Piperidinedione ring derivative, preparation method therefor and use thereof

Abstract

The present invention relates to a piperidinedione derivative, a preparation method therefor, and a pharmaceutical use of a pharmaceutical composition containing the derivative. Specifically, the present invention relates to a piperidinedione derivative represented by general formula (I), a preparation method therefor and a pharmaceutically acceptable salt thereof, and uses of said derivative and said salt as a therapeutic agent, particularly as a VAV1 degrader, wherein the definitions of substituents in general formula (I) are the same as those in the description.

Description

Piperidine dione cyclic derivatives, their preparation methods and uses

[0001] Cross-references to related applications

[0002] This application claims priority to the following patent applications filed with the China National Intellectual Property Administration (CNIPO) on January 21, 2025, entitled "Piperidine dione ring derivatives and their preparation methods and uses", application number CN202510092006.4; on July 11, 2025, entitled "Piperidine dione ring derivatives and their preparation methods and uses", application number CN202510961830.9; on November 11, 2025, entitled "Piperidine dione ring derivatives and their preparation methods and uses", application number CN202511641128.0; and on December 4, 2025, entitled "Piperidine dione ring derivatives and their preparation methods and uses", application number CN202511825985.6, the entire contents of which are incorporated herein by reference. Technical Field

[0003] This invention relates to a piperidine dione derivative, its preparation method, pharmaceutical compositions containing the derivative, and its use as a therapeutic agent, particularly as a VAV1 degrading agent. Background Technology

[0004] The VAV family, a group of signal transduction proteins, consists of phosphorylation-dependent GDP / GTP guanine nucleotide exchange factors (GEFs) and adaptor molecules of Rho subfamily GTPases. In vertebrates, this family comprises three members—VAV1, VAV2, and VAV3. VAV1 primarily encodes and expresses GEFs in human hematopoietic stem cells, including T cells, B cells, monocytes, natural killer (NK) cells, granulocytes, and dendritic cells. Family members VAV2 and VAV3 are more widely expressed.

[0005] Studies have shown that VAV1 plays a crucial role in TCR-mediated activation and T cell effector function. VAV1 functions as a scaffold protein in the GEF-independent pathway. Lymph node T cells isolated from GEF-inactivated mice exhibited normal TCR-mediated calcium release and NFAT pathway activation in vitro. Conversely, transfection of human VAV1-deficient J.Vav1 T cells with a GEF-retaining N-terminal truncated mutant resulted in incomplete calcium release and NFAT pathway activation in vitro due to the inability to interact with phospholipase C-γ (PLCγ)1. 2+VAV1 releases, binds to calmodulin, and activates the NFAT pathway. It regulates various cellular functions and signaling pathways in hematopoietic-derived cells (such as T cells and B cells, natural killer cells, and osteoclasts) by activating certain GTPases. Its functions include actin remodeling, F-actin polymerization, TCR aggregation, integrin-mediated cell adhesion activation, immune synapse formation between T cells and antigen-presenting cells (APCs), and chemokine-mediated cell migration. VAV1 also regulates cytoskeleton remodeling in B cells.

[0006] Inflammation is a physiological response of the immune system to damage and infection. In this process, the immune system signals and activates immune cells to repair damaged tissue and protect against infections from viruses, bacteria, and other pathogens. However, inappropriate activation can also lead to disease. Chronic inflammation is a major cause of several diseases, including rheumatoid arthritis (RA), inflammatory bowel disease (IBD), and psoriasis. Although the rise of immunotherapy in recent years has made progress in treating these diseases, significant unmet medical needs remain.

[0007] Currently, treatment options for autoimmune diseases and chronic inflammatory diseases remain limited. Many drugs work by blocking single proteins (e.g., drugs targeting TNF or IL-17A) or signaling pathways (e.g., JAK inhibitors), but their efficacy is insufficient and they have certain side effects. Numerous pieces of evidence suggest that VAV1 is associated with autoimmune and chronic inflammatory diseases, supporting its potential as a therapeutic target.

[0008] Targeting VAV1 expression or function offers various therapeutic approaches. One approach, based on azathioprine activity, involves designing more specific thiopurine analogs to provide a new avenue for VAV1 / Rac1 pathway blockade, but this has not yet been tested in clinical trials. Another emerging approach utilizes the in vivo ubiquitin-proteasome system to target VAV1 protein degradation. PROTAC degraders need to be able to simultaneously bind to both the target protein and the E3 ubiquitin ligase via different binding pockets, leading to the ubiquitination of the target protein and its subsequent removal from the cell. While effective, this approach presents a challenge for VAV1, a protein lacking a clearly defined binding pocket. Molecular glue degraders can bind to the surface of the E3 ligase complex to promote polyubiquitination of novel protein substrates involved in disease development and ultimately proteasome degradation. Studies have shown that targeting VAV1 protein degradation using molecular glue technology can modulate T-cell and B-cell receptor-mediated activity, significantly reducing cytokine secretion both in vivo and in vitro. Cytokines are essential proteins for maintaining autoimmune diseases.

[0009] There are currently no effective marketed drugs targeting VAV1 molecular adhesive degradation agents. Only one company is in development: Monte Rosa Therapeutics' MRT-6160, which is in Phase I clinical trials. There is a significant unmet clinical need for effective VAV1 degradation agents. Summary of the Invention

[0010] To address the aforementioned technical problems, the present invention provides a compound of general formula (I) or its stereoisomers, tautomers, deuterated derivatives, or pharmaceutically usable salts thereof:

[0011] in:

[0012] W is selected from:

[0013] 1) Where “-*” indicates that the group is related to the general formula (I) Connection sites; This indicates the connection site between the group and L1 in general formula (I); ring A is selected from 3-12 membered heterocyclic groups, C 3-12 Cycloalkylene, 5-membered monocyclic heteroarylene, naphthylene, 8-10-membered bicyclic heteroarylene, and 8-10-membered bicyclic fused ring, wherein the 8-10-membered bicyclic fused ring is preferably a fused ring of a monocyclic aryl or a monocyclic heteroaryl with a monocyclic heterocyclic group or a monocyclic cycloalkyl; R e Whether the groups are the same or different, they are each independently selected from deuterium atoms, halogens, hydroxyl groups, cyano groups, SF5, and C. 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkyl groups;

[0014] And / or, two Rs e It forms a -C (=O) with the same carbon atom it is attached to;

[0015] m is selected from 0, 1, 2, 3, 4, and 5;

[0016] The conditions are: Not selected from the following groups:

[0017] 2)C 2-6 imide or C 2-6 Idemynyl, wherein the C 2-6 imide or C 2-6 The ethynyl group may be further selected by one or more atoms selected from =O, deuterium, halogen, hydroxyl, cyano, SF5, C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 Substituents of haloalkyl groups;

[0018] 3) Where "-*" indicates that the group is related to the general formula (I) Connection sites; This indicates the connection site between the group and L1 in general formula (I);

[0019] L2 is selected from -C(=O)-, -O(C 0-4 alkylene)-, -NR j (C 0-4 alkylene)-, -NR j C(=O)(C 0-4 alkylene)-, -(C 0-4 Alkylene C(=O)-, C 2-6 imide and C 2-6 Idemynyl, wherein the C 0-4 Alkylene, C 2-6 imide or C 2-6 The ynylene group is optionally surrounded by one or more atoms selected from deuterium, halogen, hydroxyl, cyano, C. 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 Substituents of haloalkyl groups;

[0020] 4) Where "-*" indicates that the group is related to the general formula (I) Connection sites; This indicates the connection site between the group and L1 in general formula (I);

[0021] Z is selected from -C(=O)- and -NR. j C(=O)(C 0-4 alkylene)-, -(C 0-4 Alkylene C(=O)-, C 2-6 imide and C 2-6 Idemynyl, wherein the C 0-4 Alkylene, C 2-6 imide or C 2-6 The ynylene group is optionally surrounded by one or more atoms selected from deuterium, halogen, hydroxyl, cyano, C. 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 Substituents of haloalkyl groups;

[0022] R j Each is independently selected from hydrogen atoms and C atoms. 1-6 alkyl;

[0023] R 6 Each is independently selected from halogen, hydroxyl, cyano, C 1-6 Alkyl and C1-6 Alkoxy, wherein the C 1-6 Alkyl or C 1-6 Alkoxy groups may optionally be further selected from halogens, hydroxyl groups, cyano groups, and C. 1-6 Substituents of alkoxy groups;

[0024] n is independently selected from 0, 1, 2, 3, and 4;

[0025] R 2 Selected from hydrogen atom, deuterium atom, hydroxyl group, halogen, cyano group, C 1-6 Alkyl and C 1-6 Alkoxy, wherein the C 1-6 Alkyl or C 1-6 Alkoxy groups may optionally be further selected from halogens, hydroxyl groups, cyano groups, and C. 1-6 Substituents of alkoxy groups;

[0026] R 3 and R 4 Each is independently selected from hydrogen atom, deuterium atom, hydroxyl group, cyano group, C 1-6 Alkyl and C 1-6 Alkoxy;

[0027] L1 is selected from key, -C(=O)-, -C 1-4 Alkylene-, -O(C) 0-4 alkylene)-, -NR a (C 0-4 alkylene)-, -NR a C(=O)(C 0-4 alkylene)- and -(C 0-4 alkylene C(=O)-, wherein the C 0-4 The alkylene group is optionally surrounded by one or more atoms selected from deuterium, halogen, hydroxyl, cyano, C. 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 Substituents of haloalkyl groups;

[0028] R a Each is independently selected from hydrogen atoms and C atoms. 1-6 alkyl;

[0029] R 1 The group is selected from phenyl, 3-12-membered heterocyclic, 5-10-membered heteroaryl, and 8-10-membered fused ring, wherein the phenyl, 3-12-membered heterocyclic, 5-10-membered heteroaryl, or 8-10-membered fused ring is optionally further selected from one or more groups selected from =O, halogen, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl and C 1-6 The alkoxy group is replaced by a substituent.

[0030] A preferred embodiment of the present invention is a compound of general formula (I) or a stereoisomer, tautomer, deuterated product or a pharmaceutically acceptable salt thereof, wherein the compound of general formula (II) or a stereoisomer, tautomer, deuterated product or a pharmaceutically acceptable salt thereof is:

[0031] Among them, ring A is selected from 3-12 membered heterocyclic groups, C 3-12 Cycloalkyl, 5-membered monocyclic heteroaryl, 8-10-membered bicyclic heteroaryl, naphthylene, and 8-10-membered bicyclic fused ring; wherein the bicyclic fused ring is preferably a fused ring of monocyclic aryl or monocyclic heteroaryl with monocyclic heterocyclic group or monocyclic cycloalkyl.

[0032] R e Whether the groups are the same or different, they are each independently selected from deuterium atoms, halogens, hydroxyl groups, cyano groups, SF5, and C. 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkyl groups;

[0033] And / or, two Rs e It forms a -C (=O) with the same carbon atom it is attached to;

[0034] m is selected from 0, 1, 2, 3, 4, and 5;

[0035] The conditions are: Not selected from the following groups:

[0036] L1, R 1 R 2 R 3 and R 4 The definition is as stated in general formula (I).

[0037] A preferred embodiment of the present invention is a compound of formula (I) or (II) or a stereoisomer, tautomer, deuterated derivative or pharmaceutically acceptable salt thereof, wherein R e They may be the same or different, each independently selected from deuterium, halogen, hydroxyl, cyano, SF5, methyl, methoxy and trifluoromethoxy;

[0038] And / or, two Rs e It forms a -C (=O) with the same carbon atom it is attached to.

[0039] A preferred embodiment of the present invention is a compound of formula (I) or (II) or a stereoisomer, tautomer, deuterated derivative or pharmaceutically acceptable salt thereof, wherein... Selected from the following groups:

[0040] A preferred embodiment of the present invention is a compound of general formula (I) or a stereoisomer, tautomer, deuterated derivative or pharmaceutically acceptable salt thereof, wherein W is selected from C 2-6 imide and C 2-6 Idemynyl, wherein the C 2-6 imide or C 2-6 The ethynyl group may be further selected by one or more atoms selected from =O, deuterium, halogen, hydroxyl, cyano, SF5, C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 The alkyl halogroup is substituted by a substituent.

[0041] A preferred embodiment of the present invention is a compound of general formula (I) or a stereoisomer, tautomer, deuterated derivative or pharmaceutically acceptable salt thereof, wherein W is selected from...

[0042] A preferred embodiment of the present invention is a compound of general formula (I) or a stereoisomer, tautomer, deuterated product or a pharmaceutically acceptable salt thereof, wherein the compound of general formula (III) or a stereoisomer, tautomer, deuterated product or a pharmaceutically acceptable salt thereof is:

[0043] L2 is selected from -O- and -NR. j -、C 2-6 imide and C 2-6 Ethyne group;

[0044] R j Selected from hydrogen atoms and C 1-6 alkyl;

[0045] R 6 Each is independently selected from halogen, hydroxyl, cyano, methyl, methoxy, trifluoromethyl, and trifluoromethoxy;

[0046] n is selected from 0, 1, 2, 3, and 4;

[0047] L1, R 1 R 2 R 3 and R 4 The definition is as stated in general formula (I).

[0048] A preferred embodiment of the present invention is a compound of general formula (I) or (III) or a stereoisomer, tautomer, deuterated derivative or pharmaceutically acceptable salt thereof, wherein: L2 is selected from -O-, vinylene and ethynylene groups.

[0049] A preferred embodiment of the present invention is a compound of general formula (I) or a stereoisomer, tautomer, deuterated derivative or pharmaceutically acceptable salt thereof, wherein the compound is of general formula (IV) or a stereoisomer, tautomer, deuterated derivative or pharmaceutically acceptable salt thereof:

[0050] Where Z is selected from C 2-6 imide and C 2-6 Ethyne group;

[0051] R 6 Each is independently selected from halogen, hydroxyl, cyano, methyl, methoxy, trifluoromethyl, and trifluoromethoxy;

[0052] n is selected from 0, 1, 2, 3, and 4;

[0053] L1, R 1 R 2 R 3 and R 4 The definition is as stated in general formula (I).

[0054] A preferred embodiment of the present invention is a compound of formula (I) or (IV) or a stereoisomer, tautomer, deuterated derivative or pharmaceutically acceptable salt thereof, wherein Z is selected from vinylidene and ethynylidene.

[0055] A preferred embodiment of the present invention is a compound of general formula (I) or a stereoisomer, tautomer, deuterated derivative or pharmaceutically acceptable salt thereof, wherein W is selected from the following groups:

[0056] A preferred embodiment of the present invention is a compound of formula (I), (II), (III) or (IV) or a stereoisomer, tautomer, deuterated derivative or pharmaceutically acceptable salt thereof, wherein L1 is selected from the bond, -O(C 0-4 alkylene)-, -C(O)- and -C 1-4 Alkylene-.

[0057] A preferred embodiment of the present invention is a compound of formula (I), (II), (III) or (IV) or a stereoisomer, tautomer, deuterated derivative or pharmaceutically acceptable salt thereof, wherein L1 is selected from bond, -O-, -C(O)- and -C 1-4 Alkylene.

[0058] A preferred embodiment of the present invention is a compound of formula (I), (II), (III) or (IV) or a stereoisomer, tautomer, deuterated derivative or pharmaceutically acceptable salt thereof, wherein R 1The group is selected from phenyl, 3-12-membered heterocyclic, and 5-10-membered heteroaryl, wherein the phenyl, 3-12-membered heterocyclic, and 5-10-membered heteroaryl groups are optionally further selected from one or more groups selected from =O, halogen, hydroxyl, cyano, methyl, isopropyl, and C. 1-6 Substituents of haloalkyl and methoxy groups.

[0059] A preferred embodiment of the present invention is a compound of formula (I), (II), (III) or (IV) or a stereoisomer, tautomer, deuterated derivative or pharmaceutically acceptable salt thereof, wherein R 1 Selected from phenyl,

[0060] A preferred embodiment of the present invention is a compound of formula (I), (II), (III) or (IV) or a stereoisomer, tautomer, deuterated derivative or pharmaceutically acceptable salt thereof, wherein R 2 Selected from halogens, preferably chlorine.

[0061] A preferred embodiment of the present invention is a compound of formula (I), (II), (III) or (IV) or a stereoisomer, tautomer, deuterated derivative or pharmaceutically acceptable salt thereof, wherein R 3 R 4 It is a hydrogen atom.

[0062] In a preferred embodiment of the present invention, the compounds of the general formula are selected from:

[0063] Or its stereoisomers, tautomers, deuterated derivatives, or medicinal salts thereof.

[0064] Note: If there is a discrepancy between the drawn structure and the given name of the structure, the drawn structure shall prevail.

[0065] Furthermore, the present invention provides a pharmaceutical composition comprising a compound of formula (I), (II), (III) or (IV) or a stereoisomer, tautomer, deuterated compound or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0066] The present invention provides the use of a compound of formula (I), (II), (III) or (IV) or its stereoisomer, tautomer, deuterated product or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the preparation of a VAV1 degrading agent.

[0067] The present invention also provides the use of a compound of formula (I), (II), (III) or (IV) or its stereoisomers, tautomers, deuterated derivatives or pharmaceutically acceptable salts thereof, or a pharmaceutical composition thereof, in the preparation of a medicament for treating or preventing VAV1-mediated diseases; preferably, wherein the VAV1-mediated disease is an autoimmune disease or an inflammatory disease; more preferably, the autoimmune disease or inflammatory disease is selected from multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus, idiopathic dermatitis, and Hashimoto's thyroiditis. Inflammation, myasthenia gravis, type I or II diabetes and related diseases, vasculitis, pernicious anemia, Sjögren's syndrome, uveitis, psoriasis, Graves' ophthalmopathy, alopecia areata, allergic asthma, atopic dermatitis, allergic rhinitis, conjunctivitis, allergic contact dermatitis, 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, eczematous dermatitis, seborrheic dermatitis, inflammatory eye disease, keratoconjunctivitis, myocarditis or hepatitis.

[0068] Accordingly, this application provides a method for treating or preventing VAV1-mediated diseases, comprising administering to a subject in need a compound of formula (I), (II), (III) or (IV) of this application or a stereoisomer, tautomer, deuterated form or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described in this application. Preferably, the VAV1-mediated disease is an autoimmune disease or an inflammatory disease; more preferably, the autoimmune disease or inflammatory disease is selected from multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus, idiopathic dermatitis, Hashimoto's thyroiditis, myasthenia gravis, type I or type II diabetes and related diseases, vasculitis, pernicious anemia, Sjögren's syndrome, uveitis, psoriasis, Graves' ophthalmopathy, alopecia areata, allergic asthma, atopic dermatitis, allergic rhinitis, conjunctivitis, allergic contact dermatitis, 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, eczematous dermatitis, seborrheic dermatitis, inflammatory eye disease, keratoconjunctivitis, myocarditis or hepatitis.

[0069] The present invention also provides the use of a compound of formula (I), (II), (III) or (IV) or its stereoisomer, tautomer, deuterated product or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the preparation of a medicament for treating or preventing autoimmune diseases or inflammatory diseases; preferably, wherein the autoimmune disease or inflammatory disease is selected from multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus, idiopathic dermatitis, Hashimoto's thyroiditis, myasthenia gravis, type I or type II. Diabetes and related diseases, vasculitis, pernicious anemia, Sjögren's syndrome, uveitis, psoriasis, Graves' ophthalmopathy, alopecia areata, allergic asthma, atopic dermatitis, allergic rhinitis, conjunctivitis, allergic contact dermatitis, 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, eczematous dermatitis, seborrheic dermatitis, inflammatory eye disease, keratoconjunctivitis, myocarditis or hepatitis.

[0070] Accordingly, this application also provides a treatment or prevention method for multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus, idiopathic dermatitis, Hashimoto's thyroiditis, myasthenia gravis, type I or type II diabetes and related diseases, vasculitis, pernicious anemia, Sjögren's syndrome, uveitis, psoriasis, Graves' ophthalmopathy, alopecia areata, allergic asthma, atopic dermatitis, allergic rhinitis, conjunctivitis, allergic contact dermatitis, inflammatory bowel disease, Crohn's disease or ulcerative colitis, and other related conditions. Methods for treating inflammatory asthma, inflammatory lung injury, inflammatory liver injury, inflammatory glomerular injury, atherosclerosis, osteoarthritis, irritant contact dermatitis, eczematous dermatitis, seborrheic dermatitis, inflammatory eye disease, keratoconjunctivitis, myocarditis, or hepatitis, comprising administering to a subject in need a compound of formula (I), (II), (III), or (IV) of this application, or a stereoisomer, tautomer, deuterated form, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described in this application.

[0071] Experimental results show that the compounds of the present invention have good in vivo and in vitro activities; the compounds of the present invention have good degradation effects on VAV1 protein; the compounds of the present invention have good enzymatic and cellular activities; in addition, the compounds of the present invention have good pharmacokinetic characteristics and efficacy.

[0072] Detailed description of the invention

[0073] Unless otherwise stated, some terms used in this specification and claims are defined as follows:

[0074] When "alkyl" is used as a group or part of a group, it refers to a group consisting of C1-C2. 20 Straight-chain or branched aliphatic hydrocarbon groups. Preferably C1-C.10 Alkyl groups, more preferably C1-C6 and C1-C4 alkyl groups. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, etc. The alkyl group may be substituted or unsubstituted.

[0075] "Alkylene" refers to saturated C1-C 20 A straight-chain or branched aliphatic hydrocarbon group having two residues derived from the removal of two hydrogen atoms from the same carbon atom or two different carbon atoms of the parent alkane, preferably C1-C. 10 Alkylene, more preferably C1-C6 alkylene. Examples of alkylene groups include, but are not limited to, methylene, 1,1-ethylene, 1,2-ethylene, 1,1-propylene, 1,2-propylene, 1,3-propylene, 1,4-butylene, etc. Alkylenes may be substituted or unsubstituted.

[0076] "Alkenyl" refers to an alkyl group as defined above, consisting of at least two carbon atoms and at least one carbon-carbon double bond. Representative examples include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, 1-, 2-, or 3-butenyl. C2-C6 alkenyl groups are preferred. Alkenyl groups may be optionally substituted or unsubstituted.

[0077] "Alkenyl" refers to an alkylene group as defined above, consisting of at least two carbon atoms and at least one carbon-carbon double bond, having two residues derived from the same carbon atom or two different carbon atoms of the parent alkane by removing two hydrogen atoms, preferably C2-C. 10 The alkenyl group, more preferably a C2-C6 alkenyl group, is used. Examples of alkenyl groups include, but are not limited to, those described above. Etc. The alkenyl group can be substituted or unsubstituted.

[0078] "Alkyne group" refers to an aliphatic hydrocarbon group containing a single carbon-carbon triple bond, which can be straight-chain or branched. C2-C is preferred. 10 The alkynyl group is preferred, more preferably C2-C6 alkynyl, and most preferably C2-C4 alkynyl. Examples of alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-, 2-, or 3-butynyl. The alkynyl group may be substituted or unsubstituted.

[0079] "Alynyl group" refers to an alkylene group as defined above, consisting of at least two carbon atoms and at least one carbon-carbon triple bond, having two residues derived from the same carbon atom or two different carbon atoms of the parent alkane by removing two hydrogen atoms, preferably C2-C. 10 The ynyl group, more preferably a C2-C6 ynyl group. Examples of ynyl groups include, but are not limited to, those described above. The ynylene group can be substituted or unsubstituted.

[0080] "Cycloalkyl" refers to a non-aromatic cyclic alkyl group in which one or more of the cyclic atoms are carbon atoms and the ring contains 0, 1 or more double bonds, including monocyclic, polycyclic, fused, bridged and spirocyclic, preferably 3-12 membered cycloalkyl, more preferably having 3 to 7 membered monocyclic, or 5 to 12 membered bicyclic or tricyclic.

[0081] Examples of "monocycloalkyl" include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Monocyclic alkyl groups can be substituted or unsubstituted.

[0082] "Spirocycloalkyl" refers to a polycyclic group consisting of 5 to 18 quintiles, two or more cyclic structures, where the monocyclic rings share a carbon atom (called a spiro atom) with each other, containing 0, 1, or more double bonds within the rings, but without any ring having fully conjugated π electrons. Preferably, it is a 6 to 14 quintile group, more preferably a 7 to 10 quintile group. Based on the number of spiro atoms shared between the rings, spirocycloalkyl groups are classified as monospiro, bispiro, or polyspirocycloalkyl groups, preferably monospiro and bispirocycloalkyl groups, and preferably 4 / 5, 4 / 4, 4 / 6, 3 / 6, 5 / 5, or 5 / 6 quintile groups. Non-limiting examples of "spirocycloalkyl" include, but are not limited to: spiro[4.5]decyl, spiro[4.4]nonyl, spiro[3.5]nonyl, spiro[2.4]heptyl, Spirocycloalkyl groups can be substituted or unsubstituted.

[0083] "Fused cycloalkyl" refers to a 5- to 18-membered, all-carbon polycyclic group containing two or more cyclic structures sharing a pair of carbon atoms. One or more rings may contain 0, 1, or more double bonds, but none of the rings has fully conjugated π electrons. It is preferably a 6- to 14-membered aromatic system, more preferably a 6- to 10-membered system. Depending on the number of rings, it can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic fused cycloalkyl, preferably bicyclic or tricyclic, more preferably 3-membered / 5-membered, 5-membered / 5-membered, or 5-membered / 6-membered bicyclic fused cycloalkyl. Non-limiting examples of "fused cycloalkyl" include, but are not limited to: bicyclo[3.1.0]hexyl, bicyclo[3.2.0]hept-1-enyl, bicyclo[3.2.0]heptyl, decahydronaphthyl, tetradecahydrophenanthrene, etc. The fused cycloalkyl group can be substituted or unsubstituted.

[0084] "Bridged cycloalkyl" refers to an aromatic system with 5 to 18 members, containing two or more cyclic structures, sharing two non-directly connected carbon atoms, and one or more rings may contain 0, 1, or more double bonds, but none of the rings has fully conjugated π electrons. It is preferably 6 to 14 members, more preferably 7 to 10 members. Depending on the number of constituent rings, it can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic bridged cycloalkyl, preferably bicyclic, tricyclic, or tetracyclic, and more preferably bicyclic or tricyclic. Non-limiting examples of "bridged cycloalkyl" include, but are not limited to: (1s,4s)-bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl, (1s,5s)-bicyclo[3.3.1]nonyl, bicyclo[2.2.2]octyl, (1r,5r)-bicyclo[3.3.2]decyl, Bridged cycloalkyl groups can be substituted or unsubstituted.

[0085] The terms “heterocyclic group,” “heterocyclic alkyl group,” “heterocyclic,” or “heterocyclic” are used interchangeably in this application and all refer to a non-aromatic heterocyclic group in which one or more cyclic atoms are selected from nitrogen, oxygen, or S(O). r (where r is selected from 0, 1 or 2) heteroatoms, containing 0, 1 or more double bonds in the ring, including monocyclic, polycyclic, fused ring, bridged ring and spirocyclic, preferably 3-12 membered heterocyclic group, more preferably having 3 to 8 membered monocyclic or 5 to 12 membered bicyclic or tricyclic, which may contain 1, 2 or 3 atoms selected from nitrogen, oxygen and / or sulfur.

[0086] The heterocyclic group can be substituted or unsubstituted.

[0087] Examples of "monocyclic heterocyclic groups" include, but are not limited to, morpholino, oxetane, aza-butane, thiomorpholino, tetrahydrofurano, tetrahydropyrano, piperidino, pyrrolidinyl, 8-oxa-3-aza-bicyclo[3.2.1]octyl, piperazine, hexahydropyrimidine,

[0088] "Spirocycloheterocyclic group" refers to a polycyclic group with 5 to 18 members, two or more ring structures, in which the monocyclic rings share an atom with each other, and contains 0, 1 or more double bonds within the rings, but none of the rings has fully conjugated π electrons. One or more ring atoms are selected from nitrogen, oxygen or S(O). r(where r is selected from 0, 1 or 2) heteroatoms, and the remaining ring atoms are carbon. Preferably, it is 6 to 14 membered, more preferably 7 to 10 membered. Spirocycloalkyl groups are classified into monospirocycloalkyl, bispirocycloalkyl or polyspirocycloalkyl groups according to the number of shared spiroatoms between rings, preferably monospirocycloalkyl and bispirocycloalkyl. More preferably, it is 3 / 6 membered, 4 / 4 membered, 4 / 5 membered, 4 / 6 membered, 5 / 5 membered, 5 / 6 membered or 6 / 6 membered monospirocycloalkyl. Non-limiting examples of "spirocycloalkyl" include, but are not limited to: 1,7-dioxaspiro[4.5]decyl, 2-oxa-7-azaspiro[4.4]nonyl, 7-oxaspiro[3.5]nonyl, 5-oxaspiro[2.4]heptyl,

[0089] "Fused heterocyclic group" refers to a polycyclic group containing two or more ring structures that share a pair of atoms. One or more rings may contain 0, 1 or more double bonds, but none of the rings have fully conjugated π electrons. One or more ring atoms are selected from nitrogen, oxygen or S(O). r (where r is selected from 0, 1 or 2) heteroatoms, and the remaining ring atoms are carbon. Preferably 6 to 14 members, more preferably 7 to 10 members. Depending on the number of constituent rings, it can be classified as bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic group, preferably bicyclic or tricyclic, more preferably 5-membered / 5-membered or 5-membered / 6-membered bicyclic fused heterocyclic group. Non-limiting embodiments of "fused heterocyclic group" include, but are not limited to: octahydropyrrolo[3,4-c]pyrrol, octahydro-1H-isoindolyl, 3-azabicyclo[3.1.0]hexyl, octahydrobenzo[b][1,4]dioxin,

[0090] "Bridged heterocyclic group" refers to a polycyclic group with 5 to 18 members, containing two or more ring structures that share two atoms that are not directly connected. One or more rings may contain 0, 1, or more double bonds, but none of the rings have fully conjugated π electrons. One or more ring atoms are selected from nitrogen, oxygen, or S(O). r (where r is selected from 0, 1 or 2) heteroatoms, and the remaining ring atoms are carbon. Preferably, it is 6 to 14-membered, more preferably 7 to 10-membered. Depending on the number of rings, it can be classified as bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups, preferably bicyclic, tricyclic or tetracyclic, and more preferably bicyclic or tricyclic. Non-limiting embodiments of "bridged heterocyclic groups" include, but are not limited to: 2-azabicyclo[2.2.1]heptyl, 2-azabicyclo[2.2.2]octyl, 2-azabicyclo[3.3.2]decyl.

[0091] "Aryl" refers to a carbocyclic aromatic system containing one or two rings, wherein the rings may be linked together in a fused manner. The term "aryl" includes monocyclic or bicyclic aryl groups, such as phenyl, naphthyl, and tetrahydronaphthyl aromatic groups. Preferably, the aryl group is C6-C. 10 Aryl, more preferably phenyl and naphthyl, most preferably naphthyl. The aryl group can be substituted or unsubstituted.

[0092] "Heteroaryl" refers to an aromatic 5- to 6-membered monocyclic or 8- to 10-membered bicyclic ring, which may contain 1 to 4, for example 1, 2, 3, or 4 atoms selected from nitrogen, oxygen, and sulfur. Preferred heteroaryls are 5- to 10-membered heteroaryls, such as 5- to 6-membered heteroaryls; the heteroaryl may contain 1, 2, 3, or 4 heteroatoms selected from nitrogen, oxygen, and sulfur. Examples of "heteroaryl" compounds include, but are not limited to, furanyl, pyridyl, 2-oxo-1,2-dihydropyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiopheneyl, isoxazolyl, oxazolyl, oxadiazolyl, imidazolyl, pyrroleyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl, benzo[m]dioxacyclopentenyl, benzo[thiophene], benzimidazolyl, indoleyl, isoyindolyl, 1,3-dioxo-isoindolyl, quinolinyl, indoleyl, benzo[isothiazolyl], benzo[oxazolyl], benzo[isothiazolyl], isothiazolyl, 1H-1,2,4-triazolyl, 4H-1,2,4-triazolyl, pyridyl, pyridine- 2(1H)-keto, pyrimidinyl, pyrazin-2(1H)-keto, pyrimidin-4(3H)-keto, pyrimidin-2(1H)-keto, pyridazin-3(2H)-keto, 1H-indolyl, 1H-benzo[d]imidazolyl, 1H-pyrrolo[2,3-c]pyridyl, 3H-imidazo[4,5-c]pyridyl, isoquinolinyl, quinazolinyl, 2H-isoindolyl, furan[3,2-b]pyridyl, furan[2,3-c]pyridyl, thieno[2,3-c]pyridyl, benzofuranyl, benzo[b]thienoyl, 1H-pyrrolo[3,2-b]pyridyl, 2H-pyrrolo[3,4-c]pyridyl

[0093] The heteroaryl group can be substituted or unsubstituted.

[0094] A "fused ring" refers to a polycyclic group in which two or more ring structures share a pair of atoms, wherein at least one ring has a fully conjugated π electron aromatic system, and one or more rings may contain 0, 1 or more double bonds, but at least one ring does not have a fully conjugated π electron aromatic system, wherein the ring atoms are selected from 0, 1 or more nitrogen, oxygen or S(O). r(where r is selected from 0, 1, or 2) heteroatoms, and the remaining ring atoms are carbon. The fused ring preferably comprises a bicyclic or tricyclic fused ring, wherein the bicyclic fused ring is preferably a fused ring of an aryl or heteroaryl group with a monocyclic heterocyclic group or a monocyclic cycloalkyl group. Preferably, it is 6 to 14 quinary, more preferably 8 to 10 quinary. Examples of "fused rings" include, but are not limited to:

[0095] "Alkoxy" refers to an (alkyl-O-) group. Alkyl groups are defined in the relevant section of this document. C1-C6 alkoxy groups are preferred. Examples include, but are not limited to: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, etc.

[0096] "Alkylthio" refers to a (alkyl-S-) group. Alkyl groups are defined in the relevant section of this document. C1-C6 alkylthio groups are preferred. Examples include, but are not limited to: methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, tert-butylthio, etc.

[0097] "Nitro" refers to the -NO2 group.

[0098] "Hydroxy" refers to the -OH group.

[0099] "Halogens" refers to fluorine, chlorine, bromine, and iodine.

[0100] "Amino" refers to -NH2.

[0101] "Hydroxyamino group" refers to -NHOH.

[0102] “Cyano” refers to -CN.

[0103] "Benzyl" refers to -CH2-phenyl.

[0104] "Carboxyl group" refers to -C(=O)OH.

[0105] "Carboxylic acid ester group" refers to -C(=O)O-alkyl or -C(=O)O-cycloalkyl, where the definitions of alkyl and cycloalkyl are as described above.

[0106] “Hydroxyalkyl” refers to an alkyl group substituted with a hydroxyl group, where the definition of alkyl is as described above.

[0107] "Aminoalkyl" refers to an amino-substituted alkyl group, where the definition of alkyl is as described above.

[0108] "Halogenated alkyl" refers to halogen-substituted alkyl groups, where the definition of alkyl is as described above.

[0109] "Haloalkoxy" refers to halogen-substituted alkoxy groups, where the definition of alkoxy groups is as described above.

[0110] "DMSO" refers to dimethyl sulfoxide.

[0111] “BOC” refers to tert-butoxycarbonyl.

[0112] “Bn” refers to benzyl.

[0113] "THP" refers to 2-tetrahydropyranyl.

[0114] "TFA" refers to trifluoroacetic acid.

[0115] “Ts” refers to p-toluenesulfonyl group.

[0116] “Bn” refers to benzyl.

[0117] “SEM” refers to (trimethylsilyl)ethoxymethyl.

[0118] "Formyl group" refers to

[0119] A "leaving group," or simply a group, is an atom or functional group that breaks off from a larger molecule in a chemical reaction. It's a term used in nucleophilic substitution and elimination reactions. In a nucleophilic substitution reaction, the reactant attacked by the nucleophile is called the substrate, and the atom or group of atoms that breaks off with a pair of electrons from the substrate molecule is called the leaving group. Groups that readily accept electrons and have a strong ability to accept negative charges are desirable leaving groups. The smaller the pKa of the conjugate acid of the leaving group, the easier it is for the leaving group to break off from other molecules. This is because a smaller pKa means the leaving group doesn't need to bond with other atoms and has a stronger tendency to exist as an anion (or an electrically neutral leaving group). Common leaving groups include, but are not limited to, halogens, methanesulfonyl groups, -OTs, or -OH.

[0120] "Substituted" refers to a group in which one or more hydrogen atoms, preferably up to five, and more preferably one to three hydrogen atoms, are independently substituted by the corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art can determine (through experiment or theory) possible or impossible substitutions without much effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom having an unsaturated bond (such as an alkene).

[0121] In this application, "one or more" means one or more, such as one, two, three, four or five or more.

[0122] Unless otherwise specified, the terms "substitution" or "substituted" in this specification refer to the substitution of a group by one or more (e.g., 1, 2, or 3) groups selected from the following: deuterium, alkyl, alkenyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocyclic, arylene, heteroarylene, cycloalkoxy, heterocyclic alkoxy, cycloalkylthio, heterocyclic alkylthio, amino, haloalkyl, haloalkoxy, hydroxyalkyl, carboxyl, carboxylic acid ester, SF5, =O, -OR 5 -C(=O)R 5 -C(=O)OR 5 -N(R) 6 )C(=O)R 7 -N(R) 6 )C(=O)OR 7 -NR 6 R 7 -C(=O)NR 6 R 7 -CH2NHC(=O)OR 5 -CH2NR 6 R 7 -S (=O) r NR 6 R 7 or -S(O) r R 5 The substituents are replaced;

[0123] R 5 Each is independently selected from alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl groups, wherein the alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally further selected by one, two, or three groups from deuterium, hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, =O, -C(=O)R 8 -C(=O)OR 8 -OC(=O)R 8 -NR 9 R 10 -C(=O)NR 9 R 10 -S(=O)2NR 9 R 10 or -N(R) 9 )C(=O)R 10 The substituents are replaced;

[0124] R 6 and R 7Each is independently selected from hydrogen atom, hydroxyl, alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl, wherein the alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl group is optionally further selected by one, two or three groups from hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, =O, -C(=O)R 8 -C(=O)OR 8 -OC(=O)R 8 -NR 9 R 10 -C(=O)NR 9 R 10 -S(=O)2NR 9 R 10 or -N(R) 9 )C(=O)R 10 The substituents are replaced;

[0125] Or, R 6 and R 7 The atoms bonded to them together form a structure containing one or more N, O, or S atoms (=O). r The 4-8 membered heterocyclic group, wherein the 4-8 membered heterocyclic group is optionally further selected by one, two or three of the following groups: hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclic, arylene, heteroarylene, =O, -C(=O)R 8 -C(=O)OR 8 -OC(=O)R 8 -NR 9 R 10 -C(=O)NR 9 R 10 -S(=O)2NR 9 R 10 or -N(R) 9 )C(=O)R 10 The substituents are replaced;

[0126] R 8 R 9 and R 10 Each is independently selected from hydrogen atoms, alkyl, amino, cycloalkyl, heterocyclic, aryl or heteroaryl, wherein the alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl group is optionally further substituted by one, two or three substituents selected from hydroxyl, halogen, nitro, amino, cyano, alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, carboxyl or carboxylic acid ester group;

[0127] r is independently selected from 0, 1, and 2.

[0128] In this paper, the "-*" in a group usually indicates that the group is related to the group in general formula (I). Connection sites; This usually indicates the connection site between the group and L1 in general formula (I).

[0129] The compounds of this invention may contain asymmetric or chiral centers, and thus exist in different stereoisomer forms. It is contemplated that all stereoisomer forms of the compounds of this invention, including but not limited to diastereomers, enantiomers, atropisomers, and geometric (conformal) isomers, and mixtures thereof, such as racemic mixtures, are within the scope of this invention.

[0130] Unless otherwise stated, the structures described in this invention also include all isomers of this structure (e.g., diastereomers, enantiomers, and trans-isomers, and geometric (conformal) isomers; for example, R and S configurations of each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers). Therefore, individual stereoisomers of the compounds of this invention, as well as mixtures of enantiomers, mixtures of diastereomers, and mixtures of geometric (conformal) isomers, are all within the scope of this invention.

[0131] "Medicinal salts" refer to certain salts of the above-mentioned compounds that retain their original biological activity and are suitable for medicinal use. Medicinal salts of compounds represented by general formula (I) can be metal salts or amine salts formed with suitable acids.

[0132] "Pharmaceutical composition" means a mixture containing one or more of the compounds described herein or their physiologically pharmaceutically acceptable salts or prodrugs, along with other chemical components, such as a physiologically pharmaceutically acceptable carrier. The purpose of a pharmaceutical composition is to facilitate administration to a living organism, thereby promoting the absorption of the active ingredient and the exertion of its biological activity. Detailed Implementation

[0133] The following embodiments are used to further describe the present invention, but these embodiments are not intended to limit the scope of the present invention.

[0134] Example

[0135] The examples provide preparation and structural identification data for representative compounds represented by formula (I). It must be noted that the following examples are illustrative of the invention and not intended to limit it. 1 The 1H NMR spectra were obtained using a Bruker instrument (400 MHz), and chemical shifts are expressed in ppm. Tetramethylsilane internal standard (0.00 ppm) was used. 1 H NMR representation: s = singlet, d = doublet, t = triplet, m = multiplet, br = broadened, dd = doublet of doublet, dt = doublet of triplet. If the coupling constant is provided, the unit is Hz.

[0136] Mass spectrometry is performed using an LC / MS instrument, and the ionization method can be ESI or APCI.

[0137] Thin-layer chromatography silica gel plates are Yantai Huanghai HSGF254 or Qingdao GF254. The silica gel plates used in thin-layer chromatography (TLC) have a diameter of 0.15 mm to 0.2 mm, and the diameter of the silica gel plates used for thin-layer chromatography separation and purification products is 0.4 mm to 0.5 mm.

[0138] Column chromatography typically uses Yantai Huanghai silica gel with a mesh size of 200-300 as the carrier.

