dimethyl-6-(3,3,3-trifluoro-2-oxopropyl)-4H-1,3-dioxin-4-one

[0428] 2,2,6-Trimethyl-4H-1,3-dioxane-4-one (20.31 g, 142.8 mmol) was dissolved in tetrahydrofuran (135 mL), and the solution was cooled to -78 °C. Bistrimethylsilylaminolithium (1.0 M, 160 mL) was added dropwise to the reaction solution. After the addition was complete, the reaction was stirred at -78 °C for 1 hour. A solution of trifluoroacetic anhydride (15 g, 71.43 mmol) in tetrahydrofuran (15 mL) was then added dropwise to the reaction solution, and the reaction was stirred at -78 °C for 16 hours. The reaction was quenched by adding 30 mL of saturated sodium bicarbonate solution to the reaction solution under ice bath conditions. The reaction solution was filtered, and the filtrate was purified by silica gel column chromatography, eluting with a dichloromethane / methanol system to obtain the target compound 2,2-dimethyl-6-(3,3,3-trifluoro-2-oxopropyl)-4H-1,3-dioxin-4-one (15.6 g, 63.4 mmol), yield: 44%. LC / MS (ESI+) calcd for C9H 10 F3O4([M+H)) + )m / z 239.05; found 239.1.

[0429] Step 2: Synthesis of 1-(4-bromophenyl)-4-hydroxy-6-(trifluoromethyl)pyridine-2(1H)-one

[0430] 2,2-Dimethyl-6-(3,3,3-trifluoro-2-oxopropyl)-4H-1,3-dioxin-4-one (4.76 g, 20.0 mmol) and p-bromoaniline (4.13 g, 24.0 mmol) were dissolved in 1,4-dioxane (60 mL), and the reaction mixture was heated to 90 °C and stirred for 3.5 h. Concentrated sulfuric acid (1.48 mL) was added to the reaction mixture, and the reaction was stirred at 90 °C for 1 h. Water (50 mL) was added to the reaction mixture, and the mixture was extracted three times with ethyl acetate. The organic phases were combined, concentrated, purified by silica gel column chromatography, and eluted with a petroleum ether / ethyl acetate system to give the target compound 1-(4-bromophenyl)-4-hydroxy-6-(trifluoromethyl)pyridin-2(1H)-one (2.01 g, 6.02 mmol), yield: 30%. LC / MS (ESI+) calcd for C 12 H8BrF3NO2([M+H) + )m / z 333.96; found 334.1.

[0431] Step 3: Synthesis of 1-(4-bromophenyl)-4-methoxy-6-(trifluoromethyl)pyridine-2(1H)-one

[0432] 1-(4-bromophenyl)-4-hydroxy-6-(trifluoromethyl)pyridin-2(1H)-one (2.01 g, 6.02 mmol), potassium hydroxide (0.75 g, 13.3 mmol), and dimethyl sulfate (1.68 g, 13.3 mmol) were dissolved in acetone (60 mL), and the reaction mixture was heated to 40 °C and stirred for 2 hours. After cooling to room temperature, the mixture was extracted three times with ethyl acetate, washed with saturated brine, and the organic phases were combined, concentrated, and purified by silica gel column chromatography. The purified compound was eluted with petroleum ether / ethyl acetate to give 1-(4-bromophenyl)-4-methoxy-6-(trifluoromethyl)pyridin-2(1H)-one (1.1 g, 3.16 mmol), yield: 52%. LC / MS (ESI+) calcd for C 13 H 10 BrF3NO2([M+H] + )m / z 347.98; found 348.1.

[0433] Steps four, five, and six: Synthesis of 3-(2-ethynyl-4'-(4-methoxy-2-oxo-6-(trifluoromethyl)pyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0434] It was prepared using a synthesis procedure similar to that of Example 15. 1 H NMR(400MHz,DMSO-d6)δ10.92(s,1H),7.69–7.62(m,2H),7.51–7.47(m,1H),7.4 1–7.32(m,4H),6.70(d,J=2.6Hz,1H),6.22(d,J=2.6Hz,1H),4.39(s,1H),4.33( dd,J=11.9,5.0Hz,1H),3.87(s,3H),2.76(ddd,J=17.5,12.6,5.3Hz,1H),2.56( m,1H),2.38(d,J=12.9Hz,1H),2.06(dd,J=10.6,5.9Hz,1H).LC / MS(ESI+)calcd for C 26 H 20 F3N2O4([M+H) + )m / z 481.1; found 481.1.

[0435] Example 69: 3-(2-ethynyl-4'-(4-methoxy-6-methyl-2-oxopyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0436] It was prepared using a synthesis procedure similar to that of Example 15.1 H NMR (400MHz, DMSO-d6) δ10.93(s,1H),7.72–7.63(m,2H),7.49(t,J=7.7Hz,1H),7.39(dd,J=7.8,1 .3Hz,1H),7.33(dd,J=7.8,1.3Hz,1H),7.31–7.27(m,2H),6.02(dd,J=2.7,1.0Hz,1H),5.80(d,J=2 .7Hz,1H),4.41(s,1H),4.34(dd,J=11.9,5.1Hz,1H),3.77(s,3H),2.76(ddd,J=17.5,12.6,5.3Hz, 1H),2.54–2.52(m,1H),2.38(d,J=13.0Hz,1H),2.12–2.02(m,1H),1.90(s,3H).LC / MS(ESI+)calcd for C 26 H 23 F2O4([M+H)) + )m / z 427.16; found 427.2.

[0437] Example 70: 3-(1-(3-(4-(dimethylamino)-2-oxo-6-(trifluoromethyl)pyridin-1(2H)-yl)phenyl)-1H-indazol-4-yl)piperidin-2,6-dione

[0438] Step 1: Synthesis of 4-chloro-1-(3-iodophenyl)-6-(trifluoromethyl)pyridin-2(1H)-one and 2-chloro-1-(3-iodophenyl)-6-(trifluoromethyl)pyridin-4(1H)-one

[0439] 200 mg (0.52 mmol) of 4-hydroxy-1-(3-iodophenyl)-6-(trifluoromethyl)pyridin-2(1H)-one was dissolved in 10 mL of POCl3 and reacted at 70 °C for 3 h. After the reaction was complete, the solvent was removed by rotary evaporation, the reaction solution was quenched in ice water, extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate. The solvent was removed by rotary evaporation, and the target analyte (50 mg) and its isomer (2-chloro-1-(3-iodophenyl)-6-(trifluoromethyl)pyridin-4(1H)-one) were separated by column chromatography, yielding 31% overall. LC / MS (ESI+) calcd for C 12 H6ClF3INO([M+H) + )m / z 399.9; found 399.9.

[0440] Step 2: Synthesis of 4-(dimethylamino)-1-(3-iodophenyl)-6-(trifluoromethyl)pyridine-2(1H)-one

[0441] 4-Chloro-1-(3-iodophenyl)-6-(trifluoromethyl)pyridin-2(1H)-one (50 mg, 0.13 mmol) was dissolved in DMF (8 mL), and Cs₂CO₃ (122 mg, 0.37 mmol) and dimethylamine hydrochloride (53 mg, 0.65 mmol) were added. The reaction was carried out overnight at 80 °C. After the reaction was monitored by TLC until complete, it was cooled to room temperature, quenched with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, the solvent was removed by rotary evaporation, and the target analyte was separated by column chromatography to obtain 35 mg of the target analyte, yield: 68%. LC / MS (ESI+) calcd for C 14 H 12 F3IN2O([M+H) + )m / z 408.9; found 409.0.

[0442] Step 3: Synthesis of 3-(1-(3-(4-(dimethylamino)-2-oxo-6-(trifluoromethyl)pyridin-1(2H)-yl)phenyl)-1H-indazol-4-yl)piperidin-2,6-dione

[0443] 4-(dimethylamino)-1-(3-iodophenyl)-6-(trifluoromethyl)pyridin-2(1H)-one (35 mg, 0.09 mmol) was dissolved in dry DMSO (3 mL), and 3-(1H-indazol-4-yl)piperidin-2,6-dione (20 mg, 0.09 mmol), CuI (9 mg, 0.05 mmol), 2-pyridinecarboxylic acid (6 mg, 0.05 mmol), potassium carbonate (37 mg, 0.27 mmol) were added. The mixture was substituted three times with Ar, and reacted at 110 °C for 1 h. After the reaction was complete as monitored by TLC, the mixture was cooled and filtered. The filtrate was quenched with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and evaporated to dryness. The crude product was separated by prep-TLC to obtain 15 mg of the target compound, yield: 34%. LC / MS (ESI+) calcd for C 26 H 22 F3N5O3([M+H) + )m / z 510.2; found 510.1. 1H NMR(400MHz,DMSO-d6)δ10.96(s,1H),8.44(d,J=0.9Hz,1H),7.92–7.85(m,1H),7.7 5–7.71(m,1H),7.68(d,J=8.5Hz,2H),7.48(dd,J=8.6,7.1Hz,1H),7.29(d,J=8.1Hz ,1H),7.13(d,J=7.1Hz,1H),6.69(d,J=2.7Hz,1H),5.53(d,J=2.7Hz,1H),4.42(dd, J=12.2,4.8Hz,1H),3.05(s,6H),2.81–2.74(m,1H),2.61(s,2H),2.17–2.10(m,1H).

[0444] Example 71: 3-(1-(3-(4-methyl-2-oxo-6-(2,2,2-trifluoroethoxy)pyridin-1(2H)-yl)phenyl)-1H-indazol-4-yl)piperidin-2,6-dione

[0445] Step 1: Synthesis of intermediate 6-chloro-1-(3-iodophenyl)-4-methylpyridin-2(1H)-one

[0446] Compound 6-chloro-4-methylpyridin-2-ol (7.15 g, 50 mmol), 3-iodophenylboronic acid (14.89 g, 60 mmol), copper trifluoromethanesulfonate (9.04 g, 25 mmol), TMEDA (2.91 g, 25 mmol), and pyridine (12 g, 150 mmol) were dissolved in hexafluoroisopropanol (150 mL) and reacted overnight at 60 °C in an oxygen atmosphere. The mixture was filtered through diatomaceous earth, concentrated, and column chromatography to give 1.18 g of the compound, in a 7% yield. LC / MS (ESI+) calcd for C 12 H 10 ClINO([M+H)) + )m / z:346.0; found 346.0.

[0447] Step 2: Synthesis of intermediate 1-(3-iodophenyl)-4-methyl-6-(2,2,2-trifluoroethoxy)pyridine-2(1H)-one

[0448] The compound 6-chloro-1-(3-iodophenyl)-4-methylpyridin-2(1H)-one (690 mg, 2.0 mmol) and sodium trifluoroethanol (2.48 g, 20 mmol) were dissolved in trifluoroethanol (15 mL) and reacted under microwave conditions at 120 °C for 15 min. The reaction was monitored by TLC until complete. The reaction was quenched with water, extracted with ethyl acetate, washed with water and saturated brine, and the organic phases were combined, dried, concentrated, and subjected to column chromatography to give 578 mg of the compound, with a yield of 71%. LC / MS (ESI+) calcd for C 14 H 12 F3INO2([M+H) + )m / z:410.0; found 409.9.

[0449] Part Three: Synthesis of the Target Compound

[0450] Compounds 1-(3-iodophenyl)-4-methyl-6-(2,2,2-trifluoroethoxy)pyridin-2(1H)-one (41 mg, 0.1 mmol), 3-(1H-indazol-4-yl)piperidin-2,6-dione (23 mg, 0.1 mmol), cuprous iodide (7.6 mg, 0.04 mmol), 2-pyridinecarboxylic acid (5 mg, 0.04 mmol), and potassium carbonate (42 mg, 0.3 mmol) were dissolved in dimethyl sulfoxide and reacted at 110 °C for 1 hour under a nitrogen atmosphere. The mixture was filtered through diatomaceous earth, concentrated, and column chromatography was performed to give 12 mg of the compound, in 23% yield. 1 H NMR (400MHz, DMSO-d6) δ10.96 (s, 1H), 8.44 (s, 1H), 7.84 (dd, J = 8.3, 2.2Hz, 1H), 7.79-7.62 (m, 3H), 7.4 6(dd,J=8.6,7.1Hz,1H),7.25(dd,J=8.0,2.0Hz,1H),7.13(d,J=7.1Hz,1H),6.07(t,J=1.3Hz,1H),5.94 (d,J=1.5Hz,1H),4.85(q,J=8.6Hz,2H),4.42(dd,J=12.2,4.9Hz,1H),2.78(ddd,J=17.2,12.3,5.2Hz,1 H),2.82-2.54(m,1H),2.49-2.43(m,1H),2.21(s,3H),2.13(dt,J=12.9,4.6Hz,1H).LC / MS(ESI+)calcd for C 26 H 21 F3N4O4([M+H) + )m / z:510.2; found 509.8.

[0451] Example 72: 3-(1-(3-(4-methyl-6-morpholin-2-oxopyridin-1(2H)-yl)phenyl)-1H-indazol-4-yl)piperidin-2,6-dione

[0452] Step 1: Synthesis of intermediate 1-(3-iodophenyl)-4-methyl-6-morpholinopyridine-2(1H)-one

[0453] Compound 6-chloro-1-(3-iodophenyl)-4-methylpyridin-2(1H)-one (172 mg, 0.5 mmol), morpholine (174 mg, 2.0 mmol), and cesium carbonate (656 mg, 2.0 mmol) were dissolved in DMF (2 mL) and reacted under microwave conditions at 130 °C for 1.5 h. The reaction was quenched with water, extracted with ethyl acetate, washed with water and saturated brine, the organic phases were combined, dried, concentrated, and column chromatography was performed to give 60 mg of the compound, in a yield of 30%. LC / MS (ESI+) calcd for C 16 H 18 IN₂O₂([M+H)) + )m / z:397.0; found 396.9.

[0454] Step 2: Synthesis of the target compound

[0455] Compounds 1-(3-iodophenyl)-4-methyl-6-morpholinopyridin-2(1H)-one (40 mg, 0.1 mmol), 3-(1H-indazol-4-yl)piperidin-2,6-dione (23 mg, 0.1 mmol), cuprous iodide (7.6 mg, 0.04 mmol), 2-pyridinecarboxylic acid (5 mg, 0.04 mmol), and potassium carbonate (42 mg, 0.3 mmol) were dissolved in dimethyl sulfoxide and reacted at 110 °C for 1 hour under a nitrogen atmosphere. The mixture was filtered through diatomaceous earth, concentrated, and column chromatography was performed to give 4 mg of the compound, in 8% yield. 1H NMR(400MHz, DMSO-d6)δ10.96(s,1H),8.43(d,J=0.9Hz,1H),7.83-7.76(m,2H),7.73(t,J=2.0Hz,1H), 7.68(t,J=8.0Hz,1H),7.47(dd,J=8.6,7.1Hz,1H),7.35(ddd,J=7.9,2.0,1.0Hz,1H),7.13(d,J=7.1Hz, 1H),6.08(t,J=1.4Hz,1H),5.83(d,J=1.7Hz,1H),4.42(dd,J=12.2,4.9Hz,1H),3.28-3.20(m,4H),2.86 -2.71(m,5H),2.63-2.55(m,1H),2.48-2.41(m,1H),2.17(s,3H),2.16-2.10(m,1H).LC / MS(ESI+)calcd for C 28 H 28 N5O4([M+H)) + )m / z:498.2; found 498.1.

[0456] Example 73: 3-(1-(3-(6-(4,4-difluoropiperidin-1-yl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)phenyl)-1H-indazol-4-yl)piperidin-2,6-dione

[0457] The synthesis was carried out using a method similar to that of Example 72. 1 H NMR (400MHz, DMSO-d6) δ10.96(s,1H),8.45(s,1H),7.94(s,1H),7.86(d,J=8.2Hz,1H),7.7 8(d,J=8.5Hz,1H),7.73(t,J=8.0Hz,1H),7.48(t,J=7.6Hz,2H),7.14(d,J=7.2Hz,1H),6.6 3(s,1H),6.20(d,J=1.9Hz,1H),4.42(dd,J=12.2,4.9Hz,1H),3.16-2.97(m,4H),2.84-2.7 2(m,1H),2.71-2.56(m,2H),2.14(d,J=11.5Hz,1H),1.66–1.52(m,4H).LC / MS(ESI+)calcd for C 29 H 25 F5N5O3([M+H) + )m / z:586.2; found 485.9.

[0458] Example 74: 3-(1-(3-(6-(4,4-difluoropiperidin-1-yl)-4-methyl-2-oxopyridin-1(2H)-yl)phenyl)-1H-indazol-4-yl)piperidin-2,6-dione

[0459] The synthesis was carried out using a method similar to that of Example 72. 1 H NMR(400MHz,DMSO-d6)δ10.96(s,1H),8.43(s,1H),7.85-7.72(m,3H),7.68(t,J=8.0Hz,1H ),7.47(dd,J=8.5,7.1Hz,1H),7.40-7.36(m,1H),7.13(d,J=7.1Hz,1H),6.09(d,J=1.5Hz,1 H),5.89(d,J=1.6Hz,1H),4.42(dd,J=12.2,4.8Hz,1H),3.02-2.89(m,4H),2.82-2.74(m,1H ),2.65-2.55(m,1H),2.48-2.40(m,1H),2.24-2.05(m,5H),1.59(s,4H).LC / MS(ESI+)calcd for C 29 H 28 F2N5O3([M+H) + )m / z:532.2;found 431.9.

[0460] Example 75: 3-(1-(3-(2-oxo-6-(2,2,2-trifluoroethoxy)-4-(trifluoromethyl)pyridin-1(2H)-yl)phenyl)-1H-indazol-4-yl)piperidin-2,6-dione

[0461] Step 1: Synthesis of intermediate 1-(3-iodophenyl)-6-(2,2,2-trifluoroethoxy)-4-(trifluoromethyl)pyridine-2(1H)-one

[0462] Sodium (230 mg, 10 mmol) was added to trifluoroethanol (5 mL) and stirred at room temperature for 1 hour. Then, 6-bromo-1-(3-iodophenyl)-4-(trifluoromethyl)pyridin-2(1H)-one (442 mg, 1.0 mmol) was added, and the reaction was carried out under microwave conditions at 120 °C for 1 hour, with TLC monitoring to ensure complete consumption of the starting material. The reaction was quenched with saturated ammonium chloride, extracted with ethyl acetate, washed with water and saturated brine, dried, and the organic layer was concentrated. Column chromatography yielded 382 mg of the compound, with a yield of 83%. LC / MS (ESI+) calcd for C 14 H9F6INO2([M+H)+ )m / z:464.0; found 463.8.

[0463] Step 2: Synthesis of the target compound 3-(1-(3-(2-oxo-6-(2,2,2-trifluoroethoxy)-4-(trifluoromethyl)pyridin-1(2H)-yl)phenyl)-1H-indazol-4-yl)piperidin-2,6-dione

[0464] Compounds 1-(3-iodophenyl)-6-(2,2,2-trifluoroethoxy)-4-(trifluoromethyl)pyridin-2(1H)-one (92 mg, 0.2 mmol), 3-(1H-indazol-4-yl)piperidin-2,6-dione (46 mg, 0.2 mmol), cuprous iodide (15.2 mg, 0.08 mmol), 2-pyridinecarboxylic acid (10 mg, 0.08 mmol), and potassium carbonate (83 mg, 0.6 mmol) were dissolved in dimethyl sulfoxide and reacted at 110 °C for 1 hour under a nitrogen atmosphere. The mixture was filtered through diatomaceous earth, concentrated, and column chromatography was performed to give 11 mg of the compound, in 10% yield. 1 H NMR (400MHz, DMSO-d6) δ10.96(s,1H),8.45(s,1H),7.96-7.87(m,1H),7.83(t,J=2.1Hz ,1H),7.81-7.70(m,2H),7.47(t,J=7.8Hz,1H),7.34(d,J=8.0Hz,1H),7.13(d,J=7.1Hz, 1H),6.65(s,1H),6.34(d,J=1.7Hz,1H),5.00(tq,J=8.7,4.9Hz,2H),4.42(dd,J=12.1, 4.8Hz,1H),2.81-2.73(m,1H),2.66-2.54(m,2H),2.18-2.06(m,1H).LC / MS(ESI+)calcd for C 26 H 19 F6N4O4([M+H) + )m / z:565.1; found 564.9.

[0465] Example 76: 3-(1-(3-(4-(difluoromethyl)-2-oxo-6-(2,2,2-trifluoroethoxy)pyridin-1(2H)-yl)phenyl)-1H-indazol-4-yl)piperidin-2,6-dione

[0466] Step 1: Synthesis of intermediate 6-chloro-1-(3-iodophenyl)-2-oxo-1,2-dihydropyridine-4-carboxaldehyde

[0467] 103 mg (3.0 mmol) of 6-chloro-1-(3-iodophenyl)-4-methylpyridin-2(1H)-one was dissolved in chlorobenzene (5 mL), and selenium dioxide (1.0 g, 9.0 mmol) was added. The mixture was reacted at 150 °C for 10 minutes under microwave conditions. The reactant was completely consumed by TLC. After diatomaceous earth filtration, the solution was concentrated and column chromatography was performed to give 812 mg of the compound, with a yield of 75%. LC / MS (ESI+) calcd for C 12 H8ClINO2([M+H) + )m / z:359.9; found 359.7.

[0468] Step 2: Synthesis of intermediate 6-chloro-4-(difluoromethyl)-1-(3-iodophenyl)pyridine-2(1H)-one

[0469] 6-Chloro-1-(3-iodophenyl)-2-oxo-1,2-dihydropyridine-4-carboxaldehyde (359 mg, 2.0 mmol) was dissolved in dichloromethane (10 mL), and DAST (644 mg, 4.0 mmol) was added. The reaction was carried out at room temperature for 1 hour. TLC monitoring showed complete consumption of the starting material. The reaction was quenched with water, extracted with dichloromethane, washed with water and saturated brine, dried, and the organic layer was concentrated. Column chromatography yielded 562 mg of the compound, with a yield of 74%. LC / MS (ESI+) calcd for C 12 H8ClF2INO([M+H) + )m / z:381.9; found 381.7.

[0470] The subsequent synthesis steps were carried out using a method similar to that in Example 71 to obtain the target compound. 1 H NMR (400MHz, CDCl3) δ8.14(s,1H),8.05(s,1H),7.86(d,J=8.0Hz,1H),7.75(d,J=8.5 Hz,1H),7.69(t,J=8.0Hz,1H),7.62(s,1H),7.43(t,J=7.8Hz,1H),7.22(d,J=7.8Hz,1 H),7.06(d,J=7.1Hz,1H),6.54(s,1H),6.46(t,J=7.8Hz,1H),4.40(q,J=7.5Hz,2H),4 .23(dd,J=10.0,5.3Hz,1H),2.91-2.69(m,2H),2.55-2.36(m,2H).LC / MS(ESI+)calcd for C 26 H 20 F5N4O4([M+H) + )m / z:547.1; found 546.9.

[0471] Example 77: 3-(1-(3-(4-(difluoromethyl)-6-morpholino-2-oxopyridin-1(2H)-yl)phenyl)-1H-indazol-4-yl)piperidin-2,6-dione

[0472] The synthesis was carried out using a method similar to that of Example 72.

[0473] 1 H NMR (400MHz, DMSO-d6) δ10.96(s,1H),8.44(s,1H),7.92-7.77(m,3H),7.71(t,J=8.0Hz,1H),7.48(d d,J=8.5,7.1Hz,1H),7.42(d,J=7.9Hz,1H),7.13(d,J=7.1Hz,1H),6.91(t,J=55.0Hz,1H),6.50-6.4 1(m,1H),6.02(d,J=1.7Hz,1H),4.42(dd,J=12.1,4.9Hz,1H),3.26(d,J=5.1Hz,4H),2.86(dq,J=12. 0,7.1,5.8Hz,4H),2.80-2.71(m,1H),2.67-2.53(m,2H),2.18-2.05(m,1H).LC / MS(ESI+)calcdforC 28 H 26 F2N5O4([M+H) + )m / z:534.2; found 534.1.

[0474] Example 78: 3-(1-(3-(4-(difluoromethyl)-6-(4,4-difluoropiperidin-1-yl)-2-oxopyridin-1(2H)-yl)phenyl)-1H-indazole-4-yl)piperidin-2,6-dione

[0475]

[0476] The synthesis was carried out using a method similar to that of Example 72. 1H NMR (400MHz, DMSO-d6) δ10.96 (s, 1H), 8.44 (s, 1H), 7.90 (d, J = 2.1Hz, 1H), 7.87-7.81 (m, 1H), 7.7 8(d,J=8.6Hz,1H),7.72(t,J=8.0Hz,1H),7.53-7.43(m,2H),7.13(d,J=7.1Hz,1H),6.90(t,J=55 .1Hz,1H),6.47(s,1H),6.09(d,J=1.7Hz,1H),4.42(dd,J=12.2,4.9Hz,1H),3.10-2.95(m,4H),2 .82-2.73(m,1H),2.70-2.58(m,2H),2.19-2.09(m,1H),1.69-1.50(m,4H).LC / MS(ESI+)calcdfor C 29 H 26 F4N5O3([M+H) + )m / z:568.2; found 568.1.

[0477] Example 79: 3-(4'-(6-(cyclopropylmethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-2-ethynyl-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0478] Step 1: Synthesis of intermediate 1-(4-bromophenyl)-6-methyl-4-(trifluoromethyl)pyridine-2(1H)-one

[0479] Compound 6-methyl-4-(trifluoromethyl)pyridin-2-ol (8.85 g, 50 mmol), 4-bromophenylboronic acid (14 g, 70 mmol), copper trifluoromethanesulfonate (7.23 g, 20 mmol), TMEDA (2.32 g, 20 mmol), and pyridine (12 g, 150 mmol) were dissolved in dichloroethane (100 mL) and reacted overnight at 60 °C in an oxygen atmosphere. The reaction was monitored by TLC until the starting material was completely consumed. After diatomaceous earth filtration, concentration, and column chromatography, 2.3 g of the compound was obtained, with a yield of 13.9%. LC / MS (ESI+) calcd for C 13 H 10 BrF3NO([M+H] + )m / z:332.0; found 331.9.

[0480] Step 2: Synthesize intermediate 1-(4-bromophenyl)-6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-2-carboxaldehyde

[0481] 1-(4-bromophenyl)-6-methyl-4-(trifluoromethyl)pyridin-2(1H)-one (993 mg, 3.0 mmol) was dissolved in chlorobenzene (10 mL), and selenium dioxide (1.0 g, 9.0 mmol) was added. The mixture was reacted at 150 °C for 10 minutes under microwave conditions. The reactant was completely consumed by TLC. After diatomaceous earth filtration, the solution was concentrated and column chromatography was performed to give 821 mg of the compound, with a yield of 79%. LC / MS (ESI+) calcd for C 13 H8BrF3NO2([M+H) + )m / z:346.0; found 345.9.

[0482] Step 3: Synthesis of intermediate 1-(4-bromophenyl)-6-(cyclopropyl(hydroxy)methyl)-4-(trifluoromethyl)pyridine-2(1H)-one

[0483] 1-(4-bromophenyl)-6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-2-carboxaldehyde (690 mg, 2.0 mmol) was dissolved in anhydrous tetrahydrofuran (10 mL), and cyclopropylmagnesium bromide (2.2 mL, 1.0 M) was added under ice bath conditions. The reaction was carried out at room temperature for 1 hour after the addition. TLC monitoring showed complete consumption of the starting material, and the reaction was quenched by saturated ammonium chloride. The mixture was extracted with ethyl acetate, washed with water and saturated brine, dried, and the organic phase was concentrated. Column chromatography yielded 581 mg of the compound, with a yield of 75%. LC / MS (ESI+) calcd for C 16 H 14 BrF3NO2([M+H] + )m / z:388.0; found 388.0.

[0484] Step 4: Synthesis of intermediate 6-(bromo(cyclopropyl)methyl)-1-(4-bromophenyl)-4-(trifluoromethyl)pyridine-2(1H)-one

[0485] 1-(4-bromophenyl)-6-(cyclopropyl(hydroxy)methyl)-4-(trifluoromethyl)pyridin-2(1H)-one (581 mg, 1.5 mmol) was dissolved in dichloromethane (10 mL), and phosphorus tribromide (813 mg, 3.0 mmol) was added under ice bath conditions. The reaction was maintained under ice bath conditions for 2 hours. TLC was used to monitor complete consumption of the starting material, and the reaction was quenched with saturated sodium bicarbonate. The mixture was extracted with dichloromethane, washed with water and saturated brine, dried, and the organic phase was concentrated. Column chromatography yielded 388 mg of the compound, with a yield of 57%. LC / MS (ESI+) calcd for C 16 H 13 Br2F3NO([M+H] + )m / z:451.9; found 451.7.

