VAV1-targeting degradation agent

Abstract

The present disclosure provides a VAV1 protein-targeting degradation agent as shown in the following formula (II), a preparation method, a pharmaceutical composition, and a use of the compound in the preparation of a drug for treating VAV1-mediated related diseases.

Description

Vav1 targeted degrader

[0001] This application claims priority to Chinese Patent Application No. 2024112380984, filed on September 4, 2024, Chinese Patent Application No. 2024117972682, filed on December 6, 2024, Chinese Patent Application No. 2024118844925, filed on December 19, 2024, Chinese Patent Application No. 2025100538648, filed on January 13, 2025, Chinese Patent Application No. 202510169542X, filed on February 14, 2025, Chinese Patent Application No. 2025103362981, filed on March 20, 2025, Chinese Patent Application No. 2025104195971, filed on April 2, 2025, Chinese Patent Application No. 2025105600081, filed on April 29, 2025, Chinese Patent Application No. 2025107271695, filed on May 30, 2025, Chinese Patent Application No. 2025108398890, filed on June 20, 2025, and Chinese Patent Application No. 2025112123640, filed on August 27, 2025. This application incorporates the entire contents of the above-mentioned Chinese patent applications. TECHNICAL FIELD

[0002] The present disclosure belongs to the field of medicine, and in particular relates to a compound degrading human proto-oncogene VAV1 protein, a preparation method and use thereof. BACKGROUND

[0003] The ubiquitin-proteasome system is a system in which a target protein is ubiquitinated labeled by inducing ubiquitin enzymes, and then degraded by a proteasome. The molecular glue technology is one of the main types of technologies based on the ubiquitin-proteasome degradation system. In the field of targeted protein degradation, the molecular glue is usually a monovalent small molecule (molecular weight less than 500 Da), and the specific mechanism is to change the surface of E3 ligase, thereby blocking the binding of E3 ligase and the natural substrate, inducing the specific protein to be degraded to bind to the E3 ligase, further promoting the ubiquitination modification of the specific protein, and finally making it be degraded by the proteasome. Examples of molecular glue of E3 ligase cereblon include thalidomide, lenalidomide and pomalidomide, and the above are all currently FDA-approved immunomodulatory imide drugs (IMiD) for hematological cancers. The molecular glue gradually becomes a new type of treatment technology that attracts attention in the pharmaceutical industry due to its small molecular weight, easy drug development, and regulation of protein-protein interactions.

[0004] VAV family proteins, including VAV1, VAV2 and VAV3, are guanine nucleotide exchange factors (GEFs) for Rho family GTPases. VAV1 protein has a relative molecular mass of 95 kDa and is mainly expressed in human hematopoietic cells, including T and B cells, monocytes, natural killer (NK) cells, granulocytes and dendritic cells. In the resting state, VAV1 is located in the cytoplasm and is recruited to the inner side of the cell membrane to perform functions after activation. The structure of VAV1 is relatively complex, and from the amino terminus to the carboxyl terminus, it is: a calponin homology (CH) domain, an AC (acidic motif, AC motif) domain containing multiple tyrosine phosphorylation sites, a Dbl homology (DH) domain with guanine nucleotide exchange factor (GEF) activity, a Pleckstrin homology (PH) domain binding to phospholipids, a C1 zinc finger (Zinc finger, ZF) domain, and finally a Src homology 3 (Src homology 3, SH3)-Src homology 2 (Src homology 2, SH2)-SH3 tandem domain.

[0005] VAV1 is rapidly phosphorylated on tyrosine in response to a variety of stimuli, including stimulation of the T cell receptor (TCR), B cell receptor (BCR) and various cytokine receptors. VAV1 regulates a variety of cellular functions and signaling pathways in hematopoietic-derived cells (e.g., T and B cells, natural killer cells and osteoclasts) by activating certain GTPases. VAV1-mediated functions include gene transcription, development and activation of immune cells (e.g., T and B cells). VAV1 is a positive regulator of TCR signals such as nuclear factor of activated T cells (NF-AT), interferon gamma (IFNγ) and interleukin-2 (IL-2).

[0006] In a systemic graft-versus-host model, knock-in mice carrying a mutant VAV1 with GEF activity disrupted but function independent of GEF showed reduced proliferation and activation of reactive T cells to allogeneic stimuli, and reduced T cell expansion. VAV1-deficient mice were resistant to MOG(35-55)-induced experimental autoimmune encephalomyelitis (EAE), a commonly used model of multiple sclerosis. Finally, whole genome CRISPR activation (CRISPRa) and interference (CRISPRi) screening on primary human T cells identified VAV1 as an important positive regulator of T cell function.

[0007] Although the exact role of VAV1 in human diseases remains to be clinically verified, multiple lines of evidence suggest that VAV1 is associated with autoimmune and chronic inflammatory diseases, supporting its role as a therapeutic target. Interventions targeting VAV1 have the potential to act under a variety of T cell and T / B cell-mediated conditions, covering a variety of autoimmune and inflammatory diseases. SUMMARY

[0008] The present disclosure provides a compound with novel structure, which targets degradation of human proto-oncogene VAV1 protein, and has good in vitro and in vivo pharmacodynamic activity and pharmacokinetic properties.

[0009] In a first aspect, the present disclosure provides a compound as shown in the following formula (II), a pharmaceutically acceptable salt thereof, an isomer thereof, a nitroxide thereof,

[0010] wherein X is CR 4 or N;

[0011] Ring A is selected from C 6-10 aryl, 5-10 membered heteroaryl, 5-10 membered heterocyclyl;

[0012] L1is selected from a chemical bond, C 1-6 alkylene, C 2-6 alkenylene, C 2-6 alkynylene, wherein any methylene unit is optionally replaced by -O-, -C(O)-, -N(R a )-, -S-, -S(O)-, -S(O)2-;

[0013] Ring B is selected from C 6-10 aryl, 5-10 membered heteroaryl, 5-12 membered heterocyclyl, C 5-12 bridged cycloalkyl, C 5-12 spirocycloalkyl, 5-12 membered bridged heterocyclyl, 5-12 membered spiroheterocyclyl;

[0014] R is selected from R 2-1 , R 2-2 ;

[0015] R 1 is selected from hydrogen, deuterium, cyano, halogen, oxo, thioxo, hydroxyl, C 1-6 alkyl, halogenated C 1-6 alkyl, deuterated C 1-6 alkyl, hydroxyl C 1-6 alkyl, cyano C 1-6 alkyl, C 2-6 alkenyl, halogenated C 2-6 alkenyl, deuterated C 2-6 alkenyl, C 2-6 alkynyl, halogenated C 2-6 alkynyl, deuterated C2-6 alkynyl group, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, deuterated C 1-6 Alkoxy, (C 1-6 Alkyl)2P(O)-, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 1-6 Alkyl-S(=O)(=NH)-, (R d (R) e N-, C 1-6 Alkoxy-C 1-6 Alkylene-, C 1-6 Alkyl-S(O)2-, C 1-6 Alkoxy-C(O)-, C 1-6 Alkyl-C(O)-, (R d (R) e )NC(O)-C 1-6 Alkylene, C 3-6 cycloalkyl-O-, 3-6 membered heterocyclic-O-;

[0016] R 2-1 Selected from hydrogen, deuterium, cyano, halogen, oxo, thio, hydroxyl, C 1.6 Alkyl, Halogenated C 1-6 Alkyl, hydroxyl C 1.6 Alkyl, cyano C 1-6 Alkyl, C 2-6 alkenyl, halogenated C 2-6 alkenyl, deuterated C 2-6 alkenyl, C 2-6 alkynyl, halogenated C 2-6 Alkyne group, deuterated C 2-6 alkynyl group, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, (C 1-6 Alkyl)2P(O)-, C 1-6 Alkyl-S(=O)(=NH)-, (R d (R) e N-, C 1-6 Alkoxy-C1-6 alkylene-, C 1-6 Alkyl-S(O)2-, C 1-6 Alkoxy-C(O)-, C 1-6 Alkyl-C(O)-, (R d (R) e )NC(O)-C 1-6 Alkylene, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 3-6 Cycloalkyl-O-, 3-6 membered heterocyclic-O-, (R d (R) e)N-C(O)-, (R d )(R e )N-C(O)O-, 1-6 alkyl-C(O)-NR d -, 1-6 alkoxy-C(O)-NR d -, 1-6 alkoxy-C 1-6 alkylene-C(O)-, (R d )(R e )N-C(O)NR d -, d )(R e )N-C 1-6 alkylene-C(O)-, 1.6 alkoxy-C 1-6 alkylene-OC(O)-, 1-6 alkyl-NR d -, 1-6 alkoxy-C(O)-, 1-6 alkoxy-C(O)-NR d -, d )(R e )N-S(O)2-, 1-6 3-6 membered heterocyclyl, 5-6 membered heteroaryl, deuterated C 1-6 alkyl, deuterated C 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkyl, C 1-6 alkoxy, haloC

[0017] R 2-2 is selected from- hydrogen, deuterium, cyano, halogen, oxo, thioxo, hydroxy, C 1-6 alkyl, haloC 1-6 alkyl, hydroxyC 1-6 alkyl, cyanoC 1-6 alkyl, deuterated C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, haloC 2-6 alkenyl, deuterated C 2-6 alkenyl, haloC 2-6 alkynyl, deuterated C 2-6 alkynyl, C 1-6 alkoxy, haloC 1-6 alkoxy, deuterated C 1-6 alkoxy, (C 1.6 alkyl)2P(O)-, C1-6 Alkyl-S(=O)(=NH)-, (R d (R) e N-, C 1-6 Alkoxy-C 1-6 Alkylene-, C 1-6 Alkyl-S(O)2-, C 1-6 Alkoxy-C(O)-, C 1- 6alkyl-C(O)-, (R d (R) e )NC(O)-C 1-6 Alkylene, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 3-6 Cycloalkyl-O-, 3-6 membered heterocyclic-O-, (R d (R) e )NC(O)-、(R d (R) e )NC(O)O-、C 1-6 Alkyl-C(O)-NR d -、C 1-6 Alkoxy-C(O)-NR d -、C 1-6 Alkoxy-C 1-6 Alkylene-C(O)-, (R d (R) e )NC(O)NR d -、(R d (R) e )NC 1-6 Alkylene-C(O)-, C 1-6 Alkoxy-C 1-6 Alkylene-OC(O)-, hydroxyl C 1-6 Alkyl-NR d -、(R d (R) e )NS(O)2-、C 1-6 Alkoxy-C 1-6 Alkylene-OC(O)N(R) d )-, hydroxyl C 1-6 Alkoxy-C(O)-, hydroxy-C 1-6 Alkoxy-C(O)-NR d -、(R d (R) e )NC(O)-C(O)-N(R d )-、3-6-membered heterocyclic group-OC(O)-N(R d )-、(R g (R) h )-S(O)=N-; where, the C3-6 cycloalkyl, 3-6 membered heterocyclic, C 3-6 Cycloalkyl-O-, 3-6 membered heterocyclic-O-, 3-6 membered heterocyclic-OC(O)-N(R) d -Optionally selected by one or more elements selected from deuterium, cyano, halogen, oxo, thio, hydroxyl, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, cyano C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl, halogenated C 2-6 alkenyl, deuterated C 2-6 alkenyl, halogenated C 2-6 Alkyne group, deuterated C 2-6 alkynyl group, C 1.6 Alkoxy, halogenated C 1-6 Alkoxy, deuterated C 1-6 The alkoxy group is replaced;

[0018] L2 is selected from chemical bonds, C 1-6 Alkylene, *-N(R) b )-C 1-6 Alkylene-, *-N(R) b -C(O)-, -C(O)-, -N(R) b )-, -O-, -S-, -S(O)-, -S(O)2-, -S(=O)(=NH)-, -P(O)-, *-OC(O)-、*-OC(O)-N(R b )-、*-OC 1-6 Alkylene-, *-N(R) b )-C(O)-O-、*-N(R b )-C(O)-N(R b )-; The "*" sign indicates connection to ring B; wherein C 1-6 Alkylene, *-N(R) b )-C 1-6 Alkylene-, *-OC 1-6 Alkylene – optionally dimethyl etherified with one or more halogens, hydroxyl groups, cyano groups, C6 groups 1-6 Alkyl, hydroxyl C 1-6 Alkyl groups are substituted;

[0019] R a R b Selected independently from hydrogen and C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6Alkoxy, C 1-6 Alkyl-C(O)-, (R a-1 (R) b-2 )NC(O)-、C 1-6 Alkyloxy-C(O)-;

[0020] R a-1 R b-1 Selected independently from hydrogen and C 1-6 Alkyl, Halogenated C 1-6 alkyl;

[0021] The ring C is selected from 5-10 aryl, 5-10 heteroaryl, 5-12 heterocyclic, and C 3-6 cycloalkyl, C 3-6 Cycloalkenyl, 8-12 membered fused aryl;

[0022] R 3 Selected from hydrogen, deuterium, cyano, halogen, oxo, thio, amino, hydroxyl, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, cyano C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl, halogenated C 2-6 alkenyl, halogenated C 2-6 Alkyne group, deuterated C 2-6 alkenyl, deuterated C 2-6 alkynyl group, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, deuterated C 1-6 Alkoxy, hydroxy C 1-6 Alkoxy, (C 1-6 Alkyl)2P(O)-, C 1-6 Alkyl-S(=O)(=NH)-, (R j (R) k N-, C 1-6 Alkoxy-C 1-6 Alkylene-, C 1-6 Alkyl-S(O)2-, C 1-6 Alkoxy-C(O)-, C 1- 6alkyl-C(O)-, (R j (R) k )NC(O)-C 1-6 Alkylene, =NR f 、(R j (R) k )NC 1-6 Alkylene-, C 1-6 Alkoxy-C 1-6alkylene-O-, haloC 1-6 alkoxy-C 1-6 alkylene-, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 3-6 cycloalkyl-O-, 3-6 membered heterocyclyl-O-, 5-6 membered heteroaryl, C 1-6 alkoxy-C(O)N(R j )-C 1-6 alkylene, (R j )(R k )N-C(O)-, (R j )(R k )N-C(O)-O-, (R j )(R k )N-C(O)N(R j )-, deuterium substituted haloC 1-6 alkyl, deuterium substituted haloC 1-6 alkoxy, 3-6 membered heterocyclyl-O-C(O)-N(R j )-; wherein said C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 3-6 cycloalkyl-O-, 3-6 membered heterocyclyl-O-, 3-6 membered heterocyclyl-O-C(O)-N(R j )- optionally substituted with one or more groups selected from hydroxy, cyano, C 1-6 alkyl, haloC 1-6 alkyl, hydroxyC 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 substituted with one or more groups selected from hydroxy, cyano, C

[0023] R f is selected from CN, C 1-6 alkyl, haloC 1-6 alkyl, C 1-6 alkyl-C(O)-;

[0024] R g , R h are each independently selected from C 1-6 alkyl, haloC 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl;

[0025] R d , R e , R j , R k are each independently selected from hydrogen, deuterium, cyano, halogen, oxo, thioxo, amino, hydroxy, C 1-6 alkyl, haloC1-6 alkyl, deuterated C 1-6 alkyl, hydroxy C 1-6 alkyl, cyano C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, halo C 2-6 alkenyl, halo C 2-6 alkynyl, deuterated C 2-6 alkenyl, deuterated C 2-6 alkynyl, C 1-6 alkoxy, halo C 1-6 alkoxy, deuterated C 1-6 alkoxy, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 5-8 membered bridged cyclyl, C 1-6 alkoxy-C1-6alkylene, (R d-1 )(R e - 1 )N-, (R d-1 )(R e - 1 )N-C(O)-, (R d- 1 )(R e-2 )N-C 1-6 alkylene, C 3-6 cycloalkyl-C 1-6 alkylene, C 1-6 alkyl-C(O)-, C 1-6 alkoxy-C(O)-, C 1-6 alkyl-S(O)2-, (R d-1 )(R e-2 )N-C(O)-C 1-6 alkylene, 5-6 membered heteroaryl, C 1-6 alkyl-S(O)2-C 1-6 alkylene, halo C 1-6 alkoxy-C 1-6 alkylene, or R d , R e and the N atom to which they are attached together form a 3-6 membered heterocyclyl, 3-12 membered spiroheterocyclyl, 6-12 membered fused heterocyclyl, wherein said C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 3-6 cycloalkyl-C 1-6 alkylene, 5-6 membered heteroaryl, 3-12 membered spiroheterocyclyl, 6-12 membered fused heterocyclyl is optionally substituted with one or more selected from hydroxy, cyano, halo, amino, C 1-6 alkyl, halo C 1-6 alkyl, hydroxy C 1- 6alkyl, cyano C 1-6 alkyl, deuterated C1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, deuterated C 1-6 Alkoxy, (R d-2 (R) e-2 )NC(O)-C 1-6 Alkylene, (R) d-1 (R) e-1 N-, C 1-6 Alkoxy-C 1-6 Alkylene, Halogenated C 1-6 Alkoxy-C 1-6 Alkylene, =CH2, C 1-6 Substituted with alkyl-S(O)2- groups;

[0026] R d-1 R e-1 Selected independently from H and C respectively 1-6 Alkyl, Halogenated C 1-6 Alkyl, or R d-1 R e-1 Together with the N atom it is attached to, they form a 3-6 membered heterocyclic group; the 3-6 membered heterocyclic group is selected from hydroxyl, halogen, amino, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl groups are substituted;

[0027] R d-2 R e-2 Selected independently from H and C respectively 1-6 Alkyl, Halogenated C 1-6 alkyl;

[0028] Or, R 1 and R 2-1 Together with the atoms they are attached, they form groups that are optionally substituted with one or more Rc groups, such as 3-6 membered heterocyclic groups, C-membered heterocyclic groups, and C-membered heterocyclic groups. 3-6 Cycloalkenyl, C 3-6 cycloalkyl;

[0029] Or, R 2-2 and R 3 Together with the atoms they are attached to, they form an array that is optionally bounded by one or more R atoms. c The substituted ring E is selected from the following groups: 3-8 membered heterocyclic groups, C 3-8 Cycloalkenyl, C 3-8 cycloalkyl, 5-6 membered heteroaryl;

[0030] Or, two Rs 2-1together with the ring atom to which they are attached form a group optionally substituted with one or more Rc; 3-6 C1-6alkyl, C 3-6 C3-6cycloalkyl, C

[0031] or, two R 3 together with the ring atom to which they are attached form a group optionally substituted with one or more Rc; c together with the ring atom to which they are attached form a group optionally substituted with one or more Rc; 3-6 C1-6alkyl, C 3-6 C3-6cycloalkyl, C

[0032] R c selected from hydrogen, halogen, oxo, thioxo, C 1-6 alkyl, haloC 1-6 alkyl, C 1-6 alkyl, haloC 1-6 alkyl, C 1-6 alkyl, C 1-6 alkyl, C

[0033] R 4 selected from hydrogen, cyano, halogen, C 1-6 alkyl, C 1-6 alkyl, haloC 1-6 alkyl, haloC 1-6 alkyl, C

[0034] m, p, q, t are each independently selected from 0, 1, 2, 3, 4, 5.

[0035] In another embodiment of the present disclosure, the compound represented by formula (II), pharmaceutically acceptable salts thereof, isomers thereof, nitrogen oxides thereof, do not include the following molecules:

[0036] In another embodiment of the present disclosure, ring B is selected from phenyl, 5-9 membered heteroaryl, 5-11 membered heterocyclyl, 5-8 membered bridged cycloalkyl.

[0037] In another embodiment of the present disclosure, ring B is selected from phenyl, 5-6 membered heteroaryl, 8-11 membered fused heterocyclyl.

[0038] In another embodiment of the present disclosure, ring B is selected from phenyl, benzo 5-7 membered heterocyclyl.

[0039] In another embodiment of the present disclosure, ring B is selected from phenyl, benzo 5-7 membered heterocyclyl; wherein the heterocyclyl ring of ring B contains 1-4 atoms or atom groups selected from N, S(O) 0-2 , O, C(O) in the ring atoms of the heterocyclyl ring.

[0040] In another embodiment of the present disclosure, ring B is selected from phenyl, wherein ring D is selected from 5-7 membered heterocyclyl, wherein said heterocyclyl contains 1-4 atoms selected from N, S(O) 0-2 , O, C(O) or atom groups, the *-end indicates the end connected to L1.

[0041] In another embodiment of the present disclosure, the structural unit is selected from t-1 is selected from 0, 1, 2, 3, 4; preferably 0, 1, 2, 3.

[0042] In another embodiment of the present disclosure, R 2-1 is selected from hydrogen, deuterium, cyano, halogen, oxo, thioxo, C 1-4 alkyl, halogenated C 1-4 alkyl, deuterated C 1-4 alkyl, hydroxy C 1-4 alkyl, cyano C 1-4 alkyl, C 2-4 alkenyl, halogenated C 2-4 alkenyl, deuterated C 2-4 alkenyl, C 2-4 alkynyl, halogenated C 2-4 alkynyl, deuterated C 2-4 alkynyl, C 1-4 alkoxy, halogenated C 1-4 alkoxy, deuterated C 1-4 alkoxy, C 3-6 membered cycloalkyl;

[0043] Alternatively, two R 2-1 on the same ring atom together form, together with the ring atom to which they are attached, a group selected from C 3-6 membered cycloalkyl, C 3-6 cycloalkenyl, 3-6 membered heterocyclyl;

[0044] Alternatively, two R 2-1 on adjacent ring atoms together form, together with the ring atoms to which they are attached, a group selected from C 3-6 membered cycloalkyl, C 3-6 cycloalkenyl, 3-6 membered heterocyclyl;

[0045] Preferably, R 2-1 is selected from hydrogen, cyano, halogen, C 1-4 alkyl, deuterated C 1-4 alkyl;

[0046] More preferably, R 2-1 is selected from halogen, C 1-4 alkyl and deuterated C1-4 alkyl.