[0139] In the following examples, all temperatures are in Celsius unless otherwise specified. Unless otherwise specified, all starting materials and reagents are commercially available or synthesized according to known methods. Commercially available materials and reagents are used directly without further purification. Unless otherwise specified, they are purchased from manufacturers including but not limited to Aldrich Chemical Company, ABCR GmbH & Co. KG, Acros Organics, Guangzan Chemical Technology Co., Ltd., and Jingyan Chemical Technology Co., Ltd.

[0140] CD3OD: Deuterated methanol.

[0141] CDCl3: Deuterated chloroform.

[0142] DMSO-d6: Deuterated dimethyl sulfoxide.

[0143] LCMS: Liquid Chromatography-Mass Spectrometry

[0144] HPLC: High Performance Liquid Chromatography

[0145] FA: Formic acid

[0146] TFA: Trifluoroacetic acid

[0147] ACN: Acetonitrile

[0148] Argon atmosphere refers to a reaction flask connected to an argon gas balloon with a volume of approximately 1L.

[0149] Unless otherwise specified in the examples, the solution in the reaction refers to an aqueous solution.

[0150] The compounds were purified using silica gel column chromatography and reversed-phase column chromatography. The eluent system was selected from: A: petroleum ether and ethyl acetate; B: dichloromethane and methanol; C: dichloromethane: ethyl acetate; D: trifluoroacetic acid aqueous solution and acetonitrile. The volume ratio of the solvent varied depending on the polarity of the compound and could be adjusted by adding small amounts of acidic or basic reagents, such as acetic acid or triethylamine.

[0151] Example 1

[0152] 3-(3-(4-benzoylpiperazin-1-yl)-2-chlorophenyl)piperidine-2,6-dione

[0153] 3-(3-(4-benzoylpiperazin-1-yl)-2-chlorophenyl)piperidine-2,6-dione

[0154] 3-(3-bromo-2-chloro-phenyl)piperidin-2,6-dione 1a (200 mg, 661.04 μmol, prepared according to the published patent "WO2024151547A1") was dissolved in 1,4-dioxane (3 mL), and phenyl(piperazin-1-yl)methyl ketone 1b (188.64 mg, 991.57 μmol, commercially available), (SP-4-1)-[1,3-bis[2,6-bis(1-propylbutyl)phenyl]-4,5-dichloro-1,3-dihydro-2H-imidazol-2-ylylene]dichloro(3-chloropyridine-KN)palladium (64.30 mg, 66.10 μmol, commercially available) and cesium carbonate (646.14 mg, 1.98 mmol) were added. The mixture was stirred at 90 °C for 12 hours. The reaction solution was evaporated to dryness, and the residue was added to N,N-dimethylformamide (2 mL). The mixture was then subjected to reversed-phase column chromatography (Waters 3767 / Qda Column: SunFire Sunfire C18, 19*250mm, 10µm; Mobile Phase A: 0.1% FA / H2O, B: ACN; flow rate: 20 mL / min; gradient: 37-47%; retention time: 9.7 min of 16 min) to obtain product 3-(3-(4-benzoylpiperazin-1-yl)-2-chlorophenyl)piperidine-2,6-dione 1 (73.27 mg), yield: 177.89 μmol.

[0155] MS m / z(ESI): 411.9 [M+H]+

[0156] 1H NMR (400MHz, DMSO-d6) δ10.88(s,1H),7.51–7.41(m,5H),7.29(t,J=7.8Hz,1H),7.13(dd,J=8.0,1.3Hz,1H),7.04(dd,J=7.6,1.2Hz,1H),4.26(dd,J=1 2.1,5.0Hz,1H),3.88–3.65(m,2H),3.62–3.43(m,2H),3.08–2.87(m,4H),2 .82–2.70(m,1H),2.55–2.52(m,1H),2.33–2.21(m,1H),2.04–1.91(m,1H).

[0157] Example 2

[0158] 3-(2-chloro-3-((4-(2-oxopiperidin-1-yl)phenyl)ethynyl)phenyl)piperidine-2,6-dione

[0159] 3-(2-chloro-3-((4-(2-oxopiridin-1-yl)phenyl)ethynyl)phenyl)piperidin-2,6-dione

[0160] first step

[0161] 1-(4-((trimethylsilyl)ethynyl)phenyl)piperidin-2-one

[0162] 1-(4-((trimethylsilyl)ethynyl)phenyl)piperidin-2-one

[0163] 1-(4-iodophenyl)piperidin-2-one 2a (1 g, 3.32 mmol) and ethynyl(trimethyl)silane 2b (326.17 mg, 3.32 mmol, 469.31 μL) were added sequentially to a solution of N,N-dimethylformamide (10 mL), followed by zinc bromide (3.74 g, 16.60 mmol), triethylamine (1.01 g, 9.96 mmol), and bis(triphenylphosphine)palladium dichloride (233.13 mg, 332.09 μmol). The reaction mixture was heated to 70 °C under nitrogen protection and the reaction was continued for 16 hours. After the reaction was complete, the reaction mixture was cooled to room temperature, quenched with water (30 mL), and extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with saturated ammonium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: system B) to give 1-(4-((trimethylsilyl)ethynyl)phenyl)piperidin-2-one 2b (750 mg), yield 83.2%. MS m / z (ESI): 272.1 [M+1]

[0164] Step 2

[0165] 1-(4-ethynylphenyl)piperidin-2-one

[0166] 1-(4-ethynylphenyl)piperidin-2-one

[0167] 1-(4-((trimethylsilyl)ethynyl)phenyl)piperidin-2-one 2b (1.3 g, 4.79 mmol) was added to methanol (2 mL), followed by potassium carbonate (1.32 g, 9.58 mmol). The reaction mixture was allowed to react for 2 hours at room temperature. After the reaction was complete, the reaction solution was concentrated under reduced pressure, quenched with water (30 mL), and extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (evolving solvent: system B) to give 1-(4-ethynylphenyl)piperidin-2-one 2c (826 mg), yield 86.6%.

[0168] MS m / z (ESI): 200.0 [M+1]

[0169] Step 3

[0170] 3-(2-chloro-3-((4-(2-oxopiperidin-1-yl)phenyl)ethynyl)phenyl)piperidine-2,6-dione

[0171] 3-(2-chloro-3-((4-(2-oxopiridin-1-yl)phenyl)ethynyl)phenyl)piperidin-2,6-dione

[0172] 1-(4-ethynylphenyl)piperidin-2-one 2c (197.57 mg, 991.57 μmol) and 3-(3-bromo-2-chloro-phenyl)piperidin-2,6-dione 1a (200 mg, 661.04 μmol, prepared according to the known method "Patent WO2024 / 151547") were dissolved in tetrahydrofuran (3 mL), and cuprous iodide (25.25 mg, 132.21 μmol), triethylamine (200.67 mg, 1.98 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloromethane (54.01 mg, 66.10 μmol) were added. The reaction mixture was heated to 60 °C under nitrogen protection and stirred for 16 hours. After the reaction was complete, it was cooled to room temperature. Quenching with water (20 mL), extraction with ethyl acetate (20 mL × 3), washing the combined organic phases with saturated sodium chloride (30 mL), drying with anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure, and purging the residue by preparative liquid chromatography (Waters 3767 / Qda column: Pursuit XRs 10C18, 19*250 mm, 10 μm; mobile phase A: 0.1% FA / H2O, mobile phase B: ACN; flow rate: 20 mL / min; gradient: 43-53%; retention time: 9.2-9.8 min, 16 min) to give 3-(2-chloro-3-((4-(2-oxopiridin-1-yl)phenyl)ethynyl)phenyl)piperidin-2,6-dione 2 (11.02 mg), yield 4.0%.

[0173] MS m / z(ESI): 421.2 [M+1]

[0174] 1 H NMR (400MHz, DMSO) δ10.94(s,1H),7.64–7.56(m,3H),7.43–7.35(m,4H),4.36–4.27(m,1H),3.64(t,J=5.6Hz,2H),2 .86–2.75(m,1H),2.60–2.54(m,1H),2.42(t,J=6.4Hz,2H),2.37–2.28(m,1H),2.07–1.97(m,1H),1.92–1.79(m,4H).

[0175] Example 3

[0176] 3-(2-chloro-3-(phenylethynyl)phenyl)piperidine-2,6-dione

[0177] 3-(2-chloro-3-(phenylethynyl)phenyl)piperidine-2,6-dione

[0178] At room temperature, cuprous iodide (25 mg, 130.89 μmol), triethylamine (201 mg, 1.99 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloromethane complex (54 mg, 66.10 μmol) were added to a tetrahydrofuran (3 mL) solution of acetylenylbenzene 3a (200 mg, 661.04 μmol) and 3-(3-bromo-2-chloro-phenyl)piperidine-2,6-dione 1a (101.27 mg, 991.57 μmol). The reaction mixture was heated to 60 °C and reacted for 16 hours under nitrogen protection. After the reaction was complete, the mixture was cooled to room temperature, and water (10 mL) was added to quench the reaction mixture. The mixture was then extracted with ethyl acetate (15 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative liquid chromatography (Waters 3767 / Qda column: XBridge XBridge C18, 19*250 mm, 10 μm; mobile phase A: 0.01% NH4HCO3 / H2O, mobile phase B: ACN; flow rate: 20 mL / min; gradient: 58-68%, retention time: 7.0 min, 17 min) to obtain 3-(2-chloro-3-(phenylethynyl)phenyl)piperidine-2,6-dione 3 (8 mg), yield 3.7%.

[0179] MS m / z(ESI): 324.1 [M+1]

[0180] 1H NMR (400MHz, DMSO) δ7.70–7.34(m,8H),4.37–4.28(m,1H),2.86–2.75(m,1H),2.62–2.55(m,1H),2.41–2.29(m,1H),2.10–1.96(m,1H).

[0181] Example 4

[0182] 3-(2-chloro-3-(2-(2-oxopiperidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)phenyl)piperidine-2,6-dione

[0183] 3-(2-chloro-3-(2-(2-oxopiperidin-1-yl)-7-azaspiro[3.5]nonane-7-yl)phenyl)piperidin-2,6-dione

[0184] first step

[0185] tert-butyl 2-(5-bromopentanamido)-7-azaspiro[3.5]nonane-7-carboxylate

[0186] 2-(5-bromopentamido)-7-azaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester

[0187] 2-Amino-7-azaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester 4a (5 g, 20.80 mmol, commercially available) was added to dichloromethane (50 mL), followed by pyridine (4.94 g, 62.41 mmol). 5-Bromopentanoyl chloride (4.98 g, 24.96 mmol) was added to the system at 0 °C. The reaction mixture was allowed to react at room temperature for 12 hours. After the reaction was complete, water (50 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (50 mL × 3). The combined organic phases were washed with saturated sodium chloride solution (50 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reversed-phase column chromatography (developing solvent: system D) to give 2-(5-bromopentamido)-7-azaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester 4b (7.23 g), in 86.2% yield.

[0188] MS m / z (ESI): 347.1 [M+1-56]

[0189] Step 2

[0190] tert-butyl 2-(2-oxopiperidin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate

[0191] 2-(2-oxopiperidin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester

[0192] 3 g (7.44 mmol) of 2-(5-bromopentamido)-7-azaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester 4b was added to tetrahydrofuran (120 mL), followed by the addition of sodium hydrogen (892.43 mg, 37.19 mmol, 60% wt) at 0 °C. The reaction mixture was reacted at 70 °C for 12 h. After the reaction was complete, water (50 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with saturated sodium chloride solution (50 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reversed-phase column chromatography (developing solvent: system D) to give 1.48 g (1.48 g) of 2-(2-oxopiperidin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester 4c, with a yield of 61.7%.

[0193] MS m / z (ESI): 267.2 [M+1-56]

[0194] Step 3

[0195] 1-(7-azaspiro[3.5]nonan-2-yl)piperidin-2-one

[0196] 1-(7-azaspiro[3.5]non-2-yl)piperidin-2-one

[0197] 4c (700 mg, 2.17 mmol) of 2-(2-oxopiperidin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester was added to dichloromethane (21 mL), followed by the addition of trifluoroacetic acid (7 mL). The reaction mixture was reacted at room temperature for 1 hour. After the reaction was complete, the mixture was concentrated under reduced pressure to give 4d (600 mg) of 1-(7-azaspiro[3.5]non-2-yl)piperidin-2-one in 99.6% yield, which was used directly in the next step.

[0198] MS m / z (ESI): 223.3 [M+1]

[0199] Step 4

[0200] 3-(2-chloro-3-(2-(2-oxopiperidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)phenyl)piperidine-2,6-dione

[0201] 3-(2-chloro-3-(2-(2-oxopiperidin-1-yl)-7-azaspiro[3.5]nonane-7-yl)phenyl)piperidin-2,6-dione

[0202] 3-(3-bromo-2-chloro-phenyl)piperidin-2,6-dione 1a (50 mg, 165.26 μmol) was added to 1,4-dioxane (2.5 mL), followed by 1-(7-azaspiro[3.5]non-2-yl)piperidin-2-one 4d (55.11 mg, 247.89 μmol), (SP-4-1)-[1,3-bis[2,6-bis(1-propylbutyl)phenyl]-4,5-dichloro-1,3-dihydro-2H-imidazol-2-ylylene]dichloro(3-chloropyridine-KN)palladium (16.08 mg, 16.53 μmol), and cesium carbonate (269.23 mg, 826.31 μmol). The reaction mixture was reacted at 80 °C under nitrogen protection for 16 hours. After the reaction was complete, water (10 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (15 mL × 3). The combined organic phases were washed with saturated sodium chloride solution (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative liquid chromatography (Pursuit XRs 10C18 column; 19*250 mm, 10 μm, 20 mL / min; mobile phase A: 0.1% FA / H2O, mobile phase B: CH3CN, gradient: 41-51%, retention time: 8.6 min-9.2 min, 16 min) to obtain 3-(2-chloro-3-(2-(2-oxopiperidin-1-yl)-7-azaspiro[3.5]nonane-7-yl)phenyl)piperidin-2,6-dione 4 (1.14 mg), yield 1.6%.

[0203] MS m / z (ESI): 444.2 [M+1]

[0204] 1 H NMR (400MHz, DMSO) δ10.87(s,1H),7.27-7.23(m,1H),7.11–7.05(m,1H),7.00–6.94(m,1H),5.02–4.86(m,1H),4.24( dd,J=4.0,4.0Hz,1H),3.30-3.27(m,1H),2.90-2.70(m,5H),2.23-2.19(m,3H),2.05-1.90(m,7H),1.78-1.61(m,8H).

[0205] Example 5

[0206] 3-(2-chloro-3-(6-(2-oxopiperidin-1-yl)-2-azaspiro[3.3]heptan-2-yl)phenyl)piperidine-2,6-dione

[0207] 3-(2-chloro-3-(6-(2-oxopiperidin-1-yl)-2-azaspiro[3.3]hept-2-yl)phenyl)piperidin-2,6-dione

[0208] first step

[0209] tert-butyl 6-(5-bromopentanamido)-2-azaspiro[3.3]heptane-2-carboxylate

[0210] 6-(5-bromopentamido)-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester

[0211] Pyridine (1.12 g, 14.13 mmol) was added to a solution of 6-amino-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester 5a (1 g, 4.71 mmol, commercially available) in dichloromethane (10 mL). The reaction mixture was then cooled to 0 °C, and 5-bromopentanoyl chloride 5b (1.03 g, 5.18 mmol) was added. The reaction mixture was then heated to room temperature under nitrogen protection and the reaction was continued for 1 hour. After the reaction was completed, the reaction mixture was quenched with water (20 mL), extracted with ethyl acetate (50 mL × 3), and the combined organic phases were washed with saturated sodium chloride (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (developing solvent: system B) to give 6-(5-bromopentanoyl)-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester 5c (930 mg), yield 52.6%. MS m / z (ESI): 319.1 [M+1-56]

[0212] Step 2

[0213] tert-butyl 6-(2-oxopiperidin-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate

[0214] 6-(2-oxopiperidin-1-yl)-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester

[0215] 5c (960 mg, 2.56 mmol) of 6-(5-bromopentamido)-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester was dissolved in tetrahydrofuran (50 mL). Sodium hydride (306.95 mg, 12.79 mmol, 60% wt) was added under nitrogen protection, and the reaction was continued at 70 °C for 16 hours. After the reaction was complete, the reaction mixture was cooled to room temperature and quenched with water (20 mL). Extraction was performed with ethyl acetate (30 mL × 3). The combined organic phases were washed with saturated sodium chloride (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: system B) to give 5d (629 mg) of 6-(2-oxopiperidin-1-yl)-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester, yield 83.5%.

[0216] MS m / z (ESI): 239.2 [M+1-56]

[0217] Step 3

[0218] 1-(2-azaspiro[3.3]heptan-6-yl)piperidin-2-one

[0219] 1-(2-azaspiro[3.3]heptane-6-yl)piperidin-2-one

[0220] 5d (300 mg, 1.02 mmol) of 6-(2-oxopiperidin-1-yl)-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (116.19 mg, 1.02 mmol, 1 mL) was added. The reaction mixture was allowed to react for 2 hours at room temperature. After the reaction was complete, the reaction solution was concentrated under reduced pressure to give 5e (190 mg) of 1-(2-azaspiro[3.3]heptane-6-yl)piperidin-2-one, with a yield of 96.0%. This crude product was used directly in the next step.

[0221] MS m / z (ESI): 195.1 [M+1]

[0222] Step 4

[0223] 3-(2-chloro-3-(6-(2-oxopiperidin-1-yl)-2-azaspiro[3.3]heptan-2-yl)phenyl)piperidine-3-(2-chloro

[0224] -3-(6-(2-oxopiperidin-1-yl)-2-azaspiro[3.3]heptane-2-yl)phenyl)piperidin-2,6-dione

[0225] 1-(2-azaspiro[3.3]heptane-6-yl)piperidin-2-one 5e (48.16 mg, 247.89 μmol) and 3-(3-bromo-2-chloro-phenyl)piperidin-2,6-dione 1a (50 mg, 165.26 μmol) were added to a 1,4-dioxane (1 mL) solution, followed by cesium carbonate (269.23 mg, 826.31 μmol) and (SP-4-1)-[1,3-bis[2,6-bis(1-propylbutyl)phenyl]-4,5-dichloro-1,3-dihydro-2H-imidazol-2-ylyl]dichloro(3-chloropyridine-KN)palladium (13.09 mg, 16.53 μmol). The reaction mixture was heated to 90 °C under nitrogen protection and the reaction was continued for 16 hours. After the reaction was completed, the reaction solution was cooled to room temperature, quenched with water (10 mL), extracted with ethyl acetate (15 mL × 3), and the combined organic phases were washed with saturated ammonium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by preparative liquid chromatography (Waters 3767 / Qda column: XBridge XBridge C18, 19*250 mm, 10 μm; mobile phase A: 10 mmol / L NH4HCO3 / H2O, mobile phase B: ACN; flow rate: 20 mL / min; gradient: 35-45%, retention time: 6.2-7.0 min, 17 min) to give 3-(6-(2-oxopiperidin-1-yl)-2-azaspiro[3.3]heptane-2-yl)phenyl)piperidin-2,6-dione 5 (2.14 mg), yield 3.1%.

[0226] MS m / z(ESI): 416.2 [M+1]

[0227] 1 H NMR (400MHz, DMSO) δ10.84(s,1H),7.14(t,J=7.6Hz,1H),6.69(d,J=7.6Hz,1H),6.53(d,J=8.0Hz,1H),4.92–4.71(m,1H),4.22–4.12 (m,1H),4.05(s,2H),3.93(s,2H),3.23(t,J=5.6Hz,2H),2.78–2.67(m,1H),2.43–2.18(m,8H),2.02–1.92(m,1H),1.76–1.63(m,4H).

[0228] Example 6

[0229] 3-(2-chloro-3-(5-(2-oxopiperidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)phenyl)piperidine

[0230] -2,6-dione

[0231] 3-(2-chloro-3-(5-(2-oxopiperidin-1-yl)hexahydrocyclopentan[c]pyrrole-2(1H)-yl)phenyl)piperidin-2,6-dione

[0232] first step

[0233] tert-butyl 5-((5-methoxy-5-oxopentyl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate

[0234] 5-((5-methoxy-5-oxopentyl)amino)hexahydrocyclopentane[c]pyrrole-2(1H)-carboxylic acid tert-butyl ester

[0235] Sodium cyanoborohydride (1.68 g, 26.63 mmol) was added to an ethanol (20 mL) solution of tert-butyl 5-oxohexahydrocyclopentane[c]pyrrole-2(1H)-carboxylic acid 6a (2 g, 8.88 mmol) and methyl 5-aminopentanoate hydrochloride 6b (2.33 g, 17.76 mmol) under nitrogen protection at 0 °C. The mixture was stirred for 16 hours at room temperature under nitrogen protection. After the reaction was completed, saturated ammonium chloride (30 mL) was added to the reaction solution to quench the reaction, and the mixture was extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with saturated sodium chloride (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent: system A) to give 6c (2.1 g) of 5-((5-methoxy-5-oxopentyl)amino)hexahydrocyclopentane[c]pyrrole-2(1H)-carboxylic acid tert-butyl ester, with a yield of 69.5%.

[0236] MS m / z(ESI): 341.3 [M+1]

[0237] Step 2

[0238] 5-((2-(tert-butoxycarbonyl)octahydrocyclopenta[c]pyrrol-5-yl)amino)pentanoic acid

[0239] 5-((2-(tert-Butoxycarbonyl)octahydrocyclopentan[c]pyrrole-5-yl)amino)valeric acid

[0240] Sodium hydroxide (740.18 mg, 18.50 mmol) was added to a solution of 5-((5-methoxy-5-oxopentyl)amino)hexahydrocyclopentan[c]pyrrole-2(1H)-carboxylic acid tert-butyl ester 6c (3 g, 8.81 mmol) in methanol (20 mL), tetrahydrofuran (12 mL), and water (2 mL). The reaction mixture was stirred at 55 °C for 1 hour. After the reaction was complete, the pH of the reaction mixture was adjusted to 3–4 by adding dilute hydrochloric acid (1 M), and the mixture was extracted with ethyl acetate (30 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give 5-((2-(tert-butoxycarbonyl)octahydrocyclopentan[c]pyrrole-5-yl)amino)pentanoic acid 6d (530 mg), yield 18.4%. The crude product was directly used for the next step.

[0241] MS m / z(ESI): 327.2 [M+1]

[0242] Step 3

[0243] tert-butyl 5-(2-oxopiperidin-1-yl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate

[0244] 5-(2-oxopiperidin-1-yl)hexahydrocyclopentano[c]pyrrole-2(1H)-carboxylic acid tert-butyl ester

[0245] N,N-diisopropylethylamine (534.49 mg, 4.14 mmol) was added to a solution of 5-((2-(tert-butyloxycarbonyl)octahydrocyclopentano[c]pyrrole-5-yl)amino)valerate 6d (450 mg, 1.38 mmol) and 1-butylphosphine anhydride (1.49 g, 2.07 mmol, 50% purity) in dichloromethane (5 mL). The reaction mixture was mixed at room temperature for 16 hours under nitrogen protection. After the reaction was complete, the reaction solution was quenched with water (10 mL), extracted with dichloromethane (20 mL × 3), the combined organic phases were dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (evolving solvent: system B) to give 5-(2-oxopiperidin-1-yl)hexahydrocyclopentano[c]pyrrole-2(1H)-carboxylic acid tert-butyl ester 6e (260 mg), yield 61.2%.

[0246] MS m / z(ESI): 209.3 [M-100]

[0247] Step 4

[0248] 1-(octahydrocyclopenta[c]pyrrol-5-yl)piperidin-2-one

[0249] 1-(octahydrocyclopentan[c]pyrrolo-5-yl)piperidin-2-one

[0250] Trifluoroacetic acid (1 mL) was added to a solution of 400 mg (1.30 mmol) of 5-(2-oxopiridine-1-yl)hexahydrocyclopentano[c]pyrrole-2(1H)-carboxylic acid tert-butyl ester 6e in dichloromethane (4 mL). The reaction mixture was stirred at room temperature for 5 hours. After the reaction was complete, the reaction solution was concentrated directly to give 200 mg (octahydrocyclopentano[c]pyrrole-5-yl)piperidin-2-one 6f), which was used directly in the next step.

[0251] MS m / z(ESI): 209.0 [M+1]

[0252] Step 5

[0253] 3-(2-chloro-3-(5-(2-oxopiperidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)phenyl)piperidine-2,6-dione

[0254] 3-(2-chloro-3-(5-(2-oxopiperidin-1-yl)hexahydrocyclopentan[c]pyrrole-2(1H)-yl)phenyl)piperidin-2,6-dione

[0255] Cesium carbonate (161.54 mg, 495.78 μmol) and (SP-4-1)-[1,3-bis[2,6-bis(1-propylbutyl)phenyl]-4,5-dichloro-1,3-dihydro-2H-imidazol-2-yl]dichloro(3-chloropyridine-KN)palladium (16.08 mg, 16.53 μmol) were added to a solution of 3-(3-bromo-2-chloro-phenyl)piperidin-2,6-dione 1a (50 mg, 165.26 μmol) and 1-(octahydrocyclopentan[c]pyrrole-5-yl)piperidin-2-one 6f (51.64 mg, 247.89 μmol) in 1,4-dioxane (2 mL). After the reaction was complete, the reaction mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by preparative liquid chromatography (Gilson GX281 column: Agilent Pursuit XRs 21.2*250mm, 10μm; mobile phase A: 0.1% FA / H2O, mobile phase B: ACN; flow rate: 25ml / min; gradient: 38-46%; retention time: 9.3-9.9min, 17min) to obtain 3-(2-chloro-3-(5-(2-oxopiridin-1-yl)hexahydrocyclopentan[c]pyrrole-2(1H)-yl)phenyl)piperidin-2,6-dione 6 (2.3mg), yield 3.2%.

[0256] MS m / z(ESI): 430.2 [M+1]

[0257] 1 H NMR (400MHz, DMSO-d6) δ10.88(s,1H),7.23(t,J=7.6Hz,1H),7.06(d,J=6.8Hz,1H),6.96 (d,J=6.8Hz,1H),4.76–4.66(m,1H),4.24(dd,J=12.4,5.2Hz,1H),3.24(d,J=9.2Hz,1H) ,3.20–3.13(m,3H),2.88–2.79(m,2H),2.76–2.57(m,4H),2.34–2.28(m,1H),2.23(d,J= 6.4Hz,2H),2.02–1.95(m,1H),1.92–1.84(m,2H),1.72–1.63(m,4H),1.60–1.50(m,2H).

[0258] Example 7

[0259] 3-(2-chloro-4'-(2-oxopiperidin-1-yl)-2',3',4',5'-tetrahydro-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione

[0260] 3-(2-chloro-4'-(2-oxopiridin-1-yl)-2',3',4',5'-tetrahydro-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0261] first step

[0262] 5-bromo-N-(1,4-dioxaspiro[4.5]decan-8-yl)pentanamide

[0263] 5-Bromo-N-(1,4-dioxaspiro[4,5]dec-8-yl)pentanamide

[0264] 1,4-Dioxaspiro[4.5]dec-8-amine 7a (4.7 g, 29.90 mmol, commercially available) was added to dichloromethane (50 mL), followed by pyridine (7.09 g, 89.69 mmol). The reaction mixture was cooled to 0 °C, and 5-bromopentanoyl chloride 5b (6.56 g, 32.89 mmol) was added. The mixture was then heated to room temperature and reacted for 1 hour. After the reaction was complete, the mixture was quenched with water (50 mL), extracted with ethyl acetate (100 mL × 3), and the combined organic phases were washed with saturated sodium chloride (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: system B) to obtain 5-bromo-N-(1,4-dioxaspiro[4.5]dec-8-yl)pentanoylamide 7b (6 g), with a yield of 62.7%.

[0265] MS m / z (ESI): 320.1 [M+1]

[0266] Step 2

[0267] 1-(1,4-dioxaspiro[4.5]decan-8-yl)piperidin-2-one

[0268] 1-(1,4-dioxaspiro[4.5]dec-8-yl)piperidin-2-one

[0269] 5-Bromo-N-(1,4-dioxaspiro[4.5]dec-8-yl)pentanamide 7b (3 g, 9.37 mmol) was dissolved in tetrahydrofuran (120 mL), and sodium hydride (1.12 g, 46.84 mmol, 60% wt) was added. The reaction mixture was heated to 70 °C under nitrogen protection and the reaction was continued for 16 hours. After the reaction was completed, the reaction mixture was cooled to room temperature, quenched with water (50 mL), and extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with saturated sodium chloride (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (evolving solvent: system B) to give 1-(1,4-dioxaspiro[4.5]dec-8-yl)piperidin-2-one 7c (1.9 g), yield 84.8%.

[0270] MS m / z (ESI): 240.1 [M+1]

[0271] Step 3

[0272] 1-(4-oxocyclohexyl)piperidin-2-one

[0273] 1-(4-oxocyclohexyl)piperidin-2-one

[0274] 1-(1,4-dioxaspiro[4.5]dec-8-yl)piperidin-2-one 7c (1.2 g, 5.01 mmol) was dissolved in tetrahydrofuran (6 mL), and hydrochloric acid (182.83 mg, 5.01 mmol, 2 mL) was added. The reaction mixture was heated to 60 °C and reacted for 48 hours. After the reaction was complete, the reaction solution was cooled to room temperature, quenched with saturated sodium bicarbonate solution to pH 8-9, extracted with dichloromethane (30 mL × 3), and the combined organic phases were washed with saturated sodium chloride (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (developing solvent: system B) to give 1-(4-oxocyclohexyl)piperidin-2-one 7d (500 mg), yield 51.1%.

[0275] MS m / z (ESI): 196.2 [M+1]

[0276] Step 4

[0277] 4-(2-oxopiperidin-1-yl)cyclohex-1-en-1-yl trifluoromethanesulfonate

[0278] 4-(2-oxopiperidin-1-yl)cyclohex-1-en-1-yltrifluoromethanesulfonate

[0279] Under nitrogen protection at -78°C, 7d (630 mg, 3.23 mmol) of 1-(4-oxocyclohexyl)piperidin-2-one was dissolved in 5 mL of tetrahydrofuran, followed by the addition of a solution of potassium tert-butoxide (722.74 mg, 6.45 mmol) dissolved in 5 mL of tetrahydrofuran. The reaction mixture was stirred for 0.5 hours. A solution of 1,1,1-trifluoro-N-phenyl-N-(trifluoromethyl)sulfonyl)methanesulfonamide (1.73 g, 4.84 mmol) in 5 mL of tetrahydrofuran was then slowly added dropwise to the reaction mixture, which was then stirred at -78°C for another 2 hours. After the reaction was complete, water (20 mL) was added to the reaction solution to quench the reaction, and the mixture was extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with saturated sodium chloride (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent: system B) to give 4-(2-oxopiperidin-1-yl)cyclohex-1-en-1-yltrifluoromethanesulfonate 7e (1 g), with a yield of 85.2%.

[0280] MS m / z (ESI): 328.1 [M+1]

[0281] Step 5

[0282] 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-en-1-yl)piperidin-2-one

[0283] 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)cyclohex-3-en-1-yl)piperidin-2-one

[0284] 4-(2-oxopiperidin-1-yl)cyclohexyl-1-en-1-yltrifluoromethanesulfonate 7e (400 mg, 1.22 mmol) was dissolved in 1,4-dioxane (8 mL), and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxaborane) (465.60 mg, 1.83 mmol), potassium acetate (359.80 mg, 3.67 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (90.65 mg, 122.20 μmol) were added. The reaction mixture was heated to 90 °C and stirred for 16 hours under nitrogen protection. After the reaction was complete, the reaction solution was cooled to room temperature to obtain 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)cyclohex-3-en-1-yl)piperidin-2-one 7f (315 mg). This crude product was used directly in the next step without purification.

[0285] MS m / z (ESI): 306.2 [M+1]

[0286] Step 6

[0287] 3-(2-chloro-4'-(2-oxopiperidin-1-yl)-2',3',4',5'-tetrahydro-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione

[0288] 3-(2-chloro-4'-(2-oxopiridin-1-yl)-2',3',4',5'-tetrahydro-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0289] In the previous step, crude 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)cyclohexyl-3-en-1-yl)piperidin-2-one 7f (315 mg, 1.03 mmol) was added with 1,4-dioxane (5 mL) and water (0.5 mL), followed by 3-(3-bromo-2-chloro-phenyl)piperidin-2,6-dione 1a (240 mg, 793.25 μmol), potassium carbonate (328.41 mg, 2.38 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (58.84 mg, 79.33 μmol). The reaction mixture was stirred at 90 °C for 16 hours under nitrogen protection. After the reaction was complete, the reaction mixture was cooled to room temperature, quenched with water (20 mL), extracted with ethyl acetate (20 mL × 3), the combined organic phases were washed with saturated sodium chloride (420 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (developing solvent: system B) to give 3-(2-chloro-4'-(2-oxopiperidin-1-yl)-2',3',4',5'-tetrahydro-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione 7 (100 mg), yield 31.36%. 30 mg of compound 7 was further purified by preparative liquid chromatography (Waters 3767 / Qda column: SunFire Sunfire C18, 19*250 mm, 10 μm; mobile phase A: 0.1% FA / H2O, mobile phase B: ACN; flow rate: 20 ml / min; gradient: 33-53%, retention time: 9.3-10 min, 16 min) to obtain 3-(2-chloro-4'-(2-oxopiridin-1-yl)-2',3',4',5'-tetrahydro-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione 7 (10.91 mg), with a separation yield of 36.4%.

[0290] MS m / z(ESI): 401.2 [M+1]

[0291] 1 H NMR (400MHz, DMSO) δ10.89(s,1H),7.30–7.22(m,2H),7.19–7.13(m,1H),5.64–5.56(m,1H),4.63(t,J=13.2Hz,1H),4.32–4. 22(m,1H),3.25–3.18(m,2H),2.84–2.71(m,1H),2.56–2.51(m,2H),2.37–2.22(m,5H),2.13–1.82(m,3H),1.76–1.64(m,5H).

[0292] Example 8

[0293] 3-(2-chloro-3-(4-(2-oxopiperidin-1-yl)cyclohexyl)phenyl)piperidine-2,6-dione

[0294] 3-(2-chloro-3-(4-(2-oxopiridin-1-yl)cyclohexyl)phenyl)piperidin-2,6-dione

[0295] Platinum dioxide (39.64 mg, 174.61 μmol) was added to a 1 mL solution of 3-(2-chloro-4'-(2-oxopiridin-1-yl)-2',3',4',5'-tetrahydro-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione 7 (70 mg, 174.61 μmol). The reaction mixture was reacted at room temperature for 16 hours under a hydrogen atmosphere (30 psi). After the reaction was complete, the reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by preparative liquid chromatography (Waters 3767 / Qda column: XBridge XBridge Prep 10C18, 19*250mm, 10μm; mobile phase A: 0.1% FA / H2O, mobile phase B: ACN; flow rate: 20ml / min; gradient: 40-50%, retention time: 7.4 / 8.0min, 16min) to obtain 3-(2-chloro-3-(4-(2-oxopiridin-1-yl)cyclohexyl)phenyl)piperidin-2,6-dione 8 (7.41mg), yield 10.5%).

[0296] MS m / z(ESI): 403.2 [M+1]

[0297] 1H NMR (400MHz, DMSO) δ10.88(s,1H),7.40–7.22(m,2H),7.20–7.13(m,1H),4.47–4.37(m,1H),4.29–4.23(m,1H),3.21(t,J=5.6Hz,2H), 3.03–2.91(m,1H),2.83–2.65(m,1H),2.55–2.51(m,1H),2.34–2.21(m,3H),2.05–1.94(m,1H),1.91–1.80(m,2H),1.74–1.55(m,10H).

[0298] Example 9

[0299] 3-(2-chloro-3-(2-oxo-[1,4'-bipiperidin]-1'-yl)phenyl)piperidine-2,6-dione

[0300] 3-(2-chloro-3-(2-oxo-[1,4'-dipiperidin]-1'-yl)phenyl)piperidin-2,6-dione

[0301] first step

[0302] tert-butyl 4-(5-bromopentanamido)piperidine-1-carboxylate

[0303] 4-(5-bromopentamido)piperidine-1-carboxylic acid tert-butyl ester

[0304] 4-Aminopiperidin-1-carboxylic acid tert-butyl ester 9a (2 g, 9.99 mmol, commercially available) was added to dichloromethane (30 mL), followed by pyridine (2.37 g, 29.96 mmol). The mixture was cooled to 0 °C, and 5-bromopentanoyl chloride 5b (2.19 g, 10.98 mmol) was added. The reaction mixture was then brought to room temperature and reacted for 1 hour. After the reaction was complete, the reaction solution was quenched with water (30 mL), extracted with dichloromethane (30 mL × 3), and the combined organic phases were washed with saturated sodium chloride solution (60 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent: system B) to give 4-(5-bromopentanoyl)piperidin-1-carboxylic acid tert-butyl ester 9b (2.1 g), with a yield of 57.9%.

[0305] MS m / z (ESI): 307.1 [M+1-56]

[0306] Step 2

[0307] tert-butyl 2-oxo-[1,4'-bipiperidine]-1'-carboxylate

[0308] 2-O-[1,4'-Bioperidin]-1'-carboxylic acid tert-butyl ester

[0309] At room temperature, tert-butyl 4-(5-bromopentamido)piperidine-1-carboxylate 9b (1 g, 2.75 mmol) was dissolved in tetrahydrofuran (50 mL), and sodium hydrogen (330.32 mg, 13.76 mmol, 60% wt) was added. The reaction mixture was heated to 70 °C under nitrogen protection and the reaction was continued for 16 hours. After the reaction was completed, the mixture was cooled to room temperature, quenched with water (20 mL), extracted with ethyl acetate (20 mL × 3), and the combined organic phases were washed with saturated sodium chloride solution (30 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (evolving solvent: system B) to give tert-butyl 2-oxo-[1,4'-bipiperidine]-1'-carboxylic acid 9c (677 mg), yield 87.1%.

[0310] MS m / z (ESI): 227.2 [M+1-56]

[0311] Step 3

[0312] [1,4'-bipiperidin]-2-one

[0313] [1,4'-Bipiperidin]-2-one

[0314] At room temperature, 200 mg (708.27 μmol) of tert-butyl 2-oxo-[1,4'-bipiperidine]-1'-carboxylic acid ester 9c was dissolved in dichloromethane (2 mL), followed by the addition of 2 mL (4 M) of 1,4-dioxane hydrochloride solution. The reaction mixture was allowed to react for 2 hours at room temperature. After the reaction was complete, the reaction solution was concentrated under reduced pressure to give 120 mg (93.0%) of [1,4'-bipiperidine]-2-one 9d, which was used directly in the next step.

[0315] MS m / z (ESI): 183.2 [M+1]

[0316] Step 4

[0317] 3-(2-chloro-3-(2-oxo-[1,4'-bipiperidin]-1'-yl)phenyl)piperidine-2,6-dione

[0318] 3-(2-chloro-3-(2-oxo-[1,4'-dipiperidin]-1'-yl)phenyl)piperidin-2,6-dione

[0319] [1,4'-Bipiperidine]-2-one 9d (9.04 mg, 49.58 μmol) and 3-(3-bromo-2-chloro-phenyl)piperidine-2,6-dione 1a (10 mg, 33.05 μmol) were added to 1,4-dioxane (1 mL). Then, cesium carbonate (53.85 mg, 165.26 μmol) and (SP-4-1)-[1,3-bis[2,6-bis(1-propylbutyl)phenyl]-4,5-dichloro-1,3-dihydro-2H-imidazol-2-ylyl]dichloro(3-chloropyridine-KN)palladium (2.62 mg, 3.31 μmol) were added to the system. The reaction mixture was heated to 90 °C under nitrogen protection and the reaction was continued for 16 hours. After the reaction was complete, the mixture was cooled to room temperature, quenched with water (10 mL), and extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with saturated ammonium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by preparative liquid chromatography (Waters 2767 / Qda column: SunFire Sunfire C18, 19*250 mm, 10 μm; mobile phase A: 0.1% FA / H2O, mobile phase B: ACN; flow rate: 20 mL / min; gradient: 32-42%, retention time: 8.8-9.2 min, 16 min) to give 3-(2-chloro-3-(2-oxo-[1,4'-dipiperidin]-1'-yl)phenyl)piperidin-2,6-dione 9 (2.23 mg), yield 16.7%.

[0320] MS m / z(ESI): 404.2 [M+1]

[0321] 1 H NMR (400MHz, DMSO) δ10.88(s,1H),7.26(t,J=7.6Hz,1H),7.13(d,J=6.8Hz,1H),6 .99(d,J=6.8Hz,1H),4.52–4.39(m,1H),4.25(dd,J=12.0,6.0Hz,1H),3.29–3.24( m,2H),3.22(t,J=5.6Hz,2H),2.79–2.69(m,3H),2.54–2.52(m,1H),2.33–2.22(m ,3H),2.02–1.94(m,1H),1.92–1.81(m,2H),1.76–1.64(m,4H),1.63–1.54(m,2H).

[0322] Example 10

[0323] 3-(2-chloro-4'-(1-(pyridin-2-yloxy)vinyl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione

[0324] 3-(2-chloro-4'-(1-(pyridin-2-oxy)vinyl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0325] first step

[0326] 1-bromo-4-(2-chloroethynyl)benzene

[0327] 1-Bromo-4-(2-Chloroethynyl)benzene

[0328] 1-Bromo-4-ethynylbenzene 10a (5 g, 27.62 mmol) was added to carbon tetrachloride (40 mL), followed by potassium carbonate (3.81 g, 27.62 mmol) and tetrabutylammonium fluoride trihydrate (871.42 mg, 2.76 mmol). The reaction mixture was allowed to react for 16 hours at room temperature. After the reaction was complete, the mixture was quenched with water (30 mL), extracted with ethyl acetate (50 mL × 3), and the organic phases were combined. The mixture was washed with saturated sodium chloride (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent: system A) to give 1-bromo-4-(2-chloroethynyl)benzene 10b (4.3 g), in 72.3% yield.

[0329] 1 H NMR (400MHz, CDCl3) δ7.47–7.42(m,2H),7.33–7.27(m,2H).