[0486] Step 5: Synthesis of intermediate 1-(4-bromophenyl)-6-(cyclopropylmethyl)-4-(trifluoromethyl)pyridine-2(1H)-one

[0487] 6-(bromo(cyclopropyl)methyl)-1-(4-bromophenyl)-4-(trifluoromethyl)pyridin-2(1H)-one (581 mg, 0.86 mmol) was dissolved in dimethyl sulfoxide (5 mL), and sodium borohydride (114 mg, 4.3 mmol) was added under ice bath conditions. The reaction was allowed to proceed overnight at room temperature. TLC monitoring showed complete consumption of the starting material, and the reaction was quenched by saturated ammonium chloride. The mixture was extracted with ethyl acetate, washed with water and saturated brine, dried, and the organic phase was concentrated. Column chromatography yielded 69 mg of the compound, with a yield of 22%. LC / MS (ESI+) calcd for C 16 H 14 BrF3NO([M+H] + )m / z:372.0; found 371.9.

[0488] The subsequent synthesis steps were carried out using a method similar to that in Example 15 to synthesize the target compound. 1 H NMR(400MHz, DMSO-d6)δ10.92(s,1H),7.74-7.65(m,2H),7.50(t,J=7.7Hz,1H),7.41(td,J=6.3,1.7Hz,3H), 7.34(dd,J=7.8,1.3Hz,1H),6.81(s,1H),6.63(d,J=2.0Hz,1H),4.40(s,1H),4.34(dd,J=11.9,5.3Hz,1H),2 .76(ddd,J=17.5,12.5,5.3Hz,1H),2.63-2.53(m,1H),2.41-2.31(m,1H),2.20(d,J=6.9Hz,2H),2.08(dq,J= 8.4,4.4Hz,1H),0.82(ddd,J=12.8,7.7,5.3Hz,1H),0.53-0.44(m,2H),0.13-0.03(m,2H).LC / MS(ESI+)calcd for C 29 H 24 F3N2O3([M+H) + )m / z:505.2; found 505.1.

[0489] Example 80: 3-(1-(3-(6-(3,3-difluoropyrrolidone-1-yl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)phenyl)-1H-indazol-4-yl)piperidin-2,6-dione

[0490] The synthesis was carried out using a method similar to that of Example 72. 1 H NMR (400MHz, DMSO-d6) δ10.96(s,1H),8.46(s,1H),7.93-7.85(m,2H),7.79(d,J=8.6Hz,1H),7.74(t ,J=8.0Hz,1H),7.48(dd,J=8.6,7.1Hz,1H),7.40(dt,J=8.1,1.2Hz,1H),7.14(d,J=7.2Hz,1H),6.34( d,J=1.6Hz,1H),5.96(d,J=1.8Hz,1H),4.42(dd,J=12.2,4.9Hz,1H),3.29-3.12(m,4H),2.82-2.74(m ,1H),2.61-2.57(m,1H),2.46–2.44(m,1H),2.31–2.20(m,2H),2.19-2.08(m,1H).LC / MS(ESI+)calcd for C 29 H 26 F4N5O3([M+H) + )m / z:572.2; found 572.0.

[0491] Example 81: 3-(4'-(4-(difluoromethyl)-6-morpholino-2-oxopyridin-1(2H)-yl)-2-ethynyl-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0492] Step 1: Synthesis of intermediate 1-(4-bromophenyl)-4-(difluoromethyl)-6-morpholinpyridine-2(1H)-one

[0493] Compound 1-(4-bromophenyl)-6-chloro-4-(difluoromethyl)pyridin-2(1H)-one (333 mg, 1.0 mmol), morpholine (261 mg, 3.0 mmol), and DIPEA (390 mg, 3.0 mmol) were dissolved in dimethyl sulfoxide (5 mL) and reacted under microwave conditions at 130 °C for 1 h. The reaction was monitored by TLC until complete. The reaction was quenched with water, extracted with ethyl acetate, washed with water and saturated brine, and the organic layer was concentrated. Column chromatography was performed to give 260 mg of the compound, in a yield of 68%. LC / MS (ESI+) calcd for C 11 H9IN([M+H) + )m / z:385.0; found 385.0.

[0494] The target compound was then synthesized using a method similar to that in Example 15. 1H NMR (400MHz, DMSO-d6) δ10.92(s,1H),7.61(d,J=7.9Hz,2H),7.49(t,J=7.7Hz,1H ),7.46-7.31(m,4H),6.90(t,J=55.1Hz,1H),6.47-6.40(m,1H),5.98(d,J=1.7Hz, 1H),4.42-4.31(m,2H),3.24(t,J=4.5Hz,4H),2.82(t,J=4.5Hz,4H),2.79-2.70(m ,1H),2.58-2.56(m,1H),2.44-2.31(m,1H),2.12-2.02(m,1H).LC / MS(ESI+)calcd for C 29 H 26 F4N5O3([M+H) + )m / z:518.2; found 518.1.

[0495] Example 82: 3-(1-(3-(4-methyl-2-oxo-6-phenylpyridin-1(2H)-yl)phenyl)-1H-indazol-4-yl)piperidin-2,6-dione

[0496] Step 1: Synthesis of 3-(1-(3-(6-chloro-4-methyl-2-oxopyridin-1(2H)-yl)phenyl)-1H-indazol-4-yl)piperidine-2,6-dione

[0497] The target compound was prepared using a method similar to that in Example 71. LC / MS (ESI+) calcd for C 24 H 20 ClN4O3(M+H + )m / z,447.1;found,447.1.

[0498] Step 2: Synthesis of 3-(1-(3-(4-methyl-2-oxo-6-phenylpyridin-1(2H)-yl)phenyl)-1H-indazol-4-yl)piperidine-2,6-dione

[0499] Compound 3-(1-(3-(6-chloro-4-methyl-2-oxopyridin-1(2H)-yl)phenyl)-1H-indazol-4-yl)piperidin-2,6-dione (20 mg, 0.04 mmol), phenylboronic acid (10 mg, 0.08 mmol), and NaHCO3 (7 mg, 0.08 mmol) were added to a mixture of 4 mL of 1,4-dioxane and 1 mL of water. The mixture was stirred overnight at 80 °C. Water was added, and the mixture was extracted three times by EA extraction. The combined organic phases were washed with saturated NaCl solution, dried over anhydrous sodium sulfate, and subjected to rotary evaporation and column chromatography to obtain the target compound (3 mg, 15% yield). LC / MS (ESI+) calcd for C 30 H 25 N4O3(M+H + )m / z,489.2;found,489.2. 1 H NMR (400MHz, DMSO-d6) δ10.93 (s, 1H), 8.37 (s, 1H), 7.58 (dd, J = 7.5, 1.2Hz, 2H), 7. 49–7.38(m,3H),7.32–7.22(m,6H),7.17(dt,J=8.0,1.4Hz,1H),7.10(d,J=7.1Hz,1 H),6.39(t,J=1.5Hz,1H),6.24(d,J=1.8Hz,1H),4.39(dd,J=12.2,4.9Hz,1H),2.6 7(p,J=1.9Hz,1H),2.62–2.52(m,2H),2.33(p,J=1.9Hz,1H),2.25(d,J=1.1Hz,3H).

[0500] Example 83: 1-(2-chloro-4'-(4-methyl-2-oxo-6-(2,2,2-trifluoroethoxy)pyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

[0501] The target compound was prepared using a method similar to that of Example 28. LC / MS (ESI+) calcd for C 24 H 20 ClF3N3O4(M+H + )m / z,506.1;found,506.1. 1H NMR (400MHz, DMSO-d6) δ10.51(s,1H),7.58–7.49(m,4H),7.45(dd,J=7.3,2.1Hz,1H),7.33–7.26(m,2H),6.06(t,J=1.3Hz,1H),5.92(d,J =1.5Hz,1H),4.83(q,J=8.5Hz,2H),3.78(dt,J=12.3,7.1Hz,1H),3.67(dt,J=12.4,6.3Hz,1H),2.76(t,J=6.7Hz,2H),2.24–2.17(m,3H).

[0502] Example 84: 3-(1-(3-(4-methyl-2-oxo-6-(piperidin-1-yl)pyridin-1(2H)-yl)phenyl)-1H-indazol-4-yl)piperidin-2,6-dione

[0503] The target compound was prepared using a method similar to that in Example 72. LC / MS (ESI+) calcd for C 29 H 30 N5O3(M+H + )m / z,496.2; found,496.2. 1 H NMR(400MHz, DMSO-d6)δ10.97(s,1H),8.43(d,J=0.9Hz,1H),7.80–7.75(m,2H),7.71–7.64( m,2H),7.47(dd,J=8.5,7.1Hz,1H),7.31(ddd,J=7.9,1.9,1.0Hz,1H),7.13(d,J=7.1Hz,1H), 6.03(t,J=1.3Hz,1H),5.77(d,J=1.7Hz,1H),4.42(dd,J=12.2,4.9Hz,1H),2.85–2.70(m,6H) ,2.69–2.59(m,1H),2.16(q,J=2.3Hz,3H),2.00(q,J=7.0,6.6Hz,1H),1.25(d,J=9.7Hz,6H).

[0504] Example 85: 3-(1-(3-(6-(3-azabicyclo[3.1.0]hexane-3-yl)-4-methyl-2-oxopyridin-1(2H)-yl)phenyl)-1H-indazol-4-yl)piperidin-2,6-dione

[0505] Step 1: Synthesis of 6-(3-azabicyclo[3.1.0]hexane-3-yl)-1-(3-iodophenyl)-4-methylpyridin-2(1H)-one

[0506] Compound 6-chloro-1-(3-iodophenyl)-4-methylpyridin-2(1H)-one (300 mg, 0.87 mmol), 3-azabicyclo[3.1.0]hexane hydrochloride (145 mg, 1.74 mmol), DIEA (224 mg, 1.74 mmol), and Cs₂CO₃ (567 mg, 1.74 mmol) were added to 4 mL of DMAc and stirred at 130 °C for 4 h. Water was added, and the mixture was extracted three times with EA. The organic phases were combined, washed with saturated NaCl solution, dried over anhydrous sodium sulfate, and subjected to rotary evaporation and column chromatography to obtain the target compound (90 mg, 26% yield). LC / MS (ESI+) calcd for C 17 H 18 IN2O(M+H + )m / z,393.1;found,393.1.

[0507] Step 2: Synthesis of 3-(1-(3-(6-(3-azabicyclo[3.1.0]hexane-3-yl)-4-methyl-2-oxopyridin-1(2H)-yl)phenyl)-1H-indazol-4-yl)piperidine-2,6-dione

[0508] The target compound was prepared using a method similar to that in Example 72. LC / MS (ESI+) calcd for C 29 H 28 N5O3(M+H + )m / z,494.2; found,494.2. 1 H NMR(400MHz,DMSO-d6)δ10.96(s,1H),8.44(s,1H),7.84–7.77(m,2H),7.71–7.6 3(m,2H),7.48(dd,J=8.6,7.1Hz,1H),7.21(dt,J=7.3,1.2Hz,1H),7.14(d,J=7. 2Hz,1H),5.89(t,J=1.3Hz,1H),5.72(d,J=1.6Hz,1H),4.42(dd,J=12.2,4.9Hz, 1H),3.03–2.84(m,5H),2.84–2.72(m,2H),2.17–2.09(m,5H),1.40–1.27(m,3H).

[0509] Example 86: 1-(2-chloro-4'-(4-(difluoromethyl)-2-oxo-6-(2,2,2-trifluoroethoxy)pyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

[0510] The target compound was prepared using a method similar to that in Example 83. LC / MS (ESI+) calcd for C 26 H 20 N5O3(M+H + )m / z,542.1;found,542.1. 1 H NMR (400MHz, DMSO-d6) δ10.50(s,1H),7.59–7.54(m,3H),7.54–7.50(m,1H),7.46(dd,J=7.4,2.0Hz,1H),7.38(dq,J=9.4,3.0,2.3Hz,2H),7.09(d, J=14.5Hz,1H),6.46(d,J=1.5Hz,1H),6.17(d,J=1.5Hz,1H),5.32(t,J=4. 9Hz, 1H), 4.95 (q, J = 8.5Hz, 2H), 2.77 (t, J = 6.7Hz, 2H), 2.04–1.96 (m, 2H).

[0511] Example 87: 3-(1-(3-(6-(3,3-difluoropiperidin-1-yl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)phenyl)-1H-indazol-4-yl)piperidin-2,6-dione

[0512] The target compound was prepared using a method similar to that in Example 72. LC / MS (ESI+) calcd for C 29 H 25 F5N5O3(M+H + )m / z,586.2;found,586.2. 1H NMR (400MHz, DMSO-d6) δ10.96(s,1H),8.43(s,1H),7.89(t,J=2.1Hz,1H),7.85–7.76(m,2H ),7.69(t,J=8.1Hz,1H),7.46(dd,J=8.6,7.1Hz,1H),7.38–7.34(m,1H),7.13(d,J=7.1Hz,1 H),6.66(s,1H),6.20(d,J=1.9Hz,1H),4.42(dd,J=12.2,4.9Hz,1H),3.02–2.71(m,7H),2. 67(p,J=1.9Hz,1H),2.63–2.55(m,2H),2.33(p,J=1.9Hz,1H),2.13(dt,J=12.8,4.2Hz,2H).

[0513] Example 88: 3-(1-(3-(6-(cyclopentoxy)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)phenyl)-1H-indazol-4-yl)piperidin-2,6-dione

[0514] Step 1: Synthesis of 6-(cyclopentoxy)-1-(3-iodophenyl)-4-(trifluoromethyl)pyridin-2(1H)-one

[0515] Cyclopentanol (43 mg, 0.50 mmol) was dissolved in 3 mL of anhydrous THF. NaH (30 mg, 0.75 mmol) was added under ice bath conditions, and stirring was continued for 30 min. Then, 6-chloro-1-(3-iodophenyl)-4-(trifluoromethyl)pyridin-2(1H)-one (100 mg, 0.25 mmol) was added. The ice bath was removed, and the mixture was stirred at room temperature for 2 h. Water was added, and the mixture was extracted three times with EA. The organic phases were combined, washed with saturated NaCl solution, dried over anhydrous sodium sulfate, and subjected to rotary evaporation and column chromatography to obtain the target compound (105 mg, 93% yield). LC / MS (ESI+) calcd for C 17 H 16 F3INO2(M+H + )m / z,450.1;found,450.1.

[0516] Step 2: Synthesis of 3-(1-(3-(6-(cyclopentoxy)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)phenyl)-1H-indazol-4-yl)piperidine-2,6-dione

[0517] The target compound was prepared using a method similar to that in Example 71. LC / MS (ESI+) calcd for C 29 H26 F3N4O4(M+H + )m / z,551.2;found,551.2. 1 H NMR(400MHz,DMSO-d6)δ10.96(s,1H),8.44(s,1H),7.88–7.83(m,1H),7.79–7.67(m,3H),7.46(dt ,J=7.4,6.1Hz,1H),7.32–7.26(m,1H),7.13(d,J=7.1Hz,1H),6.47(s,1H),6.08(d,J=1.8Hz,1H),5 .11(s,1H),4.42(dd,J=12.2,4.8Hz,1H),2.96(s,1H),2.78(ddd,J=17.2,12.3,5.2Hz,1H),2.69–2 .59(m,1H),2.21–2.07(m,1H),2.00(q,J=7.0Hz,1H),1.83–1.70(m,2H),1.62(m,2H),1.44(m,3H).

[0518] Example 89: 3-(1-(3-(6-(cyclopentoxy)-4-(difluoromethyl)-2-oxopyridin-1(2H)-yl)phenyl)-1H-indazol-4-yl)piperidin-2,6-dione

[0519] The target compound was prepared using a method similar to that in Example 88. LC / MS (ESI+) calcd for C 29 H 27 F2N4O4(M+H + )m / z,533.2;found,533.2. 1H NMR (400MHz, DMSO-d6) δ10.96(s,1H),8.44(s,1H),7.84(dd,J=8.1,2.2Hz,1H),7.75(d,J=8.6Hz,1H), 7.72–7.66(m,2H),7.47(dd,J=8.5,7.1Hz,1H),7.28–7.24(m,1H),7.13(d,J=7.1Hz,1H),6.31–6.29(m, 1H), 5.95 (d, J=1.6Hz, 1H), 5.02 (tt, J=5.4, 2.3Hz, 2H), 4.42 (dd, J=12.2, 4.9Hz, 1H), 2.78 (ddd, J=17. 2,12.3,5.1Hz,2H),2.69–2.55(m,2H),2.21–2.08(m,2H),2.03–1.98(m,1H),1.77(m,3H),1.62(m,3H).

[0520] Example 90: 1-(2-chloro-4'-(4-methyl-2-oxo-6-(2,2,2-trifluoroethyl)pyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

[0521] 1. Synthesis of 1-(4-bromophenyl)-4-methyl-6-(2,2,2-trifluoro-1-hydroxyethyl)pyridine-2(1H)-one

[0522] 1-(4-bromophenyl)-4-methyl-6-oxo-1,6-dihydropyridine-2-carboxaldehyde (2 g, 6.8 mmol) and TMSCF3 (1.5 g, 10.2 mmol) were added to 20 mL of tetrahydrofuran, followed by TBAF (1.4 mL, 1 M, 1.4 mmol). The mixture was stirred at room temperature for 16 h. Ethyl acetate and water were added, and the mixture was extracted. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, evaporated to dryness, and purified by silica gel column chromatography. The yield was 1-(4-bromophenyl)-4-methyl-6-(2,2,2-trifluoro-1-hydroxyethyl)pyridine-2(1H)-one (1.2 g, 3.3 mmol), 48%.

[0523] 2. Synthesis of 1-(4-bromophenyl)-4-methyl-6-(2,2,2-trifluoroethyl)pyridine-2(1H)-one

[0524] 1-(4-bromophenyl)-4-methyl-6-(2,2,2-trifluoro-1-hydroxyethyl)pyridin-2(1H)-one (600 mg, 1.6 mmol) and N,N'-thiocarbonyldiimidazole (353 mg, 2 mmol) were added to 10 mL of THF, followed by DMAP (20 mg, 0.1 mmol). The mixture was heated to 60 °C and stirred for 2 h. After cooling to room temperature, ethyl acetate and water were added, and the mixture was extracted. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, evaporated to dryness, and purified by silica gel column chromatography. 150 mg of the intermediate was obtained. Under nitrogen protection, 5 mL of toluene was added to the intermediate, followed by DMAP (10 mg). The mixture was heated to 80 °C and stirred for 20 min. After cooling to room temperature, ethyl acetate and water were added, and the mixture was extracted. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, evaporated to dryness, and purified by silica gel column chromatography. 1-(4-bromophenyl)-4-methyl-6-(2,2,2-trifluoroethyl)pyridin-2(1H)-one (37 mg, 0.1 mmol) was obtained in 6% yield.

[0525] 3. Synthesis of 4-methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)-6-(2,2,2-trifluoroethyl)pyridin-2(1H)-one

[0526] Under nitrogen protection, 1-(4-bromophenyl)-4-methyl-6-(2,2,2-trifluoroethyl)pyridin-2(1H)-one (37 mg, 0.1 mmol), bipinacol borate (30 mg, 0.11 mmol), potassium acetate (31 mg, 0.3 mmol), and Pd(dppf)Cl2 (8 mg, 0.01 mmol) were added to 3 mL of anhydrous dioxane. The mixture was heated to 90 °C and stirred for 16 h. After cooling to room temperature, ethyl acetate and water were added, and the mixture was extracted. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness to give crude 4-methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)-6-(2,2,2-trifluoroethyl)pyridin-2(1H)-one (40 mg, 0.1 mmol), in 100% yield.

[0527] 4. Synthesis of 1-(2-chloro-4'-(4-methyl-2-oxo-6-(2,2,2-trifluoroethyl)pyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

[0528] Under nitrogen protection, 4-methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborin-2-yl)phenyl)-6-(2,2,2-trifluoroethyl)pyridin-2(1H)-one (40 mg, 0.1 mmol), 1-(3-bromo-2-chlorophenyl)dihydropyrimidine-2,4(1H,3H)-dione (31 mg, 0.1 mmol), sodium bicarbonate (26 mg, 0.3 mmol), and Pd(dppf)Cl2 (8 mg, 0.01 mmol) were added to 3 mL of anhydrous dioxane and 0.5 mL of water. The mixture was heated to 90 °C and stirred for 3 h. After cooling to room temperature, ethyl acetate and water were added, and the mixture was extracted. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness to prepare purified saturated plates. 1-(2-chloro-4'-(4-methyl-2-oxo-6-(2,2,2-trifluoroethyl)pyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)dihydropyrimidin-2,4(1H,3H)-dione (12 mg, 0.02 mmol) was obtained in 24% yield. LC / MS (ESI+) calcd for C 24 H 20 ClF3N3O3 + ([M+H)) + )m / z:490.1; found 490.1. 1 H NMR (400MHz, DMSO-d6) δ10.52(s,1H),7.65–7.60(m,2H),7.58–7.53(m,2H),7.52–7.48(m,1H),7.34(dd,J=8.4,1.9Hz,2H),6.40–6.36(m, 1H), 6.33 (d, J = 6.0Hz, 1H), 3.78 (dt, J = 12.2, 7.1Hz, 1H), 3.68 (q, J = 6.2Hz, 1H), 3.43 (q, J = 10.6Hz, 2H), 2.77 (t, J = 6.7Hz, 2H), 2.22 (s, 3H).

[0529] Example 91: 1-(2-chloro-4'-(4-methyl-2-oxo-6-(3,3,3-trifluoropropyl)pyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

[0530] The synthesis of the raw materials is described in Example 132. Under nitrogen protection, 4-methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)-6-(3,3,3-trifluoropropyl)pyridin-2(1H)-one (27 mg, 0.06 mmol), 1-(3-bromo-2-chlorophenyl)dihydropyrimidine-2,4(1H,3H)-dione (20 mg, 0.06 mmol), sodium bicarbonate (15 mg, 0.18 mmol), and Pd(dppf)Cl2 (6 mg, 0.01 mmol) were added to 3 mL of anhydrous dioxane and 0.5 mL of water. The mixture was heated to 90 °C and stirred for 3 h. After cooling to room temperature, ethyl acetate and water were added, and the mixture was extracted. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness to prepare purified saturated plates. 1-(2-chloro-4'-(4-methyl-2-oxo-6-(3,3,3-trifluoropropyl)pyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)dihydropyrimidin-2,4(1H,3H)-dione (12 mg, 0.02 mmol) was obtained in 36% yield. LC / MS (ESI+) calcd for C 25 H 22 F3ClN3O3 + ([M+H)) + )m / z:504.1; found 504.1. 1 H NMR (400MHz, DMSO-d6) δ10.51(s,1H),7.63–7.58(m,2H),7.58–7.50(m,2H),7.47(dd,J=7.3,2.1Hz,1H),7.43–7.38(m,2H),6.25(dd,J=5. 4,1.5Hz,2H),3.77(dt,J=12.3,7.1Hz,1H),3.67(dt,J=12.4,6.3Hz,1H),2.76(t,J=6.7Hz,2H),2.48–2.33(m,4H),2.18(d,J=1.1Hz,3H).

[0531] Example 92: 1-(4'-(6-(3-azabicyclo[3.1.0]hexane-3-yl)-4-(difluoromethyl)-2-oxopyridin-1(2H)-yl)-2-chloro-[1,1'-biphenyl]-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

[0532] It was prepared using a method similar to that of Example 83. LC / MS (ESI+) calcd for C 27 H 24 F2ClN4O3 + ([M+H))+ )m / z:525.1; found 525.1. 1 H NMR (400MHz, DMSO-d6) δ10.51(s,1H),7.59–7.47(m,5H),7.37(d,J=8.7Hz,2H),6.82( t,J=55.3Hz,1H),6.17(d,J=1.6Hz,1H),5.86(d,J=1.7Hz,1H),3.78(ddd,J=12.3,7.6 ,6.5Hz,1H),3.67(dt,J=12.4,6.3Hz,1H),3.03–2.92(m,2H),2.86(dd,J=9.3,3.1Hz, 2H),2.76(t,J=6.5Hz,2H),1.42–1.34(m,2H),0.37–0.28(m,1H),0.02–-0.07(m,1H).

[0533] Example 93: 3-(4'-(6-(3-azabicyclo[3.1.0]hexane-3-yl)-4-(difluoromethyl)-2-oxopyridin-1(2H)-yl)-2-ethynyl-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0534] It was prepared using a method similar to that of Example 81. LC / MS (ESI+) calcd for C 30 H 26 F2N3O3 + ([M+H)) + )m / z:514.1; found 514.1. 1 H NMR(400MHz,DMSO-d6)δ10.93(s,1H),7.67–7.58(m,2H),7.49(d,J=7.7Hz,1H),7.42– 7.30(m,4H),6.83(t,J=55.3Hz,1H),6.15(s,1H),5.83(d,J=1.7Hz,1H),4.32(s,2H), 2.97(d,J=9.4Hz,2H),2.85(d,J=9.3Hz,1H),2.81–2.69(m,1H),2.40(d,J=12.1Hz,2H ),2.11–2.03(m,1H),1.37(d,J=3.8Hz,2H),0.39–0.26(m,1H),-0.01(d,J=7.8Hz,1H).

[0535] Example 94: 3-(1-(3-(4-(difluoromethyl)-2-oxo-6-(3,3,3-trifluoropropoxy)pyridin-1(2H)-yl)phenyl)-1H-indazol-4-yl)piperidin-2,6-dione

[0536] It was prepared using a method similar to that of Example 76. LC / MS (ESI+) calcd for C 27 H 22 F5N4O4 + ([M+H)) + )m / z:561.1;found 561.1. 1 H NMR (400MHz, DMSO-d6) δ10.96(s,1H),8.43(d,J=0.9Hz,1H),7.85(dd,J=8.1,2.1Hz,1H),7.75(d,J=8.6 Hz,1H),7.74–7.67(m,2H),7.46(dd,J=8.6,7.1Hz,1H),7.27(dd,J=6.7,2.4Hz,1H),7.13(d,J=7.1Hz,1 H),6.83(t,J=56.0Hz,1H),,6.38(d,J=1.5Hz,1H),6.04(d,J=1.5Hz,1H),4.42(dd,J=12.2,4.9Hz,1H), 4.35(t,J=5.6Hz,2H),2.82–2.74(m,1H),2.60(q,J=5.9,5.4Hz,2H),2.20–2.07(m,2H),1.99–1.94(m).

[0537] Example 95: 3-(1-(3-(2-oxo-4-(trifluoromethyl)-2,5,6,7,8,9-hexahydro-1H-cycloheptane[b]pyridin-1-yl)phenyl)-1H-indazol-4-yl)piperidin-2,6-dione

[0538] It was prepared using a method similar to that of Example 63. LC / MS (ESI+) Calcd for C 29 H 25 F3N4O3(M+H + )m / z,534.2;found 534.2. 1H NMR(400MHz,Chloroform-d)δ9.37(s,1H),8.43(s,1H),8.22(dd,J=7.4,1.6Hz,1H),7.82(t,J=1.4Hz,1H ),7.64(dt,J=7.5,1.5Hz,1H),7.52(dt,J=7.5,1.6Hz,1H),7.40(t,J=7.5Hz,1H),7.32(t,J=7.5Hz,1H), 7.24(dd,J=7.5,1.5Hz,1H),6.61(s,1H),4.18–4.12(m,1H),2.60(td,J=7.1,0.8Hz,2H),2.45(dtt,J=11 .5,7.1,1.1Hz,2H),2.28(tq,J=7.3,1.0Hz,2H),2.07–1.92(m,2H),1.74–1.56(m,4H),1.46–1.37(m,2H).

[0539] Example 96: 1-(2-chloro-4'-(4-(difluoromethyl)-6-morpholino-2-oxopyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

[0540] The starting material synthesis follows the method described in Example 125. The target compound was synthesized using a method similar to that in Example 91. LC / MS (ESI+) Calcd for C 25 H 21 ClF3N3O4(M+H + )m / z,520.1;found 520.1. 1 H NMR(400MHz,Chloroform-d)δ9.39(s,1H),7.62–7.57(m,2H),7.43–7.37(m,2H),7.37–7.30(m,3H),6.13(d,J=0.7Hz,1H),5.96(q ,J=1.0Hz,1H),3.86(t,J=7.1Hz,2H),3.76(s,3H),2.94(td,J=7.1,1.0Hz,2H),2.71(t,J=7.1Hz,2H),2.34(qt,J=9.0,7.1Hz,2H).