[0047] In another embodiment of this disclosure, R 2-2 Selected from Hydrogen, deuterium, cyano, halogen, oxo, thio, hydroxyl, C 1-4 Alkyl, Halogenated C 1-4 Alkyl, hydroxyl C 1-4 Alkyl, cyano C 1-4 Alkyl, deuterated C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halogenated C 2-4 alkenyl, deuterated C 2-4 alkenyl, halogenated C 2-4 Alkyne group, deuterated C 2-4 alkynyl group, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, deuterated C 1-4 Alkoxy, (R d (R) e )N-、(R d (R) e )NC(O)O-、C 1-4 Alkoxy-C 1-4 Alkylene-, C 1-4 Alkyl-S(O)2-, C 1-4 Alkoxy-C(O)-, C 1-4 Alkyl-C(O)-, (R d (R) e )NC(O)-C 1-4 Alkylene, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 3-6 Cycloalkyl-O-, 3-6 membered heterocyclic-O-, (R d (R) e )NC(O)-、(R d (R) e )NC(O)O-、C 1-4 Alkyl-C(O)-NR d -、C 1-4 Alkoxy-C(O)-NR d -、C 1- 4alkoxy-C 1-4 Alkylene-C(O)-, (R d (R) e )NC(O)NR d -、(R d (R) e )NC 1-4 Alkylene-C(O)-, C 1-4 Alkoxy-C1-4 alkylene-OC(O)-, hydroxyC 1-4 alkyl-NR d -, (R d )(R e )N-S(O)2-, 1-4 alkoxy-C 1-4 alkylene-O-C(O)N(R d )-, hydroxyC 1-4 alkoxy-C(O)-, hydroxyC 1-4 alkoxy-C(O)-NR d -, (R d )(R e )N-C(O)-C(O)-N(R d )-, 3-6 membered heterocyclyl-O-C(O)-N(R d )-, (R g )(R h )-S(O)=N-; wherein said C 3-6 ycloalkyl, 3-6 membered heterocyclyl, C 3-6 ycloalkyl-O-, 3-6 membered heterocyclyl-O-, 3-6 membered heterocyclyl-O-C(O)-N(R d )- is optionally substituted with one or more groups selected from deuterium, cyano, halogen, hydroxy, C 1-4 alkyl, haloC 1-4 alkyl, hydroxyC 1-4 alkyl, cyanoC 1-4 alkyl, deuterated C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, haloC 2-4 alkenyl, deuterated C 2-4 alkenyl, haloC 2-4 alkynyl, deuterated C 2-4 alkynyl, C 1-4 alkoxy, haloC 1-4 alkoxy, deuterated C 1-4 alkoxy;

[0048] L2is selected from a bond, C 1-4 alkylene, *-N(R b )-C 1-4 alkylene-, *-N(R b )-C(O)-, *-N(R b )-C(O)-N(R b )-, *-OC(O)-, -C(O)-;

[0049] R b is selected from hydrogen, C 1-4alkyl, (R a-1 )(R b-1 )N-C(O)-;

[0050] R a-1 , R b-1 are each independently selected from hydrogen, C 1-4 alkyl, haloC 1-4 alkyl;

[0051] cycloC 3-6 alkyl;;

[0052] R d , R e are each independently selected from hydrogen, deuterium, cyano, halogen, oxo, thioxo, amino, hydroxy, C 1-4 alkyl, haloC 1-4 alkyl, deuterated C 1-4 alkyl, hydroxyC 1-4 alkyl, cyanoC 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, haloC 2-4 alkenyl, haloC 2-4 alkynyl, deuterated C 2-4 alkenyl, deuterated C 2-4 alkynyl, C 1-4 alkoxy, haloC 1-4 alkoxy, deuterated C 1-4 alkoxy, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 1-4 alkoxy-C 1-4 alkylene, (R d-1 )(R e-1 )N-, (R d-1 )(R e-1 )N-C(O)-, (R d-1 )(R e-1 )N-C 1-4 alkylene, C 3- 6cycloalkyl-C 1-4 alkylene, C 1-4 alkyl-C(O)-, C 1-4 alkoxy-C(O)-, C 1-4 alkyl-S(O)2-, (R d-1 )(R e-1 )N-C(O)-C 1-4 alkylene, 5-6 membered heteroaryl, C 1-4 alkyl-S(O)2-C 1-4 alkylene, haloC 1-4 alkoxy-C 1-4 alkylene, or Rd R e R 3-6 R 3-6 R 1-4 R 1-4 R 1-4 R 1-4 R 1-4 R 1-4 R 1-4 R 1-4 R 1-4 R d-2 R e R 2 R 1-4 R d-2 R e- R 2 R 1-4 R 1-4 R 1-4 R 1-4 R 1-4 R R

[0053] R d-1 R e-1 R 1-4 R 1-4 R d-1 R e-1 R 1-4 R 1-4 R 1-4 R 1-4 R 1-4 R R

[0054] R d-2 R e-2 R 1-4 R 1-4 R R

[0055] R g R h R1-4 alkyl, C 3-6 cycloalkyl;

[0056] provided that the following molecules are excluded;

[0057] In another embodiment of the present disclosure, R 2-2 is selected from C 1-4 alkoxy-C(O)-, C 1-4 alkyl-C(O)-, (R d )(R e )N-C(O)-, (R d )(R e )N-C(O)O-, (R d )(R e )N-C(O)-C(O)-N(R d )-, (R d )(R e )N-C(O)NR d - and hydroxy C 1-6 alkoxy-C(O)-N(R d )-;

[0058] R a-1 , R b-1 are each independently selected from hydrogen, C 1-4 alkyl;

[0059] L2is selected from a bond, *-N(R b )-C(O)- and *-N(R b )-C(O)-N(R b );

[0060] R b is selected from C 1-4 alkyl;

[0061] cycloC is selected from 4-6 membered heterocyclyl;

[0062] R d , R e are each independently selected from hydrogen, C 1-4 alkyl, haloC 1-4 alkyl, C 3-6 cycloalkyl, deuterated C 1-4 alkyl, C 1-4 alkoxy-C 1-4 alkylene and C 2-4 alkynyl;

[0063] Preferably,

[0064] R d , R eare each independently selected from hydrogen, C 1-4 alkyl, C 3-6 cycloalkyl, deuterated C 1-4 alkyl and C 2-4 alkynyl.

[0065] In another embodiment of the disclosure, R 2-1 is selected from hydrogen, halogen, C 1-4 alkyl, halogenated C 1-4 alkyl, deuterated C 1-4 alkyl, C 1-4 alkoxy, halogenated C 1-4 alkoxy, deuterated C 1-4 alkoxy;

[0066] R 2-2 is selected from (R d )(R e )N-C(O)NR d -;

[0067] R d , R e are each independently selected from hydrogen, C 1-4 alkyl, halogenated C 1-4 alkyl, deuterated C 1-4 alkyl, C 1-4 alkoxy, halogenated C 1-4 alkoxy, deuterated C 1-4 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, halogenated C 2-4 alkenyl, halogenated C 2-4 alkynyl, deuterated C 2-4 alkenyl, deuterated C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 5-6 bridged ring group; or R d , R e together with the N atom to which they are attached form a 3-6 membered heterocyclyl; wherein said 3-6 membered heterocyclyl is optionally substituted with one or more groups selected from hydroxyl, halogen, C 1-4 alkyl, halogenated C 1-4 alkyl, deuterated C 1-4 alkyl, cyano C 1-4 alkyl, C 1-4 alkoxy, halogenated C 1-4 alkoxy, deuterated C 1-4 alkoxy, C 1-4 alkoxy-C 1-4 alkylene;

[0068] with the proviso that the following molecules are excluded; with the proviso that the following molecules are excluded;

[0069] In another embodiment of the present disclosure, the compound is selected from the group consisting of the following compounds of formula (II) as shown below:

[0070] wherein, t-1 is selected from 0, 1, 2, 3, 4;

[0071] R 1 , R 2-1 , R 2-2 , L2, ring C, R 3 , ring E, R d , R e , R, ring D, p are as described above.

[0072] In another embodiment of the present disclosure, the compound is a compound of formula (I) as shown below:

[0073] wherein, X is CR 4 or N;

[0074] ring A is selected from C 6-10 aryl, 5-10 membered heteroaryl, 5-10 membered heterocyclyl;

[0075] L1 is selected from a bond, C 1-6 alkylene, C 2-6 alkenylene, C 2-6 alkynylene, wherein any methylene unit is optionally replaced by -O-, -C(O)-, -N(R a )-, -S-, -S(O)-, -S(O)2-;

[0076] ring B is selected from absent, C 6-10 aryl, 5-10 membered heteroaryl, 5-12 membered heterocyclyl, C 5-12 bridged cycloalkyl, C 5-12 spirocycloalkyl, 5-12 membered bridged heterocyclyl, 5-12 membered spiroheterocyclyl;

[0077] L2 is selected from absent, a bond, C 1-6 alkylene, *-N(R b )-C 1-6 alkylene-, *-N(R b )-C(O)-, -C(O)-, -N(R b )-, -O-, -S-, -S(O)-, -S(O)2-, -S(=O)(=NH)-, -P(O)-, *-OC(O)-, *-O-C(O)-N(R b )-, *-O-C 1-6alkylene-, -OC(O)-N(R b )-, *-N(R b )-C(O)-N(R b )-; the * indicates attachment to ring B; wherein said C 1-6 alkylene, *-N(R b )-C 1-6 alkylene-, *-O-C 1-6 alkylene- is optionally substituted with one or more halo, hydroxy, cyano, hydroxyC 1-6 alkyl;

[0078] R a , R b are each independently selected from hydrogen, C 1-6 alkyl, C 1-6 alkyl-C(O)-, (R a-1 )(R b-2 )N-C(O)-, C 1-6 alkoxy-C(O)-;

[0079] R a-1 , R b-1 are each independently selected from hydrogen, C 1-6 alkyl, haloC 1-6 alkyl;

[0080] ring C is selected from absent, 5-10 membered heteroaryl, 5-12 membered heterocyclyl, C 3-6 cycloalkyl, C 3-6 cycloalkenyl, 8-12 membered fused heteroaryl;

[0081] R 1 is selected from hydrogen, deuterium, deuterated C 1-6 alkyl, deuterated C 2-6 alkenyl, deuterated C 1-6 alkoxy, cyano, halo, oxo, thioxo, C 1- 6alkyl, C 2-6 alkynyl, C 1-6 haloC 1-6 alkyl, haloC 1-6 alkoxy, (C 1-6 alkyl)2P(O)-, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 1-6 alkyl-S(=O)(=NH)-, (R d )(R e )N-, C 1-6 alkoxy-C 1-6 alkylene-, hydroxyC 1-6 alkyl, cyanoC 1-6 alkyl, hydroxy, C 1-6alkyl-S(O)2-, C 1-6 alkoxy-C(O)-, C 1-6 alkyl-C(O)-, (R d )(R e )N-C(O)-C 1-6 alkylene, C 3-6 cycloalkyl-O-, 3-6 membered heterocyclyl-O-, C 2-6 alkenyl, haloC 2-6 alkenyl, haloC 2-6 alkynyl, deuterated C 2-6 alkynyl;

[0082] R 2 selected from hydrogen, deuterium, cyano, halogen, oxo, thia, C 1-6 alkyl, deuterated C 1-6 alkyl, C 2-6 alkynyl, C 1-6 alkoxy, haloC 1-6 alkyl, haloC 1-6 alkoxy, (C 1-6 alkyl)2P(O)-, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 1-6 alkyl-S(=O)(=NH)-, (R d )(R e )N-, C 1-6 alkoxy-C 1-6 alkylene-, hydroxyC 1-6 alkyl, cyanoC 1-6 alkyl, hydroxy, C 1-6 alkyl-S(O)2-, C 1-6 alkoxy-C(O)-, C 1-6 alkyl-C(O)-, (R d )(R e )N-C(O)-C 1-6 alkylene, C 3-6 cycloalkyl-O-, 3-6 membered heterocyclyl-O-, C 2-6 alkenyl, haloC 2-6 alkenyl, haloC 2-6 alkynyl, deuterated C 2-6 alkynyl, (R d )(R e )N-C(O)-, (R d )(R e )N-C(O)O-, (R d )(R e )N-C(O)-C(O)NR d -, C 1-6 alkyl-C(O)-NR d -, C1-6 alkyl, haloC d alkyl, haloC 1-6 alkyl, haloC d alkyl, haloC 1-6 alkyl, haloC 1-6 alkyl, haloC d alkyl, haloC e alkyl, haloC d alkyl, haloC d alkyl, haloC e alkyl, haloC 1-6 alkyl, haloC 1-6 alkyl, haloC 1-6 alkyl, haloC 1-6 alkyl, haloC d alkyl, haloC

[0083] alkyl, haloC 3 alkyl, haloC 1-6 alkyl, haloC 2-6 alkyl, haloC 1-6 alkyl, haloC 1-6 alkyl, haloC 1- alkyl, haloC 1-6 alkyl, haloC 1-6 alkyl, haloC 1-6 alkyl, haloC 3-6 alkyl, haloC 1-6 alkyl, haloC d alkyl, haloC e alkyl, haloC 1-6 alkyl, haloC 1-6 alkyl, haloC 1-6 alkyl, haloC 1-6 alkyl, haloC 1-6 alkyl, haloC 1-6 alkyl, haloC 1-6 alkyl, haloC d alkyl, haloC e alkyl, haloC 1-6 alkyl, haloC 3-6 alkyl, haloC 2-6 alkyl, haloC 2-6 alkyl, haloC 2-6 alkyl, haloC 2-6 alkyl, haloC f alkyl, haloC d alkyl, haloC e alkyl, haloC 1-6alkylene-, hydroxyl C 1-6 Alkoxy, C 1-6 Alkoxy-C 1-6 Alkylene-O-, Halogenated C 1-6 Alkoxy-C 1-6 alkylene-, 5-6-membered heteroaryl, C 1-6 Alkoxy-C(O)N(R) d )-C 1-6 Alkylene, (R) d (R) e )NC(O)-; wherein the C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 3- 6-cycloalkyl-O-, 3-6-membered heterocyclic-O-, optionally with one or more groups selected from hydroxyl, C, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 The alkoxy group is replaced;

[0084] R f Selected from CN, C 1-6 Alkyl, C 1-6 Alkyl-C(O)-;

[0085] R d R e Selected independently from hydrogen and C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 3-6 cycloalkyl, C 5-8 Bridge ring base, deuterated C 1-6 Alkyl, 3-6 membered heterocyclic group, hydroxyl C 1-6 Alkyl, C 1-6 Alkoxy-C 1-6 Alkylene, C 2-6 alkenyl, C 2-6 alkynyl group, (R d-1 (R) e-1 )NC 1-6 Alkylene, C 3-6 cycloalkyl-C 1-6 Alkylene, C 1-6 Alkoxy, the C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 3-6 cycloalkyl-C 1-6 Alkylene is optionally surrounded by one or more molecules selected from hydroxyl, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6Alkyl groups are substituted;

[0086] R d-1 R e-1 Selected independently from H and C respectively 1-6 Alkyl, Halogenated C 1-6 alkyl;

[0087] Or, R 1 and R 2 Together with the atoms they are attached to, they form an array that is optionally bounded by one or more R atoms. c Substitution of the following groups: 3-6 membered heterocyclic groups, C 3-6 Cycloalkenyl, C 3-6 cycloalkyl;

[0088] Or, R 2 and R 3 Together with the atoms they are attached to, they form an array that is optionally bounded by one or more R atoms. c Substituted groups include: 3-8 membered heterocyclic groups, C 3-8 Cycloalkenyl, C 3-8 cycloalkyl, 5-6 membered heteroaryl;

[0089] Or, two Rs 2 Together with the ring atoms to which it is attached, it forms an optional ring with one or more R atoms. c The following groups are substituted: C 3-6 Cycloalkyl, C 3-6 Cycloalkenyl, 3-6 membered heterocyclic groups,

[0090] Or, two R atoms located on the same ring atom 3 Together with the ring atoms to which it is attached, it forms an optional ring with one or more R atoms. c The following groups are substituted: C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 3-6 Cycloalkenyl;

[0091] Rc is selected from hydrogen, halogen, oxo, thio, and C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Alkoxy-C 1-6 alkylene-;

[0092] R 4 Selected from hydrogen, cyano, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy;

[0093] m, n, p, q are each independently selected from 0, 1, 2, 3, 4, 5.

[0094] In another embodiment of the present disclosure, the present disclosure provides a compound as shown in the following formula (I), a pharmaceutically acceptable salt thereof, an isomer thereof, characterized in that,

[0095] wherein, X is CR 4 or N;

[0096] Ring A is selected from C 6-10 aryl, 5-10 membered heteroaryl, 5-10 membered heterocyclyl;

[0097] L1is selected from a bond, C 1-6 alkylene, C 2-6 alkenylene, C 2-6 alkynylene, wherein any methylene unit is optionally replaced by -O-, -C(O)-, -N(R a )-, -S-, -S(O)-, -S(O)2-;

[0098] Ring B is selected from absent, C 6-10 aryl, 5-10 membered heteroaryl, 5-12 membered heterocyclyl, C 5-12 bridged cycloalkyl, C 5-12 spirocycloalkyl, 5-12 membered bridged heterocyclyl, 5-12 membered spiroheterocyclyl;

[0099] L2is selected from absent, a bond, C 1-6 alkylene, *-N(R b )-C 1-6 alkylene-, *-N(R b )-C(O)-, -C(O)-, -N(R b )-, -O-, -S-, -S(O)-, -S(O)2-, -S(=O)(=NH)-, -P(O)-, *-OCO-, *-O-C(O)-N(R b )-, *-O-C 1- 6alkylene-, -OC(O)-N(R b )-; the “*” end indicates attachment to Ring B; wherein said C 1-6 alkylene, *-N(R b )-C 1-6 alkylene-, *-O-C 1-6 alkylene- is optionally substituted with one or more halogen, hydroxyl, cyano, hydroxyl C 1-6 alkyl;

[0100] R a , R bare each independently selected from hydrogen, C 1-6 alkyl, C 1-6 alkyl-C(O)-, (R a-1 )(R b-1 )N-C(O)-, C 1-6 alkoxy-C(O)-;

[0101] R a-1 , R b-1 are each independently selected from hydrogen, C 1-6 alkyl;

[0102] ring C is selected from absent, 5-10 membered heteroaryl, 5-12 membered heterocyclyl, C 3-6 cycloalkyl, C 3-6 cycloalkenyl, 8-12 membered fused heteroaryl;

[0103] R 1 is selected from hydrogen, cyano, halogen, oxo, thioxo, C 1-6 alkyl, C 2-6 alkynyl, C 1-6 alkoxy, haloC 1-6 alkyl, haloC 1- 6alkoxy, (C 1-6 alkyl)2P(O)-, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 1-6 alkyl-S(=O)(=NH)-, (R d )(R e )N-, C 1-6 alkoxy-C 1-6 alkylene-, hydroxyC 1-6 alkyl, cyanoC 1-6 alkyl, hydroxy, C 1-6 alkyl-S(O)2-, C 1-6 alkoxy-C(O)-, C 1-6 alkyl-C(O)-, (R d )(R e )N-C(O)-C 1-6 alkylene, C 3-6 cycloalkyl-O-, 3-6 membered heterocyclyl-O-, C 2-6 alkenyl, C 2-6 alkynyl, haloC 2-6 alkenyl, haloC 2-6 alkynyl, deuterated C 2-6 alkynyl;

[0104] R 2 is selected from hydrogen, cyano, halogen, oxo, thioxo, C 1-6 alkyl, C 2-6 alkynyl, C 1-6 alkoxy, haloC1-6 alkyl, haloC 1- 6alkoxy, (C 1-6 alkyl)2P(O)-, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 1-6 alkyl-S(=O)(=NH)-, (R d )(R e )N-, C 1-6 alkoxy-C 1-6 alkylene-, hydroxyC 1-6 alkyl, cyanoC 1-6 alkyl, hydroxy, C 1-6 alkyl-S(O)2-, C 1-6 alkoxy-C(O)-, C 1-6 alkyl-C(O)-, (R d )(R e )N-C(O)-C 1-6 alkylene, C 3-6 cycloalkyl-O-, 3-6 membered heterocyclyl-O-, C 2-6 alkenyl, haloC 2-6 alkenyl, haloC 2-6 alkynyl, deuteratedC 2-6 alkynyl, (R d )(R e )N-C(O)-, (R d )(R e )N-C(O)O-, C 1-6 alkyl-C(O)-NR d -, C 1-6 alkoxy-C(O)-NR d -, C 1-6 alkoxy-C 1-6 alkylene-C(O)-, (R d )(R e )N-C(O)NR d -, (R d )(R e )N-C 1-6 alkylene-C(O)-, C 1-6 alkoxy-C 1-6 alkylene-OC(O)-, hydroxyC 1-6 alkyl-NR d -;

[0105] R 3 is selected from hydrogen, cyano, halogen, oxo, thioxo, C 1-6 alkyl, C 2-6 alkynyl, C 1-6 alkoxy, haloC 1-6 alkyl, haloC 1-6alkoxy, (C 1-6 alkyl)2P(O)-, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 1-6 alkyl-S(=O)(=NH)-, (R d )(R e )N-; C 1-6 alkoxy-C 1-6 alkylene-, hydroxy C 1-6 alkyl, cyano C 1-6 alkyl, hydroxy, C 1-6 alkyl-S(O)2-, C 1-6 alkoxy-C(O)-, C 1-6 alkyl-C(O)-, (R d )(R e )N-C(O)-C 1-6 alkylene, C 3-6 cycloalkyl-O-, 3-6 membered heterocyclyl-O-, amino, C 2-6 alkenyl, halo C 2-6 alkenyl, halo C 2-6 alkynyl, deuterated C 2-6 alkynyl, =NR f , (R d )(R e )N-C 1-6 alkylene-, hydroxy C 1-6 alkoxy, C 1-6 alkoxy-C 1-6 alkylene-O-, halo C 1-6 alkoxy-C 1-6 alkylene-, 5-6 membered heteroaryl, C 1-6 alkoxy-C(O)N(R d )-C 1-6 alkylene, (R d )(R e )N-C(O)-; wherein said C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 3-6 cycloalkyl-O-, 3-6 membered heterocyclyl-O- optionally substituted with one or more groups selected from hydroxy, CN, C 1-6 alkyl, halo C 1-6 alkyl, hydroxy C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkoxy;

[0106] R f is selected from CN, C 1-6 alkyl, C 1-6 alkyl-C(O)-;

[0107] Rd , R e are each independently selected from hydrogen, C 1-6 alkyl, haloC 1-6 alkyl, C 3-6 ycloalkyl, 3-6 membered heterocyclyl, hydroxyC 1-6 alkyl, C 1-6 lkyl, C 1-6 lkyl, C 2-6 lkyl, C 2-6 lkyl, (R d-1 )(R e-1 )N-C 1-6 lkyl, C 3-6 ycloalkyl-C 1-6 lkyl, C 1-6 lkyl, C 3-6 ycloalkyl, 3-6 membered heterocyclyl, C 3-6 ycloalkyl-C 1-6 lkyl, C 1-6 lkyl, haloC 1-6 lkyl, hydroxyC 1-6 lkyl, C 1-6 lkyl, C 1-6 lkyl, C

[0108] R d-1 , R e-1 are each independently selected from H, C 1-6 lkyl, haloC 1-6 lkyl;

[0109] and / or, R 1 and R 2 together with the atom to which they are attached form a 3-6 membered heterocyclyl, C c ycloalkenyl, C 3-6 ycloalkyl group optionally substituted by one or more R 3-6 groups;

[0110] and / or, R 2 and R 3 together with the atom to which they are attached form a 3-8 membered heterocyclyl, C c ycloalkenyl, C 3-8 ycloalkyl, 5-6 membered heteroaryl group optionally substituted by one or more R 3-8 groups;

[0111] and / or, two R 2 together with the ring atoms to which they are attached form a C c ycloalkyl, C 3-6 ycloalkyl group optionally substituted by one or more R 3-6 groups.cycloalkenyl, 3-6 membered heterocyclyl, and / or,

[0112] and / or two R 3 together with the ring atom to which they are attached form a group optionally substituted with one or more Rc; 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 3-6 cycloalkenyl;

[0113] R c selected from hydrogen, halogen, oxo, thioxo, C 1-6 alkyl, haloC 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkoxy, C 1-6 alkoxy-C 1-6 alkylene-;

[0114] R 4 selected from hydrogen, cyano, halogen, C 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkyl, haloC 1-6 alkoxy;

[0115] m, n, p, q are each independently selected from 0, 1, 2, 3, 4, 5.