[0330] Step 2

[0331] 2-((1-(4-bromophenyl)-2-chlorovinyl)oxy)pyridine

[0332] 2-((1-(4-bromophenyl)-2-chloroethylene)oxy)pyridine

[0333] 1-(1-(4-bromophenyl)-2-chlorovinyl)pyridin-2(1H)-one

[0334] 1-(1-(4-bromophenyl)-2-chlorovinyl)pyridine-2(1H)-one

[0335] At room temperature, 1-bromo-4-(2-chloroethynyl)benzene 10b (1.14 g, 5.29 mmol) was dissolved in dimethyl sulfoxide (15 mL), followed by the addition of cesium carbonate (6.9 g, 21.16 mmol) and 1H-pyridin-2-one (503.14 mg, 5.29 mmol, commercially available). The reaction mixture was then heated to 70 °C and reacted for 1 hour. After the reaction was complete, the reaction mixture was cooled to room temperature, quenched with water (20 mL), extracted with ethyl acetate (30 mL × 3), the organic phases were combined, washed with saturated sodium chloride (20 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (developing solvent: system A) to give 2-((1-(4-bromophenyl)-2-chloroethylene)oxy)pyridine 10c-P1 (60 mg), yield 5.8%, and 1-(1-(4-bromophenyl)-2-chloroethylene)pyridine-2(1H)-one 10c-P2 (420 mg), yield 40.7%.

[0336] MS m / z (ESI): 309.9 [M+1]

[0337] 2-(1-(4-bromophenyl)-2-chlorovinyl)oxy)pyridine 10c-P1

[0338] 1 H NMR (400MHz, DMSO) δ8.15–8.02(m,1H),7.96–7.80(m,1H),7.59(d,J=8.4Hz,2H ),7.47(d,J=8.4Hz,2H),7.22(s,1H),7.15(d,J=8.4Hz,1H),7.11–7.05(m,1H).

[0339] 2-((2-(4-bromophenyl)-1-chlorovinyl)oxy)pyridine 10c-P2

[0340] 1 H NMR (400MHz, DMSO) δ7.66 (s, 1H), 7.63–7.56 (m, 3H), 7.53–7.49 (m, 1H), 7.27–7.21 (m, 2H), 6.52 (d, J = 8.8Hz, 1H), 6.41–6.36 (m, 1H).

[0341] Step 3

[0342] 2-((2-chloro-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)vinyl)oxy)pyridine

[0343] 2-((2-chloro-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)vinyl)oxy)pyridine

[0344] 2-((1-(4-bromophenyl)-2-chloroethylene)oxy)pyridine 10c-P1 (30 mg, 109.44 μmol) was dissolved in 1,4-dioxane (1 mL), and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxaborane) (83.38 mg, 328.33 μmol, commercially available), potassium acetate (32.22 mg, 328.33 μmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (8.12 mg, 10.94 μmol) were added. The reaction mixture was heated to 90 °C under nitrogen protection and the reaction was continued for 16 hours. After the reaction was completed, the reaction solution was cooled to room temperature. The reaction solution was left untreated to yield 10 d of 2-((2-chloro-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)vinyl)oxy)pyridine, which was used directly in the next step.

[0345] MS m / z (ESI): 358.0 [M+1]

[0346] Step 4

[0347] 3-(2-chloro-4'-(1-(pyridin-2-yloxy)vinyl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione

[0348] 3-(2-chloro-4'-(1-(pyridin-2-oxy)vinyl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0349] 2-((2-chloro-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)vinyl)oxy)pyridine 10d (30 mg, 125.51 μmol) and 3-(3-bromo-2-chloro-phenyl)piperidine-2,6-dione 1a (45.57 mg, 150.61 μmol) were dissolved in 1,4-dioxane (1 mL) and water (0.1 mL), followed by the addition of potassium carbonate (52.04 mg, 376.52 μmol) and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (8.18 mg, 12.55 μmol). The reaction mixture was heated to 90 °C under nitrogen protection and reacted for 16 hours. After the reaction was complete, the reaction mixture was cooled to room temperature. Quenching with water (5 mL), extraction with ethyl acetate (10 mL × 3), combining the organic phases, washing with saturated sodium chloride (15 mL), drying with anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure, and purifying the residue by preparative HPLC (Waters 3767 / Qda column: XBridge C18, 19*250 mm, 10 μm; mobile phase A: 10 mmol / L NH4HCO3 / H2O, mobile phase B: ACN; flow rate: 20 mL / min; gradient: 50-55%, retention time: 8.3-9 min, 16 min) to give 10 (1.60 mg) of 3-(2-chloro-4'-(1-(pyridin-2-oxy)vinyl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione, yield 3.0%.

[0350] MS m / z(ESI): 419.1 [M+1]

[0351] 1 H NMR(400MHz,DMSO)δ10.92(s,1H),8.18–8.13(m,1H),7.86–7.81(m,1H),7.65(d, J=8.4Hz,2H),7.41(d,J=8.4Hz,2H),7.39–7.33(m,2H),7.32–7.29(m,1H),7.12–7 .07(m,2H),5.66(d,J=2.0Hz,1H),4.97(d,J=2.0Hz,1H),4.34(dd,J=12.0,5.2Hz ,1H),2.84–2.73(m,1H),2.58–2.54(m,1H),2.36–2.29(m,1H),2.08–2.01(m,1H).

[0352] Example 11

[0353] 3-(2-chloro-4'-(1-(2-oxopyridin-1(2H)-yl)vinyl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione

[0354] 3-(2-chloro-4'-(1-(2-oxopyridin-1(2H)-yl)vinyl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0355] Route a:

[0356] first step

[0357] 1-(1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)vinyl)pyridin-2(1H)-one

[0358] 1-(1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxoborane-2-yl)phenyl)vinyl)pyridine-2(1H)-one)

[0359] 1-(1-(4-bromophenyl)-2-chlorovinyl)pyridine-2(1H)-one 10c-P2 (50 mg, 182.41 μmol) was dissolved in 1,4-dioxane (1 mL), followed by 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxaborane) (138.96 mg, 547.22 μmol), potassium acetate (53.71 mg, 547.22 μmol), and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (13.53 mg, 18.24 μmol). The reaction mixture was heated to 90 °C under nitrogen protection and the reaction was continued for 4 hours. After the reaction was complete, the reaction mixture was cooled to room temperature, quenched with water (5 mL), extracted with ethyl acetate (10 mL × 3), the organic phases were combined, washed with saturated sodium chloride (15 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by preparative HPLC (electrolyte: system D) to give 1-(1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxoboran-2-yl)phenyl)vinyl)pyridin-2(1H)-one 11a (20 mg), yield 34.1%.

[0360] MS m / z (ESI): 324.2 [M+1]

[0361] Step 2

[0362] 3-(2-chloro-4'-(1-(2-oxopyridin-1(2H)-yl)vinyl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione

[0363] 3-(2-chloro-4'-(1-(2-oxopyridin-1(2H)-yl)vinyl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0364] 1-(1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxoboran-2-yl)phenyl)vinyl)pyridin-2(1H)-one 11a (20.00 mg, 83.67 μmol) and 3-(3-bromo-2-chloro-phenyl)piperidin-2,6-dione 1a (30.38 mg, 100.40 μmol) were dissolved in 1,4-dioxane (1 mL) and water (0.1 mL), and potassium carbonate (34.69 mg, 251.01 μmol) and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (5.45 mg, 8.37 μmol) were added. The reaction mixture was heated to 90 °C under nitrogen protection and the reaction was continued for 4 hours. After the reaction was completed, the reaction solution was cooled to room temperature, quenched with water (5 mL), extracted with ethyl acetate (10 mL × 3), the organic phases were combined, washed with saturated sodium chloride (15 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (Waters 3767 / Qda column: SunFire Sunfire C18, 19*250 mm, 10 μm; mobile phase A: 0.1% FA / H2O, mobile phase B: ACN; flow rate: 20 mL / min; gradient: 36-46%, retention time: 8.4 min, 17 min) to give 11 (2.11 mg) of 3-(2-chloro-4'-(1-(2-oxopyridin-1(2H)-yl)vinyl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione, yield 6.0%.

[0365] MS m / z(ESI): 419.3 [M+1]

[0366] 1H NMR(400MHz,DMSO)δ10.92(s,1H),7.67–7.62(m,1H),7.60–7.54(m,1H),7 .45–7.41(m,2H),7.40–7.33(m,4H),7.32–7.29(m,1H),6.45(d,J=9.2Hz, 1H),6.35(t,J=6.4Hz,1H),6.15(s,1H),5.48(s,1H),4.39–4.30(m,1H),2 .84–2.74(m,1H),2.57–2.54(m,1H),2.35–2.29(m,1H),2.09–2.01(m,1H).

[0367] Route b:

[0368] first step

[0369] 1-(1-(4-bromophenyl)vinyl)pyridin-2(1H)-one

[0370] 1-(1-(4-bromophenyl)vinyl)pyridine-2(1H)-one

[0371] 1-(4-bromophenyl)ethyl ketone 11b (5 g, 25.12 mmol, commercially available) was added to dichloroethane (50 mL), followed by 2-fluoropyridine (7.32 g, 75.36 mmol, commercially available) and trifluoromethanesulfonic anhydride (10.63 g, 37.68 mmol). The reaction mixture was heated to 80 °C under nitrogen protection and reacted for 1 hour. Then, 1M sodium hydroxide (2.01 g, 50.24 mmol, 10 mL) was added, and the reaction mixture was reacted at 80 °C for another hour. After the reaction was complete, the mixture was cooled to room temperature. The reaction mixture was extracted with dichloromethane (15 mL × 3), the organic phases were combined, washed with saturated sodium chloride (20 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (developing solvent: system A) to give 1-(1-(4-bromophenyl)vinyl)pyridin-2(1H)-one 11c (5.4 g), yield 77.9%.

[0372] MS m / z (ESI): 276.1 [M+1]

[0373] Step 2

[0374] 1-(1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)vinyl)pyridin-2(1H)-one

[0375] 1-(1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)vinyl)pyridine-2(1H)-one

[0376] 1-(1-(4-bromophenyl)vinyl)pyridine-2(1H)-one 11c (2 g, 7.24 mmol) was dissolved in 1,4-dioxane (20 mL), and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxaborane) (5.52 g, 21.73 mmol), potassium acetate (2.13 g, 21.73 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (530.19 mg, 724.30 μmol) were added. The reaction mixture was heated to 90 °C under nitrogen protection and the reaction was continued for 16 hours. After the reaction was complete, the reaction mixture was cooled to room temperature, quenched with water (50 mL), extracted with ethyl acetate (50 mL × 3), the organic phases were combined, washed with saturated sodium chloride (90 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (developing solvent: system A) to give 1-(1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)vinyl)pyridin-2(1H)-one 11a (550 mg), yield 23.5%.

[0377] MS m / z (ESI): 324.2 [M+1]

[0378] Step 3

[0379] 3-(2-chloro-4'-(1-(2-oxopyridin-1(2H)-yl)vinyl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione

[0380] 3-(2-chloro-4'-(1-(2-oxopyridin-1(2H)-yl)vinyl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0381] 1-(1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)vinyl)pyridin-2(1H)-one 11a (200 mg, 618.83 μmol) and 3-(3-bromo-2-chloro-phenyl)piperidin-2,6-dione 1a (205.95 mg, 680.71 μmol) were dissolved in 1,4-dioxane (2 mL) and water (0.2 mL), and potassium carbonate (256.58 mg, 1.86 mmol) and [1,1'-bis(di-tert-butylphosphine)ferrocene]palladium dichloride (40.33 mg, 61.88 μmol) were added. The reaction mixture was heated to 80 °C under nitrogen protection and the reaction was continued for 4 hours. After the reaction was completed, the reaction solution was cooled to room temperature, quenched with water (20 mL), extracted with ethyl acetate (30 mL × 3), the organic phases were combined, washed with saturated sodium chloride (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (Waters 2767 / Qda column: Waters Sunfire C18, 19*250 mm, 5 μm; mobile phase A: 0.1% FA / H2O, mobile phase B: ACN; flow rate: 20 mL / min; gradient: 35-40%, retention time: 8.4 min, 17 min) to give 3-(2-chloro-4'-(1-(2-oxopyridin-1(2H)-yl)vinyl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione 11 (91.27 mg), yield 35.2%.

[0382] MS m / z(ESI): 419.2 [M+1]

[0383] 1 H NMR(400MHz, DMSO-d6)δ10.92(s,1H),7.65(dd,J=6.8,1.6Hz,1H),7.59–7.54(m,1H ),7.45–7.34(m,6H),7.31(dd,J=7.2,2.0Hz,1H),6.45(d,J=9.2Hz,1H),6.36(td,J= 6.8,1.2Hz,1H),6.15(d,J=1.2Hz,1H),5.48(d,J=1.2Hz,1H),4.35(dd,J=12.0,5.2 Hz,1H),2.85–2.74(m,1H),2.58–2.52(m,1H),2.40–2.27(m,1H),2.10–1.98(m,1H).

[0384] Example 12

[0385] Step 3

[0386] 3-(2-chloro-3-(4-(2-oxopyridin-1(2H)-yl)naphthalen-1-yl)phenyl)piperidine-2,6-dione

[0387] 3-(2-chloro-3-(4-(2-oxopyridin-1(2H)-yl)naphth-1-yl)phenyl)piperidin-2,6-dione

[0388] first step

[0389] 1-(4-bromonaphthalen-1-yl)pyridin-2(1H)-one

[0390] 1-(4-bromonaphth-1-yl)pyridin-2(1H)-one

[0391] 12a of 4-bromo-1-naphthyl)boronic acid (1 g, 3.99 mmol) was dissolved in 10 mL of dichloroethane, and 1H-pyridin-2-one (454.87 mg, 4.78 mmol), copper acetate (725.43 mg, 3.99 mmol, commercially available) and triethylamine (1.21 g, 11.96 mmol) were added. The reaction was continued at room temperature under nitrogen protection for 16 hours. After the reaction was complete, the mixture was filtered directly, and the filtrate was concentrated under reduced pressure. The mixture was purified by silica gel column chromatography (developing solvent: system A) to give 1-(4-bromonaphthyl)pyridin-2(1H)-one 12b (234 mg), in 19.6% yield.

[0392] MS m / z (ESI): 300.0 [M+1]

[0393] Step 2

[0394] 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)pyridin-2(1H)-one

[0395] 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)naphth-1-yl)pyridin-2(1H)-one

[0396] 1-(4-bromonaphth-1-yl)pyridin-2(1H)-one 12b (184 mg, 613.03 μmol) was added to a 2 mL solution of 1,4-dioxane, followed by the addition of 4,4,5,5-tetramethyl-2-(4,4,5,5-4-tetramethyl-1,3,2-dioxaborane-2-yl)-1,3,2-dioxaborane (467.01 mg, 1.84 mmol), potassium acetate (180.23 mg, 1.84 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (44.87 mg, 61.30 μmol). The reaction was continued at room temperature under nitrogen protection for 16 hours. After the reaction was complete, the mixture was cooled to room temperature, quenched with water (5 mL), extracted with ethyl acetate (20 mL × 3), the organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the mixture was purified by silica gel column chromatography (developing solvent: system A) to give 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)naphth-1-yl)pyridin-2(1H)-one 12c (160 mg), yield 75.2%.

[0397] MS m / z (ESI): 348.2 [M+1]

[0398] Step 3

[0399] 3-(2-chloro-3-(4-(2-oxopyridin-1(2H)-yl)naphthalen-1-yl)phenyl)piperidine-2,6-dione

[0400] 3-(2-chloro-3-(4-(2-oxopyridin-1(2H)-yl)naphth-1-yl)phenyl)piperidin-2,6-dione

[0401] 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)naphth-1-yl)pyridin-2(1H)-one 12c (20 mg, 57.60 μmol) and 3-(3-bromo-2-chloro-phenyl)piperidin-2,6-dione 1a (17.43 mg, 57.60 μmol) were added to 1,4-dioxane (1 mL) and water (0.1 mL). Then, potassium carbonate (23.88 mg, 172.80 μmol) and [1,1'-bis(diphenylphosphine)ferrocene]dichloropalladium(II) (3.75 mg, 5.76 μmol) were added to the system. The reaction mixture was heated to 90 °C under nitrogen protection and the reaction was continued for 16 hours. After the reaction was complete, the mixture was cooled to room temperature, quenched with water (5 mL), extracted with ethyl acetate (10 mL × 3), and the organic phases were combined. The mixture was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was subjected to preparative HPLC (Waters 3767 / Qda column: XBridge C18, 19*250 mm, 10 μm; mobile phase A: 10 mmol / L NH4HCO3 / H2O, mobile phase B: ACN; flow rate: 20 mL / min; gradient: 55-62%) to give 12 (3.89 mg) of 3-(2-chloro-3-(4-(2-oxopyridin-1(2H)-yl)naphth-1-yl)phenyl)piperidin-2,6-dione, yield 15.3%. MS m / z (ESI): 443.1 [M+1]

[0402] 1 H NMR(400MHz,DMSO)δ10.94(s,1H),8.14(dd,J=4.8,1.6Hz,1H),7.99–7.91(m,2 H),7.56–7.48(m,4H),7.46–7.42(m,1H),7.41–7.36(m,2H),7.35–7.32(m,1H) ,7.24(d,J=8.4Hz,1H),7.17(dd,J=6.8,5.2Hz,1H),4.38(dd,J=12.0,4.0Hz,1 H),2.88–2.75(m,1H),2.60–2.53(m,1H),2.44–2.35(m,1H),2.16–2.08(m,1H).

[0403] Example 13

[0404] 3-(2-chloro-3-(7-(2-oxopyridin-1(2H)-yl)-2,3-dihydrobenzofuran-4-yl)phenyl)piperidine-2,6-dione

[0405] 3-(2-chloro-3-(7-(2-oxopyridin-1(2H)-yl)-2,3-dihydrobenzofuran-4-yl)phenyl)piperidin-2,6-dione

[0406] first step

[0407] 7-iodo-2,3-dihydrobenzofuran-4-amine

[0408] 7-Iodo-2,3-dihydrobenzofuran-4-amine

[0409] 2,3-Dihydrobenzofuran-4-amine 13a (2 g, 14.80 mmol) was added to an acetonitrile (20 mL) solution, and N-iodosuccinimide (3.66 g, 16.28 mmol) was added at 0 °C. The reaction solution was reacted at 0 °C for half an hour. Then the reaction was continued at room temperature for 3 hours. After the reaction was completed, the reaction solution was quenched with sodium thiosulfate (30 mL) solution, extracted with ethyl acetate (30 mL × 3), the organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The mixture was purified by silica gel column chromatography (developing solvent: system A) to give 7-iodo-2,3-dihydrobenzofuran-4-amine 13b (3.1 g), yield 80.3%.

[0410] MS m / z (ESI): 262.0 [M+1]

[0411] Step 2

[0412] 1-(4-amino-2,3-dihydrobenzofuran-7-yl)pyridin-2(1H)-onee

[0413] 1-(4-amino-2,3-dihydrobenzofuran-7-yl)pyridin-2(1H)-one

[0414] 7-Iodo-2,3-dihydrobenzofuran-4-amine 13b (2 g, 7.66 mmol) was added to a solution of 1,4-dioxane (13 mL) and dimethyl sulfoxide (7 mL), followed by 1H-pyridin-2-one (1.46 g, 15.32 mmol), 8-hydroxyquinoline (222.42 mg, 1.53 mmol), cesium carbonate (5.00 g, 15.32 mmol), and cuprous iodide (291.81 mg, 1.53 mmol). The reaction mixture was heated to 120 °C under nitrogen protection and reacted for 16 h. After the reaction was complete, the mixture was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase column chromatography (evolving solvent: system D) to give 1-(4-amino-2,3-dihydrobenzofuran-7-yl)pyridin-2(1H)-one 13c (350 mg), yield 20.0%.

[0415] MS m / z (ESI): 229.1 [M+1]

[0416] Step 3

[0417] 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydrobenzofuran-7-yl)pyridin-2(1H)-one

[0418] 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-2,3-dihydrobenzofuran-7-yl)pyridin-2(1H)-one

[0419] 1-(4-amino-2,3-dihydrobenzofuran-7-yl)pyridin-2(1H)-one 13c (300 mg, 1.31 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-4-tetramethyl-1,3,2-dioxaborane-2-yl)-1,3,2-dioxaborane (500.65 mg, 1.97 mmol) were added to acetonitrile (10 mL), followed by the addition of tert-butyl nitrite (149.09 mg, 1.45 mmol), and the reaction was continued at room temperature for 16 hours. After the reaction was complete, water (10 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent: system A) to give 13d (70 mg) of 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-2,3-dihydrobenzofuran-7-yl)pyridin-2(1H)-one, with a yield of 15.7%.

[0420] MS m / z (ESI): 340.1 [M+1]

[0421] Step 4

[0422] 3-(2-chloro-3-(7-(2-oxopyridin-1(2H)-yl)-2,3-dihydrobenzofuran-4-yl)phenyl)piperidine-2,6-dione

[0423] 3-(2-chloro-3-(7-(2-oxopyridin-1(2H)-yl)-2,3-dihydrobenzofuran-4-yl)phenyl)piperidin-2,6-dione was prepared by adding 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-2,3-dihydrobenzofuran-7-yl)pyridin-2(1H)-one 13d (70 mg, 206.37 μmol) to 1,4-dioxane (2 mL) and water. The mixture was added to a 0.2 mL solution, followed by the addition of 3-(3-bromo-2-chloro-phenyl)piperidine-2,6-dione 1a (74.93 mg, 247.65 μmol), potassium carbonate (85.57 mg, 619.12 μmol), and [1,1'-bis(diphenylphosphine)ferrocene]dichloropalladium(II) (13.45 mg, 20.64 μmol). The reaction mixture was heated to 80 °C under nitrogen protection and the reaction continued for 4 h. After the reaction was complete, the reaction mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was subjected to preparative HPLC (Gilson GX-281 column: Waters Sunfire C18, 19*250mm, 10μm; mobile phase A: 0.1% FA / H2O, mobile phase B: ACN; flow rate: 25ml / min; gradient: 30-40%) to give 3-(2-chloro-3-(7-(2-oxopyridin-1(2H)-yl)-2,3-dihydrobenzofuran-4-yl)phenyl)piperidin-2,6-dione 13 (31.79mg), yield 35.4%. MS m / z (ESI): 435.2 [M+1]

[0424] 1H NMR (400MHz, DMSO) δ10.93 (s, 1H), 7.60 (dd, J = 6.8, 1.6Hz, 1H), 7.54–7.47 (m, 1H), 7.45–7.38 ( m,2H),7.34(dd,J=6.8,2.8Hz,1H),7.21(d,J=8.4Hz,1H),6.86(d,J=8.4Hz,1H),6.49(d,J=9. 2Hz,1H),6.29(td,J=6.8,1.2Hz,1H),4.58(t,J=8.8Hz,2H),4.35(dd,J=12.4,5.2Hz,1H),3.0 8(t,J=8.8Hz,2H),2.86–2.74(m,1H),2.59–2.52(m,1H),2.41–2.29(m,1H),2.11–2.01(m,1H).

[0425] Example 14

[0426] 3-(2-chloro-3-(6-(2-oxopyridin-1(2H)-yl)naphthalen-2-yl)phenyl)piperidine-2,6-dione

[0427] 3-(2-chloro-3-(6-(2-oxopyridin-1(2H)-yl)naphth-2-yl)phenyl)piperidin-2,6-dione

[0428] first step

[0429] 1-(6-bromonaphthalen-2-yl)pyridin-2(1H)-one

[0430] 1-(6-bromonaphth-2-yl)pyridin-2(1H)-one

[0431] At room temperature, (6-bromonaphthyl-2-yl)boronic acid 14a (850 mg, 3.39 mmol, commercially available), 1H-pyridin-2-one (500 mg, 5.25 mmol), copper acetate (500 mg, 2.75 mmol), triethylamine (800 mg, 7.91 mmol), pyridine (700 mg, 8.85 mmol), and dichloromethane (20 mL) were sequentially added to a 100 mL single-necked flask. The reaction mixture was stirred overnight under oxygen protection. After the reaction was complete, the reaction mixture was directly concentrated, and the residue was separated by silica gel column chromatography (eluent: system A) to give 1-(6-bromonaphthyl-2-yl)pyridin-2(1H)-one 14b (790 mg), yield: 77.7%.

[0432] MS m / z(ESI): 300.0 [M+1]

[0433] Step 2

[0434] 1-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-yl)pyridin-2(1H)-one

[0435] 1-(6-(4,4,5,5-tetramethyl-1,3,2-dioxoboran-2-yl)naphth-2-yl)pyridin-2(1H)-one

[0436] At room temperature, 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)-1,3,2-dioxoboronylpentane (254 mg, 1.0 mmol), 1-(6-bromonaphthyl-2-yl)pyridin-2(1H)-one 14b (200 mg, 0.66 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (60 mg, 82.00 μmol), potassium acetate (200 mg, 2.04 mmol), and 1,4-dioxane (20 mL) were sequentially added to a 100 mL single-necked flask. After purging with nitrogen three times, the mixture was stirred at 100 °C for 2 hours. LC-MS analysis confirmed complete reaction of the starting materials. The reaction solution was used directly in the next step without purification. MS m / z (ESI): 348.2 [M+1]

[0437] Step 3

[0438] 3-(2-chloro-3-(6-(2-oxopyridin-1(2H)-yl)naphthalen-2-yl)phenyl)piperidine-2,6-dione

[0439] 3-(2-chloro-3-(6-(2-oxopyridin-1(2H)-yl)naphth-2-yl)phenyl)piperidin-2,6-dione

[0440] At room temperature, 1-[6-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)-2-naphthyl]pyridin-2-one 14c (250 mg, 0.72 mmol), 3-(3-bromo-2-chloro-phenyl)piperidin-2,6-dione 1a (370 mg, 1.24 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (60 mg, 82.00 μmol), sodium bicarbonate (150 mg, 1.79 mmol), 1,4-dioxane (20 mL), and water (2.5 mL) were sequentially added to a 100 mL single-necked flask. After purging with nitrogen three times, the mixture was stirred at 85 °C for 1.5 h. The reaction proceeds were determined by LC-MS to be complete. The reaction solution was concentrated and purified by reverse phase (developing solvent: system D) to obtain 14 (60 mg) of 3-(2-chloro-3-(6-(2-oxopyridin-1(2H)-yl)naphth-2-yl)phenyl)piperidin-2,6-dione, yield: 18.8%.

[0441] MS m / z(ESI): 443.1 [M+1]

[0442] 1 H NMR (400MHz, DMSO-d6) δ10.91 (s, 1H), 8.08 (t, J = 8.1Hz, 2H), 8.04 (s, 2H), 7.78 (dd,J=6.9,2.0Hz,1H),7.63(d,J=8.5Hz,1H),7.60–7.54(m,2H),7.48–7.41(m ,3H),6.54(d,J=9.3Hz,1H),6.38(t,J=6.6Hz,1H),4.38(dd,J=12.1,5.0Hz,1H ),2.85–2.76(m,1H),2.60-2.56(m,1H),2.43–2.35(m,1H),2.12-2.04(m,1H).

[0443] Example 15

[0444] 3-(2-chloro-3-(5-(2-oxopyridin-1(2H)-yl)naphthalen-2-yl)phenyl)piperidine-2,6-dione

[0445] 3-(2-chloro-3-(5-(2-oxopyridin-1(2H)-yl)naphth-2-yl)phenyl)piperidin-2,6-dione

[0446] first step

[0447] (6-bromonaphthalen-1-yl)boronic acid

[0448] (6-Bromonaphth-1-yl)boronic acid

[0449] At 0°C, 6-bromonaphthyl-1-amine 15a (320 mg, 1.44 mmol, commercially available), methanol (5 ml), water, and dilute hydrochloric acid (2.0 M, 1.5 ml) were sequentially added to a 50 ml single-necked flask and stirred for 5 minutes. Sodium nitrite (200 mg, 2.88 mmol) was then dissolved in water (1 ml) and slowly added dropwise to the reaction mixture, maintaining the reaction at 0°C for 30 minutes. Tetrahydroxydiboron (260 mg, 2.90 mmol) was added in portions to the reaction mixture, and the mixture was heated to room temperature and stirred overnight. TLC was used to confirm the complete reaction of the starting materials. Dichloromethane (100 ml) and water (50 ml) were added to the reaction mixture. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain 15b, which was used directly in the next reaction step.

[0450] Step 2

[0451] 1-(6-bromonaphthalen-1-yl)pyridin-2(1H)-one

[0452] 1-(6-bromonaphth-1-yl)pyridin-2(1H)-one

[0453] At room temperature, (6-bromonaphth-1-yl)boronic acid 15b (320 mg, 1.28 mmol), pyridin-2(1H)-one (182 mg, 1.91 mmol), anhydrous copper acetate (230 mg, 1.28 mmol), triethylamine (260 mg, 2.56 mmol), and dichloromethane (5 mL) were sequentially added to a 50 mL single-necked flask. The mixture was purged with oxygen three times and stirred overnight at room temperature. The target product was detected by LC-MS. Dichloromethane (50 mL) and water (20 mL) were added to the reaction mixture. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The purified product was obtained by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1:1) to give 1-(6-bromonaphth-1-yl)pyridin-2(1H)-one 15c (45 mg), yield 11.8%.

[0454] MS m / z(ESI): 300.0 [M+1]

[0455] Step 3

[0456] 1-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)pyridin-2(1H)-one

[0457] 1-(6-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)naphth-1-yl)pyridin-2(1H)-one

[0458] At room temperature, 1-(6-bromonaphth-1-yl)pyridin-2(1H)-one 15c (45 mg, 0.15 mmol), pinacol borate (60 mg, 0.23 mmol), Pd(dppf)Cl2 (15 mg, 0.02 mmol), potassium acetate (45 mg, 0.45 mmol), and anhydrous dioxane (5 ml) were sequentially added to a 50 ml single-necked flask. After purging with nitrogen three times, the mixture was heated to 100°C and stirred for 3 hours. LC-MS analysis confirmed complete reaction of the starting materials. The reaction solution was used directly in the next step without further treatment.

[0459] MS m / z(ESI): 348.2 [M+1]

[0460] Step 4

[0461] 3-(2-chloro-3-(5-(2-oxopyridin-1(2H)-yl)naphthalen-2-yl)phenyl)piperidine-2,6-dione

[0462] 3-(2-chloro-3-(5-(2-oxopyridin-1(2H)-yl)naphth-2-yl)phenyl)piperidin-2,6-dione

[0463] At room temperature, 1-(6-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)naphth-1-yl)pyridin-2(1H)-one 15d (35 mg, 0.1 mmol), 3-(3-bromo-2-chloro-phenyl)piperidin-2,6-dione 1a (40 mg, 0.13 mmol), Pd(dppf)Cl2 (15 mg, 0.02 mmol), sodium bicarbonate (30 mg, 0.35 mmol), dioxane (5 ml), and water (1 ml) were sequentially added to a 50 ml single-necked flask. After purging with nitrogen three times, the mixture was heated to 90°C and stirred for 3 hours. The reaction was confirmed to be complete by LC-MS. The reaction solution was purified by reverse-phase column chromatography to obtain 15 (8 mg) of 3-(2-chloro-3-(5-(2-oxopyridin-1(2H)-yl)naphth-2-yl)phenyl)piperidin-2,6-dione, in 17.6% yield.

[0464] MS m / z(ESI): 443.1 [M+1]

[0465] 1 H NMR (400MHz, DMSO-d6) δ10.92(s,1H),8.18–8.10(m,2H),7.73–7.56(m,5H),7.48–7.39(m,4H),6.59(d,J=9.2Hz,1H),6.4 3-6.40(m,1H),4.38(dd,J=12.2,5.0Hz,1H),2.85-2.75(m,1H),2.60-2.55(m,1H),2.40–2.31(m,1H),2.02–1.97(m,1H).

[0466] Example 16

[0467] 3-(2-chloro-3-(5-(6-methyl-2-oxopyridin-1(2H)-yl)naphthalen-2-yl)phenyl)piperidine-2,6-dione

[0468] 3-(2-chloro-3-(5-(6-methyl-2-oxopyridin-1(2H)-yl)naphth-2-yl)phenyl)piperidin-2,6-dione

[0469] first step

[0470] 1-(6-bromonaphthalen-1-yl)-6-methylpyridin-2(1H)-one

[0471] 1-(6-bromonaphth-1-yl)-6-methylpyridin-2(1H)-one

[0472] At room temperature, (6-bromonaphth-1-yl)boronic acid 15b (250 mg, 1.0 mmol), 6-methyl-1H-pyridin-2-one (200 mg, 1.83 mmol), copper acetate (90 mg, 0.50 mmol), triethylamine (300 mg, 3.0 mmol), pyridine (160 mg, 2.0 mmol), and dichloromethane (10 mL) were sequentially added to a 100 mL single-necked flask. The mixture was purged with oxygen three times and stirred overnight at room temperature. The reaction mixture was analyzed by LC-MS to confirm complete reaction. The reaction solution was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:1) to give 1-(6-bromonaphth-1-yl)-6-methylpyridin-2(1H)-one 16a (80 mg), yield 25%.

[0473] MS m / z(ESI): 314.0 [M+1]

[0474] Step 2

[0475] 6-methyl-1-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)pyridin-2(1H)-one

[0476] 6-Methyl-1-(6-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)naphth-1-yl)pyridin-2(1H)-one

[0477] At room temperature, 1-(6-bromonaphth-1-yl)-6-methylpyridin-2(1H)-one 16a (80 mg, 0.25 mmol), pinacol borate (100 mg, 0.39 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (20 mg, 0.03 mmol), potassium acetate (50 mg, 0.50 mmol), and 1,4-dioxane (10 mL) were sequentially added to a 50 mL single-necked flask. The mixture was purged with nitrogen three times and stirred at 100°C for 3 hours. LC-MS analysis confirmed complete reaction of the starting materials. The reaction solution was not purified and was used directly in the next step of the reaction.

[0478] MS m / z(ESI): 362.2 [M+1]

[0479] Step 3

[0480] 3-(2-chloro-3-(5-(6-methyl-2-oxopyridin-1(2H)-yl)naphthalen-2-yl)phenyl)piperidine-2,6-dione

[0481] 3-(2-chloro-3-(5-(6-methyl-2-oxopyridin-1(2H)-yl)naphth-2-yl)phenyl)piperidin-2,6-dione

[0482] At room temperature, 3-(3-bromo-2-chloro-phenyl)piperidin-2,6-dione 1a (75 mg, 0.25 mmol), 6-methyl-1-(6-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)naphth-1-yl)pyridin-2(1H)-one 16b (60 mg, 0.16 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (20 mg, 0.03 mmol), sodium bicarbonate (50 mg, 0.60 mmol), 1,4-dioxane (6.0 mL), and water (1.0 mL) were sequentially added to a 50 mL single-necked flask. The mixture was purged with nitrogen three times and stirred at 90 °C for 3 hours. The reaction proceeds were determined by LC-MS to be complete. The reaction solution was purified by silica gel column chromatography and reversed-phase chromatography (developing solvent: system D) to give 16 (15 mg) of 3-(2-chloro-3-(5-(6-methyl-2-oxopyridin-1(2H)-yl)naphth-2-yl)phenyl)piperidin-2,6-dione, in a yield of 18.8%.

[0483] MS m / z(ESI): 457.1 [M+1]

[0484] 1 H NMR(400MHz,DMSO-d6)δ10.90(s,1H),8.03(brs,1H),7.97(d,J=8.7Hz,1H),7.87(d,J =8.2Hz,1H),7.76(t,J=7.8Hz,1H),7.62–7.54(m,2H),7.49–7.40(m,3H),7.28(d,J=7. 5Hz,1H),7.01(d,J=7.3Hz,1H),6.88(d,J=8.1Hz,1H),4.37(dd,J=12.2,5.0Hz,1H),2. 85–2.75(m,1H),2.59–2.54(m,1H),2.38-2.32(m,1H),2.29(s,3H),2.13–2.04(m,1H).

[0485] Example 17

[0486] 3-(2-chloro-3-(7-(2-oxopyridin-1(2H)-yl)-1,3-dihydroisobenzofuran-4-yl)phenyl)piperidine-2,6-dione

[0487] 3-(2-chloro-3-(7-(2-oxopyridin-1(2H)-yl)-1,3-dihydroisobenzofuran-4-yl)phenyl)piperidin-2,6-dione

[0488] first step

[0489] 7-iodo-1,3-dihydroisobenzofuran-4-amine

[0490] 7-Iodo-1,3-dihydroisobenzofuran-4-amine

[0491] At 0°C, N-iodosuccinimide (1.75 g, 7.77 mmol) was added in portions to a solution of 1,3-dihydroisobenzofuran-4-amine 17a (1.0 g, 7.40 mmol) in N,N-dimethylformamide (20 mL). The reaction mixture was stirred overnight at room temperature. LC-MS analysis confirmed the reaction was complete. Ethyl acetate (150 mL x 2) and water (300 mL) were added to the reaction mixture. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. Purification was performed by silica gel column chromatography (petroleum ether / ethyl acetate = 1:1) to obtain 7-iodo-1,3-dihydroisobenzofuran-4-amine 17b (1.7 g), yield 88.0%.

[0492] MS m / z(ESI): 262.0 [M+1]

[0493] Step 2

[0494] 1-(7-amino-1,3-dihydroisobenzofuran-4-yl)pyridin-2(1H)-one

[0495] 1-(7-amino-1,3-dihydroisobenzofuran-4-yl)pyridin-2(1H)-one

[0496] At room temperature, pyridine-2(1H)-one (500 mg, 5.26 mmol), 7-iodo-1,3-dihydroisobenzofuran-4-amine 17b (980 mg, 3.75 mmol), cuprous iodide (400 mg, 2.10 mmol), potassium carbonate (1.5 g, 10.85 mmol), 8-hydroxyquinoline (370 mg, 2.55 mmol), and dimethyl sulfoxide (20 mL) were sequentially added to a 100 mL single-necked flask. The mixture was purged with nitrogen three times and stirred at 150 °C for 8 hours. The reaction mixture was analyzed by LC-MS to confirm complete reaction. The reaction solution was filtered and purified by reverse-phase chromatography (evolving solvent: system D) to give 1-(7-amino-1,3-dihydroisobenzofuran-4-yl)pyridine-2(1H)-one 17c (250 mg), yield 29.2%.

[0497] MS m / z(ESI): 229.1 [M+1]

[0498] Step 3

[0499] 1-(7-iodo-1,3-dihydroisobenzofuran-4-yl)pyridin-2(1H)-one

[0500] 1-(7-iodo-1,3-dihydroisobenzofuran-4-yl)pyridin-2(1H)-one

[0501] At 0°C, 1-(7-amino-1,3-dihydroisobenzofuran-4-yl)pyridin-2(1H)-one 17c (80 mg, 0.35 mmol), water (3 mL), and concentrated hydrochloric acid (180 mg, 1.75 mmol) were sequentially added to a 25 mL single-necked flask. Sodium nitrite (50 mg, 0.70 mmol) was then added to the reaction mixture, and the mixture was stirred at 0°C for 0.5 hours. Sodium iodide (105 mg, 0.70 mmol) was then added to the reaction mixture, and the mixture was stirred at room temperature for 2 hours. LC-MS analysis confirmed that the reaction proceeded completely. Dichloromethane (100 mL) and saturated sodium bicarbonate (20 mL) were added to the reaction solution. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The purified product was obtained by silica gel column chromatography (petroleum ether / ethyl acetate = 1:1) to give 17d (60 mg) of 1-(7-iodo-1,3-dihydroisobenzofuran-4-yl)pyridin-2(1H)-one, with a yield of 50.5%.

[0502] MS m / z(ESI): 340.0 [M+1]

[0503] Step 4

[0504] 1-(7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-dihydroisobenzofuran-4-yl)pyridin-2(1H)-one

[0505] 1-(7-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1,3-dihydroisobenzofuran-4-yl)pyridin-2(1H)-one

[0506] At room temperature, 1-(7-iodo-1,3-dihydroisobenzofuran-4-yl)pyridin-2(1H)-one 17d (60 mg, 0.17 mmol), pinacol borate (65 mg, 0.25 mmol), potassium acetate (50 mg, 0.50 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (20 mg, 0.03 mmol), and 1,4-dioxane (10 mL) were sequentially added to a 50 mL single-necked flask. The mixture was purged with nitrogen three times and stirred at 110°C for 3 hours. LC-MS analysis confirmed complete reaction of the starting materials. The reaction solution was not purified and was used directly in the next reaction step.

[0507] MS m / z(ESI): 340.1 [M+1]

[0508] Step 5

[0509] 3-(2-chloro-3-(7-(2-oxopyridin-1(2H)-yl)-1,3-dihydroisobenzofuran-4-yl)phenyl)piperidine-2,6-dione

[0510] 3-(2-chloro-3-(7-(2-oxopyridin-1(2H)-yl)-1,3-dihydroisobenzofuran-4-yl)phenyl)piperidin-2,6-dione

[0511] At room temperature, 3-(3-bromo-2-chloro-phenyl)piperidin-2,6-dione 1a (80 mg, 0.26 mmol), 1-(7-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)-1,3-dihydroisobenzofuran-4-yl)pyridin-2(1H)-one 17e (60 mg, 0.17 mmol), sodium bicarbonate (50 mg, 0.60 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (20 mg, 0.03 mmol), 1,4-dioxane (5 mL), and water (0.5 mL) were sequentially added to a 50 mL single-necked flask. The mixture was purged with nitrogen three times and stirred at 90 °C for 2 hours. The reaction proceeds were determined by LC-MS to be complete. Water (20 mL) and dichloromethane (100 mL) were added to the reaction solution. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The mixture was then purified by reverse-phase chromatography (developing solvent: system D) to give 17 (8.0 mg) of 3-(2-chloro-3-(7-(2-oxopyridin-1(2H)-yl)-1,3-dihydroisobenzofuran-4-yl)phenyl)piperidin-2,6-dione, in 10.4% yield.

[0512] MS m / z(ESI): 435.1 [M+1]

[0513] 1 H NMR(400MHz,DMSO-d6)δ10.93(s,1H),7.72-7.70(m,1H),7.58-7.53(m,1H),7 .46–7.41(m,2H),7.38(brs,2H),7.35-7.33(m,1H),6.53(d,J=9.2Hz,1H),6. 36(td,J=6.7,1.3Hz,1H),4.91(d,J=11.7Hz,4H),4.35(dd,J=12.2,5.0Hz,1H ),3.12-3.08(m,1H),2.85-2.76(m,1H),2.38–2.30(m,1H),2.12–2.03(m,1H).