[0541] Example 97: 1-(2-chloro-4'-(4-(difluoromethyl)-6-morpholino-2-oxopyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

[0542] It was prepared using a method similar to that of Example 83. LC / MS (ESI+) Calcd for C 26 H 23 ClF2N4O4(M+H + )m / z,529.1;found 529.1. 1 ¹H NMR (400MHz, Chloroform-d) δ 7.62–7.56 (m, 2H), 7.43–7.32 (m, 5H), 6.56–6.50 (m, 2H), 6.10 (dd, J = 1.8, 0.7Hz, 1H), 3.86 (t, J = 7.1Hz, 2H), 3.75 (td, J = 7.0, 0.9Hz, 4H), 3.64 (td, J = 7.0, 1.0Hz, 4H), 2.72 (t, J = 7.1Hz, 2H) Example 98: 3-(1-(3-(6-(3,3-difluoroazacyclobutane-1-yl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)phenyl)-1H-indazol-4-yl)piperidin-2,6-dione

[0543] It was prepared using a method similar to that of Example 72. LC / MS (ESI+) Calcd for C 27 H 20 F5N5O3(M+H + )m / z,558.1;found 558.1. 1 H NMR (400MHz, DMSO-d6) δ10.96(s,1H),8.47(s,1H),7.99–7.92(m,1H),7.84(d,J=8.2Hz,2H),7.77(t ,J=8.0Hz,1H),7.49(t,J=7.8Hz,1H),7.39(d,J=7.8Hz,1H),7.15(d,J=7.1Hz,1H),6.27(s,1H),5.71 (d,J=1.9Hz,1H),4.43(dd,J=12.5,4.9Hz,1H),4.06(q,J=11.7Hz,2H),3.91(q,J=11.7Hz,2H),2.78( ddd,J=17.2,12.3,5.1Hz,1H),2.59(d,J=17.6Hz,1H),2.12(d,J=10.3Hz,1H),2.00(q,J=7.2Hz,1H).

[0544] Example 99: 3-(1-(3-(2-oxo-4-(trifluoromethyl)-6-(3,3,3-trifluoropropoxy)pyridin-1(2H)-yl)phenyl)-1H-indazol-4-yl)piperidin-2,6-dione

[0545] 1. Preparation of 1-(3-iodophenyl)-4-(trifluoromethyl)-6-(3,3,3-trifluoropropoxy)pyridine-2(1H)-one:

[0546] 4 mL of trifluoropropanol was transferred to a single-necked flask and cooled in an ice bath under inert gas protection. Sodium hydroxide (60%) (24 mg, 0.6 mmol) was added in portions, and the mixture was stirred in an ice bath for 30 min. Then, 200 mg of 6-chloro-1-(3-iodophenyl)-4-(trifluoromethyl)pyridin-2(1H)-one (0.5 mmol) was added, and the reaction was allowed to proceed overnight at room temperature. The reaction was quenched with water, extracted with DCM, and the organic phase was dried over anhydrous sodium sulfate. The solution was purified by TLC to obtain 150 mg of 1-(3-iodophenyl)-4-(trifluoromethyl)-6-(3,3,3-trifluoropropoxy)pyridin-2(1H)-one. LC / MS (ESI+) Calcd for C 15 H 10 F6INO2(M+H + )m / z,478.0; found 478.0.

[0547] 2. Preparation of 3-(1-(3-(2-oxo-4-(trifluoromethyl)-6-(3,3,3-trifluoropropoxy)pyridin-1(2H)-yl)phenyl)-1H-indazol-4-yl)piperidine-2,6-dione:

[0548] Take 60 mg (0.13 mmol) of 1-(3-iodophenyl)-4-(trifluoromethyl)-6-(3,3,3-trifluoropropoxy)pyridin-2(1H)-one into a microwave reaction flask, then add 3-(1H-indazol-4-yl)piperidin-2,6-dione (37 mg, 0.16 mmol), cuprous iodide (12 mg, 0.07 mmol), potassium phosphate (55 mg, 0.26 mmol), and N2O. 1 N 2-Dimethylethane-1,2-diamine (6 mg, 0.07 mmol), DMAc 4 mL. While stirring, inert gas was passed under the liquid surface for 1 min. The cap was quickly tightened. The reaction was microwaved at 90 °C for 1 h. The mixture was quenched with water, extracted with EA, and the organic phase was dried over anhydrous sodium sulfate. The product was purified by TLC to give 27 mg of 3-(1-(3-(2-oxo-4-(trifluoromethyl)-6-(3,3,3-trifluoropropoxy)pyridin-1(2H)-yl)phenyl)-1H-indazol-4-yl)piperidin-2,6-dione. LC / MS (ESI+) Calcd for C 27 H 20 F6N4O4(M+H + )m / z,579.1;found 579.1. 1 H NMR(400MHz,DMSO-d6)δ10.96(s,1H),8.48–8.42(m,1H),7.89–7.84(m,1H),7.80–7.7 4(m,2H),7.70(t,J=8.0Hz,1H),7.47(dd,J=8.6,7.1Hz,1H),7.30(dt,J=8.1,1.2Hz,1H ),7.13(d,J=7.2Hz,1H),6.55(s,1H),6.21(d,J=1.8Hz,1H),4.40(t,J=5.6Hz,2H),2.9 4(s,1H),2.61(q,J=5.8Hz,2H),2.56(d,J=5.1Hz,1H),2.17–2.08(m,1H),1.96(s,1H).

[0549] Example 100: 3-(1-(3-(2-oxy-6-(pyrrolidin-1-yl)-4-(trifluoromethyl)pyridin-1(2H)-yl)phenyl)-1H-indazol-4-yl)piperidin-2,6-dione

[0550] Step 1: Preparation of 1-(3-iodophenyl)-6-(pyrrolidone-1-yl)-4-(trifluoromethyl)pyridin-2(1H)-one:

[0551] Potassium carbonate (157 mg, 1.14 mmol, 3.0 eq) was added to a DMSO solution (2 mL) of tetrahydropyrrole (95 μL, 1.14 mmol, 3.0 eq) and 6-chloro-1-(3-iodophenyl)-4-(trifluoromethyl)pyridin-2(1H)-one (150 mg, 0.38 mmol, 1.0 eq) and reacted in an oil bath at 90 °C for 1 hour. After cooling, the reaction solution was quenched with saturated ammonium chloride aqueous solution, extracted with ethyl acetate, and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by PTLC (DCM-MeOH = 18:1) to give 1-(3-iodophenyl)-6-(pyrrolidine-1-yl)-4-(trifluoromethyl)pyridin-2(1H)-one (pale yellow solid, 140 mg, 85%). LC / MS (ESI) + ): calcd for C 16 H 15 F3IN2O([M+H) + )m / z 435.0, found 434.9.

[0552] Step 2: Preparation of 3-(1-(3-(2-oxy-6-(pyrrolidone-1-yl)-4-(trifluoromethyl)pyridin-1(2H)-yl)phenyl)-1H-indazol-4-yl)piperidine-2,6-dione:

[0553] 3-(1H-indazol-4-yl)piperidin-2,6-dione (50.0 mg, 0.22 mmol, 1.0 eq), 1-(3-iodophenyl)-6-(pyrrolidin-1-yl)-4-(trifluoromethyl)pyridine-2(1H)-one (95.5 mg, 0.22 mmol, 1.0 eq), 2-pyridinecarboxylic acid (13.5 mg, 0.11 mmol, 0.5 eq), cuprous iodide (21.0 mg, 0.11 mmol, 0.5 eq), and potassium carbonate (75.9 mg, 0.55 mmol, 2.0 eq) were weighed into a dry reaction flask. After purging with argon three times, 2 mL of dry DMSO was added, and the reaction was carried out in an oil bath at 110 °C for 1 hour. After cooling, the reaction solution was filtered through diatomaceous earth, quenched with saturated ammonium chloride aqueous solution, extracted with ethyl acetate, and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by PTLC (DCM-MeOH = 18:1) to give 3-(1-(3-(2-oxy-6-(pyrrolidone-1-yl)-4-(trifluoromethyl)pyridin-1(2H)-yl)phenyl)-1H-indazol-4-yl)piperidin-2,6-dione (pale yellow solid, 26 mg, 22%).

[0554] LC / MS (ESI) + ): calcd for C 28 H 25F3N5O3([M+H) + )m / z 563.2, found 536.2.

[0555] 1 H NMR (400MHz, DMSO-d6) δ10.96(s,1H),8.45(s,1H),7.87–7.82(m,2H),7.79(d,J=8.5Hz,1H),7.70(t, J=8.2Hz,1H),7.48(dd,J=8.6,7.1Hz,1H),7.39–7.32(m,1H),7.14(d,J=7.1Hz,1H),6.12–6.06(m,1H) ,5.78(d,J=1.8Hz,1H),4.42(dd,J=12.2,4.8Hz,1H),3.05–2.97(m,2H),2.92–2.84(m,2H),2.78(ddd, J=17.3,12.4,5.2Hz,1H),2.69–2.61(m,1H),2.61–2.55(m,1H),2.18–2.07(m,1H),1.75–1.61(m,4H).

[0556] Example 101: 3-(1-(2-fluoro-5-((1-methyl-1H-pyrrolo[3,2-b]pyridin-5-yl)amino)phenyl)-1H-indazol-4-yl)piperidin-2,6-dione

[0557] Step 1: Preparation of 5-bromo-1-methyl-1H-pyrrolo[3,2-b]pyridine:

[0558] Cesium carbonate (3.26 g, 10.0 mmol, 1.0 eq) and iodomethane (0.62 mL, 10.0 mmol, 1.0 eq) were added sequentially to a 20 mL solution of acetonitrile in 5-bromo-1H-pyrrolo[3,2-b]pyridine (1.96 g, 10.0 mmol, 1.0 eq) under an ice-water bath, and the reaction was carried out at room temperature for 2 hours. After complete conversion of the starting materials, the reaction solution was filtered through diatomaceous earth, concentrated, and the crude product was purified by silica gel column chromatography (PE-EA = 3:1) to obtain 5-bromo-1-methyl-1H-pyrrolo[3,2-b]pyridine (pale yellow solid, 1.89 g, 90%). LC-MS (ESI) was then performed. + ): calcd for C8H8BrN2([M+H] + )m / z 211.0, found 211.1.

[0559] Step 2: Preparation of N-(3-bromo-4-fluorophenyl)-1-methyl-1H-pyrrolo[3,2-b]pyridine-5-amine:

[0560] 5-Bromo-1-methyl-1H-pyrrolo[3,2-b]pyridine (500 mg, 2.37 mmol, 1.0 eq), 3-bromo-4-fluoroaniline (450 mg, 2.37 mmol, 1.0 eq), palladium acetate (105 mg, 0.47 mmol, 0.2 eq), xantphos (272 mg, 0.47 mmol, 0.2 eq), and cesium carbonate (1.55 g, 4.74 mmol, 2.0 eq) were weighed into a dry reaction flask. After purging with argon three times, 10 mL of dry 1,4-dioxane was added, and the reaction was carried out in an oil bath at 110 °C for 20 hours. The reaction solution was cooled, filtered through diatomaceous earth, quenched with saturated ammonium chloride aqueous solution, extracted with ethyl acetate, and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (PE-EA = 5:1) to give N-(3-bromo-4-fluorophenyl)-1-methyl-1H-pyrrolo[3,2-b]pyridine-5-amine (pale yellow solid, 260 mg, 27%). LC / MS (ESI) + ): calcd for C 14 H 12 BrFN3([M+H] + )m / z 320.0, found 320.0.

[0561] Step 3: 3-(1-(2-fluoro-5-((1-methyl-1H-pyrrolo[3,2-b]pyridin-5-yl)amino)phenyl)-1H-indazol-4-yl)piperidin-2,6-dione

[0562] 3-(1H-indazol-4-yl)piperidin-2,6-dione (80.0 mg, 0.78 mmol, 1.0 eq), N-(3-bromo-4-fluorophenyl)-1-methyl-1H-pyrrolo[3,2-b]pyridine-5-amine (256 mg, 0.70 mmol, 0.9 eq), 2-pyridinecarboxylic acid (48.0 mg, 0.39 mmol, 0.5 eq), cuprous iodide (74.2 mg, 0.29 mmol, 0.5 eq), and potassium phosphate (331 mg, 0.156 mmol, 2.0 eq) were weighed into a dry reaction flask. After purging with argon three times, 3 mL of dry DMSO was added, and the reaction was carried out in an oil bath at 130 °C for 4 hours. The reaction solution was cooled, filtered through diatomaceous earth, quenched with saturated ammonium chloride aqueous solution, extracted with ethyl acetate, and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by PTLC (DCM-MeOH = 18:1) to give 3-(1-(2-fluoro-5-((1-methyl-1H-pyrrolo[3,2-b]pyridin-5-yl)amino)phenyl)-1H-indol-4-yl)piperidin-2,6-dione (pale yellow solid, 5.0 mg, 5%). LC / MS (ESI) + ): calcd for C 26 H 22 FN6O2([M+H) + )m / z 469.2, found 469.2. 1 H NMR(400MHz,DMSO-d6)δ10.98(s,1H),8.44(s,1H),7.79(s,1H),7.51–7.45(m ,2H),7.44–7.36(m,2H),7.24–7.18(m,1H),7.13(dd,J=5.0,2.9Hz,1H),6.82 –6.58(m,2H),6.28(d,J=3.0Hz,1H),4.43(dd,J=12.2,4.9Hz,1H),3.77(s,3H ),2.79(ddd,J=17.1,12.0,5.0Hz,1H),2.71–2.55(m,2H),2.24–2.11(m,1H).

[0563] Example 102: 3-(1-(3-(6-cyclohexyl-4-methyl-2-oxopyridin-1(2H)-yl)phenyl)-1H-indazol-4-yl)piperidin-2,6-dione

[0564] Step 1: Preparation of 6-cyclohexyl-1-(3-iodophenyl)-4-methylpyridin-2(1H)-one:

[0565] 3-Iodoaniline (4.38 g, 20.0 mmol, 1.0 eq) and NaH (800 mg, 20.0 mmol, 1.0 eq) were weighed sequentially into a reaction flask. After stirring for 20 minutes, 6-cyclohexyl-4-methyl-2H-pyran-2-one (3.86 g, 20.0 mmol, 1.0 eq) was added, and the mixture was then heated to 140 °C and reacted for 24 hours. The crude product was purified by silica gel column chromatography (PE-EA = 1:1) to obtain 6-cyclohexyl-1-(3-iodophenyl)-4-methylpyridin-2(1H)-one (brown oil, 480 mg, 6%). LC-MS (ESI) was used for further analysis. + ): calcd for C 18 H 21 INO([M+H)) + )m / z 394.1, found 393.9.

[0566] Step 2: 3-(1-(3-(6-cyclohexyl-4-methyl-2-oxopyridin-1(2H)-yl)phenyl)-1H-indazol-4-yl)piperidin-2,6-dione

[0567] 3-(1H-indazol-4-yl)piperidin-2,6-dione (50.0 mg, 0.22 mmol, 1.0 eq), 6-cyclohexyl-1-(3-iodophenyl)-4-methylpyridin-2(1H)-one (86.5 mg, 0.22 mmol, 1.0 eq), 2-pyridinecarboxylic acid (13.5 mg, 0.11 mmol, 0.5 eq), cuprous iodide (21.0 mg, 0.11 mmol, 0.5 eq), and potassium carbonate (75.9 mg, 0.55 mmol, 2.0 eq) were weighed into a dry reaction flask. After purging with argon three times, 2 mL of dry DMSO was added, and the reaction was carried out in an oil bath at 110 °C for 1 hour. The reaction solution was cooled, filtered through diatomaceous earth, quenched with saturated ammonium chloride aqueous solution, extracted with ethyl acetate, and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by PTLC (DCM-MeOH = 18:1) to give 3-(1-(3-(6-cyclohexyl-4-methyl-2-oxopyridin-1(2H)-yl)phenyl)-1H-indazol-4-yl)piperidin-2,6-dione (pale yellow solid, 16.0 mg, 15%). LC / MS (ESI) + ): calcd for C 29 H 31 N4O3([M+H)) + )m / z 495.2, found 495.1. 1H NMR (400MHz, DMSO-d6) δ10.94(s,1H),8.45(s,1H),7.89(dd,J=8.0,2.0Hz,1H),7.74(t,J=8.0Hz,1H),7.72(d,J=8.5Hz,1 H),7.66(t,J=2.0Hz,1H),7.57–7.41(m,1H),7.28(d,J=8.7Hz,1H),7.14(d,J=7.1Hz,1H),6.27–6.08(m,2H),4.42(dd,J= 12.2,4.9Hz,1H),2.78(ddd,J=17.3,12.4,5.2Hz,1H),2.69–2.59(m,1H),2.55–2.51(m,1H),2.18(s,3H),2.16–2.11(m,1 H),2.12–2.06(m,1H),1.81(d,2H),1.64(t,J=13.0Hz,2H),1.52(d,J=13.0Hz,1H),1.41–1.25(m,4H),1.16–1.10(m,1H).

[0568] Example 103: 3-(1-(3-(4,5,6-trimethyl-2-oxopyridin-1(2H)-yl)phenyl)-1H-indazol-4-yl)piperidin-2,6-dione

[0569] Step 1: Preparation of 4,5,6-trimethylpyridin-2(1H)-one:

[0570] 2-Butanone (4.32 g, 60.0 mmol, 2.0 eq), 1,3-butanedioneamine (3.03 g, 30.0 mmol, 1.0 eq), and polyphosphoric acid (22 g) were added sequentially to a reaction flask, and the mixture was reacted in an oil bath at 120 °C for 3 hours. After the reaction solution cooled to room temperature, 150 mL of an ice-water mixture was added, and the pH was adjusted to 7 using a saturated sodium bicarbonate aqueous solution. The mixture was then stirred for another 11 hours. The reaction solution was filtered, and the resulting filter cake was purified by silica gel column chromatography (DCM-MeOH = 6:1) to give 4,5,6-trimethylpyridin-2(1H)-one (white solid, 1.50 g, 36%). LC / MS (ESI) + ): calcd for C8H 12 NO([M+H] + )m / z 138.1, found 138.3.

[0571] Step 2: Preparation of 1-(3-iodophenyl)-4,5,6-trimethylpyridin-2(1H)-one:

[0572] 4,5,6-Trimethylpyridin-2(1H)-one (500 mg, 3.64 mmol, 1.0 eq), 3-iodophenylboronic acid (1.90 g, 5.47 mmol, 1.5 eq), TMEDA (218 μL, 1.46 mmol, 0.4 eq), pyridine (0.72 mL, 9.10 mmol, 2.5 eq), and copper trifluoromethanesulfonate (462 mg, 1.46 mmol, 0.4 eq) were weighed into a dry reaction flask. DCE solution (20 mL) was added, and the reaction was carried out in an oil bath at 50 °C under an oxygen atmosphere for 10 hours. The reaction solution was cooled to room temperature, quenched with saturated ammonium chloride aqueous solution, extracted with DCM, and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (PE-EA = 1:2) to obtain 1-(3-iodophenyl)-4,5,6-trimethylpyridin-2(1H)-one (pale yellow solid, 95.0 mg, 8%). LC-MS (ESI) + ): calcd for C 14 H 15 INO([M+H)) + )m / z 340.0, found 340.0.

[0573] Step 3: Preparation of 3-(1-(3-(4,5,6-trimethyl-2-oxopyridin-1(2H)-yl)phenyl)-1H-indazol-4-yl)piperidine-2,6-dione:

[0574] 3-(1H-indazol-4-yl)piperidin-2,6-dione (60.0 mg, 0.26 mmol, 1.0 eq), 1-(3-iodophenyl)-4,5,6-trimethylpyridin-2(1H)-one (88.0 mg, 0.26 mmol, 1.0 eq), 2-pyridinecarboxylic acid (16.0 mg, 0.13 mmol, 0.5 eq), cuprous iodide (24.8 mg, 0.13 mmol, 0.5 eq), and potassium carbonate (89.7 mg, 0.65 mmol, 2.5 eq) were weighed into a dry reaction flask. After purging with argon gas three times, 2 mL of dry DMSO was added, and the reaction was carried out in an oil bath at 110 °C for 1.5 hours. The reaction solution was cooled, filtered through diatomaceous earth, quenched with saturated ammonium chloride aqueous solution, extracted with ethyl acetate, and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by PTLC (DCM-MeOH = 18:1) to give 3-(1-(3-(4,5,6-trimethyl-2-oxopyridin-1(2H)-yl)phenyl)-1H-indazol-4-yl)piperidin-2,6-dione (pale yellow solid, 18.0 mg, 29%). LC / MS (ESI) + ): calcd for C 26 H 25N4O3([M+H)) + )m / z 441.2, found 441.0. 1 H NMR (400MHz, DMSO-d6) δ10.93(s,1H),8.44(s,1H),7.87(dd,J=8.2,1.9Hz,1H),7.77(d,J=8. 6Hz,1H),7.73(t,J=8.0Hz,1H),7.60(t,J=2.0Hz,1H),7.48(dd,J=8.5,7.1Hz,1H),7.26–7.20 (m,1H),7.13(d,J=7.2Hz,1H),6.27(s,1H),4.42(dd,J=12.2,4.8Hz,1H),2.78(ddd,J=17.3,1 2.3,5.2Hz,1H),2.70–2.52(m,2H),2.18(s,3H),2.16–2.08(m,1H),2.02(s,3H),1.99(s,3H).

[0575] Example 104: 3-(2-ethynyl-4'-(4,5,6-trimethyl-2-oxypyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0576] Step 1: Preparation of 1-(4-bromophenyl)-4,5,6-trimethylpyridin-2(1H)-one:

[0577] 4,5,6-Trimethylpyridin-2(1H)-one (500 mg, 3.64 mmol, 1.0 eq), 4-bromo-phenylboronic acid (1.10 g, 5.47 mmol, 1.5 eq), TMEDA (218 μL, 1.46 mmol, 0.4 eq), pyridine (0.72 mL, 9.10 mmol, 2.5 eq), and copper trifluoromethanesulfonate (462 mg, 1.46 mmol, 0.4 eq) were weighed into a dry reaction flask. DCE solution (20 mL) was added, and the reaction was carried out in an oil bath at 50 °C under an oxygen atmosphere for 10 hours. The reaction solution was cooled to room temperature, quenched with saturated ammonium chloride aqueous solution, extracted with DCM, and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (PE-EA = 1:2) to obtain 1-(3-iodophenyl)-4,5,6-trimethylpyridin-2(1H)-one (pale yellow solid, 190 mg, 18%). LC-MS (ESI) + ): calcd for C 14 H 15 BrNO([M+H] + )m / z 292.0, found 292.0.

[0578] Step 2: Preparation of 4,5,6-trimethyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxoboran-2-yl)phenyl)pyridin-2(1H)-one:

[0579] 1-(4-bromophenyl)-4,5,6-trimethylpyridin-2(1H)-one (80.0 mg, 0.27 mmol, 1.0 eq), B2Pin2 (103 mg, 0.41 mmol, 1.5 eq), potassium acetate (66.2 mg, 0.68 mmol, 2.0 eq), and Pd(dppf)Cl2 (40.0 mg, 0.054 mmol, 0.2 eq) were sequentially added to a dry 1,4-dioxane solution (2 mL), and reacted in an oil bath at 80 °C for 15 hours under an argon atmosphere. After cooling, the reaction solution was filtered through diatomaceous earth, washed with ethyl acetate, concentrated under reduced pressure, and used directly in the next reaction without further purification. LC-MS (ESI) was performed. + ): calcd for C 20 H 27 BrNO3([M+H] + )m / z340.2, found 340.1.

[0580] Step 3: Preparation of 3-(4'-(4,5,6-trimethyl-2-oxypyridin-1(2H)-yl)-2-((trimethylsilyl)acetylene)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione:

[0581] 4,5,6-Trimethyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxoboron-2-yl)phenyl)pyridin-2(1H)-one (crude), 3-(3-bromo-2-((trimethylsilyl)ethynyl)phenyl)piperidin-2,6-dione (98.0 mg, 0.27 mmol, 1.0 eq), Xhpos-Pd-G3 (22.8 mg, 0.027 mmol, 0.1 eq), and triethylamine (113 μL, 0.81 mmol, 3.0 eq) were sequentially added to a THF / H2O solution (4 mL / 1 mL), and reacted in an oil bath at 50 °C for 12 hours under argon protection. The reaction solution was cooled, filtered through diatomaceous earth, quenched with saturated ammonium chloride aqueous solution, extracted with ethyl acetate, and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by PTLC (DCM-MeOH = 25:1) to give 3-(4'-(4,5,6-trimethyl-2-oxypyridin-1(2H)-yl)-2-((trimethylsilyl)acetylene)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione (pale yellow solid, 35.0 mg, 26% yield in two steps). LC / MS (ESI) +): calcd for C 30 H 33 N₂O₃Si([M+H)) + )m / z 497.2, found 497.1.

[0582] Step 4: Preparation of 3-(2-ethynyl-4'-(4,5,6-trimethyl-2-oxypyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione:

[0583] TBAF (1.0 M in THF, 0.11 mL, 0.11 mmol, 1.5 eq) was added to a 5 mL solution of 3-(4'-(4,5,6-trimethyl-2-oxypyridin-1(2H)-yl)-2-((trimethylsilyl)acetylene)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione (35.0 mg, 0.070 mmol, 1.0 eq) in THF, and the reaction was allowed to proceed at room temperature for 0.5 h. The reaction was quenched with saturated sodium chloride aqueous solution, extracted with ethyl acetate, and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by PTLC (DCM-MeOH = 18:1) to give 3-(2-ethynyl-4'-(4,5,6-trimethyl-2-oxypyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione (pale yellow solid, 28 mg, 94%). LC / MS (ESI) + ): calcd for C 27 H 25 N₂O₃([M+H)) + )m / z 425.2, found 425.1. 1 H NMR(400MHz, DMSO-d6)δ10.92(s,1H),7.73–7.65(m,2H),7.49(t,J=7.7Hz,1H),7.40( dd,J=7.7,1.3Hz,1H),7.34(dd,J=7.8,1.2Hz,1H),7.28–7.21(m,2H),6.26(s,1H),4.4 1(s,1H),4.34(dd,J=11.9,5.1Hz,1H),2.77(ddd,J=17.5,12.7,5.3Hz,1H),2.61–2.5 3(m,1H),2.42–2.28(m,1H),2.17(s,3H),2.12–2.04(m,1H),2.01(s,3H),1.91(s,3H).

[0584] Example 105: 1-(2-chloro-4'-(4,5,6-trimethyl-2-oxypyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

[0585] Step 1: Preparation of 4,5,6-trimethyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxoboran-2-yl)phenyl)pyridin-2(1H)-one:

[0586] 1-(4-bromophenyl)-4,5,6-trimethylpyridin-2(1H)-one (80.0 mg, 0.27 mmol, 1.0 eq), B2Pin2 (103 mg, 0.41 mmol, 1.5 eq), potassium acetate (66.2 mg, 0.68 mmol, 2.0 eq), and Pd(dppf)Cl2 (40.0 mg, 0.054 mmol, 0.2 eq) were sequentially added to a dry 1,4-dioxane solution (2 mL), and reacted in an oil bath at 80 °C for 15 hours under an argon atmosphere. After cooling, the reaction solution was filtered through diatomaceous earth, washed with ethyl acetate, concentrated under reduced pressure, and used directly in the next reaction without further purification. LC-MS (ESI) was performed. + ): calcd for C 20 H 27 BrNO3([M+H] + )m / z 340.2, found 340.1.

[0587] Step 2: Preparation of 1-(2-chloro-4'-(4,5,6-trimethyl-2-oxypyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)dihydropyrimidine-2,4(1H,3H)-dione:

[0588] 4,5,6-Trimethyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxoboran-2-yl)phenyl)pyridin-2(1H)-one (crude), 1-(3-bromo-2-chlorophenyl)dihydropyridimidazole-2,4(1H,3H)-dione (63.6 mg, 0.21 mmol, 0.8 eq), Pd(dppf)Cl2 (19.7 mg, 0.027 mmol, 0.1 eq), and sodium bicarbonate (68.0 mg, 0.81 mmol, 3.0 eq) were sequentially added to a 1,4-dioxane / H2O solution (4 mL / 1 mL), and reacted in an oil bath at 50 °C for 12 hours under argon protection. After cooling, the reaction solution was filtered through diatomaceous earth, quenched with saturated ammonium chloride aqueous solution, extracted with ethyl acetate, and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by PTLC (DCM-MeOH = 20:1) to give 1-(2-chloro-4'-(4,5,6-trimethyl-2-oxypyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (pale yellow solid, 20.0 mg, 17% yield in two steps). LC / MS (ESI) + ): calcd for C 24 H 23 ClN3O3([M+H) + )m / z 436.1, found 436.0. 1 H NMR (400MHz, DMSO-d6) δ10.51(s,1H),7.59(d,J=8.5Hz,2H),7.56(d,J=2.1Hz,1H),7.53(t,J=7.5Hz,1H),7.48(dd,J=7.4,2.2Hz,1H),7.29(d,J=8.5H z,2H),6.26(s,1H),3.78(ddd,J=12.3,7.8,6.3Hz,1H),3.67(dt,J=12.4,6 .3Hz,1H),2.86–2.73(m,2H),2.25–2.12(m,3H),2.01(s,3H),1.93(s,3H).