[0116] In another embodiment of the present disclosure, the present disclosure provides a compound as illustrated in formula (I), a pharmaceutically acceptable salt thereof, an isomer thereof, characterized in that,

[0117] wherein X is CR 4 or N;

[0118] Ring A is selected from C 6-10 aryl, 5-10 membered heteroaryl, 5-10 membered heterocyclyl;

[0119] L1is selected from a bond, C 1-6 alkylene, C 2-6 alkenylene, C 2-6 alkynylene, wherein any methylene unit is optionally replaced by -O-, -C(O)-, -N(R a )-, -S-, -S(O)-, -S(O)2-;

[0120] Ring B is selected from absent, C 6-10 aryl, 5-10 membered heteroaryl, 5-12 membered heterocyclyl, C 5-12 bridged cycloalkyl, C 5-12 spirocycloalkyl, 5-12 membered bridged heterocyclyl, 5-12 membered spiroheterocyclyl;

[0121] L2is selected from the group consisting of absent, a chemical bond, C 1-6 alkylene, *-N(R b )-C 1-6 alkylene-, *-N(R b )-C(O)-, -C(O)-, -N(R b )-, -O-, -S-, -S(O)-, -S(O)2-, -S(=O)(=NH)-, -P(O)-, *-OCO-, *-O-C(O)-N(R b )-; the "*" end denotes attachment to ring B;

[0122] R a , R b are each independently selected from the group consisting of hydrogen, C 1-6 alkyl;

[0123] ring C is selected from the group consisting of absent, 5-10 membered heteroaryl, 5-12 membered heterocyclyl, C 3-6 cycloalkyl, C 3-6 cycloalkenyl;

[0124] R 1 , R 2 , R 3 are each independently selected from the group consisting of:

[0125] (1) hydrogen, cyano, halogen, oxo, thioxo, C 1-6 alkyl, C 2-6 alkynyl, C 1-6 alkoxy, haloC 1-6 alkyl, haloC 1- 6alkoxy, (C 1-6 alkyl)2P(O)-, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 1-6 alkyl-S(=O)(=NH)-, (R d )(R e )N-, C 1-6 alkoxy-C 1-6 alkylene-, hydroxyC 1-6 alkyl, cyanoC 1-6 alkyl, hydroxy, C 1-6 alkyl-S(O)2-, C 1-6 alkoxy-C(O)-, C 1-6 alkyl-C(O)-, (R d )(R e )N-C(O)-C 1-6 alkylene, C 3-6 cycloalkyl-O-, 3-6 membered heterocyclyl-O-; and / or,

[0126] (2) R 1 and R 2 together with the atom to which they are attached form a group selected from C c 3-6 membered heterocyclyl, C 3-6 cycloalkenyl, and C 3-6 cycloalkyl; and / or,

[0127] (3) R 2 and R 3 together with the atom to which they are attached form a group selected from C c 3-8 membered heterocyclyl, C 3-8 cycloalkenyl, C 3-8 cycloalkyl, and 5-6 membered heteroaryl; and / or,

[0128] (4) two R 2 together with the ring atoms to which they are attached form a group selected from C c 3-6 membered heterocyclyl, C 3-6 cycloalkenyl, and C 3-6 cycloalkyl; and / or,

[0129] (5) two R 3 together with the ring atom to which they are attached form a group selected from C c 3-6 membered heterocyclyl, C 3-6 cycloalkenyl, and C 3-6 cycloalkyl; and / or,

[0130] R c is selected from hydrogen, halogen, oxo, thioxo, C 1-6 alkyl, haloC 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkoxy, C 1-6 alkoxy-C 1-6 alkylene-; and / or,

[0131] R d and R e are each independently selected from hydrogen, C 1-6 alkyl, haloC 1-6 alkyl; and / or,

[0132] R 4 is selected from hydrogen, cyano, halogen, C 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkyl, and haloC 1-6 alkoxy; and / or,

[0133] m, n, p, q are each independently selected from 0, 1, 2, 3, 4, 5.

[0134] In another embodiment of the present disclosure, the present disclosure provides a compound as shown in the following formula (I), a pharmaceutically acceptable salt thereof, an isomer thereof, characterized in that,

[0135] wherein, X is CR 4 or N;

[0136] Ring A is selected from C 6-10 aryl, 5-10 membered heteroaryl, 5-10 membered heterocyclyl;

[0137] L1is selected from a bond, C 1-6 alkylene, C 2-6 alkenylene, C 2-6 alkynylene, wherein any methylene unit is optionally replaced by -O-, -C(O)-, -N(R a )-, -S-, -S(O)-, -S(O)2-;

[0138] Ring B is selected from absent, C 6-10 aryl, 5-10 membered heteroaryl, 5-12 membered heterocyclyl, C 5-12 bridged cycloalkyl, C 5-12 spirocycloalkyl, 5-12 membered bridged heterocyclyl, 5-12 membered spiroheterocyclyl;

[0139] L2is selected from absent, a bond, C 1-6 alkylene, *-N(R b )-C 1-6 alkylene-, *-N(R b )-C(O)-, -C(O)-, -N(R b )-, -O-, -S-, -S(O)-, -S(O)2-, -S(=O)(=NH)-, -P(O)-, *-OCO-; the “*” end indicates the connection with Ring B;

[0140] R a , R b are each independently selected from hydrogen, C 1-6 alkyl;

[0141] Ring C is selected from absent, 5-10 membered heteroaryl, 5-12 membered heterocyclyl, C 3-6 cycloalkyl, C 3-6 cycloalkenyl;

[0142] R 1 , R 2 , R 3 are each independently selected from the following groups:

[0143] (1) Hydrogen, cyano, halogen, oxo, thio, C 1-6 Alkyl, C 2-6 alkynyl group, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, Halogenated C 1- 6-alkoxy, (C 1-6 Alkyl)2P(O)-, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 1-6 Alkyl-S(=O)(=NH)-, (R d (R) e N-, C 1-6 Alkoxy-C 1-6 alkylene-, hydroxyl C 1-6 Alkyl, cyano C 1-6 Alkyl, hydroxyl, C 1-6 Alkyl-S(O)2-, C 1-6 alkoxy-C(O)-; and / or,

[0144] (2)R 1 and R 2 Together with the atoms they are attached, they form groups that are optionally substituted with one or more Rc groups, such as 3-6 membered heterocyclic groups, C-membered heterocyclic groups, and C-membered heterocyclic groups. 3-6 Cycloalkenyl, C 3-6 cycloalkyl; and / or,

[0145] (3)R 2 and R 3 Together with the atoms they are attached to, they form groups that are optionally substituted with one or more Rc groups, such as 3-8 membered heterocyclic groups, C-membered heterocyclic groups, etc. 3-8 Cycloalkenyl, C 3-8 cycloalkyl, 5-6-membered heteroaryl; and / or,

[0146] (4) Two Rs 2 Together with the ring atoms to which they are attached, they form the following groups, which may be optionally substituted with one or more Rc groups: C 3-6 Cycloalkyl, C 3-6 Cycloalkenyl, 3-6 membered heterocyclic groups, and / or,

[0147] (5) Two R atoms located on the same ring atom 3 Together with the ring atoms to which they are attached, they form the following groups, which may be optionally substituted with one or more Rc groups: C 3-6 cycloalkyl groups, 3-6 membered heterocyclic groups;

[0148] R c Selected from hydrogen, halogen, oxo, thio, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy;

[0149] R d , R e are each independently selected from hydrogen, C 1-6 alkyl, haloC 1-6 alkyl;

[0150] R 4 is selected from hydrogen, cyano, halogen, C 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkyl, haloC 1-6 alkoxy;

[0151] m, n, p, q are each independently selected from 0, 1, 2, 3, 4, 5.

[0152] In another embodiment of the present disclosure, the present disclosure provides a compound as illustrated in formula (I), a pharmaceutically acceptable salt thereof, an isomer thereof, characterized in that,

[0153] wherein, X is CR 4 or N;

[0154] Ring A is selected from C 6-10 aryl, 5-10 membered heteroaryl, 5-10 membered heterocyclyl;

[0155] L1is selected from a bond, C 1-6 alkylene, C 2-6 alkenylene, C 2-6 alkynylene, wherein any methylene unit is optionally replaced by -O-, -C(O)-, -N(R a )-, -S-, -S(O)-, -S(O)2-;

[0156] Ring B is selected from absent, C 6-10 aryl, 5-10 membered heteroaryl, 5-11 membered heterocyclyl, C 5-10 bridged cycloalkyl, C 5-10 spirocycloalkyl, C 5-10 bridged heterocyclyl, C 5-10 spiroheterocyclyl;

[0157] L2is selected from absent, a bond, C 1-6 alkylene, *-N(R b )-C1 -6 alkylene-, *-N(R b )-C(O)-, -C(O)-, -N(R b )-, -O-, -S-, -S(O)-, -S(O)2-, -S(=O)(=NH)-, -P(O)-, * -OCO-; the end marked with "*" is connected to ring B;

[0158] R a , R b are each independently selected from hydrogen, C 1-6 alkyl;

[0159] ring C is selected from absent, 5-10 membered heteroaryl, 5-10 membered heterocyclyl, C 3-6 cycloalkyl, C 3-6 cycloalkenyl;

[0160] R 1 , R 2 , R 3 are each independently selected from the following groups:

[0161] (1) hydrogen, cyano, halogen, oxo, thioxo, C 1-6 alkyl, C 2-6 alkenyl, C 1-6 alkynyl, C 1-6 haloalkyl, C 1- 6alkoxy, (C 1-6 alkyl)2P(O)-, C 3-6 cycloalkyl, 3-6 membered heterocyclyl; and / or,

[0162] (2) R 1 and R 2 together with the atom to which they are attached form a group selected from 3-6 membered heterocyclyl, C 3-6 cycloalkenyl; and / or,

[0163] (3) R 2 and R 3 together with the atom to which they are attached form a group selected from 3-6 membered heterocyclyl, C 3-6 cycloalkenyl, 5-6 membered heteroaryl; and / or,

[0164] (4) two R 2 together with the ring atom to which they are attached form a group selected from C 3-6 membered cycloalkyl, C 3-6 cycloalkenyl, 3-6 membered heterocyclyl; and / or,

[0165] (5) two R 3 on the same ring atom together with the ring atom to which they are attached form a group selected from C 3-6 cycloalkyl;

[0166] R c is selected from hydrogen, halogen, oxo, thioxo, C 1-6alkyl, haloC 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkoxy;

[0167] R 4 selected from hydrogen, cyano, halogen, C 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkyl, haloC 1-6 alkoxy;

[0168] m, n, p, q are each independently selected from 0, 1, 2, 3, 4, 5.

[0169] In another embodiment of the present disclosure, the present disclosure provides a compound as shown below, a pharmaceutically acceptable salt thereof, an isomer thereof,

[0170] wherein, X is CR 4 or N;

[0171] Ring A is selected from C 6-10 aryl, 5-10 membered heteroaryl, 5-10 membered heterocyclyl;

[0172] L1is selected from a bond, C 1-6 alkylene, C 2-6 alkenylene, C 2-6 alkynylene, wherein any methylene unit is optionally replaced by -O-, -C(O)-, -N(R a )-, -S-, -S(O)-, -S(O)2-;

[0173] Ring B is selected from absent, C 6-10 aryl, 5-10 membered heteroaryl, 5-11 membered heterocyclyl, C 5-10 bridged cycloalkyl, C 5-10 spirocycloalkyl, C 5-10 bridged heterocyclyl, C 5-10 spiroheterocyclyl;

[0174] L2is selected from absent, a bond, C 1-6 alkylene, *-N(R b )-C 1-6 alkylene-, *-N(R b )-C(O)-, -C(O)-, -N(R b )-, -O-, -S-, -S(O)-, -S(O)2-, -S(=O)(=NH)-, -P(O)-, “*” end indicates connection to Ring B;

[0175] R a , R bare each independently selected from hydrogen, C 1-6 alkyl;

[0176] Ring C is selected from absent, 5-10 membered heteroaryl, 5-10 membered heterocyclyl, C 3-6 cycloalkyl, C 3-6 cycloalkenyl;

[0177] R 1 , R 2 , R 3 are each independently selected from the following groups of radicals:

[0178] (1) hydrogen, cyano, halogen, oxo, thioxo, C 1-6 alkyl, C 2-6 alkynyl, C 1-6 alkoxy, halogenated C 1-6 alkyl, halogenated C 1- 6alkoxy, (C 1-6 alkyl)2P(O)-; and / or,

[0179] (2) R 1 and R 2 together with the atom to which they are attached form a 3-6 membered heterocyclyl, C 3-6 cycloalkenyl radical optionally substituted by one or more Rc; and / or,

[0180] (3) R 2 and R 3 together with the atom to which they are attached form a 3-6 membered heterocyclyl, C 3-6 cycloalkenyl, 5-6 membered heteroaryl radical optionally substituted by one or more Rc; and / or,

[0181] (4) two R 2 together with the ring atom to which they are attached form a C 3-6 membered cycloalkyl, C 3-6 cycloalkenyl, 3-6 membered heterocyclyl radical optionally substituted by one or more Rc; and / or,

[0182] (5) two R 3 together with the ring atom to which they are attached form a C c cycloalkyl radical optionally substituted by one or more Rc; 3-6

[0183] R c is selected from hydrogen, halogen, oxo, thioxo, C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy;

[0184] R​4 selected from hydrogen, cyano, halogen, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy;

[0185] m, n, p, q are each independently selected from 0, 1, 2, 3, 4, 5.

[0186] In another embodiment of the present disclosure, q is 0.

[0187] In another embodiment of the present disclosure, X is CR 4 .

[0188] In another embodiment of the present disclosure, R 4 is selected from hydrogen and halogen, preferably hydrogen.

[0189] In another embodiment of the present disclosure, ring A is selected from phenyl, naphthyl, 5-6 membered heteroaryl, 5-6 membered heterocyclyl.

[0190] In another embodiment of the present disclosure, ring A is phenyl.

[0191] In another embodiment of the present disclosure, ring A is selected from 5-6 membered heteroaryl, said heteroaryl containing 1 to 3 heteroatoms selected from N, S(O) 0-2 , O.

[0192] In another embodiment of the present disclosure, ring A is selected from 5-6 membered heterocyclyl, said heterocyclyl containing 1 to 3 heteroatoms selected from N, S(O) 0-2 , O.

[0193] In another embodiment of the present disclosure, wherein ring A is selected from phenyl, naphthyl, pyridine, pyrimidine, thiophene,

[0194] In another embodiment of the present disclosure, wherein ring A is selected from

[0195] In another embodiment of the present disclosure, R 1 is selected from hydrogen, cyano, halogen, oxo, C 2-4 alkynyl, C 3-4 cycloalkyl, 3-4 membered heterocyclyl, deuterated C 2-4 alkynyl.

[0196] In another embodiment of the present disclosure, R 1 is selected from hydrogen, cyano, halogen, oxo, C 2-4 alkynyl.

[0197] In another embodiment of the present disclosure, m is 1. In another embodiment of the present disclosure, R 1 selected from halogen and C 2-4 alkynyl.

[0198] In another embodiment of the present disclosure, R 1 selected from C 3-4 cycloalkyl, 3-4 membered heterocyclyl.

[0199] In another embodiment of the present disclosure, R 1 selected from H, CN, F, Cl, I, oxo, ethynyl, cyclopropyl, deuterated ethynyl.

[0200] In another embodiment of the present disclosure, R 1 selected from Cl, ethynyl.

[0201] In another embodiment of the present disclosure, R 1 selected from H, CN, F, Cl, I, oxo, ethynyl.

[0202] In another embodiment of the present disclosure, R 1 selected from cyclopropyl.

[0203] In another embodiment of the present disclosure, structural unit selected from The “*” end indicates connection to X.

[0204] In another embodiment of the present disclosure, structural unit selected from For example The “*” end indicates connection to X.

[0205] In another embodiment of the present disclosure, structural unit selected from The “*” end indicates connection to X.

[0206] In another embodiment of the present disclosure, structural unit selected from The “*” end indicates connection to X.

[0207] In another embodiment of the present disclosure, L1is selected from a chemical bond.

[0208] In another embodiment of the present disclosure, wherein L1is selected from a chemical bond, C 1-4 alkylene, C 2-4 alkynylene, wherein any methylene unit is optionally replaced by -O-, -C(O)-.

[0209] In another embodiment of the present disclosure, L1is selected from a chemical bond, -CH2-, -O-, * The left end of the " " indicates the connection with ring A.

[0210] In another embodiment of the present disclosure, ring B is selected from phenyl and 5-12 membered heterocyclyl.

[0211] In another embodiment of the present disclosure, ring B is selected from phenyl, benzo 5-7 membered heterocyclyl, more preferably phenyl; wherein the heterocyclyl in ring B contains 1-4 ring atoms selected from N, S(O) 0-2 , O, C(O) or atom or atom group.

[0212] In another embodiment of the present disclosure, ring B is selected from phenyl, 5-9 membered heteroaryl, 5-11 membered heterocyclyl, 5-8 membered bridged cycloalkyl.

[0213] In another embodiment of the present disclosure, ring B is selected from phenyl, 5-6 membered mono-heteroaryl, 8-9 membered fused heteroaryl, 5-6 membered mono-heterocyclyl, 8-11 membered fused heterocyclyl, 5-8 membered bridged cycloalkyl.

[0214] In another embodiment of the present disclosure, ring B is selected from phenyl, 5-6 membered heteroaryl, 5-6 membered mono-heterocyclyl, benzo 5-7 membered heterocyclyl, benzo 6-8 membered bridged heterocyclyl, benzo 5-6 membered heteroaryl, 5-6 membered heteroaryl and 5-7 membered heterocyclyl, 5-6 membered heteroaryl and 5-6 membered heteroaryl.

[0215] In another embodiment of the present disclosure, ring B is selected from phenyl, 5-6 membered heteroaryl, 5-6 membered mono-heterocyclyl, benzo 5-7 membered heterocyclyl, benzo 6-8 membered bridged heterocyclyl, benzo 5-6 membered heteroaryl, 5-6 membered heteroaryl and 5-7 membered heterocyclyl, 5-6 membered heteroaryl and 5-6 membered heteroaryl; wherein the heteroaryl, heterocyclyl, bridged heterocyclyl in ring B contains 1-4 ring atoms selected from N, S(O) 0-2 , O, C(O) or atom or atom group.

[0216] In another embodiment of the present disclosure, ring B is selected from

[0217] In another embodiment of the present disclosure, ring B is selected from The left end of the "*" indicates the connection with L1.

[0218] In another embodiment of the present disclosure, wherein ring B is selected from The left end of the "*" indicates the connection with L1.