[0514] Example 18

[0515] 3-(2-chloro-3-(7-(2-oxopyridin-1(2H)-yl)benzo[d][1,3]dioxol-4-yl)phenyl)piperidine-2,6-dione

[0516] 3-(2-chloro-3-(7-(2-oxopyridin-1(2H)-yl)benzo[d][1,3]dioxacyclopenten-4-yl)phenyl)piperidin-2,6-dione

[0517] first step

[0518] 3-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine-2,6-dione

[0519] 3-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxoborhecyclopentan-2-yl)phenyl)piperidine-2,6-dione

[0520] At room temperature, 3-(3-bromo-2-chloro-phenyl)piperidin-2,6-dione 1a (110 mg, 0.36 mmol), pinacol borate (120 mg, 0.47 mmol), potassium acetate (100 mg, 1.02 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (30 mg, 0.04 mmol), and 1,4-dioxane (10 ml) were sequentially added to a 50 ml single-necked flask. The mixture was purged with nitrogen three times, and the reaction solution was stirred at 85°C for 3 hours. LC-MS analysis showed that the starting materials reacted almost completely. The reaction solution was used directly in the next step without further treatment.

[0521] MS m / z(ESI): 350.1 [M+1]

[0522] Step 2

[0523] 7-iodobenzo[d][1,3]dioxol-4-amine

[0524] 7-Iodobenzo[d][1,3]dioxacyclopenten-4-amine

[0525] Benzo[d][1,3]dioxacyclopenten-4-amine 18b (1.5 g, 10.94 mmol) and N,N-dimethylformamide (20 ml) were added sequentially to a 50 ml single-necked flask at room temperature, and the reaction solution was cooled to -40 °C. N-iodosuccinimide (2.7 g, 12.0 mmol) was added to the reaction solution in portions, and the reaction was stirred at -40 °C for 1 hour. The reaction mixture was checked by LCMS to ensure complete reaction of the starting materials. Ethyl acetate (150 ml) and water (200 ml) were added to the reaction solution. The organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The resulting product was then subjected to silica gel column chromatography (electrolyte: petroleum ether / ethyl acetate = 1:1) to obtain 7-iodobenzo[d][1,3]dioxacyclopenten-4-amine 18c (2.0 g), with a yield of 69.5%.

[0526] MS m / z(ESI): 264.0 [M+1]

[0527] Step 3

[0528] 1-(7-aminobenzo[d][1,3]dioxol-4-yl)pyridin-2(1H)-one

[0529] 1-(7-aminobenzo[d][1,3]dioxacyclopenten-4-yl)pyridin-2(1H)-one

[0530] At room temperature, 7-iodobenzo[d][1,3]dioxacyclopenten-4-amine 18c (1.0 g, 3.80 mmol), 8-hydroxyquinoline (110 mg, 0.75 mmol), cesium carbonate (2.2 g, 6.75 mmol), cuprous iodide (200 mg, 1.05 mmol), pyridin-2(1H)-one (450 mg, 4.73 mmol), and N,N-dimethylformamide (20 mL) were sequentially added to a 50 mL single-necked flask. The mixture was purged with nitrogen three times, and the reaction solution was stirred at 150 °C for 8 hours. LC-MS analysis showed that the starting materials were essentially completely reacted. After filtration, the reaction solution was purified by reverse reaction (system D) to give 1-(7-aminobenzo[d][1,3]dioxacyclopenten-4-yl)pyridin-2(1H)-one 18d (800 mg), with a yield of 45.7%.

[0531] MS m / z(ESI): 231.1 [M+1]

[0532] Step 4

[0533] 1-(7-iodobenzo[d][1,3]dioxol-4-yl)pyridin-2(1H)-one

[0534] 1-(7-iodobenzo[d][1,3]dioxacyclopenten-4-yl)pyridin-2(1H)-one

[0535] At 0°C, 1-(7-aminobenzo[d][1,3]dioxacyclopenten-4-yl)pyridin-2(1H)-one 18d (800 mg, 1.74 mmol), acetonitrile (5 mL), and water (5 mL) were sequentially added to a 50 mL single-necked flask. Then, concentrated hydrochloric acid (12 mol / L, 0.72 mL) and sodium nitrite (250 mg, 3.62 mmol) were sequentially added to the reaction mixture, and the mixture was stirred at 0°C for 30 minutes. Sodium iodide (500 mg, 3.34 mmol) was added to the reaction mixture in portions, and the mixture was stirred overnight at room temperature. LC-MS analysis confirmed that the reaction proceeded completely. The pH was adjusted to 8 by adding saturated sodium bicarbonate solution to the reaction solution, followed by the addition of dichloromethane (150 ml). The organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The purified phase was then purified by silica gel column chromatography (developing solvent: petroleum ether / ethyl acetate = 1:1) to obtain 1-(7-iodobenzo[d][1,3]dioxane-4-yl)pyridin-2(1H)-one 18e (370 mg), with a yield of 62.4%.

[0536] MS m / z(ESI): 342.0 [M+1]

[0537] Step 5

[0538] 3-(2-chloro-3-(7-(2-oxopyridin-1(2H)-yl)benzo[d][1,3]dioxol-4-yl)phenyl)piperidine-2,6-dione

[0539] 3-(2-chloro-3-(7-(2-oxopyridin-1(2H)-yl)benzo[d][1,3]dioxacyclopenten-4-yl)phenyl)piperidin-2,6-dione

[0540] At room temperature, 1-(7-iodobenzo[d][1,3]dioxacyclopenten-4-yl)pyridin-2(1H)-one 18e (150 mg, 0.44 mmol), 3-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)phenyl)piperidine-2,6-dione 18a (120 mg, 0.36 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (30 mg, 0.04 mmol), sodium bicarbonate (100 mg, 1.20 mmol), 1,4-dioxane (10 ml), and water (1.5 ml) were sequentially added to a 50 ml single-necked flask. The mixture was purged with nitrogen three times, and the reaction mixture was stirred at 90°C for 3 hours. The reaction proceeded to completion as determined by LC-MS. Water (50 ml) and dichloromethane (100 ml) were added to the reaction solution. The organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The solution was purified by reverse reaction to obtain 18 (10 mg) of 3-(2-chloro-3-(7-(2-oxopyridin-1(2H)-yl)benzo[d][1,3]dioxacyclopenten-4-yl)phenyl)piperidin-2,6-dione, with a yield of 6.2%.

[0541] MS m / z(ESI): 437.1 [M+1]

[0542] 1 H NMR (400MHz, DMSO-d6) δ10.93(s,1H),7.70(dd,J=6.9,2.0Hz,1H),7.56-7.51(m,1H),7.45–7.38(m,3H),7.02–6.93(m,2H),6.51(d,J=9.3Hz, 1H),6.36-6.32(m,1H),6.09(s,2H),4.36(dd,J=12.3,5.0Hz,1H),2.85 -2.75(m,1H),2.58-2.55(m,1H),2.40-2.30(m,1H),2.07–1.98(m,1H).

[0543] Example 19

[0544] 3-(2-chloro-3-(6-(2-oxopyridin-1(2H)-yl)-7,8-dihydronaphthalen-2-yl)phenyl)piperidine-2,6-dione

[0545] 3-(2-chloro-3-(6-(2-oxopyridin-1(2H)-yl)-7,8-dihydronaphth-2-yl)phenyl)piperidin-2,6-dione

[0546] first step

[0547] 6-chloro-3,4-dihydronaphthalen-2-yl trifluoromethanesulfonate

[0548] 6-Chloro-3,4-dihydronaphth-2-yltrifluoromethanesulfonate

[0549] Under argon protection, 6-chloro-3,4-dihydronaphthyl-2(1H)-one 19a (3 g, 16.61 mmol) was added to a tetrahydrofuran (30 mL) solution. The reaction mixture was cooled to -78 °C, and sodium bis(trimethylsilyl)amino (18.3 mL, 18.27 mmol, 1 M) was added. The reaction mixture was allowed to react at -78 °C for 1 hour, and then 1,1,1-trifluoro-N-phenyl-N-(trifluoromethanesulfonyl)methanesulfonamide (6.53 g, 18.27 mmol) was added. The reaction mixture was allowed to react at room temperature for 1 hour under argon protection. After the reaction was complete, the reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography (evolving solvent: system A) to give 6-chloro-3,4-dihydronaphthyl-2-yltrifluoromethanesulfonate 19b (3.7 g), in 71.2% yield.

[0550] 1 H NMR (400MHz, DMSO) δ7.31 (s, 1H), 7.28 (s, 2H), 6.82 (s, 1H), 3.04 (t, J = 8.4Hz, 2H), 2.68 (t, J = 8.5Hz, 2H).

[0551] Step 2

[0552] 2-(6-chloro-3,4-dihydronaphthalen-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

[0553] 2-(6-chloro-3,4-dihydronaphth-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxoborhecyclopentane

[0554] 6-Chloro-3,4-dihydronaphth-2-yltrifluoromethanesulfonate 19b (4 g, 12.79 mmol) was added to a 40 mL solution of 1,4-dioxane, followed by 4,4,5,5-tetramethyl-2-(4,4,5,5-4-tetramethyl-1,3,2-dioxoborhexacyclopentan-2-yl)-1,3,2-dioxoborhexacyclopentane (3.25 g, 12.79 mmol), potassium acetate (3.77 g, 38.38 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (948.90 mg, 1.28 mmol). The reaction mixture was heated to 90 °C and reacted for 16 hours under argon protection. After the reaction was complete, the reaction mixture was cooled to room temperature, quenched with water (30 mL), extracted with ethyl acetate (50 mL × 3), the organic phases were combined, washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (developing solvent: system A) to give 2-(6-chloro-3,4-dihydronaphth-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxoborane 19c (3 g), yield 80.7%.

[0555] 1 H NMR (400MHz, DMSO) δ7.23(s,1H),7.22(s,2H),7.11(s,1H),2.68(t,J=8.2Hz,2H),2.25(td,J=8.3,1.5Hz,2H),1.25(s,12H).

[0556] Step 3

[0557] (6-chloro-3,4-dihydronaphthalen-2-yl)boronic acid

[0558] (6-Chloro-3,4-dihydronaphth-2-yl)boronic acid

[0559] 2-(6-chloro-3,4-dihydronaphthyl-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxoboronylcyclopentane 19c (3 g, 10.32 mmol) was added to a solution of acetone (20 mL) and water (20 mL). The system was then cooled to 0 °C, and ammonium acetate (1.19 g, 15.49 mmol) and sodium periodate (3.31 g, 15.49 mmol) were added. The reaction mixture was then brought to room temperature and the reaction continued for 16 hours. After the reaction was complete, the reaction mixture was extracted with acetone (50 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The filtrate was purified by silica gel column chromatography (developing solvent: system A) to obtain a partial product. This was then washed again by silica gel column chromatography (developing solvent: system B), and the combined filtrate yielded (6-chloro-3,4-dihydronaphthyl-2-yl)boronic acid 19d (1.3 g), with a yield of 60.4%.

[0560] 1 H NMR (400MHz, DMSO) δ7.72(s,1H),7.21(s,2H),7.08(d,J=9.5Hz,1H),2.76–2.62(m,2H),2.31(dt,J=36.3,7.8Hz,2H).

[0561] Step 4

[0562] 1-(6-chloro-3,4-dihydronaphthalen-2-yl)pyridin-2(1H)-one

[0563] 1-(6-chloro-3,4-dihydronaphth-2-yl)pyridin-2(1H)-one

[0564] and

[0565] 2-((6-chloro-3,4-dihydronaphthalen-2-yl)oxy)pyridine

[0566] 2-((6-chloro-3,4-dihydronaphth-2-yl)oxy)pyridine

[0567] (6-chloro-3,4-dihydronaphthyl-2-yl)boronic acid 19d (1.3 g, 6.24 mmol) was added to dichloroethane (13 mL), followed by 1H-pyridin-2-one (711.71 mg, 7.48 mmol), copper acetate (1.13 g, 6.24 mmol), and triethylamine (1.89 g, 18.71 mmol). The reaction mixture was allowed to react for 16 hours at room temperature. After the reaction was complete, water (20 mL) was added to quench the reaction, followed by extraction with ethyl acetate (30 mL × 3). The organic phases were combined, washed with saturated sodium chloride (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (developing solvent: system A) to give 1-(6-chloro-3,4-dihydronaphthyl-2-yl)pyridin-2(1H)-one 19e (260 mg), yield 16.2%; and 2-((6-chloro-3,4-dihydronaphthyl-2-yl)oxy)pyridin 19f (360 mg), yield 22.4%.

[0568] MS m / z(ESI): 258.2 [M+1]

[0569] Step 5

[0570] 3-(2-chloro-3-(6-(2-oxopyridin-1(2H)-yl)-7,8-dihydronaphthalen-2-yl)phenyl)piperidine-2,6-dione

[0571] 3-(2-chloro-3-(6-(2-oxopyridin-1(2H)-yl)-7,8-dihydronaphth-2-yl)phenyl)piperidin-2,6-dione

[0572] 1-(6-chloro-3,4-dihydronaphthyl-2-yl)pyridin-2(1H)-one 19e (50 mg, 194.01 μmol) and 3-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxoborhexacyclopentan-2-yl)phenyl)piperidin-2,6-dione 18a (81.40 mg, 232.82 μmol) were dissolved in 1,4-dioxane (1 mL) and water (0.1 mL), and potassium carbonate (80.44 mg, 582.04 μmol) and methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tris-isopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (16.42 mg, 19.40 μmol) were added. The reaction mixture was heated to 90°C under nitrogen protection and the reaction continued for 1 hour. After the reaction was completed, the reaction mixture was cooled to room temperature, quenched with water (5 mL), extracted with ethyl acetate (10 mL × 3), the organic phases were combined, washed with saturated sodium chloride (15 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by preparative HPLC (Gilson GX-281 column: Sunfire C18, 19*250 mm, 10 μm; mobile phase A: 0.1% FA / H2O, mobile phase B: ACN; flow rate: 20 mL / min; gradient: 52-62%, retention time: 7.8-8.3 min, 18 min) to give 3-(2-chloro-3-(6-(2-oxopyridin-1(2H)-yl)-7,8-dihydronaphth-2-yl)phenyl)piperidin-2,6-dione 19 (32.23 mg), which was identified as the target compound by mass spectrometry, nuclear magnetic resonance (NMR), and two-dimensional NMR, with a yield of 37.3%.

[0573] MS m / z (ESI): 445.2 [M+1]

[0574] 1 H NMR(400MHz,DMSO)δ10.92(s,1H),7.65(dd,J=6.8,1.6Hz,1H),7.53–7.46(m,1H),7 .43–7.31(m,3H),7.29–7.21(m,3H),6.67(s,1H),6.43(d,J=9.2Hz,1H),6.30(td,J= 6.8,1.2Hz,1H),4.34(dd,J=12.0,5.2Hz,1H),3.01(t,J=8.0Hz,2H),2.85–2.74(m, 1H), 2.65 (t, J = 8.0Hz, 2H), 2.58–2.52 (m, 1H), 2.42–2.29 (m, 1H), 2.10–2.01 (m, 1H).

[0575] Example 20

[0576] 3-(2-chloro-3-(6-(pyridin-2-yloxy)-7,8-dihydronaphthalen-2-yl)phenyl)piperidine-2,6-dione

[0577] 3-(2-chloro-3-(6-(pyridin-2-yloxy)-7,8-dihydronaphth-2-yl)phenyl)piperidin-2,6-dione

[0578] first step

[0579] 3-(2-chloro-3-(6-(pyridin-2-yloxy)-7,8-dihydronaphthalen-2-yl)phenyl)piperidine-2,6-dione

[0580] 3-(2-chloro-3-(6-(pyridin-2-yloxy)-7,8-dihydronaphth-2-yl)phenyl)piperidin-2,6-dione

[0581] 2-((6-chloro-3,4-dihydronaphthyl-2-yl)oxy)pyridine 19f (100.00 mg, 388.03 μmol) and 3-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxoborhexacyclopentan-2-yl)phenyl)piperidine-2,6-dione 18a (162.79 mg, 465.63 μmol) were dissolved in 1,4-dioxane (1 mL) and water (0.1 mL), and potassium carbonate (160.88 mg, 1.16 mmol) and methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tri-isopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (32.84 mg, 38.80 μmol) were added. The reaction mixture was heated to 90°C under nitrogen protection and the reaction continued for 1 hour. After the reaction was complete, the reaction mixture was cooled to room temperature. Quenching with water (5 mL), extraction with ethyl acetate (10 mL × 3), combining the organic phases, washing with saturated sodium chloride (15 mL), drying with anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure, and purifying the residue by preparative HPLC (Gilson GX-281 column: Sunfire C18, 19*250 mm, 10 μm; mobile phase A: 0.1% FA / H2O, mobile phase B: ACN; flow rate: 20 mL / min; gradient: 63-73%, retention time: 10.1-10.6 min, 18 min) to obtain 20 (21.30 mg) of 3-(2-chloro-3-(6-(pyridin-2-yloxy)-7,8-dihydronaphth-2-yl)phenyl)piperidin-2,6-dione, which was identified as the target compound by mass spectrometry, NMR, and 2D NMR, with a yield of 12.3%.

[0582] MS m / z (ESI): 445.2 [M+1]

[0583] 1 H NMR (400MHz, DMSO) δ10.92 (s, 1H), 8.25 (dd, J = 4.8, 1.6Hz, 1H), 7.91–7.82 ( m,1H),7.41–7.29(m,3H),7.20–7.14(m,3H),7.13–7.05(m,2H),6.19(s,1H ),4.34(dd,J=12.0,5.2Hz,1H),3.02(t,J=8.0Hz,2H),2.84–2.74(m,1H),2 .58–2.54(m,2H),2.53–2.50(m,1H),2.40–2.26(m,1H),2.10–2.00(m,1H).

[0584] Example 21

[0585] 3-(2-chloro-3-(6-hydroxy-7,7-dimethyl-8-oxo-5-(2-oxopyridin-1(2H)-yl)-5,6,7,8-tetrahydronaphthalen-2-yl)phenyl)piperidine-2,6-dione

[0586] 3-(2-chloro-3-(6-hydroxy-7,7-dimethyl-8-oxo-5-(2-oxopyridin-1(2H)-yl)-5,6,7,8-tetrahydronaphth-2-yl)phenyl)piperidin-2,6-dione

[0587] first step

[0588] 3-(2-chloro-3-(6-hydroxy-7,7-dimethyl-8-oxo-5-(2-oxopyridin-1(2H)-yl)-5,6,7,8-tetrahydronaphthalen-2-yl)phenyl)piperidine-2,6-dione

[0589] 3-(2-chloro-3-(6-hydroxy-7,7-dimethyl-8-oxo-5-(2-oxopyridin-1(2H)-yl)-5,6,7,8-tetrahydronaphth-2-yl)phenyl)piperidin-2,6-dione

[0590] 1-(6-bromo-2-hydroxy-3,3-dimethyl-4-oxo-1,2,3,4-tetrahydronaphth-1-yl)pyridin-2(1H)-one 21a (20 mg, 55.22 μmol), prepared according to the known method “Patent US5208246”) and 3-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxoborhexacyclopentan-2-yl)phenyl)piperidine-2 6-Diketone 18a (21.23 mg, 60.74 μmol) was added to 1,4-dioxane (3 mL) and water (0.3 mL), followed by the addition of potassium carbonate (22.89 mg, 165.65 μmol) and [1,1'-bis(diphenylphosphine)ferrocene]dichloropalladium (3.61 mg, 5.52 μmol). The reaction mixture was heated to 90 °C and reacted for 1 hour under argon protection. After the reaction was complete, the reaction mixture was cooled to room temperature, quenched with water (5 mL), extracted with ethyl acetate (10 mL × 3), the organic phases were combined, washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The filtrate was then purified by preparative HPLC (Waters 3767 / QDA Column: Boston green ODS, 30*150 mm, 5 μm; mobile phase A: 0.05% TFA / H2O, mobile phase B: ACN; flow rate: 30 mL / min; gradient: 32-42%, retention time: 8.5 min, 17 min) to obtain 21 (6.02 mg) of 3-(2-chloro-3-(6-hydroxy-7,7-dimethyl-8-oxo-5-(2-oxopyridin-1(2H)-yl)-5,6,7,8-tetrahydronaphth-2-yl)phenyl)piperidin-2,6-dione, with a yield of 21.6%.

[0591] MS m / z(ESI): 505.0 [M+1]

[0592] 1 H NMR(400MHz,DMSO-d6)δ10.92(s,1H),7.98–7.88(m,1H),7.70–7.64(m,1H),7.64–7.5 0(m,1H),7.50–7.44(m,1H),7.43–7.36(m,2H),7.35–7.28(m,1H),6.99–6.79(m,1H), 6.58–6.42(m,1H),6.37–6.26(m,1H),5.75–5.24(m,1H),4.76–4.26(m,2H),2.80–2.7 5(m,1H),2.57–2.55(m,1H),2.37–2.32(m,1H),2.15–1.91(m,1H),1.30–1.10(m,6H).

[0593] Example 22

[0594] 3-(2-chloro-3-(7,7-dimethyl-8-oxo-5-(2-oxopyridin-1(2H)-yl)-7,8-dihydronaphthalen-2-yl)phenyl)piperidine-2,6-dione

[0595] 3-(2-chloro-3-(7,7-dimethyl-8-oxo-5-(2-oxopyridin-1(2H)-yl)-7,8-dihydronaphth-2-yl)phenyl)piperidin-2,6-dione

[0596] first step

[0597] 1-(6-bromo-3,3-dimethyl-4-oxo-3,4-dihydronaphthalen-1-yl)pyridin-2(1H)-one

[0598] 1-(6-bromo-3,3-dimethyl-4-oxo-3,4-dihydronaphth-1-yl)pyridin-2(1H)-one

[0599] 1-(6-bromo-2-hydroxy-3,3-dimethyl-4-oxo-1,2,3,4-tetrahydronaphth-1-yl)pyridin-2(1H)-one 21a (90 mg, 248.47 μmol), sodium hydroxide (99 mg, 2.48 mmol), and silica gel (200 mg) were added to a 5 mL solution of 1,4-dioxane. The reaction mixture was then stirred under reflux for 30 min. After the reaction was complete, the mixture was concentrated under reduced pressure and purified by silica gel column chromatography (system A) to give 1-(6-bromo-3,3-dimethyl-4-oxo-3,4-dihydronaphth-1-yl)pyridin-2(1H)-one 22a (35 mg), yield: 40.9%.

[0600] MS m / z (ESI): 344.0 [M+1]

[0601] Step 2

[0602] 3-(2-chloro-3-(7,7-dimethyl-8-oxo-5-(2-oxopyridin-1(2H)-yl)-7,8-dihydronaphthalen-2-yl)phenyl)piperidine-2,6-dione

[0603] 3-(2-chloro-3-(7,7-dimethyl-8-oxo-5-(2-oxopyridin-1(2H)-yl)-7,8-dihydronaphth-2-yl)phenyl)piperidin-2,6-dione

[0604] 1-(6-bromo-3,3-dimethyl-4-oxo-3,4-dihydronaphth-1-yl)pyridin-2(1H)-one 22a (25 mg, 72.63 μmol) and 3-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxoborhexacyclopentan-2-yl)phenyl)piperidin-2,6-dione 18a (28 mg, 79.89 μmol) were added to 1,4-dioxane (3 mL) and water (0.3 mL). Then, potassium carbonate (30 mg, 217.90 μmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (5 mg, 7.26 μmol) were added to the system. The reaction mixture was heated to 90 °C under argon protection and the reaction was continued for 1 hour. After the reaction was complete, the reaction mixture was cooled to room temperature, quenched with water (5 mL), extracted with ethyl acetate (10 mL × 3), the organic phases were combined, washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (Waters 3767 / Qda column: SunFire Sunfire C18, 21.2*250 mm, 10 μm; mobile phase A: 0.1% FA / H2O, mobile phase B: ACN; flow rate: 20 mL / min; gradient: 42-52%, retention time: 8.6 min, 16 min) to give 22 (4.60 mg) of 3-(2-chloro-3-(7,7-dimethyl-8-oxo-5-(2-oxopyridin-1(2H)-yl)-7,8-dihydronaphth-2-yl)phenyl)piperidin-2,6-dione, yield 13.0%.

[0605] MS m / z(ESI): 487.0 [M+1]

[0606] 1H NMR (400MHz, DMSO-d6) δ10.93 (s, 1H), 8.00 (s, 1H), 7.73 (dd, J = 14.4, 7.6Hz, 2H), 7. 66–7.58(m,1H),7.47–7.39(m,2H),7.38–7.32(m,1H),6.88(d,J=8.0Hz,1H),6.54(d ,J=9.2Hz,1H),6.47(s,1H),6.40(t,J=6.4Hz,1H),4.47–4.28(m,1H),2.83–2.75(m, 1H),2.60–2.55(m,1H),2.40–2.30(m,1H),2.12–1.99(m,1H),1.35(d,J=5.6Hz,6H).

[0607] Example 23

[0608] 3-(2-chloro-3-(5-(2-oxopyridin-1(2H)-yl)-5,6,7,8-tetrahydronaphthalen-2-yl)phenyl)piperidine-2,6-dione

[0609] 3-(2-chloro-3-(5-(2-oxopyridin-1(2H)-yl)-5,6,7,8-tetrahydronaphth-2-yl)phenyl)piperidin-2,6-dione

[0610] first step

[0611] 6-bromo-1-chloro-1,2,3,4-tetrahydronaphthalene

[0612] 6-Bromo-1-chloro-1,2,3,4-tetrahydronaphthalene

[0613] To a solution of 6-bromo-1,2,3,4-tetrahydronaphthyl-1-ol 23a (200 mg, 0.88 mmol, prepared according to published patent "WO2020205455") in dichloromethane (3 mL), thionyl chloride (209.55 mg, 1.76 mmol) was added, and the mixture was stirred at room temperature for 5 hours. After the reaction was complete, the solution was directly concentrated to give 6-bromo-1-chloro-1,2,3,4-tetrahydronaphthyl 23b (185 mg) in 85.6% yield, which was used directly in the next reaction without purification.

[0614] Step 2

[0615] 1-(6-bromo-1,2,3,4-tetrahydronaphthalen-1-yl)pyridin-2(1H)-one

[0616] 1-(6-bromo-1,2,3,4-tetrahydronaphth-1-yl)pyridin-2(1H)-one

[0617] Sodium hydride (33.15 mg, 0.83 mmol, 60% purity) was added to a solution of pyridin-2(1H)-one (71.65 mg, 0.75 mmol) in N,N-dimethylformamide (3 mL) at 0 °C. The mixture was stirred at room temperature for 1 hour. Subsequently, 6-bromo-1-chloro-1,2,3,4-tetrahydronaphthalene 23b (185 mg, 0.75 mmol) and sodium iodide (11.29 mg, 75.34 μmol) were added. The mixture was stirred at 80 °C for 2 hours. After the reaction was complete, 30 mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by reversed-phase column chromatography (0.1% formic acid system) to give 23c (30 mg) of 1-(6-bromo-1,2,3,4-tetrahydronaphthyl-1-yl)pyridin-2(1H)-one, yield: 13.1%.

[0618] MS m / z(ESI): 304.1 [M+1]

[0619] Step 3

[0620] 3-(2-chloro-3-(5-(2-oxopyridin-1(2H)-yl)-5,6,7,8-tetrahydronaphthalen-2-yl)phenyl)piperidine-2,6-dione

[0621] 3-(2-chloro-3-(5-(2-oxopyridin-1(2H)-yl)-5,6,7,8-tetrahydronaphth-2-yl)phenyl)piperidin-2,6-dione

[0622] To a mixture of 1-(6-bromo-1,2,3,4-tetrahydronaphthyl-1-yl)pyridin-2(1H)-one 23c (20 mg, 65.75 μmol) of dioxane (1.5 mL) and water (0.15 mL), 3-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxoborhexacyclopentan-2-yl)phenyl)piperidin-2,6-dione 18a (22.99 mg, 65.75 μmol), potassium carbonate (28.17 mg, 203.83 μmol), and [1,1'-bis(di-tert-butylphosphine)ferrocene]palladium dichloride (4.30 mg, 6.58 μmol) were added. The reaction mixture was further reacted at 90 °C under argon protection for 2 hours. After the reaction was completed, the reaction solution was directly concentrated and subjected to preparative HPLC (Waters 3767 / QDA column: Boston green ODS, 30*150mm, 5μm; mobile phase A: 0.1% FA / H2O, mobile phase B: ACN; flow rate: 30mL / min; gradient: 41%-51%, retention time: 8.5min, 17min) to obtain 23 (8.91mg) of 3-(2-chloro-3-(5-(2-oxopyridin-1(2H)-yl)-5,6,7,8-tetrahydronaphthyl-2-yl)phenyl)piperidin-2,6-dione, with a yield of 30.3%.

[0623] MS m / z (ESI): 447.3 [M+1]

[0624] 1 H NMR(400MHz,DMSO)δ10.91(s,1H),7.45–7.32(m,4H),7.30-7.28(m,1H),7. 23(s,1H),7.20-7.15(m,1H),6.76(d,J=8.0Hz,1H),6.48(d,J=8.0Hz,1H),6 .24-6.21(m,1H),6.16-6.13(m,1H),4.35-4.31(m,1H),3.04–2.91(m,1H), 2.90–2.73(m,2H),2.58–2.52(m,1H),2.38–2.26(m,1H),2.14–1.80(m,5H).

[0625] Example 24

[0626] 3-(2-chloro-3-(5-(2-oxopyridin-1(2H)-yl)-7,8-dihydronaphthalen-2-yl)phenyl)piperidine-2,6-dione

[0627] 3-(2-chloro-3-(5-(2-oxopyridin-1(2H)-yl)-7,8-dihydronaphth-2-yl)phenyl)piperidin-2,6-dione

[0628] first step

[0629] 1-(6-bromo-2-hydroxy-1,2,3,4-tetrahydronaphthalen-1-yl)pyridin-2(1H)-one

[0630] 1-(6-bromo-2-hydroxy-1,2,3,4-tetrahydronaphth-1-yl)pyridin-2(1H)-one

[0631] To a 30 mL ethanol solution of 5-bromo-1a,2,3,7b-tetrahydronaphtho[1,2-b]ethylene oxide 24a (2.78 g, 0.012 mol, prepared according to the published patent “CN104591988”), pyridine (1.17 g, 0.015 mol) and 1H-pyridin-2-one (1.76 g, 0.018 mol) were added. The reaction mixture was stirred at 80 °C under nitrogen protection for 48 hours. After the reaction was completed, the mixture was concentrated under reduced pressure and purified by reversed-phase column chromatography (0.1% HCOOH system) to give 1-(6-bromo-2-hydroxy-1,2,3,4-tetrahydronaphtho-1-yl)pyridin-2(1H)-one 24b (1.48 g), with a yield of 37.4%.

[0632] MS m / z(ESI): 320.1 [M+1]

[0633] Step 2

[0634] 1-(6-bromo-3,4-dihydronaphthalen-1-yl)pyridin-2(1H)-one

[0635] 1-(6-bromo-3,4-dihydronaphth-1-yl)pyridin-2(1H)-one

[0636] 1-(6-bromo-2-hydroxy-1,2,3,4-tetrahydronaphthyl-1-yl)pyridin-2(1H)-one 24b (700 mg, 2.19 mmol) was added to a toluene (20 mL) solution, followed by the addition of p-toluenesulfonic acid (752.96 mg, 4.37 mmol). The reaction mixture was stirred at 110 °C under nitrogen protection for 12 hours. After the reaction was complete, the reaction mixture was directly concentrated and purified by reversed-phase column chromatography (system D) to give 1-(6-bromo-3,4-dihydronaphthyl-1-yl)pyridin-2(1H)-one 24c (480 mg), yield 72.7%.

[0637] MS m / z(ESI): 302.1 [M+1]

[0638] Step 3

[0639] 3-(2-chloro-3-(5-(2-oxopyridin-1(2H)-yl)-7,8-dihydronaphthalen-2-yl)phenyl)piperidine-2,6-dione

[0640] 3-(2-chloro-3-(5-(2-oxopyridin-1(2H)-yl)-7,8-dihydronaphth-2-yl)phenyl)piperidin-2,6-dione

[0641] 1-(6-bromo-3,4-dihydronaphthyl-1-yl)pyridin-2(1H)-one 24c (240 mg, 794.27 μmol) and 3-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxoborhexacyclopentan-2-yl)phenyl)piperidin-2,6-dione 18a (277.69 mg, 794.27 μmol) were added to 1,4-dioxane (10 mL) and water (1 mL). Then, potassium carbonate (340.29 mg, 2.46 mmol) and [1,1'-bis(di-tert-butylphosphine)ferrocene]palladium dichloride (51.77 mg, 79.43 μmol) were added to the system. The reaction mixture was continued to react for 2 hours under argon protection at 90 °C. After the reaction was completed, the reaction mixture was directly concentrated under reduced pressure and subjected to preparative HPLC (Waters 3767 / QDA column: Boston green ODS, 30*150mm, 5μm; mobile phase A: 0.1% FA / H2O, mobile phase B: ACN; flow rate: 30mL / min; gradient: 38%-48%, retention time: 8.6min, 17min) to give 3-(2-chloro-3-(5-(2-oxopyridin-1(2H)-yl)-7,8-dihydronaphth-2-yl)phenyl)piperidin-2,6-dione 24 (105.51mg), yield 29.9%.

[0642] MS m / z (ESI): 445.2 [M+1]

[0643] 1H NMR (400MHz, DMSO) δ10.91(s,1H),7.60-7.54(m,2H),7.41–7.33(m,2H),7.30-7.28(m ,2H),7.20–7.15(m,1H),6.58(d,J=8.0Hz,1H),6.47(d,J=12Hz,1H),6.35-6.32(m,1H) ,6.20-6.17(m,1H),4.36-4.32(m,1H),2.97–2.89(m,2H),2.86–2.73(m,1H),2.59-2. 55(m,1H),2.53-2.50(m,1H),2.49–2.42(m,1H),2.38-2.31(m,1H),2.08–2.00(m,1H).

[0644] Example 25

[0645] 3-(2-chloro-3-(6-oxo-5-(2-oxopyridin-1(2H)-yl)-5,6,7,8-tetrahydronaphthalen-2-yl)phenyl)piperidine-2,6-dione

[0646] 3-(2-chloro-3-(6-oxo-5-(2-oxopyridin-1(2H)-yl)-5,6,7,8-tetrahydronaphth-2-yl)phenyl)piperidin-2,6-dione

[0647] first step

[0648] 3-(2-chloro-3-(6-oxo-5-(2-oxopyridin-1(2H)-yl)-5,6,7,8-tetrahydronaphthalen-2-yl)phenyl)piperidine-2,6-dione

[0649] 3-(2-chloro-3-(6-oxo-5-(2-oxopyridin-1(2H)-yl)-5,6,7,8-tetrahydronaphth-2-yl)phenyl)piperidin-2,6-dione

[0650] Under nitrogen protection at 0 °C, sodium bicarbonate (33 mg, 393.34 μmol) and potassium peroxide monosulfonate (97 mg, 157.34 μmol) were added to a solution of 3-(2-chloro-3-(5-(2-oxopyridin-1(2H)-yl)-7,8-dihydronaphth-2-yl)phenyl)piperidin-2,6-dione 24 (35 mg, 78.67 μmol) in acetone (1 mL) and water (1 mL). The reaction mixture was then stirred at room temperature under nitrogen protection for 2 hours. The reaction was monitored by LCMS. After the reaction was complete, the reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The filtrate was then purified by preparative HPLC (Waters 3767 / QDA column: Boston green ODS, 30*150mm, 5μm; mobile phase A: 0.1% FA / H2O, mobile phase B: ACN; flow rate: 30ml / min; gradient: 52-62%, retention times: 9.2min, 17min) to obtain 25 (3.82mg) of 3-(2-chloro-3-(6-oxo-5-(2-oxopyridin-1(2H)-yl)-5,6,7,8-tetrahydronaphthyl-2-yl)phenyl)piperidin-2,6-dione, yield 10.5%).

[0651] MS m / z(ESI): 461.2 [M+1]

[0652] 1 H NMR (400MHz, DMSO) δ10.93(s,1H),8.11(dd,J=4.8,1.6Hz,1H),7.92(d,J=8.0Hz,1H),7.80– 7.73(m,1H),7.48–7.39(m,4H),7.36(dd,J=6.4,2.4Hz,1H),7.03–6.98(m,1H),6.93(d,J=8 .4Hz,1H),6.07(dd,J=13.2,5.2Hz,1H),4.36(dd,J=12.4,5.2Hz,1H),3.42–3.35(m,1H),3. 20–3.12(m,1H),2.89–2.74(m,1H),2.59–2.52(m,1H),2.47–2.27(m,3H),2.09–2.02(m,1H).

[0653] Example 26

[0654] 3-(2-chloro-3-(6-hydroxy-5-(2-oxopyridin-1(2H)-yl)-5,6,7,8-tetrahydronaphthalen-2-yl)phenyl)piperidine-2,6-dione

[0655] 3-(2-chloro-3-(6-hydroxy-5-(2-oxopyridin-1(2H)-yl)-5,6,7,8-tetrahydronaphth-2-yl)phenyl)piperidin-2,6-dione

[0656] first step

[0657] 3-(2-chloro-3-(6-hydroxy-5-(2-oxopyridin-1(2H)-yl)-5,6,7,8-tetrahydronaphthalen-2-yl)phenyl)piperidine-2,6-dione

[0658] 3-(2-chloro-3-(6-hydroxy-5-(2-oxopyridin-1(2H)-yl)-5,6,7,8-tetrahydronaphth-2-yl)phenyl)piperidin-2,6-dione

[0659] 1-(6-bromo-2-hydroxy-1,2,3,4-tetrahydronaphth-1-yl)pyridin-2(1H)-one 24b (50 mg, 156.16 μmol) and 3-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxoborhexacyclopentan-2-yl)phenyl)piperidin-2,6-dione 18a (60.06 mg, 171.78 μmol) were added to 1,4-dioxane (2 mL) and water (0.2 mL). Then, potassium carbonate (66.91 mg, 484.10 μmol) and [1,1'-bis(di-tert-butylphosphine)ferrocene]palladium dichloride (10.18 mg, 15.62 μmol) were added to the system. The reaction mixture was continued to react for 2 hours under argon protection at 90 °C. After the reaction was completed, the reaction mixture was directly concentrated under reduced pressure and subjected to preparative HPLC (Waters 3767 / QDA column: Boston green ODS, 30*150mm, 5μm; mobile phase A: 0.1% FA / H2O, mobile phase B: ACN; flow rate: 30ml / min; gradient: 29%-39%; retention times: 8.8min, 17min) to obtain 26 (20.7mg) of 3-(2-chloro-3-(6-hydroxy-5-(2-oxopyridin-1(2H)-yl)-5,6,7,8-tetrahydronaphth-2-yl)phenyl)piperidin-2,6-dione, yield 28.6%.

[0660] MS m / z(ESI): 463.3 [M+1]

[0661] 1H NMR(400MHz,DMSO)δ10.91(s,1H),7.48(s,1H),7.45-7.40(m,1H),7.39–7.32(m,2H),7.28-7.26 (m,1H),7.20(s,1H),7.17-7.15(m,1H),6.68(d,J=8.0Hz,1H),6.46(d,J=8.0Hz,1H),6.24-6.21 (m,1H),6.01(brs,1H),5.20(d,J=8.0Hz,1H),4.35-4.31(m,1H),4.21(s,1H),3.04-2.91(m,2H) ,2.83–2.72(m,1H),2.56-2.54(m,1H),2.38–2.25(m,1H),2.11-2.01(m,2H),1.95-1.83(m,1H).

[0662] Example 27

[0663] 3-(2-chloro-3-(4-(2-oxopyridin-1(2H)-yl)-2H-thiochromen-7-yl)phenyl)piperidine-2,6-dione

[0664] 3-(2-chloro-3-(4-(2-oxopyridin-1(2H)-yl)-2H-thiochromen-7-yl)phenyl)piperidin-2,6-dione

[0665] first step

[0666] 3-((3-chlorophenyl)thio)propanoic acid

[0667] 3-((3-chlorophenyl)thio)propionic acid

[0668] 3-Chlorophenylthiophenol 27a (16 g, 110.63 mmol) was refluxed in sodium hydroxide solution (2 mol / L, 165.95 mL) for 2 hours. Then, 3-chloropropionic acid (13.21 g, 121.70 mmol) was added, and the resulting mixture was stirred at 60 °C for 16 hours. The reaction solution was cooled to zero °C and acidified to pH 2.0 with 2 mol / L hydrochloric acid solution, resulting in the precipitation of a large amount of solid. The solid was filtered, washed with water, and dried to obtain 3-((3-chlorophenyl)thio)propionic acid 27b (16 g), yield: 64.7%. The product was used directly in the next step without further purification.

[0669] 1H NMR (400MHz, DMSO) δ7.40–7.36(m,1H),7.35–7.32(m,1H),7.32–7.27(m,1H),7.27–7.23(m,1H),3.19(t,J=7.0Hz,2H),2.56(t,J=7.0Hz,2H).

[0670] Step 2

[0671] 7-chlorothiochroman-4-one

[0672] 7-Chlorothiochroman-4-one

[0673] 3-((3-chlorophenyl)thio)propionic acid 27b (16 g, 73.84 mmol) was added to a solution of concentrated sulfuric acid (100 mL) under ice bath conditions. The reaction mixture was stirred at 25 °C for 3 hours. After the reaction was complete, the reaction mixture was poured into ice water. A large amount of solid precipitated out, which was filtered and dried under reduced pressure to give 7-chlorothiochroman-4-one 27c (10 g); yield: 68.2%. MS m / z (ESI): 199.0 [M+1]

[0674] 1 H NMR (400MHz, DMSO-d6) δ7.94(d,J=8.5Hz,1H),7.52(d,J=2.0Hz,1H),7.28(dd,J=8.5,2.1Hz,1H),3.40–3.32(m,2H),2.93–2.86(m,2H)..