[0589] Example 106: 3-(2-ethynyl-4'-(2-oxy-6-(2,2,2-trifluoroethoxy)-4-(trifluoromethyl)pyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0590] Step 1: Preparation of 3-(4'-(2-oxy-6-(2,2,2-trifluoroethoxy)-4-(trifluoromethyl)pyridin-1(2H)-yl)-2-((trimethylsilyl)acetylene)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione:

[0591] 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxoboron-2-yl)phenyl)-6-(2,2,2-trifluoroethoxy)-4-(trifluoromethyl)pyridin-2(1H)-one (65.0 mg, 0.14 mmol, 1.0 eq), 3-(3-bromo-2-((trimethylsilyl)ethynyl)phenyl)piperidin-2,6-dione (56.0 mg, 0.15 mmol, 1.1 eq), Xphos-Pd-G3 (11.8 mg, 0.014 mmol, 0.1 eq) and triethylamine (60 μL, 0.42 mmol, 3.0 eq) were added sequentially to a THF / H2O solution (4 mL / 1 mL), and the mixture was reacted in an oil bath at 50 °C for 12 hours under argon protection. The reaction solution was cooled and filtered through diatomaceous earth, quenched with saturated ammonium chloride aqueous solution, extracted with ethyl acetate, and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by PTLC (DCM-MeOH = 25:1) to give 3-(4'-(2-oxy-6-(2,2,2-trifluoroethoxy)-4-(trifluoromethyl)pyridin-1(2H)-yl)-2-((trimethylsilyl)acetylene)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione (pale yellow solid, 40.0 mg, 23%). LC / MS (ESI) + ): calcd for C 30 H 27 F6N2O4Si([M+H) + )m / z 621.1, found 621.1.

[0592] Step 2: Preparation of 3-(2-ethynyl-4'-(2-oxy-6-(2,2,2-trifluoroethoxy)-4-(trifluoromethyl)pyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione:

[0593] TBAF (1.0 M in THF, 0.10 mL, 0.096 mmol, 1.5 eq) was added to a 5 mL solution of 3-(4'-(2-oxy-6-(2,2,2-trifluoroethoxy)-4-(trifluoromethyl)pyridin-1(2H)-yl)-2-((trimethylsilyl)acetylene)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione (40.0 mg, 0.064 mmol, 1.0 eq) in THF and reacted at room temperature for 2 hours. The reaction was quenched with saturated ammonium chloride solution, extracted with ethyl acetate, and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by PTLC (DCM-MeOH = 18:1) to give 3-(2-ethynyl-4'-(2-oxy-6-(2,2,2-trifluoroethoxy)-4-(trifluoromethyl)pyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione (pale yellow solid, 25.0 mg, 71%). LC / MS (ESI) + ): calcd for C 27 H 19 F6N2O6([M+H) + )m / z 549.1, found 549.0. 1 H NMR (400MHz, DMSO-d6) δ10.93(s,1H),7.67(d,J=8.3Hz,2H),7.49(t,J=7.7Hz,1H),7.44–7.30(m,4H),6.64(s,1H),6.32(d,J=1.7Hz,1 H),4.98(q,J=8.5Hz,2H),4.38–4.32(m,1H),4.31(s,1H),2.85–2.65(m,1H),2.59–2.55(m,1H),2.42–2.30(m,1H),2.12–2.03(m,1H).

[0594] Example 107: 3-(1-(3-(6-cyclohexyl-4-(difluoromethyl)-2-oxopyridin-1(2H)-yl)phenyl)-1H-indazole-4-yl)piperidin-2,6-dione

[0595] Step 1: Preparation of 6-cyclohexyl-1-(3-iodophenyl)-2-oxo-1,2-dihydropyridine-4-carboxaldehyde:

[0596] Selenium dioxide (133 mg, 1.20 mmol, 3.0 eq), 6-cyclohexyl-1-(3-iodophenyl)-4-methylpyridin-2(1H)-one (160 mg, 0.40 mmol, 1.0 eq), and chlorobenzene solution (1.5 mL) were sequentially added to a sealed reaction tube, and the mixture was reacted in an oil bath at 165 °C for 8 hours. After cooling, the reaction solution was filtered through diatomaceous earth, and the crude product obtained after concentration was purified by silica gel column chromatography (PE-EA = 1:1) to give 6-cyclohexyl-1-(3-iodophenyl)-2-oxo-1,2-dihydropyridin-4-carboxaldehyde (brown oil, 90.0 mg, 55%). LC / MS (ESI) + ): calcd for C 18 H 19 INO2([M+H)) + )m / z 408.0, found 407.9.

[0597] Step 2: Preparation of 6-cyclohexyl-4-(difluoromethyl)-1-(3-iodophenyl)pyridin-2(1H)-one:

[0598] DAST (44 μL, 0.33 mmol, 3.0 eq) was added to a 1.5 mL solution of 6-cyclohexyl-1-(3-iodophenyl)-2-oxo-1,2-dihydropyridine-4-carboxaldehyde (45.0 mg, 0.11 mmol, 1.0 eq) in dichloromethane and reacted at room temperature for 2 hours. The reaction was quenched by adding 4 mL of saturated sodium bicarbonate solution under an ice-water bath, followed by dichloromethane extraction. The crude product was concentrated and purified by PTLC (PE-EA = 1:1) to give 6-cyclohexyl-4-(difluoromethyl)-1-(3-iodophenyl)pyridine-2(1H)-one (brown oil, 26.0 mg, 54%). LC / MS (ESI) + ): calcd for C 18 H 19 F2INO([M+H)) + )m / z 430.0, found 430.0.

[0599] Step 3: Preparation of 3-(1-(3-(6-cyclohexyl-4-(difluoromethyl)-2-oxopyridin-1(2H)-yl)phenyl)-1H-indazol-4-yl)piperidine-2,6-dione:

[0600] 3-(1H-indazol-4-yl)piperidin-2,6-dione (16.8 mg, 0.073 mmol, 1.2 eq), 6-cyclohexyl-4-(difluoromethyl)-1-(3-iodophenyl)pyridin-2(1H)-one (26.0 mg, 0.061 mmol, 1.0 eq), 2-pyridinecarboxylic acid (3.8 mg, 0.031 mmol, 0.5 eq), cuprous iodide (5.9 mg, 0.031 mmol, 0.5 eq), and potassium carbonate (11.0 mg, 0.078 mmol, 2.5 eq) were weighed into a dry reaction flask. After purging with argon three times, 2 mL of dry DMSO was added, and the reaction was carried out in an oil bath at 110 °C for 1.5 hours. The reaction solution was cooled, filtered through diatomaceous earth, quenched with saturated ammonium chloride aqueous solution, extracted with ethyl acetate, and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by PTLC (DCM-MeOH = 18:1) to give 3-(1-(3-(6-cyclohexyl-4-(difluoromethyl)-2-oxopyridin-1(2H)-yl)phenyl)-1H-indazol-4-yl)piperidin-2,6-dione (pale yellow solid, 9 mg, 28%). LC / MS (ESI) + ): calcd for C 30 H 29 F2N4O3([M+H) + )m / z 531.2, found 531.9. 1 H NMR (400MHz, DMSO-d6) δ10.96(s,1H),7.93(dd,J=8.0,2.1Hz,1H),7.81(t,J=2.0Hz,1H),7.8 0–7.76(m,1H),7.76–7.71(m,1H),6.93(t,J=55.0Hz,1H),6.63–6.53(m,1H),6.39(d,J=1.8Hz ,1H),4.42(dd,J=12.2,4.8Hz,1H),2.84–2.71(m,1H),2.70–2.58(m,1H),2.16–2.14(m,1H),1 .92–1.79(m,2H),1.71–1.60(m,2H),1.54–1.50(m,1H),1.41–1.33(m,4H),1.20–1.17(m,1H).

[0601] Example 108: 3-(1-(3-(6-(2-azabicyclo[3.1.0]hexane-2-yl)-4-(difluoromethyl)-2-oxopyridin-1(2H)-yl)phenyl)-1H-indazol-4-yl)piperidin-2,6-dione

[0602] Step 1: Preparation of 6-(2-azabicyclo[3.1.0]hexane-2-yl)-4-(difluoromethyl)-1-(3-iodophenyl)pyridin-2(1H)-one:

[0603] DIPEA (322 μL, 1.80 mmol, 10.0 eq) was added to a dry DMSO solution of 2-azabicyclo[3.1.0]hexane hydrochloride (171 mg, 1.44 mmol, 8.0 eq) and 6-chloro-4-(difluoromethyl)-1-(3-iodophenyl)pyridin-2(1H)-one (70.0 mg, 0.18 mmol, 1.0 eq) and reacted under microwave irradiation at 130 °C for 1 h. After cooling, the reaction solution was quenched with saturated ammonium chloride aqueous solution, extracted with ethyl acetate, and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by PTLC (PE-EA = 2:1) to give 6-(2-azabicyclo[3.1.0]hexane-2-yl)-4-(difluoromethyl)-1-(3-iodophenyl)pyridin-2(1H)-one (white solid, 62.0 mg, 80%). LC / MS (ESI) + ): calcd for C 17 H 16 F2IN2O([M+H) + )m / z 429.0, found 429.0.

[0604] Step 2: Preparation of 3-(1-(3-(6-(2-azabicyclo[3.1.0]hexane-2-yl)-4-(difluoromethyl)-2-oxopyridin-1(2H)-yl)phenyl)-1H-indazol-4-yl)piperidine-2,6-dione:

[0605] 3-(1H-indazol-4-yl)piperidin-2,6-dione (38.6 mg, 0.17 mmol, 1.2 eq), 6-(2-azabicyclo[3.1.0]hexan-2-yl)-4-(difluoromethyl)-1-(3-iodophenyl)pyridin-2(1H)-one (62.0 mg, 0.14 mmol, 1.0 eq), 2-pyridinecarboxylic acid (8.61 mg, 0.070 mmol, 0.5 eq), cuprous iodide (13.3 mg, 0.070 mmol, 0.5 eq), and potassium carbonate (48.3 mg, 0.35 mmol, 2.5 eq) were weighed into a dry reaction flask, purged with argon gas three times, and then dry DMSO (2 mL) was added. The mixture was reacted in an oil bath at 110 °C for 1 hour. The reaction solution was cooled and filtered through diatomaceous earth, quenched with saturated ammonium chloride aqueous solution, extracted with ethyl acetate, and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by PTLC (DCM-MeOH = 18:1) to give hexane-2-yl)-4-(difluoromethyl)-2-oxopyridin-1(2H)-yl)phenyl)-1H-indazol-4-yl)piperidin-2,6-dione (white solid, 5.0 mg, 7%). LC / MS (ESI) + ): calcd for C 29 H 26 F2N5O3([M+H) + )m / z 530.2, found 530.0.

[0606] 1 H NMR (400MHz, DMSO-d6) δ10.96(s,1H),8.44(s,1H),7.84(d,J=7.1Hz,1H),7.81–7.75(m,1H),7.74(d,J=7.6Hz,1H),7. 70(d,J=7.8Hz,1H),7.53–7.45(m,1H),7.45–7.22(m,1H),7.19–7.10(m,1H),6.90(t,J=55.2Hz,1H),6.28–6.19(m,1H) ,6.18(s,1H),4.42(dd,J=12.2,4.8Hz,1H),3.32–3.30(m,2H),3.08–2.98(m,1H),2.78(ddd,J=17.2,12.3,5.2Hz,1H) ,2.71–2.58(m,2H),2.23–2.07(m,1H),1.76(d,J=8.4Hz,2H),1.65–1.49(m,1H),0.85–0.81(m,1H),0.74–0.59(m,1H).

[0607] Example 109: 3-(1-(3-(6-(2-azabicyclo[3.1.0]hexane-2-yl)-4-methyl-2-oxypyridin-1(2H)-yl)phenyl)-1H-indazol-4-yl)piperidin-2,6-dione

[0608] Step 1: Preparation of 6-(2-azatricyclo[3.1.0]hexane-2-yl)-1-(3-iodophenyl)-4-methylpyridin-2(1H)-one:

[0609] Cesium carbonate (137 mg, 0.42 mmol, 3.0 eq) was added to a dry DMF solution of 2-azabicyclo[3.1.0]hexane hydrochloride (50.2 mg, 0.42 mmol, 3.0 eq) and 6-chloro-1-(3-iodophenyl)-4-methylpyridin-2(1H)-one (50.0 mg, 0.14 mmol, 1.0 eq) and reacted under microwave irradiation at 130 °C for 3 hours. After cooling, the reaction solution was quenched with saturated ammonium chloride aqueous solution, extracted with ethyl acetate, and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by PTLC (PE-EA = 1:1) to give 6-(2-azabicyclo[3.1.0]hexane-2-yl)-4-(difluoromethyl)-1-(3-iodophenyl)pyridin-2(1H)-one (white solid, 15.0 mg, 29%). LC / MS (ESI) + ): calcd for C 17 H 18 IN2O([M+H)) + )m / z 393.0, found 393.2.

[0610] Step 2: Preparation of 3-(1-(3-(6-(2-azabicyclo[3.1.0]hexane-2-yl)-4-methyl-2-oxypyridin-1(2H)-yl)phenyl)-1H-indazol-4-yl)piperidine-2,6-dione:

[0611] 3-(1H-indazol-4-yl)piperidin-2,6-dione (10.5 mg, 0.046 mmol, 1.2 eq), 6-(2-azabicyclo[3.1.0]hexan-2-yl)-4-(difluoromethyl)-1-(3-iodophenyl)pyridin-2(1H)-one (15.0 mg, 0.038 mmol, 1.0 eq), 2-pyridinecarboxylic acid (2.34 mg, 0.019 mmol, 0.5 eq), cuprous iodide (3.63 mg, 0.019 mmol, 0.5 eq), and potassium carbonate (13.1 mg, 0.095 mmol, 2.5 eq) were weighed into a dry reaction flask, purged with argon gas three times, and then dry DMSO (2 mL) was added. The mixture was reacted in an oil bath at 110 °C for 1 hour. The reaction solution was cooled and filtered through diatomaceous earth, quenched with saturated ammonium chloride aqueous solution, extracted with ethyl acetate, and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by PTLC (DCM-MeOH = 15:1) to give 3-(1-(3-(6-(2-azabicyclo[3.1.0]hexane-2-yl)-4-methyl-2-oxypyridin-1(2H)-yl)phenyl)-1H-indazol-4-yl)piperidin-2,6-dione (grayish-white solid, 3.0 mg, 16%). LC / MS (ESI) + ): calcd for C 29 H 28 F3N5O3([M+H) + )m / z 494.2, found 494.1. 1 H NMR (400MHz, DMSO-d6) δ10.96(s,1H),8.43(s,1H),7.79(dd,J=10.7,3.1Hz,1H),7.65–7.57(m,1H),7.4 7(dd,J=8.7,7.2Hz,1H),7.43–7.34(m,2H),7.29–7.24(m,1H),7.23–7.17(m,2H),7.13(d,J=7.2Hz,1H) ,4.48–4.37(m,1H),3.27–3.21(m,2H),2.95(d,J=7.9Hz,1H),2.83–2.75(m,1H),2.64–2.54(m,2H),2.1 6(s,3H),2.13–2.09(m,1H),1.96–1.94(m,2H),1.91–1.83(m,1H),1.40–1.35(m,1H),1.20–1.16(m,1H).

[0612] Example 110: 3-(1-(3-(6-(2-azabicyclo[3.1.0]hexane-2-yl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)phenyl)-1H-indazol-4-yl)piperidin-2,6-dione

[0613] Step 1: Preparation of 6-(2-azabicyclo[3.1.0]hexen-2-yl)-1-(3-iodophenyl)-4-(trifluoromethyl)pyridin-2(1H)-one:

[0614] DIPEA (190 μL, 1.04 mmol, 8.0 eq) was added to a dry DMSO solution (1 mL) of 2-azabicyclo[3.1.0]hexane hydrochloride (77.7 mg, 0.65 mmol, 5.0 eq) and 6-chloro-1-(3-iodophenyl)-4-(trifluoromethyl)pyridin-2(1H)-one (50.0 mg, 0.13 mmol, 1.0 eq) and reacted under microwave irradiation at 130 °C for 1 h. After cooling, the reaction solution was quenched with saturated ammonium chloride aqueous solution, extracted with ethyl acetate, and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by PTLC (PE-EA = 2:1) to give 6-(2-azabicyclo[3.1.0]hexen-2-yl)-1-(3-iodophenyl)-4-(trifluoromethyl)pyridin-2(1H)-one (white solid, 25.0 mg, 43%). LC / MS (ESI) + ): calcd for C 17 H 15 F3IN2O([M+H) + )m / z 470.0, found 446.9.

[0615] Step 2: Preparation of 3-(1-(3-(6-(2-azabicyclo[3.1.0]hexane-2-yl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)phenyl)-1H-indazol-4-yl)piperidine-2,6-dione:

[0616] 3-(1H-indazol-4-yl)piperidin-2,6-dione (15.5 mg, 0.067 mmol, 1.2 eq), 6-(2-azabicyclo[3.1.0]hexen-2-yl)-1-(3-iodophenyl)-4-(trifluoromethyl)pyridin-2(1H)-one (25.0 mg, 0.056 mmol, 1.0 eq), 2-pyridinecarboxylic acid (3.40 mg, 0.028 mmol, 0.5 eq), cuprous iodide (5.32 mg, 0.028 mmol, 0.5 eq), and potassium carbonate (19.3 mg, 0.14 mmol, 2.5 eq) were weighed into a dry reaction flask, purged with argon three times, and then dry DMSO (2 mL) was added. The mixture was reacted in an oil bath at 110 °C for 1 hour. The reaction solution was cooled and filtered through diatomaceous earth, quenched with saturated ammonium chloride aqueous solution, extracted with ethyl acetate, and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by PTLC (DCM-MeOH = 18:1) to give 3-(1-(3-(6-(2-azabicyclo[3.1.0]hexane-2-yl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)phenyl)-1H-indazol-4-yl)piperidin-2,6-dione (white solid, 7.0 mg, 23%). LC / MS (ESI) + ): calcd for C 28 H 25 F3N5O3([M+H) + )m / z 548.2, found 548.1. 1 H NMR(400MHz,DMSO-d6)δ10.96(s,1H),8.45(s,1H),7.93–7.87(m,1H),7.87–7.84(m,1H),7.82–7.75(m, 1H),7.73(d,J=8.1Hz,1H),7.54–7.42(m,2H),7.13(d,J=7.1Hz,1H),6.31(d,J=5.7Hz,1H),6.23–6.14( m,1H),4.42(dd,J=12.2,4.8Hz,1H),3.37–3.28(m,2H),3.12–2.95(m,1H),2.84–2.72(m,1H),2.63–2.5 8(m,2H),1.99–1.92(m,1H),1.84–1.70(m,2H),1.58–1.51(m,1H),0.84–0.80(m,1H),0.75–0.63(m,1H).

[0617] Example 111: 3-(1-(3-(6-(2-azabicyclo[2.2.1]heptane-2-yl)-4-methyl-2-oxopyridin-1(2H)-yl)phenyl)-1H-indazol-4-yl)piperidin-2,6-dione

[0618] It was prepared using a method similar to that of Example 108. LC / MS (ESI) + calcd for C 30 H 29 N5O3([M+H)) + )m / z,508.2;found,508.1. 1 H NMR (400MHz, DMSO-d6) δ10.96(s,1H),8.43(s,1H),7.80(t,J=11.6Hz,2H),7.66(dt,J=22.7,7 .8Hz,2H),7.53–7.36(m,2H),7.13(d,J=6.9Hz,1H),5.66(d,J=5.9Hz,1H),5.53(d,J=16.2Hz,1 H),4.42(dd,J=12.1,4.4Hz,1H),2.86–2.70(m,1H),2.70–2.55(m,3H),2.44–2.39(m,2H),2.39 –2.30(m,2H),2.31–2.21(m,2H),2.11(s,3H),1.99(dt,J=12.3,6.9Hz,2H),1.80–1.61(m,2H).

[0619] Example 112: 3-(1-(3-(6-(2-azabicyclo[2.2.1]heptane-2-yl)-4-(difluoromethyl)-2-oxopyridin-1(2H)-yl)phenyl)-1H-indazol-4-yl)piperidin-2,6-dione

[0620] It was prepared using a method similar to that of Example 109. LC / MS (ESI) + calcd for C 30 H 27 FN5O3([M+H) + )m / z,544.2;found,543.8. 1H NMR(400MHz, DMSO-d6)δ10.96(s,1H),8.44(d,J=5.0Hz,1H),7.92–7.80(m,2H),7.74–7.57(m,2H),7.47(q,J= 7.4Hz,2H),7.18(d,J=8.5Hz,1H),7.14(d,J=7.1Hz,1H),6.82(t,J=55.3Hz,1H),5.94(d,J=4.1Hz,1H),5.74– 5.67(m,1H),4.42(dd,J=12.1,4.4Hz,1H),2.86–2.71(m,1H),2.69–2.54(m,3H),2.36–2.26(m,2H),2.23(d,J =9.1Hz,1H),2.13(dd,J=8.2,4.1Hz,1H),1.99(dt,J=13.0,6.8Hz,1H),1.81–1.66(m,1H),1.59–1.45(m,3H).

[0621] Example 113: 3-(1-(3-(6-(2-azabicyclo[2.2.1]heptane-2-yl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)phenyl)-1H-indazol-4-yl)piperidin-2,6-dione

[0622] The target compound was prepared using a synthetic procedure similar to that of Example 108. LC / MS (ESI) + calcd for C 30 H 26 F3N5O3([M+H) + )m / z,562.2; found,562.1. 1H NMR(400MHz, DMSO-d6)δ10.96(s,1H),8.45(d,J=5.6Hz,1H),7.95(s,1H),7.88–7.79(m,1H),7.75–7.69(m,1 H),7.67(d,J=7.5Hz,1H),7.49(t,J=7.8Hz,2H),7.21(d,J=7.8Hz,1H),7.14(d,J=7.1Hz,1H),6.02(br,1H), 5.75–5.70(m,1H),4.43(dd,J=11.9,4.6Hz,1H),2.86–2.65(m,2H),2.65–2.54(m,2H),2.39–2.27(m,2H),2. 27–2.19(m,1H),2.17–2.06(m,1H),1.99(dt,J=12.9,7.0Hz,1H),1.73(q,J=10.4Hz,1H),1.61–1.45(m,3H).

[0623] Example 114: 3-(1-(3-(6-cyclopropyloxy-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)phenyl)-1H-indazol-4-yl)piperidin-2,6-dione

[0624] 1. Synthesis of compound 6-cyclopropyloxy-1-(3-iodophenyl)-4-(trifluoromethyl)pyridine-2(1H)-one

[0625] Cyclopropanol (145 mg, 2.50 mmol) was weighed into a round-bottom flask, and 4 mL of dry THF was added. The mixture was stirred and clarified at room temperature. Argon purging was performed, followed by cooling and stirring in an ice-water bath. After 15 min, a dry THF solution containing 100 mg, 0.25 mmol of 6-chloro-1-(3-iodophenyl)-4-(trifluoromethyl)pyridin-2(1H)-one was added dropwise. The reaction was then stirred at room temperature. After 2 h, LC-MS showed the reaction was complete. Saturated ammonium chloride solution was added to quench the reaction, followed by extraction with ethyl acetate and water. The organic phase was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation to obtain the crude product. Prep-TLC purification yielded the target compound 6-cyclopropyloxy-1-(3-iodophenyl)-4-(trifluoromethyl)pyridin-2(1H)-one (57 mg). Yield: 54%. LC / MS (ESI) + calcd for C 15 H 11 F3INO2([M+H) + )m / z,422.0;found,442.9.

[0626] 2. Synthesis of compound 3-(1-(3-(6-cyclopropyloxy-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)phenyl)-1H-indazol-4-yl)piperidine-2,6-dione

[0627] Weigh 3-(1H-indazol-4-yl)piperidin-2,6-dione (37 mg, 0.16 mmol), 6-cyclopropyloxy-1-(3-iodophenyl)-4-(trifluoromethyl)pyridin-2(1H)-one (57 mg, 0.14 mmol), iodide ionone (13 mg, 0.07 mmol), 2-pyridinecarboxylic acid (8 mg, 0.07 mmol), and anhydrous potassium carbonate (37 mg, 0.28 mmol) into a round-bottom flask. After purging with argon gas three times, add 3 mL of dry DMSO. Purge with argon gas five times while stirring, then transfer to an oil bath at 110 °C and heat to react. After 1.5 h, LCMS monitoring showed the starting material had disappeared. After the system cooled to room temperature, filter using diatomaceous earth. Wash the filter cake several times with ethyl acetate. The filtrates were combined, and water and ethyl acetate were added to complete the extraction. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation to obtain the crude product. Prep-TLC purification yielded the target compound 3-(1-(3-(6-cyclopropyloxy-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)phenyl)-1H-indazol-4-yl)piperidin-2,6-dione (14 mg). Yield: 20%. LC / MS (ESI) + calcd for C 27 H 21 F3N4O4([M+H) + )m / z,523.2;found,523.0. 1H NMR (400MHz, DMSO-d6) δ10.96(s,1H),8.45(s,1H),7.90–7.83(m,1H),7.80–7.73(m,2H),7.70(t,J=8.1Hz,1H) ,7.48(dd,J=8.4,7.3Hz,1H),7.30(d,J=8.7Hz,1H),7.14(d,J=7.1Hz,1H),6.55(br,1H),6.26(d,J=1.7Hz,1H) ,4.42(dd,J=12.1,4.8Hz,1H),4.15(tt,J=5.1,2.3Hz,1H),2.78(ddd,J=17.1,12.4,5.1Hz,1H),2.59(dt,J=17 .0,3.1Hz,1H),2.13(dq,J=12.2,4.4Hz,1H),1.99(p,J=7.0,6.6Hz,1H),0.82–0.75(m,2H),0.71–0.65(m,2H).

[0628] Example 115: 3-(4'-(4-ethoxy-2-oxo-6-(3,3,3-trifluoropropyl)pyridin-1(2H)-yl)-2-ethynyl-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0629] Step 1: Synthesis of 1-(4-bromophenyl)-4-ethoxy-6-(3,3,3-trifluoropropyl)pyridine-2(1H)-one

[0630] 1-(4-bromophenyl)-4-hydroxy-6-(3,3,3-trifluoropropyl)pyridine-2(1H)-one (180 mg, 0.50 mmol) was dissolved in dry DMF (5 mL). NaH (60%) (40 mg, 1.00 mmol) was added at 0 °C, and the reaction was maintained at this temperature for 30 mins. Then, bromoethane (109 mg, 1.00 mmol) was added dropwise. After the addition was complete, the mixture was slowly brought to room temperature and reacted for 2 h. After the reaction was complete, saturated ammonium chloride was added to quench the reaction. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation. The target analyte was separated by prep-TLC to obtain 191 mg of the analyte, yield: 98%. LC / MS (ESI+) calcd for C 16 H 15 BrF3NO2([M+H] + )m / z 390.0; found 389.8.

[0631] Step 2: Synthesis of 4-ethoxy-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)-6-(3,3,3-trifluoropropyl)pyridine-2(1H)-one

[0632] 1-(4-bromophenyl)-4-ethoxy-6-(3,3,3-trifluoropropyl)pyridine-2(1H)-one (191 mg, 0.49 mmol) was dissolved in 15 mL of dry 1,4-dioxane, and pinacol diboronic acid ester (150 mg, 0.59 mmol), PdCl2 (dppf) (37 mg, 0.05 mmol), and KOAc (96 mg, 0.98 mmol) were added. The reaction was carried out at 85 °C for 6 h. After the reaction was complete, the mixture was cooled to room temperature, filtered with diatomaceous earth, and the filtrate was directly evaporated to dryness. The target analyte was separated by column chromatography to obtain 199 mg of the target analyte, yield: 93%. LC / MS (ESI+) calcd for C 22 H 27 BF3NO4([M+H) + )m / z 438.2; found 437.9.

[0633] Step 3: Synthesis of 3-(4'-(4-ethoxy-2-oxo-6-(3,3,3-trifluoropropyl)pyridin-1(2H)-yl)-2-((trimethylsilyl)ethynyl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0634] 4-ethoxy-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborin-2-yl)phenyl)-6-(3,3,3-trifluoropropyl)pyridin-2(1H)-one (100 mg, 0.23 mmol) was dissolved in THF / H2O (10 mL / 2 mL), and 3-(3-bromo-2-((trimethylsilyl)ethynyl)phenyl)piperidin-2,6-dione (100 mg, 0.28 mmol), Xphos-PdG3 (39 mg, 0.046 mmol), and triethylamine (70 mg, 0.69 mmol) were added. The reaction was carried out at 60 °C for 5 h. After the reaction was complete, it was cooled to room temperature, quenched with saturated ammonium chloride, extracted with ethyl acetate, dried the organic phase, evaporated to dryness, and separated by prep-TLC to obtain 115 mg of the target analyte, yield: 84%. LC / MS (ESI+) calcd for C 32 H 33 F3N2O4Si([M+H) + )m / z 595.2; found 594.8.