[0219] In another embodiment of the disclosure, wherein ring B is selected from the group consisting of:

[0220] (1) The "*" end indicates attachment to L1and the other end is attached to L2.

[0221] (2) The "*" end indicates attachment to L1.

[0222] In another embodiment of the disclosure, wherein ring B is selected from the group consisting of: The "*" end indicates attachment to L1and the other end is attached to L2.

[0223] In another embodiment of the disclosure, wherein ring B is selected from the group consisting of:

[0224] (1) The "*" end indicates attachment to L1.

[0225] (2) The "*" end indicates attachment to L1.

[0226] In another embodiment of the disclosure, R 2 is selected from the group consisting of hydrogen, cyano, halogen, oxo, C 1-4 alkyl, deuterated C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkoxy-C(O)-, C 1-4 alkyl-C(O)-, (R d )(R e )N-C(O)-, (R d )(R e )N-C(O)O-, (R d )(R e )N-C(O)-C(O)NR d -, (R d )(R e )N-C(O)N(R d )- and hydroxy C 1-6 alkoxy-C(O)-N(R d )-; preferably halogen, C 1-4 alkyl, deuterated C 1-4 alkyl and (R d )(Re )N-C(O)NR d -; most preferably (R d )N-C(O)NR e -. d

[0227] In another embodiment of the present disclosure, R d , R e are each independently selected from the group consisting of hydrogen, C 1-4 alkyl, halo-C 1-4 alkyl, C 3-6 cycloalkyl, deuterated-C 1-4 alkyl, C 1-4 alkoxy-C 1-4 alkylene, and C 2-4 alkynyl; preferably hydrogen, C 1-4 alkyl, C 3-6 cycloalkyl, deuterated-C

[0228] C 1-4 alkyl, and C 2-4 alkynyl; more preferably hydrogen or C 1-4 alkyl.

[0229] In another embodiment of the present disclosure, two R 2 on adjacent ring atoms, together with the ring atoms to which they are attached, form a group selected from C 3-6 cycloalkenyl, and C 3-6 cycloalkyl, optionally substituted with one or more Rc.

[0230] In another embodiment of the present disclosure, two R 2 on adjacent ring atoms, together with the ring atoms to which they are attached, form a group selected from:

[0231] In another embodiment of the present disclosure, two R 2 on the same ring atom, together with the ring atom to which they are attached, form a C c cycloalkyl group, optionally substituted with one or more R 3-6 c.

[0232] In another embodiment of the present disclosure, two R 2 on the same ring atom, together with the ring atom to which they are attached, form a cyclopropyl group.

[0233] In another embodiment of the present disclosure, R 2 is selected from the group consisting of:

[0234] (1) H, halogen, C 1-4 alkyl, (C 1-4 alkyl)2P(O)-, C 1-4 alkoxy-C​1-4 alkylene, hydroxyC 1-4 alkyl, C 1-4 alkoxy-C(O)-, cyanoC 1-4 alkyl, hydroxyC 1-4 alkyl-S(O)2-, C 1-4 alkoxy, haloC 1-4 alkyl, haloC 1-4 alkoxy, C 3-6 cycloalkyl, C 1-4 alkyl-C(O)-, (R d )(R e )N-C(O)-C 1-4 alkylene, cyano, (R d )(R e )N-C(O)-, (R d )(R e )N-C(O)O-, C 1- 4alkyl-C(O)-NR d -, C 1-4 alkoxy-C(O)-NR d -, C 1-4 alkoxy-C 1-4 alkylene-C(O)-, (R d )(R e )N-C(O)NR d -, (R d )(R e )N-C 1-4 alkylene-C(O)-, C 1-4 alkoxy-C 1-4 alkylene-OC(O)-, (R d )(R e )N-, hydroxyC 1-4 alkyl-NR d -;

[0235] R d , R e are each independently selected from hydrogen, C 1-4 alkyl, haloC 1-4 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, hydroxyC 1-4 alkyl, C 1-4 alkoxy-C 1-4 alkylene, C 2-4 alkenyl, C 2-4 alkynyl, (R d-1 )(R e-1 )N-C 1-4 alkylene, C 3-6 cycloalkyl-C 1-4 alkylene, C1-4 Alkoxy, the C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 3-6 cycloalkyl-C 1-4 Alkylene is optionally surrounded by one or more molecules selected from hydroxyl, C 1-4 Alkyl, Halogenated C 1-4 Alkyl, hydroxyl C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl groups are substituted;

[0236] R d-1 R e-1 Selected independently from H and C respectively 1-4 Alkyl, Halogenated C 1-4 Alkyl; or,

[0237] (2) R on two adjacent ring atoms 2 Together with the ring atoms to which it is attached, it forms an optional ring with one or more R atoms. c The following groups are substituted: C 3-6 Cycloalkenyl, 3-6 membered heterocyclic alkenyl, C 3-6 cycloalkyl, or,

[0238] (3) Two R atoms located on the same ring atom 2 Together with the ring atoms to which it is attached, it forms an optional ring with one or more R atoms. c The following groups are substituted: C 3-6 cycloalkyl, 3-6 membered heterocyclic groups, or,

[0239] (4) Two Rs of non-adjacent ring atoms 2 Together with the ring atoms to which it is attached, it forms an optional ring with one or more R atoms. c Substitution with the following groups: 3-6 membered heterocyclic alkenyl groups;

[0240] Rc is selected from hydrogen, halogen, oxo, thio, and C. 1-4 Alkyl, Halogenated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, C 1-4 Alkoxy-C 1-4 Alkylene-.

[0241] In another embodiment of this disclosure, R 2 Selected from the following groups:

[0242] (1) H, halogens, C 1-4 Alkyl, (C 1-4 Alkyl)2P(O)-, C 1-4 Alkoxy-C 1-4 Alkylene, hydroxyl C 1-4Alkyl, C 1-4 Alkoxy-C(O)-, cyano-C 1-4 Alkyl, hydroxyl, C 1-4 Alkyl-S(O)2-, C 1-4 Alkoxy, halogenated C 1-4 Alkyl, Halogenated C 1-4 Alkoxy, C 3-6 cycloalkyl, C 1-4 Alkyl-C(O)-, (R d (R) e )NC(O)-C 1-4 Alkylene; R d R e Selected independently from hydrogen and C 1-4 Alkyl, Halogenated C 1- 4 alkyl groups; or,

[0243] (2) R on two adjacent ring atoms 2 Together with the ring atoms to which it is attached, it forms an optional ring with one or more R atoms. c The following groups are substituted: C 3-6 Cycloalkenyl, 3-6 membered heterocyclic alkenyl, C 3-6 cycloalkyl, or,

[0244] (3) Two R atoms located on the same ring atom 2 Together with the ring atoms to which it is attached, it forms an optional ring with one or more R atoms. c The following groups are substituted: C 3-6 cycloalkyl, 3-6 membered heterocyclic groups, or,

[0245] (4) Two Rs of non-adjacent ring atoms 2 Together with the ring atoms to which it is attached, it forms an optional ring with one or more R atoms. c Substitution with the following groups: 3-6 membered heterocyclic alkenyl groups;

[0246] R c Selected from hydrogen, halogen, oxo, thio, C 1-4 Alkyl, Halogenated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, C 1-4 Alkoxy-C 1-4 Alkylene-.

[0247] In another embodiment of this disclosure, R 2 Selected from the following groups:

[0248] (1) H, halogens, C 1-4 Alkyl, (C 1-4 Alkyl)2P(O)-, C 1-4 Alkoxy-C1-4 alkylene, hydroxyC 1-4 alkyl, C 1-4 alkoxy-C(O)-, cyanoC 1-4 alkyl, hydroxyC 1-4 alkyl-S(O)2-, or,

[0249] (2) two R 2 together with the ring atom to which they are attached form C 3-6 cycloalkenyl, 3-6 membered heterocycloalkenyl, C 3-6 cycloalkyl, or,

[0250] (3) two R 2 together with the ring atom to which they are attached form C 3-6 cycloalkyl, 3-6 membered heterocyclyl, or,

[0251] (4) two R 2 together with the ring atom to which they are attached form 3-6 membered heterocycloalkenyl.

[0252] In another embodiment of the present disclosure, wherein R 2 is selected from the group consisting of:

[0253] (1) H, halogen, C 1-4 alkyl, (C 1-4 alkyl)2P(O)-, or two R 2 together with the ring atom to which they are attached form C 3-6 cycloalkenyl, 3-6 membered heterocycloalkenyl, or,

[0254] (2) two R 2 together with the ring atom to which they are attached form C 3-6 membered cycloalkyl, 3-6 membered heterocyclyl, or,

[0255] (3) two R 2 together with the ring atom to which they are attached form 3-6 membered heterocycloalkenyl.

[0256] In another embodiment of the present disclosure, R 2 is selected from the group consisting of: H, F, Cl, -CH3, CN, -CD3,

[0257] In another embodiment of the present disclosure, R 2 is selected from the group consisting of:

[0258] (1) H, F, -CH3, (CH3)2-P(O)-, Cl, CH3OCH2CH2-, HOCH2CH2-, CH3CH2-, CH3OC(O)-, CNCH2-, OH, (CH3)2CH-S(O)2-, (CH3)2CH-, HF2CCH2-, CH3C(O)-, CN, -OCH3, CH3OCH2-, HF2C-, CH3C(O)-, CH3NHC(O)-, (CH3)2NC(O)-, (CH3)2NC(O)O-, (CH3)HNC(O)O-, CH3C(O)NH-, CH3OC(O)NH-, CH3OCH2C(O)-, CH3CH2NHC(O)-, HF2CO-, or,

[0259] (2) R 2 on two adjacent ring atoms together with the ring atoms to which they are attached form a group selected from: or,

[0260] (3) two R 2 on the same ring atom together with the ring atom to which they are attached form a group selected from: the "*" indicates the point of attachment to ring B, or,

[0261] (4) two R 2 on non-adjacent ring atoms together with the ring atoms to which they are attached form a group selected from:

[0262] In another embodiment of the disclosure, R 2 is selected from the group consisting of:

[0263] (1) H, F, -CH3, (CH3)2-P(O)-, Cl, CH3OCH2CH2-, HOCH2CH2-, CH3CH2-, CH3OC(O)-, CNCH2-, OH, (CH3)2CH-S(O)2-, (CH3)2CH-, HF2CCH2-, CH3C(O)-, or,

[0264] (2) R 2 on two adjacent ring atoms together with the ring atoms to which they are attached form a group selected from: or,

[0265] (3) two R on the same ring atom 2 together with the ring atom to which they are attached form a group selected from: the "*" indicates the point of attachment to ring B, or,

[0266] (4) two R on non-adjacent ring atoms 2 together with the ring atom to which they are attached form a group selected from:

[0267] In another embodiment of the disclosure, R 2 is selected from the group consisting of:

[0268] (1) H, F, -CH3, (CH3)2-P(O)-, Cl, CH3OCH2CH2-, HOCH2CH2-, CH3CH2-, CH3OC(O)-, CNCH2-, OH, (CH3)2CH-S(O)2-, (CH3)2CH-, or,

[0269] (2) two R on adjacent ring atoms 2 together with the ring atom to which they are attached form a group selected from: or,

[0270] (3) two R on the same ring atom 2 together with the ring atom to which they are attached form a group selected from: the "*" indicates the point of attachment to ring B, or,

[0271] (4) two R on non-adjacent ring atoms 2 together with the ring atom to which they are attached form a group selected from:

[0272] In another embodiment of the disclosure, wherein R 2 is selected from the group consisting of:

[0273] (1) H, F, -CH3, (CH3)2-P(O)-, or, two R on adjacent ring atoms 2 together with the ring atom to which they are attached form a group selected from: or,

[0274] (2) two R on the same ring atom 2 together with the ring atom to which they are attached form a group selected from: the "*" indicates the point of attachment to ring B, or,

[0275] (3) two R of non-adjacent ring atoms 2 together with the ring atom to which they are attached form a group selected from:

[0276] In another embodiment of the present disclosure, the structural unit is selected from

[0277] In another embodiment of the present disclosure, the structural unit is selected from

[0278] In another embodiment of the present disclosure, the structural unit is selected from The “*” end indicates connection to L1.

[0279] In another embodiment of the present disclosure, the structural unit is selected from The “*” end indicates connection to L1.

[0280] In another embodiment of the present disclosure, the structural unit is selected from the group consisting of:

[0281] (1) The “*” end indicates connection to L1, and the other end indicates connection to L2.

[0282] (2)

[0283] In another embodiment of the present disclosure, the structural unit is selected from: The “*” end indicates connection to L1, and the other end indicates connection to L2.

[0284] (2)

[0285] In another embodiment of the present disclosure, the structural unit is selected from: The “*” end indicates connection to L1, and the other end indicates connection to L2.

[0286] (2)

[0287] In another embodiment of the present disclosure, L2is selected from absent, a bond, -CH2-, 1-4 alkylene, *-N(R b )-C 1-4 alkylene-, *-N(R b )-C(O)-, *-N(R b )-C(O)-N(R b )- and *-OC(O)-; preferably a bond, *-N(R b )-C(O)- and *-N(R b )-C(O)-N(R b ).

[0288] In another embodiment of the present disclosure, R b is selected from hydrogen, C 1-4 alkyl and (R a-1 )(R b-1 )N-C(O)-; preferably C 1-4 alkyl.

[0289] In another embodiment of the present disclosure, R a-1 and R b-1 are each independently selected from hydrogen and C 1-4 alkyl.

[0290] In another embodiment of the present disclosure, L2is selected from absent, a bond, -CH2-, *-O-C(O)-, *-NH-C(O)-, preferably a bond, *-NH-C(O)- or The “*” end indicates the connection to ring B.

[0291] In another embodiment of the present disclosure, L2is selected from absent, a bond, -CH2-, *-O-C(O)-, -CH(CH3)-, -NH-, *-O-C(O)-NH-, *-O-CH2-, *-NH-C(O)-, *-O-C(O)-NH-, *-NH-C(O)-O-, The “*” end indicates the connection to ring B.

[0292] In another embodiment of the disclosure, L2is selected from absent, a chemical bond, -CH2-, -C(O)-, -O-, -S(=O)(=NH)-, * -O-C(O)-, -CH(CH3)-, -NH-; the "*" end indicates attachment to ring B.

[0293] In another embodiment of the disclosure, L2is selected from absent, a chemical bond, -CH2-, -C(O)-, -O-, -S(=O)(=NH)-, the "*" end indicates attachment to ring B.

[0294] In another embodiment of the disclosure, L2is selected from *-O-C(O)-; the "*" end indicates attachment to ring B.

[0295] In another embodiment of the disclosure, L2is selected from *-O-C(O)-NH-; the "*" end indicates attachment to ring B.

[0296] In another embodiment of the disclosure, ring C is selected from absent, 4-6 membered heterocyclyl, 5-6 membered heteroaryl, and C 3-6 cycloalkyl; preferably 4-6 membered heterocyclyl.

[0297] In another embodiment of the disclosure, when ring C is 4-6 membered heterocyclyl, it satisfies at least one of the following schemes 1, 2, 3, and 4:

[0298] Scheme 1: R 1 is C 2-4 alkynyl;

[0299] Scheme 2: R 3 is selected from haloC 1-4 alkoxy, and C 3-6 cycloalkyl-O-;

[0300] Scheme 3: n is 1, 2, 3, 4, or 5 ；

[0301] Scheme 4: L2is *-OC(O)-.

[0302] In another embodiment of the disclosure, ring C is selected from absent, 5-6 membered heterocyclyl, 5-6 membered heteroaryl, C 3-6 cycloalkyl, C 3-6 cycloalkenyl, 8-12 membered fused heterocyclyl.

[0303] In another embodiment of the disclosure, ring C is selected from absent, 5-6 membered heterocyclyl, 5-6 membered heteroaryl, C 3-6 cycloalkyl, C 3-6 cycloalkenyl.

[0304] In another embodiment of the present disclosure, ring C is selected from 5-6 membered heterocyclyl, 5-6 membered heteroaryl, wherein the ring atoms of said heterocyclyl, heteroaryl contain 1-3 atoms or atom groups selected from N, O, S(O) 0-2 0-2

[0305] In another embodiment of the present disclosure, ring C is selected from In another embodiment of the present disclosure, ring C is selected from

[0306] In another embodiment of the present disclosure, R 3 is selected from hydrogen, deuterium, cyano, halogen, oxo, thioxo, amino, hydroxy, C 1-4 alkyl, haloC 1-4 alkyl, deuteriumC 1-6 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, haloC 2-4 alkenyl, haloC 2-4 alkynyl, deuteriumC 2-4 alkenyl, deuteriumC 2-4 alkynyl, C 1-4 alkoxy, haloC 1-4 alkoxy, deuteriumC 1-4 alkoxy, deuterium-substituted haloC 1-4 alkyl, deuterium-substituted haloC 1-4 alkoxy, C 3-6 cycloalkyl-O-, (R j )(R k )N-C 1-4 alkylene-, (R j )(R k )N-C(O)N(R j )-, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 3-6 cycloalkyl-O-, 3-6 membered heterocyclyl-O-; wherein said C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 3-6 cycloalkyl-O-, 3-6 membered heterocyclyl-O- are optionally substituted with one or more groups selected from hydroxy, cyano, C 1-4 alkyl, haloC 1-4 alkyl, hydroxyC 1-4 alkyl, C 1-4 alkoxy, haloC 1-4 alkoxy;

[0307] or, two R 3 ​​together with the ring atom to which they are attached form a group optionally substituted with one or more Rc; 3-6 cycloalkyl, 3-6 membered heterocyclyl;

[0308] R g , R h are each independently selected from C 1-4 alkyl, haloC 1-4 alkyl, C 1-4 alkoxy, haloC 1-4 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl;

[0309] R j , R k are each independently selected from hydrogen, deuterium, cyano, halogen, oxo, thioxo, amino, hydroxy, C 1-4 alkyl, haloC 1-4 alkyl, deuterated C 1-4 alkyl, hydroxyC 1-4 alkyl, cyanoC 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, haloC 2-4 alkenyl, haloC 2-4 alkynyl, deuterated C 2-4 alkenyl, deuterated C 2-4 alkynyl, C 1-4 alkoxy, haloC 1-4 alkoxy, deuterated C 1-4 alkoxy;

[0310] or, R 2-1 and R 3 together with the atoms to which they are attached form a ring E optionally substituted with one or more Rc, ring E is selected from 3-8 membered heterocyclyl;

[0311] R c is selected from hydrogen, halogen, oxo, thioxo, C 1-4 alkyl, haloC 1-4 alkyl, C 1-4 alkoxy, haloC 1-4 alkoxy, C 1-4 alkoxy-C 1-4 alkylene-.

[0312] In another embodiment of the disclosure, R 3 is selected from hydrogen, halogen, oxo, C 1-4 alkyl, C 1-4 alkoxy, haloC 1- 4alkoxy, deuterated C 1-4 alkoxy, deuterium substituted haloC 1-4 alkyl, C1-4 alkoxy-C 1-4 alkylene-, cyano C 1-4 alkyl, hydroxy and C 3-6 cycloalkyl-O-; preferably hydrogen, oxo, C 1-4 alkoxy, halo C 1-4 alkoxy, deuterated C 1-4 alkoxy, deuterium substituted halo C 1-4 alkyl or hydroxy.

[0313] In another embodiment of the present disclosure, R 3 is selected from the group consisting of:

[0314] (1) hydrogen, C 1-4 alkyl, oxo, thioxo, halogen, hydroxy, amino, (C 1-4 alkyl)2-P(O)-, C 1-4 alkyl-S(=O)(=NH)-, C 1-4 alkyl-NH-, halo C 1-4 alkyl, C 1-4 alkoxy-C 1-4 alkylene-, C 3-6 cycloalkyl, hydroxy C 1-4 alkyl, halo C 1-4 alkoxy, C 3-6 cycloalkyl-O-, CN, =NR f , C 2-4 alkenyl, C 2-4 alkynyl, halo C 2-4 alkenyl, halo C 2-4 alkynyl, (R d )(R e )N-C 1-4 alkylene-, hydroxy C 1-4 alkoxy, C 1-4 alkoxy-C 1-4 alkylene-O-, halo C 1-4 alkoxy-C 1-4 alkylene-, cyano C 1-4 alkyl, 5-6 membered heteroaryl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 1-4 alkoxy-C(O)N(R d )-C 1-4 alkylene, (R d )(R e )N-C(O)-, (R d )(R e )N-C(O)-C 1-4 alkylene, (R d )(R e )N-, wherein said C3-6 cycloalkyl, 3-6 membered heterocyclyl optionally substituted with one or more groups selected from hydroxy, CN, C 1-4 alkyl, hydroxy C 1-4 alkyl, C 1-4 alkoxy;

[0315] R f selected from CN, C 1-4 alkyl, C 1-4 alkyl-C(O)-, or,

[0316] (2) two R 3 together with the ring atom to which they are attached form C 3-6 cycloalkyl; or,

[0317] (3) two R 3 together with the ring atom to which they are attached form C 3-6 cycloalkyl, C 3-6 cycloalkenyl.

[0318] In another embodiment of the disclosure, R 3 is selected from the group consisting of:

[0319] (1) hydrogen, C 1-4 alkyl, oxo, thioxo, halogen, (C 1-4 alkyl)2-P(O)-, C 1-4 alkyl-S(=O)(=NH)-, C 1-4 alkyl-NH-, halogen C 1-4 alkyl, C 1-4 alkoxy-C 1-4 alkylene-, C 3-6 cycloalkyl, hydroxy C 1-4 alkyl, halogen C 1-4 alkoxy, C 3-6 cycloalkyl-O-, CN, or,

[0320] (2) two R 3 together with the ring atom to which they are attached form C 3-6 cycloalkyl; or,

[0321] (3) two R 3 together with the ring atom to which they are attached form C 3-6 cycloalkyl, C 3-6 cycloalkenyl.