[0675] Step 3

[0676] 7-chloro-2H-thiochromen-4-yl trifluoromethanesulfonate

[0677] 7-Chloro-2H-thiochromene-4-yltrifluoromethanesulfonate

[0678] Under nitrogen protection at -78°C, a tetrahydrofuran solution (1M, 37.7mL) of sodium bis(trimethylsilyl)amino in 27c (5g, 25.17mmol) dissolved in tetrahydrofuran (120mL) was added. After stirring the mixture for 1 hour, 1,1,1-trifluoro-N-phenyl-N-(trifluoromethylsulfonyl)methanesulfonamide (9.9g, 27.7mmol) was added. After the addition was complete, the reaction mixture was brought to room temperature and stirred overnight. After the reaction was complete, the reaction solution was poured into ice water (80mL) and extracted with ethyl acetate (80mL × 3). The organic phases were combined, washed with saturated sodium chloride (50 mL), dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (system A) to give 27d (4 g) of 7-chloro-2H-thiochromen-4-yltrifluoromethanesulfonate, with a yield of 48.1%.

[0679] MS m / z (ESI): 331.0 [M+1]

[0680] 1 H NMR (400MHz, DMSO-d6) δ7.52(d,J=1.6Hz,1H),7.36–7.32(m,2H),6.36(t,J=5.6Hz,1H),3.78(d,J=5.6Hz,2H).

[0681] Step 4

[0682] 2-(7-chloro-2H-thiochromen-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

[0683] 2-(7-chloro-2H-thiochromene-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentane

[0684] Add 4,4,4',4',5,5'-hexamethyl-2,2'-bis(1,3,2-dioxaborane) (1.5 g, 6.1 mmol), potassium acetate (890 mg, 9.1 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (220 mg, 302 μmol) to a solution of 7-chloro-2H-thiochromen-4-yltrifluoromethanesulfonate 27d (1 g, 3.02 mmol) in 1,4-dioxane (25 mL), potassium acetate (890 mg, 9.1 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (220 mg, 302 μmol) to the solution of 7-chloro-2H-thiochromen-4-yltrifluoromethanesulfonate 27d (1 g, 3.02 mmol) in 1,4-dioxane (25 mL). The reaction mixture was stirred at 90°C for 12 hours under argon protection. After the reaction was completed, the reaction mixture was filtered, the filtrate was concentrated under reduced pressure, and purified by reversed-phase column chromatography (C18, 0.1% FA) to give 2-(7-chloro-2H-thiochromen-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentane 27e (450 mg), with a yield of 48.2%.

[0685] MS m / z (ESI): 309.0 [M+1]

[0686] 1 H NMR (400MHz, DMSO) δ7.63(d,J=8.4Hz,1H),7.34(d,J=2.2Hz,1H),7.21(dd,J=8.4,2.3Hz,1H),6.82(t,J=5.6Hz,1H),3.38(d,J=5.6Hz,2H),1.27(s,12H).

[0687] Step 5

[0688] (7-chloro-2H-thiochromen-4-yl)boronic acid

[0689] (7-chloro-2H-thiochromen-4-yl)boronic acid

[0690] 2-(7-chloro-2H-thiochromen-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentane 27e (500 mg, 1.62 mmol) was dissolved in methanol (5 mL), and a hydrochloric acid-dioxane solution (4 M, 10 mL) was added. The reaction mixture was stirred at 60 °C for 16 hours under nitrogen protection. The reaction mixture was directly concentrated under reduced pressure, and the product was purified by reversed-phase column chromatography (C18, 0.1% FA) to give (7-chloro-2H-thiochromen-4-yl)boronic acid 27f (100 mg), in 27.2% yield.

[0691] 1H NMR (400MHz, DMSO) δ8.06 (s, 2H), 7.51 (d, J = 8.4Hz, 1H), 7.31 (d, J = 2.3Hz, 1H), 7.17 (dd, J = 8.4, 2.3Hz, 1H), 6.55 (t, J = 5.4Hz, 1H), 3.33 (s, 2H).

[0692] Step 6

[0693] 1-(7-chloro-2H-thiochromen-4-yl)pyridin-2(1H)-one

[0694] 1-(7-chloro-2H-thiochromen-4-yl)pyridin-2(1H)-one

[0695] 2-((7-chloro-2H-thiochromen-4-yl)oxy)pyridine

[0696] 2-[(7-chloro-2H-thiochromen-4-yl)oxy]pyridine

[0697] Copper acetate (80.2 mg, 441.5 μmol) was added to a solution of (7-chloro-2H-thiochrome-4-yl)boronic acid 27f (200 mg, 883 μmol) and pyridin-2(1H)-one (100 mg, 1.0 mmol) in acetonitrile (30 mL) and tert-butanol (30 mL). Molecular sieves were then used. Type 1 (1.9 g, 4.4 mmol) and triethylamine (268 mg, 2.6 mmol). The reaction mixture was stirred at 80 °C under an oxygen (50 psi) atmosphere for 48 hours. The reaction mixture was directly concentrated under reduced pressure, then diluted with ethyl acetate (50 mL), washed with saturated ammonium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by reversed-phase column chromatography (C18, 0.1% FA) to give 27 g (17 mg) of 1-(7-chloro-2H-thiochromen-4-yl)pyridin-2(1H)-one, yield: 7.0%; and 27 h (80 mg) of 2-[(7-chloro-2H-thiochromen-4-yl)oxy]pyridine, yield: 32.8%.

[0698] 27g LCMS:MS m / z(ESI): 276.0[M+1]

[0699] 27-hour MRI: 1H NMR(400MHz, DMSO)δ8.14(dd,J=4.8,1.6Hz,1H),7.86–7.79(m,1H),7.39(d,J=1.2Hz,1H ),7.12–7.06(m,3H),7.03(d,J=8.4Hz,1H),5.78(t,J=5.6Hz,1H),3.70(d,J=5.6Hz,2H).

[0700] Step 7

[0701] 3-(2-chloro-3-(4-(2-oxopyridin-1(2H)-yl)-2H-thiochromen-7-yl)phenyl)piperidine-2,6-dion

[0702] e

[0703] 3-(2-chloro-3-(4-(2-oxopyridin-1(2H)-yl)-2H-thiochromen-7-yl)phenyl)piperidin-2,6-dione

[0704] 27 g (17 mg, 61.6 μmol) of 1-(7-chloro-2H-thiochromen-4-yl)pyridin-2(1H)-one and 3-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxoborhexacyclopentan-2-yl)phenyl)piperidin-2,6-dione 18a (32.3 mg, 92.4 μmol) were added to 1,4-dioxane (2 mL) and water (0.2 mL). Then, potassium carbonate (25.5 mg, 185 μmol) and methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (XPhos Pd G3, 5.2 mg, 6.1 μmol) were added to the system. Under argon protection, the reaction mixture was heated to 80°C and reacted for 1 hour. After the reaction was complete, the reaction mixture was cooled to room temperature, quenched with water (5 mL), extracted with ethyl acetate (10 mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The filtrate was purified by preparative HPLC (Waters 3767 / Qda column: Boston green ODS, 30*150 mm, 5 μm; mobile phase A: 0.1% FA / H2O, mobile phase B: ACN; flow rate: 30 mL / min; gradient: 37-47%, retention time: 9 min, 17 min) to obtain 27 (4.53 mg) of 3-(2-chloro-3-(4-(2-oxopyridin-1(2H)-yl)-2H-thiochromen-7-yl)phenyl)piperidin-2,6-dione. The compound was identified as the target compound by mass spectrometry, NMR, and 2D NMR, with a yield of 15.8%.

[0705] MS m / z(ESI): 462.9 [M+1]

[0706] 1 H NMR (400MHz, DMSO) δ10.92(s,1H),7.61–7.53(m,2H),7.43–7.35(m,2H),7.34–7.27(m ,2H),7.13(d,J=8.0Hz,1H),6.65(d,J=8.0Hz,1H),6.47(d,J=9.2Hz,1H),6.35(t,J=6. 8Hz,1H),6.26–6.16(m,1H),4.34(dd,J=12.2,4.8Hz,1H),3.86–3.77(m,1H),3.72–3. 64(m,1H),2.84–2.73(m,1H),2.59–2.54(m,1H),2.41–2.26(m,1H),2.08–1.98(m,1H).

[0707] Example 28

[0708] 3-(2-chloro-3-(4-(pyridin-2-yloxy)-2H-thiochromen-7-yl)phenyl)piperidine-2,6-dione

[0709] 3-[2-chloro-3-[4-(pyridin-2-yloxy)-2H-thiochromen-7-yl]phenyl]piperidin-2,6-dione

[0710] first step

[0711] 3-(2-chloro-3-(4-(pyridin-2-yloxy)-2H-thiochromen-7-yl)phenyl)piperidine-2,6-dione

[0712] 3-[2-chloro-3-[4-(pyridin-2-yloxy)-2H-thiochromen-7-yl]phenyl]piperidin-2,6-dione

[0713] 2-[(7-chloro-2H-thiochrome-4-yl)oxy]pyridine 27h (20 mg, 72.5 μmol) and 3-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxoborhexacyclopentan-2-yl)phenyl)piperidine-2,6-dione 18a (38 mg, 108.7 μmol) were added to 1,4-dioxane (3 mL) and water (0.3 mL). Then, potassium carbonate (30 mg, 217.6 μmol) and XPhos Pd G3 (6.1 mg, 7.3 μmol) were added to the system. The reaction mixture was heated to 80 °C and reacted for 1 hour under argon protection. After the reaction was completed, the reaction mixture was cooled to room temperature, quenched with water (5 mL), extracted with ethyl acetate (10 mL × 3), the organic phases were combined, washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The filtrate was then purified by preparative HPLC (Waters 3767 / QDA Column: Boston green ODS, 30*150 mm, 5 μm; mobile phase A: 0.05% TFA / H2O, mobile phase B: ACN; flow rate: 30 mL / min; gradient: 52-62%, retention times: 9.7 min, 17 min) to obtain 3-[2-chloro-3-[4-(pyridin-2-yloxy)-2H-thiochromen-7-yl]phenyl]piperidin-2,6-dione 28 (3.56 mg), which was identified as the target compound by mass spectrometry, nuclear magnetic resonance (NMR), and two-dimensional NMR, with a yield of 16.6%.

[0714] MS m / z(ESI): 463.0 [M+1]

[0715] 1 H NMR (400MHz, DMSO) δ10.92 (s, 1H), 8.17 (dd, J = 4.8, 1.6Hz, 1H), 7.88–7.77 (m, 1H),7.41–7.34(m,2H),7.32–7.27(m,2H),7.21(d,J=8.1Hz,1H),7.13–7.05(m ,3H),5.80(t,J=5.6Hz,1H),4.33(dd,J=12.4,5.2Hz,1H),3.73(d,J=5.6Hz,2H ),2.85–2.71(m,1H),2.59–2.52(m,1H),2.39–2.25(m,1H),2.08–1.98(m,1H).

[0716] Example 29

[0717] 3-(2-chloro-3-(7,7-dimethyl-5-(2-oxopyridin-1(2H)-yl)-7,8-dihydronaphthalen-2-yl)phenyl)piperidine-2,6-dione

[0718] 3-(2-chloro-3-(7,7-dimethyl-5-(2-oxopyridin-1(2H)-yl)-7,8-dihydronaphth-2-yl)phenyl)piperidin-2,6-dione

[0719] first step

[0720] 6-bromo-3,3-dimethyl-1,2,3,4-tetrahydronaphthalen-1-ol

[0721] 6-Bromo-3,3-dimethyl-1,2,3,4-tetrahydronaphth-1-ol

[0722] Sodium borohydride (896.73 mg, 23.70 mmol) was added to an ethanol (20 mL) solution of 6-bromo-3,3-dimethyl-3,4-dihydronaphth-1(2H)-one 29a (1.2 g, 4.74 mmol, prepared according to published patent "WO2022188735"). The mixture was stirred at room temperature for 2 hours. After the reaction was complete, 50 mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (system A) to give 6-bromo-3,3-dimethyl-1,2,3,4-tetrahydronaphth-1-ol 29b (1.1 g), yield 90.9%.

[0723] 1 H NMR (400MHz, DMSO) δ7.44(d,J=8.0Hz,1H),7.34(d,J=8.0Hz,1H),7.24(s,1H),5.25(d,J=4.0Hz,1H),4.62–4.50(m, 1H),2.57(d,J=16.0Hz,1H),2.43(d,J=16.0Hz,1H),1.84-1.79(m,1H),1.46-1.40(m,1H),1.01(s,3H),0.87(s,3H).

[0724] Step 2

[0725] 7-bromo-2,2-dimethyl-1,2-dihydronaphthalene

[0726] 7-Bromo-2,2-dimethyl-1,2-dihydronaphthalene

[0727] To a solution of 6-bromo-3,3-dimethyl-1,2,3,4-tetrahydronaphthalene-1-ol 29b (800 mg, 3.14 mmol) in toluene (15 mL), p-toluenesulfonic acid (53.99 mg, 313.54 μmol) was added. The reaction mixture was stirred at 110 °C for 3 hours. After the reaction was complete, the mixture was directly concentrated and purified by column chromatography (system A) to give 7-bromo-2,2-dimethyl-1,2-dihydronaphthalene 29c (702 mg), yield: 94.4%.

[0728] 1 H NMR (400MHz, DMSO) δ7.34-7.32(m,2H),7.10–7.00(m,1H),6.35(d,J=8.0Hz,1H),5.82(d,J=8.0Hz,1H),2.64(s,2H),0.99(s,6H).

[0729] Step 3

[0730] 5-bromo-2,2-dimethyl-1a,2,3,7b-tetrahydronaphtho[1,2-b]oxirene

[0731] 5-Bromo-2,2-dimethyl-1a,2,3,7b-tetrahydronaphtho[1,2-b]oxetane

[0732] 7-Bromo-2,2-dimethyl-1,2-dihydronaphthalene 29c (702 mg, 2.96 mmol) was dissolved in acetone (10 mL) and water (10 mL). Sodium bicarbonate (1.24 g, 14.80 mmol) and potassium peroxymonosulfonate (2.73 g, 4.44 mmol) were added, and the mixture was stirred at room temperature for 12 hours. After the reaction was complete, 30 mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (system A) to give 5-bromo-2,2-dimethyl-1a,2,3,7b-tetrahydronaphtho[1,2-b]oxetane 29d (652 mg), yield: 87.0%.

[0733] 1H NMR (400MHz, DMSO) δ7.47-7.40 (m, 2H), 7.33 (s, 1H), 3.95 (d, J = 4.0Hz, 1H), 3 .34-3.29(m,1H),2.47(s,1H),2.31-2.27(m,1H),1.21(s,3H),0.74(s,3H).

[0734] Step 4

[0735] 1-(6-bromo-2-hydroxy-3,3-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)pyridin-2(1H)-one

[0736] 1-(6-bromo-2-hydroxy-3,3-dimethyl-1,2,3,4-tetrahydronaphth-1-yl)pyridin-2(1H)-one

[0737] 5-Bromo-2,2-dimethyl-1a,2,3,7b-tetrahydronaphtho[1,2-b]oxepane 29d (400 mg, 1.58 mmol) was dissolved in ethanol (10 mL), and pyridine-2(1H)-one (225.41 mg, 2.37 mmol) and pyridine (149.99 mg, 1.90 mmol) were added. The mixture was stirred at 80 °C for 48 hours. After the reaction was complete, the reaction mixture was directly concentrated and separated by reversed-phase column chromatography (0.1% ammonium bicarbonate system) to give 1-(6-bromo-2-hydroxy-3,3-dimethyl-1,2,3,4-tetrahydronaphtho-1-yl)pyridine-2(1H)-one 29e (70 mg), yield: 12.7%.

[0738] MS m / z(ESI): 347.9 [M+1]

[0739] Step 5

[0740] 1-(6-bromo-3,3-dimethyl-3,4-dihydronaphthalen-1-yl)pyridin-2(1H)-one

[0741] 1-(6-bromo-3,3-dimethyl-3,4-dihydronaphth-1-yl)pyridin-2(1H)-one

[0742] 1-(6-bromo-2-hydroxy-3,3-dimethyl-1,2,3,4-tetrahydronaphthyl-1-yl)pyridin-2(1H)-one 29e (50 mg, 143.58 μmol) was dissolved in dioxane (4 mL) solution, and sodium hydroxide (57.43 mg, 1.44 mmol) was added. The mixture was stirred at 100 °C for 2 hours. After the reaction was complete, the reaction mixture was directly concentrated under reduced pressure and separated by reversed-phase column chromatography (0.1% trifluoroacetic acid system) to give 1-(6-bromo-3,3-dimethyl-3,4-dihydronaphthyl-1-yl)pyridin-2(1H)-one 29f (23 mg), yield: 48.5%. MS m / z (ESI): 329.8 [M+1]

[0743] Step 6

[0744] 3-(2-chloro-3-(7,7-dimethyl-5-(2-oxopyridin-1(2H)-yl)-7,8-dihydronaphthalen-2-yl)phenyl)piperidine-2,6-dione

[0745] 3-(2-chloro-3-(7,7-dimethyl-5-(2-oxopyridin-1(2H)-yl)-7,8-dihydronaphth-2-yl)phenyl)piperidin-2,6-dione was dissolved in a solution of 1-(6-bromo-3,3-dimethyl-3,4-dihydronaphth-1-yl)pyridin-2(1H)-one 29f (35 mg, 105.99 μmol) in dioxane (1.5 mL) and water (0.15 mL). To the mixture, 3-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)phenyl)piperidine-2,6-dione 18a (40.76 mg, 116.59 μmol), potassium carbonate (45.41 mg, 328.57 μmol), and [1,1'-bis(di-tert-butylphosphine)ferrocene]palladium dichloride (6.91 mg, 10.60 μmol) were added. The reaction mixture was stirred at 90 °C for 2 hours. After the reaction was completed, the reaction mixture was directly concentrated under reduced pressure and subjected to preparative HPLC (Waters 2767 column: Waters Sunfire C18, 19*150mm, 5μm; mobile phase A: 0.1% FA / H2O, mobile phase B: ACN; flow rate: 20mL / min; gradient: 50%-53%, retention time: 7.73-8.3min, 18min) to obtain 29 (20.7mg) of 3-(2-chloro-3-(7,7-dimethyl-5-(2-oxopyridin-1(2H)-yl)-7,8-dihydronaphth-2-yl)phenyl)piperidin-2,6-dione. The compound was identified as the target compound by mass spectrometry, NMR, and 2D NMR, with a yield of 41.3%.

[0746] MS m / z(ESI): 473.2 [M+1]

[0747] 1 H NMR(400MHz,DMSO)δ10.91(s,1H),7.58-7.53(m,2H),7.42–7.33(m,2H),7.32 –7.24(m,2H),7.19(d,J=8.0Hz,1H),6.60(d,J=8.0Hz,1H),6.47(d,J=8.0Hz,1 H),6.35–6.31(m,1H),5.94(s,1H),4.36–4.32(m,1H),2.92–2.74(m,3H),2.56 –2.55(m,1H),2.35–2.31(m,1H),2.06–2.03(m,1H),1.19(s,3H),1.08(s,3H).

[0748] Example 30

[0749] 3-(2-chloro-3-(6-fluoro-5-(2-oxopyridin-1(2H)-yl)-5,6,7,8-tetrahydronaphthalen-2-yl)phenyl)piperidine-2,6-dione

[0750] 3-(2-chloro-3-(6-fluoro-5-(2-oxopyridin-1(2H)-yl)-5,6,7,8-tetrahydronaphth-2-yl)phenyl)piperidin-2,6-dione

[0751] first step

[0752] 6-chloro-2-fluoro-3,4-dihydronaphthalen-1(2H)-one

[0753] 6-Chloro-2-fluoro-3,4-dihydronaphthyl-1(2H)-one

[0754] 6-Chloro-3,4-dihydronaphthyl-1(2H)-one 30a (4.5 g, 24.91 mmol, commercially available) and 1-chloromethyl-4-fluoro-1,4-diazabicyclo[2.2.2]octane di(tetrafluoroborate) salt (10.6 g, 29.90 mmol, commercially available) were dissolved in methanol (50 mL), and concentrated H2SO4 (244 mg, 2.49 mmol) was added to the solution at room temperature. The reaction mixture was then reacted at 50 °C under nitrogen protection for 16 hours. After the reaction was complete, the mixture was quenched with water (100 mL), extracted with ethyl acetate (3 × 50 mL), the organic phases were combined, washed with saturated sodium chloride (2 × 80 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (system A) to give 6-chloro-2-fluoro-3,4-dihydronaphthyl-1(2H)-one 30b (3.7 g), yield 74.8%.

[0755] MS m / z (ESI): 199.2 [M+1]

[0756] Step 2

[0757] 6-chloro-2-fluoro-1,2,3,4-tetrahydronaphthalen-1-ol

[0758] 6-Chloro-2-fluoro-1,2,3,4-tetrahydronaphth-1-ol

[0759] 3.7 g (15.22 mmol) of 6-chloro-2-fluoro-3,4-dihydronaphthyl-1(2H)-one 30b was dissolved in 40 mL of ethanol, and sodium borohydride (864 mg, 22.83 mmol) was added. The reaction mixture was then reacted at 0 °C under nitrogen protection for 0.5 h. The reaction was monitored by LCMS. After the reaction was complete, the mixture was quenched with 50 mL of water, extracted with ethyl acetate (3 × 50 mL), and the organic phases were combined. The mixture was washed with saturated sodium chloride (2 × 80 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (system A) to give 2.5 g (67.0%) of 6-chloro-2-fluoro-1,2,3,4-tetrahydronaphthyl-1-ol 30c.

[0760] 1 H NMR (400MHz, DMSO) δ7.46–7.39(m,1H),7.29–7.21(m,1H),7.19(s,1H),5.88–5.56( m,1H),5.00–4.74(m,1H),4.69–4.51(m,1H),2.93–2.68(m,2H),2.24–1.87(m,2H).

[0761] Step 3

[0762] 1-(6-chloro-2-fluoro-1,2,3,4-tetrahydronaphthalen-1-yl)pyridin-2(1H)-one

[0763] 1-(6-chloro-2-fluoro-1,2,3,4-tetrahydronaphth-1-yl)pyridin-2(1H)-one

[0764] 2-((6-chloro-2-fluoro-1,2,3,4-tetrahydronaphthalen-1-yl)oxy)pyridine

[0765] 2-((6-chloro-2-fluoro-1,2,3,4-tetrahydronaphth-1-yl)oxy)pyridine

[0766] 6-Chloro-2-fluoro-1,2,3,4-tetrahydronaphthyl-1-ol 30c (1 g, 4.98 mmol) and pyridin-2(1H)-one (616 mg, 6.48 mmol) were dissolved in tetrahydrofuran (1.82 mL). Diisopropyl azodicarbonate (1.51 g, 7.48 mmol, commercially available) and triphenylphosphine (1.96 g, 7.48 mmol) were added under nitrogen protection at 0 °C. The reaction mixture was then reacted at room temperature for 16 hours. The reaction was monitored by LCMS. After the reaction was complete, the mixture was quenched with water (10 mL), extracted with ethyl acetate (3 × 10 mL), the organic phases were combined, washed with saturated sodium chloride (2 × 10 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (system A) to give 30d (60 mg) of 1-(6-chloro-2-fluoro-1,2,3,4-tetrahydronaphthyl-1-yl)pyridin-2(1H)-one, yield 4.3%; and 30e (30 mg) of 2-((6-chloro-2-fluoro-1,2,3,4-tetrahydronaphthyl-1-yl)oxy)pyridine, which was identified as the target compound by mass spectrometry, nuclear magnetic resonance (NMR), and two-dimensional NMR, yield 2.2%.

[0767] 30e:

[0768] MS m / z (ESI): 278.1 [M+1]

[0769] 1H NMR(400MHz,DMSO-d6)δ8.30–8.20(m,1H),7.83–7.68(m,1H),7.40–7.36(m,1H),7.26(s,1H),7.24–7.18(m,1H),7.10–7.0 1(m,1H),6.88(d,J=8.4Hz,1H),6.51(dd,J=12.8,5.6Hz,1H),5.30–5.01(m,1H),2.91(t,J=6.4Hz,2H),2.28–2.06(m,2H).

[0770] 30d:

[0771] MS m / z (ESI): 278.1 [M+1]

[0772] Step 4

[0773] 3-(2-chloro-3-(6-fluoro-5-(2-oxopyridin-1(2H)-yl)-5,6,7,8-tetrahydronaphthalen-2-yl)phenyl)piperidine-2,6-dione

[0774] 3-(2-chloro-3-(6-fluoro-5-(2-oxopyridin-1(2H)-yl)-5,6,7,8-tetrahydronaphth-2-yl)phenyl)piperidin-2,6-dione

[0775] 1-(6-chloro-2-fluoro-1,2,3,4-tetrahydronaphth-1-yl)pyridin-2(1H)-one 30d (60 mg, 216.04 μmol) and 3-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxoborhexacyclopentan-2-yl)phenyl)piperidin-2,6-dione 18a (113 mg, 324.07 μmol) were dissolved in a solution of 1,4-dioxane (1 mL) and water (0.2 mL), and potassium carbonate (89 mg, 648.13 μmol) and methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tris-isopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (18 mg, 21.60 μmol) were added. The reaction mixture was then reacted at 80°C under nitrogen protection for 2 hours, and the reaction was monitored by LCMS. After the reaction was completed, the reaction mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by preparative HPLC (Waters 3767 / QDA column: Boston green ODS, 30*150mm, 5μm; mobile phase A: 0.1% FA / H2O, mobile phase B: ACN; flow rate: 30ml / min; gradient: 27-37%; retention time: 8.2-10min, 17min) to give 30 (7.06mg) of 3-(2-chloro-3-(6-fluoro-5-(2-oxopyridin-1(2H)-yl)-5,6,7,8-tetrahydronaphth-2-yl)phenyl)piperidin-2,6-dione, yield 6.9%.

[0776] MS m / z (ESI): 465.2 [M+1]

[0777] 1 H NMR(400MHz, DMSO-d6)δ10.92(s,1H),7.61(d,J=6.0Hz,1H),7.52–7.46(m,1H),7.41–7.33 (m,2H),7.30–7.25(m,2H),7.24–7.19(m,1H),6.74(d,J=8.0Hz,1H),6.49(d,J=9.2Hz,1H) ,6.34–6.28(m,1H),6.24–6.07(m,1H),5.49–5.25(m,1H),4.33(d,J=12.0,5.2Hz,1H),3.1 3–2.97(m,2H),2.85–2.70(m,2H),2.39–2.28(m,2H),2.25–2.11(m,1H),2.10–1.98(m,1H).

[0778] Example 31

[0779] 3-(2-chloro-3-(6-fluoro-5-(pyridin-2-yloxy)-5,6,7,8-tetrahydronaphthalen-2-yl)phenyl)piperidine-2,6-dione

[0780] 3-(2-chloro-3-(6-fluoro-5-(pyridin-2-oxy)-5,6,7,8-tetrahydronaphth-2-yl)phenyl)piperidine-2,6-dione

[0781] first step

[0782] 3-(2-chloro-3-(6-fluoro-5-(pyridin-2-yloxy)-5,6,7,8-tetrahydronaphthalen-2-yl)phenyl)piperidine-2,6-dione

[0783] 3-(2-chloro-3-(6-fluoro-5-(pyridin-2-oxy)-5,6,7,8-tetrahydronaphth-2-yl)phenyl)piperidine-2,6-dione

[0784] 2-((6-chloro-2-fluoro-1,2,3,4-tetrahydronaphthyl-1-yl)oxy)pyridine 30e (30 mg, 108.02 μmol) and 3-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxoborhexacyclopentan-2-yl)phenyl)piperidine-2,6-dione 18a (57 mg, 162.03 μmol) were dissolved in a solution of 1,4-dioxane (1 mL) and water (0.2 mL). Potassium carbonate (45 mg, 324.07 μmol) and methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tri-isopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (9 mg, 10.80 μmol) were added. The reaction mixture was then reacted at 80°C under nitrogen protection for 2 hours, and the reaction was monitored by LCMS. After the reaction was completed, the reaction mixture was filtered, the filtrate was concentrated under reduced pressure, and purified by preparative HPLC (Waters 3767 / QDA column: Boston green ODS, 30*150mm, 5μm; mobile phase A: 0.1% FA / H2O, mobile phase B: ACN; flow rate: 30ml / min; gradient: 43-53% retention time: 9.1min, 17min) to obtain 3-(2-chloro-3-(6-fluoro-5-(pyridin-2-oxy)-5,6,7,8-tetrahydronaphth-2-yl)phenyl)piperidine 2,6-dione 31 (9.38mg), which was identified as the target compound by mass spectrometry, NMR, and 2D NMR, with a yield of 18.5%.

[0785] MS m / z (ESI): 465.2 [M+1]

[0786] 1 H NMR (400MHz, DMSO) δ10.91 (s, 1H), 8.26 (dd, J = 5.2, 1.2Hz, 1H), 7.81–7.76 (m, 1H), 7.42–7.34 ( m,2H),7.32–7.27(m,2H),7.26–7.20(m,2H),7.10–7.05(m,1H),6.90(d,J=8.4Hz,1H),6.55(d ,J=13.2,5.6Hz,1H),5.25–5.06(m,1H),4.33(dd,J=12.0,5.2Hz,1H),2.98(t,J=6.4Hz,2H),2 .84–2.73(m,1H),2.58–2.52(m,1H),2.39–2.27(m,1H),2.26–2.15(m,2H),2.10–1.99(m,1H).

[0787] Example 32

[0788] 3-(2-chloro-3-(6-(6-methyl-2-oxopyridin-1(2H)-yl)-7,8-dihydronaphthalen-2-yl)phenyl)piperidine-2,6-dione

[0789] 3-(2-chloro-3-(6-(6-methyl-2-oxopyridin-1(2H)-yl)-7,8-dihydronaphth-2-yl)phenyl)piperidin-2,6-dione

[0790] first step

[0791] 1-(6-chloro-3,4-dihydronaphthalen-2-yl)-6-methylpyridin-2(1H)-one

[0792] 1-(6-chloro-3,4-dihydronaphth-2-yl)-6-methylpyridin-2(1H)-one

[0793] and

[0794] 2-((6-chloro-3,4-dihydronaphthalen-2-yl)oxy)-6-methylpyridine

[0795] 2-((6-chloro-3,4-dihydronaphth-2-yl)oxy)-6-methylpyridine

[0796] (6-chloro-3,4-dihydronaphthyl-2-yl)boronic acid 19d (500 mg, 2.40 mmol) was added to dichloroethane (7 mL), followed by 6-methylpyridin-2(1H)-one (314.11 mg, 2.88 mmol), copper acetate (435.68 mg, 2.40 mmol), and triethylamine (728.16 mg, 7.20 mmol). The reaction mixture was allowed to react at room temperature for 16 hours. After the reaction was complete, water (20 mL) was added to quench the reaction, followed by extraction with ethyl acetate (30 mL × 3). The organic phases were combined, washed with saturated sodium chloride (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The filtrate was purified by preparative HPLC to obtain 1-(6-chloro-3,4-dihydronaphthyl-2-yl)-6-methylpyridin-2(1H)-one 32a (56 mg), which was identified as the target compound by mass spectrometry, nuclear magnetic resonance (NMR), and two-dimensional NMR (8.6% yield) and 2-((6-chloro-3,4-dihydronaphthyl-2-yl)oxy)-6-methylpyridinium 32b (120 mg), with a yield of 18.4%.

[0797] MS m / z(ESI): 272.1 [M+1]

[0798] 32a:

[0799] 1 H NMR (400MHz, DMSO) δ7.42–7.30(m,2H),7.29–7.23(m,1H),7.21–7.15(m,1H),6.55(s,1H),6.28(d,J=9.2 Hz,1H),6.20(d,J=6.8Hz,1H),3.00(t,J=8.4Hz,2H),2.65–2.53(m,1H),2.39–2.29(m,1H),2.25(s,3H).

[0800] 32b:

[0801] MS m / z(ESI): 272.1 [M+1]

[0802] 1 H NMR(400MHz,DMSO)δ7.74(t,J=7.7Hz,1H),7.22(s,1H),7.19–7.13(m,1H),7.08–6.99(m,2H), 6.86(d,J=8.0Hz,1H),6.11(s,1H),2.96(t,J=8.0Hz,2H),2.49(t,J=8.0Hz,2H),2.40(s,3H).

[0803] Step 2

[0804] 3-(2-chloro-3-(6-(6-methyl-2-oxopyridin-1(2H)-yl)-7,8-dihydronaphthalen-2-yl)phenyl)piperidine-2,6-dione

[0805] 3-(2-chloro-3-(6-(6-methyl-2-oxopyridin-1(2H)-yl)-7,8-dihydronaphth-2-yl)phenyl)piperidin-2,6-dione

[0806] 1-(6-chloro-3,4-dihydronaphthyl-2-yl)-6-methylpyridin-2(1H)-one 32a (10 mg, 36.80 μmol) and 3-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxoborhexacyclopentan-2-yl)phenyl)piperidin-2,6-dione 18a (15.44 mg, 44.16 μmol) were dissolved in 1,4-dioxane ( Potassium carbonate (15.26 mg, 110.40 μmol) and methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tris-isopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (3.11 mg, 3.68 μmol) were added to 1 mL of water and 0.1 mL of water. The mixture was heated to 90 °C and reacted for 1 hour under nitrogen protection. After the reaction was complete, the mixture was cooled to room temperature. Quenching with water (5 mL), extraction with ethyl acetate (10 mL × 3), combining the organic phases, washing with saturated sodium chloride (15 mL), drying to anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure, and purifying by preparative HPLC (Waters 3767QDA column: Agilent Poroshell 1204HPH-C18, 21.2*150 mm, 4 μm; mobile phase A: 10 mmol / L NH4HCO3 / H2O, mobile phase B: ACN; flow rate: 20 mL / min; gradient: 35-38%; retention times: 9.13 min, 17 min) to give 32 (2.1 mg) of 3-(2-chloro-3-(6-(6-methyl-2-oxopyridin-1(2H)-yl)-7,8-dihydronaphth-2-yl)phenyl)piperidin-2,6-dione, yield 12.4%. MS m / z (ESI): 459.3 [M+1]

[0807] 1H NMR(400MHz,DMSO)δ10.92(s,1H),7.43–7.37(m,2H),7.37–7.31(m,2H),7. 29–7.20(m,3H),6.59(s,1H),6.29(d,J=9.2Hz,1H),6.21(d,J=6.8Hz,1H), 4.38–4.31(m,1H),3.05(t,J=8.2Hz,2H),2.83–2.75(m,1H),2.65–2.61(m, 1H),2.58–2.55(m,1H),2.42–2.38(m,1H),2.37–2.32(m,2H),2.30(s,3H).

[0808] Example 33

[0809] 3-(2-chloro-3-(6-((6-methylpyridin-2-yl)oxy)-7,8-dihydronaphthalen-2-yl)phenyl)piperidine-2,6-dione

[0810] 3-(2-chloro-3-(6-((6-methylpyridin-2-yl)oxy)-7,8-dihydronaphth-2-yl)phenyl)piperidin-2,6-dione

[0811] first step

[0812] 3-(2-chloro-3-(6-(pyridin-2-yloxy)-7,8-dihydronaphthalen-2-yl)phenyl)piperidine-2,6-dione

[0813] 3-(2-chloro-3-(6-(pyridin-2-yloxy)-7,8-dihydronaphth-2-yl)phenyl)piperidin-2,6-dione

[0814] Dissolve 2-((6-chloro-3,4-dihydronaphthyl-2-yl)oxy)-6-methylpyridine 32b (120 mg, 441.60 μmol) and 3-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxoborhexacyclopentan-2-yl)phenyl)piperidine-2,6-dione 18a (185.27 mg, 529.92 μmol) in 1,4-dioxane ( Potassium carbonate (183.09 mg, 1.32 mmol) and methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tris-isopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (37.38 mg, 44.16 μmol) were added to a mixture of 1 mL of water and 0.1 mL of water. The mixture was heated to 90 °C and reacted for 1 hour under nitrogen protection. After the reaction was complete, the reaction mixture was cooled to room temperature. Quenching with water (5 mL), extraction with ethyl acetate (20 mL × 3), combining the organic phases, washing with saturated sodium chloride (15 mL), drying with anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure, and purifying by preparative HPLC (Waters 3767 / QDA column: Boston green ODS, 30*150 mm, 5 μm; mobile phase A: 0.05% TFA / H2O, mobile phase B: ACN; flow rate: 20 mL / min; gradient: 67-72%, retention time: 11 min, 17 min) to give 33 (21.37 mg) of 3-(2-chloro-3-(6-((6-methylpyridin-2-yl)oxy)-7,8-dihydronaphth-2-yl)phenyl)piperidin-2,6-dione, yield 10.5%.

[0815] MS m / z(ESI): 459.2 [M+1]

[0816] 1 H NMR (400MHz, DMSO) δ10.93 (s, 1H), 7.75 (t, J = 7.6Hz, 1H), 7.41–7.30 (m, 3H), 7.21–7 .15(m,2H),7.13–7.08(m,1H),7.02(d,J=7.2Hz,1H),6.87(d,J=8.0Hz,1H),6.16(s ,1H),4.35(dd,J=12.0,4.8Hz,1H),3.01(t,J=8.0Hz,2H),2.84–2.76(m,1H),2.59– 2.55(m,1H),2.55–2.52(m,2H),2.40(s,3H),2.37–2.26(m,1H),2.12–2.00(m,1H).

[0817] Example 34

[0818] 3-(2-chloro-3-(6-methyl-5-(2-oxopyridin-1(2H)-yl)-7,8-dihydronaphthalen-2-yl)phenyl)piperidine-2,6-dione

[0819] 3-(2-chloro-3-(6-methyl-5-(2-oxopyridin-1(2H)-yl)-7,8-dihydronaphth-2-yl)phenyl)piperidin-2,6-dione

[0820] first step

[0821] 7-bromo-3-methyl-1,2-dihydronaphthalene

[0822] 7-Bromo-3-methyl-1,2-dihydronaphthalene

[0823] 6-Bromo-3,4-dihydronaphthyl-2(1H)-one 34a (5 g, 22.21 mmol, commercially available) and diphenyl chlorophosphate (6.5 g, 24.44 mmol) were dissolved in tetrahydrofuran (80 mL). The solution was cooled to 0 °C, and 2-isopropylacetone magnesium bromide (1 M, 22.21 mL) was added under nitrogen protection. The mixture was stirred at room temperature for 1 hour, and then palladium dichloride bis(triphenylphosphine) (1.5 g, 2.22 mmol) was added. The temperature was raised to 65 °C, and then magnesium methyl chloride (1 M, 26.66 mL) was added. The mixture was stirred at 65 °C under nitrogen protection for 30 minutes. The reaction was monitored by LCMS. After the reaction was complete, the reaction solution was quenched with 3 mol / L hydrochloric acid (100 mL) and extracted with n-pentane (3 × 50 mL). The organic phases were combined, washed with saturated sodium chloride (2 × 80 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure at low temperature, and purified by silica gel column chromatography (developing solvent: system A) to give 7-bromo-3-methyl-1,2-dihydronaphthalene 34b (3.3 g), yield 66.6%.

[0824] 1 H NMR (400MHz, DMSO) δ7.31–7.25(m,2H),6.91(d,J=7.6Hz,1H),6.21(s,1H),2.75(t,J=8.0Hz,2H),2.15(d,J=8.4Hz,2H),1.86(s,3H).

[0825] Step 2

[0826] 5-bromo-1a-methyl-1a,2,3,7b-tetrahydronaphtho[1,2-b]oxirene

[0827] 5-Bromo-1a-methyl-1a,2,3,7b-tetrahydronaphtho[1,2-b]oxazine

[0828] 7-Bromo-3-methyl-1,2-dihydronaphthalene 34b (200 mg, 896.42 μmol) was dissolved in dichloromethane (3 mL), and m-chloroperoxybenzoic acid (201 mg, 1.17 mmol) was added at 0 °C. The reaction was carried out at room temperature under nitrogen protection for 2 hours. The reaction was monitored by LCMS. After the reaction was completed, saturated sodium thiosulfate (5 mL) was added to quench the reaction, and the mixture was extracted with dichloromethane (3 × 5 mL). The organic phases were combined, washed with sodium bicarbonate (2 × 10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (evolving solvent: system A) to give 5-bromo-1a-methyl-1a,2,3,7b-tetrahydronaphtho[1,2-b]oxazine 34c (60 mg), yield 28.0%.

[0829] 1 H NMR(400MHz,DMSO-d6)δ7.40(s,2H),7.36(s,1H),3.76(s,1H),2.60–2.54(m,2 H), 2.11 (d, J=7.2, 3.6Hz, 1H), 1.72 (t, J=14.4, 11.6, 7.2Hz, 1H), 1.47 (s, 3H).

[0830] Step 3

[0831] 1-(6-bromo-2-hydroxy-2-methyl-1,2,3,4-tetrahydronaphthalen-1-yl)pyridin-2(1H)-one

[0832] 1-(6-bromo-2-hydroxy-2-methyl-1,2,3,4-tetrahydronaphth-1-yl)pyridin-2(1H)-one

[0833] Pyridin-2(1H)-one (238 mg, 2.51 mmol) was dissolved in dimethyl sulfoxide (2 mL), and potassium tert-butoxide (131 mg, 1.17 mmol) was added. The mixture was stirred at room temperature for 0.5 h. Then, 5-bromo-1a-methyl-1a,2,3,7b-tetrahydronaphtho[1,2-b]oxazine 34c (400 mg, 1.67 mmol) was added, and the mixture was stirred at 90 °C under nitrogen protection for 0.5 h. The reaction was monitored by LCMS. After the reaction was complete, the mixture was concentrated under reduced pressure and purified by (evolving solvent: system D) to give 1-(6-bromo-2-hydroxy-2-methyl-1,2,3,4-tetrahydronaphtho-1-yl)pyridin-2(1H)-one 34d (120 mg), yield 21.5%.