[0635] Step 4: Synthesis of 3-(4'-(4-ethoxy-2-oxo-6-(3,3,3-trifluoropropyl)pyridin-1(2H)-yl)-2-ethynyl-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0636] 3-(4'-(4-ethoxy-2-oxo-6-(3,3,3-trifluoropropyl)pyridin-1(2H)-yl)-2-((trimethylsilyl)ethynyl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione (115 mg, 0.19 mmol) was dissolved in THF (10 mL), and TBAF (1 M) (0.39 mL, 0.39 mmol) was added. The reaction was carried out at room temperature for 30 mins. After the reaction was complete, saturated ammonium chloride was added to quench the reaction, and the mixture was extracted with ethyl acetate. The organic phase was dried, evaporated to dryness, and separated by prep-TLC to obtain 52 mg of the target analyte, yield: 53%. LC / MS (ESI+) calcd for C 29 H 25 F3N2O4([M+H) + )m / z 523.2; found 522.9.

[0637] 1 H NMR(400MHz,DMSO-d6)δ10.93(s,1H),7.73–7.63(m,2H),7.49(t,J=7.7Hz,1H),7 .41–7.29(m,4H),6.08(d,J=2.6Hz,1H),5.83(d,J=2.6Hz,1H),4.33(dd,J=12.0,5 .0Hz,1H),4.30(s,1H),4.06(q,J=7.0Hz,2H),2.76(ddd,J=17.5,12.6,5.3Hz,1H ),2.57–2.52(m,1H),2.46–2.30(m,5H),2.14–2.03(m,1H),1.34(t,J=7.0Hz,3H).

[0638] Example 116: 3-(2-chloro-4'-(4-ethoxy-2-oxo-6-(3,3,3-trifluoropropyl)pyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0639] The target compound was prepared using a method similar to that in Example 105. LC / MS (ESI+) calcd for C 26 H 23 ClF3N3O4([M+H) + )m / z 534.1; found 533.8.1 H NMR (400MHz, DMSO-d6) δ10.51 (s, 1H), 7.59 (d, J = 8.2Hz, 2H), 7.57–7.50 (m, 2H), 7.46(dd,J=7.4,2.0Hz,1H),7.40(d,J=7.9Hz,2H),6.10(d,J=2.6Hz,1H),5.84( d,J=2.6Hz,1H),4.06(q,J=7.0Hz,2H),3.77(dt,J=12.3,7.1Hz,1H),3.67(dt,J =12.4,6.3Hz,1H),2.76(t,J=6.7Hz,2H),2.46–2.36(m,4H),1.34(t,J=6.9Hz,3

[0640] Example 117: 3-(2-ethynyl-4'-(2-oxo-6-(pyrrolidin-1-yl)-4-(trifluoromethyl)pyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0641] It was prepared using a method similar to that of Example 106. LC / MS (ESI+) calcd for C 29 H 24 F3N3O3([M+H) + )m / z 520.2; found 520.1. 1 H NMR(400MHz,DMSO-d6)δ10.92(s,1H),7.64–7.56(m,2H),7.49(t,J=7.7Hz,1H),7.43 –7.36(m,3H),7.34(dd,J=7.7,1.3Hz,1H),6.06(d,J=1.7Hz,1H),5.74(d,J=1.9Hz,1H ),4.36(s,1H),4.32(dd,J=11.9,5.1Hz,1H),2.84(d,J=6.4Hz,4H),2.78–2.69(m,1H) ,2.56(d,J=4.0Hz,1H),2.39(d,J=13.9Hz,1H),2.10–2.02(m,1H),1.73–1.60(m,4H).

[0642] Example 118: 3-(1-(3-(4-ethoxy-2-oxo-6-(trifluoromethyl)pyridin-1(2H)-yl)phenyl)-1H-indazol-4-yl)piperidin-2,6-dione

[0643] Step 1: Synthesis of 4-ethoxy-1-(3-iodophenyl)-6-(trifluoromethyl)pyridine-2(1H)-one

[0644] 4-Hydroxy-1-(3-iodophenyl)-6-(trifluoromethyl)pyridin-2(1H)-one (80 mg, 0.21 mmol) was dissolved in dry DMF (5 mL). NaH (60%) (17 mg, 0.42 mmol) was added at 0 °C, and the reaction was maintained at this temperature for 30 min. Then, bromoethane (45 mg, 0.42 mmol) was added dropwise. After the addition was complete, the mixture was slowly brought to room temperature and reacted for 2 h. After the reaction was complete, saturated ammonium chloride was added to quench the reaction. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation. The target analyte was separated by prep-TLC to obtain 40 mg of the analyte, yield: 47%. LC / MS (ESI+) calcd for C 14 H 11 F3INO2([M+H) + )m / z 409.9; found 409.8.

[0645] Step 2: Synthesis of 3-(1-(3-(4-ethoxy-2-oxo-6-(trifluoromethyl)pyridin-1(2H)-yl)phenyl)-1H-indazol-4-yl)piperidin-2,6-dione

[0646] 4-Ethoxy-1-(3-iodophenyl)-6-(trifluoromethyl)pyridin-2(1H)-one (40 mg, 0.10 mmol) was dissolved in dry DMSO (5 mL), and 3-(1H-indazol-4-yl)piperidin-2,6-dione (25 mg, 0.11 mmol), CuI (10 mg, 0.05 mmol), 2-pyridinecarboxylic acid (6 mg, 0.05 mmol), potassium carbonate (28 mg, 0.20 mmol) were added. The mixture was substituted with Ar three times, and the reaction was carried out at 110 °C for 1 h. After the reaction was complete as monitored by TLC, the mixture was cooled and filtered. The filtrate was quenched with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and evaporated to dryness. The crude product was separated by prep-TLC to obtain 13 mg of the target compound, yield: 26%. LC / MS (ESI+) calcd for C 26 H 21 F3N4O4([M+H) + )m / z 511.1; found 510.9. 1H NMR (400MHz, DMSO-d6) δ10.96 (s, 1H), 8.45 (s, 1H), 7.92 (dd, J = 8.1, 2.2Hz, 1H), 7.80 (d, J = 2. 4Hz,1H),7.72(t,J=8.2Hz,2H),7.48(dd,J=8.6,7.1Hz,1H),7.36(d,J=7.8Hz,1H),7.14(d,J= 7.1Hz,1H),6.69(d,J=2.6Hz,1H),6.21(d,J=2.6Hz,1H),4.42(dd,J=12.2,4.9Hz,1H),4.14(q ,J=7.0Hz,2H),2.81–2.73(m,1H),2.68–2.54(m,2H),2.17–2.10(m,1H),1.36(t,J=7.0Hz,3H)

[0647] Example 119: (R)-3-(2-ethynyl-4'-(4-methyl-2-oxo-6-(trifluoromethyl)pyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0648] Example 120: (S)-3-(2-ethynyl-4'-(4-methyl-2-oxo-6-(trifluoromethyl)pyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0649] Racemic 3-(2-ethynyl-4'-(4-methyl-2-oxo-6-(trifluoromethyl)pyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione (50 mg, 0.11 mmol) was resolved by chiral SFC to obtain fractions P1 (Example 119): 23 mg, T = 2.039 min; P2 (Example 120): 21 mg, T = 2.513 min. Column: CHIRALCEL OJ-3 (4.6*100 mm 5 μm) (Daicel), mobile phase: A = CO2, cosolvent B = EtOH. The two compounds were characterized identically: LC / MS (ESI+) calcd for C 26 H 19 F3N2O3([M+H) + )m / z 465; found 465; 1H NMR(400MHz,DMSO-d6)δ10.93(s,1H),7.70–7.62(m,2H),7.49(t,J=7.7Hz,1H),7.4 4–7.31(m,4H),6.89(d,J=1.7Hz,1H),6.65(t,J=1.5Hz,1H),4.40(s,1H),4.34(dd, J=12.0,5.1Hz,1H),2.76(ddd,J=17.5,12.6,5.4Hz,1H),2.57(t,J=3.9Hz,1H),2.3 7(dt,J=13.2,6.5Hz,1H),2.29(d,J=1.2Hz,3H),2.07(dtd,J=13.4,5.3,3.4Hz,1H).

[0650] Example 121: 3-(1-(3-(4-cyclopropyl-2-oxo-6-(trifluoromethyl)pyridin-1(2H)-yl)phenyl)-1H-indazol-4-yl)piperidin-2,6-dione

[0651] Step 1: Synthesis of 3-(1-(3-(4-hydroxy-2-oxo-6-(trifluoromethyl)pyridin-1(2H)-yl)phenyl)-1H-indazol-4-yl)piperidin-2,6-dione

[0652] 4-Hydroxy-1-(3-iodophenyl)-6-(trifluoromethyl)pyridin-2(1H)-one (150 mg, 0.40 mmol) was dissolved in dry DMSO (5 mL), and 3-(1H-indazol-4-yl)piperidin-2,6-dione (100 mg, 0.43 mmol), CuI (38 mg, 0.20 mmol), 2-pyridinecarboxylic acid (25 mg, 0.20 mmol), potassium carbonate (110 mg, 0.80 mmol) were added. The mixture was substituted with Ar three times, and reacted at 110 °C for 1 h. After the reaction was complete as monitored by TLC, the mixture was cooled and filtered. The filtrate was quenched with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and evaporated to dryness. The crude product was separated by prep-TLC to obtain 60 mg of the target compound, yield: 28%. LC / MS (ESI+) calcd for C 24 H 17 F3N4O4([M+H) + )m / z 483.1; found 482.9.

[0653] Step 2: Synthesis of 1-(3-(4-(2,6-dioxopiridine-3-yl)-1H-indazol-1-yl)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-4-yltrifluoromethanesulfonate

[0654] 3-(1-(3-(4-hydroxy-2-oxo-6-(trifluoromethyl)pyridin-1(2H)-yl)phenyl)-1H-indazol-4-yl)piperidin-2,6-dione (60 mg, 0.12 mmol) was dissolved in DCM (10 mL). Triethylamine (24 mg, 0.24 mmol) was added at 0 °C, followed by slow dropwise addition of trifluoromethanesulfonic anhydride (42 mg, 0.15 mmol). After the addition was complete, the mixture was slowly brought to room temperature and reacted for 0.5 h. After the reaction was monitored by TLC until complete, the mixture was quenched with water, extracted with DCM, dried over anhydrous sodium sulfate, and evaporated to dryness. The crude product was separated by prep-TLC to obtain 40 mg of the target compound, yield: 53%. LC / MS (ESI+) calcd for C 25 H 16 F6N4O6S([M+H) + )m / z 615.0; found 614.9.

[0655] Step 3: Synthesis of 3-(1-(3-(4-cyclopropyl-2-oxo-6-(trifluoromethyl)pyridin-1(2H)-yl)phenyl)-1H-indazol-4-yl)piperidin-2,6-dione

[0656] 1-(3-(4-(2,6-dioxopiperidin-3-yl)-1H-indazol-1-yl)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-4-yltrifluoromethanesulfonate (40 mg, 0.07 mmol) was dissolved in THF / H2O (6 mL / 1 mL), and PdCl2 (dppf) (10 mg, 0.014 mmol), triethylamine (20 mg, 0.20 mmol), and 2-cyclopropyl-4,4,5,5-tetramethyl-1,3,2-dioxaborane (35 mg, 0.21 mmol) were added. The reaction was carried out at 45 °C for 6 h. After the reaction was completed by TLC monitoring, it was cooled to room temperature, quenched with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and evaporated to dryness. The crude product was separated by prep-TLC to obtain 4 mg of the target compound, yield: 12%. LC / MS (ESI+) calcd for C 27 H 21 F3N4O3([M+H) + )m / z 507.1; found 506.9. 1H NMR (400MHz, DMSO-d6) δ10.96(s,1H),8.45(d,J=0.9Hz,1H),7.91(dt,J=8.1,1.5Hz,1H),7.81(s, 1H),7.72(t,J=8.2Hz,2H),7.48(dd,J=8.6,7.1Hz,1H),7.35(d,J=7.8Hz,1H),7.13(d,J=7.1Hz,1 H),6.70(d,J=1.8Hz,1H),6.55(d,J=1.8Hz,1H),4.42(dd,J=12.1,4.8Hz,1H),2.82–2.74(m,1H), 2.60(d,J=4.2Hz,2H),2.15–2.09(m,1H),2.00–1.98(m,1H),1.11–1.06(m,2H),0.96–0.91(m,2H).

[0657] Example 122: 3-(1-(3-(6-(3,4-difluoro-1H-pyrrolo-1-yl)-4-methyl-2-oxopyridin-1(2H)-yl)phenyl)-1H-indazol-4-yl)piperidin-2,6-dione

[0658] Step 1: Synthesis of 6-(3,4-difluoro-1H-pyrrolo-1-yl)-1-(3-iodophenyl)-4-methylpyridin-2(1H)-one

[0659] 6-Chloro-1-(3-iodophenyl)-4-methylpyridin-2(1H)-one (200 mg, 0.58 mmol) was added to a microwave-safe tube, followed by 5 mL of dry DMF, 3,3,4,4-tetrafluoropyrrolidine hydrochloride (312 mg, 1.74 mmol), and Cs₂CO₃ (756 mg, 2.32 mmol). The mixture was microwave-safe at 130 °C for 2 h. After the reaction was complete as monitored by TLC, the mixture was quenched with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and evaporated to dryness. The crude product was separated by column chromatography to obtain 114 mg of the target compound, yield: 46%. LC / MS (ESI+) calcd for C 16 H 11 F2IN2O([M+H) + )m / z 412.9; found 412.8.

[0660] Step 2: Synthesis of 3-(1-(3-(6-(3,4-difluoro-1H-pyrrolo-1-yl)-4-methyl-2-oxopyridin-1(2H)-yl)phenyl)-1H-indazol-4-yl)piperidin-2,6-dione

[0661] 6-(3,4-difluoro-1H-pyrrolo-1-yl)-1-(3-iodophenyl)-4-methylpyridin-2(1H)-one (50 mg, 0.12 mmol) was dissolved in dry DMSO (5 mL), and 3-(1H-indazol-4-yl)piperidin-2,6-dione (34 mg, 0.14 mmol), CuI (12 mg, 0.06 mmol), 2-pyridinecarboxylic acid (8 mg, 0.06 mmol), potassium carbonate (33 mg, 0.24 mmol) were added. The mixture was substituted with Ar three times, and reacted at 110 °C for 1 h. After the reaction was complete as monitored by TLC, the mixture was cooled and filtered. The filtrate was quenched with saturated ammonium chloride, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and evaporated to dryness. The crude product was separated by prep-TLC to obtain 9 mg of the target compound, yield: 15%. LC / MS (ESI+) calcd for C 28 H 21 F2N5O3([M+H) + )m / z 514.2; found 513.9. 1 H NMR (400MHz, DMSO-d6) δ10.96(s,1H),8.43(s,1H),7.79–7.73(m,2H),7.70(d,J=8.5Hz,1H),7.57(t ,J=8.0Hz,1H),7.50–7.44(m,1H),7.22(ddd,J=7.9,2.0,1.0Hz,1H),7.13(d,J=7.2Hz,1H),6.98(d,J =1.5Hz,2H),6.51–6.47(m,1H),6.41(d,J=1.6Hz,1H),4.42(dd,J=12.2,4.8Hz,1H),2.77(dd,J=10.4 ,5.8Hz,1H),2.59(d,J=17.3Hz,1H),2.46(d,J=4.2Hz,1H),2.25(d,J=1.1Hz,3H),2.16–2.10(m,1H).

[0662] Example 123: 1-(2-chloro-4'-(2-oxo-6-(2,2,2-trifluoroethoxy)-4-(trifluoromethyl)pyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

[0663] Step 1: Synthesis of 1-(4-bromophenyl)-6-chloro-4-(trifluoromethyl)pyridine-2(1H)-one

[0664] 6-Chloro-4-(trifluoromethyl)pyridin-2-ol (3.00 g, 15.23 mmol), p-bromophenylboronic acid (4.59 g, 22.84 mmol), and copper trifluoromethanesulfonate (2.75 g, 7.62 mmol) were placed in a single-necked flask. Hexafluoroisopropanol (30 mL) was added, followed by the addition of TMEDA (884 mg, 7.62 mmol) and pyridine (3.61 g, 45.69 mmol). The mixture was purged three times with Ar gas and stirred overnight at 50 °C. After the reaction was complete as monitored by TLC, it was cooled to room temperature, filtered through diatomaceous earth, quenched with dilute hydrochloric acid, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and evaporated to dryness. The crude product was separated by column chromatography to obtain 481 mg of the target compound, yield: 9%. LC / MS (ESI+) calcd for C 12 H6BrClF3NO([M+H) + )m / z 351.9; found 351.7.

[0665] Step 2: Synthesis of 1-(4-bromophenyl)-6-(2,2,2-trifluoroethoxy)-4-(trifluoromethyl)pyridine-2(1H)-one

[0666] 200 mg (0.57 mmol) of 1-(4-bromophenyl)-6-chloro-4-(trifluoromethyl)pyridin-2(1H)-one was added to a single-necked flask, followed by 10 mL of freshly prepared sodium trifluoroethoxide solution. The mixture was purged three times with Ar gas and reacted overnight at 80 °C. After the reaction was complete as monitored by TLC, it was cooled to room temperature, quenched with saturated ammonium chloride, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and evaporated to dryness. The crude product was separated by column chromatography to obtain 208 mg of the target compound, yield: 88%. LC / MS (ESI+) calcd for C 14 H8BrF6NO2([M+H) + )m / z 415.9; found 415.7.

[0667] Step 3: Synthesis of 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)-6-(2,2,2-trifluoroethoxy)-4-(trifluoromethyl)pyridine-2(1H)-one

[0668] 1-(4-bromophenyl)-6-(2,2,2-trifluoroethoxy)-4-(trifluoromethyl)pyridin-2(1H)-one (182 mg, 0.44 mmol) was dissolved in 10 mL of dry 1,4-dioxane, and pinacol diboronic acid ester (123 mg, 0.48 mmol), PdCl2 (dppf) (32 mg, 0.044 mmol), and KOAc (86 mg, 0.88 mmol) were added. The reaction was carried out at 85 °C for 6 h. After the reaction was complete, the mixture was cooled to room temperature, filtered with diatomaceous earth, and directly evaporated to dryness. The target analyte was separated by column chromatography to obtain 187 mg of the target analyte, yield: 92%. LC / MS (ESI+) calcd for C 20 H 20 BF6NO4([M+H) + )m / z 464.1; found 463.8.

[0669] Step 4: Synthesis of 1-(2-chloro-4'-(2-oxo-6-(2,2,2-trifluoroethoxy)-4-(trifluoromethyl)pyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

[0670] 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)-6-(2,2,2-trifluoroethoxy)-4-(trifluoromethyl)pyridin-2(1H)-one (90 mg, 0.19 mmol) was dissolved in 1,4-dioxane / H₂O (10 mL / 2 mL), and 1-(3-bromo-2-chlorophenyl)dihydropyrimidine-2,4(1H,3H)-dione (57 mg, 0.19 mmol), PdCl₂ (dppf) (14 mg, 0.02 mmol), and NaHCO₃ (32 mg, 0.38 mmol) were added. The mixture was purged three times with Ar gas, and reacted at 80 °C for 2 h. After the reaction was complete, it was cooled to room temperature, quenched with saturated ammonium chloride, extracted with ethyl acetate, dried the organic phase, evaporated to dryness, and separated by prep-TLC to obtain 32 mg of the target compound, yield: 30%. LC / MS(ESI+)calcd for C 24 H 16 ClF6N3O4([M+H) + )m / z 560.0; found 559.9. 1H NMR (400MHz, DMSO-d6) δ10.51(s,1H),7.62–7.55(m,3H),7.53(s,1H),7.46(dd,J=7.4,2.1Hz,1H),7.41(d,J=8.1Hz,2H) ,6.65(s,1H),6.33(d,J=1.7Hz,1H),4.99(q,J=8.5Hz,2H),3.85–3.73(m,1H),3.72–3.63(m,1H),2.77(t,J=6.7Hz,2H).

[0671] Example 124: 3-(1-(3-(4-methoxy-2-oxo-6-(3,3,3-trifluoropropyl)pyridin-1(2H)-yl)phenyl)-1H-indazol-4-yl)piperidin-2,6-dione

[0672] Step 1: Synthesis of tert-butyl 8,8,8-trifluoro-3,5-dioxooctanoate

[0673] Under Ar protection, 60% NaH (1.62 g, 40.4 mmol) was added to a three-necked flask containing 100 mL of dry THF. The flask was purged with Ar three times. tert-butyl 3-oxobutyrate (5.80 g, 36.74 mmol) was added dropwise at 0 °C. After 30 min, 2.5 Mn-BuLi (14.7 mL, 36.74 mmol) was added dropwise, and the reaction was maintained at this temperature for 1 h. The reaction system was then cooled to -50 °C, and ethyl 4,4,4-trifluorobutyrate (5.00 g, 29.40 mmol) and boron trifluoride ether (4.17 g, 29.40 mmol) were added dropwise. After the addition was complete, the temperature was slowly raised to room temperature, and the reaction was allowed to proceed for 1 h. After the reaction was monitored by TLC until complete, saturated ammonium chloride was added to quench the reaction in an ice bath. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and evaporated to dryness. The crude product was separated by column chromatography to obtain 4.00 g of the target compound, yield: 48%. LC / MS(ESI+)calcd for C 12 H 17 F3O4([M+H)) + )m / z 283.1; found 227.0.

[0674] Step 2: Synthesis of 8,8,8-trifluoro-3,5-dioxooctanoic acid

[0675] 4.00 g (14.18 mmol) of tert-butyl 8,8,8-trifluoro-3,5-dioxooctanoate was dissolved in 15 mL of DCM, and 5 mL of TFA was added dropwise at 0 °C. The reaction was maintained at this temperature for 2 h. After the reaction was complete as monitored by TLC, the TFA was removed by rotary evaporation to obtain 2.9 g of crude product (yield: 92%), which was directly used in the next step. LC / MS (ESI+) calcd for C8H9F3O4 ([M+H) + )m / z 227.0; found 226.9.

[0676] Step 3: Synthesis of 4-hydroxy-6-(3,3,3-trifluoropropyl)-2H-pyran-2-one

[0677] 8,8,8-trifluoro-3,5-dioxooctanoic acid (2.90 g, 10.2 mmol) was dissolved in acetic anhydride (20 mL) and reacted overnight at room temperature. After the reaction was complete, the solvent was removed by rotary evaporation, and MeOH (20 mL) and K₂CO₃ (4.91 g, 35.6 mmol) were added. The reaction was continued at room temperature for 3 h. After the reaction was complete, the solvent was removed by rotary evaporation, the crude product was adjusted to weakly acidic with dilute hydrochloric acid, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and evaporated to dryness. The product was then separated by column chromatography to obtain 1.10 g of the target analyte, yield: 51%. LC / MS (ESI+) calcd for C₈H₇F₃O₃([M+H)₂) + )m / z 209.0; found 208.9.

[0678] Step 4: Synthesis of 4-hydroxy-1-(3-iodophenyl)-6-(3,3,3-trifluoropropyl)pyridine-2(1H)-one

[0679] 3-Iodoaniline (1.05 g, 4.80 mmol) and 4-hydroxy-6-(3,3,3-trifluoropropyl)-2H-pyran-2-one (1.00 g, 4.80 mmol) were dissolved in AcOH / H2O (5 mL / 5 mL) and reacted at 90 °C for 6 h. After the reaction was complete as monitored by TLC, the mixture was cooled to room temperature, extracted with ethyl acetate, dried over anhydrous sodium sulfate, evaporated to dryness, and separated by column chromatography to obtain 196 mg of the target analyte, yield: 10%. LC / MS (ESI+) calcd for C 14 H 11 F3INO2([M+H) + )m / z 409.9; found 409.7.

[0680] Step 5: Synthesis of 1-(3-iodophenyl)-4-methoxy-6-(3,3,3-trifluoropropyl)pyridine-2(1H)-one

[0681] 100 mg (0.24 mmol) of 4-hydroxy-1-(3-iodophenyl)-6-(3,3,3-trifluoropropyl)pyridin-2(1H)-one was dissolved in acetone (10 mL), and KOH (27 mg, 0.49 mmol) was added. Dimethyl sulfate (62 mg, 0.49 mmol) was added dropwise at room temperature, and the reaction was carried out at 50 °C for 2 h. After the reaction was completed by TLC monitoring, it was cooled to room temperature, adjusted to weak acidity with dilute HCl, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation. The target analyte was separated by prep-TLC to obtain 59 mg, yield: 58%. LC / MS (ESI+) calcd for C 15 H 13 F3INO2([M+H) + )m / z 423.9; found 423.7.

[0682] Step 6: Synthesis of 3-(1-(3-(4-methoxy-2-oxo-6-(3,3,3-trifluoropropyl)pyridin-1(2H)-yl)phenyl)-1H-indazol-4-yl)piperidin-2,6-dione

[0683] 1-(3-iodophenyl)-4-methoxy-6-(3,3,3-trifluoropropyl)pyridine-2(1H)-one (59 mg, 0.14 mmol) was dissolved in dry DMSO (5 mL), and 3-(1H-indazol-4-yl)piperidin-2,6-dione (38 mg, 0.17 mmol), CuI (13 mg, 0.07 mmol), 2-pyridinecarboxylic acid (9 mg, 0.07 mmol), potassium carbonate (39 mg, 0.28 mmol) were added. The mixture was substituted with Ar three times, and the reaction was carried out at 110 °C for 1 h. After the reaction was complete as monitored by TLC, the mixture was cooled and filtered. The filtrate was quenched with saturated ammonium chloride, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and evaporated to dryness. The crude product was separated by prep-TLC to obtain 17 mg of the target compound, yield: 23%. LC / MS (ESI+) calcd for C 27 H 23 F3N4O4([M+H) + )m / z 525.1; found 524.8. 1H NMR(400MHz,DMSO-d6)δ10.96(s,1H),8.45(s,1H),7.95–7.87(m,1H),7.79–7.67(m,3H),7 .48(dd,J=8.6,7.1Hz,1H),7.38–7.30(m,1H),7.14(d,J=7.1Hz,1H),6.11(d,J=2.6Hz,1H) ,5.88(d,J=2.6Hz,1H),4.43(dd,J=12.2,4.9Hz,1H),3.80(s,3H),2.77(td,J=12.3,6.1Hz ,1H),2.64(d,J=24.4Hz,1H),2.57(s,2H),2.46(dd,J=7.4,2.4Hz,3H),2.17–2.08(m,1H).

[0684] Example 125: 3-(1-(3-(4-ethoxy-2-oxo-6-(3,3,3-trifluoropropyl)pyridin-1(2H)-yl)phenyl)-1H-indazol-4-yl)piperidin-2,6-dione

[0685] The target compound was prepared using a method similar to that in Example 125. LC / MS (ESI+) calcd for C 28 H 25 F3N4O4([M+H) + )m / z 539.2; found 538.9. 1 H NMR (400MHz, DMSO-d6) δ10.96(s,1H),8.45(s,1H),7.90(dd,J=8.2,2.1Hz,1H),7.79–7.70(m,3H),7. 48(dd,J=8.5,7.1Hz,1H),7.34(dd,J=7.9,2.0Hz,1H),7.14(d,J=7.1Hz,1H),6.09(d,J=2.6Hz,1H),5 .85(d,J=2.6Hz,1H),4.42(dd,J=12.2,4.9Hz,1H),4.07(q,J=7.0Hz,2H),2.77(td,J=12.3,6.1Hz,1H ),2.69–2.59(m,1H),2.57–2.51(m,3H),2.48–2.41(m,2H),2.18–2.10(m,1H),1.34(t,J=7.0Hz,3H).

[0686] Example 126: 3-(4'-(6-cyclohexyl-4-(difluoromethyl)-2-oxopyridin-1(2H)-yl)-2-ethynyl-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0687] Step 1: Synthesis of 1-(4-bromophenyl)-6-cyclohexyl-4-methylpyridin-2(1H)-one

[0688] 1.92 g (10.00 mmol) of 6-cyclohexyl-4-methyl-2H-pyran-2-one was placed in a single-necked flask, and xylene (2 mL) and NaH (400 mg, 10 mmol) were added. The mixture was stirred at room temperature for 30 mins, and then reacted overnight at 130 °C. After the reaction was complete, it was cooled to room temperature, quenched with saturated ammonium chloride, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation. The target analyte was then separated by column chromatography to obtain 400 mg of 6-cyclohexyl-4-methyl-2H-pyran-2-one, yield: 11%. LC / MS (ESI+) calcd for C 18 H 20 BrNO([M+H] + )m / z 346.0; found 345.8.