[0322] In another embodiment of the disclosure, wherein R 3 is selected from hydrogen, C 1-4 alkyl, oxo, thioxo, halogen, (C 1-4alkyl)2-P(O)-, C 1-4 alkyl-S(=O)(=NH)-, C 1-4 alkyl-NH-, haloC 1-4 alkyl, C 1-4 alkoxy-C 1-4 alkylene-, C 3-6 cycloalkyl, or two R 3 together with the ring atom to which they are attached form C 3-6 cycloalkyl.

[0323] In another embodiment of the present disclosure, wherein R 3 is selected from the group consisting of hydrogen, C 1-4 alkyl, oxo, thioxo, or two R 3 together with the ring atom to which they are attached form C 3-6 cycloalkyl.

[0324] In another embodiment of the present disclosure, wherein R 3 is selected from the group consisting of -CH3, oxo, HF2C-O-, DF2C-O-, CH3OCH2-, CNCH2-, F and CD3O-.

[0325] In another embodiment of the present disclosure, wherein R 3 is selected from the group consisting of:

[0326] (1) H, -CH3, oxo, thioxo, F, CH3CH2-NH-, (CH3)2-P(O)-, CH3-S(=O)(=NH)-, HF2C-, CH3O-CH2-, HOCH2-, HF2C-O-, CN, CH3CH2-, -OCH3, HOCH2CH2-, =N-C(O)-CH3, =N-CH3, =N-CN, CF3CH2-, CH2=CH2-, (CH3)2N-CH2-, CH2FCH2-, CF2=CH2-, HOCH2CH2O-, OH, -NH2, -OCH2CH2OCH3, -OCH2CH2OH, HF2C-O-CH2-, CN-CH2-, CH3-NH-, (CH3)2NC(O)-, CH3NHC(O)-, CH3CH2-O-, (CH3)2N-, or,

[0327] (2) two R 3 on the same ring atom together with the ring atom to which they are attached form cyclopropyl, cyclobutyl; or,

[0328] (3) two R on adjacent ring atoms 3 together with the ring atom to which they are attached form a cyclopropyl, cyclobutyl, cyclopentyl, cyclopropenyl, cyclobutenyl, cyclopentenyl.

[0329] In another embodiment of the present disclosure, wherein R 3 is selected from the group consisting of:

[0330] (1) H, -CH3, oxo, thioxo, F, CH3CH2-NH-, (CH3)2-P(O)-, CH3-S(=O)(=NH)-, HF2C-, CH3O-CH2-, HOCH2-, HF2C-O-, CN, or,

[0331] (2) two R on the same ring atom 3 together with the ring atom to which they are attached form a cyclopropyl, cyclobutyl; or,

[0332] (3) two R on adjacent ring atoms 3 together with the ring atom to which they are attached form a cyclopropyl, cyclobutyl, cyclopentyl, cyclopropenyl, cyclobutenyl, cyclopentenyl.

[0333] In another embodiment of the present disclosure, wherein R 3 is selected from the group consisting of H, -CH3, oxo, thioxo, F, CH3CH2-NH-, (CH3)2-P(O)-, CH3-S(=O)(=NH)-, HF2C-, CH3O-CH2-, or, two R on the same ring atom 3 together with the ring atom to which they are attached form a cyclopropyl, cyclobutyl.

[0334] In another embodiment of the present disclosure, wherein R 3 is selected from the group consisting of H, -CH3, oxo, thioxo, or, two R on the same ring atom 3 together with the ring atom to which they are attached form a cyclopropyl.

[0335] In another embodiment of the present disclosure, the structural unit is selected from

[0336] In another embodiment of the present disclosure, wherein the structural unit is selected from

[0337] In another embodiment of the present disclosure, wherein the structural unit is selected from

[0338] In another embodiment of the present disclosure, the structural unit is selected from

[0339] In another embodiment of the present disclosure, the structural unit is selected from

[0340] In another embodiment of the present disclosure, R 1 and R 2 together with the atom to which they are attached form a group:

[0341] In another embodiment of the present disclosure, R 1 and R 2 together with the atom to which they are attached form a group:

[0342] In another embodiment of the present disclosure, the structural unit is selected from

[0343] In another embodiment of the present disclosure, the structural unit is selected from

[0344] In another embodiment of the present disclosure, R 2 and R 3 together with the atom to which they are attached form a group optionally substituted by one or more R c selected from 5-7 membered heterocyclyl, C 5-7 cycloalkenyl, 5-6 membered heteroaryl; the ring atoms of said 5-7 membered heterocyclyl contain 1-3 atoms or atom groups selected from N, S(O) 0-2 , O, C(O); said 5-6 membered heteroaryl contains 1-3 atoms selected from N, S, O;

[0345] R c is selected from hydrogen, halogen, oxo, thioxo, C 1-4 alkyl, haloC 1-4 alkyl, C 1-4 alkoxy, haloC 1-4 alkoxy.

[0346] In another embodiment of the present disclosure, R 2 and R 3 together with the atom to which they are attached form a group:

[0347] In another embodiment of the present disclosure, wherein R 2 and R 3 together with the atom to which they are attached form a group:

[0348] In another embodiment of the present disclosure, wherein R 2 and R 3 together with the atom to which they are attached form a group:

[0349] In another embodiment of the present disclosure, wherein R 2 and R 3 together with the atom to which they are attached form a group:

[0350] In another embodiment of the present disclosure, wherein R 2 and R 3 together with the atom to which they are attached form a group:

[0351] In another embodiment of the present disclosure, the structural unit is selected from

[0352] In another embodiment of the present disclosure, wherein the structural unit is selected from

[0353] In another embodiment of the present disclosure, wherein the structural unit is selected from

[0354] In another embodiment of the present disclosure, wherein the structural unit is selected from

[0355] In another embodiment of the present disclosure, wherein the structural unit is selected from

[0356] In another embodiment of the present disclosure, the compound, the pharmaceutically acceptable salt thereof, the isomer thereof is selected from the structure as shown below:

[0357] Ring B, Ring C, R 1 , R 2 , R 3 , L2, n, p are defined as in any of the preceding embodiments.

[0358] In another embodiment of the present disclosure, the compound, the pharmaceutically acceptable salt thereof, the isomer thereof is selected from the structure as shown below:

[0359] wherein the structural unit is a moiety as defined in the ring B in the preceding embodiments; Ring B1 is selected from 7-membered heterocycloalkenyl;

[0360] the structural unit is a moiety as defined in the structural unit in the preceding embodiments;

[0361] Preferably, Ring B1 is selected from 7-membered nitrogen-containing heterocycloalkenyl;

[0362] Preferably, Ring B1 is selected from 7-membered heterocycloalkenyl, which contains one N atom and 0 to 2 atoms or atom groups selected from N, NH, O, S or C(O) as ring atoms;

[0363] Preferably, L2 is connected to the nitrogen atom on Ring B1;

[0364] Ring C, R 1 , R 2 , R 3 , L2, n, p are defined as in any of the preceding embodiments.

[0365] In another embodiment of the present disclosure of formula (I-C), wherein,

[0366] R 1 is selected from halogen, C 2-4 alkynyl;

[0367] L2 is selected from C 1-4 alkylene, -C(O)-, -O-C(O)-; the “*” end indicates the connection to Ring B;

[0368] Ring C is selected from 5-6 membered heterocyclyl, 5-6 membered heteroaryl; preferably 5-6 membered nitrogen-containing heterocyclyl, 5-6 membered nitrogen-containing heteroaryl;

[0369] R 3 selected from C 1-4 alkyl, C 1-4 alkoxy;

[0370] p, n are independently selected from 0, 1, 2.

[0371] In another embodiment of the present disclosure, the compound, pharmaceutically acceptable salt thereof, isomer thereof or nitroxide thereof is selected from the structure as shown below:

[0372] In a second aspect, the present disclosure further provides a pharmaceutical composition containing a therapeutically effective amount of the compound, pharmaceutically acceptable salt thereof, isomer thereof of the first aspect, and one or more pharmaceutically acceptable carriers.

[0373] In another embodiment of the present disclosure, the content of the compound, pharmaceutically acceptable salt thereof, isomer thereof in the pharmaceutical composition is 1% to 95%.

[0374] In another embodiment of the present disclosure, the pharmaceutically acceptable carrier in the pharmaceutical composition includes one or more of a filler, a disintegrant, a binder, a glidant, and a lubricant.

[0375] In a third aspect, the present disclosure provides the use of the compound, pharmaceutically acceptable salt thereof, isomer thereof of the first aspect in the preparation of a medicament for treating a VAV1-mediated related disease.

[0376] In another embodiment of the present disclosure, the VAV1-mediated related disease is a disease caused by disorder of lymphocyte development or activation.

[0377] In another embodiment of the present disclosure, the VAV1-mediated related disease is an autoimmune disease or an inflammatory disease.

[0378] In another embodiment of the disclosure, the VAVl-mediated related disease is a disorder caused by or associated with a dysregulation of T cell receptor signaling.

[0379] In another embodiment of the disclosure, the VAVl-mediated related disease is a disorder caused by or associated with a VAVl polymorphism.

[0380] In another embodiment of the disclosure, the VAVl-mediated related disease is an autoimmune disease selected from the group consisting of multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus, Hashimoto's thyroiditis, myasthenia gravis, type I or type II diabetes and related diseases thereof, vasculitis, pernicious anemia, Sjogren's syndrome, uveitis, psoriasis, Graves' ophthalmopathy, alopecia areata, allergic diseases (e.g., allergic asthma, atopic dermatitis, allergic rhinitis / conjunctivitis, allergic contact dermatitis), inflammatory diseases optionally with underlying abnormal reactions (e.g., inflammatory bowel disease, Crohn's disease or ulcerative colitis, intrinsic asthma, inflammatory lung injury, inflammatory liver injury, inflammatory glomerular injury), atherosclerosis, osteoarthritis, irritant contact dermatitis and further eczematous dermatitis, seborrheic dermatitis, cutaneous manifestations of immune-mediated diseases, inflammatory eye diseases, keratoconjunctivitis, myocarditis or hepatitis.

[0381] Explanation and Definitions

[0382] Unless otherwise indicated, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase should not be construed as undefined or unclear unless specifically defined, but should be interpreted in accordance with the ordinary meaning.

[0383] The term "pharmaceutically acceptable" means those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0384] The term "pharmaceutically acceptable salt" means a derivative of a compound of the disclosure prepared by reaction with a relatively nontoxic acid or base. These salts can be prepared in situ during the synthesis, isolation, and purification of the compound, or separately by reacting the purified compound with a suitable acid or base. When the compound contains relatively acidic functionalities, base addition salts can be formed with alkali metals, alkaline earth metal hydroxides, or organic amines, including those based on the cations of the alkali and alkaline earth metals, and those of nontoxic, quaternary ammonium and quaternary amine cations, and also those of amino acids, etc. When the compound contains relatively basic functionalities, acid addition salts can be formed with organic or inorganic acids.

[0385] The term "pharmaceutically acceptable carrier" refers to a medium generally accepted in the art for the delivery of biologically active agents to animals, particularly mammals, and includes, as non-limiting examples, adjuvants, excipients or vehicles, such as diluents, preservatives, fillers, flow conditioners, disintegrants, wetting agents, emulsifiers, suspending agents, sweetening agents, flavoring agents, perfuming agents, antibacterial agents, antifungal agents, lubricants, and dispersing agents, depending upon the nature of the dosage form and the means of administration. Pharmaceutically acceptable carriers are formulated in accordance with routine procedures, as is understood in the art, and are within the scope of sound medical judgment based on a variety of factors related to the active agent being formulated, the subject the composition containing the agent is intended to be administered to, the intended route of administration of the composition, and the targeted therapeutic indication. Pharmaceutically acceptable carriers include both aqueous and non-aqueous media, as well as a variety of solid and semi-solid dosage forms. Such carriers include a wide variety of different ingredients and additives, in addition to the active agent, such additional ingredients and additives included in the formulation for a variety of reasons (e.g., to stabilize the active agent, to bind the agent, etc.) are well known to those of ordinary skill in the art.

[0386] The term "effective prophylactic or therapeutic amount" refers to a sufficient amount of a compound of the present disclosure, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof to treat a disorder at a reasonable benefit / risk ratio applicable to any medical treatment and / or prevention. It will be recognized by those of ordinary skill that the total daily dose of the compounds of the present disclosure, the pharmaceutically acceptable salts thereof, isomers, and compositions shown herein will be decided by the attending physician within the scope of sound medical judgment. The specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex, and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed; and like factors well known in the medical arts.

[0387] The term "isomers" as used herein encompasses geometric isomers and stereoisomers, such as atropisomers, cis-trans isomers, enantiomers, diastereomers, tautomers, as well as racemic mixtures and other mixtures of the same, all of which are intended to be within the scope of the present disclosure. The term "enantiomers" refers to stereoisomers that are mirror images of one another. The term "tautomers" refers to functional group isomers that differ in the bonding of one or more atoms, such as a keto and its enol form, which are keto-enol tautomers. The term "diastereomers" refers to stereoisomers that have two or more chiral centers and are not mirror images of one another. The term "cis-trans isomers" refers to different spatial orientations of a double bond or ring atom that cannot freely rotate. The term "stereoisomers" refers primarily to isomers that have a chiral center and includes enantiomers, diastereomers, and mixtures of enantiomers and diastereomers, racemates, non-racemic mixtures; "stereoisomers" include, but are not limited to, the absolute configuration R and the absolute configuration S of a chiral center, mixtures of R and S isomers, and diastereomers of a chiral center having 2-4 chiral centers. The term "atropisomers" are stereoisomers that are separated due to hindered rotation or very slow rotation of a single bond. Stereoisomers of the compounds of the present disclosure can be prepared using chiral synthesis or chiral reagents or other conventional techniques. For example, one enantiomer of a compound of the present disclosure can be prepared using asymmetric catalytic techniques or chiral auxiliary derivatization techniques. Alternatively, a single stereoisomer can be obtained from a mixture by chiral resolution techniques. Alternatively, a single stereoisomer can be prepared directly using a chiral starting material. Separation of optically pure compounds is typically accomplished using preparative chromatography on a chiral column to achieve separation of the chiral compounds.

[0388] The absolute stereochemistry of the compounds can be determined by conventional techniques. For example, single crystal X-ray diffraction analysis, by the chiral structure of the starting material and the reaction mechanism of asymmetric synthesis, or by comparison with the absolute configuration of the product after resolution. The compounds marked herein as "absolute configuration unknown / undetermined" are typically resolved from racemic compounds by chiral preparative SFC to single isomers, which are then characterized and tested.

[0389] The term "nitroso" or "N-oxide" as used herein refers to derivatives of nitrogen containing groups in which the nitrogen atom is further oxidized. Common N-oxides include N-oxides of tertiary amines or N-oxides of nitrogen containing heterocycles. Methods for the synthesis of N-oxides are well known to those skilled in the art and include the oxidation of heterocycles and tertiary amines with peroxy acids such as peroxyacetic acid and meta-chloroperoxybenzoic acid, hydrogen peroxide, alkylhydroperoxides such as tert-butyl hydroperoxide, sodium perborate and dioxiranes such as dimethyldioxirane.

[0390] The term "optionally substituted" as used herein refers to two possibilities, either the hydrogen atom(s) of the substituent group can be "substituted" by one or more substituents or "unsubstituted".

[0391] When a bond in a substituent group is interrupted by a broken line, it indicates that the bond is the point of attachment of the substituent, for example indicates that the pyrimidine ring is attached to the given group or the given formula via a C atom. The occurrence of a dash "-" in a substituent group indicates the point of attachment of the substituent, for example -SCH3is attached to the given group or the given formula via the sulfur atom.

[0392] indicates the absolute configuration of a stereogenic center, i.e. R or S configuration. indicates the cis or trans configuration, a double solid or double dashed bond indicates the cis configuration, a solid-dashed bond indicates the trans configuration.

[0393] When a bond of a substituent can cross over to a ring, it indicates that this substituent can be bonded to any atom of the ring. For example, the structural element indicates that the substituent R can be substituted at any position on the phenyl ring.

[0394] When a listed substituent is not specified as to its attachment point to the given group or the given formula, then the substituent can be attached by any bondable atom thereof. For example, when ring A is selected from then it can be attached to X or L1via any ring atom of the group.

[0395] When any variable (e.g. R d ) occurs more than one time in a compound or a structure, its definition in each instance is independent of its definition at every other place. For example, indicates that the cyclopentyl group is substituted with 3 R d groups, and each R d has independent options.

[0396] In the present disclosure, when L2is selected from absent, it means that L2and the groups ring C, R 3 are all absent.

[0397] In the present disclosure, when L2 is absent, ring C is absent, the structural unit is

[0398] In the present disclosure, the "two R 2 together with the ring atom to which they are attached to form a ring", wherein the two R 2 may be located on adjacent ring atoms of ring B, may be located on non-adjacent ring atoms, or may be located on the same ring atom.

[0399] In the present disclosure, S(O) 0-2 refers to S, S(O), S(O)2.

[0400] Unless otherwise specified, the term "halogen" means a fluorine, chlorine, bromine, or iodine atom.

[0401] Unless otherwise specified, the term "alkyl" means a branched or straight chain saturated aliphatic hydrocarbon radical derived by the removal of one hydrogen atom from a parent alkane. For example, the term "C 1-10 alkyl" means a radical derived from a C1, C2, C3, C4, C5, C6, C7, C8, C9, C 10 alkyl, "C 1-6 alkyl", "C 1-4 alkyl", "C 1-3 alkyl"; specific examples include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, sec-butyl, 2-methylbutyl, 1,1-dimethylbutyl, and the like.

[0402] Unless otherwise specified, the term "alkenyl" means a straight or branched chain alkyne radical (containing at least one carbon-carbon double bond) derived by the removal of one hydrogen atom from a parent alkene, including "C 2-6 alkenyl", "C 2-5 alkenyl", "C 2-4 alkenyl", "C 2-3 alkenyl"; specific examples include, but are not limited to, -CH=CH2, -CH=CHCH3, -C(CH2)=CH2, -CH=CHCH2CH3, -CH2CH=CHCH3, and the like.

[0403] Unless otherwise specified, the term "alkynyl" means a straight or branched chain alkyne radical (containing at least one carbon-carbon triple bond) derived by the removal of one hydrogen atom from a parent alkane, including "C 2-5 alkynyl", "C 2-4 alkynyl", "C 2-3 alkynyl"; specific examples include, but are not limited to, -C=CH, -C=CHCH3, HC≡CHCH2-, HC≡C-C≡C-, and the like.

[0404] Unless otherwise specified, the term "alkylene" refers to a group derived by the removal of two hydrogen atoms from a straight or branched chain saturated aliphatic alkane, the removed hydrogen atoms can be removed from the same carbon atom or different carbon atoms; "alkylene" as described herein preferably is "straight chain alkylene"; "alkylene" includes "C 1-6 alkylene", "C 1-4 alkylene", "C 1-2 alkylene"; specific examples include, but are not limited to, -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH(CH2)CH2-, -CH2CH2CH2CH2-, -CH(CH2)CH2CH2-, -CH(CH2CH2)CH2-, -C(CH2)(CH2)CH2-, -CH2CH2CH2CH2CH2-, and the like.

[0405] Unless otherwise specified, the term "alkenylene" refers to a group derived by the removal of two hydrogen atoms from a straight or branched chain alkene (containing at least one carbon-carbon double bond), the removed hydrogen atoms can be removed from the same carbon atom or different carbon atoms; "alkenylene" includes "C 2-6 alkenylene", "C 2-4 alkenylene"; specific examples include, but are not limited to, -CH=CH-, -CH=CHCH2-, -CH=C(CH3)CH2-, -CH=CHCH2CH=CH-, -CH2CH=CHCH2-, -CH2CH=CHCH2CH2-.

[0406] Unless otherwise specified, the term "alkynylene" refers to a group derived by the removal of two hydrogen atoms from a straight or branched chain alkyne (containing at least one carbon-carbon triple bond); "alkynylene" includes "C 2-6 alkynylene", "C 2-4 alkynylene"; specific examples include, but are not limited to, -C≡C-, -C≡C-CH2-, -C≡C-CH2CH2CH2-, -CH2-C≡C-CH2CH2CH2-, -C≡C-CH2C≡C-, -C≡C-CH2CH=CH-.

[0407] Unless otherwise specified, the term "haloalkyl" refers to an alkyl group in which one or more hydrogen atoms are replaced by a halogen atom. Preferably, haloC 1-6 alkyl, more preferably haloC 1-4 alkyl. Examples of haloalkyl groups include, but are not limited to, monofluoromethyl, difluoromethyl, trifluoromethyl, trichloromethyl, tribromomethyl, 2,2,2-trifluoroethyl, 2,2,2-trichloroethyl, and the like. Alkyl is as previously defined.

[0408] Unless otherwise specified, the term "haloalkenyl" refers to an alkenyl group in which one or more hydrogen atoms are replaced by a halogen atom. Preferably, haloC 2-6Alkenyl, more preferably halogenated C 2-4 Alkenyl groups. Examples of haloalkenyl groups include, but are not limited to, -CH=CHF, -CH=CF2, -CH=CHCF3, -CH=CHCCl3, etc.

[0409] Unless otherwise specified, the term "haloynyl" refers to an ynyl group in which one or more hydrogen atoms are replaced by halogen atoms. Preferred halogenated C 2-6 Alkyne group, more preferably halogenated C 2-4 Alkyne groups. Examples of halogenated alkyne groups include, but are not limited to, -C≡CF, -C≡CHCF3, ClC≡CHCH2-, FC≡CC≡C-, etc.