[0834] MS m / z (ESI): 334.1 [M+1]

[0835] Step 4

[0836] 1-(6-bromo-2-methyl-3,4-dihydronaphthalen-1-yl)pyridin-2(1H)-one

[0837] 1-(6-bromo-2-methyl-3,4-dihydronaphth-1-yl)pyridin-2(1H)-one

[0838] 1-(6-bromo-2-hydroxy-2-methyl-1,2,3,4-tetrahydronaphthyl-1-yl)pyridin-2(1H)-one 34d (110 mg, 329.14 μmol) was dissolved in toluene (2 mL), and p-toluenesulfonic acid (28 mg, 164.57 μmol) was added. The mixture was stirred at 110 °C under nitrogen protection for 3 hours. The reaction was monitored by LCMS. After the reaction was complete, the solution was concentrated under reduced pressure and purified by (evolving solvent: system D) to give 1-(6-bromo-2-methyl-3,4-dihydronaphthyl-1-yl)pyridin-2(1H)-one 34e (40 mg), yield 38.4%.

[0839] MS m / z (ESI): 316.1 [M+1]

[0840] Step 5

[0841] 3-(2-chloro-3-(6-methyl-5-(2-oxopyridin-1(2H)-yl)-7,8-dihydronaphthalen-2-yl)phenyl)piperidine-2,6-dione

[0842] 3-(2-chloro-3-(6-methyl-5-(2-oxopyridin-1(2H)-yl)-7,8-dihydronaphth-2-yl)phenyl)piperidin-2,6-dione

[0843] 1-(6-bromo-2-methyl-3,4-dihydronaphth-1-yl)pyridin-2(1H)-one 34e (40 mg, 126.51 μmol) and 3-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxoborhexacyclopentan-2-yl)phenyl)piperidin-2,6-dione 18a (66 mg, 189.76 μmol) were dissolved in a solution of 1,4-dioxane (2 mL) and water (0.2 mL). Potassium carbonate (52 mg, 379.52 μmol) and [1,1'-bis(di-tert-butylphosphine)ferrocene]palladium dichloride (8 mg, 12.65 μmol) were added, and the reaction was carried out at 80 °C under nitrogen protection for 2 hours. The reaction was monitored by LCMS. After the reaction was completed, the mixture was filtered and concentrated, and then purified by preparative liquid chromatography (Waters 3767 / QDA column: Boston green ODS, 30*150mm, 5μm; mobile phase A: 0.1% FA / H2O, mobile phase B: ACN; flow rate: 30mL / min; gradient: 42-52%, retention time: 8.0-8.8min) to obtain 34 (6.24mg) of 3-(2-chloro-3-(6-methyl-5-(2-oxopyridin-1(2H)-yl)-7,8-dihydronaphth-2-yl)phenyl)piperidin-2,6-dione, with a yield of 10.7%.

[0844] MS m / z (ESI): 459.3 [M+1]

[0845] 1 H NMR(400MHz,DMSO-d6)δ10.91(s,1H),7.61–7.54(m,1H),7.49–7.44(m,1H),7. 41–7.32(m,2H),7.30–7.23(m,2H),7.18–7.12(m,1H),6.56–6.44(m,2H),6.35( t,J=6.4Hz,1H),4.33(dd,J=12.0,5.2Hz,1H),2.93(t,J=8.4Hz,2H),2.83–2.7 4(m,1H),2.69–2.54(m,2H),2.41–2.25(m,2H),2.07–2.00(m,1H),1.68(s,3H).

[0846] Example 35

[0847] 3-(2-chloro-3-(6-hydroxy-6-methyl-5-(2-oxopyridin-1(2H)-yl)-5,6,7,8-tetrahydronaphthalen-2-yl)phenyl)piperidine-2,6-dione

[0848] 3-(2-chloro-3-(6-hydroxy-6-methyl-5-(2-oxopyridin-1(2H)-yl)-5,6,7,8-tetrahydronaphth-2-yl)phenyl)piperidin-2,6-dione

[0849] first step

[0850] 3-(2-chloro-3-(6-hydroxy-6-methyl-5-(2-oxopyridin-1(2H)-yl)-5,6,7,8-tetrahydronaphthalen-2-yl)phenyl)piperidine-2,6-dione

[0851] 3-(2-chloro-3-(6-hydroxy-6-methyl-5-(2-oxopyridin-1(2H)-yl)-5,6,7,8-tetrahydronaphth-2-yl)phenyl)piperidin-2,6-dione

[0852] 1-(6-bromo-2-hydroxy-2-methyl-1,2,3,4-tetrahydronaphth-1-yl)pyridin-2(1H)-one 34d (30 mg, 89.77 μmol) and 3-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxoborhexacyclopentan-2-yl)phenyl)piperidin-2,6-dione 18a (41 mg, 116.70 μmol) were dissolved in a solution of 1,4-dioxane (2 mL) and water (0.2 mL). Potassium carbonate (37 mg, 269.31 μmol) and [1,1'-bis(di-tert-butylphosphine)ferrocene]palladium dichloride (6 mg, 8.98 μmol) were then added. The reaction mixture was then reacted at 80 °C under nitrogen protection for 2 hours, and the reaction was monitored by LCMS. After the reaction was completed, the mixture was filtered and concentrated, and then purified by preparative liquid chromatography (Waters 3767 / QDA column: Boston green ODS, 30*150mm, 5μm; mobile phase A: 0.1% FA / H2O, mobile phase B: ACN; flow rate: 30mL / min; gradient: 32-40%; retention time: 9.4-10.0min) to obtain 35 (8.17mg) of 3-(2-chloro-3-(6-hydroxy-6-methyl-5-(2-oxopyridin-1(2H)-yl)-5,6,7,8-tetrahydronaphthyl-2-yl)phenyl)piperidin-2,6-dione, with a yield of 19.1%.

[0853] MS m / z (ESI): 477.2 [M+1]

[0854] 1H NMR(400MHz,DMSO-d6)δ10.92(s,1H),7.41–7.34(m,3H),7.33–7.24(m,2H),7.20(d,J=8.0Hz ,1H),7.06(dd,J=7.2,1.6Hz,1H),6.90(d,J=8.0Hz,1H),6.49(d,J=8.4Hz,1H),6.18(s,1H), 6.13(dt,J=6.8,1.2Hz,1H),4.34(dd,J=12.0,5.2Hz,1H),3.10–2.98(m,1H),2.91–2.73(m,2 H),2.58–2.51(m,2H),2.39–2.26(m,1H),2.09–2.00(m,1H),1.89–1.72(m,2H),1.04(s,3H).

[0855] Example 36

[0856] 3-(2-chloro-3-(6-(6-methyl-2-oxopyridin-1(2H)-yl)naphthalen-2-yl)phenyl)piperidine-2,6-dione

[0857] 3-(2-chloro-3-(6-(6-methyl-2-oxopyridin-1(2H)-yl)naphth-2-yl)phenyl)piperidin-2,6-dione

[0858] first step

[0859] 1-(6-bromonaphthalen-2-yl)-6-methylpyridin-2(1H)-one

[0860] 1-(6-bromonaphth-2-yl)-6-methylpyridin-2(1H)-one

[0861] At room temperature, (6-bromonaphthyl-2-yl)boronic acid 14a (0.47 g, 1.87 mmol), 6-methylpyridin-2(1H)-one (305 mg, 2.79 mmol), copper acetate (170 mg, 0.93 mmol), pyridine (296.37 mg, 3.75 mmol), triethylamine (380 mg, 3.75 mmol), and dichloromethane (15 mL) were added sequentially to a reaction flask. The reaction mixture was stirred overnight under oxygen conditions. The product was detected by LCMS. Water (50 mL) and dichloromethane (150 mL) were added to the reaction mixture. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The purified product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:1) to give 1-(6-bromonaphthyl-2-yl)-6-methylpyridin-2(1H)-one 36a (30 mg), yield: 5.1%.

[0862] MS m / z(ESI): 314.0 [M+1]

[0863] Step 2

[0864] 6-methyl-1-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-yl)pyridin-2(1H)-one

[0865] 6-Methyl-1-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)naphth-2-yl)pyridin-2(1H)-one

[0866] At room temperature, 1-(6-bromonaphth-2-yl)-6-methylpyridin-2(1H)-one 36a (30 mg, 0.1 mmol), pinacol diboronate (40 mg, 0.15 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (20 mg, 0.03 mmol), potassium acetate (30 mg, 0.30 mmol), and 1,4-dioxane (5 mL) were sequentially added to a reaction flask. The mixture was purged with nitrogen three times and stirred at 100°C for 3 hours. The reaction was confirmed to be complete by LC-MS. The reaction solution was not purified and was used directly in the next step. MS m / z (ESI): 362.1 [M+1]

[0867] Step 3

[0868] 3-(2-chloro-3-(6-(6-methyl-2-oxopyridin-1(2H)-yl)naphthalen-2-yl)phenyl)piperidine-2,6-dione

[0869] 3-(2-chloro-3-(6-(6-methyl-2-oxopyridin-1(2H)-yl)naphth-2-yl)phenyl)piperidin-2,6-dione

[0870] At room temperature, 3-(3-bromo-2-chloro-phenyl)piperidin-2,6-dione 1a (35 mg, 0.11 mmol), 6-methyl-1-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)naphth-2-yl)pyridin-2(1H)-one 36b (30 mg, 0.10 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (15 mg, 0.02 mmol), sodium bicarbonate (30 mg, 0.35 mmol), 1,4-dioxane (6.0 mL), and water (1.0 mL) were added sequentially to a reaction flask. The mixture was purged with nitrogen three times and stirred at 90°C for 3 hours. The reaction was confirmed to be complete by LC-MS. Purification via reverse-phase preparation (developing solvent: system D) yielded 36 (8.0 mg) of 3-(2-chloro-3-(6-(6-methyl-2-oxopyridin-1(2H)-yl)naphth-2-yl)phenyl)piperidin-2,6-dione, yield: 17.2%.

[0871] MS m / z(ESI): 457.1 [M+1]

[0872] 1 H NMR (400MHz, DMSO-d6) δ10.95 (s, 1H), 8.13 (d, J = 8.7Hz, 1H), 8.07-8.03 (m ,2H),7.93(s,1H),7.63(d,J=8.6Hz,1H),7.50-7.40(m,5H),6.39(d,J=9.2 Hz,1H),6.30(d,J=6.9Hz,1H),4.39(dd,J=12.2,5.1Hz,1H),2.86-2.76(m, 1H),2.54-2.50(m,1H),2.42–2.36(m,1H),1.98(s,3H),1.67-1.63(m,1H).

[0873] Example 37

[0874] 3-(2-chloro-3-(6-((6-(trifluoromethyl)pyridin-2-yl)oxy)naphthalen-2-yl)phenyl)piperidine-2,6-dione

[0875] 3-(2-chloro-3-(6-(6-(trifluoromethyl)pyridin-2-yl)oxy)naphth-2-yl)phenyl)piperidin-2,6-dione

[0876] first step

[0877] 2-((6-bromonaphthalen-2-yl)oxy)-6-(trifluoromethyl)pyridine

[0878] 2-((6-bromonaphth-2-yl)oxy)-6-(trifluoromethyl)pyridine

[0879] At room temperature, (6-bromonaphth-2-yl)boronic acid 14a (200 mg, 0.79 mmol), 6-(trifluoromethyl)pyridin-2(1H)-one (250 mg, 1.53 mmol), copper acetate (72.4 mg, 0.40 mmol), pyridine (126.11 mg, 1.59 mmol), triethylamine (160 mg, 1.59 mmol), and dichloromethane (10 mL) were added sequentially to a reaction flask, and the mixture was stirred overnight under oxygen conditions. The reaction was confirmed to be complete by LC-MS. Dichloromethane (50 mL) and water (20 mL) were added to the reaction solution. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The solution was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3:1) to give 2-((6-bromonaphth-2-yl)oxy)-6-(trifluoromethyl)pyridine 37a (100 mg), yield: 34.0%.

[0880] MS m / z(ESI): 368.0 [M+1]

[0881] Step 2

[0882] 3-((6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-yl)oxy)-6-(trifluoromethyl)pyridine

[0883] 3-((6-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)naphth-2-yl)oxy)-6-(trifluoromethyl)pyridine

[0884] At room temperature, 2-((6-bromonaphthyl-2-yl)oxy)-6-(trifluoromethyl)pyridine 37a (100 mg, 0.27 mmol), pinacol diboronate (140 mg, 0.55 mmol), [1,1-bis(diphenylphosphino)ferrocene]palladium dichloride (30 mg, 0.04 mmol), potassium acetate (120 mg, 1.22 mmol), and 1,4-dioxane (10 mL) were added sequentially to a reaction flask. After purging with nitrogen three times, the mixture was heated to 100°C and stirred for 2 hours. The reaction was confirmed to be complete by LC-MS. The reaction solution was used directly for the next reaction without further treatment. MS m / z (ESI): 416.2 [M+1]

[0885] Step 3

[0886] 3-(2-chloro-3-(6-((6-(trifluoromethyl)pyridin-2-yl)oxy)naphthalen-2-yl)phenyl)piperidine-2,6-dione

[0887] 3-(2-chloro-3-(6-(6-(trifluoromethyl)pyridin-2-yl)oxy)naphth-2-yl)phenyl)piperidin-2,6-dione

[0888] At room temperature, 3-((6-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)naphth-2-yl)oxy)-6-(trifluoromethyl)pyridine 37b (100 mg, 0.24 mmol), 3-(3-bromo-2-chloro-phenyl)piperidin-2,6-dione 1a (110 mg, 0.36 mmol), [1,1-bis(diphenylphosphine)ferrocene]palladium dichloride (30 mg, 0.04 mmol), sodium bicarbonate (91.0 mg, 1.08 mmol), 1,4-dioxane (5 mL), and water (1 mL) were added sequentially to a reaction flask. After purging with nitrogen three times, the mixture was heated to 90°C and stirred for 3 hours. The reaction was confirmed to be complete by LC-MS. Dichloromethane (50 mL) and water (20 mL) were added to the reaction solution. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. Purification was performed by reverse-phase preparation (developing solvent: system D) to give 37 (20 mg) of 3-(2-chloro-3-(6-(6-(trifluoromethyl)pyridin-2-yl)oxy)naphth-2-yl)phenyl)piperidin-2,6-dione, yield: 16.0%.

[0889] MS m / z(ESI): 511.1 [M+1]

[0890] 1H NMR (400MHz, DMSO-d6) δ10.95(s,1H),8.16(t,J=7.9Hz,1H),8.09(d,J=8.9Hz,1H),8.03–7.96(m,2H),7.80(s,1H),7.68(d,J=7.4Hz,1H),7.60 (d,J=8.4Hz,1H),7.48-7.40(m,5H),4.38(dd,J=12.3,5.0Hz,1H),2.86 –2.76(m,1H),2.58-2.54(m,1H),2.39-2.35(m,1H),2.11-2.05(m,1H).

[0891] Example 38

[0892] 3-(2-chloro-3-(6-((6-chloropyridin-2-yl)oxy)naphthalen-2-yl)phenyl)piperidine-2,6-dione

[0893] 3-(2-chloro-3-(6-(6-chloropyridin-2-yl)oxy)naphth-2-yl)phenyl)piperidin-2,6-dione

[0894] first step

[0895] 2-((6-bromonaphthalen-2-yl)oxy)-6-chloropyridine

[0896] 2-((6-bromonaphth-2-yl)oxy)-6-chloropyridine

[0897] At room temperature, (6-bromonaphth-2-yl)boronic acid 14a (200 mg, 0.79 mmol), 6-chloropyridin-2(1H)-one (150 mg, 1.16 mmol), copper acetate (72.4 mg, 0.40 mmol), pyridine (126.11 mg, 1.59 mmol), triethylamine (160 mg, 1.59 mmol), and dichloromethane (10 mL) were added sequentially to a reaction flask and stirred overnight under oxygen conditions. The reaction was confirmed to be complete by LC-MS. Dichloromethane (50 mL) and water (20 mL) were added to the reaction solution. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The purified phase was then purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3:1) to give 2-((6-bromonaphth-2-yl)oxy)-6-chloropyridine 38a (70 mg), yield: 26.2%.

[0898] MS m / z(ESI): 334.0 [M+1]

[0899] Step 2

[0900] 2-chloro-6-((6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-yl)oxy)pyridine

[0901] 2-Chloro-6-((6-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)naphth-2-yl)oxy)pyridine

[0902] At room temperature, 2-((6-bromonaphthyl-2-yl)oxy)-6-chloropyridine 38a (70 mg, 0.21 mmol), pinacol diboronate (80 mg, 0.31 mmol), [1,1-bis(diphenylphosphino)ferrocene]palladium dichloride (30 mg, 0.04 mmol), potassium acetate (120 mg, 1.22 mmol), and 1,4-dioxane (10 mL) were added sequentially to a reaction flask. After purging with nitrogen three times, the mixture was heated to 100°C and stirred for 2 hours. The reaction was confirmed to be complete by LC-MS. The reaction solution was used directly for the next reaction without further treatment. MS m / z (ESI): 382.2 [M+1]

[0903] Step 3

[0904] 3-(2-chloro-3-(6-((6-chloropyridin-2-yl)oxy)naphthalen-2-yl)phenyl)piperidine-2,6-dione

[0905] 3-(2-chloro-3-(6-(6-chloropyridin-2-yl)oxy)naphth-2-yl)phenyl)piperidin-2,6-dione

[0906] At room temperature, 2-chloro-6-((6-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)naphth-2-yl)oxy)pyridine 38b (70 mg, 0.18 mmol), 3-(3-bromo-2-chloro-phenyl)piperidin-2,6-dione 1a (80 mg, 0.27 mmol), 1,1-bis(diphenylphosphine)ferrocene]palladium dichloride (30 mg, 0.04 mmol), sodium bicarbonate (91.0 mg, 1.08 mmol), 1,4-dioxane (5 mL), and water (1 mL) were added sequentially to a reaction flask. After purging with nitrogen three times, the mixture was heated to 90°C and stirred for 3 hours. The reaction was confirmed to be complete by LC-MS. Dichloromethane (50 mL) and water (20 mL) were added to the reaction solution. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The solution was purified by reverse-phase Flash synthesis to obtain 38 (15 mg) of 3-(2-chloro-3-(6-(6-chloropyridin-2-yl)oxy)naphth-2-yl)phenyl)piperidin-2,6-dione, yield: 16.9%.

[0907] MS m / z(ESI): 477.1 [M+1]

[0908] 1 H NMR (400MHz, DMSO-d6) δ10.95(s,1H),8.08(d,J=8.9Hz,1H),8.00-7.93(m,3H),7.77(brs,1H),7.59(d,J=8.5Hz,1H),7.48-7.40(m,4H),7.29(d ,J=7.7Hz,1H),7.12(d,J=8.1Hz,1H),4.38(dd,J=12.2,5.0Hz,1H),2.8 7–2.76(m,1H),2.60–2.53(m,1H),2.46-2.36(m,1H),2.12–2.04(m,1H).

[0909] Example 39

[0910] 3-(2-chloro-3-(4-(2-oxopyridin-1(2H)-yl)-2,3-dihydrobenzofuran-7-yl)phenyl)piperidine-2,6-dione

[0911] 3-(2-chloro-3-(4-(2-oxopyridin-1(2H)-yl)-2,3-dihydrobenzofuran-7-yl)phenyl)piperidin-2,6-dione

[0912] first step

[0913] 4-iodo-2,3-dihydrobenzofuran-7-amine

[0914] 4-Iodo-2,3-dihydrobenzofuran-7-amine

[0915] Under ice bath conditions, N-iodosuccinimide (2.75 g, 12.21 mmol) was added in portions to a solution of 2,3-dihydrobenzofuran-7-amine 39a (1.5 g, 11.10 mmol, commercially available) in N,N-dimethylformamide (20 mL), and stirred at the same temperature for 2 hours. The reaction was confirmed to be complete by LC-MS. Water (200 mL) and ethyl acetate (200 mL) were added to the reaction mixture. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The purified phase was then purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2:1) to give 4-iodo-2,3-dihydrobenzofuran-7-amine 39b (1.4 g), yield: 48.3%.

[0916] MS m / z(ESI): 262.0 [M+1]

[0917] Step 2

[0918] 1-(7-amino-2,3-dihydrobenzofuran-4-yl)pyridin-2(1H)-one

[0919] 1-(7-amino-2,3-dihydrobenzofuran-4-yl)pyridin-2(1H)-one

[0920] At room temperature, 4-iodo-2,3-dihydrobenzofuran-7-amine 39b (750 mg, 2.87 mmol), pyridin-2(1H)-one (460 mg, 4.84 mmol), 8-hydroxyquinoline (166 mg, 1.14 mmol), cuprous iodide (270 mg, 1.42 mmol), potassium carbonate (1.2 g, 8.68 mmol), and dimethyl sulfoxide (10 mL) were sequentially added to a reaction flask. After purging with nitrogen three times, the mixture was heated to 150 °C and stirred for 8 hours. The reaction was confirmed to be complete by LC-MS. The reaction solution was purified by reverse-phase preparation (evolving solvent: system D) to give 1-(7-amino-2,3-dihydrobenzofuran-4-yl)pyridin-2(1H)-one 39c (300 mg), yield: 45.7%.

[0921] MS m / z(ESI): 229.1 [M+1]

[0922] Step 3

[0923] 1-(7-iodo-2,3-dihydrobenzofuran-4-yl)pyridin-2(1H)-one

[0924] 1-(7-iodo-2,3-dihydrobenzofuran-4-yl)pyridin-2(1H)-one

[0925] Under ice bath conditions, 1-(7-amino-2,3-dihydrobenzofuran-4-yl)pyridin-2(1H)-one 39c (400 mg, 1.75 mmol), water (10 mL), concentrated hydrochloric acid (12 mol / L, 0.8 mL), and sodium nitrite (240 mg, 3.50 mmol) were added sequentially to a reaction flask, and stirred at the same temperature for 30 minutes. Sodium iodide (525 mg, 3.50 mmol) was added in portions to the above reaction solution, and stirred at room temperature for 2 hours. The reaction was confirmed to be complete by LC-MS. Dichloromethane (100 mL) and saturated sodium bicarbonate solution were added to the reaction solution. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The solution was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:2) to obtain 39d (160 mg) of 1-(7-iodo-2,3-dihydrobenzofuran-4-yl)pyridin-2(1H)-one, yield: 26.9%.

[0926] MS m / z(ESI): 340.0 [M+1]

[0927] Step 4

[0928] 1-(7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydrobenzofuran-4-yl)pyridin-2(1H)-one

[0929] 1-(7-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-2,3-dihydrobenzofuran-4-yl)pyridin-2(1H)-one

[0930] At room temperature, 1-(7-iodo-2,3-dihydrobenzofuran-4-yl)pyridin-2(1H)-one 39d (130 mg, 0.38 mmol), bipinacol borate ester (195 mg, 0.76 mmol), potassium acetate (170 mg, 1.77 mmol), [1,1-bis(diphenylphosphino)ferrocene]palladium dichloride (65 mg, 0.09 mmol), and 1,4-dioxane (5 mL) were sequentially added to a reaction flask. After purging with nitrogen three times, the mixture was heated to 110°C and stirred for 4 hours. The reaction was confirmed to be complete by LCMS. The reaction solution was used directly for the next reaction without further treatment.

[0931] MS m / z(ESI): 340.2 [M+1]

[0932] Step 5

[0933] 3-(2-chloro-3-(4-(2-oxopyridin-1(2H)-yl)-2,3-dihydrobenzofuran-7-yl)phenyl)piperidine-2,6-dione

[0934] 3-(2-chloro-3-(4-(2-oxopyridin-1(2H)-yl)-2,3-dihydrobenzofuran-7-yl)phenyl)piperidin-2,6-dione

[0935] At room temperature, 1-(7-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)-2,3-dihydrobenzofuran-4-yl)pyridin-2(1H)-one 39e (130 mg, 0.38 mmol), 3-(3-bromo-2-chloro-phenyl)piperidin-2,6-dione 1a (116 mg, 0.38 mmol), [1,1-bis(diphenylphosphine)ferrocene]palladium dichloride (27.89 mg, 0.04 mmol), sodium bicarbonate (128.79 mg, 1.53 mmol), 1,4-dioxane (6.0 mL), and water (1.0 mL) were added sequentially to a reaction flask. After purging with nitrogen three times, the mixture was heated to 90°C and stirred for 3 hours. The reaction was confirmed to be complete by LC-MS. Dichloromethane (50 mL) and water (20 mL) were added to the reaction solution. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The solution was purified by reverse-phase preparation (developing solvent: system D) to give 39 (20 mg) of 3-(2-chloro-3-(4-(2-oxopyridin-1(2H)-yl)-2,3-dihydrobenzofuran-7-yl)phenyl)piperidin-2,6-dione, yield: 11.6%.

[0936] MS m / z(ESI): 435.1 [M+1]

[0937] 1H NMR(400MHz, DMSO-d6)δ10.93(s,1H),7.70(dd,J=6.9,1.9Hz,1H),7.57-7.51(m,1H), 7.43–7.30(m,3H),7.20(d,J=8.1Hz,1H),6.90(d,J=8.1Hz,1H),6.52(d,J=9.2Hz,1H), 6.34(t,J=6.7Hz,1H),4.56(t,J=8.7Hz,2H),4.35(dd,J=12.2,5.0Hz,1H),3.09(t,J=8 .7Hz,2H),2.84-2.74(m,1H),2.59–2.52(m,1H),2.37–2.28(m,1H),2.10-2.00(m,1H).

[0938] Example 40

[0939] 3-(2-chloro-3-(4-(2-oxopyridin-1(2H)-yl)benzofuran-7-yl)phenyl)piperidine-2,6-dione

[0940] 3-(2-chloro-3-(4-(2-oxopyridin-1(2H)-yl)benzofuran-7-yl)phenyl)piperidin-2,6-dione

[0941] first step

[0942] 4-iodobenzofuran-7-amine

[0943] 4-Iodobenzofuran-7-amine

[0944] Benzofuran-7-amine 40a (1 g, 7.51 mmol) and calcium carbonate (977.21 mg, 9.76 mmol, commercially available) were added to a solution of methanol (20 mL) and dichloromethane (40 mL). The reaction solution was cooled to 0°C, and benzyltrimethyldichloroiodate ammonium (2.61 g, 7.51 mmol) was added. The reaction was then continued at 0°C for 1.5 hours. After the reaction was complete, water (20 mL) was added to quench the reaction, and the mixture was extracted with dichloromethane (30 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (developing solvent: system A) to give 4-iodobenzofuran-7-amine 40b (1.2 g), with a yield of 61.7%.

[0945] MS m / z (ESI): 260.0 [M+1]

[0946] Step 2

[0947] 1-(7-aminobenzofuran-4-yl)pyridin-2(1H)-one

[0948] 1-(7-Aminobenzofuran-4-yl)pyridin-2(1H)-one

[0949] 4-Iodobenzofuran-7-amine 40b (500 mg, 1.93 mmol) was added to a 5 mL solution of dimethyl sulfoxide, followed by pyridin-2(1H)-one (367.12 mg, 3.86 mmol), 8-hydroxyquinoline (56.04 mg, 386.04 μmol), cesium carbonate (1.26 g, 3.86 mmol), and cuprous iodide (73.73 mg, 386.04 μmol). The reaction was continued at 100 °C for 48 hours under nitrogen protection. After the reaction was complete, the temperature was lowered to room temperature, and the filtrate was concentrated under reduced pressure and purified by (eluent: system D) to obtain 1-(7-aminobenzofuran-4-yl)pyridin-2(1H)-one 40c (180 mg), with a yield of 41.2%.

[0950] MS m / z (ESI): 227.2 [M+1]

[0951] Step 3

[0952] 1-(7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-4-yl)pyridin-2(1H)-one

[0953] 1-(7-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)benzofuran-4-yl)pyridin-2(1H)-one

[0954] 1-(7-aminobenzofuran-4-yl)pyridin-2(1H)-one 40c (210 mg, 928.26 μmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-4-tetramethyl-1,3,2-dioxaborane-2-yl)-1,3,2-dioxaborane (353.58 mg, 1.39 mmol) were added to acetonitrile (3 mL), followed by the addition of tert-butyl nitrite (105.29 mg, 1.02 mmol). The reaction was continued at room temperature for 4 hours under nitrogen protection. After the reaction was complete, water (3 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The filtrate was purified by (eluent: system D) to give 40 d (15 mg) of 1-(7-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)benzofuran-4-yl)pyridin-2(1H)-one, with a yield of 4.8%.

[0955] MS m / z (ESI): 338.2 [M+1]

[0956] Step 4

[0957] 3-(2-chloro-3-(4-(2-oxopyridin-1(2H)-yl)benzofuran-7-yl)phenyl)piperidine-2,6-dione

[0958] 3-(2-chloro-3-(4-(2-oxopyridin-1(2H)-yl)benzofuran-7-yl)phenyl)piperidin-2,6-dione

[0959] 1-(7-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)benzofuran-4-yl)pyridin-2(1H)-one 40d (10 mg, 39.21 μmol) was added to a solution of 1,4-dioxane (1 mL) and water (0.1 mL). Then, 3-(3-bromo-2-chloro-phenyl)piperidin-2,6-dione 1a (14.24 mg, 47.05 μmol), potassium carbonate (14.24 mg, 47.05 μmol), and [1,1'-bis(di-tert-butylphosphine)ferrocene]palladium dichloride (2.56 mg, 3.92 μmol) were added to the system. The reaction was continued at 90 °C for 1 hour under nitrogen protection. After the reaction was completed, the filtrate was concentrated under reduced pressure and subjected to preparative HPLC (Waters 3767 / QDA column: Boston green ODS, 30*150mm, 5μm; mobile phase A: 0.1% FA / H2O, mobile phase B: ACN; flow rate: 30mL / min; gradient: 36-41%, retention time: 8-8.9min) to obtain 40 (4.75mg) of 3-(2-chloro-3-(4-(2-oxopyridin-1(2H)-yl)benzofuran-7-yl)phenyl)piperidin-2,6-dione, yield 28.0%.

[0960] MS m / z(ESI): 433.2 [M+1]

[0961] 1 H NMR (400MHz, DMSO) δ10.95(s,1H),8.05(d,J=2.0Hz,1H),7.77(d,J=6.0Hz,1H),7.62–7.56(m,1H),7.50–7.36(m,5H),6.74(d,J=2.0Hz,1H),6.57 (d,J=9.2Hz,1H),6.39(t,J=6.8Hz,1H),4.40(dd,J=12.0,5.2Hz,1H),2. 87–2.77(m,1H),2.58–2.53(m,1H),2.44–2.32(m,1H),2.14–2.05(m,1H).

[0962] Example 41

[0963] 3-(2-chloro-3-(6-(4-methyl-2-oxopyridin-1(2H)-yl)-7,8-dihydronaphthalen-2-yl)phenyl)piperidine-2,6-dione

[0964] 3-(2-chloro-3-(6-(4-methyl-2-oxopyridin-1(2H)-yl)-7,8-dihydronaphth-2-yl)phenyl)piperidin-2,6-dione

[0965] first step

[0966] 6-bromo-3,4-dihydronaphthalen-2-yl trifluoromethanesulfonate

[0967] 6-Bromo-3,4-dihydronaphth-2-yltrifluoromethanesulfonate

[0968] Under argon protection, 25 g (111.07 mmol) of 6-bromo-3,4-dihydronaphthyl-2(1H)-one 34a was added to a tetrahydrofuran (400 mL) solution. The reaction mixture was cooled to -78 °C, and sodium bis(trimethylsilyl)amino (144.39 mL, 1 M) was added. After reacting at -78 °C for 1 hour, 51.58 g (144.39 mmol) of 1,1,1-trifluoro-N-phenyl-N-(trifluoromethanesulfonyl)methanesulfonamide (51.58 g, 144.39 mmol) was added. The reaction mixture was then allowed to rise to room temperature under argon protection and reacted for another hour. After the reaction was complete, the reactants were directly concentrated under reduced pressure and purified by silica gel column chromatography (evolving solvent: system A) to give 25.0 g (63.0%) of 6-bromo-3,4-dihydronaphthyl-2-yltrifluoromethanesulfonate 41a.

[0969] 1 H NMR (400MHz, DMSO) δ7.45-7.36(m,1H),7.22–7.16(m,1H),6.82(s,1H),3.08-2.98(m,2H),2.69-2.61(m,2H).

[0970] Step 2

[0971] 2-(6-bromo-3,4-dihydronaphthalen-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

[0972] 2-(6-bromo-3,4-dihydronaphth-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxoborane

[0973] 6-Bromo-3,4-dihydronaphthyl-2-yltrifluoromethanesulfonate 41a (7 g, 19.60 mmol) was added to a solution of 1,4-dioxane (80 mL), followed by 4,4,5,5-tetramethyl-2-(4,4,5,5-4-tetramethyl-1,3,2-dioxoborhexacyclopentan-2-yl)-1,3,2-dioxoborhexacyclopentane (3.98 g, 15.68 mmol), potassium acetate (5.77 g, 58.80 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (1.45 g, 1.96 mmol). The reaction mixture was heated to 90 °C and reacted for 16 hours under argon protection. After the reaction was complete, the reactants were cooled to room temperature, quenched with water (60 mL), extracted with ethyl acetate (10 mL × 3), the organic phases were combined, washed with saturated sodium chloride solution (200 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and purified by silica gel column chromatography (developing solvent: system A) to give 2-(6-bromo-3,4-dihydronaphth-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxoboranecyclopentane 41b (2.6 g), yield 39.6%.

[0974] 1 H NMR (400MHz, DMSO) δ7.40-7.34(m,2H),7.22-7.11(m,2H),2.72–2.64(m,2H),2.29 -2.23(m,2H),1.24(s,12H).

[0975] Step 3

[0976] (6-bromo-3,4-dihydronaphthalen-2-yl)boronic acid

[0977] (6-bromo-3,4-dihydronaphth-2-yl)boronic acid

[0978] 2-(6-bromo-3,4-dihydronaphthyl-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxoboronylcyclopentane 41b (2.6 g, 7.76 mmol) was added to a solution of acetone (30 mL) and water (30 mL). The system was then cooled to 0 °C, and ammonium acetate (897.26 mg, 11.64 mmol) and sodium periodate (2.49 g, 11.64 mmol) were added. The reaction mixture was then brought to room temperature and reacted for another 16 hours. After the reaction was complete, the reactants were extracted with acetone (100 mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The filtrate was purified by silica gel column chromatography (developing solvent: system A) to obtain a partial product. The solution was then washed again by silica gel column chromatography (developing solvent: system B), and the samples were combined to obtain 41c (270 mg) of (6-bromo-3,4-dihydronaphth-2-yl)boronic acid, with a yield of 13.8%.

[0979] 1 H NMR (400MHz, DMSO) δ7.74(s,2H),7.37–7.32(m,2H),7.10–7.00(m,2H),2.69–2.60(m,2H),2.30–2.21(m,2H).

[0980] Step 4

[0981] 1-(6-bromo-3,4-dihydronaphthalen-2-yl)-4-methylpyridin-2(1H)-one

[0982] 1-(6-bromo-3,4-dihydronaphth-2-yl)-4-methylpyridin-2(1H)-one

[0983] and

[0984] 2-((6-bromo-3,4-dihydronaphthalen-2-yl)oxy)-4-methylpyridine

[0985] 2-((6-bromo-3,4-dihydronaphth-2-yl)oxy)-4-methylpyridine

[0986] 41c of (6-bromo-3,4-dihydronaphth-2-yl)boronic acid (200 mg, 790.83 μmol) was added to dichloroethane (4 mL), followed by 4-methylpyridin-2(1H)-one (105.47 mg, 948.99 μmol), copper acetate (143.64 mg, 790.83 μmol), and triethylamine (240.07 mg, 2.37 mmol). The reaction mixture was then allowed to react for 16 hours at room temperature under an oxygen atmosphere. After the reaction was complete, water (20 mL) was added to quench the reaction, followed by extraction with dichloromethane (30 mL × 3). The organic phases were combined, washed with saturated sodium chloride (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (developing solvent: system A) to give 1-(6-bromo-3,4-dihydronaphthyl-2-yl)-4-methylpyridin-2(1H)-one 41d (50 mg), yield 20.0%, and 2-((6-bromo-3,4-dihydronaphthyl-2-yl)oxy)-4-methylpyridinium 41e (80 mg), which were identified as the target compounds by mass spectrometry, nuclear magnetic resonance (NMR), and two-dimensional NMR, with a yield of 32.0%. MS m / z (ESI): 316.1 [M+1]

[0987] 41d:

[0988] 1 H NMR(400MHz,DMSO)δ7.50(d,J=6.8Hz,1H),7.47–7.33(m,2H),7.14(d,J=8.0Hz,1H),6.58(s,1H ),6.23(s,1H),6.15(d,J=6.8Hz,1H),2.94(t,J=8.2Hz,2H),2.57(t,J=8.2Hz,2H),2.16(s,3H).

[0989] 41e:

[0990] MS m / z(ESI): 316.2 [M+1]

[0991] 1 H NMR(400MHz,DMSO)δ8.09(d,J=5.2Hz,1H),7.36(s,1H),7.30(d,J=8.0Hz,1H),7.04–6.94 (m,2H),6.89(s,1H),6.08(s,1H),2.95(t,J=8.0Hz,2H),2.49–2.42(m,2H),2.33(s,3H).

[0992] Step 5

[0993] 3-(2-chloro-3-(6-(4-methyl-2-oxopyridin-1(2H)-yl)-7,8-dihydronaphthalen-2-yl)phenyl)piperidine-2,6-dione

[0994] 3-(2-chloro-3-(6-(4-methyl-2-oxopyridin-1(2H)-yl)-7,8-dihydronaphth-2-yl)phenyl)piperidin-2,6-dione

[0995] 1-(6-bromo-3,4-dihydronaphthyl-2-yl)-4-methylpyridin-2(1H)-one 41d (51 mg, 161.29 μmol) and 3-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxoborhexacyclopentan-2-yl)phenyl)piperidin-2,6-dione 18a (67.67 mg, 193.55 μmol) were dissolved in 1,4-dioxane (1 mL) and water (0.1 mL). Potassium carbonate (66.88 mg, 483.88 μmol) and [1,1'-bis(di-tert-butylphosphine)ferrocene]palladium dichloride (10.51 mg, 16.13 μmol) were added. The reaction mixture was heated to 90 °C under nitrogen protection and reacted for 1 hour. After the reaction was completed, the mixture was cooled to room temperature. Quenching with water (5 mL), extraction with ethyl acetate (10 mL × 3), combining the organic phases, washing with saturated sodium chloride (15 mL), drying with anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure, and purifying by preparative HPLC (Waters 3767QDA column: XBridge C18, 19*150 mm, 5 μm; mobile phase A: 10 mmol / L NH4HCO3 / H2O, mobile phase B: ACN; flow rate: 20 mL / min; gradient: 37-42%, retention time: 8.5-9.2 min, 16 min) to give 41 (23.06 mg) of 3-(2-chloro-3-(6-(4-methyl-2-oxopyridin-1(2H)-yl)-7,8-dihydronaphth-2-yl)phenyl)piperidin-2,6-dione, yield 31.2%.

[0996] MS m / z(ESI): 459.2 [M+1]

[0997] 1H NMR (400MHz, DMSO) δ10.93 (s, 1H), 7.54 (d, J = 6.8Hz, 1H), 7.43–7.31 (m, 3H), 7.29–7.22(m,3H),6.64(s,1H),6.25(s,1H),6.17(d,J=6.8Hz,1H),4.35(dd, J=12.0,4.8Hz,1H),3.00(t,J=8.0Hz,2H),2.84–2.76(m,1H),2.64(t,J=8.0H z,2H),2.59–2.53(m,1H),2.38–2.32(m,1H),2.18(s,3H),2.10–2.03(m,1H).

[0998] Example 42

[0999] 3-(2-chloro-3-(6-((4-methylpyridin-2-yl)oxy)-7,8-dihydronaphthalen-2-yl)phenyl)piperidine-2,6-dione

[1000] 3-(2-chloro-3-(6-((4-methylpyridin-2-yl)oxy)-7,8-dihydronaphth-2-yl)phenyl)piperidin-2,6-dione

[1001] first step

[1002] 3-(2-chloro-3-(6-((4-methylpyridin-2-yl)oxy)-7,8-dihydronaphthalen-2-yl)phenyl)piperidine-2,6-dione

[1003] 3-(2-chloro-3-(6-((4-methylpyridin-2-yl)oxy)-7,8-dihydronaphth-2-yl)phenyl)piperidin-2,6-dione

[1004] Dissolve 2-((6-bromo-3,4-dihydronaphthyl-2-yl)oxy)-4-methylpyridine 41e (60 mg, 189.76 μmol) and 3-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxoborhexacyclopentan-2-yl)phenyl)piperidine-2,6-dione 18a (79.61 mg, 227.71 μmol) in 1,4-dioxane (1 mL) and water (0.1 mL), then add potassium carbonate (78.68 mg, 569.27 μmol) and [1,1'-bis(di-tert-butylphosphine)ferrocene]palladium dichloride (12.37 mg, 18.98 μmol). The reaction mixture was heated to 90 °C under nitrogen protection and reacted for 1 hour. After the reaction was complete, the mixture was cooled to room temperature. Quenching with water (5 mL), extraction with ethyl acetate (20 mL × 3), combining the organic phases, washing with saturated sodium chloride (15 mL), drying with anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure, and purifying by preparative HPLC (Waters 3767 / QDA column: Boston green ODS, 30*150 mm, 5 μm; mobile phase A: 0.1% FA / H2O, mobile phase B: ACN; flow rate: 30 mL / min; gradient: 64-66%; retention times: 9.6 min, 17 min) to give 42 (16.64 mg) of 3-(2-chloro-3-(6-((4-methylpyridin-2-yl)oxy)-7,8-dihydronaphth-2-yl)phenyl)piperidin-2,6-dione, yield 19.1%.

[1005] MS m / z(ESI): 459.0 [M+1]

[1006] 1 H NMR (400MHz, DMSO) δ10.93(s,1H),8.10(d,J=4.8Hz,1H),7.41–7.29(m,3H),7.20–7.14(m,2H),7.12–7.08(m,1H),7.00(d,J=4.8Hz,1H),6.91(s, 1H), 6.16 (s, 1H), 4.34 (dd, J=11.6, 4.0Hz, 1H), 3.01 (t, J=8.0Hz, 2H), 2. 83–2.75(m,1H),2.59–2.52(m,3H),2.38–2.29(m,4H),2.10–2.00(m,1H).