[0689] Step 2: Synthesis of 1-(4-bromophenyl)-6-cyclohexyl-2-oxo-1,2-dihydropyridine-4-carboxaldehyde

[0690] 1-(4-bromophenyl)-6-cyclohexyl-4-methylpyridin-2(1H)-one (400 mg, 1.16 mmol) was placed in a sealed tube, and chlorobenzene (5 mL) and selenium dioxide (386 mg, 3.48 mmol) were added. The reaction was carried out overnight at 140 °C. After the reaction was complete, it was cooled to room temperature, quenched with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation. The target analyte was separated by column chromatography to obtain 220 mg of the target analyte, yield: 53%. LC / MS (ESI+) calcd for C 18 H 18 BrNO2([M+H] + )m / z 356.0; found 359.9.

[0691] Step 3: Synthesis of 1-(4-bromophenyl)-6-cyclohexyl-4-(difluoromethyl)pyridine-2(1H)-one

[0692] 1-(4-bromophenyl)-6-cyclohexyl-2-oxo-1,2-dihydropyridine-4-carboxaldehyde (220 mg, 0.61 mmol) was dissolved in DCM (10 mL), and DAST (197 mg, 1.22 mmol) was added dropwise under ice bath conditions. After the addition was complete, the mixture was slowly brought to room temperature and reacted for 1 h. After the reaction was complete, the mixture was quenched with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation. The target analyte was separated by column chromatography to obtain 140 mg of the target analyte, yield: 60%. LC / MS (ESI+) calcd for C 18 H 18 BrF2NO([M+H] + )m / z 382.0; found 381.8.

[0693] Step 4: Synthesis of 6-cyclohexyl-4-(difluoromethyl)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)pyridin-2(1H)-one

[0694] 1-(4-bromophenyl)-6-cyclohexyl-4-(difluoromethyl)pyridin-2(1H)-one (140 mg, 0.37 mmol) was dissolved in 10 mL of dry 1,4-dioxane, and then Pinacol diboronic acid ester (112 mg, 0.44 mmol), PdCl2 (dppf) (27 mg, 0.037 mmol), and KOAc (72 mg, 0.74 mmol) were added. The mixture was reacted at 85 °C for 6 h. After the reaction was complete, the mixture was cooled to room temperature, filtered with diatomaceous earth, and the filtrate was directly evaporated to dryness. The target analyte was separated by column chromatography to obtain 143 mg of the target analyte, yield: 90%. LC / MS (ESI+) calcd for C 24 H 30 BF2NO3([M+H) + )m / z 430.2; found 430.1.

[0695] Step 5: Synthesis of 3-(4'-(6-cyclohexyl-4-(difluoromethyl)-2-oxopyridin-1(2H)-yl)-2-((trimethylsilyl)ethynyl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0696] 6-Cyclohexyl-4-(difluoromethyl)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborin-2-yl)phenyl)pyridin-2(1H)-one (90 mg, 0.21 mmol) was dissolved in THF / H₂O (10 mL / 2 mL), and 3-(3-bromo-2-((trimethylsilyl)ethynyl)phenyl)piperidin-2,6-dione (91 mg, 0.25 mmol), Xphos-PdG3 (36 mg, 0.042 mmol), and triethylamine (64 mg, 0.63 mmol) were added. The reaction was carried out at 50 °C for 5 h. After the reaction was complete, it was cooled to room temperature, quenched with saturated ammonium chloride, extracted with ethyl acetate, dried the organic phase, evaporated to dryness, and separated by prep-TLC to obtain 58 mg of the target analyte, yield: 47%. LC / MS (ESI+) calcd for C 34 H 36 F2N2O3Si([M+H) + )m / z 587.2; found 587.1.

[0697] Step 6: Synthesis of 3-(4'-(6-cyclohexyl-4-(difluoromethyl)-2-oxopyridin-1(2H)-yl)-2-ethynyl-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0698] 3-(4'-(6-cyclohexyl-4-(difluoromethyl)-2-oxopyridin-1(2H)-yl)-2-((trimethylsilyl)ethynyl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione (58 mg, 0.10 mmol) was dissolved in THF (5 mL), and TBAF (1 M) (0.20 mL, 0.20 mmol) was added. The reaction was carried out at room temperature for 30 mins. After the reaction was complete, saturated ammonium chloride was added to quench the reaction, and the mixture was extracted with ethyl acetate. The organic phase was dried, evaporated to dryness, and separated by prep-TLC to obtain 22 mg of the target analyte, yield: 44%. LC / MS (ESI+) calcd for C 31 H 28 F2N2O3([M+H) + )m / z 515.2; found 514.9. 1H NMR (400MHz, DMSO-d6) δ10.93(s,1H),7.74–7.63(m,2H),7.50(t,J=7.7Hz,1H),7.42(dd,J=7.7,1.3Hz,1H),7. 36(ddd,J=10.8,7.5,1.3Hz,3H),6.92(t,J=55.1Hz,1H),6.56(q,J=1.5Hz,1H),6.36(d,J=1.8Hz,1H),4.36(s, 1H),4.35–4.29(m,1H),2.80–2.72(m,1H),2.58–2.52(m,1H),2.42–2.33(m,1H),2.10–2.01(m,2H),1.77(d,J= 12.4Hz,2H),1.64(d,J=13.0Hz,2H),1.56–1.50(m,1H),1.38–1.22(m,4H),1.13(ddd,J=13.4,9.2,2.5Hz,1H).

[0699] Example 127: 3-(4'-(4-(difluoromethyl)-2-oxo-6-(trifluoromethyl)pyridin-1(2H)-yl)-2-ethynyl-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0700] The target compound was prepared using a method similar to that in Example 126. LC / MS (ESI+) calcd for C 26 H 17 F5N2O3([M+H) + )m / z 501.1; found 500.8. 1 H NMR(400MHz,DMSO-d6)δ10.93(s,1H),7.71–7.62(m,2H),7.48(t,J=7.7Hz,3H ),7.40(dd,J=7.8,1.4Hz,1H),7.34(dd,J=7.6,1.2Hz,1H),7.08(s,1H),7.04 (d,J=1.5Hz,1H),7.03–6.88(m,1H),4.40(s,1H),4.33(dd,J=11.9,5.1Hz,1H ),2.80–2.72(m,1H),2.57(s,1H),2.38(d,J=12.6Hz,1H),2.09–2.02(m,1H).

[0701] Example 128: 3-(4'-(4,6-dimethyl-2-oxopyridin-1(2H)-yl)-2-ethynyl-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0702] The target compound was prepared using a synthesis procedure similar to that of Example 81. 1 H NMR (400MHz, DMSO-d6) δ10.93(s,1H),7.72–7.64(m,2H),7.49(t,J=7.7Hz,1H),7.40(dd,J=7.7,1 .3Hz,1H),7.34(dd,J=7.8,1.3Hz,1H),7.32–7.26(m,2H),6.19(t,J=1.4Hz,1H),6.13(dd,J=1.9,0 .9Hz,1H),4.41(s,1H),4.34(dd,J=12.0,5.1Hz,1H),2.77(ddd,J=17.5,12.7,5.3Hz,1H),2.53(d ,J=3.0Hz,1H),2.45–2.35(m,1H),2.15(s,3H),2.12–2.02(m,1H),1.92(s,3H).LC / MS(ESI+)calcd for C 26 H 23 N₂O₃([M+H)) + )m / z 411.16; found 411.1.

[0703] Example 129: 3-(2-ethynyl-4'-(4-methyl-2-oxo-6-(2,2,2-trifluoroethoxy)pyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0704] Step 1: Synthesis of 1-(4-bromophenyl)-6-chloro-4-methylpyridin-2(1H)-one

[0705] 6-Chloro-4-methylpyridin-2(1H)-one (1.43 g, 10.0 mmol), p-bromophenylboronic acid (3.01 g, 15.0 mmol), TMEDA (465 mg, 4.0 mmol), copper trifluoromethanesulfonate (1.15 g, 4.0 mmol), and pyridine (2.37 g, 30.0 mmol) were added to dry DCE solvent. The reaction mixture was purged with oxygen three times, then heated to 50 °C and reacted for 4 hours. After cooling to room temperature, the mixture was extracted with dichloromethane, concentrated under reduced pressure, purified by silica gel column chromatography, and eluted with ethyl acetate / petroleum ether to give the target compound 1-(4-bromophenyl)-6-chloro-4-methylpyridin-2(1H)-one (420 mg, 1.41 mmol), yield: 14%. LC / MS (ESI+) calcd for C 12 H 10 BrClNO([M+H] + )m / z 297.96; found 297.9.

[0706] Step 2: Synthesis of 1-(4-bromophenyl)-4-methyl-6-(2,2,2-trifluoroethoxy)pyridine-2(1H)-one

[0707] 1-(4-bromophenyl)-6-chloro-4-methylpyridin-2(1H)-one (420 mg, 1.41 mmol) and sodium trifluoroethoxide (3.44 g, 28.2 mmol) were added to 15 mL of trifluoroethanol. The reaction mixture was heated to 130 °C and irradiated with microwave for 12 hours. After cooling to room temperature, it was extracted with ethyl acetate, concentrated under reduced pressure, and then purified by silica gel column chromatography. The purified compound was eluted with ethyl acetate / petroleum ether to give 1-(4-bromophenyl)-4-methyl-6-(2,2,2-trifluoroethoxy)pyridin-2(1H)-one (267 mg, 0.74 mmol), yield: 52%. LC / MS (ESI+) calcd for C 14 H 12 BrF3NO2([M+H] + )m / z 361.99; found 361.9.

[0708] Steps 3, 4, and 5: Synthesis of 3-(2-ethynyl-4'-(4-methyl-2-oxo-6-(2,2,2-trifluoroethoxy)pyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0709] The target compound was prepared using a synthesis procedure similar to that of Example 81. 1H NMR (400MHz, DMSO-d6) δ10.93 (s, 1H), 7.66–7.60 (m, 2H), 7.49 (t, J = 7.7Hz, 1H), 7.35 (ddd, J=13.3,7.7,1.2Hz,2H),7.28–7.23(m,2H),6.05(t,J=1.3Hz,1H),5.91(d,J=1.5Hz,1H),4. 82(q,J=8.6Hz,2H),4.39–4.31(m,1H),4.31(s,1H),2.76(ddd,J=17.5,12.6,5.4Hz,1H),2 .57(t,J=3.8Hz,1H),2.43–2.35(m,1H),2.20(s,3H),2.13–2.04(m,1H).LC / MS(ESI+)calcd for C 27 H 22 F3N2O4([M+H) + )m / z 495.15; found 495.1.

[0710] Example 130: 3-(2-ethynyl-4'-(4-(methoxy-d3)-2-oxo-6-(trifluoromethyl)pyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0711] Step 1: Synthesis of 1-(4-bromophenyl)-4-(methoxy-d3)-6-(trifluoromethyl)pyridine-2(1H)-one

[0712] 1-(4-bromophenyl)-4-hydroxy-6-(trifluoromethyl)pyridin-2(1H)-one (100 mg, 0.30 mmol), deuterated methanol (11 mg, 0.30 mmol), and triphenylphosphine (118 mg, 0.45 mmol) were added to dry THF solvent. DIAD (91 mg, 0.45 mmol) was added in an ice bath. The reaction was carried out overnight at room temperature under nitrogen protection with stirring. After the reaction was complete, the mixture was extracted with ethyl acetate and concentrated under reduced pressure. The solution was purified by silica gel agar plate preparation and developed with petroleum ether / ethyl acetate to give the target compound 1-(4-bromophenyl)-4-(methoxy-d3)-6-(trifluoromethyl)pyridin-2(1H)-one (73 mg, 0.21 mmol), yield: 70%. LC / MS (ESI+) calcd for C 13 H7D3BrF3NO2([M+H) + )m / z 351.00; found 351.0.

[0713] Steps 2, 3, and 4: Synthesis of 3-(2-ethynyl-4'-(4-(methoxy-d3)-2-oxo-6-(trifluoromethyl)pyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0714] The target compound was prepared using a synthesis procedure similar to that of Example 81. 1 H NMR (400MHz, DMSO-d6) δ10.90(s,1H),7.70–7.61(m,2H),7.49(t,J=7.7Hz,1H),7.41–7.31(m,4H),6.69(d,J=2.6Hz,1H),6.21(d,J=2.6Hz,1H),4.3 8(s,1H),4.33(dd,J=12.0,5.1Hz,1H),2.75(td,J=12.4,6.2Hz,1H),2.57(t,J=3.8Hz,1H),2.43–2.34(m,1H),2.12–2.03(m,1H).LC / MS(ESI+)calcd for C 26 H 17 D3F3N2O4([M+H) + )m / z 484.15; found 484.1.

[0715] Example 131: 3-(2-ethynyl-4'-(4-methyl-2-oxo-6-(3,3,3-trifluoropropyl)pyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0716] Step 1: Synthesis of 4,4,4-trifluorobutyryl chloride

[0717] 10 g (70.4 mmol) of 4,4,4-trifluorobutyric acid was added to 15 mL of dichloromethane, followed by 11 g (93.1 mmol) of thionyl chloride and 2 drops of DMF as a catalyst. The reaction mixture was heated to 40 °C and stirred for 12 hours. After cooling to room temperature, a dichloromethane solution of the target compound, 4,4,4-trifluorobutyryl chloride, was obtained and used directly in the next reaction step without further processing.

[0718] Step 2: Synthesis of 4-methyl-6-(3,3,3-trifluoropropyl)-2H-pyran-2-one

[0719] The dichloromethane solution of 4,4,4-trifluorobutyryl chloride prepared in the previous step was added to 50 mL of dichloromethane solution of ethyl 3-methylbut-2-enoate (7.2 g, 56.0 mmol). After mixing thoroughly, the solution was slowly added dropwise to 150 mL of dichloromethane solution of aluminum trichloride (18.7 g, 140.0 mmol) under ice bath conditions. The mixture was then heated to 40 °C and stirred for 5 hours. After cooling to room temperature, the reaction solution was poured into 100 mL of ice water, extracted with dichloromethane, dried over anhydrous magnesium sulfate, and concentrated. The concentrated oily liquid was slowly dissolved in a pre-prepared mixed solution of 50 mL of sulfuric acid and 100 mL of glacial acetic acid, heated to 40 °C, and stirred for 12 hours. After cooling to room temperature, the reaction solution was poured into 200 mL of ice water, extracted with dichloromethane, washed twice with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. Purification was performed by silica gel column chromatography, followed by elution with petroleum ether / ethyl acetate, to give the target compound 4-methyl-6-(3,3,3-trifluoropropyl)-2H-pyran-2-one (273 mg, 1.32 mmol), yield: 2%. LC / MS (ESI+) calcd for C9H 10 F3O2([M+H) + )m / z 207.06; found 206.9.

[0720] Step 3: Synthesis of 1-(4-bromophenyl)-4-methyl-6-(3,3,3-trifluoropropyl)pyridine-2(1H)-one

[0721] 4-Methyl-6-(3,3,3-trifluoropropyl)-2H-pyran-2-one (273 mg, 1.32 mmol) and p-bromoaniline (227 mg, 1.32 mmol) were added to 3 mL of xylene, and the reaction was heated to 140 °C and stirred for 24 hours. After the reaction was complete, it was cooled to room temperature, extracted with ethyl acetate, concentrated under reduced pressure, purified by silica gel agar plate preparation, and developed with petroleum ether / ethyl acetate system to obtain the target compound 1-(4-bromophenyl)-4-methyl-6-(3,3,3-trifluoropropyl)pyridin-2(1H)-one (82 mg, 0.23 mmol), yield: 17%. LC / MS (ESI+) calcd for C 15 H 14 BrF3NO([M+H] + )m / z 360.01; found 359.8.

[0722] Step 4: Synthesis of 4-methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)-6-(3,3,3-trifluoropropyl)pyridine-2(1H)-one

[0723] 1-(4-bromophenyl)-4-methyl-6-(3,3,3-trifluoropropyl)pyridin-2(1H)-one (82 mg, 0.23 mmol), pinacol diboronate (64 mg, 0.25 mmol), catalyst Pd(dppf)Cl2 (17 mg, 0.02 mmol), and potassium acetate (68 mg, 0.69 mmol) were added to 10 mL of dry dioxane solvent. The reaction mixture was purged with nitrogen three times, then heated to 80 °C and reacted for 12 hours. The extract was cooled to room temperature, extracted with ethyl acetate, concentrated under reduced pressure, and then purified by silica gel column chromatography. The extract was eluted with ethyl acetate / petroleum ether to yield the target compound 4-methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)phenyl)-6-(3,3,3-trifluoropropyl)pyridin-2(1H)-one (86 mg, 0.21 mmol), yield: 92%. LC / MS (ESI+) calcd for C 21 H 26 BF3NO3([M+H) + )m / z 408.19; found 408.2.

[0724] Step 5: Synthesis of 3-(4'-(4-methyl-2-oxo-6-(3,3,3-trifluoropropyl)pyridin-1(2H)-yl)-2-((trimethylsilyl)ethynyl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0725] 4-Methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)phenyl)-6-(3,3,3-trifluoropropyl)pyridin-2(1H)-one (57 mg, 0.14 mmol), 6-methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)phenyl)pyridin-2(1H)-one (51 mg, 0.14 mmol), triethylamine (43 mg, 0.42 mmol), and catalyst Xphos-Pd-G3 (15 mg, 0.02 mmol) were added to a mixed solvent (10 / 1) of tetrahydrofuran and water. The reaction mixture was purged three times with nitrogen and then heated to 45 °C for 12 hours. The solution was cooled to room temperature and concentrated under reduced pressure, then purified by silica gel column chromatography to obtain the target compound 3-(4'-(4-methyl-2-oxo-6-(3,3,3-trifluoropropyl)pyridin-1(2H)-yl)-2-((trimethylsilyl)ethynyl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione (20 mg, 0.035 mmol), yield: 25%. LC / MS (ESI+) calcd for C 31 H 32F3N2O3Si([M+H) + )m / z 565.21; found 565.2.

[0726] Step 6: Synthesis of 3-(2-ethynyl-4'-(4-methyl-2-oxo-6-(3,3,3-trifluoropropyl)pyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0727] The compound 3-(4'-(4-methyl-2-oxo-6-(3,3,3-trifluoropropyl)pyridin-1(2H)-yl)-2-((trimethylsilyl)ethynyl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione (20 mg, 0.035 mmol) was dissolved in 10 mL of dry tetrahydrofuran, and 0.5 mL of TBAF (1 M) tetrahydrofuran solution was added. The mixture was stirred at room temperature for 1 hour. When the reaction was determined to be complete based on TLC and LCMS analysis, the mixture was extracted with ethyl acetate, concentrated under reduced pressure, and then purified by silica gel column chromatography to obtain the target compound 3-(2-ethynyl-4'-(4-methyl-2-oxo-6-(3,3,3-trifluoropropyl)pyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione (12 mg, 0.024 mmol), yield: 70%. 1 H NMR(400MHz, DMSO-d6)δ10.93(s,1H),7.71–7.65(m,2H),7.50(t,J=7.7Hz,1H), 7.40–7.33(m,4H),6.24(dd,J=8.0,1.7Hz,2H),4.33(dd,J=11.3,4.4Hz,1H),4. 30(s,1H),2.78–2.70(m,1H),2.53(d,J=3.8Hz,1H),2.46–2.42(m,3H),2.39(q, J=3.9,3.4Hz,2H),2.18(s,3H),2.08(dd,J=10.0,5.3Hz,1H).LC / MS(ESI+)calcd for C 28 H 24 F3N2O3([M+H) + )m / z 493.17; found 493.2.

[0728] Example 132: 3-(4'-(4-(difluoromethyl)-2-oxo-6-(2,2,2-trifluoroethoxy)pyridin-1(2H)-yl)-2-ethynyl-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0729] Step 1: Synthesis of 1-(4-bromophenyl)-6-chloro-4-methylpyridin-2(1H)-one

[0730] 6-Chloro-4-methylpyridin-2(1H)-one (6.92 g, 34.5 mmol), p-bromophenylboronic acid (3.30 g, 23.0 mmol), TMEDA (1.07 g, 9.2 mmol), copper trifluoromethanesulfonate (3.33 g, 4.09 mmol), and pyridine (5.45 g, 69.0 mmol) were added to 50 mL of dry hexafluoroisopropanol solvent. The reaction mixture was purged with oxygen three times, then heated to 50 °C and reacted for 12 h. After cooling to room temperature, the mixture was extracted with dichloromethane, concentrated under reduced pressure, purified by silica gel column chromatography, and eluted with ethyl acetate / petroleum ether to give the target compound 1-(4-bromophenyl)-6-chloro-4-methylpyridin-2(1H)-one (1.25 g, 4.19 mmol), yield: 12%. LC / MS (ESI+) calcd for C 12 H 10 BrClNO([M+H] + )m / z 297.96; found 297.9.

[0731] Step 2: Synthesis of 1-(4-bromophenyl)-6-chloro-2-oxo-1,2-dihydropyridine-4-carboxaldehyde

[0732] 1-(4-bromophenyl)-6-chloro-4-methylpyridin-2(1H)-one (1.25 g, 4.19 mmol) was added to 20 mL of chlorobenzene, followed by selenium dioxide (1.39 g, 12.6 mmol). The reaction mixture was heated to 130 °C and stirred for 12 hours. After the reaction was complete, the mixture was cooled to room temperature, filtered, washed with ethyl acetate, and the filtrate was concentrated under reduced pressure. The filtrate was purified by column chromatography and developed with petroleum ether / ethyl acetate to give the target compound 1-(4-bromophenyl)-6-chloro-2-oxo-1,2-dihydropyridin-4-carboxaldehyde (600 mg, 1.92 mmol), yield: 46%. LC / MS (ESI+) calcd for C 12 H8BrClNO2([M+H) + )m / z 311.93; found 311.8.

[0733] Step 3: Synthesis of 1-(4-bromophenyl)-6-chloro-4-(difluoromethyl)pyridine-2(1H)-one

[0734] 1-(4-bromophenyl)-6-chloro-2-oxo-1,2-dihydropyridine-4-carboxaldehyde (600 mg, 1.92 mmol) was added to 20 mL of dichloromethane, and DAST (618 mg, 3.84 mmol) was added under ice bath conditions. The mixture was stirred at room temperature for 2 hours. After the reaction was complete, the mixture was extracted with dichloromethane, concentrated under reduced pressure, purified by column chromatography, and developed with petroleum ether / ethyl acetate to give the target compound 1-(4-bromophenyl)-6-chloro-4-(difluoromethyl)pyridine-2(1H)-one (583 mg, 1.74 mmol), yield: 91%. LC / MS (ESI+) calcd for C 12 H8BrClF2NO([M+H) + )m / z 333.94; found 333.8.

[0735] Step 4: Synthesis of 1-(4-bromophenyl)-4-(difluoromethyl)-6-(2,2,2-trifluoroethoxy)pyridine-2(1H)-one

[0736] 1-(4-bromophenyl)-6-chloro-4-(difluoromethyl)pyridin-2(1H)-one (583 mg, 1.74 mmol) and sodium trifluoroethoxide (0.65 g, 5.23 mmol) were added to 10 mL of trifluoroethanol. The reaction mixture was heated to 80 °C and reacted for 12 hours. After cooling to room temperature, the mixture was extracted with ethyl acetate, concentrated under reduced pressure, and purified by silica gel column chromatography. The purified compound was eluted with ethyl acetate / petroleum ether to give 1-(4-bromophenyl)-4-(difluoromethyl)-6-(2,2,2-trifluoroethoxy)pyridin-2(1H)-one (334 mg, 0.84 mmol), yield: 48%. LC / MS (ESI+) calcd for C 14 H 10 BrF5NO2([M+H] + )m / z 397.97; found 397.8.

[0737] Step 5: Synthesis of 4-(difluoromethyl)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)-6-(2,2,2-trifluoroethoxy)pyridine-2(1H)-one

[0738] 1-(4-bromophenyl)-4-(difluoromethyl)-6-(2,2,2-trifluoroethoxy)pyridin-2(1H)-one (334 mg, 0.84 mmol), pinacol diboronate (234 mg, 0.92 mmol), catalyst Pd(dppf)Cl2 (62 mg, 0.08 mmol), and potassium acetate (247 mg, 2.52 mmol) were added to 20 mL of dry dioxane solvent. The reaction mixture was purged with nitrogen three times, then heated to 80 °C and reacted for 12 hours. The extract was cooled to room temperature, extracted with ethyl acetate, concentrated under reduced pressure, and then purified by silica gel column chromatography. The extract was eluted with ethyl acetate / petroleum ether to yield the target compound 4-(difluoromethyl)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)-6-(2,2,2-trifluoroethoxy)pyridin-2(1H)-one (130 mg, 0.29 mmol), yield: 35%. LC / MS (ESI+) calcd for C 20 H 22 BF5NO4([M+H) + )m / z 446.15; found 446.2.

[0739] Step 6: Synthesis of 3-(4'-(4-(difluoromethyl)-2-oxo-6-(2,2,2-trifluoroethoxy)pyridin-1(2H)-yl)-2-((trimethylsilyl)ethynyl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0740] 4-(difluoromethyl)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)phenyl)-6-(2,2,2-trifluoroethoxy)pyridin-2(1H)-one (110 mg, 0.25 mmol), 6-methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)phenyl)pyridin-2(1H)-one (90 mg, 0.25 mmol), triethylamine (76 mg, 0.75 mmol), and catalyst Xphos-Pd-G3 (43 mg, 0.05 mmol) were added to a mixed solvent (10 / 1) of tetrahydrofuran and water. The reaction mixture was purged three times with nitrogen and then heated to 60 °C for 12 hours. The solution was cooled to room temperature and concentrated under reduced pressure, then purified by silica gel column chromatography to obtain the target compound 3-(4'-(4-(difluoromethyl)-2-oxo-6-(2,2,2-trifluoroethoxy)pyridin-1(2H)-yl)-2-((trimethylsilyl)ethynyl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione (21 mg, 0.035 mmol), yield: 14%. LC / MS (ESI+) calcd for C30 H 28 F5N2O4Si([M+H) + )m / z 603.17; found 603.2.

[0741] Step 7: Synthesis of 3-(4'-(4-(difluoromethyl)-2-oxo-6-(2,2,2-trifluoroethoxy)pyridin-1(2H)-yl)-2-ethynyl-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0742] Compound 3-(4'-(4-(difluoromethyl)-2-oxo-6-(2,2,2-trifluoroethoxy)pyridin-1(2H)-yl)-2-((trimethylsilyl)ethynyl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione (21 mg, 0.035 mmol) was dissolved in 10 mL of dry tetrahydrofuran, and 0.5 mL of TBAF (1 M) tetrahydrofuran solution was added. The mixture was stirred at room temperature for 1 minute. After hours, when the reaction was determined to be complete based on TLC and LCMS analysis, the mixture was extracted with ethyl acetate, concentrated under reduced pressure, and then purified by silica gel column chromatography to obtain the target compound 3-(4'-(4-(difluoromethyl)-2-oxo-6-(2,2,2-trifluoroethoxy)pyridin-1(2H)-yl)-2-ethynyl-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione (7 mg, 0.013 mmol), yield: 37%. 1 H NMR (400MHz, DMSO-d6) δ10.92(s,1H),7.66(d,J=8.3Hz,2H),7.49(t,J=7.7Hz,1H),7.37(dd,J=7.8 ,1.3Hz,1H),7.33(dd,J=8.7,2.2Hz,3H),6.94(t,J=54.8Hz,1H),6.45(d,J=1.5Hz,1H),6.16(d,J=1 .5Hz,1H),4.94(q,J=8.5Hz,2H),4.38–4.32(m,1H),4.31(s,1H),2.76(ddd,J=17.3,12.4,5.2Hz,1 H),2.57(t,J=3.7Hz,1H),2.41–2.35(m,1H),2.07(ddd,J=13.2,8.9,4.8Hz,1H).LC / MS(ESI+)calcd for C 27 H 20 F5N2O4([M+H) + )m / z 531.13; found 531.2.

[0743] Example 133: 3-(4'-(4-methoxy-2-oxo-6-(trifluoromethyl)pyridin-1(2H)-yl)-2-((trimethylsilyl)ethynyl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0744] See Example 66 for the synthesis. 1 H NMR (400MHz, DMSO-d6) δ10.91 (s, 1H), 7.65 (ddd, J = 8.7, 6.6, 1.7Hz, 2H), 7.48 (t, J =7.6Hz,1H),7.42(dd,J=7.8,1.4Hz,1H),7.38–7.29(m,3H),6.68(d,J=2.6Hz,1H) ,6.21(d,J=2.6Hz,1H),4.20(d,J=7.2Hz,1H),3.86(s,3H),2.71(dd,J=10.8,6.3H z,1H),2.56(s,2H),2.03(dd,J=12.1,6.5Hz,1H),0.07(s,9H).LC / MS(ESI+)calcd for C 29 H 28 F3N2O4Si([M+H) + )m / z 553.17; found 553.2.