[0410] Unless otherwise specified, the term "deuterated alkenyl" refers to an alkenyl group in which one or more hydrogen atoms are replaced by deuterium atoms.

[0411] Unless otherwise specified, the term "deuterated ynyl" refers to an ynyl group in which one or more hydrogen atoms are replaced by deuterium atoms.

[0412] Unless otherwise specified, the term "hydroxyalkyl" refers to a group derived from an alkyl group in which one or more hydrogen atoms are replaced by a hydroxyl group, and "hydroxyalkyl" as used in this disclosure includes "hydroxyl C". 1-6 Alkyl group, hydroxyl group 1-4 Alkyl groups; specific examples include, but are not limited to, -CH2OH, -CH2CH2OH, -CH(OH)CH3, and -CH2CH2CH2OH. wait.

[0413] Unless otherwise specified, the term "cyanoalkyl" refers to an alkyl group in which one or more hydrogen atoms are replaced by a cyano group. "Cyanoalkyl" as used in this disclosure includes "cyanoC 1-6 Alkyl", "cyano C" 1-4 Alkyl groups; specific examples include, but are not limited to, -CH2CN, -CH2CH2CN, -CH(CN)CH2CN, etc.

[0414] Unless otherwise specified, the term "alkoxy" refers to an alkyl group as defined herein, in which an alkyl group is attached to another group by an oxygen atom, i.e., "alkyl-O-". This includes "C". 1-6 Alkoxy (structure is C) 1-6 alkyl-O-), "C 1-4 "Alkoxy" is a suffix, specifically including but not limited to methoxy, ethoxy, propoxy, 1-methylethoxy, butoxy, 2-methylbutoxy, 3-methylbutoxy, 1,1-dimethylpropoxy, 1,2-dimethylpropoxy, etc.; preferably, the "alkoxy" in this disclosure is preferably C 1-4 Alkoxy, more preferably C 1-3 Alkyl group.

[0415] Unless otherwise specified, the term "haloalkoxy" refers to a group obtained by substituting one or more hydrogen atoms in an alkoxy group with a halogen. Preferably, the "haloalkoxy" described in this disclosure is "haloC". 1-6 Alkoxy, halogenated C 1-4 Alkyl groups. Specific examples described in this disclosure include: fluoromethoxy groups (including monofluoromethoxy, difluoromethoxy, and trifluoromethoxy), -OCH2CF3, -OCHFCH3, etc. Alkyl groups are as defined above.

[0416] Unless otherwise specified, the term "hydroxyalkoxy" refers to a group derived from which one or more hydrogen atoms in an alkoxy group are replaced by a hydroxyl group, and "hydroxyalkyl" as used in this disclosure includes "hydroxy C". 1-6 Alkoxy, hydroxyl C 1-4 "alkoxy group"; specific examples include, but are not limited to, -O-CH2OH, -O-CH2CH2OH, -O-CH(OH)CH3, -O-CH2CH2CH2OH,

[0417] Unless otherwise specified, the term "thio" refers to the group "=S". For example, when a thio group is present on a carbon atom, its structure is -C(=S)-.

[0418] Unless otherwise specified, the term "cycle" refers to a saturated, partially saturated, or unsaturated monocyclic or polycyclic ring, including spirocyclic, fused, or bridged rings. A group derived from a ring by removing a hydrogen atom is called a "cycloyl group," which includes monovalent, divalent (commonly referred to as a subcyclic ring), trivalent, and tetravalent rings, with the specific valence depending on the number of substituents attached to the ring. This disclosure no longer specifically distinguishes the valence of the ring in its description of "cycloyl groups." Representative "cycloyl groups" include substituted or unsubstituted cycloalkyl, heterocyclic alkyl, cycloalkenyl, heterocyclic alkenyl, cycloynyl, heterocyclic alynyl, aryl, or heteroaryl groups. The term "hetero" refers to substituted or unsubstituted heteroatoms and heterogroups, wherein the heteroatoms are generally selected from N, O, S, and P, and the heterogroups generally include NO, SO, S(O)2, P(O), S(=O)(=NR) (R is H or other substituents defined herein). The nitrogen atom may be substituted, i.e., NR (R is H or other substituents defined herein). The number of atoms on the ring is usually defined as the ring number. For example, "3-6 membered heterocyclic alkyl" refers to a ring consisting of 3-6 atoms arranged in a ring, each ring optionally containing 1 to 3 heteroatoms and / or heterogroups, i.e., N, O, S, NO, SO, S(O)2, P(O), or NR, each ring optionally being substituted by an R group, R being a group defined herein.

[0419] Unless otherwise specified, the term "cycloalkyl" refers to saturated cyclic groups derived from monocyclic cycloalkanes by removal of a hydrogen atom, the carbon atoms in said cycloalkyl groups can be further oxidized, i.e., form C(O). Said cycloalkyl groups include "3-8 membered cycloalkyl", "3-6 membered cycloalkyl", "3-5 membered cycloalkyl", "4-6 membered cycloalkyl". Specific examples include, but are not limited to: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl.

[0420] Unless otherwise specified, "cycloalkenyl" refers to "cycloalkyl" in which one or more of the ring-forming bonds is a double bond and said cycloalkenyl does not have aromaticity. The carbon atoms in said cycloalkenyl groups can be further oxidized, i.e., form C(O). Said cycloalkenyl groups include "C 3-8 cycloalkenyl", "C 3- 6cycloalkenyl", "C 3-5 cycloalkenyl", "C 5-6 cycloalkenyl". Specific examples include, but are not limited to

[0421] Unless otherwise specified, the term "spirocycloalkyl" refers to cyclic structures formed by two or more cycloalkyl groups sharing one ring atom with each other, the carbon atoms in said spirocycloalkyl groups can be further oxidized, i.e., form C(O), the oxidized form is also included within the scope of spirocycloalkyl. Said cycloalkyl groups include "C 5-12 spirocycloalkyl", "6-11 membered spirocycloalkyl", "7-11 membered spirocycloalkyl", "7-9 membered spirocycloalkyl", specific examples include, but are not limited to

[0422] Unless otherwise specified, the term "bridged cycloalkyl" refers to saturated cyclic structures formed by two or more carbocyclic rings sharing two non-adjacent carbon atoms with each other. Optionally, the carbon atoms in the cyclic structure can be oxidized, i.e., form C(O), the oxidized form is also included within the scope of bridged cycloalkyl. "Bridged cycloalkyl" includes, for example, "C s-12 bridged cycloalkyl", "5-11 membered bridged cycloalkyl", "6-11 membered bridged cycloalkyl", "5-10 membered bridged cycloalkyl", "7-10 membered bridged cycloalkyl", "6-9 membered bridged cycloalkyl", "7-8 membered bridged cycloalkyl", "9-10 membered bridged cycloalkyl", etc. Specific examples include, but are not limited to:

[0423] Unless otherwise specified, the term "heterocyclyl" refers to a monocyclic or polycyclic group, which is non-aromatic, saturated or partially saturated, having at least one ring atom which is a heteroatom or a heteroatom group, i.e., including heterocycloalkyl, heterocycloalkenyl. The polycyclic group includes fused heterocyclyl, spiro heterocyclyl, bridged heterocyclyl, preferably fused heterocyclyl, which refers to a cyclic group having at least one ring atom which is a heteroatom, saturated or partially saturated, formed by two or more cyclic structures sharing two adjacent atoms with each other. The ring carbon atom in the heterocyclyl group is optionally oxidized, i.e., forms -C(O), which includes the oxo form of the heterocyclyl group. Preferably, the heteroatoms are independently selected from 1-3 N and / or O. Preferably, the heterocyclyl group is a "nitrogen-containing heterocyclyl" which refers to at least one ring atom which is N, and optionally contains one or more additional heteroatoms; preferably, the "nitrogen-containing heterocyclyl" contains 1 N atom and 0-2 atoms selected from N and / or O. The heterocyclyl groups disclosed herein include "5-12 membered heterocyclyl", "5-10 membered heterocyclyl", "5-10 membered heterocycloalkyl", "5-10 membered heterocycloalkenyl", "6-10 membered heterocycloalkenyl", "5-6 membered heterocyclyl", "5-8 membered heterocycloalkenyl", "5-7 membered heterocycloalkenyl", "6-7 membered heterocycloalkenyl", "5-6 membered heterocycloalkenyl", "6-7 membered nitrogen-containing heterocycloalkenyl", "5-6 membered nitrogen-containing heterocycloalkenyl", "8-10 membered fused heterocyclyl", "8-14 membered fused heterocyclyl", "8-12 membered fused heterocyclyl". The fused heterocyclyl groups can be fused in the manner of 5-6 membered heterocyclyl and 5-6 membered heterocyclyl, 5-6 membered heterocyclyl and 5-6 membered cycloalkyl, benzo 5-6 membered heterocyclyl, 5-6 membered heteroaryl and 5-6 membered heterocyclyl, 5-6 membered heteroaryl and 5-6 membered cycloalkyl, 5-6 membered heteroaryl and 5-7 membered heterocyclyl, benzo 5-7 membered heterocyclyl, 5-6 membered heterocyclyl and 5-6 membered heteroaryl and 5-6 membered cycloalkyl, 5-6 membered heterocyclyl and 5-6 membered heteroaryl and 5-6 membered heterocyclyl, etc. Specific examples of the heterocyclyl groups include, but are not limited to: azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl,

[0424] Unless otherwise specified, the term "aryl" refers to an unsaturated, typically aromatic, hydrocarbon group, which can be monocyclic or multiple rings fused together. Preferably, the aryl group is a C 6-10 Examples of aryl groups include, but are not limited to, phenyl, naphthyl.

[0425] ​Unless otherwise specified, the term "heteroaryl" refers to a monocyclic or polycyclic group having aromaticity, comprising one or more heteroatoms in the ring, which heteroatoms are typically selected from N, O, S; preferably, the heteroatoms are independently selected from 1-3 N and / or O, in addition, N atoms and S atoms can optionally be oxidized and N atoms can optionally be quaternized. The "heteroaryl" includes "monocyclic heteroaryl" and "fused heteroaryl", which refers to a group comprising one or more heteroatoms, having aromaticity as a whole, formed by two or more cyclic structures sharing two adjacent atoms with each other. Unless otherwise specified, the "heteroaryl" described herein can be generally understood as "monocyclic heteroaryl", for example, the "5-6 membered heteroaryl" described herein, which does not have the possibility of forming a fused heteroaryl; when it is a "fused heteroaryl", it will be specifically indicated as "fused" heteroaryl structure, such as "8-10 membered fused heteroaryl", the fused manner includes but is not limited to 5-6 membered heteroaryl and 5-6 membered heteroaryl, benzo 5-6 membered heteroaryl. The heteroaryl described in the present disclosure is preferably "nitrogen-containing heteroaryl", preferably "5-6 membered nitrogen-containing heteroaryl", the "nitrogen-containing heteroaryl" contains at least one nitrogen atom, for example, contains only 1, 2 or 3 nitrogen atoms, or contains one nitrogen atom and other 1 or 2 heteroatoms (for example, S and / or O atoms), or contains 2 nitrogen atoms and other 1 or 2 heteroatoms. Specific examples of the heteroaryl group include but are not limited to: furanyl, thienyl, pyrrolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, imidazolyl, pyrazolyl etc.

[0426] Unless otherwise specified, the term "spiroheterocyclyl" refers to a saturated or partially saturated cyclic structure formed by two or more rings sharing one ring atom with each other, and at least one ring atom is a heteroatom or heteroatom group, which is selected from N, O, S, P, NO, SO, S(O)2, P(O), and NR, R is H or any available substituent. Optionally, a carbon atom in the cyclic structure can be oxo, i.e. form C(O), and the oxo form is also included in the scope of "spiroheterocyclyl". It includes but is not limited to cyclic structures formed by heterocyclic spiroheterocyclic rings, heterocyclic spirocycloalkanes. The spiroheterocyclic ring preferably contains 1-2 heteroatoms selected from NR and / or O, more preferably contains 1 NR and 0-1 NR or O heteroatom. The spiroheterocyclic ring is preferably "nitrogen-containing spiroheterocyclic ring", which refers to a spiroheterocyclic ring in which at least one ring atom is NR. The spiroheterocyclic ring includes "5-12 membered spiroheterocyclic ring", "7-11 membered spiroheterocyclic ring", "7-9 membered spiroheterocyclic ring", "7-11 membered nitrogen-containing spiroheterocyclic ring", "7-9 membered nitrogen-containing spiroheterocyclic ring". Specific examples include but are not limited to: etc.

[0427] Unless otherwise specified, the term "bridged heterocyclyl" refers to a saturated or partially saturated ring structure formed by two or more rings sharing two non-adjacent carbon atoms with each other and wherein at least one ring atom is a heteroatom or heteroatom group selected from N, O, S, P, NO, SO, S(O)2, P(O), and NR, R being H or any substituent that can be present. Optionally, a carbon atom in the ring structure can be oxidized to an oxo, i.e., to C(O), which is also included in the scope of "bridged heterocyclyl". "Bridged heterocyclyl" includes, for example, "5-12 membered bridged heterocyclyl", "5-11 membered bridged heterocyclyl", "6-11 membered bridged heterocyclyl", "5-10 membered bridged heterocyclyl", "7-10 membered bridged heterocyclyl", "6-9 membered bridged heterocyclyl", "7-8 membered bridged heterocyclyl", "9-10 membered bridged heterocyclyl", "6-10 membered bridged heterocycloalkenyl", "6-8 membered bridged heterocycloalkenyl", "7-8 membered nitrogen-containing bridged heterocycloalkenyl", and the like. Preferably, the heteroatoms are independently selected from 1-3 N and / or O. Preferably, the bridged heterocyclyl is a "nitrogen-containing bridged heterocyclyl", meaning that at least one ring atom is N, and optionally contains one or more additional heteroatoms; preferably, the "nitrogen-containing bridged heterocyclyl" contains 1 N atom and 0-2 atoms selected from N and / or O and / or S. Preferably, the "nitrogen-containing bridged heterocyclyl" contains 1 N atom and 0-1 atoms selected from O and / or S. Preferably, the bridged heterocyclyl is an "oxygen-containing bridged heterocyclyl", meaning that at least one ring atom is O, and optionally contains one or more additional heteroatoms; preferably, the "oxygen-containing bridged heterocyclyl" contains 1 O atom and 0-2 atoms selected from N and / or O. Specific examples include, but are not limited to: and the like.

[0428] In the present disclosure, when fused, spiro or bridged rings combine to form a complex polycyclic structure, it can be understood to belong to any one of the fused, spiro or bridged rings; as which can be understood as a fused heterocycle or a bridged heterocycle.

[0429] Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds or useful synthetic intermediates. A stable compound or stable structure is meant to imply a compound that is sufficiently robust to survive chemical reactions that can be employed in a synthetic sequence without appreciable degradation. DETAILED DESCRIPTION

[0430] The compounds of the present disclosure can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments set forth below, embodiments formed by a combination of the specific embodiments set forth below with other chemical synthetic methods well known in the art, and equivalents thereof as appreciated by those skilled in the art, preferred embodiments including but not limited to the examples of the present disclosure.

[0431] The structure of the compounds of the present disclosure is determined by nuclear magnetic resonance (NMR) or / and liquid chromatography-mass spectrometry (LC-MS), or ultra-performance liquid chromatography-mass spectrometry (UPLC-MS). NMR chemical shifts (δ) are given in parts per million (ppm). NMR measurements are determined by Bruker Neo 400M or Bruker Ascend 400 NMR instrument, with deuterated dimethyl sulfoxide (DMSO-d6), deuterated methanol (CD3OD) and deuterated chloroform (CDCl3), heavy water (D2O) as the determination solvent, and tetramethylsilane (TMS) as the internal standard.

[0432] The starting materials in the examples of the present disclosure are known and commercially available, or can be synthesized using or according to methods known in the art.

[0433] Intermediate INT-1 and intermediate INT-2:

[0434] 3-(3-bromo-2-chlorophenyl)piperidine-2,6-dione and 3-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine-2,6-dione

[0435] Reaction scheme:

[0436] Operation steps:

[0437] Step A: To a solution of 3-bromo-2-chlorotoluene (7.0 g, 34.06 mmol) and NBS (6.6 g, 37.07 mmol) in carbon tetrachloride (50 mL) was added dibenzoyl peroxide (412 mg, 1.70 mmol). Nitrogen was replaced for three times. The reaction was stirred at 90 °C for 8 hours.

[0438] LC-MS was used to monitor the completion of the reaction. The reaction solution was concentrated under reduced pressure. The residue was diluted with ethyl acetate (30 mL), filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography to obtain 6.5 g of 1-bromo-3-(bromomethyl)-2-chlorobenzene.

[0439] 1H NMR (400 MHz, CDC13) δ 7.59 (dd, J = 8.0, 1.5 Hz, 1H), 7.39 (dd, J = 7.7, 1.4 Hz, 1H), 7.11 (t, J = 7.8 Hz, 1H), 4.61 (s, 2H).

[0440] Step B: To a solution of 1-bromo-3-(bromomethyl)-2-chlorobenzene (6.5 g, 22.9 mmol) and trimethylsilyl cyanide (3.4 g, 34.3 mmol) in dichloromethane (100 mL) was added tetrabutylammonium fluoride (1.0 M in tetrahydrofuran, 35 mL, 35.0 mmol) at 0 °C. The reaction was stirred at room temperature for 2 hours.

[0441] TLC showed the starting material was consumed completely. The reaction was diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic phase was washed with saturated brine (50 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography to give 5.0 g of 2-(3-bromo-2-chlorophenyl)acetonitrile.

[0442] MS (ESI) M / Z: 229.8 [M+H] + .

[0443] Step C: To a solution of 2-(3-bromo-2-chlorophenyl)acetonitrile (5.0 g, 21.74 mmol) in tetrahydrofuran (50 mL) was added sodium formate (235 mg, 4.35 mmol) and tert-butyl acrylate (2.8 g, 21.74 mmol) at 0 °C. The reaction was stirred at room temperature for 2 hours.

[0444] LCMS showed the reaction was complete. The reaction was diluted with water (100 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic phase was washed with saturated brine (50 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography to give 6.8 g of tert-butyl 4-(3-bromo-2-chlorophenyl)-4-cyanobutanoate.

[0445] 1 H NMR (400 MHz, CDC13) δ 7.64 (dd, J = 8.0, 1.4 Hz, 1H), 7.52 (dd, J = 7.8, 1.4 Hz, 1H), 7.21 (t, J = 7.9 Hz, 1H), 4.49 (dd, J = 8.8, 5.8 Hz, 1H), 2.46 (dd, J = 15.2, 7.9 Hz, 2H), 2.32 - 2.07 (m, 2H), 1.45 (s, 9H).

[0446] Step D: To a solution of tert-butyl 4-(3-bromo-2-chlorophenyl)-4-cyanobutanoate (6.8 g, 19.00 mmol) in acetic acid (50 mL) was added sulfuric acid (5 mL). The reaction was stirred at 90 °C for 3 h.

[0447] LCMS was used to monitor the reaction completion. After the reaction solution was cooled to room temperature, it was poured into ice water (150 mL). The solid was collected by filtration, washed with water (50 mL x 2), and dried to give 4.5 g of 3-(3-bromo-2-chlorophenyl)piperidine-2,6-dione, noted as INT-1.

[0448] MS (ESI) M / Z: 303.9 [M+H] + .

[0449] 1 H NMR (400 MHz, DMSO-d6) δ 10.94 (s, 1H), 7.72 (dd, J = 7.9, 1.4 Hz, 1H), 7.39 (dd, J = 7.7, 1.3 Hz, 1H), 7.28 (t, J = 7.8 Hz, 1H), 4.33 (dd, J = 12.5, 5.0 Hz, 1H), 2.86 - 2.71 (m, 1H), 2.60 - 2.52 (m, 1H), 2.33 (qd, J = 13.0, 4.3 Hz, 1H), 2.06 - 1.95 (m, 1H).

[0450] Step E: To a solution of 3-(3-bromo-2-chlorophenyl)piperidine-2,6-dione (2.0 g, 6.62 mmol) in 1,4-dioxane (30 mL) was added bis(pinacolato)diboron (2.1 g, 8.00 mmol). (1,1'-Bis(diphenylphosphino)ferrocene)palladium(II) dichloride (485 mg, 0.66 mmol) and potassium acetate (1.95 g, 19.9 mmol) were added under nitrogen. The reaction was stirred at 85 °C for 3 h.

[0451] LCMS was used to monitor the reaction completion. The reaction solution was filtered, and the filter cake was washed with ethyl acetate (30 mL x 2). The combined filtrate and washings were concentrated under reduced pressure. The crude product was purified by column chromatography to give 1.9 g of 3-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine-2,6-dione, noted as INT-2.

[0452] MS (ESI) M / Z: 350.1 [M+H] + .

[0453] 1H NMR (400 MHz, DMSO-d6) δ 10.90 (s, 1H), 7.52 (dd, J = 2.0, 7.2 Hz, 1H), 7.41 (dd, J = 2.0, 7.6 Hz, 1H), 7.32 (d, J = 7.6 Hz, 1H), 4.26 (dd, J = 5.2, 12.4 Hz, 1H), 2.81 - 2.70 (m, 1H), 2.59 - 2.53 (m, 1H), 2.33 - 2.23 (m, 1H), 1.99 - 1.93 (m, 1H), 1.31 (s, 12H).

[0454] Intermediate INT-3 and Intermediate INT-4:

[0455] 1-(4-Bromophenyl)pyridin-2(lH)-one and 1-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenyl)pyridin-2(lH)-one

[0456] Reaction Scheme:

[0457] Procedure:

[0458] Step A: To a mixture of (4-bromophenyl)boronic acid (35.3 g, 176 mmol), pyridin-2(lH)-one (20.0 g, 211 mmol) and copper acetate (31.9 g, 176 mmol) in dichloroethane (500 mL) was added triethylamine (53.3 g, 527 mmol). Oxygen was purged for 3 times. The reaction was stirred at 25 °C for 3 hours.