[1007] Example 43

[1008] 3-(2-chloro-3-(6-(4-chloro-2-oxopyridin-1(2H)-yl)-7,8-dihydronaphthalen-2-yl)phenyl)piperidine-2,6-dione

[1009] 3-(2-chloro-3-(6-(4-chloro-2-oxopyridin-1(2H)-yl)-7,8-dihydronaphth-2-yl)phenyl)piperidin-2,6-dione

[1010] first step

[1011] 1-(6-bromo-3,4-dihydronaphthalen-2-yl)-4-chloropyridin-2(1H)-one

[1012] 1-(6-bromo-3,4-dihydronaphth-2-yl)-4-chloropyridin-2(1H)-one

[1013] and

[1014] 2-((6-bromo-3,4-dihydronaphthalen-2-yl)oxy)-4-chloropyridine

[1015] 2-((6-bromo-3,4-dihydronaphth-2-yl)oxy)-4-chloropyridine

[1016] (6-bromo-3,4-dihydronaphthyl-2-yl)boronic acid 41c (50 mg, 197.71 μmol) and 4-chloropyridin-2(1H)-one (31 mg, 237.25 μmol) were dissolved in dichloroethane (2 mL), and copper acetate (36 mg, 197.71 μmol) and triethylamine (60 mg, 593.12 μmol) were added. The reaction mixture was stirred at room temperature under an oxygen atmosphere for 16 hours, and the reaction was monitored by LCMS. The reaction was quenched with water (10 mL) and then extracted with dichloromethane (10 mL × 3). The combined organic phases were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Purification was performed using silica gel column chromatography (developing solvent: system A) to obtain 1-(6-bromo-3,4-dihydronaphth-2-yl)-4-chloropyridin-2(1H)-one 43a (10 mg), which was identified as the target compound by mass spectrometry, nuclear magnetic resonance (NMR), and two-dimensional NMR, with a yield of 15.0%; 2-((6-bromo-3,4-dihydronaphth-2-yl)oxy)-4-chloropyridinium 43b (10 mg) was also identified as the target compound by mass spectrometry, NMR, and two-dimensional NMR, with a yield of 15%.

[1017] 43a:

[1018] MS m / z (ESI): 336.0 [M+1]

[1019] 1 H NMR (400MHz, DMSO) δ7.79(d,J=7.2Hz,1H),7.51(s,1H),7.47(d,J=8.0Hz,1H),7.21(d,J=8.0Hz,1 H), 6.72 (s, 1H), 6.66 (s, 1H), 6.49 (d, J = 7.2Hz, 1H), 3.02 (t, J = 8.0Hz, 2H), 2.64 (t, J = 8.0Hz, 2H).

[1020] 43b:

[1021] MS m / z (ESI): 336.0 [M+1]

[1022] 1 ¹H NMR (400MHz, DMSO) δ 8.28 (d, J = 5.2Hz, 1H), 7.43 (s, 1H), 7.40–7.33 (m, 2H), 7.31 (s, 1H), 7.06 (d, J = 8.0Hz, 1H), 6.25 (s, 1H), 3.02 (t, J = 8.0Hz, 2H), 2.55 (t, J = 8.0Hz, 2H). Second step

[1023] 3-(2-chloro-3-(6-(4-chloro-2-oxopyridin-1(2H)-yl)-7,8-dihydronaphthalen-2-yl)phenyl)piperidine-2,6-dione

[1024] 3-(2-chloro-3-(6-(4-chloro-2-oxopyridin-1(2H)-yl)-7,8-dihydronaphth-2-yl)phenyl)piperidin-2,6-dione

[1025] 1-(6-bromo-3,4-dihydronaphthyl-2-yl)-4-chloropyridin-2(1H)-one 43a (15 mg, 44.56 μmol) and 3-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxoborhexacyclopentan-2-yl)phenyl)piperidin-2,6-dione 18a (20 mg, 57.93 μmol) were dissolved in a solution of 1,4-dioxane (2 mL) and water (0.2 mL). Potassium carbonate (18 mg, 133.69 μmol) and [1,1'-bis(di-tert-butylphosphine)ferrocene]palladium dichloride (3 mg, 4.46 μmol) were then added. The reaction mixture was then reacted at 80 °C under nitrogen protection for 2 hours, and the reaction was monitored by LCMS. After the reaction was completed, the mixture was filtered and concentrated, and then purified by preparative liquid chromatography (Waters 3767 / QDA column: Green ODS, 30*150mm, 5μm; mobile phase A: 0.1% FA / H2O, mobile phase B: ACN; flow rate: 30mL / min; gradient: 55-65%; retention time: 9.2min) to obtain 43 (2.04mg) of 3-(2-chloro-3-(6-(4-chloro-2-oxopyridin-1(2H)-yl)-7,8-dihydronaphth-2-yl)phenyl)piperidin-2,6-dione, with a yield of 9.4%.

[1026] MS m / z (ESI): 479.2 [M+1]

[1027] 1 H NMR(400MHz,DMSO-d6)δ10.92(s,1H),7.76(d,J=7.2Hz,1H),7.43–7.35(m,2H ),7.29–7.22(m,1H),7.28–7.23(m,3H),6.71(s,1H),6.61(d,J=2.4Hz,1H),6 .45(dd,J=7.2,2.4Hz,1H),4.34(d,J=12.4,5.2Hz,1H),3.01(t,J=8.0Hz,2H) ,2.83–2.74(m,1H),2.64–2.60(m,2H),2.59–2.55(m,2H),2.09–2.02(m,1H).

[1028] Example 44

[1029] 3-(2-chloro-3-(6-((4-chloropyridin-2-yl)oxy)-7,8-dihydronaphthalen-2-yl)phenyl)piperidine-2,6-dione

[1030] 3-(2-chloro-3-(6-((4-chloropyridin-2-yl)oxy)-7,8-dihydronaphth-2-yl)phenyl)piperidin-2,6-dione

[1031] first step

[1032] 3-(2-chloro-3-(6-((4-chloropyridin-2-yl)oxy)-7,8-dihydronaphthalen-2-yl)phenyl)piperidine-2,6-dione

[1033] 3-(2-chloro-3-(6-((4-chloropyridin-2-yl)oxy)-7,8-dihydronaphth-2-yl)phenyl)piperidin-2,6-dione

[1034] 2-((6-bromo-3,4-dihydronaphthyl-2-yl)oxy)-4-chloropyridine 43b (30 mg, 89.12 μmol) and 3-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxoborhexacyclopentan-2-yl)phenyl)piperidine-2,6-dione 18a (40 mg, 115.86 μmol) were dissolved in a solution of 1,4-dioxane (2 mL) and water (0.2 mL). Potassium carbonate (37 mg, 267.37 μmol) and [1,1'-bis(di-tert-butylphosphine)ferrocene]palladium dichloride (6 mg, 8.91 μmol) were then added. The reaction mixture was then reacted at 80 °C under nitrogen protection for 2 hours, and the reaction was monitored by LCMS. After the reaction was completed, the mixture was filtered and concentrated, and then purified by preparative HPLC (Waters 3767 / QDA column: Green ODS, 30*150mm, 5μm; mobile phase A: 0.1% FA / H2O, mobile phase B: ACN; flow rate: 30mL / min; gradient: 70-80% retention time: 9.2min) to obtain 44 (2.29mg) of 3-(2-chloro-3-(6-((4-chloropyridin-2-yl)oxy)-7,8-dihydronaphthyl-2-yl)phenyl)piperidin-2,6-dione, yield 5.4%.

[1035] MS m / z (ESI): 479.2 [M]

[1036] 1H NMR(400MHz,DMSO-d6)δ10.92(s,1H),8.23(d,J=5.2Hz,1H),7.41–7.33(m ,2H),7.32–7.29(m,2H),7.28–7.26(m,1H),7.22–7.16(m,2H),7.15–7.11 (m,1H),6.27(s,1H),4.34(d,J=12.0,5.2Hz,1H),3.02(t,J=8.0Hz,2H),2 .87–2.72(m,1H),2.59–2.53(m,3H),2.40–2.27(m,1H),2.10–2.00(m,1H).

[1037] Example 45

[1038] 3-(2-chloro-3-(6-(3-methyl-2-oxotetrahydropyrimidin-1(2H)-yl)-7,8-dihydronaphthalen-2-yl)phenyl)piperidine-2,6-dione

[1039] 3-(2-chloro-3-(6-(3-methyl-2-oxotetrahydropyrimidin-1(2H)-yl)-7,8-dihydronaphth-2-yl)phenyl)piperidin-2,6-dione

[1040] first step

[1041] 1-(6-bromo-3,4-dihydronaphthalen-2-yl)-3-methyltetrahydropyrimidin-2(1H)-one

[1042] 1-(6-bromo-3,4-dihydronaphthyl-2-yl)-3-methyltetrahydropyrimidin-2(1H)-one

[1043] 6-Bromo-3,4-dihydronaphthyl-2-yltrifluoromethanesulfonate 41a (320 mg, 896.00 μmol) and 1-methyltetrahydropyrimidin-2(1H)-one (122 mg, 1.08 mmol) were dissolved in N,N-dimethylformamide (2 mL), and cesium carbonate (875 mg, 2.69 mmol), tris(dibenzylacetone)dipalladium (61 mg, 89.60 μmol), and 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (103 mg, 179.20 μmol) were added. The reaction mixture was then reacted at 110 °C under nitrogen protection for 16 hours. The reaction was monitored by LCMS. After the reaction was completed, the reactants were directly concentrated, and the residue was purified by silica gel column chromatography (developing solvent: system A) to obtain 1-(6-bromo-3,4-dihydronaphthyl-2-yl)-3-methyltetrahydropyrimidine-2(1H)-one 45a (50 mg), with a yield of 17.4%.

[1044] MS m / z (ESI): 321.1 [M+1]

[1045] 1 H NMR(400MHz,DMSO-d6)δ7.28(d,J=9.6Hz,2H),6.96(d,J=8.0Hz,1H),6.07(s,1H),3.56(t,J=5.6Hz,2H), 3.26(t,J=6.0Hz,2H),2.83(s,3H),2.75(d,J=9.6,6.4Hz,2H),2.54(d,J=8.4Hz,2H),2.02–1.93(m,2H).

[1046] Step 2

[1047] 3-(2-chloro-3-(6-(3-methyl-2-oxotetrahydropyrimidin-1(2H)-yl)-7,8-dihydronaphthalen-2-yl)phenyl)piperidine-2,6-dione

[1048] 3-(2-chloro-3-(6-(3-methyl-2-oxotetrahydropyrimidin-1(2H)-yl)-7,8-dihydronaphth-2-yl)phenyl)piperidin-2,6-dione

[1049] 1-(6-bromo-3,4-dihydronaphthyl-2-yl)-3-methyltetrahydropyrimidin-2(1H)-one 45a (20 mg, 62.26 μmol) and 3-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxoborhexacyclopentan-2-yl)phenyl)piperidin-2,6-dione 18a (28 mg, 80.94 μmol) were dissolved in a solution of 1,4-dioxane (1 mL) and water (0.1 mL). Potassium carbonate (26 mg, 186.79 μmol) and [1,1'-bis(di-tert-butylphosphine)ferrocene]palladium dichloride (4 mg, 6.23 μmol) were then added. The reaction mixture was then reacted at 80 °C under nitrogen protection for 2 hours, and the reaction was monitored by LCMS. After the reaction was completed, the mixture was filtered and concentrated, and then purified by preparative liquid chromatography (Waters 3767 / QDA column: Green ODS, 30*150mm, 5μm; mobile phase A: 0.1% FA / H2O, mobile phase B: ACN; flow rate: 20mL / min; gradient: 49-57% retention time: 9.3-9.8min, 18min) to obtain 45 (3.22mg) of 3-(2-chloro-3-(6-(3-methyl-2-oxotetrahydropyrimidin-1(2H)-yl)-7,8-dihydronaphth-2-yl)phenyl)piperidin-2,6-dione, with a yield of 10.9%.

[1050] MS m / z (ESI): 464.0 [M+1]

[1051] 1 H NMR (400MHz, DMSO-d6) δ10.91(s,1H),7.42–7.26(m,3H),7.18–7.04(m,3H),6.15(s,1H),4.38–4.29(m,1H),3.63–3.55( m,2H),3.30–3.24(m,2H),2.90–2.83(m,4H),2.82–2.74(m,2H),2.62–2.55(m,3H),2.39–2.25(m,1H),2.12–1.92(m,3H).

[1052] Example 46

[1053] 3-(2-chloro-3-(8-methoxy-6-(2-oxopyridin-1(2H)-yl)naphthalen-2-yl)phenyl)piperidine-2,6-dione

[1054] 3-(2-chloro-3-(8-methoxy-6-(2-oxopyridin-1(2H)-yl)naphth-2-yl)phenyl)piperidin-2,6-dione

[1055] first step

[1056] ethyl 4-(4-chlorophenyl)-3-methylbut-2-enoate

[1057] Ethyl 4-(4-chlorophenyl)-3-methylbut-2-enoate

[1058] At room temperature, sodium hydroxide (417.47 mg, 10.44 mmol) and tetrahydrofuran (10 mL) were added to a reaction flask. Under argon atmosphere and at 0–5 °C, diethyl(2-ethoxy-2-oxoethyl)phosphonate (2.34 g, 10.44 mmol) was added to the reaction solution. The reaction solution was stirred at 0–5 °C for 0.5 h. 1-(4-chlorophenyl)prop-2-one 46a (1.6 g, 9.49 mmol) was added dropwise to the reaction solution. The reaction solution was stirred at 0–25 °C for 12 h. Ethyl acetate (15 mL * 3) and water (10 mL) were added to the reaction solution, and the organic phase was evaporated to dryness. Purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:10), ethyl 4-(4-chlorophenyl)-3-methylbut-2-enoate 46b (1.8 g) was obtained, yield: 79.5%.

[1059] Step 2

[1060] 7-chloro-3-methylnaphthalen-1-ol

[1061] 7-Chloro-3-methylnaphthalene-1-ol

[1062] Ethyl 4-(4-chlorophenyl)-3-methylbut-2-enoate 46b (1.6 g, 9.49 mmol) was added to a reaction flask containing concentrated sulfuric acid (6 mL) at room temperature and stirred at 50 °C for 1.5 h. The reaction mixture was slowly poured into ice water (20 mL), extracted with ethyl acetate (20 mL x 3), and the organic phase was washed with water (20 mL x 2) and evaporated to dryness. Purification by silica gel column chromatography (0–15% ethyl acetate / petroleum ether) yielded 7-chloro-3-methylnaphthalene-1-ol 46c (400 mg), yield: 49.6%.

[1063] 1 H NMR (400MHz, DMSO-d6) δ10.25(s,1H),8.01(d,J=2.4Hz,1H),7.76(d,J=8.8Hz,1 H),7.42(dd,J=8.8,2.4Hz,1H),7.16(s,1H),6.76(d,J=1.4Hz,1H),2.37(s,3H).

[1064] Step 3

[1065] 7-chloro-1-methoxy-3-methylnaphthalene

[1066] 7-Chloro-1-methoxy-3-methylnaphthalene

[1067] At room temperature, 7-chloro-3-methylnaphthalene-1-ol 46c (4.2 g, 21.80 mmol), potassium carbonate (6.33 g, 45.78 mmol), and N,N-dimethylformamide (42 mL) were added sequentially to a reaction flask. Iodomethane (4.64 g, 32.70 mmol) was added dropwise to the reaction solution at 0–5 °C. The reaction solution was stirred at 25 °C for 2 hours. Ethyl acetate (50 mL x 3) and water (70 mL) were added to the reaction solution, and the organic phase was washed with water (60 mL x 2) and evaporated to dryness. Purification by column chromatography yielded 7-chloro-1-methoxy-3-methylnaphthalene 46d (3 g), yield: 66.6%.

[1068] 1 H NMR (400MHz, DMSO-d6) δ8.02(d,J=2.2Hz,1H),7.81(d,J=8.8Hz,1H),7.48(dd,J=8.8,2.2 Hz,1H),7.29(d,J=1.6Hz,1H),6.90(d,J=1.4Hz,1H),3.96(s,3H),2.45(d,J=1.0Hz,3H).

[1069] Step 4

[1070] 7-chloro-3-(dibromomethyl)-1-methoxynaphthalene

[1071] 7-Chloro-3-(dibromomethyl)-1-methoxynaphthalene

[1072] At room temperature, 7-chloro-1-methoxy-3-methylnaphthalene 46d (138 mg, 667.74 μmol), N-bromosuccinimide (169.28 mg, 868.06 μmol), carbon tetrachloride (4 mL), and 2-2'-azobisisobutyronitrile (16.45 mg, 100.16 μmol) were sequentially added to a reaction flask. The reaction mixture was stirred at 80 °C under argon protection for 24 hours. Dichloromethane (10 mL x 3) and water (10 mL) were added to the reaction mixture, and the organic phase was washed with water (15 mL) and evaporated to dryness. 7-chloro-3-(dibromomethyl)-1-methoxynaphthalene 46e (160 mg) was obtained, yield: 65.7%.

[1073] Step 5

[1074] 6-chloro-4-methoxy-2-naphthaldehyde

[1075] 6-Chloro-4-methoxy-2-naphthaldehyde

[1076] At room temperature, 7-chloro-3-(dibromomethyl)-1-methoxynaphthalene 46e (160 mg, 439.01 μmol), 1,4-dioxane (2 mL), and saturated sodium carbonate aqueous solution (2 M, 2 mL) were sequentially added to a reaction flask, and the reaction mixture was stirred at 70 °C for 2 hours. Dichloromethane (10 mL x 3) and water (10 mL) were added to the reaction mixture, and the organic phase was washed with water (15 mL) and evaporated to dryness. Purification was performed by silica gel column chromatography (0–15% ethyl acetate / petroleum ether) to give 6-chloro-4-methoxy-2-naphthaldehyde 46f (21 mg), yield: 21.7%.

[1077] 1 H NMR (400MHz, DMSO-d6) δ10.10(s,1H),8.26–8.15(m,3H),7.72(dd,J=8.8,2.2Hz,1H),7.32(s,1H),4.06(s,3H).

[1078] Step 6

[1079] 6-chloro-4-methoxy-2-naphthoic acid

[1080] 6-Chloro-4-methoxy-2-naphthoic acid

[1081] At room temperature, 46f of 6-chloro-4-methoxy-2-naphthaldehyde (150 mg, 679.81 μmol) was added to dimethyl sulfoxide (4 mL), water (3 mL), and acetonitrile (6 mL). Sodium dihydrogen phosphate (244.68 mg, 2.04 mmol) was added to the reaction solution, and sodium chlorite (245.93 mg, 2.72 mmol) was added dropwise to the reaction solution. The reaction was carried out at 25 °C for 10 min, and the reaction solution was stirred at 25 °C for 30 min. Dichloromethane (15 mL x 3) and water (15 mL) were added to the reaction solution. The organic phase was washed with water (20 mL) and evaporated to dryness. The solution was purified by silica gel column chromatography (0–15% methanol / dichloromethane) to obtain 46 g (120 mg) of 6-chloro-4-methoxy-2-naphtholic acid, yield: 74.6%.

[1082] 1H NMR (400MHz, DMSO-d6) δ13.22(s,1H),8.24(s,1H),8.18–8.12(m,2H),7.65(dd,J=8.8,2.2Hz,1H),7.43(s,1H),4.04(s,3H).

[1083] Step 7

[1084] 7-chloro-3-iodo-1-methoxynaphthalene

[1085] 7-Chloro-3-iodo-1-methoxynaphthalene

[1086] At room temperature, 46 g (170 mg, 718.36 μmol) of 6-chloro-4-methoxy-2-naphthoic acid, 15 mL of toluene, tris(dibenzylacetone)dipalladium (65.78 mg, 71.84 μmol), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (83.13 mg, 143.67 μmol), 1,8-bis(dimethylamino)naphthalene (169.34 mg, 790.19 μmol), 1-(chloro-1-pyrrolylmethylene)pyrrolidineonium hexafluorophosphate (334.55 mg, 1.01 mmol), and 1-iodobutane (290.82 mg, 1.58 mmol) were added sequentially to a reaction flask. The reaction mixture was stirred at 100 °C under argon protection for 16 h. Ethyl acetate (15 mL * 3) and water (15 mL) were added to the reaction solution. The organic phase was washed with water (20 mL) and evaporated to dryness. The solution was purified by silica gel column chromatography (0–15% ethyl acetate / petroleum ether) to give 7-chloro-3-iodo-1-methoxynaphthalene 46 h (15 mg), yield: 6.56%.

[1087] 1 H NMR (400MHz, Chloroform-d) δ8.10(d,J=2.0Hz,1H),7.72(s,1H),7.52(d,J=8.8Hz,1H),7.35(dd,J=8.8,2.0Hz,1H),6.98(s,1H),3.91(s,3H).

[1088] Step 8

[1089] 1-(6-chloro-4-methoxynaphthalen-2-yl)pyridin-2(1H)-one

[1090] 1-(6-chloro-4-methoxynaphth-2-yl)pyridin-2(1H)-one

[1091] At room temperature, 7-chloro-3-iodo-1-methoxynaphthalene (200 mg, 627.87 μmol), pyridin-2(1H)-one (77.62 mg, 816.23 μmol), potassium phosphate (333.19 mg, 1.57 mmol), 1,10-phenanthroline (56.60 mg, 314.08 μmol), cuprous iodide (59.79 mg, 313.93 μmol), and N,N-dimethylformamide (15 mL) were sequentially added to a reaction flask. The reaction mixture was stirred at 140 °C under argon protection for 4 h. Ethyl acetate (15 mL * 3) and water (15 mL) were added to the reaction mixture. The organic phase was washed with water (20 mL) and evaporated to dryness. Purified by silica gel column chromatography (0-50% ethyl acetate / petroleum ether), 46i (123 mg) of 1-(6-chloro-4-methoxynaphth-2-yl)pyridin-2(1H)-one were obtained, yield: 68.5%.

[1092] MS m / z(ESI): 286.0 [M+1]

[1093] Step 9

[1094] 1-(4-methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-yl)pyridin-2(1H)-one

[1095] 1-(4-methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)naphth-2-yl)pyridin-2(1H)-one

[1096] At room temperature, 1-(6-chloro-4-methoxynaphthyl-2-yl)pyridine-2(1H)-one 46i (55 mg, 192.49 μmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxoborane) (146.64 mg, 577.48 μmol), palladium acetate (21.61 mg, 96.25 μmol), potassium acetate (154.00 mg, 1.57 mmol), dicyclohexyl-[2-[2,4,6-tris(propyl-2-yl)phenyl]phenyl]phosphine (91.76 mg, 192.49 μmol) and dioxane (10 mL) were added sequentially to a reaction flask. The reaction solution was stirred at 100 °C under argon protection for 5 h. Ethyl acetate (20 mL * 3) and water (20 mL) were added to the reaction solution. The organic phase was washed with water (25 mL) and evaporated to dryness. Purification by silica gel column chromatography (0–70% ethyl acetate / petroleum ether) yielded 46 mg (42.3 mg) of 1-(4-methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)naphth-2-yl)pyridin-2(1H)-one, yield: 58.2%.

[1097] MS m / z(ESI): 378.2 [M+1]

[1098] Step 10

[1099] 3-(2-chloro-3-(8-methoxy-6-(2-oxopyridin-1(2H)-yl)naphthalen-2-yl)phenyl)piperidine-2,6-dione

[1100] 3-(2-chloro-3-(8-methoxy-6-(2-oxopyridin-1(2H)-yl)naphth-2-yl)phenyl)piperidin-2,6-dione

[1101] At room temperature, 46 mg (68 mg, 180.26 μmol) of 1-(4-methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)naphth-2-yl)pyridin-2(1H)-one, 70.90 mg (234.33 μmol) of 3-(3-bromo-2-chlorophenyl)piperidine-2,6-dione, 45.43 mg (540.77 μmol) of sodium bicarbonate, 26.23 mg (36.05 μmol) of [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride, 10 mL of dioxane, and 2 mL of water were added sequentially to a reaction flask. The reaction mixture was stirred at 90 °C under argon protection for 3 h. Ethyl acetate (15 mL * 3) and water (15 mL) were added to the reaction solution. The organic phase was washed with water (20 mL) and evaporated to dryness. A chromatography plate (petroleum ether: ethyl acetate = 1:1) was prepared to give 46 (60 mg) of 3-(2-chloro-3-(8-methoxy-6-(2-oxopyridin-1(2H)-yl)naphth-2-yl)phenyl)piperidin-2,6-dione, yield: 69.5%.

[1102] MS m / z(ESI): 473.1 [M+1]

[1103] 1 H NMR(400MHz,Chloroform-d)δ8.23(s,1H),8.04(s,1H),7.79(d,J=8.4Hz,1H),7.55(d,J=8.4Hz,1H),7.37(dd,J=23.8,7.2Hz,5H),6.8 2(s,1H),6.70(d,J=8.8Hz,1H),6.26(t,J=6.6Hz,1H),4.27(dd,J=10.8,5.4Hz,1H),3.95(s,3H),2.78–2.61(m,2H),2.34–2.19(m,2H).

[1104] Example 47

[1105] 3-(2-chloro-3-(6-((6-methoxypyridin-2-yl)oxy)naphthalen-2-yl)phenyl)piperidine-2,6-dione

[1106] 3-(2-chloro-3-(6-((6-methoxypyridin-2-yl)oxy)naphth-2-yl)phenyl)piperidin-2,6-dione

[1107] first step

[1108] 2-((6-bromonaphthalen-2-yl)oxy)-6-methoxypyridine

[1109] 2-((6-bromonaphth-2-yl)oxy)-6-methoxypyridine

[1110] At room temperature, (6-bromonaphthyl-2-yl)boronic acid 14a (250 mg, 0.99 mmol), 6-methoxypyridin-2(1H)-one (150 mg, 1.20 mmol), copper acetate (72.4 mg, 0.40 mmol), pyridine (156 mg, 1.99 mmol), triethylamine (202 mg, 1.99 mmol), and dichloromethane (10 mL) were added sequentially to a reaction flask and stirred overnight under oxygen conditions. The reaction mixture was checked by LCMS to ensure complete reaction of the starting materials. Dichloromethane (50 mL) and water (20 mL) were added to the reaction mixture. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. Purification was performed by silica gel column chromatography (petroleum ether / ethyl acetate = 3:1) to give 2-((6-bromonaphthyl-2-yl)oxy)-6-methoxypyridine 47a (30 mg), yield: 9.2%.

[1111] MS m / z(ESI): 330.0 [M+1]

[1112] Step 2

[1113] 2-methoxy-6-((6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-yl)oxy)pyridine

[1114] 2-Methoxy-6-((6-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)naphth-2-yl)oxy)pyridine

[1115] At room temperature, 2-((6-bromonaphthyl-2-yl)oxy)-6-methoxypyridine 47a (30 mg, 0.09 mmol), pinacol diboronate (35 mg, 0.13 mmol), [1,1-bis(diphenylphosphino)ferrocene]palladium dichloride (15 mg, 0.02 mmol), potassium acetate (30 mg, 0.30 mmol), and 1,4-dioxane (5 mL) were added sequentially to a reaction flask. After purging with nitrogen three times, the mixture was heated to 100°C and stirred for 2 hours. LC-MS analysis confirmed complete reaction of the starting materials. The reaction solution was used directly in the next step without further treatment. MS m / z (ESI): 378.2 [M+1]

[1116] Step 3

[1117] 3-(2-chloro-3-(6-((6-methoxypyridin-2-yl)oxy)naphthalen-2-yl)phenyl)piperidine-2,6-dione

[1118] 3-(2-chloro-3-(6-((6-methoxypyridin-2-yl)oxy)naphth-2-yl)phenyl)piperidin-2,6-dione

[1119] At room temperature, 2-methoxy-6-((6-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)naphth-2-yl)oxy)pyridine 47b (35 mg, 0.09 mmol), 3-(3-bromo-2-chloro-phenyl)piperidine-2,6-dione 1a (40 mg, 0.13 mmol), 1,1-bis(diphenylphosphine)ferrocene]palladium dichloride (15 mg, 0.02 mmol), sodium bicarbonate (40.0 mg, 0.45 mmol), 1,4-dioxane (5 mL), and water (1 mL) were added sequentially to a reaction flask. After purging with nitrogen three times, the mixture was heated to 90°C and stirred for 3 hours. The reaction was confirmed to be complete by LCMS. Dichloromethane (50 mL) and water (20 mL) were added to the reaction solution. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The mixture was purified by reverse-phase preparation to yield 47 (8 mg) of 3-(2-chloro-3-(6-((6-methoxypyridin-2-yl)oxy)naphth-2-yl)phenyl)piperidin-2,6-dione, yield: 17.7%.

[1120] MS m / z(ESI): 473.1 [M+1]

[1121] 1 H NMR (400MHz, DMSO-d6) δ10.95(s,1H),8.05(d,J=9.0Hz,1H),7.97(d,J=8.5Hz,2H),7.81–7.72(m,2H),7.57(d,J=8.5Hz,1H),7.48–7.39(m,4H) ,6.58(t,J=7.5Hz,2H),4.38(dd,J=12.3,4.9Hz,1H),3.67(s,3H),2.87 –2.76(m,1H),2.60–2.53(m,1H),2.43–2.35(m,1H),2.12–2.03(m,1H).

[1122] Example 48

[1123] 3-(2-chloro-3-(6-(4-methyl-2-oxopyridin-1(2H)-yl)naphthalen-2-yl)phenyl)piperidine-2,6-dione

[1124] 3-(2-chloro-3-(6-(4-methyl-2-oxopyridin-1(2H)-yl)naphth-2-yl)phenyl)piperidin-2,6-dione

[1125] first step

[1126] 1-(6-bromonaphthalen-2-yl)-4-methylpyridin-2(1H)-one

[1127] 1-(6-bromonaphth-2-yl)-4-methylpyridin-2(1H)-one

[1128] At room temperature, (6-bromonaphthyl-2-yl)boronic acid 14a (160 mg, 0.63 mmol), 4-methylpyridin-2(1H)-one (128 mg, 1.20 mmol), copper acetate (72.4 mg, 0.40 mmol), pyridine (156 mg, 1.99 mmol), triethylamine (202 mg, 1.99 mmol), and dichloromethane (10 mL) were added sequentially to a reaction flask and stirred overnight under oxygen conditions. The reaction mixture was checked by LCMS to ensure complete reaction of the starting materials. Dichloromethane (50 mL) and water (20 mL) were added to the reaction mixture. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. Purification by silica gel column chromatography (petroleum ether / ethyl acetate = 3:1) yielded 1-(6-bromonaphthyl-2-yl)-4-methylpyridin-2(1H)-one 48a (90 mg), yield: 45.0%.

[1129] MS m / z(ESI): 314.0 [M+1]

[1130] Step 2

[1131] 4-methyl-1-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-yl)pyridin-2(1H)-one

[1132] 4-Methyl-1-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)naphth-2-yl)pyridin-2(1H)-one

[1133] At room temperature, 1-(6-bromonaphthyl-2-yl)-4-methylpyridin-2(1H)-one 48a (50 mg, 0.16 mmol), pinacol diboronate (60 mg, 0.23 mmol), [1,1-bis(diphenylphosphino)ferrocene]palladium dichloride (15 mg, 0.02 mmol), potassium acetate (45 mg, 0.46 mmol), and 1,4-dioxane (10 mL) were added sequentially to a reaction flask. After purging with nitrogen three times, the mixture was heated to 100°C and stirred for 2 hours. LC-MS analysis confirmed complete reaction of the starting materials. The reaction solution was used directly in the next step without further treatment. MS m / z (ESI): 362.2 [M+1]

[1134] Step 3

[1135] 3-(2-chloro-3-(6-(4-methyl-2-oxopyridin-1(2H)-yl)naphthalen-2-yl)phenyl)piperidine-2,6-dione

[1136] 3-(2-chloro-3-(6-(4-methyl-2-oxopyridin-1(2H)-yl)naphth-2-yl)phenyl)piperidin-2,6-dione

[1137] At room temperature, 4-methyl-1-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)naphth-2-yl)pyridin-2(1H)-one 48b (50 mg, 0.14 mmol), 3-(3-bromo-2-chloro-phenyl)piperidin-2,6-dione 1a (50 mg, 0.17 mmol), 1,1-bis(diphenylphosphine)ferrocene]palladium dichloride (15 mg, 0.02 mmol), sodium bicarbonate (40.0 mg, 0.45 mmol), 1,4-dioxane (5 mL), and water (1 mL) were added sequentially to a reaction flask. After purging with nitrogen three times, the mixture was heated to 90°C and stirred for 3 hours. The reaction proceeded to completion as determined by LC-MS. Dichloromethane (50 mL) and water (20 mL) were added to the reaction solution. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. After reverse-phase purification, 48 (20 mg) of 3-(2-chloro-3-(6-(4-methyl-2-oxopyridin-1(2H)-yl)naphth-2-yl)phenyl)piperidin-2,6-dione was obtained, yield: 31.2%.

[1138] MS m / z(ESI): 457.1 [M+1]

[1139] 1H NMR (400MHz, DMSO-d6) δ10.95 (s, 1H), 8.09-8.01 (m, 4H), 7.69 (d, J = 7.0Hz ,1H),7.63(d,J=8.5Hz,1H),7.57(d,J=8.8Hz,1H),7.49-7.42(m,3H),6.35 (s,1H),6.25(d,J=7.0Hz,1H),4.38(dd,J=12.2,4.9Hz,1H),2.87–2.75(m, 1H),2.58-2.55(m,1H),2.40-2.34(m,1H),2.23(s,3H),2.10-2.06(m,1H).

[1140] Example 49

[1141] 3-(2-chloro-3-(6-(1-methyl-1H-pyrazol-3-yl)naphthalen-2-yl)phenyl)piperidine-2,6-dione

[1142] 3-(2-chloro-3-(6-(1-methyl-1H-pyrazol-3-yl)naphth-2-yl)phenyl)piperidin-2,6-dione

[1143] first step

[1144] 3-(6-bromonaphthalen-2-yl)-1-methyl-1H-pyrazole

[1145] 3-(6-bromonaphth-2-yl)-1-methyl-1H-pyrazole

[1146] At room temperature, 2,6-dibromonaphthalene 49a (600 mg, 2.10 mmol), 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)pyrazole (440 mg, 2.10 mmol), tetra(triphenylphosphine)palladium (50 mg, 0.04 mmol), potassium carbonate (580 mg, 4.20 mmol), 1,4-dioxane (15 ml), and water (2 ml) were added sequentially to a reaction flask. After purging with nitrogen three times, the mixture was heated to 70°C and stirred for 3 hours. LC-MS analysis confirmed complete reaction of the starting materials. Ethyl acetate (150 ml) and water (50 ml) were added to the reaction mixture. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. Purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:1), 3-(6-bromonaphthyl-2-yl)-1-methyl-1H-pyrazole 49b (260 mg) was obtained in 43.1% MS m / z (ESI): 287.0 [M+1]

[1147] Step 2

[1148] 1-methyl-3-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-yl)-1H-pyrazole

[1149] 1-Methyl-3-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)naphth-2-yl)-1H-pyrazole

[1150] At room temperature, 3-(6-bromonaphthyl-2-yl)-1-methyl-1H-pyrazole 49b (55 mg, 0.19 mmol), pinacol diboronate (75 mg, 0.29 mmol), [1,1-bis(diphenylphosphino)ferrocene]palladium dichloride (15 mg, 0.02 mmol), potassium acetate (45 mg, 0.46 mmol), and 1,4-dioxane (10 mL) were added sequentially to a reaction flask. After purging with nitrogen three times, the mixture was heated to 100°C and stirred for 2 hours. LC-MS analysis confirmed complete reaction of the starting materials. The reaction solution was used directly in the next step without further treatment. MS m / z (ESI): 335.2 [M+1]

[1151] Step 3

[1152] 3-(2-chloro-3-(6-(1-methyl-1H-pyrazol-3-yl)naphthalen-2-yl)phenyl)piperidine-2,6-dione

[1153] 3-(2-chloro-3-(6-(1-methyl-1H-pyrazol-3-yl)naphth-2-yl)phenyl)piperidin-2,6-dione

[1154] At room temperature, 1-methyl-3-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)naphth-2-yl)-1H-pyrazole 49c (65 mg, 0.19 mmol), 3-(3-bromo-2-chloro-phenyl)piperidin-2,6-dione 1a (65 mg, 0.21 mmol), 1,1-bis(diphenylphosphine)ferrocene]palladium dichloride (15 mg, 0.02 mmol), sodium bicarbonate (40.0 mg, 0.45 mmol), 1,4-dioxane (5 mL), and water (1 mL) were added sequentially to a reaction flask. After purging with nitrogen three times, the mixture was heated to 90°C and stirred for 3 hours. The reaction was confirmed to be complete by LC-MS. Dichloromethane (50 mL) and water (20 mL) were added to the reaction solution. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The mixture was purified by reverse-phase preparation to yield 49 (15 mg) of 3-(2-chloro-3-(6-(1-methyl-1H-pyrazol-3-yl)naphth-2-yl)phenyl)piperidin-2,6-dione, yield: 17.8%.

[1155] MS m / z(ESI): 430.1 [M+1]

[1156] 1 H NMR (400MHz, DMSO-d6) δ10.95(s,1H),8.37(s,1H),8.06-7.98(m,3H),7.93(s,1H),7.80(brs,1H),7.55(d,J=8.5Hz,1H),7.48–7.38(m,3 H),6.87(brs,1H),4.38(dd,J=12.2,5.0Hz,1H),3.94(s,3H),2.87–2.76(m,1H),2.60–2.52(m,1H),2.42-2.35(m,1H),2.10-2.05(m,1H).

[1157] Example 50

[1158] 3-(2-chloro-3-(6-(1-methyl-1H-pyrazol-4-yl)naphthalen-2-yl)phenyl)piperidine-2,6-dione

[1159] 3-(2-chloro-3-(6-(1-methyl-1H-pyrazol-4-yl)naphth-2-yl)phenyl)piperidin-2,6-dione

[1160] first step

[1161] 4-(6-bromonaphthalen-2-yl)-1-methyl-1H-pyrazole

[1162] 4-(6-bromonaphth-2-yl)-1-methyl-1H-pyrazole

[1163] At room temperature, 2,6-dibromonaphthalene 49a (560 mg, 1.96 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrazole (440 mg, 2.10 mmol), tetra(triphenylphosphine)palladium (50 mg, 0.04 mmol), potassium carbonate (580 mg, 4.20 mmol), 1,4-dioxane (15 mL), and water (2 mL) were added sequentially to a reaction flask. After purging with nitrogen three times, the mixture was heated to 70°C and stirred for 3 hours. LC-MS analysis confirmed the reaction was complete. Ethyl acetate (150 mL) and water (50 mL) were added to the reaction mixture. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. Purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:1), 4-(6-bromonaphthyl-2-yl)-1-methyl-1H-pyrazole 50a (250 mg) was obtained in 44.5% yield.

[1164] MS m / z(ESI): 287.0 [M+1]

[1165] Step 2

[1166] 1-methyl-4-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-yl)-1H-pyrazole

[1167] 1-Methyl-4-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)naphth-2-yl)-1H-pyrazole

[1168] At room temperature, 4-(6-bromonaphthyl-2-yl)-1-methyl-1H-pyrazole 50a (110 mg, 383.07 μmol), pinacol diboronate (145.91 mg, 574.60 μmol), [1,1-bis(diphenylphosphino)ferrocene]palladium dichloride (27.87 mg, 38.31 μmol), potassium acetate (112.79 mg, 1.15 mmol), and 1,4-dioxane (10 mL) were sequentially added to a reaction flask. After purging with nitrogen three times, the mixture was heated to 100°C and stirred for 2 hours. LC-MS analysis confirmed complete reaction of the starting materials. The reaction solution was used directly in the next step without further treatment.

[1169] MS m / z(ESI): 335.2 [M+1]

[1170] Step 3

[1171] 3-(2-chloro-3-(6-(1-methyl-1H-pyrazol-4-yl)naphthalen-2-yl)phenyl)piperidine-2,6-dione

[1172] 3-(2-chloro-3-(6-(1-methyl-1H-pyrazol-4-yl)naphth-2-yl)phenyl)piperidin-2,6-dione

[1173] At room temperature, 1-methyl-4-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)naphth-2-yl)-1H-pyrazole 50b (65 mg, 0.19 mmol), 3-(3-bromo-2-chloro-phenyl)piperidin-2,6-dione 1a (65 mg, 0.21 mmol), 1,1-bis(diphenylphosphine)ferrocene]palladium dichloride (15 mg, 0.02 mmol), sodium bicarbonate (40.0 mg, 0.45 mmol), 1,4-dioxane (5 mL), and water (1 mL) were added sequentially to a reaction flask. After purging with nitrogen three times, the mixture was heated to 90°C and stirred for 3 hours. The reaction was confirmed to be complete by LCMS. Dichloromethane (50 mL) and water (20 mL) were added to the reaction solution. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. Purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:3), 50 (46 mg) of 3-(2-chloro-3-(6-(1-methyl-1H-pyrazol-4-yl)naphth-2-yl)phenyl)piperidin-2,6-dione was obtained, yield: 59.3%. MS m / z (ESI): 430.1 [M+1]

[1174] 1 H NMR (400MHz, DMSO-d6) δ10.94(s,1H),8.30(s,1H),8.14(s,1H),8.03(s,1H),7.99–7.88(m,3H),7.80(dd,J=8.5,1.7Hz,1H),7.54(dd,J=8.4,1.7 Hz,1H),7.47–7.38(m,3H),4.37(dd,J=12.2,5.0Hz,1H),3.91(s,3H),2. 85-2.76(m,1H),2.60–2.53(m,1H),2.42–2.32(m,1H),2.11–2.04(m,1H).