[0745] Example 134: 1-(2-chloro-4'-(4-(difluoromethyl)-2-oxo-6-(trifluoromethyl)pyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

[0746] 1-(3-bromo-2-chlorophenyl)dihydropyrimidine-2,4(1H,3H)-dione (40 mg, 0.13 mmol), 4-(difluoromethyl)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)-6-(trifluoromethyl)pyridin-2(1H)-one (54 mg, 0.13 mmol), sodium bicarbonate (34 mg, 0.39 mmol), and catalyst Pd(dppf)Cl2 (9.5 mg, 0.02 mmol) were added to a mixed solvent (10 / 1) of dioxane and water. The reaction mixture was purged with nitrogen three times and then heated to 85 °C for 4 hours. The compound was cooled to room temperature and concentrated under reduced pressure, then purified by silica gel column chromatography to obtain the target compound 1-(2-chloro-4'-(4-(difluoromethyl)-2-oxo-6-(trifluoromethyl)pyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (21 mg, 0.041 mmol), yield: 32%. 1 H NMR(400MHz, DMSO-d6)δ10.51(s,1H),7.59(ddd,J=12.4,7.7,1.6Hz,3H),7.55–7.45(m,4H),7.22–6.87(m, 3H),3.77(ddd,J=12.7,7.9,6.7Hz,1H),3.66(dt,J=12.4,6.3Hz,1H),2.82–2.71(m,2H).LC / MS(ESI+)calcd for C 23 H 16 ClF5N3O3([M+H) + )m / z 512.07; found 512.1.

[0747] Example 135: 1-(2-chloro-4'-(6-cyclohexyl-4-(difluoromethyl)-2-oxopyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

[0748] 1-(3-bromo-2-chlorophenyl)dihydropyrimidin-2,4(1H,3H)-dione (40 mg, 0.13 mmol), 6-cyclohexyl-4-(difluoromethyl)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)pyridin-2(1H)-one (56 mg, 0.13 mmol), sodium bicarbonate (34 mg, 0.39 mmol), and catalyst Pd(dppf)Cl2 (9.5 mg, 0.02 mmol) were added to a mixed solvent (10 / 1) of dioxane and water. The reaction mixture was purged with nitrogen three times and then heated to 85 °C for 4 hours. The compound was cooled to room temperature and concentrated under reduced pressure, then purified by silica gel column chromatography to obtain the target compound 1-(2-chloro-4'-(6-cyclohexyl-4-(difluoromethyl)-2-oxopyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (18 mg, 0.034 mmol), yield: 26%. 1 H NMR(400MHz,DMSO-d6)δ10.51(s,1H),7.63–7.49(m,5H),7.46–7.39(m,2H),7.10–6.77(m,1H),6.5 7(q,J=1.5Hz,1H),6.37(d,J=1.8Hz,1H),3.78(dt,J=12.3,7.1Hz,1H),3.67(dt,J=12.4,6.3Hz,1H) ,2.77(t,J=6.7Hz,2H),2.09–1.97(m,1H),1.77(d,J=12.5Hz,2H),1.65(d,J=13.2Hz,2H),1.52(d,J =13.1Hz,1H),1.40–1.29(m,2H),1.15(dd,J=9.2,3.9Hz,1H),0.88–0.75(m,2H).LC / MS(ESI+)calcd for C 28 H 27 ClF2N3O3([M+H) + )m / z 526.16; found 526.2.

[0749] Example 136: 3-(2-ethynyl-4'-(4-methoxy-2-oxo-6-(3,3,3-trifluoropropyl)pyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0750] The target compound was prepared using a synthetic procedure similar to that of Example 132. 1H NMR(400MHz,DMSO-d6)δ10.93(s,1H),7.72–7.63(m,2H),7.50(t,J=7.7Hz,1H) ,7.40–7.30(m,4H),6.10(d,J=2.6Hz,1H),5.86(d,J=2.6Hz,1H),4.33(dd,J=11 .9,5.0Hz,1H),4.30(s,1H),3.79(s,3H),2.76(ddd,J=17.5,12.6,5.4Hz,1H), 2.57(t,J=4.0Hz,1H),2.47–2.35(m,5H),2.14–2.00(m,1H).LC / MS(ESI+)calcd for C 28 H 24 F3N2O4([M+H) + )m / z 509.16; found 509.2.

[0751] Example 137: 3-(1-(3-(4-methyl-2-oxo-6-(5-azaspiro[2.4]heptane-5-yl)pyridin-1(2H)-yl)phenyl)-1H-indazol-4-yl)piperidin-2,6-dione

[0752] Step 1: Synthesis of 1-(3-iodophenyl)-4-methyl-6-(5-azaspiro[2,4]heptane-5-yl)pyridin-2(1H)-one

[0753] 5-azaspiro[2,4]heptane hydrochloride (160 mg, 1.2 mmol) was dissolved in DMSO, and cesium carbonate (974 mg, 3.0 mmol) was added. Then, 6-chloro-1-(3-iodophenyl)-4-methylpyridin-2(1H)-one (346 mg, 1.0 mmol) was added with stirring. The mixture was reacted at 100 °C for 4 hours, extracted with ethyl acetate, washed with water, dried, concentrated, and purified by column chromatography to give 108 mg of the product (yield: 22%). LC / MS (ESI+) calcd for C 18 H 20 IN2O([M+H)) + )m / e 407.0, found 407.0.

[0754] Step 2: Synthesis of 3-(1-(3-(4-methyl-2-oxo-6-(5-azaspiro[2.4]heptane-5-yl)pyridin-1(2H)-yl)phenyl)-1H-indazol-4-yl)piperidin-2,6-dione

[0755] The target compound was prepared using a method similar to that in Example 72. LC / MS (ESI+) calcd for C 30 H 30 N5O3([M+H)) + )m / e 508.2, found 508.2. 1 H NMR(400MHz,DMSO-d6)δ10.96(s,1H),8.44(d,J=0.9Hz,1H),7.80–7.73(m,2H),7.72–7.64(m ,2H),7.48(dd,J=8.6,7.1Hz,1H),7.28(dt,J=8.1,1.3Hz,1H),7.13(d,J=7.1Hz,1H),5.75(d ,J=1.3Hz,1H),5.61(d,J=1.6Hz,1H),4.42(dd,J=12.2,4.9Hz,1H),3.06(t,J=6.8Hz,2H),2. 83–2.70(m,3H),2.69–2.55(m,2H),2.17–2.06(m,4H),1.68–1.56(m,2H),0.43–0.40(m,4H).

[0756] Example 138: 3-(1-(3-(4-methyl-2-oxo-6-(perfluoroethyl)pyridin-1(2H)-yl)phenyl)-1H-indazol-4-yl)piperidin-2,6-dione

[0757] The target compound was prepared using a method similar to that in Example 9. LC / MS (ESI+) calcd for C 26 H 20 F5N4O3([M+H) + )m / e 531.1, found 531.1. 1 H NMR (400MHz, DMSO-d6) δ10.96(s,1H),8.45(d,J=0.9Hz,1H),7.91(d,J=8.6Hz,1 H),7.80–7.68(m,3H),7.48(dd,J=8.6,7.1Hz,1H),7.33(d,J=8.0Hz,1H),7.14(d ,J=7.1Hz,1H),6.79(s,1H),6.69(s,1H),4.42(dd,J=12.2,4.9Hz,1H),2.79(td, J=12.2,6.2Hz,1H),2.71–2.54(m,2H),2.30(d,J=1.2Hz,3H),2.16–2.09(m,1H).

[0758] Example 139: 3-(1-(3-(4-methyl-2-oxo-6-(3,3,3-trifluoropropyl)pyridin-1(2H)-yl)phenyl)-1H-indazol-4-yl)piperidin-2,6-dione

[0759] The target compound was prepared using a method similar to that in Example 9. LC / MS (ESI+) calcd for C 27 H 24 F3N4O3([M+H) + )m / e 509.1, found 509.1; 1 H NMR(400MHz,DMSO-d6)δ10.96(s,1H),8.45(s,1H),7.95–7.88(m,1H),7.81–7. 72(m,3H),7.48(dd,J=8.6,7.1Hz,1H),7.34(dd,J=7.9,2.0Hz,1H),7.14(d,J= 7.2Hz,1H),6.27(s,1H),6.25(s,1H),4.42(dd,J=12.2,4.8Hz,1H),2.82-2.74 (m,1H),2.68–2.55(m,2H),2.49–2.38(m,4H),2.19(s,3H),2.15–2.09(m,1H).

[0760] Example 140: 3-(1-(3-(4-methyl-2-oxo-6-(tetrahydrofuran-3-yl)oxy)pyridin-1(2H)-yl)phenyl)-1H-indazol-4-yl)piperidin-2,6-dione

[0761] The target compound was prepared using a method similar to that in Example 71. LC / MS (ESI+) calcd for C 28 H 27 N4O5([M+H)) + )m / e 499.2, found 499.2; 1H NMR (400MHz, DMSO-d6) δ10.96(s,1H),8.43(s,1H),7.85–7.78(m,1H),7.75(d,J=8.6Hz,1H),7.68(t,J=8 .0Hz,1H),7.61(d,J=6.6Hz,1H),7.47(t,J=7.9Hz,1H),7.22(d,J=8.0Hz,1H),7.13(d,J=7.1Hz,1H),5.97 (s,1H),5.76(d,J=1.5Hz,1H),4.42(dd,J=12.2,4.9Hz,1H),3.82–3.76(m,1H),3.63(d,J=10.2Hz,2H),3. 55–3.46(m,2H),2.79–2.73(m,1H),2.69–2.57(m,2H),2.20(s,3H),2.16–2.10(m,2H),1.86–1.80(m,1H).

[0762] Example 141: 3-(1-(3-(4-(difluoromethyl)-2-oxo-6-((tetrahydrofuran-3-yl)oxy)pyridin-1(2H)-yl)phenyl)-1H-indazol-4-yl)piperidin-2,6-dione

[0763] The target compound was prepared using a method similar to that in Example 75. LC / MS (ESI+) calcd for C 28 H 25 F2N4O5([M+H) + )m / e 535.1,found 535.1; 1 H NMR (400MHz, DMSO-d6) δ10.96(s,1H),8.44(s,1H),7.85(dd,J=8.4,2.0Hz,1H),7.73(dt,J=19.7,8.5Hz,3H ),7.47(t,J=7.9Hz,1H),7.29(t,J=7.9Hz,1H),7.13(d,J=7.1Hz,1H),6.92(t,J=55.0Hz,1H),6.38–6.33(m ,1H),5.98(d,J=1.6Hz,1H),5.23(s,1H),4.42(dd,J=12.2,4.9Hz,1H),3.79(dd,J=10.3,4.4Hz,1H),3.67– 3.58(m,2H),3.53–3.46(m,1H),2.82-2.73(m,1H),2.70–2.56(m,2H),2.20–2.08(m,2H),1.92–1.82(m,1H).

[0764] Example 142: 3-(1-(3-(4-(difluoromethyl)-6-((3S,4R)-3,4-difluoropyrrolidine-1-yl)-2-oxopyridin-1(2H)-yl)phenyl)-1H-indazole-4-yl)piperidin-2,6-dione

[0765] The target compound was prepared using a method similar to that in Example 137. LC / MS (ESI+) calcd for C 28 H 24 F4N5O3([M+H) + )m / e 554.1,found 554.1; 1 H NMR (400MHz, DMSO-d6) δ10.96(s,1H),8.45(s,1H),7.86(dd,J=4.1,2.1Hz,2H),7.80(d,J=8.6Hz,1H),7.72(t,J=8. 3Hz,1H),7.47(dd,J=8.5,7.1Hz,1H),7.35(dt,J=8.0,1.5Hz,1H),7.14(d,J=7.1Hz,1H),6.86(t,J=55.2Hz,1H),6. 15(d,J=1.6Hz,1H),5.82(d,J=1.6Hz,1H),5.29–5.22(m,1H),5.13(dd,J=10.1,5.4Hz,1H),4.42(dd,J=12.2,4.9Hz ,1H),3.22–3.10(m,2H),2.99(d,J=12.5Hz,2H),2.77(dd,J=11.3,6.3Hz,1H),2.68–2.57(m,2H),2.16–2.10(m,1H).

[0766] Example 143: 3-(1-(3-((6-chloropyridin-2-yl)oxy)phenyl)-1H-indazol-4-yl)piperidin-2,6-dione

[0767] 1. Synthesis of compound 2-chloro-6-(3-iodophenoxy)pyridine

[0768] Weigh 500 mg (3.86 mmol) of 6-chloropyridin-2(1H)-one, 1435 mg (5.79 mmol) of m-iodophenylboronic acid, 558 mg (1.54 mmol) of trifluoromethanesulfonate ketone, 179 mg (1.54 mmol) of TMEDA, and 904 mg (11.58 mmol) of pyridine into a round-bottom flask. Add 10 mL of 1,2-dichloroethane and perform a vacuum purging and oxygen purging operation three times. Heat the mixture in an oil bath at 50 °C. After 5 h, LC / MS showed that the starting materials were consumed. After the system cooled to room temperature, filter the mixture using diatomaceous earth. Wash the filter cake repeatedly with dichloromethane. Combine the filtrates, remove the solvent by rotary evaporation to obtain the crude product, and purify by column chromatography to obtain the target compound 2-chloro-6-(3-iodophenoxy)pyridine (493 mg). Yield: 39%. LC / MS (ESI) + calcd for C 11 H7ClNO([M+H) + )m / z,331.9;found,331.9.

[0769] 2. Synthesis of compound 3-(1-(3-((6-chloropyridin-2-yl)oxy)phenyl)-1H-indazol-4-yl)piperidine-2,6-dione

[0770] Weigh 50 mg (0.22 mmol) of 3-(1H-indazol-4-yl)piperidin-2,6-dione, 72 mg (0.22 mmol) of 2-chloro-6-(3-iodophenoxy)pyridine, 21 mg (0.11 mmol) of iodide ketone, 14 mg (0.11 mmol) of 2-pyridinecarboxylic acid, and 60 mg (0.44 mmol) of anhydrous potassium carbonate into a round-bottom flask. After purging with argon gas three times under vacuum, add 3 mL of dry DMSO. Purge with argon gas five times while stirring, then transfer the flask to an oil bath at 110 °C and heat to react. After 1 h, LC-MS monitoring showed the starting material had disappeared. After the system cooled to room temperature, filter using diatomaceous earth. Wash the filter cake several times with ethyl acetate. The filtrates were combined, and water and ethyl acetate were added to complete the extraction. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation to obtain the crude product. Prep-TLC purification yielded the target compound 3-(1-(3-(((6-chloropyridin-2-yl)oxy)phenyl)-1H-indazol-4-yl)piperidin-2,6-dione (19 mg). Yield: 21%. LC / MS (ESI) + calcd for C 23 H 17 ClN4O3([M+H) + )m / z,433.1;found,433.0. 1H NMR (400MHz, DMSO-d6) δ10.97(s,1H),8.43(s,1H),7.96(t,J=7.9Hz,1H),7.84(d,J=8 .5Hz,1H),7.67(d,J=4.7Hz,2H),7.63(s,1H),7.51–7.42(m,1H),7.31(d,J=7.6Hz,1H ),7.27–7.20(m,1H),7.17–7.10(m,2H),4.42(dd,J=12.1,4.7Hz,1H),2.77(ddd,J=17 .2,12.5,5.1Hz,1H),2.64–2.54(m,1H),2.18–2.07(m,1H),1.99(p,J=7.0,6.6Hz,1H).

[0771] Example 144: 3-(6-fluoro-1-(3-(6-methyl-2-oxopyridin-1(2H)-yl)phenyl)-1H-indazol-4-yl)piperidin-2,6-dione

[0772] 3-(6-fluoro-1H-indazol-4-yl)piperidin-2,6-dione (40 mg, 0.16 mmol), 2-(3-iodophenoxy)-6-methylpyridine (50 mg, 0.16 mmol), 2-pyridinecarboxylic acid (7 mg, 0.06 mmol), cuprous iodide (11 mg, 0.06 mmol), and potassium carbonate (44 mg, 0.23 mmol) were mixed with 5 mL of DMSO, and the mixture was heated to 110 °C for 1 h under nitrogen purging. After cooling to room temperature, the mixture was filtered, and the filtrate was extracted with water (EA). The EA phase was dried over anhydrous sodium sulfate, and the solution was purified by TLC to give 8 mg of 3-(1-(3-(1,6-naphthidin-2-yl)oxy)phenyl)-1H-indazol-4-yl)piperidin-2,6-dione. LC / MS (ESI+) Calcd for C 24 H 19 FN4O3(M+H + )m / z,431.1;found 431.1. 1H NMR(400MHz,Chloroform-d)δ8.12–7.99(m,2H),7.73(d,J=8.2Hz,1H),7.64(t, J=7.9Hz,1H),7.52(dt,J=4.1,2.1Hz,1H),7.35(d,J=9.1Hz,1H),7.28(dd,J=9.3 ,6.8Hz,1H),6.81(d,J=9.4Hz,1H),6.51(d,J=9.2Hz,1H),6.09(d,J=6.8Hz,1H), 4.11(dt,J=10.5,5.3Hz,1H),2.83–2.63(m,2H),2.46–2.30(m,2H),1.99(s,3H).

[0773] Example 145: 3-(1-(3-(1,6-naphthid-2-yl)oxy)phenyl)-1H-indazol-4-yl)piperidin-2,6-dione

[0774] Step 1: Preparation of 1,2-(3-iodophenoxy)-1,6-naphthidine

[0775] 1,6-Naphthyldione (300 mg, 2.05 mmol), m-diiodobenzene (677 mg, 2.05 mmol), cuprous iodide (195 mg, 1.03 mmol), 2-Picolinic acid (126 mg, 1.03 mmol), and potassium carbonate (567 mg, 4.11 mmol) were dissolved in 5 mL of DMSO. Under nitrogen protection, the mixture was heated to 110 °C and reacted for 2 h. The mixture was extracted with water and EA, and the organic phase was dried over anhydrous sodium sulfate. The solution was purified by TLC to give 60 mg of 2-(3-iodophenoxy)-1,6-naphthidine. LC / MS (ESI+) Calcd for C 19 H4IN2O(M+H + )m / z,349.0;found 349.0.

[0776] Step 2: Preparation of 3-(1-(3-(1,6-naphthid-2-yl)oxy)phenyl)-1H-indazol-4-yl)piperidin-2,6-dione

[0777] 2-(3-iodophenoxy)-1,6-naphthylidine (40 mg, 0.11 mmol), 3-(1H-indazol-4-yl)piperidin-2,6-dione (26 mg, 0.11 mmol), 2-pyridinecarboxylic acid (7 mg, 0.06 mmol), cuprous iodide (11 mg, 0.06 mmol), and potassium carbonate (32 mg, 0.23 mmol) were mixed with 5 mL of DMSO, and the mixture was heated to 110 °C for 1 h under nitrogen purging. After cooling to room temperature, the mixture was filtered, and the filtrate was extracted with water (EA). The EA phase was dried over anhydrous sodium sulfate, and the solution was purified by TLC to give 8 mg of 3-(1-(3-(1,6-naphthyl-2-yl)oxy)phenyl)-1H-indazol-4-yl)piperidin-2,6-dione. LC / MS (ESI+) Calcd for C 26 H 19 N5O3(M+H + )m / z,450.1; found 450.1. LC / MS(ESI+)Calcd for C 24 H 19 FN4O3(M+H + )m / z,431.1; 1 H NMR(400MHz,Chloroform-d)δ8.68(s,1H),8.48(s,1H),8.16(d,J=16.0Hz,2H),7.86(d,J=8.7Hz,2H),7.79–7.66(m,3H ),7.53–7.44(m,2H),7.36–7.32(m,1H),7.12(d,J=7.1Hz,1H),4.30–4.22(m,1H),2.89–2.77(m,2H),2.54–2.40(m,2H).

[0778] Example 146: 3-(1-(3-((8-fluoroquinolin-2-yl)oxy)phenyl)-1H-indazol-4-yl)piperidine-2,6-dione

[0779] Step 1: Preparation of 8-fluoro-2-(3-iodophenoxy)quinoline

[0780] 8-Fluoroquinoline-2(3H)-one (300 mg, 1.84 mmol), m-diiodobenzene (607 mg, 1.84 mmol), cuprous iodide (174 mg, 0.92 mmol), 2-Picolinic acid (106 mg, 0.92 mmol), and potassium carbonate (507 mg, 3.68 mmol) were dissolved in 5 mL DMSO under nitrogen protection and reacted at 110 °C for 2 h. The mixture was extracted with water and EA, and the organic phase was dried over anhydrous sodium sulfate. The solution was purified by TLC to give 58 mg of 8-fluoro-2-(3-iodophenoxy)quinoline. LC / MS (ESI+) Calcd for C 15 H9FINO(M+H + )m / z,366.0; found 366.0.

[0781] Step 2: Preparation of 3-(1-(3-(((8-fluoroquinolin-2-yl)oxy)phenyl)-1H-indazol-4-yl)piperidine-2,6-dione

[0782] 8-Fluoro-2-(3-iodophenoxy)quinoline (40 mg, 0.11 mmol), 3-(1H-indazol-4-yl)piperidin-2,6-dione (26 mg, 0.11 mmol), 2-pyridinecarboxylic acid (7 mg, 0.06 mmol), cuprous iodide (11 mg, 0.06 mmol), and potassium carbonate (32 mg, 0.23 mmol) were mixed with 5 mL of DMSO, and the mixture was heated to 110 °C for 1 h under nitrogen purging. After cooling to room temperature, the mixture was filtered, and the filtrate was extracted with water (EA). The EA phase was dried over anhydrous sodium sulfate, and the solution was purified by TLC to give 8 mg of 3-(1-(3-(1,6-naphthid-2-yl)oxy)phenyl)-1H-indazol-4-yl)piperidin-2,6-dione. LC / MS (ESI+) Calcd for C 27 H 19 FN4O3(M+H + )m / z,467.1;found 467.1. 1 H NMR(400MHz,Chloroform-d)δ8.24(dd,J=8.9,1.6Hz,1H),8.16(t,J=2.5Hz,2H),8.03(d,J=8.6Hz,1H),7.83(q,J=1.5,1.0Hz,1H),7.67–7.60(m,3H),7.51 –7.41(m,3H),7.37(td,J=4.5,2.3Hz,1H),7.26(d,J=8.9Hz,1H),7.08(d,J=7 .1Hz,1H),4.27(dd,J=9.8,5.3Hz,1H),2.85–2.76(m,2H),2.53–2.41(m,2H).

[0783] Example 147: 3-(1-(3-((5,6,7,8-tetrahydroquinoline-2-yl)oxy)phenyl)-1H-indazol-4-yl)piperidine-2,6-dione

[0784] Step 1: Synthesis of 2-(3-iodophenoxy)-5,6,7,8-tetrahydroquinoline

[0785] Compound 5,6,7,8-tetrahydroquinoline-2(1H)-one (600 mg, 4.00 mmol), (3-iodophenyl)boronic acid (1480 mg, 6.00 mmol), copper trifluoromethanesulfonate (360 mg, 1.00 mmol), TMEDA (116 mg, 1.00 mmol), and pyridine (948 mg, 12.00 mmol) were added to 15 mL of 1,2-dichloroethane and stirred at 50 °C for 3 h under oxygen. The mixture was filtered through diatomaceous earth, mixed, and subjected to column chromatography to obtain the target compound (90 mg, 7% yield). LC / MS (ESI+) calcd for C 15 H 15 INO(M+H + )m / z,352.1;found,352.1.

[0786] Step 2: Synthesis of 3-(1-(3-((5,6,7,8-tetrahydroquinolin-2-yl)oxy)phenyl)-1H-indazol-4-yl)piperidine-2,6-dione

[0787] Compounds 2-(3-iodophenoxy)-5,6,7,8-tetrahydroquinoline (50 mg, 0.14 mmol), 3-(1H-indazol-4-yl)piperidin-2,6-dione (32 mg, 0.14 mmol), CuI (14 mg, 0.07 mmol), 2-pyridinecarboxylic acid (9 mg, 0.07 mmol), and K₂CO₃ (58 mg, 0.42 mmol) were added to 4 mL of DMSO and stirred at 110 °C for 1 h. The mixture was filtered through diatomaceous earth, water was added, and the mixture was extracted three times with EA. The combined organic phases were washed with saturated NaCl solution, dried over anhydrous sodium sulfate, and subjected to rotary evaporation and column chromatography to obtain the target compound (12 mg, 19% yield). LC / MS (ESI+) calcd for C 27 H 25 N4O3(M+H + )m / z,453.2;found,453.2. 1H NMR (400MHz, DMSO-d6) δ10.97(s,1H),8.41(d,J=1.0Hz,1H),7.79(d,J=8.6 Hz,1H),7.62–7.55(m,3H),7.50–7.43(m,2H),7.15–7.11(m,2H),6.86(d,J= 8.2Hz,1H),4.41(dd,J=12.2,4.9Hz,1H),2.69(t,J=6.6Hz,4H),2.58(dt,J =17.2,3.9Hz,2H),2.16–1.93(m,2H),1.83–1.77(m,2H),1.75–1.68(m,2H).

[0788] Example 148: 3-(1-(3-(2-oxo-5,6,7,8-tetrahydroquinoline-1(2H)-yl)phenyl)-1H-indazol-4-yl)piperidine-2,6-dione

[0789] The intermediate 1-(3-iodophenyl)-5,6,7,8-tetrahydroquinoline-2(1H)-one was prepared using the method of Example 146. The target compound was then prepared from this starting material using a method similar to that of Example 10. LC / MS (ESI+) calcd for C 27 H 25 N4O3(M+H + )m / z,453.2;found,453.2. 1 H NMR(400MHz,DMSO-d6)δ10.97(s,1H),8.45(d,J=0.9Hz,1H),7.92–7.86(m,1H),7.82–7.7 0(m,2H),7.63(t,J=2.1Hz,1H),7.48(dd,J=8.6,7.1Hz,1H),7.32(d,J=9.4Hz,1H),7.26( ddd,J=7.9,2.0,1.0Hz,1H),7.14(d,J=7.2Hz,1H),6.37(d,J=9.3Hz,1H),4.43(dd,J=12. 2,4.8Hz,1H),2.84–2.55(m,3H),2.49–2.31(m,2H),2.14(d,J=23.4Hz,3H),1.62(s,4H).

[0790] Example 149: 1-(3-(4-(2,6-dioxopiperidin-3-yl)-1H-indazol-1-yl)phenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-nitrile)

[0791] The target compound was prepared using a method similar to that in Example 147. LC / MS (ESI+) calcd for C 25 H 20 N5O3(M+H + )m / z,438.1;found,438.1. 1 H NMR (400MHz, DMSO-d6) δ10.98(s,1H),8.47(s,1H),8.19(d,J=7.4Hz,1H),7.96(dd,J= 8.3,2.2Hz,1H),7.89(t,J=2.0Hz,1H),7.85–7.75(m,2H),7.50(dd,J=8.6,7.1Hz,1H), 7.40(dt,J=8.0,1.2Hz,1H),7.15(d,J=7.1Hz,1H),6.53(d,J=7.5Hz,1H),4.43(dd,J= 12.2, 4.8Hz, 1H), 2.76 (tdd, J=16.6, 12.2, 5.2Hz, 2H), 2.68–2.53 (m, 2H), 2.12 (s, 3H).

[0792] Example 150: 3-(1-(3-(2-oxopyrrolidone-1-yl)phenyl)-1H-indazol-4-yl)piperidine-2,6-dione

[0793] The target compound was prepared using a method similar to that in Example 33. LC / MS (ESI) + ): calcd for C 25 H 23 N4O3([M+H)) + )m / z 427.1, found 427.0. 1 H NMR(400MHz,DMSO-d6)δ10.97(s,1H),8.45(s,1H),7.98–7.83(m,1H),7.78(d,J=8.5Hz,1 H),7.73(t,J=8.0Hz,1H),7.66(d,J=2.1Hz,1H),7.55–7.44(m,1H),7.34–7.23(m,1H),7. 14(d,J=7.1Hz,1H),6.20(s,1H),6.15(s,1H),4.42(dd,J=12.2,4.8Hz,1H),2.84–2.73(m ,1H),2.69–2.61(m,1H),2.60–2.56(m,1H),2.15(s,3H),2.13–2.09(m,1H),1.98(s,3H).

[0794] Example 160: 6-(2-chloro-3-(2,6-dioxopiperidin-3-yl)phenyl)-N-methyl-2-naphthamide

[0795] Step 1: Synthesis of 1-(3-bromophenyl)pyrrolidine-2-one

[0796] HATU (2.27 g, 5.97 mmol) was added to a DMF solution (6 mL) of 6-bromo-2-naphthoic acid (1.00 g, 3.98 mmol), methylamine hydrochloride (649 mg, 7.96 mmol), and DIPEA (2.85 mL, 15.9 mmol). The reaction was carried out at room temperature for 4 hours. The reaction was quenched with saturated ammonium chloride solution, extracted with ethyl acetate, and the crude product was concentrated and purified by silica gel column chromatography (DCM / MeOH = 30:1) to give the target product as a white solid (988 mg, 94%). LC-MS (ESI) was then performed. + ): calcd for C 12 H 11 BrNO([M+H] + )m / z 264.0, found 263.9.