[0459] LCMS was used to monitor the completion of the reaction. The reaction was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give 24.0 g of 1-(4-bromophenyl)pyridin-2(lH)-one.

[0460] MS (ESI) M / Z: 249.9 [M+H] + .

[0461] Step B: To 1-(4-bromophenyl)pyridin-2(lH)-one (10.0 g, 40.0 mmol), bis(pinacolato)diboron (11.2 g, 44.0 mmol), (l,l'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride (2.9 g, 4.00 mmol) and potassium acetate (11.8 g, 120 mmol) was added to 1,4-dioxane (200 mL) sequentially. Nitrogen was purged for 3 times. The reaction was stirred at 80 °C for 3 hours.

[0462] The reaction was monitored by TLC. The reaction mixture was cooled to room temperature, filtered through a bed of celite, and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel to obtain 4.5 g of 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyridin-2(1H)-one.

[0463] MS (ESI) M / Z: 298.3 [M+H] + .

[0464] Intermediate INT-5 and Intermediate INT-6:

[0465] 3-(3-bromo-2-ethynylphenyl)piperidine-2,6-dione and 3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-((trimethylsilyl)ethynyl)phenyl)piperidine-2,6-dione

[0466] Reaction Scheme:

[0467] Procedure:

[0468] Step A: 1-bromo-2-iodo-3-methylbenzene (90.0 g, 303.0 mmol) was dissolved in anhydrous carbon tetrachloride (900 mL), and dibenzoyl peroxide (7.3 g, 30.3 mmol) and N-bromosuccinimide (59.3 g, 333.3 mmol) were added. The reaction mixture was stirred at 90 °C for 8 h under nitrogen.

[0469] LCMS monitoring showed the disappearance of the starting material, and the reaction mixture was concentrated under reduced pressure. The resulting residue was diluted with ethyl acetate (900 mL), filtered, and concentrated under reduced pressure. The resulting crude product was purified by column chromatography on silica gel to obtain 57.0 g of 1-bromo-3-(bromomethyl)-2-iodobenzene.

[0470] MS (ESI) M / Z: 375.3 [M+H]+.

[0471] 1H NMR (400 MHz, CDCl3) δ 7.56 (d, J = 8.0 Hz, 1H), 7.38 (d, J = 7.4 Hz, 1H), 7.20 (t, J = 7.6 Hz, 1H), 4.70 (s, 2H).

[0472] Step B: 1-bromo-3-(bromomethyl)-2-iodobenzene (57.0 g, 151.7 mmol) was dissolved in anhydrous dichloromethane (600 mL), and trimethylsilyl cyanide (22.6 g, 227.5 mmol) and tetrabutylammonium fluoride (1.0 M, 227 mL, 227 mmol) were added at 0 °C. The reaction mixture was stirred at room temperature for 2 h.

[0473] LCMS monitoring showed the disappearance of starting material, water (500 mL x 2) was added to wash, ethyl acetate (30 mL x 3) was extracted, the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography to obtain 36 g of 2-(3-bromo-2-iodophenyl)acetonitrile.

[0474] MS (ESI) M / Z: 322.3 [M+H]+.

[0475] Step C: 2-(3-bromo-2-iodophenyl)acetonitrile (36 g, 1.86 mmol) was dissolved in tetrahydrofuran (400 mL), sodium methoxide (1.2 g, 22.3 mmol) and tert-butyl acrylate (15.7 g, 123.0 mmol) were added at 0 °C, and stirred at room temperature for 2 hours.

[0476] LCMS monitoring showed the disappearance of starting material, water (500 mL) was added to quench, ethyl acetate (400 mL x 3) was extracted, the combined organic phase was washed with saturated brine (500 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography to obtain 46.0 g of tert-butyl 4-(3-bromo-2-iodophenyl)-4-cyanobutanoate.

[0477] MS (ESI) M / Z: 450.2 [M+H]+.

[0478] 1H NMR (400 MHz, CDCl3) δ 7.62 (dd, J = 8.0, 1.4 Hz, 1H), 7.48 (dd, J = 7.6, 1.4 Hz, 1H), 7.28 (dd, J = 9.6, 6.0 Hz, 1H), 4.49 (dd, J = 9.2, 5.4 Hz, 1H), 2.57-2.40 (m, 2H), 2.28-2.15 (m, 1H), 2.14-2.05 (m, 1H), 1.45 (s, 9H).

[0479] Step D: tert-Butyl 4-(3-bromo-2-iodophenyl)-4-cyanobutanoate (46.0 g, 102.2 mmol) was dissolved in acetic acid (500 mL), sulfuric acid (50 mL) was added dropwise, and stirred at 90 °C for 3 hours.

[0480] LCMS monitoring showed the disappearance of starting material, the reaction was cooled to room temperature, and then slowly poured into ice water (1500 mL) to quench, a solid was precipitated, filtered, washed with water (500 mL x 3), and the filter cake was dried to obtain 30.0 g of 3-(3-bromo-2-iodophenyl)piperidine-2,6-dione.

[0481] MS (ESI) M / Z: 394.3 [M+H]+.

[0482] Step E: 3-(3-bromo-2-iodophenyl)piperidine-2,6-dione (26.0 g, 66.16 mmol) was dissolved in tetrahydrofuran (300 mL), cuprous iodide (2.51 g, 13.23 mmol), bis(triphenylphosphine)palladium(II) chloride (4.28 g, 6.12 mmol), triethylamine (20.0 g, 198.5 mmol) and trimethylsilylacetylene (12.97 g, 132.3 mmol) were added, and the mixture was stirred at 60 °C for 3 h under nitrogen.

[0483] LCMS monitoring showed the disappearance of starting material, diluted with water (500 mL), extracted with ethyl acetate (400 mL x 3), combined organic phase was washed with saturated brine (500 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained crude product was purified by C18 column chromatography to give 10 g of 3-(3-bromo-2-((trimethylsilyl)ethynyl)phenyl)piperidine-2,6-dione.

[0484] MS (ESI) M / Z: 364.3 [M+H]+.

[0485] Step F: 3-(3-bromo-2-((trimethylsilyl)ethynyl)phenyl)piperidine-2,6-dione (150 mg, 0.41 mmol) was dissolved in tetrahydrofuran (5 mL), tetrabutylammonium bromide (0.62 mL, 0.62 mmol) was added, and the mixture was stirred at room temperature for 1 h.

[0486] LCMS monitoring showed the disappearance of starting material, diluted with water (20 mL), extracted with ethyl acetate (20 mL x 3), combined organic phase was washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography to give 120 mg of 3-(3-bromo-2-ethynylphenyl)piperidine-2,6-dione.

[0487] MS (ESI) M / Z: 292.2 [M+H]+.

[0488] Step G: To a solution of 3-(3-bromo-2-((trimethylsilyl)ethynyl)phenyl)piperidine-2,6-dione (3.0 g, 8.26 mmol) and bis(pinacolato)diboron (6.30 g, 24.79 mmol) in 1,4-dioxane (50 mL) was added (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride (1.2 g, 0.83 mmol) and potassium acetate (2.4 g, 24.79 mmol). The mixture was stirred at 100 °C for 16 h under nitrogen.

[0489] After the reaction was completed, the reaction solution was diluted with water (100 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic phase was washed with saturated brine (50 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography to obtain 2.7 g of 3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-((trimethylsilyl)ethynyl)phenyl)piperidine-2,6-dione.

[0490] MS (ESI) M / Z: 412.1 [M+H]+.

[0491] 1H NMR (400 MHz, CDCl3) δ 7.95 (s, 1H), 7.68-7.66 (m, 1H), 7.30 (t, J = 7.6 Hz, 1H), 7.23-7.21 (m, 1H), 4.29-4.25 (m, 1H), 2.78-2.54 (m, 2H), 2.50-2.33 (m, 1H), 2.4-2.17 (m, 1H), 1.36 (s, 12H), 0.25 (s, 9H).

[0492] Example 1: 3-(2-chloro-3-(5-(2-oxopyridin-1(2H)-yl)bicyclo[4.20]octa-1,3,5-trien-2-yl)phenyl)piperidine-2,6-dione

[0493] Reaction Scheme:

[0494] Operation Steps:

[0495] Step A: 2,5-dibromobicyclo[4.2.0]octa-1,3,5-triene (1.0 g, 3.82 mmol) was dissolved in N,N-dimethylformamide (10 mL), pyridine-2(1H)-one (363 mg, 3.82 mmol), potassium carbonate (1.58 g, 1.15 mmol) and cuprous iodide (72.5 mg, 0.38 mmol) were added respectively, and the reaction was carried out at 150°C for 8 hours.

[0496] After LCMS monitoring showed that the raw material disappeared, the reaction solution was diluted with water (25 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic phase was washed with saturated brine (30 mL x 3) first, then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 440 mg of 1-(5-bromobicyclo[4.2.0]octa-1(6),2,4-trien-2-ylpyridin-2(1H)-one.

[0497] MS (ESI) M / Z: 276.0 [M+H]+ .

[0498] Step B: Dissolve 1-(5-bromobicyclo[4.2.0]octa-1(6),2,4-trien-2-yl)pyridin-2(1H)-one (440 mg, 1.59 mmol) in 1,4-dioxane (5 mL), add bis(pinacolato)diboron (445 mg, 1.75 mmol), (1,1'-bis(diphenylphosphino)ferrocene)dichloropalladium(II) (117 mg, 0.16 mmol) and potassium acetate (469 mg, 4.78 mmol), replace with nitrogen for 3 times, react at 80 °C for 8 hours.

[0499] After LCMS monitoring shows the disappearance of raw materials, dilute with water (20 mL), extract the mixture with ethyl acetate (30 mL x 3), wash the combined organic phase with saturated brine (30 mL x 3) first, then dry over anhydrous sodium sulfate, filter, and finally concentrate under reduced pressure. The obtained residue is purified by silica gel column chromatography to obtain 420 mg of 1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)bicyclo[4.2.0]octa-1(6),2,4-trien-2-yl)pyridin-2(1H)-one.

[0500] MS (ESI) M / Z: 324.0 [M+H] + .

[0501] Step C: Dissolve INT-1 (100 mg, 0.33 mmol), 1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)bicyclo[4.2.0]octa-1(6),2,4-trien-2-yl)pyridin-2(1H)-one (117 mg, 0.36 mmol), (1,1'-bis(diphenylphosphino)ferrocene)dichloropalladium(II) (24.2 mg, 0.03 mmol) and potassium phosphate (210 mg, 0.99 mmol) in N,N-dimethylformamide (2 mL), replace with nitrogen for 3 times, react at 100 °C for 6 hours.

[0502] After LCMS monitoring shows the disappearance of raw materials, filter, and the filtrate is prepared by high performance liquid chromatography to obtain 16.66 mg of 3-(2-chloro-3-(5-(2-oxopyridin-1(2H)-yl)bicyclo[4.20]octa-1,3,5-trien-2-yl)phenyl)piperidine-2,6-dione.

[0503] MS (ESI) M / Z: 419.0 [M+H] + .

[0504] 1H NMR (400 MHz, DMSO-d6) δ 10.94 (s, 1H), 7.78 (dd, J = 7.1, 2.0 Hz, 1H), 7.55 - 7.49 (m, 1H), 7.48 - 7.32 (m, 5H), 6.52 (d, J = 9.2 Hz, 1H), 6.38 - 6.32 (m, 1H), 4.38 (dd, J = 12.2, 5.0 Hz, 1H), 3.21 - 3.14 (m, 4H), 2.92 - 2.72 (m, 2H), 2.40 - 2.34 (m, 1H), 2.10 - 2.04 (m, 1H).

[0505] Example 2: 3-(2-chloro-3-(3,4-dihydro-1H-[1,4]oxazino[4,3-a]indol-8-yl)phenyl)piperidine- 2,6-dione

[0506] Reaction Scheme:

[0507] Procedure:

[0508] Step A: To a solution of (5-bromo-1H-indol-2-yl)methanol (500 mg, 2.22 mmol) in fluorobenzene (60 mL) was added sodium hydride (60% dispersion in oil, 270 mg, 6.75 mmol) at 0 °C. After stirring at 0 °C for 20 min, diphenyl(vinyl)sulfonium trifluoromethanesulfonate (1.2 g, 3.31 mmol) was added. The reaction was stirred at room temperature for 30 min.

[0509] The reaction was monitored by TLC. The reaction mixture was poured into water (50 mL), diluted with water (50 mL), and the mixture was extracted with ethyl acetate (50 mL x 3). The combined organic phase was washed with saturated brine (50 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to give 290 mg of 8-bromo-3,4-dihydro-1H-[1,4]oxazino[4,3-a]indole.

[0510] MS (ESI) M / Z: 251.8 [M+H] + .

[0511] Step B: To a solution of 8-bromo-3,4-dihydro-1H-[1,4]oxazino[4,3-a]indole (100 mg, 0.40 mmol) in 1,4-dioxane (10 mL) and water (1 mL) were added INT-2 (208 mg, 0.60 mmol), potassium carbonate (110 mg, 0.80 mmol), and 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (29 mg, 0.04 mmol) successively. The reaction was purged with nitrogen three times. The reaction was stirred at 90 °C for 2 h.

[0512] LCMS monitor the reaction is complete. The reaction solution was diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The organic phase was washed with saturated brine (50 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by high performance liquid chromatography gave 41.99 mg of 3-(2-chloro-3-(3,4-dihydro-1H-[1,4]oxazepino[4,3-a]indol-8-yl)phenyl)piperidine-2,6-dione.

[0513] MS (ESI) M / Z: 394.9 [M+H] + .

[0514] 1 H NMR (400 MHz, DMSO-d6) δ 10.91 (s, 1H), 7.50 (d, J = 1.2 Hz, 1H), 7.46 (d, J = 8.4 Hz, 1H), 7.40-7.35 (m, 1H), 7.35-7.30 (m, 2H), 7.16-7.12 (m, 1H), 6.26 (s, 1H), 4.95 (s, 2H), 4.39-4.26 (m, 1H), 4.19-4.06 (m, 4H), 2.86-2.71 (m, 1H), 2.58-2.52 (m, 1H), 2.41-2.28 (m, 1H), 2.12-2.01 (m, 1H).

[0515] Example 3: 3-(2-chloro-3-(3-(2-oxopyridin-1(2H)-yl)prop-1-yn-1-yl)phenyl)piperidine-2,6-dione

[0516] Reaction Scheme:

[0517] Operation Steps:

[0518] Step A: Pyridine-2(1H)-one (1.0 g, 10.53 mmol), bromopropargyl (2.0 g, 16.84 mmol), potassium carbonate (2.0 g, 16.84 mmol) were added to a solution of acetonitrile (15 mL) in turn. Stir the reaction at 90°C for 8 hours.

[0519] LCMS monitor the reaction is complete. The reaction solution was diluted with water (50 mL) and extracted with ethyl acetate (20 mL x 3). The organic phase was washed with saturated brine (50 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by high performance liquid chromatography gave 41.99 mg of 3-(2-chloro-3-(3,4-dihydro-1H-[1,4]oxazepino[4,3-a]indol-8-yl)phenyl)piperidine-2,6-dione.

[0520] 1H NMR (400 MHz, CDC13) δ 7.64 (dd, J = 6.8, 1.8 Hz, 1H), 7.36 (ddd, J = 8.9, 6.6, 2.1 Hz, 1H), 6.63 - 6.51 (m, 1H), 6.25 (d, J = 1.3 Hz, 1H), 4.76 (d, J = 2.6 Hz, 2H), 2.51 (t, J = 2.6 Hz, 1H).

[0521] Step B: To a solution of 1-(prop-2-yn-1-yl)pyridin-2(1H)-one (200 mg, 1.50 mmol), INT-1 (227 mg, 0.75 mmol) in DMSO (3 mL) was added tetrakis(triphenylphosphine)palladium (174 mg, 0.15 mmol), triethylamine (1 mL) and cuprous iodide (57 mg, 0.30 mmol) successively. Nitrogen was replaced for three times. The reaction was stirred at 80 °C for 2 hours.

[0522] LCMS was used to monitor the reaction completion. After the reaction solution was cooled to room temperature, it was poured into ammonia water (15%, 10 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The crude product was purified by thin layer chromatography on silica gel preparative plate to give 10.84 mg of 3-(2-chloro-3-(3-(2-oxopyridin-1(2H)-yl)prop-1-yn-1-yl)phenyl)piperidine-2,6-dione.

[0523] MS (ESI) M / Z: 354.9 [M+H] + .

[0524] 1 H NMR (400 MHz, DMSO-d6) δ 10.92 (s, 1H), 7.86 (dd, J = 4.0, 1.9 Hz, 1H), 7.54 - 7.43 (m, 2H), 7.39 - 7.37 (m, 2H), 6.44 (d, J = 9.2 Hz, 1H), 6.35 - 6.27 (m, 1H), 5.04 (s, 2H), 4.27 (dd, J = 8.8, 4.9 Hz, 1H), 2.81 - 2.73 (m, 1H), 2.67 (s, 1H), 2.33 - 2.24 (m, 1H), 2.03 - 1.92 (m, 1H).

[0525] Example 4: 3-(2-chloro-3-(3-(2-oxopiperidin-1-yl)prop-1-yn-1-yl)phenyl)piperidine-2,6-dione

[0526] Reference to the preparation method of other embodiments of the application obtained 61.50 mg of 3-(2-chloro-3-(3-(2-oxopiperidin-1-yl)prop-1-yn-1-yl)phenyl)piperidine-2,6-dione.

[0527] MS (ESI) M / Z: 359.0 [M+H] + .

[0528] 1 H NMR (400 MHz, DMSO-d6) δ 10.92 (s, 1H), 7.50 (dd, J = 4.6, 1.9 Hz, 1H), 7.40 - 7.29 (m, 2H), 4.46 (s, 2H), 4.27 (dd, J = 8.8, 5.0 Hz, 1H), 3.44 (t, J = 6.0 Hz, 2H), 2.82 - 2.73 (m, 1H), 2.55 (d, J = 3.2 Hz, 1H), 2.35 - 2.24 (m, 3H), 2.05 - 1.94 (m, 1H), 1.84 - 1.76 (m, 2H), 1.75 - 1.66 (m, 2H).

[0529] Example 5: 1-(2-chloro-4'-(2-oxopyridin-1(2H)-yl)-(1,1'-biphenyl)-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

[0530] Reference to the preparation method of other embodiments of the application obtained 34 mg of 1-(2-chloro-4'-(2-oxopyridin-1(2H)-yl)-(1,1'-biphenyl)-3-yl)dihydropyrimidine-2,4(1H,3H)-dione.

[0531] MS (ESI) M / Z: 393.9 [M+H] + .

[0532] 1 H NMR (400 MHz, DMSO-d6) δ 10.50 (s, 1H), 7.74 (dd, J = 6.9, 1.6 Hz, 1H), 7.62 - 7.50 (m, 7H), 7.46 (dd, J = 7.4, 2.0 Hz, 1H), 6.52 (d, J = 9.0 Hz, 1H), 6.37 - 6.31 (m, 1H), 3.85 - 3.73 (m, 1H), 3.70 - 3.63 (m, 1H), 2.79 - 2.74 (m, 2H).

[0533] Example 6: 3-(2-chloro-3-(1,2-dimethyl-1H-benzo[d]imidazol-5-yl)phenyl)piperidine-2,6-dione

[0534] Scheme:

[0535] Procedure:

[0536] Step A: To a solution of 6-bromo-1,2-dimethyl-1H-benzo[d]imidazole (100 mg, 0.44 mmol) in 1,4-dioxane (5 mL) and water (0.5 mL) was added INT-2 (233 mg, 0.66 mmol), potassium carbonate (123 mg, 0.88 mmol) and (1,1'- bis(diphenylphosphino)ferrocene)dichloropalladium(II) (17 mg, 0.02 mmol). Nitrogen was purged for three times. The reaction was stirred at 90 °C for 2 hours.

[0537] LC-MS was used to monitor the reaction completion. The reaction was diluted with water (10 mL) and extracted with dichloromethane (10 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The crude product was purified by high performance liquid chromatography to give 61 mg of 3-(2-chloro-3-(1,2-dimethyl-1H- benzo[d]imidazol-5-yl)phenyl)piperidine-2,6-dione.

[0538] MS (ESI) M / Z: 367.9 [M+H] + .

[0539] 1 H NMR (400 MHz, DMSO-d6) δ 10.92 (s, 1H), 7.52 (dd, J = 10.0, 4.7 Hz, 2H), 7.42 - 7.31 (m, 3H), 7.20 (dd, J = 4.8, 1.5 Hz, 1H), 4.35 (dd, J = 8.6, 5.0 Hz, 1H), 3.77 (s, 3H), 2.85 - 2.72 (m, 1H), 2.58 - 2.52 (m, 4H), 2.40 - 2.26 (m, 1H), 2.11 - 2.01 (m, 1H).

[0540] Example 7: 3-(2-chloro-3-(2-methylbenzo[d]thiazol-5-yl)phenyl)piperidine-2,6-dione

[0541] Reference to the preparation method of other embodiments of the application, 37 mg of 3-(2-chloro-3-(2-methylbenzo[d]thiazol-5-yl)phenyl)piperidine-2,6-dione was obtained.

[0542] MS (ESI) M / Z: 370.9 [M+H] + .

[0543] 1H NMR (400 MHz, DMSO-d6) δ 10.93 (s, 1H), 8.11 (d, J = 8.4 Hz, 1H), 7.91 (d, J = 1.2 Hz, 1H), 7.47 - 7.36 (m, 4H), 4.37 (dd, J = 8.6, 5.0 Hz, 1H), 2.83 (s, 4H), 2.60 - 2.53 (m, 1H), 2.41 - 2.29 (m, 1H), 2.11 - 2.02 (m, 1H).