[1175] Example 51

[1176] 3-(2-chloro-3-(6-(6-oxopyridazin-1(6H)-yl)naphthalen-2-yl)phenyl)piperidine-2,6-dione

[1177] 3-(2-chloro-3-(6-(6-oxopyridazin-1(6H)-yl)naphth-2-yl)phenyl)piperidin-2,6-dione

[1178] first step

[1179] 2-(6-bromonaphthalen-2-yl)pyridazin-3(2H)-one

[1180] 2-(6-bromonaphth-2-yl)pyrazino[1,2-a]pyridin-3(2H)-one

[1181] At room temperature, (6-bromonaphth-2-yl)boronic acid 14a (100 mg, 0.40 mmol), 3-pyridazinone (60 mg, 0.62 mmol), copper acetate (72.4 mg, 0.40 mmol), pyridine (156 mg, 1.99 mmol), triethylamine (202 mg, 1.99 mmol), and dichloromethane (10 mL) were added sequentially to a reaction flask and stirred overnight under oxygen conditions. The reaction mixture was checked by LCMS to ensure complete reaction of the starting materials. Dichloromethane (50 mL) and water (20 mL) were added to the reaction mixture. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. Purification was performed by silica gel column chromatography (petroleum ether / ethyl acetate = 1:1) to give 2-(6-bromonaphth-2-yl)pyrazino[1,2-a]pyridin-3(2H)-one 51a (83 mg), yield: 69.1%.

[1182] MS m / z(ESI): 301.0 [M+1]

[1183] Step 2

[1184] 2-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-yl)pyridazin-3(2H)-one

[1185] 2-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)naphthyl-2-yl)pyridazin-3(2H)-one

[1186] At room temperature, 2-(6-bromonaphth-2-yl)pyrazino[1,2-a]pyridin-3(2H)-one 51a (83 mg, 0.26 mmol), pinacol diboronate (110 mg, 0.43 mmol), [1,1-bis(diphenylphosphino)ferrocene]palladium dichloride (15 mg, 0.02 mmol), potassium acetate (80 mg, 0.81 mmol), and 1,4-dioxane (10 mL) were sequentially added to a reaction flask. After purging with nitrogen three times, the mixture was heated to 100°C and stirred for 2 hours. The reaction proceeded to completion as determined by LC-MS. The reaction solution was evaporated to dryness and then purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:3) to give 2-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)naphthyl-2-yl)pyridazin-3(2H)-one 51b (90 mg), yield: 97.2%.

[1187] MS m / z(ESI): 349.2 [M+1]

[1188] Step 3

[1189] 3-(2-chloro-3-(6-(6-oxopyridazin-1(6H)-yl)naphthalen-2-yl)phenyl)piperidine-2,6-dione

[1190] 3-(2-chloro-3-(6-(6-oxopyridazin-1(6H)-yl)naphth-2-yl)phenyl)piperidin-2,6-dione

[1191] At room temperature, 2-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)naphthyl)pyridazin-3(2H)-one 51b (90 mg, 0.26 mmol), 3-(3-bromo-2-chloro-phenyl)piperidin-2,6-dione 1a (90 mg, 0.30 mmol), 1,1-bis(diphenylphosphino)ferrocene]palladium dichloride (15 mg, 0.02 mmol), sodium bicarbonate (70 mg, 0.83 mmol), 1,4-dioxane (10 mL), and water (1.5 mL) were added sequentially to a reaction flask. After purging with nitrogen three times, the mixture was heated to 90°C and stirred for 3 hours. The reaction was confirmed to be complete by LCMS. Dichloromethane (50 mL) and water (20 mL) were added to the reaction mixture. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. Purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:5), 51 (90 mg) of 3-(2-chloro-3-(6-(6-oxopyridazin-1(6H)-yl)naphth-2-yl)phenyl)piperidin-2,6-dione was obtained in yield of 77.8%. MS m / z (ESI): 444.1 [M+1]

[1192] 1 H NMR (400MHz, DMSO-d6) δ10.95 (s, 1H), 8.21 (brs, 1H), 8.14 (d, J = 3.9Hz, 1H), 8.09 (dd, J=8.7,2.5Hz,2H),8.03(s,1H),7.74(dd,J=8.8,2.0Hz,1H),7.63(d,J=8.5Hz,1H),7.5 6(dd,J=9.5,3.9Hz,1H),7.47-7.41(m,3H),7.14(d,J=9.5Hz,1H),4.39(dd,J=12.2,5 .0Hz,1H),2.85-2.77(m,1H),2.60-2.53(m,1H),2.42-2.38(m,1H),2.10-2.06(m,1H).

[1193] Example 52

[1194] 1-(6-(2-chloro-3-(2,6-dioxopiperidin-3-yl)phenyl)naphthalen-2-yl)-6-oxo-1,6-dihydropyridine-2-carbonitrile

[1195] 1-(6-(2-chloro-3-(2,6-dioxopiperidin-3-yl)phenyl)naphth-2-yl)-6-oxo-1,6-dihydropyridine-2-carboxynitrile)

[1196] first step

[1197] 1-(6-bromonaphthalen-2-yl)-6-oxo-1,6-dihydropyridine-2-carbonitrile

[1198] 1-(6-bromonaphth-2-yl)-6-oxo-1,6-dihydropyridine-2-carboxynitrile

[1199] At room temperature, (6-bromonaphth-2-yl)boronic acid 14a (470 mg, 1.87 mmol), 6-oxo-1,6-dihydropyridine-2-carboxynitrile (270.01 mg, 2.25 mmol), copper acetate (340.27 mg, 1.87 mmol), pyridine (296.37 mg, 3.75 mmol), triethylamine (379.13 mg, 3.75 mmol), and dichloromethane (15 mL) were added sequentially to a reaction flask. The mixture was kept under oxygen conditions at 10 °C and stirred for 18 hours. The reaction mixture was monitored by LCMS to ensure complete reaction of the starting materials. Dichloromethane (25 mL x 3) and water (20 mL) were added to the reaction mixture. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. Purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:1) to give 1-(6-bromonaphth-2-yl)-6-oxo-1,6-dihydropyridine-2-carboxynitrile 52a (65 mg), yield: 10.7%.

[1200] MS m / z(ESI): 325.0 [M+1]

[1201] Step 2

[1202] 6-oxo-1-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-yl)-1,6-dihydropyridine-2-carbonitrile

[1203] 6-Oxo-1-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)naphth-2-yl)-1,6-dihydropyridine-2-carboxynitrile

[1204] 1-(6-bromonaphthyl-2-yl)-6-oxo-1,6-dihydropyridine-2-carboxynitrile 52a (60 mg, 184.53 μmol), pinacol diboronate (93.72 mg, 369.05 μmol), [1,1-bis(diphenylphosphino)ferrocene]palladium dichloride (13.43 mg, 18.45 μmol), potassium acetate (90.55 mg, 922.63 μmol), and 1,4-dioxane (6 mL) were added sequentially to the reaction flask. After purging with argon three times, the mixture was heated to 100°C and stirred for 3 hours. LCMS analysis confirmed complete reaction of the starting materials. The reaction solution was used directly in the next step without further treatment.

[1205] MS m / z(ESI): 373.2 [M+1]

[1206] Step 3

[1207] 1-(6-(2-chloro-3-(2,6-dioxopiperidin-3-yl)phenyl)naphthalen-2-yl)-6-oxo-1,6-dihydropyridine-2-carbonitrile

[1208] 1-(6-(2-chloro-3-(2,6-dioxopiperidin-3-yl)phenyl)naphth-2-yl)-6-oxo-1,6-dihydropyridine-2-carboxynitrile)

[1209] At room temperature, 6-oxo-1-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)naphth-2-yl)-1,6-dihydropyridine-2-carboxynitrile 52b (68.68 mg, 184.51 μmol), 3-(3-bromo-2-chloro-phenyl)piperidin-2,6-dione 1a (72.57 mg, 239.87 μmol), 1,1-bis(diphenylphosphino)ferrocene]palladium dichloride (26.85 mg, 36.90 μmol), sodium bicarbonate (46.50 mg, 553.54 μmol), 1,4-dioxane (6 mL), and water (1.2 mL) were added sequentially to a reaction flask. After purging with argon three times, the mixture was heated to 90°C and stirred for 3 hours. The reaction proceeded to completion as determined by LC-MS. Ethyl acetate (20 mL x 2) and water (20 mL) were added to the reaction solution. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. After reverse-phase purification, 52 (6 mg) of 1-(6-(2-chloro-3-(2,6-dioxopiridin-3-yl)phenyl)naphth-2-yl)-6-oxo-1,6-dihydropyridine-2-carboxynitrile was obtained, yield: 6.8%.

[1210] MS m / z(ESI): 468.1 [M+1]

[1211] 1 H NMR (400MHz, DMSO-d6) δ10.94(s,1H),8.18(d,J=9.7Hz,2H),8.10(d,J=7.8H z,2H),7.73–7.59(m,3H),7.45(dt,J=14.4,4.8Hz,3H),7.28(d,J=6.8Hz,1H ),6.94(d,J=9.4Hz,1H),4.39(dd,J=12.2,5.0Hz,1H),2.82(ddd,J=17.4,12 .8,5.4Hz,1H),2.63(d,J=33.2Hz,1H),2.42–2.30(m,1H),2.13–2.02(m,1H).

[1212] Example 53

[1213] 3-(2-chloro-3-(6-morpholinonaphthalen-2-yl)phenyl)piperidine-2,6-dione

[1214] 3-(2-chloro-3-(6-morpholina-2-yl)phenyl)piperidin-2,6-dione

[1215] first step

[1216] 4-(6-bromonaphthalen-2-yl)morpholine

[1217] 4-(6-bromonaphth-2-yl)morpholine

[1218] At room temperature, (6-bromonaphthyl-2-yl)boronic acid 14a (100 mg, 0.39 mmol), 1,4-oxazacyclohexane (52 mg, 0.41 mmol), copper acetate (72.4 mg, 0.40 mmol), triethylamine (80.67 mg, 0.89 mmol), and dichloromethane (5 mL) were added sequentially to a reaction flask and stirred overnight under oxygen conditions. The reaction mixture was checked by LC-MS to ensure complete reaction. Dichloromethane (30 mL) and water (10 mL) were added to the reaction mixture. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. Purification by silica gel column chromatography (petroleum ether / ethyl acetate = 3:1) yielded 4-(6-bromonaphthyl-2-yl)morpholine 53a (51 mg), yield: 44%.

[1219] MS m / z(ESI): 292.0 [M+1]

[1220] Step 2

[1221] 4-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-yl)morpholine

[1222] 4-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)naphth-2-yl)morpholine

[1223] At room temperature, 4-(6-bromonaphthyl-2-yl)morpholine 53a (50 mg, 0.16 mmol), pinacol diboronate (44 mg, 0.17 mmol), [1,1-bis(diphenylphosphino)ferrocene]palladium dichloride (12 mg, 0.02 mmol), potassium acetate (50 mg, 0.51 mmol), and 1,4-dioxane (3 mL) were sequentially added to a reaction flask. After purging with nitrogen three times, the mixture was heated to 80°C and stirred for 3 hours. LC-MS analysis confirmed complete reaction of the starting materials. The reaction solution was directly filtered and purified to obtain 4-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)naphthyl-2-yl)morpholine 53b (48 mg), yield: 82%.

[1224] MS m / z(ESI): 340.2 [M+1]

[1225] Step 3

[1226] 3-(2-chloro-3-(6-morpholinonaphthalen-2-yl)phenyl)piperidine-2,6-dione

[1227] 3-(2-chloro-3-(6-morpholina-2-yl)phenyl)piperidin-2,6-dione

[1228] At room temperature, 4-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)naphth-2-yl)morpholine 53b (48 mg, 0.14 mmol), 3-(3-bromo-2-chloro-phenyl)piperidin-2,6-dione 1a (42 mg, 0.14 mmol), 1,1-bis(diphenylphosphine)ferrocene]palladium dichloride (20 mg, 0.03 mmol), sodium bicarbonate (24 mg, 0.28 mmol), 1,4-dioxane (2 mL), and water (0.5 mL) were added sequentially to a reaction flask. After purging with nitrogen three times, the mixture was heated to 90°C and stirred for 3 hours. The reaction mixture was analyzed by LCMS to confirm complete reaction. The reaction solution was filtered and evaporated to dryness. The product was purified by reverse-phase preparation to yield 53 (2.4 mg) of 3-(2-chloro-3-(6-morpholina-2-yl)phenyl)piperidine-2,6-dione, in a yield of 4.3%.

[1229] MS m / z(ESI): 435.1 [M+1]

[1230] Example 54

[1231] 3-(2-chloro-3-(6-hydroxy-5-(2-oxopyridin-1(2H)-yl)naphthalen-2-yl)phenyl)piperidine-2,6-dione

[1232] 3-(2-chloro-3-(6-hydroxy-5-(2-oxopyridin-1(2H)-yl)naphth-2-yl)phenyl)piperidin-2,6-dione

[1233] first step

[1234] 1-(6-bromo-2-(methoxymethoxy)naphthalen-1-yl)pyridin-2(1H)-one

[1235] 1-(6-bromo-2-(methoxymethoxy)naphth-1-yl)pyridin-2(1H)-one

[1236] At room temperature, 6-bromo-1-iodo-2-(methoxymethoxy)naphthalene 54a (200 mg, 0.51 mmol, prepared according to the known method "Organic Letters (2018), 20(16), 4959-4963"), pyridin-2(1H)-one (60 mg, 0.63 mmol), potassium phosphate (270 mg, 1.27 mmol), cuprous iodide (30 mg, 0.15 mmol), 1,10-phenanthroline (50 mg, 0.28 mmol), and anhydrous DMF (10 mL) were sequentially added to a reaction flask. After purging with nitrogen three times, the mixture was heated to 140 °C and stirred for 3 hours. The product was detected by LC-MS. The reaction solution was purified by reverse-phase chromatography to obtain 1-(6-bromo-2-(methoxymethoxy)naphthalene-1-yl)pyridin-2(1H)-one 54b (50 mg), yield: 27.1%.

[1237] MS m / z(ESI): 360.0 [M+1]

[1238] Step 2

[1239] 3-(2-chloro-3-(6-(methoxymethoxy)-5-(2-oxopyridin-1(2H)-yl)naphthalen-2-yl)phenyl)piperidine-2,6-dione

[1240] 3-(2-chloro-3-(6-(methoxymethoxy)-5-(2-oxopyridin-1(2H)-yl)naphth-2-yl)phenyl)piperidin-2,6-dione

[1241] At room temperature, 1-(6-bromo-2-(methoxymethoxy)naphth-1-yl)pyridin-2(1H)-one 54b (36.06 mg, 100.11 μmol), 3-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)phenyl)piperidin-2,6-dione 18a (50 mg, 143.01 μmol), 1,1-bis(diphenylphosphino)ferrocene]palladium dichloride (15 mg, 20.61 μmol), sodium bicarbonate (40 mg, 476.15 μmol), 1,4-dioxane (8 mL), and water (1 mL) were added sequentially to a reaction flask. After purging with nitrogen three times, the mixture was stirred at room temperature to 90°C for 3 hours. The reaction proceeded to completion as determined by LC-MS. Water and dichloromethane were added to the reaction solution. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The solution was then separated by silica gel filtration to give 54c (20mg) of 3-(2-chloro-3-(6-(methoxymethoxy)-5-(2-oxopyridin-1(2H)-yl)naphth-2-yl)phenyl)piperidin-2,6-dione, yield: 27.1%.

[1242] MS m / z(ESI): 503.1 [M+1]

[1243] Step 3

[1244] 3-(2-chloro-3-(6-hydroxy-5-(2-oxopyridin-1(2H)-yl)naphthalen-2-yl)phenyl)piperidine-2,6-dione

[1245] 3-(2-chloro-3-(6-hydroxy-5-(2-oxopyridin-1(2H)-yl)naphth-2-yl)phenyl)piperidin-2,6-dione

[1246] At room temperature, 20 mg (0.04 mmol) of 3-(2-chloro-3-(6-(methoxymethoxy)-5-(2-oxopyridin-1(2H)-yl)naphth-2-yl)phenyl)piperidin-2,6-dione 54c was dissolved in 8 mL of methanol. Concentrated hydrochloric acid (1.0 mL) was then added dropwise to the reaction mixture, and the mixture was stirred at room temperature for 3 hours. LC-MS analysis confirmed complete reaction of the starting material. The reaction mixture was then separated by reverse-phase chromatography to yield 2.0 mg (2-chloro-3-(6-hydroxy-5-(2-oxopyridin-1(2H)-yl)naphth-2-yl)phenyl)piperidin-2,6-dione 54c, yield: 10.6%.

[1247] MS m / z(ESI): 459.1 [M+1]

[1248] Example 55

[1249] 3-(2-chloro-3-(6-(6-methoxy-2-oxopyridin-1(2H)-yl)-7,8-dihydronaphthalen-2-yl)phenyl)piperidine-2,6-dione

[1250] 3-(2-chloro-3-(6-(6-methoxy-2-oxopyridin-1(2H)-yl)-7,8-dihydronaphth-2-yl)phenyl)piperidin-2,6-dione

[1251] first step

[1252] 1-(6-bromo-3,4-dihydronaphthalen-2-yl)-6-methoxypyridin-2(1H)-one

[1253] 1-(6-bromo-3,4-dihydronaphthyl-2-yl)-6-methoxypyridin-2(1H)-one

[1254] and

[1255] 2-((6-bromo-3,4-dihydronaphthalen-2-yl)oxy)-6-methoxypyridine

[1256] 2-((6-bromo-3,4-dihydronaphth-2-yl)oxy)-6-methoxypyridine

[1257] 41c of (6-bromo-3,4-dihydronaphth-2-yl)boronic acid (200 mg, 790.83 μmol) was added to dichloroethane (4 mL), followed by 6-methoxypyridine-2-ol (118.74 mg, 948.99 μmol), copper acetate (143.64 mg, 790.83 μmol), and triethylamine (240.07 mg, 2.37 mmol). The reaction mixture was allowed to react at room temperature for 16 hours. After the reaction was complete, water (10 mL) was added to quench the reaction, followed by extraction with dichloromethane (30 mL × 3). The organic phases were combined, washed with saturated sodium chloride (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The filtrate was then purified by preparative liquid chromatography to obtain 1-(6-bromo-3,4-dihydronaphthyl-2-yl)-6-methoxypyridine-2(1H)-one 55a (15 mg), yield 5.7%, and 2-((6-bromo-3,4-dihydronaphthyl-2-yl)oxy)-6-methoxypyridine 55b (46 mg), which were identified as the target compounds by mass spectrometry, nuclear magnetic resonance (NMR), and two-dimensional NMR, with a yield of 17.5%.

[1258] MS m / z(ESI): 332.0 [M+1]

[1259] 55a:

[1260] 1H NMR(400MHz, DMSO-d6)δ7.49–7.36(m,3H),7.09(d,J=8.0Hz,1H),6.43(s,1H),6.02(dd,J=9.0,0.8Hz,1H),5.76 (dd,J=8.0,0.8Hz,1H),3.83(s,3H),3.02–2.91(m,2H),2.43(t,J=16.0,8.0Hz,1H),2.31(t,J=16.0,8.0Hz,1H).

[1261] 55b:

[1262] MS m / z(ESI): 332.1 [M+1]

[1263] 1H NMR (400MHz, DMSO) δ7.75(t,J=8.0Hz,1H),7.37(s,1H),7.31(d,J=8.0,2.0Hz,1H),7.00(d,J=8.0Hz,1 H),6.58(q,J=13.8,8.0Hz,2H),6.17(s,1H),3.78(s,3H),2.98(t,J=8.0Hz,2H),2.51(t,J=8.0Hz,2H).

[1264] Step 2

[1265] 3-(2-chloro-3-(6-(6-methoxy-2-oxopyridin-1(2H)-yl)-7,8-dihydronaphthalen-2-yl)phenyl)piperidine-2,6-dione

[1266] 3-(2-chloro-3-(6-(6-methoxy-2-oxopyridin-1(2H)-yl)-7,8-dihydronaphth-2-yl)phenyl)piperidin-2,6-dione

[1267] 1-(6-bromo-3,4-dihydronaphthyl-2-yl)-6-methoxypyridin-2(1H)-one 55a (15 mg, 45.15 μmol) and 3-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxoborhexacyclopentan-2-yl)phenyl)piperidin-2,6-dione 18a (18.94 mg, 54.19 μmol) were dissolved in 1,4-dioxane (1 mL) and water (0.1 mL). Potassium carbonate (18.72 mg, 135.46 μmol) and [1,1'-bis(di-tert-butylphosphine)ferrocene]palladium dichloride (2.94 mg, 4.52 μmol) were added. The reaction mixture was heated to 90 °C under nitrogen protection and reacted for 1 hour. After the reaction was completed, the mixture was cooled to room temperature. Quenching with water (5 mL), extraction with ethyl acetate (10 mL × 3), combining the organic phases, washing with saturated sodium chloride (5 mL), drying with anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure, and preparatively purifying by liquid chromatography (Waters 3767QDA column: Boston green ODS, 30*150 mm, 5 μm; mobile phase A: 0.1% FA / H2O, mobile phase B: ACN; flow rate: 30 mL / min; gradient: 40-45%, retention time: 9.5 min) to give 55 (10.09 mg) of 3-(2-chloro-3-(6-(6-methoxy-2-oxopyridin-1(2H)-yl)-7,8-dihydronaphth-2-yl)phenyl)piperidin-2,6-dione, yield 47.1%.

[1268] MS m / z (ESI): 475.2 [M+1]

[1269] 1 H NMR (400MHz, DMSO) δ10.93(s,1H),7.50–7.31(m,4H),7.27–7.19(m,3H),6.49(s,1H),6.05(d,J=12.0,1H),5.78(d,J=8.0Hz,1H),4.35(dd,J=1 2.0,4.0Hz,1H),3.86(s,3H),3.09–2.97(m,2H),2.85–2.75(m,1H),2.5 9–2.53(m,1H),2.50–2.44(m,1H),2.41–2.28(m,2H),2.10–2.00(m,1H).

[1270] Example 56

[1271] 3-(2-chloro-3-(6-(6-oxopyridazin-1(6H)-yl)-7,8-dihydronaphthalen-2-yl)phenyl)piperidine-2,6-dione

[1272] 3-(2-chloro-3-(6-(6-oxopyridazin-1(6H)-yl)-7,8-dihydronaphthyl-2-yl)phenyl)piperidin-2,6-dione

[1273] first step

[1274] 2-(6-bromo-3,4-dihydronaphthalen-2-yl)pyridazin-3(2H)-one

[1275] 2-(6-bromo-3,4-dihydronaphthyl-2-yl)pyridazin-3(2H)-one

[1276] 41c of (6-bromo-3,4-dihydronaphthyl-2-yl)boronic acid (100 mg, 395 μmol) was added to DMF (2 mL), followed by pyridazin-3(2H)-one (26.6 mg, 276 μmol), copper acetate (107 mg, 593 μmol), and pyridine (93 mg, 1.2 mmol). The reaction mixture was then allowed to react at 50 °C for 16 hours. After the reaction was complete, water (10 mL) was added to quench the reaction, followed by extraction with ethyl acetate (10 mL × 3). The organic phases were combined, washed with saturated sodium chloride (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (developing solvent: system A) to obtain 2-(6-bromo-3,4-dihydronaphthyl-2-yl)pyridazine-3(2H)-one 56a (15 mg, 49.48 μmol). The compound was identified as the target compound by mass spectrometry, nuclear magnetic resonance (NMR), and two-dimensional NMR, with a yield of 12.5%.

[1277] MS m / z(ESI): 303.0 [M+1]

[1278] 1 H NMR (400MHz, DMSO) δ8.02(d,J=3.6Hz,1H),7.49–7.43(m,2H),7.40(d,J=8.2Hz,1H),7.17(d,J =8.0Hz,1H),7.02(d,J=9.5Hz,1H),6.92(s,1H),2.96(t,J=8.2Hz,2H),2.67(t,J=8.1Hz,2H).

[1279] Step 2

[1280] 3-(2-chloro-3-(6-(6-oxopyridazin-1(6H)-yl)-7,8-dihydronaphthalen-2-yl)phenyl)piperidine-2,6-dione

[1281] 3-(2-chloro-3-(6-(6-oxopyridazin-1(6H)-yl)-7,8-dihydronaphthyl-2-yl)phenyl)piperidin-2,6-dione

[1282] 2-(6-bromo-3,4-dihydronaphthyl-2-yl)pyridazin-3(2H)-one 56a (15 mg, 49.5 μmol) and 3-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxoborhexacyclopentan-2-yl)phenyl)piperidin-2,6-dione 18a (20.7 mg, 59.4 μmol) were dissolved in 1,4-dioxane (1 mL) and water (0.1 mL). Potassium carbonate (20.5 mg, 148 μmol) and [1,1'-bis(di-tert-butylphosphine)ferrocene]palladium dichloroisocyanurate (3.2 mg, 5.0 μmol) were added. The reaction mixture was heated to 90 °C under nitrogen protection and reacted for 1 hour. After the reaction was complete, the reaction mixture was cooled to room temperature. Quenching with water (5 mL), extraction with ethyl acetate (10 mL × 3), combining the organic phases, washing with saturated sodium chloride (15 mL), drying to anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure, and preparatively purifying by liquid chromatography (Waters 3767 / Qda column: SunFire Sunfire C18, 30*150 mm, 5 μm; mobile phase A: 0.1% FA / H2O, mobile phase B: ACN; flow rate: 30 mL / min; gradient: 41-46%, retention time: 9.8 min) yielded 56 (5.6 mg, 12.5 μmol) of 3-(2-chloro-3-(6-(6-oxopyridazin-1(6H)-yl)-7,8-dihydronaphthyl-2-yl)phenyl)piperidin-2,6-dione, yield 25.38%. MS m / z (ESI): 446.0 [M+1]

[1283] 1H NMR (400MHz, DMSO) δ10.92(s,1H),8.04(dd,J=3.8,1.5Hz,1H),7.47(dd,J=9.6,4.0Hz,1H ),7.43–7.38(m,1H),7.38–7.31(m,2H),7.31–7.27(m,1H),7.26–7.22(m,2H),7.02(dd,J =9.6,1.6Hz,1H),6.98(s,1H),4.35(dd,J=12.0,4.8Hz,1H),3.01(t,J=8.0Hz,2H),2.85– 2.76(m,1H),2.76–2.69(m,2H),2.60–2.53(m,1H),2.37–2.28(m,1H),2.10–2.00(m,1H).

[1284] Example 57

[1285] 3-(2-chloro-3-(8-hydroxy-6-(2-oxopyridin-1(2H)-yl)naphthalen-2-yl)phenyl)piperidine-2,6-dione

[1286] 3-(2-chloro-3-(8-hydroxy-6-(2-oxopyridin-1(2H)-yl)naphth-2-yl)phenyl)piperidin-2,6-dione

[1287] first step

[1288] 3-(2-chloro-3-(8-hydroxy-6-(2-oxopyridin-1(2H)-yl)naphthalen-2-yl)phenyl)piperidine-2,6-dione

[1289] 3-(2-chloro-3-(8-hydroxy-6-(2-oxopyridin-1(2H)-yl)naphth-2-yl)phenyl)piperidin-2,6-dione

[1290] At room temperature, 46 (50 mg, 105.73 μmol) of 3-(2-chloro-3-(8-methoxy-6-(2-oxopyridin-1(2H)-yl)naphth-2-yl)phenyl)piperidin-2,6-dione and 20 mL of dichloromethane were added to a reaction flask. Boron tribromide (1 M, 3.59 mL) was added dropwise to the reaction mixture at 0–5 °C. The reaction mixture was stirred at 10 °C for 4 h. The reaction mixture was quenched with ice water (15 mL), extracted with dichloromethane (20 mL x 3), and the organic phase was washed with saturated brine (20 mL) and evaporated to dryness. The purified product yielded 57 (2.3 mg) of 3-(2-chloro-3-(8-hydroxy-6-(2-oxopyridin-1(2H)-yl)naphth-2-yl)phenyl)piperidin-2,6-dione, with a yield of 4.3%.

[1291] MS m / z(ESI): 459.1 [M+1]

[1292] Biological evaluation

[1293] Test Example 1: Determination of VAV1 protein degradation by the compounds of the present invention

[1294] The following methods were used to determine the activity of the compounds of this invention against VAV1 protein degradation. Jurkat (Clone E6-1) cells were purchased from the Cell Resource Center of the Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, and cultured in RPMI 1640 medium containing 10% fetal bovine serum, 100 U penicillin, and 100 μg / mL streptomycin. The Jurkat VAV1 Hibit stable cell line was constructed internally by Hisun Pharmaceuticals and used... The HiBiT Lytic Detection System (Promega, catalog number N3030) detects HiBiT signals to quantify VAV1 protein.

[1295] The experimental method was performed according to the kit instructions, and is briefly described below: The test compound was first dissolved in DMSO to prepare a 10 mM stock solution, which was then diluted with culture medium to prepare the test sample. The final concentration range of the compound was 10000 nM-1.52 nM. Cells in the logarithmic growth phase were seeded at a density of 30,000 cells per well into 96-well cell culture plates and cultured overnight at 37°C in an air incubator. The test compound was then added, and the cells were cultured for another 24 hours. After the culture was completed, 50 μL of the solution was added to each well. HiBiT Lytic Reagent (use according to the kit instructions) HiBiT Lytic Buffer dilutes LgBiT Protein and The sample was prepared using HiBiT Lytic Substrate, shaken for 5 minutes, and then allowed to stand for 10 minutes. The luminescence values ​​of each well were then read using a microplate reader in Luminescence mode. The percentage inhibition rate of the compound at each concentration was calculated by comparing it with the control group (0.1% DMSO). Nonlinear regression analysis was then performed in GraphPad Prism 9 software using the logarithm of compound concentration versus inhibition rate to obtain the DC value of the compound in degrading VAV1 protein. 50 Values. The results are shown in Table 1.

[1296] Table 1. Degradation activity of the compounds of the present invention on VAV1 protein

[1297] Conclusion: The compounds of this invention are effective against DC degradation by VAV1 protein. 50 <100nM, exhibiting good degradation activity.

Claims

1. A compound of general formula (I) or a stereoisomer, tautomer, deuterated derivative or pharmaceutically acceptable salt thereof: in: W is selected from: 1) Where "--*" indicates that the group is related to the general formula (I) Connection sites; This indicates the connection site between the group and L1 in general formula (I); ring A is selected from 3-12 membered heterocyclic groups, C 3-12 Cycloalkylene, 5-membered monocyclic heteroarylene, naphthylene, 8-10-membered bicyclic heteroarylene, and 8-10-membered bicyclic fused ring, wherein the 8-10-membered bicyclic fused ring is preferably a monocyclic arylene or a fused ring of a monocyclic heteroarylene with a monocyclic heterocyclic group or a monocyclic cycloalkyl group; R e Whether the groups are the same or different, they are each independently selected from deuterium atoms, halogens, hydroxyl groups, cyano groups, SF5, and C. 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkyl groups; And / or, two Rs e It forms a -C (=O) with the same carbon atom it is attached to; m is selected from 0, 1, 2, 3, 4, and 5; The conditions are: Not selected from the following groups: 2)C 2-6 imide or C 2-6 Idemynyl, wherein the C 2-6 imide or C 2-6 The ethynyl group may be further selected by one or more atoms selected from =O, deuterium, halogen, hydroxyl, cyano, SF5, C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 Substituents of haloalkyl groups; 3) Wherein, "*" indicates that the group is related to the general formula (I). Connection sites; This indicates the connection site between the group and L1 in general formula (I); L2 is selected from -C(=O)-, -O(C 0-4 alkylene)-, -NR j (C 0-4 alkylene)-, -NR j C(=O)(C 0-4 alkylene)-, -(C 0-4 Alkylene C(=O)-, C 2-6 imide and C 2-6 Idemynyl, wherein the C 0-4 Alkylene, C 2-6 imide or C 2-6 The ynylene group is optionally surrounded by one or more atoms selected from deuterium, halogen, hydroxyl, cyano, C. 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 Substituents of haloalkyl groups; 4) Wherein, "*" indicates that the group is related to the general formula (I). Connection sites; This indicates the connection site between the group and L1 in general formula (I); Z is selected from -C(=O)- and -NR. j C(=O)(C 0-4 alkylene)-, -(C 0-4 Alkylene C(=O)-, C 2-6 imide and C 2-6 Idemynyl, wherein the C 0-4 Alkylene, C 2-6 imide or C 2-6 The ynylene group is optionally surrounded by one or more atoms selected from deuterium, halogen, hydroxyl, cyano, C. 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 Substituents of haloalkyl groups; R j Each is independently selected from hydrogen atoms and C atoms. 1-6 alkyl; R 6 Each is independently selected from halogen, hydroxyl, cyano, C 1-6 Alkyl and C 1-6 Alkoxy, wherein the C 1-6 Alkyl or C 1-6 Alkoxy groups may optionally be further selected from halogens, hydroxyl groups, cyano groups, and C. 1-6 Substituents of alkoxy groups; n is independently selected from 0, 1, 2, 3, and 4; R 2 Selected from hydrogen atom, deuterium atom, hydroxyl group, halogen, cyano group, C 1-6 Alkyl and C 1-6 Alkoxy, wherein the C 1-6 Alkyl or C 1-6 Alkoxy groups may optionally be further selected from halogens, hydroxyl groups, cyano groups, and C. 1-6 Substituents of alkoxy groups; R 3 and R 4 Each is independently selected from hydrogen atom, deuterium atom, hydroxyl group, cyano group, C 1-6 Alkyl and C 1-6 Alkoxy; L1 is selected from key, -C(=O)-, -C 1-4 Alkylene-, -O(C) 0-4 alkylene)-, -NR a (C 0-4 alkylene)-, -NR a C(=O)(C 0-4 alkylene)- and -(C 0-4 alkylene C(=O)-, wherein the C 0-4 The alkylene group is optionally surrounded by one or more atoms selected from deuterium, halogen, hydroxyl, cyano, C. 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 Substituents of haloalkyl groups; R a Each is independently selected from hydrogen atoms and C atoms. 1-6 alkyl; R 1 The group is selected from phenyl, 3-12-membered heterocyclic, 5-10-membered heteroaryl, and 8-10-membered fused ring, wherein the phenyl, 3-12-membered heterocyclic, 5-10-membered heteroaryl, or 8-10-membered fused ring is optionally further selected from one or more groups selected from =O, halogen, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl and C 1-6 The alkoxy group is replaced by a substituent.

2. The compound according to claim 1, or its stereoisomer, tautomer, deuterated derivative, or pharmaceutically acceptable salt thereof, wherein it is the compound according to general formula (II), or its stereoisomer, tautomer, deuterated derivative, or pharmaceutically acceptable salt thereof: in, Ring A is selected from 3-12 member subheterocyclic groups, C 3-12 Cycloalkylene, 5-membered monocyclic heteroarylene, 8-10-membered bicyclic heteroarylene, naphthylene, and 8-10-membered bicyclic fused ring; wherein the bicyclic fused ring is preferably a fused ring of monocyclic aryl or monocyclic heteroaryl with monocyclic heterocyclic group or monocyclic cycloalkyl. R e Whether the groups are the same or different, they are each independently selected from deuterium atoms, halogens, hydroxyl groups, cyano groups, SF5, and C. 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkyl groups; And / or, two Rs e It forms a -C (=O) with the same carbon atom it is attached to; m is selected from 0, 1, 2, 3, 4, and 5; The conditions are: Not selected from the following groups: L1, R 1 R 2 R 3 and R 4 The definition is as described in claim 1.

3. The compound according to claim 1 or 2, or its stereoisomers, tautomers, deuterated derivatives, or pharmaceutically acceptable salts thereof, wherein R e They may be the same or different, each independently selected from deuterium, halogen, hydroxyl, cyano, SF5, methyl, methoxy and trifluoromethoxy; And / or, two Rs e It forms a -C (=O) with the same carbon atom it is attached to.

4. The compound according to any one of claims 1-3, or a stereoisomer, tautomer, deuterated product, or pharmaceutically acceptable salt thereof, wherein... Selected from the following groups:

5. The compound according to claim 1, or its stereoisomers, tautomers, deuterated derivatives, or pharmaceutically acceptable salts thereof, wherein, W is selected from C 2-6 imide and C 2-6 Idemynyl, wherein the C 2-6 imide or C 2-6 The ethynyl group may be further selected by one or more atoms selected from =O, deuterium, halogen, hydroxyl, cyano, SF5, C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 The alkyl halogroup is substituted by a substituent.

6. The compound according to claim 1 or 5, or its stereoisomers, tautomers, deuterated derivatives, or pharmaceutically acceptable salts thereof, wherein W is selected from...

7. The compound according to claim 1, or its stereoisomer, tautomer, deuterated derivative, or pharmaceutically acceptable salt thereof, wherein it is the compound according to general formula (III), or its stereoisomer, tautomer, deuterated derivative, or pharmaceutically acceptable salt thereof: in, L2 is selected from -O-, -NR j -、C 2-6 imide and C 2-6 Ethyne group; R j Selected from hydrogen atoms and C 1-6 alkyl; R 6 Each is independently selected from halogen, hydroxyl, cyano, methyl, methoxy, trifluoromethyl, and trifluoromethoxy; n is selected from 0, 1, 2, 3, and 4; L1, R 1 R 2 R 3 and R 4 The definition is as described in claim 1.

8. The compound according to claim 1 or 7, or its stereoisomers, tautomers, deuterated derivatives, or pharmaceutically acceptable salts thereof, wherein: L2 is selected from -O-, vinylene, and ethynylene.

9. The compound according to claim 1, or its stereoisomer, tautomer, deuterated derivative, or pharmaceutically acceptable salt thereof, wherein the compound is a stereoisomer, tautomer, deuterated derivative, or pharmaceutically acceptable salt thereof of general formula (IV): in, Z is selected from C 2-6 imide and C 2-6 Ethyne group; R 6 Each is independently selected from halogen, hydroxyl, cyano, methyl, methoxy, trifluoromethyl, and trifluoromethoxy; n is selected from 0, 1, 2, 3, and 4; L1, R 1 R 2 R 3 and R 4 The definition is as described in claim 1.

10. The compound according to claim 1 or 9, or its stereoisomers, tautomers, deuterated derivatives, or pharmaceutically acceptable salts thereof, wherein Z is selected from vinylidene and ethynylidene groups.

11. The compound according to any one of claims 1-10, or a stereoisomer, tautomer, deuterated derivative, or pharmaceutically acceptable salt thereof, wherein W is selected from the following groups:

12. The compound according to any one of claims 1-11, or its stereoisomers, tautomers, deuterated derivatives, or pharmaceutically acceptable salts thereof, wherein, L1 is selected from the bond, -O(C 0-4 alkylene)-, -C(O)- and -C 1-4 Alkylene-.

13. The compound according to claims 1-12, or its stereoisomers, tautomers, deuterated derivatives, or pharmaceutically acceptable salts thereof, wherein, L1 is selected from bond, -O-, -C(O)-, and -C. 1-4 Alkylene.

14. The compound according to any one of claims 1-13, or its stereoisomers, tautomers, deuterated derivatives, or pharmaceutically acceptable salts thereof, wherein, R 1 The group is selected from phenyl, 3-12-membered heterocyclic and 5-10-membered heteroaryl, wherein the phenyl, 3-12-membered heterocyclic and 5-10-membered heteroaryl are optionally further selected by one or more groups selected from =O, halogen, hydroxyl, cyano, methyl, isopropyl, C 1-6 Substituents of haloalkyl and methoxy groups.

15. The compound according to any one of claims 1-14, or its stereoisomers, tautomers, deuterated derivatives, or pharmaceutically acceptable salts thereof, wherein, R 1 Selected from phenyl, 16. The compound according to any one of claims 1-15, or a stereoisomer, tautomer, deuterated product, or pharmaceutically acceptable salt thereof, wherein, R 2 Selected from halogens, preferably chlorine.

17. The compound according to any one of claims 1-16, or a stereoisomer, tautomer, deuterated product, or pharmaceutically acceptable salt thereof, wherein, R 3 R 4 It is a hydrogen atom.

18. The compound according to any one of claims 1-17, or a stereoisomer, tautomer, deuterated derivative, or pharmaceutically acceptable salt thereof, wherein the compound is selected from:

19. A pharmaceutical composition comprising a compound according to any one of claims 1-18, or a stereoisomer, tautomer, deuterated compound or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

20. Use of the compound or its stereoisomer, tautomer, deuterated derivative or pharmaceutically acceptable salt thereof, according to any one of claims 1-18, or the pharmaceutical composition according to claim 19, in the preparation of a VAV1 degrading agent.

21. Use of the compound or its stereoisomer, tautomer, deuterated derivative or pharmaceutically acceptable salt thereof according to any one of claims 1-18, or the pharmaceutical composition according to claim 19, in the preparation of a medicament for treating or preventing VAV1-mediated diseases; preferably, wherein the VAV1-mediated diseases are autoimmune diseases and / or inflammatory diseases; more preferably, the autoimmune diseases or inflammatory diseases are selected from multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus, idiopathic dermatitis, and Hashimoto's thyroiditis. Inflammation, myasthenia gravis, type I or II diabetes and related diseases, vasculitis, pernicious anemia, Sjögren's syndrome, uveitis, psoriasis, Graves' ophthalmopathy, alopecia areata, allergic asthma, atopic dermatitis, allergic rhinitis, conjunctivitis, allergic contact dermatitis, 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, eczematous dermatitis, seborrheic dermatitis, inflammatory eye diseases, keratoconjunctivitis, myocarditis, and hepatitis.

22. The use of the compound or its stereoisomer, tautomer, deuterated derivative or pharmaceutically acceptable salt thereof, according to any one of claims 1-18, or the pharmaceutical composition according to claim 19, in the preparation of a medicament for treating or preventing autoimmune diseases or inflammatory diseases; preferably, wherein the autoimmune disease or inflammatory disease is selected from multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus, idiopathic dermatitis, Hashimoto's thyroiditis, myasthenia gravis, type I or type II diabetes mellitus. Diabetes and related diseases, vasculitis, pernicious anemia, Sjögren's syndrome, uveitis, psoriasis, Graves' ophthalmopathy, alopecia areata, allergic asthma, atopic dermatitis, allergic rhinitis, conjunctivitis, allergic contact dermatitis, 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, eczematous dermatitis, seborrheic dermatitis, inflammatory eye diseases, keratoconjunctivitis, myocarditis, and hepatitis.

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