[0797] Step 2: Synthesis of 6-(2-chloro-3-(2,6-dioxopiperidin-3-yl)phenyl)-N-methyl-2-naphthamide

[0798] 6-Bromo-N-methyl-2-naphthamide (10.0 mg, 0.045 mmol), 3-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborin-2-yl)phenyl)piperidin-2,6-dione (11.9 mg, 1.0 mmol), and Xphos Pd G3 (3.8 mg, 0.0045 mmol) were weighed into a dry reaction flask. THF solution (1 mL) and potassium phosphate (20.9 mg, 0.099 mmol) aqueous solution (0.5 mL) were added. After purging with argon three times, the reaction mixture was reacted in an oil bath at 40 °C for 4 hours. The reaction solution was cooled, filtered through diatomaceous earth, quenched with saturated ammonium chloride aqueous solution, extracted with ethyl acetate, and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by PTLC (DCM / MeOH = 15:1) to obtain the target product as a pale yellow solid (6.0 mg, yield 33%). LC / MS (ESI) + ): calcd for C 23 H 20 ClN2O3([M+H) + )m / z 407.1, found 407.1. 1H NMR (400MHz, DMSO-d6) δ10.96(s,1H),8.66(d,J=4.9Hz,1H),8.49(s,1H),8.11–8.03(m,2H),8.01–7.93(m,2H),7.63(d,J=8.0Hz,1H),7.49– 7.40(m,3H),4.38(dd,J=12.3,5.1Hz,1H),2.85(d,J=4.1Hz,3H),2.82 –2.73(m,1H),2.70–2.57(m,1H),2.39–2.31(m,1H),2.11–2.02(m,1H).

[0799] Example 161: 3-(1-(3-(2-oxo-6-((tetrahydrofuran-2-yl)methoxy)-4-(trifluoromethyl)pyridin-1(2H)-yl)phenyl)-1H-indazol-4-yl)piperidin-2,6-dione

[0800] The target compound was prepared using a method similar to that in Example 71. LC / MS (ESI+) calcd for C 29 H 26 F3N4O5(M+H + )m / z,567.2;found,567.2. 1 H NMR (400MHz, DMSO-d6) δ10.96(s,1H),8.45(d,J=0.8Hz,1H),7.88(ddd,J=8.2,2.1,1.0Hz,1H),7.76(dddd,J=21.0,11.0,7.6,3.9Hz,3H),7 .47(t,J=7.8Hz,1H),7.41–7.27(m,1H),7.13(d,J=7.1Hz,1H),6.50(dd,J=1.8,0.9Hz,1H),6.11(d,J=1.8Hz,1H),4.42(dd,J=12.2,4.9Hz,1 H),4.25–4.16(m,1H),4.11(dd,J=10.6,4.1Hz,1H),3.99(s,1H),3.44(q,J=6.8Hz,1H),3.27–3.15(m,1H),2.78(ddd,J=17.3,12.4,5.3Hz,1 H),2.59(dt,J=17.2,3.9Hz,1H),2.19–2.07(m,1H),1.98(dq,J=15.2,8.5,7.9Hz,1H),1.69(d,J=17.9Hz,1H),1.47(tt,J=13.0,6.6Hz,3H).

[0801] Example 162: 3-(1-(3-(4-(difluoromethyl)-2-oxo-6-((tetrahydrofuran-2-yl)methoxy)pyridin-1(2H)-yl)phenyl)-1H-indazol-4-yl)piperidin-2,6-dione

[0802] The target compound was prepared using a method similar to that in Example 71. LC / MS (ESI+) calcd for C 29 H 27 F2N4O5(M+H + )m / z,549.2;found,549.2. 1 H NMR(400MHz, DMSO-d6)δ10.96(s,1H),8.44(d,J=0.9Hz,1H),7.86(ddd,J=8.2,2.2,1.0Hz,1H),7.83–7.68(m,3H), 7.47(dd,J=8.5,7.1Hz,1H),7.31(t,J=8.5Hz,1H),7.13(d,J=7.1Hz,1H),6.96–6.89(m,1H),6.34(d,J=1.5Hz,1H) ,5.96(d,J=1.6Hz,1H),4.42(dd,J=12.2,4.8Hz,1H),4.20–4.10(m,1H),4.04(ddd,J=18.4,10.9,4.1Hz,3H),3.27 –3.18(m,1H),2.78(ddd,J=17.3,12.3,5.3Hz,1H),2.69–2.53(m,1H),2.21–2.07(m,1H),1.71(s,1H),1.47(s,4H).

[0803] Example 163: 3-(1-(3-(6-(furan-3-yl)-4-methyl-2-oxopyridin-1(2H)-yl)phenyl)-1H-indazol-4-yl)piperidin-2,6-dione

[0804] The target compound was prepared using a method similar to that in Example 82. LC / MS (ESI+) calcd for C 28 H 23 N4O4(M+H + )m / z,479.1; found,479.1. 1H NMR(400MHz,DMSO-d6)δ10.95(s,1H),8.42(d,J=0.8Hz,1H),7.84–7.77(m,2H),7.67–7.60(m,3H) ,7.55–7.50(m,3H),7.49–7.41(m,3H),7.26–7.21(m,1H),7.12(d,J=7.0Hz,1H),6.44–6.32(m,3H) ,6.18(dd,J=2.0,0.8Hz,1H),4.41(dd,J=12.2,4.8Hz,1H),2.77(ddd,J=17.5,12.5,5.3Hz,2H),2 .60(d,J=4.0Hz,1H),2.56(dd,J=7.3,4.1Hz,1H),2.44(dd,J=12.5,4.2Hz,1H),2.17–2.04(m,2H).

[0805] Example 164: 3-(1-(3-(4-(difluoromethyl)-2-oxo-6-(2-(trifluoromethoxy)ethoxy)pyridin-1(2H)-yl)phenyl)-1H-indazol-4-yl)piperidin-2,6-dione

[0806] The target compound was prepared using a method similar to that in Example 71. LC / MS (ESI+) calcd for C 27 H 22 F5N4O5(M+H + )m / z,577.1;found,577.1. 1 H NMR(400MHz,DMSO-d6)δ10.96(s,1H),8.43(d,J=0.9Hz,1H),7.90–7.84(m,1H),7.77(t,J=2.0Hz ,1H),7.75(d,J=8.6Hz,1H),...

Claims

Compounds of Formula I, their pharmaceutically acceptable salts, their isotopic compounds, or their stereoisomers: in, X 1 ,X 2 Selected independently from O and NR X ,CR X1 R X2 ;X 3 Selected from N,CR X1 ;where R X ,R X1 ,R X2 Each of the following is independently selected from alkyl groups: N, H, F, Cl, Br, I, and C1-C6 alkyl groups; A X A Y Each is independently selected from CH and N; Ring A is R A1 ,R A2 ,R A3 The following groups are substituted: 6-10-membered aromatic ring, 5-10-membered aromatic heterocycle, 6-10-membered aromatic ring with 5-10-membered aromatic heterocycle, 5-10-membered aromatic heterocycle with 5-10-membered aromatic heterocycle, 6-10-membered aromatic ring with 6-10-membered aromatic ring; R A1 Selected from none, H, F, Cl, Br, I, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl. Substituted C2-C6 alkynyl groups, halogen-substituted C1-C6 alkyl groups, groups obtained by replacing one or more methylene groups with heteroatoms in C1-C6 alkyl groups, C1-C6 alkoxy groups, C1-C6 alkylamine groups, NR e1 R e2 hydroxyl, cyano, mercapto, sulfone, carboxyl, CONR e1 R e2 Oxygen; R A4 ,R A5 ,R A6 Each alkyl group is independently selected from C1-C6 alkyl groups; R A2 ,R A3 Each group is independently selected from: none, H, F, Cl, Br, I, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen-substituted C1-C6 alkyl, C1-C6 alkyl groups obtained by replacing one or more methylene groups with heteroatoms, C1-C6 alkoxy, C1-C6 alkylamine, NR e1 R e2 hydroxyl, cyano, mercapto, sulfone, carboxyl, CONR e1 R e2 Or R A1 R A2 ,R A3 Any two or three of them can be connected to form a loop; R e1 Selected from hydrogen, C1-C6 alkyl, R e2 Selected from hydrogen, C1-C6 alkyl; B is R B1 ,R B2 ,R B3 The following groups are substituted: 6-10 membered aromatic rings, 5-10 membered aromatic heterocycles, 6-10 membered aromatic rings with 6-10 membered aromatic rings, C2-C6 ynyl groups; wherein R B1 ,R B2 ,R B3 Each group is independently selected from: none, H, F, Cl, Br, I, C1-C6 alkyl, halogen-substituted C1-C6 alkyl, C1-C6 alkyl groups obtained by replacing one or more methylene groups with heteroatoms, C1-C6 alkoxy, C1-C6 alkylamine, NR d1 R d2 hydroxyl, cyano, mercapto, sulfone, carboxyl, CONR d1 R d2 Or R B1 ,R B2 ,R B3 Any two or three of them can be connected to form a loop; R d1 Selected from hydrogen, C1-C6 alkyl, R d2 Selected from hydrogen, C1-C6 alkyl; R is selected from halogens, C1-C6 alkyl groups, halogen-substituted C1-C6 alkyl groups, groups obtained by replacing one or more methylene groups with heteroatoms in C1-C6 alkyl groups, C1-C6 alkoxy groups, C1-C6 alkylamine groups, and L. 1 -NR 4 R 5 L 1 -hydroxyl group, L 1 -Cyano, L 1 -Thiol group, L 1 -sulfone group, L 1 -Carboxyl group, L 1 -CONR 4 R 5 L 2 -R 6 ; R 4 Selected from hydrogen, C1-C6 alkyl, halogen-substituted C1-C6 alkyl, groups obtained by replacing one or more CH2 or CH atoms in a C1-C6 alkyl group with heteroatoms, L 3 -OH, L 3 -NH2;R 5 Selected from hydrogen, C1-C6 alkyl, halogen-substituted C1-C6 alkyl, or R 4 Connected with R5 to form an unsubstituted or R 4a Substituted groups include: 5-12 membered saturated heterocycles, 5-12 membered heteroaromatic rings; L 3 Selected from C1-C6 alkylene groups; R 4a Selected from C1-C6 alkyl groups and halogen-substituted C1-C6 alkyl groups; L 1 Selected from C1-C6 alkylene groups; L 2 Selected from one bond, C1-C6 alkylene, (CH2) a O(CH2) b (CH2) a NR n (CH2) b ; a is 0, 1, 2, 3, or 4, b is 0, 1, 2, 3, or 4, R n Selected from hydrogen, C1-C6 alkyl; R 6 For R 1 ,R 2 ,R 3 ,R 7 ,R 8 The following groups are substituted: 5-12-membered saturated heterocycles, 5-12-membered heteroaromatic rings, 5-12-membered heteroaromatic rings with 5-12-membered heteroaromatic rings, 5-12-membered heteroaromatic rings with 6-12-membered aromatic rings, 5-12-membered saturated heteroaromatic rings with 6-12-membered aromatic rings, 5-12-membered heteroaromatic rings with 5-12-membered saturated heterocycles, and 5-12-membered heteroaromatic rings with 5-12-membered saturated carbocyclic rings; wherein R 1 ,R 2 ,R 3 ,R 7 ,R 8 Each group is independently selected from: 0, hydrogen, halogen, C1-C6 alkyl, halogen-substituted C1-C6 alkyl, C1-C6 alkyl group obtained by replacing one or more methylene groups with heteroatoms, C1-C6 alkoxy group obtained by replacing one or more methylene groups with heteroatoms, C1-C6 alkoxy, C1-C6 alkylamine, NR m1 R m2 hydroxyl, cyano, mercapto, sulfone, carboxyl, CONR m1 R m2 Oxygen, halogen or deuterium or halogenated C1-C6 alkoxy groups, hydroxyl groups substituted with 3-6 saturated carbon rings, L 4 -3-6 saturated carbon rings, L 4 -4-6 saturated heterocyclic rings, L 4 - Halogenated or C1-C6 alkyl-substituted 3-6 membered saturated carbon rings, L 4 - Halogenated or C1-C6 alkyl or halo-C1-C6 alkyl or hydroxylated 4-6 membered saturated heterocycles, L 4 -6-12 Yuanfanghuan, L 4 - Halogenated or C1-C6 alkyl-substituted 6-12-membered aromatic ring, L 4 -5-12 polyaromatic rings, L 4 - Halogenated or C1-C6 alkyl or halo-C1-C6 alkyl-substituted 5-12-membered heteroaryl ring, L 4 -5-6 membered saturated heterocyclic rings and 3-6 membered saturated carbon rings, L 4 -3-6 saturated heterocyclic spirocyclops, 3-6 saturated carbon ring, L 4 -3-6 quinary saturated carbon ring spirocyclops, 3-6 quinary saturated heterocyclic ring, L 4 -6-12 saturated carbon bridged rings, L 4 -6-12 saturated heterobridged ring; or R 1 ,R 2 ,R 3 ,R 7 ,R 8 Any two or three of them can be connected to form a loop; R m1 Selected from hydrogen, C1-C6 alkyl, halogen-substituted C1-C6 alkyl; R m2 Selected from hydrogen, C1-C6 alkyl; or R m1 and R m2 Linked into halogenated or non-halogenated 5-6 membered saturated heterocycles; L 4 Selected from one bond, C1-C6 alkylene, O, O-C1-C6 alkylene; And when X 1 ,X 2 ,X 3 Both are C, ring A is a benzene ring, and R A1 When the methyl group is substituted with F, Cl, Br, methyl, methoxy, or halogen, and ring B is a benzene ring, R is limited to R. 1 ,R 2 ,R 3 ,R 7 ,R 8 Substituted 5-12 membered heteroaryl rings, R 1 ,R 2 ,R 3 ,R 7 ,R 8 Two adjacent substituents are linked to form a 7-8 membered ring, or R 1 ,R 2 ,R 3 ,R 7 ,R 8 At least one of them is selected from halogen-substituted C1-C6 alkyl or halogen-substituted C1-C6 alkoxy. The compound, its pharmaceutically acceptable salt, its isotopic compound, or its stereoisomer according to claim 1, is characterized in that, The structure of the compound is shown in Formula II: Among them, X 3 R A1 R A2 R A3 A Y B and R are as described in claim 1. The compound according to claim 2, its pharmaceutically acceptable salt, its isotopic compound or its stereoisomer, is characterized in that, Ring A is a benzene ring, and the structure of the compound is shown in Formula III: Among them, X 3 R A1 R A2 R A3 B and R are as described in claim 2; And when X 3 For CH,R A1 When the molecule is H, F, Cl, Br, Me, CHF2, CF3, or OMe, and ring B is a benzene ring, R is limited to R. 1 ,R 2 ,R 3 ,R 7 ,R 8 Substituted 5-12 membered heteroaryl rings, R 1 ,R 2 ,R 3 ,R 7 ,R 8 Two adjacent substituents are linked to form a 7-8 membered ring, or R 1 ,R 2 ,R 3 ,R 7 ,R 8 At least one of them is selected from halogen-substituted C1-C6 alkyl or halogen-substituted C1-C6 alkoxy. The compound, its pharmaceutically acceptable salt, its isotopic compound, or its stereoisomer according to claim 3, is characterized in that, Ring A is a benzene ring, X 3 For CH, R A1 The compound is acetylene-based, and its structure is shown in Formula IV: Among them, R A2 R A3 B and R are as described in claim 3. The compound according to claim 4, its pharmaceutically acceptable salt, its isotopic compound or its stereoisomer, is characterized in that, B is a benzene ring, and the structure of the compound is shown in formula V: Among them, R A2 R A3 R is as described in claim 4. The compound according to claim 3, its pharmaceutically acceptable salt, its isotopic compound or its stereoisomer, is characterized in that... Ring, A is a benzene ring, X 3 The compound is N, and its structure is shown in Formula VI: Among them, R A1 R A2 R A3 B and R are as described in claim 3. The compound according to claim 6, its pharmaceutically acceptable salt, its isotopic compound or its stereoisomer, is characterized in that, B is a benzene ring, and the structure of the compound is shown in Formula VII: Among them, R A1 R A2 R A3 R as described in claim 6. The compound according to claim 2, its pharmaceutically acceptable salt, its isotopic compound or its stereoisomer, is characterized in that, Ring A is an indazole, and the structure of the compound is shown in Formula VIII: Among them, X 1 X 2 X 3 R A1 R A2 R A3 B and R are as described in claim 2. The compound according to claim 8, its pharmaceutically acceptable salt, its isotopic compound or its stereoisomer, is characterized in that, X 1 X 2 The compound is C, and its structure is shown in Formula IX-1: Among them, X 3 R A1 R A2 R A3 B and R are as described in claim 8. The compound according to claim 9, its pharmaceutically acceptable salt, its isotopic compound or its stereoisomer, is characterized in that, B is R B1 Substituted benzene ring, R B1 Selected from H, F, Cl, Br, I, the structure of the compound is shown in Formula IX-2: Among them, X 3 R A1 R A2 R A3 R as described in claim 9. The compound according to claim 10, its pharmaceutically acceptable salt, its isotopic compound, or its stereoisomer, is characterized in that, X 3 The compound is CH, and its structure is shown in Formula X: Among them, R A1 R A2 R A3 , R, R B1 As described in claim 10. The compound, its pharmaceutically acceptable salt, its isotopic compound, or its stereoisomer according to any one of claims 1-11, is characterized in that, R is L 2 R 6 , Where L 2 Selected from one bond, C1-C6 alkylene, (CH2) a O(CH2) b (CH2) a NH(CH2) b ;a is 0, 1, 2, 3, or 4, b is 0, 1, 2, 3, or 4. R 6 As described in claim 1. The compound according to claim 12, its pharmaceutically acceptable salt, its isotopic compound, or its stereoisomer, is characterized in that, L 2 As a key, R is R 6 , R 6 For R 1 ,R 2 ,R 3 ,R 7 ,R 8 The following groups are substituted: 5-12-membered saturated heterocycles, 5-12-membered heteroaromatic rings, 5-12-membered heteroaromatic rings with 5-12-membered heteroaromatic rings, 5-12-membered heteroaromatic rings with 6-12-membered aromatic rings, 5-12-membered saturated heteroaromatic rings with 6-12-membered aromatic rings, 5-12-membered heteroaromatic rings with 5-12-membered saturated heterocycles, and 5-12-membered heteroaromatic rings with 5-12-membered saturated carbocyclic rings; wherein R 1 ,R 2 ,R 3 ,R 7 ,R 8 Each group is independently selected from the groups of no, H, halogen, cyano, hydroxyl, C1-C6 alkylamine, and NR. m1 R m2 CONR m1 R m2 C1-C6 alkyl, halogen-substituted C1-C6 alkyl, C1-C6 alkoxy, halogenated or deuterated or halogenated C1-C6 alkoxy-substituted C1-C6 alkoxy, a group obtained by replacing one or more methylene groups of a C1-C6 alkyl group with heteroatoms, a group obtained by replacing one or more methylene groups of a C1-C6 alkoxy group with heteroatoms, L 4 -3-6 saturated carbon rings, L 4 - Halogenated or C1-C6 alkyl-substituted 3-6 membered saturated carbon rings, L 4 -4-6 saturated heterocyclic rings, L 4 - Halogenated or C1-C6 alkyl or halo-C1-C6 alkyl or hydroxylated 4-6 membered saturated heterocycles, L 4 -Benzene ring, L 4 - Halogenated or C1-C6 alkyl-substituted benzene ring, L 4 -5-6 cyclic aromatic rings, L 4 - A 5-6 membered heteroaryl ring substituted with a halogen or C1-C6 alkyl or halo-C1-C6 alkyl group, L 4 -5-6 membered saturated nitrogen heterocycles and 3-6 membered saturated carbon rings, L 4 -5-6 quinary saturated nitrogen heterocyclic spirocycloidens and 3-6 quinary saturated carbon rings, L 4 -4-6 quinary saturated carbon ring spirocyclohexane, L 4 -6-12 saturated carbon bridged rings, L 4 -7-membered saturated nitrogen-containing bridged ring; or, R 1 ,R 2 ,R 3 ,R 7 ,R 8 Any two of them are connected to form a ring, wherein the ring is selected from benzene ring, 3-6 member saturated carbon ring, 3-8 member unsaturated carbon ring, and 6-8 member unsaturated bridged ring; R m1 Selected from hydrogen, C1-C6 alkyl, halogen-substituted C1-C6 alkyl; R m2 Selected from hydrogen, C1-C6 alkyl; or R m1 and R m2 Linked into 5-6 member saturated heterocycles or halogenated 5-6 member saturated heterocycles; L 4 It is selected from one bond, C1-C6 alkylene, O, O-C1-C6 alkylene. The compounds, pharmaceutically acceptable salts thereof, isotopic compounds thereof, or stereoisomers thereof, according to claims 1-13, are characterized in that, R is a substituted pyridinone, and the structure of R is shown in XI: U and V are independently selected from N and C, respectively, and are not both C at the same time; R G1 ,R G2 ,R G3 ,R G4 Each group is independently selected from: ⇌ ⇌ H, halogen, cyano, hydroxyl, C1-C6 alkylamine, NR m1 R m2 CONR m1 R m2 C1-C6 alkyl, halogen-substituted C1-C6 alkyl, C1-C6 alkoxy, halogenated or deuterated or halogenated C1-C6 alkoxy, a group obtained by replacing one or more methylene groups of a C1-C6 alkyl group with O, S or NH, a group obtained by replacing one or more methylene groups of a C1-C6 alkoxy group with O, S or NH, L 4 -3-6 saturated carbon rings, L 4 - Halogenated or C1-C6 alkyl-substituted 3-6 membered saturated carbon rings, L 4 -4-6 saturated heterocyclic rings, L 4 - Halogenated or C1-C6 alkyl or halo-C1-C6 alkyl or hydroxylated 4-6 membered saturated heterocycles, L 4 -Benzene ring, L 4 - Halogenated or C1-C6 alkyl-substituted benzene ring, L 4 -5-6 cyclic aromatic rings, L 4 - A 5-6 membered heteroaryl ring substituted with a halogen or C1-C6 alkyl or halo-C1-C6 alkyl group, L 4 -5-6 membered saturated nitrogen heterocycles and 3-6 membered saturated carbon rings, L 4 -5-6 quinary saturated nitrogen heterocyclic spirocycloidens and 3-6 quinary saturated carbon rings, L 4 -4-6 quinary saturated carbon ring spirocyclohexane, L 4 -6-12 saturated carbon bridged rings, L 4 -7-membered saturated nitrogen-containing bridged ring; or, R G1 ,R G2 ,R G3 ,R G4 Two adjacent rings are connected to form a ring, wherein the ring is selected from benzene rings, 6-8 membered unsaturated carbon rings, and 7-8 membered unsaturated carbon bridged rings; the heteroatom in the saturated heterocycle contains at least one N, O, or S; the heteroatom in the heteroaromatic ring contains at least one N, O, or S. R m1 Selected from hydrogen, C1-C6 alkyl, halogen-substituted C1-C6 alkyl; R m2 Selected from hydrogen, C1-C6 alkyl; or R m1 and R m2 Connected to form a 5-6 member saturated nitrogen-containing heterocycle or a halogenated 5-6 member saturated nitrogen-containing heterocycle, wherein the nitrogen-containing heterocycle contains 0 or 1 O; L 4 It is selected from one bond, C1-C6 alkylene, O, O-C1-C6 alkylene. The compound according to claim 14, its pharmaceutically acceptable salt, its isotopic compound, or its stereoisomer, is characterized in that, The structure of the compound is shown in XII: Among them, U, V, R G1 R G2 R G3 R G4 As described in claim 14. The compound according to claim 14, its pharmaceutically acceptable salt, its isotopic compound, or its stereoisomer, is characterized in that, The structure of the compound is shown in XIII: Among them, U, V, R G1 R G2 R G3 R G4 As described in claim 14. The compound according to claim 14, its pharmaceutically acceptable salt, its isotopic compound, or its stereoisomer, is characterized in that, The structure of the compound is shown in XIV: Among them, U, V, R G1 R G2 R G3 R G4 As described in claim 14. The compound according to claim 14, its pharmaceutically acceptable salt, its isotopic compound, or its stereoisomer, is characterized in that, The structure of the compound is shown in XV: Wherein, U and V are as described in claim 14, R G1 and R G2 The linkage forms a 7-8 quintile unsaturated monocyclic carbon ring or a 7-8 quintile unsaturated carbon bridge ring, R G3 and R G4 Each is independently selected from H, halogen-substituted C1-C6 alkoxy, halogen-substituted C1-C6 alkyl; or R G1 R G2 R G3 R G4 One of them is selected from a halogen-substituted C1-C6 alkyl group or a halogen-substituted C1-C6 alkoxy group, and the others are independently selected from H, a halogen-substituted C1-C6 alkoxy group, a halogen-substituted C1-C6 alkyl group, and L. 4 -3-6 saturated carbon rings; L 4 It is selected from one bond, C1-C6 alkylene, O, O-C1-C6 alkylene. The compound, its pharmaceutically acceptable salt, its isotopic compound, or its stereoisomer according to claim 3, is characterized in that, B is a naphthalene ring, and the structure of the compound is shown in XVI: Among them, R 4 Selected from hydrogen, C1-C6 alkyl, halogen-substituted C1-C6 alkyl, C1-C6 alkyl groups obtained by replacing one or more CH2 or CH with O or N, L 3 -OH, L 3 -NH2;R 5 Selected from hydrogen, C1-C6 alkyl, halogen-substituted C1-C6 alkyl, or linked to form unsubstituted or R 4a The following groups are substituted: 5-6 membered saturated nitrogen-containing heterocycles, pyridinones; wherein the nitrogen-containing heterocycle contains 0 or 1 O; L 3 Selected from C1-C6 alkylene groups; R 4a Selected from C1-C6 alkyl groups and halogen-substituted C1-C6 alkyl groups. The compound, its pharmaceutically acceptable salt, its isotopic compound, or its stereoisomer according to claim 1, is characterized in that, The compounds are selected from the following structures: A pharmaceutical composition, characterized in that, It is a formulation prepared by adding pharmaceutically acceptable excipients to a compound as described in any one of claims 1-20, a pharmaceutically acceptable salt thereof, an isotopic compound thereof or a stereoisomer thereof as the active ingredient. Use of the compound of any one of claims 1-20, its pharmaceutically acceptable salt, its isotope, or its stereoisomer in the preparation of a VAV1 degrading agent. The use according to claim 22 is characterized in that, The VAV1 degrading agent is a drug for the prevention and / or treatment of autoimmune diseases, inflammation, and cancer. The use according to claim 23 is characterized in that, The autoimmune diseases or inflammations mentioned include rheumatoid arthritis, Crohn's disease, ulcerative colitis, psoriasis, multiple sclerosis, systemic lupus erythematosus, Hashimoto's thyroiditis, myasthenia gravis, type 1 or type 2 diabetes and related diseases, vasculitis, pernicious anemia, Sjögren's syndrome, uveitis, Graves' ophthalmopathy, alopecia areata, allergic diseases, inflammatory diseases, atherosclerosis, osteoarthritis, irritant contact dermatitis, eczematous dermatitis, seborrheic dermatitis, skin manifestations of immune-mediated diseases, inflammatory eye diseases, keratoconjunctivitis, myocarditis, or hepatitis; the allergic diseases are preferably allergic asthma, atopic dermatitis, allergic rhinitis / conjunctivitis, or allergic contact dermatitis; the inflammatory diseases are preferably inflammatory bowel disease, endogenous asthma, inflammatory lung injury, inflammatory liver injury, or inflammatory glomerular injury. The use according to claim 23 is characterized in that, The cancer is a solid tumor or a hematologic malignancy; the hematologic malignancy is preferably a T-cell malignancy or a B-cell malignancy. The use according to claim 25 is characterized in that, The cancers mentioned include liver cancer, stomach cancer, colorectal cancer, leukemia, lymphoma, acute myeloid leukemia (AML), T-cell prolymphocytic leukemia, T-cell granulocytic lymphocytic leukemia, aggressive natural killer cell leukemia, hairy cell leukemia, nasal and nasal NK / T-cell lymphoma, fungal granuloma and Cezari syndrome, angioimmune T-cell lymphoma, peripheral T-cell lymphoma (nonspecific type), adult T-cell leukemia / lymphoma (HTLV1), anaplastic large cell lymphoma, and primary cutaneous leukemia. CD30-positive T-cell proliferative disorders, cutaneous T-cell lymphoma, T-cell lymphoma resembling subcutaneous lipitis, enteropathy-associated lymphoma, hepatosplenic gamma / δ T-cell lymphoma, or non-Hodgkin lymphoma; wherein the non-Hodgkin lymphoma is preferably B-cell non-Hodgkin lymphoma; wherein the B-cell non-Hodgkin lymphoma is preferably Burkitt lymphoma, chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SLL), diffuse large B-cell lymphoma, follicular lymphoma, or covered cell lymphoma.

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