[0544] Example 8: 3-(2-chloro-3-(2-methyl-3-oxoisoindolin-5-yl)phenyl)piperidine-2,6- dione

[0545] Reference to the preparation method of other embodiments of the application obtained 80 mg of 3-(2-chloro-3-(2-methyl-3-oxoisoindolin-5-yl)phenyl)piperidine-2,6-dione.

[0546] MS (ESI) M / Z: 368.8 [M+H] + .

[0547] 1 H NMR (400 MHz, DMSO-d6) δ 10.93 (s, 1H), 7.68 (d, J = 7.6 Hz, 1H), 7.63 - 7.57 (m, 2H), 7.45 - 7.34 (m, 3H), 4.53 (s, 2H), 4.36 (dd, J = 8.6, 5.0 Hz, 1H), 3.10 (s, 3H), 2.86 - 2.74 (m, 1H), 2.59 - 2.52 (m, 1H), 2.41 - 2.29 (m, 1H), 2.13 - 2.01 (m, 1H).

[0548] Example 9: 3-(2-chloro-3-(2-(tetrahydro-2H-pyran-4-yl)benzo[d]oxazol-5- yl)phenyl)piperidine-2,6-dione

[0549] Reaction Scheme:

[0550] Procedure:

[0551] Step A: 2-amino-4-bromophenol (500 mg, 2.66 mmol) and tetrahydro-2H-pyran-4- carboxylic acid (380 mg, 2.92 mmol) were dissolved in polyphosphoric acid (10 mL). Stirring at 140 °C for 2 hours.

[0552] LCMS was used to monitor the reaction. The reaction was diluted with water (150 mL) and the pH was adjusted to 8 by adding ammonia. The product was extracted with ethyl acetate (200 mL x 3), and the organic phase was combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel to obtain 180 mg of 5-bromo-2-(tetrahydro-2H-pyran-4-yl)benzo[d]oxazole.

[0553] MS (ESI) M / Z: 281.9 [M+H] + .

[0554] Step B: To a solution of 5-bromo-2-(tetrahydro-2H-pyran-4-yl)benzo[d]oxazole (80 mg, 0.28 mmol) in 1,4-dioxane (10 mL) and water (1 mL), INT-2 (149 mg, 0.43 mmol), potassium carbonate (79 mg, 0.57 mmol) and 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (21 mg, 0.03 mmol) were added successively. The reaction was stirred at 90 °C for 2 hours.

[0555] LCMS was used to monitor the reaction. The reaction was diluted with water (20 mL) and the pH was adjusted to 8 by adding ammonia. The product was extracted with ethyl acetate (20 mL x 3), and the organic phase was combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by high performance liquid chromatography to obtain 61.87 mg of 3-(2-chloro-3-(2-(tetrahydro-2H-pyran-4-yl)benzo[d]oxazol-5-yl)phenyl)piperidine-2,6-dione.

[0556] MS (ESI) M / Z: 424.9 [M+H] + .

[0557] 1 H NMR (400 MHz, DMSO-d6) δ 10.93 (s, 1H), 7.76 (d, J = 8.4 Hz, 1H), 7.71 (s, 1H), 7.45-7.32 (m, 4H), 4.43-4.26 (m, 1H), 4.00-3.84 (m, 2H), 3.59-3.42 (m, 2H), 2.85-2.74 (m, 1H), 2.60-2.51 (m, 2H), 2.41-2.27 (m, 1H), 2.13-2.00 (m, 3H), 1.93-1.79 (m, 2H).

[0558] Example 10: 3-(2-chloro-3-(2-cyclopropylimidazo[1,2-a]pyridin-7-yl)phenyl)piperidine-2,6-dione

[0559] Reference to the preparation method of other embodiments of the present application obtained 34.98 mg of 3-(2-chloro-3-(2-cyclopropylimidazo[l,2- a]pyridin-7-yl)phenyl)piperidine-2,6-dione.

[0560] MS (ESI) M / Z: 380.0 [M+H] + .

[0561] 1 H NMR (400 MHz, DMSO-d6) δ 10.94 (s, 1H), 8.52-8.44 (m, 1H), 7.79 (s, 1H), 7.47-7.36 (m, 4H), 6.92-6.83 (m, 1H), 4.43-4.29 (m, 1H), 2.86-2.73 (m, 1H), 2.59-2.52 (m, 1H), 2.42-2.25 (m, 1H), 2.12-1.97 (m, 2H), 0.95-0.88 (m, 2H), 0.87-0.82 (m, 2H).

[0562] Example 11: 3-(2-chloro-4'-(cyclopropanesulfonylimino)-(l,l'-biphenyl)-3- yl)piperidine-2,6-dione

[0563] Reference to the preparation method of other embodiments of the present application obtained 34.98 mg of 3-(2-chloro-3-(2-cyclopropylimidazo[l,2- a]pyridin-7-yl)phenyl)piperidine-2,6-dione.

[0564] MS (ESI) M / Z: 380.0 [M+H] + .

[0565] 1 H NMR (400 MHz, DMSO-d6) δ 10.94 (s, 1H), 8.52-8.44 (m, 1H), 7.79 (s, 1H), 7.47-7.36 (m, 4H), 6.92-6.83 (m, 1H), 4.43-4.29 (m, 1H), 2.86-2.73 (m, 1H), 2.59-2.52 (m, 1H), 2.42-2.25 (m, 1H), 2.12-1.97 (m, 2H), 0.95-0.88 (m, 2H), 0.87-0.82 (m, 2H).

[0566] Example 12: l-(2-chloro-4'-(2-oxopyridin-l(2H)-yl)-(l,l'-biphenyl)-3-yl)dihydropyrimidine- 2,4(lH,3H)-dione

[0567] Reference to the preparation method of other embodiments of the present application, 80.17 mg of 3-(2-chloro-4'-(dimethylphosphoryl)-(1,1'-biphenyl)-3-yl)piperidine-2,6-dione was prepared.

[0568] MS (ESI) M / Z: 376.0 [M+H] + .

[0569] 1 H NMR (400 MHz, DMSO-d6) δ 10.93 (s, 1H), 7.90-7.82 (m, 2H), 7.60-7.52 (m, 2H), 7.46-7.38 (m, 2H), 7.37-7.33 (m, 1H), 4.49-4.23 (m, 1H), 2.86-2.74 (m, 1H), 2.57 (d, J=3.4 Hz, 1H), 2.42-2.28 (m, 1H), 2.10-2.01 (m, 1H), 1.70 (d, J=13.6 Hz, 6H).

[0570] Example 13: 3-(2-chloro-3-(5-((1-methyl-1H-pyrazol-3-yl)methyl)-2,3,4- 5-tetrahydrobenzo[b][1,4]oxazepin-8-yl)phenyl)piperidine-2,6-dione

[0571] Reaction Scheme:

[0572] Procedure:

[0573] Step A: To a solution of 5-bromo-2-nitrophenol (1.0 g, 4.58 mmol) in acetonitrile (10 mL) was added 1,3-dibromopropane (1.84 g, 9.16 mmol) and cesium carbonate (2.99 g, 9.16 mmol). Nitrogen was replaced for three times. It was stirred at 80 °C for 2 hours.

[0574] The reaction was monitored by TLC. The reaction mixture was diluted with water (20 mL) and extracted with dichloromethane (20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give 900 mg of 4-bromo-2-(3-bromopropoxy)-1-nitrobenzene.

[0575] 1H NMR (400 MHz, CDC13): δ 7.77 (d, J = 8.6 Hz, 1 H), 7.27 (s, 1 H), 7.19 (dd, J = 8.6, 1.9 Hz, 1 H), 4.26 (t, J = 5.6 Hz, 2 H), 3.66 (t, J = 6.2 Hz, 2 H), 2.44-2.31 (m, 2 H).

[0576] Step B: To a solution of 4-bromo-2-(3-bromopropoxy)-l-nitrobenzene (200 mg, 0.59 mmol) in ethanol (4 mL) and water (4 mL) was added ammonium chloride (156 mg, 2.95 mmol) and iron powder (166 mg, 2.95 mmol). Nitrogen was bubbled for three times. The reaction was stirred at 80 °C for 2 hours.

[0577] LCMS was used to monitor the reaction completion. The reaction was filtered, the filtrate was diluted with water (10 mL) and extracted with dichloromethane (10 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give 110 mg of 4-bromo-2-(3-bromopropoxy)aniline.

[0578] MS (ESI) M / Z: 350.9 [M+H+MeCN] + .

[0579] Step C: To a solution of 4-bromo-2-(3-bromopropoxy)aniline (110 mg, 0.35 mmol) in acetonitrile (6 mL) was added potassium carbonate (98 mg, 0.7 mmol). Nitrogen was bubbled for three times. The reaction was stirred at 80 °C for 16 hours.

[0580] LCMS was used to monitor the reaction completion. The reaction was diluted with water (10 mL) and extracted with dichloromethane (10 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give 80 mg of 8-bromo-2,3,4,5-tetrahydrobenzo[b][l,4]oxazepine.

[0581] MS (ESI) M / Z: 228.0 [M+H] + .

[0582] Step D: To a solution of 8-bromo-2,3,4,5-tetrahydrobenzo[b][l,4]oxazepine (80 mg, 0.35 mmol) in acetonitrile (6 mL) was added potassium carbonate (73 mg, 0.52 mmol) and 3-(bromomethyl)-l-methyl-lH-pyrazole (65 mg, 0.36 mmol). Nitrogen was bubbled for three times. The reaction was stirred at 80 °C for 2 hours.

[0583] The reaction was monitored by LCMS until complete. The reaction solution was diluted with water (10 mL), extracted with dichloromethane (10 mL), dried over anhydrous sodium sulfate on the organic phase, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give 50 mg of 8-bromo-5-((1-methyl-1H-pyrazol-3-yl)methyl)-2,3,4-5-tetrahydrobenzo[b][1,4]oxazapine.

[0584] MS(ESI)M / Z: 324.0 [M+H] + .

[0585] Step E: To a solution of 8-bromo-5-((1-methyl-1H-pyrazol-3-yl)methyl)-2,3,4-5-tetrahydrobenzo[b][1,4]oxazapine (50 mg, 0.15 mmol) in 1,4-dioxane (5 mL) and water (0.5 mL), add INT-2 (81 mg, 0.22 mmol), potassium carbonate (43 mg, 0.31 mmol), and (1,1'-bis(diphenylphosphine)ferrocene)dichloropalladium(II) (6 mg, 0.007 mmol). Purge with nitrogen three times. Heat to 90 °C and stir for 2 hours.

[0586] The reaction was monitored by LCMS until complete. The reaction solution was diluted with water (10 mL), extracted with dichloromethane (10 mL), dried over anhydrous sodium sulfate on the organic phase, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by high performance liquid chromatography to obtain 26 mg of 3-(2-chloro-3-(5-(((1-methyl-1H-pyrazol-3-yl)methyl)-2,3,4-5-tetrahydrobenzo[b][1,4]oxazacycloheptane-8-yl)phenyl)piperidine-2,6-dione.

[0587] MS(ESI)M / Z: 465.0 [M+H] + .

[0588] 1 H NMR (400MHz, DMSO-d6) δ10.91 (s, 1H), 7.63 (d, J=2.0Hz, 1H), 7.37-7.31 (m, 1H), 7.30-7.2 3 (m, 2H), 7.00 (d, J = 8.4Hz, 1H), 6.92 (dd, J = 5.2, 2.1Hz, 1H), 6.86 (d, J = 2.0Hz, 1H), 6.20 ( d, J=2.0Hz, 1H), 4.37-4.28 (m, 3H), 4.11 (t, J=6.0Hz, 2H), 3.81 (s, 3H), 3.29 (s, 1H), 2.82 -2.73(m, 1H), 2.67-2.55(m, 2H), 2.38-2.24(m, 1H), 2.09-1.98(m, 1H), 1.95-1.86(m, 2H).

[0589] Example 14: 3-(2-chloro-3-(2-oxo-2H-(1,3'-bipyridinyl)-6'-yl)phenyl)piperidine-2,6-dione

[0590] Reference to the procedure of other embodiments of the application resulted in 4 mg of 3-(2-chloro-3-(2-oxo-2H-(1,3'-bipyridinyl)-6'-yl)phenyl)piperidine-2,6-dione.

[0591] MS (ESI) M / Z: 394.0 [M+H] + .

[0592] 1 H NMR (400 MHz, DMSO-d6) δ 10.95 (s, 1H), 8.76 (d, J = 2.4 Hz, 1H), 8.04 (dd, J = 8.4, 2.6 Hz, 1H), 7.86 - 7.73 (m, 2H), 7.61 - 7.42 (m, 4H), 6.55 (d, J = 9.2 Hz, 1H), 6.41 - 6.37 (m, 1H), 4.41 - 4.37 (m, 1H), 2.85 - 2.79 (m, 2H), 2.19 - 1.99 (m, 2H).

[0593] Example 15: 3-(2-chloro-3-(3-oxo-3-(piperidin-l-yl)prop-l-y n-l-yl)phenyl)piperidine-2,6-dione

[0594] Reference to the procedure of other embodiments of the application resulted in 12.77 mg of 3-(2-chloro-3-(3-oxo-3-(piperidin-l-yl)prop-l-yn-l-yl)phenyl)piperidine-2,6-dione.

[0595] MS (ESI) M / Z: 359.1 [M+H] + .

[0596] 1 H NMR (400 MHz, DMSO-d6) δ 10.95 (s, 1H), 7.72 - 7.67 (m, 1H), 7.54 - 7.49 (m, 1H), 7.42 (t, J = 7.8 Hz, 1H), 4.37 - 4.26 (m, 1H), 3.82 - 3.74 (m, 2H), 3.55 - 3.50 (m, 2H), 2.87 - 2.73 (m, 1H), 2.59 - 2.55 (m, 1H), 2.40 - 2.28 (m, 1H), 2.05 - 1.96 (m, 1H), 1.67 - 1.54 (m, 4H), 1.52 - 1.45 (m, 2H).

[0597] Example 16: 3-(2-chloro-3-(1-(1-methyl-1H-pyrazole-3-carbonyl)-1,2,3,6- tetrahydropyridin-4-yl)phenyl)piperidine-2,6-dione

[0598] Reaction Scheme:

[0599] Procedure:

[0600] Step A: To a solution of INT-1 (500 mg, 1.65 mmol), 4-(tetramethyl-1,3,2- dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine-1-carboxylic acid tert-butyl ester (612 mg, 1.98 mmol) and potassium phosphate (1.05 g, 4.95 mmol) in 1,4-dioxane (20 mL) and water (6 mL) was added methanesulfonate (diamino-N-butylphosphinoyl)-2'-amino 1,1'-biphenyl-2-yl) palladium(II) (240 mg, 0.33 mmol). Nitrogen was purged for three times. The reaction was stirred at 90 °C for 6 hours.

[0601] LCMS was used to monitor the reaction completion. The reaction was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give 310 mg of 4-(2-chloro-3-(2,6-dioxopiperidin-3-yl)phenyl)-3,6- dihydropyridine-1(2H)-carboxylic acid tert-butyl ester.

[0602] 1 H NMR (400 MHz, CDCl3) δ: 8.01 (s, 1H), 7.24-7.22 (m, 1H), 7.16-7.10 (m, 2H), 5.65 (s, 1H), 4.29-4.24 (m, 1H), 4.05 (s, 2H), 3.66-3.60 (m, 2H), 2.83-2.62 (m, 2H), 2.34-2.21 (m, 4H), 1.51-1.48 (s, 9H).

[0603] Step B: To a solution of 4-(2-chloro-3-(2,6-dioxopiperidin-3-yl)phenyl)-3,6- dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (200 mg, 0.50 mmol) in dichloromethane (5 mL) was added trifluoroacetic acid (2 mL). The reaction was stirred at room temperature for 1 hour.

[0604] LCMS was used to monitor the reaction completion. The reaction was concentrated under reduced pressure to give 270 mg of 3-(2-chloro-3-(1,2,3,6-tetrahydropyridin-4- yl)phenyl)piperidine-2,6-dione as crude product.

[0605] MS (ESI) M / Z: 305.0 [M+H]+ .

[0606] Step C: To a solution of 3-(2-chloro-3-(1,2,3,6-tetrahydropyridin-4- yl)phenyl)piperidine-2,6-dione (crude, 150 mg, theoretical 0.50 mmol) and 1- methyl-1H-pyrazole-3-carboxylic acid (124 mg, 0.99 mmol) in DMF (2 mL) was added 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (376 mg, 0.99 mmol) and N,N-diisopropylethylamine (0.41 mL, 2.5 mmol). The reaction was stirred at room temperature for 2 hours.

[0607] LCMS was used to monitor the completion of the reaction. The reaction was diluted with water (10 mL) and extracted with ethyl acetate (10 mL x 2). The organic phase was combined and washed with saturated sodium bicarbonate (20 mL x 2) and saturated brine (30 mL x 2) successively, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography to give 34 mg of 3-(2-chloro-3-(1-(1-methyl-1H-pyrazole-3-carbonyl)-1,2,3,6- tetrahydropyridin-4-yl)phenyl)piperidine-2,6-dione.

[0608] MS (ESI) M / Z: 413.0 [M+H] + .

[0609] 1 H NMR (400 MHz, DMSO-d6) δ 10.90 (s, 1H), 7.78 (d, J = 2.2 Hz, 1H), 7.37 - 7.24 (m, 2H), 7.23 - 7.17 (m, 1H), 6.59 (d, J = 11.6 Hz, 1H), 5.73 (d, J = 27.7 Hz, 1H), 4.60 (s, 1H), 4.28 (dd, J = 12.1, 4.9 Hz, 1H), 4.22 (s, 1H), 4.13 - 4.04 (m, 1H), 3.90 (s, 3H), 3.83 (s, 1H), 2.85 - 2.71 (m, 1H), 2.57 - 2.52 (m, 1H), 2.45 - 2.39 (m, 2H), 2.33 - 2.23 (m, 1H), 2.08 - 1.89 (m, 1H).

[0610] Example 17: 3-(2-chloro-3-(1-(1-methyl-1H-pyrazole-3-carbonyl)-1,2,3,6- tetrahydropyridin-4-yl)phenyl)piperidine-2,6-dione

[0611] Reference to the preparation method of other embodiments of the application, 66.21 mg of 3-(2-chloro-3-((4-(2-oxopyridin-1(2H)-yl) phenyl) ethynyl) phenyl) piperidine-2,6-dione was obtained.

[0612] MS (ESI) M / Z: 417.0 [M+H] + .

[0613] 1 H NMR (400 MHz, DMSO-d6) δ 10.95 (s, 1H), 7.74-7.63 (m, 4H), 7.57-7.48 (m, 3H), 7.46-7.37 (m, 2H), 6.50 (d, J = 8.8 Hz, 1H), 6.38-6.32 (m, 1H), 4.38-4.29 (m, 1H), 2.87-2.75 (m, 1H), 2.60-2.52 (m, 1H), 2.41-2.29 (m, 1H), 2.07-1.98 (m, 1H).

[0614] Example 18: 3-(2-chloro-3-(5-((1-methyl-1H-pyrazol-3-yl)methyl)-4-oxo-2,3,4-5- tetrahydrobenzo[b][1,4]oxazepin-8-yl)phenyl)piperidine-2,6-dione

[0615] Reaction Scheme:

[0616] Operation steps:

[0617] Step A: To a solution of 5-bromo-2-nitrophenol (5.0 g, 22.9 mmol) in tetrahydrofuran (70 mL), 3-hydroxypropionic acid methyl ester (7.15 g, 68.8 mmol), triphenylphosphine (12.01 g, 45.8 mmol) and diisopropyl azodicarboxylate (9.25 g, 45.8 mmol) were added. Nitrogen was replaced three times. The reaction was stirred at 60°C for 5 hours.

[0618] LCMS was used to monitor the completion of the reaction. The reaction solution was diluted with water (300 mL) and extracted with ethyl acetate (300 mL x 3). The organic phase was combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography to obtain 2.1 g of 3-(5-bromo-2-nitrophenoxy)propionic acid methyl ester.

[0619] 1H NMR (400 MHz, CDC13) δ 7.74 (d, J = 8.6 Hz, 1H), 7.28 (d, J = 1.8 Hz, 1H), 7.20 (dd, J = 8.6, 1.9 Hz, 1H), 4.39 (t, J = 6.3 Hz, 2H), 3.75 (s, 3H), 2.88 (t, J = 6.3 Hz, 2H).

[0620] Step B: To a solution of methyl 3-(5-bromo-2-nitrophenoxy)propanoate (2.1 g, 6.9 mmol) in ethanol (20 mL) and water (20 mL) was added ammonium chloride (1.86 g, 34.6 mmol) and iron powder (1.94 mg, 34.6 mmol). The reaction was stirred at 80 °C for 2 h.

[0621] LCMS was used to monitor the reaction. The reaction was filtered, the filtrate was diluted with water (100 mL) and extracted with ethyl acetate (100 mL x 3). The organic phase was combined, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography to give 1.9 g of methyl 3-(2-amino-5-bromophenoxy)propanoate.

[0622] MS (ESI) M / Z: 274.0 [M+H] + .

[0623] Step C: To a solution of methyl 3-(2-amino-5-bromophenoxy)propanoate (1.7 g, 6.22 mmol) in ethanol (20 mL) was added a solution of sodium hydroxide (747 mg, 18.66 mmol) in water (20 mL). The reaction was stirred at room temperature for 2 h.

[0624] LCMS was used to monitor the reaction. The reaction was diluted with water (30 mL) and the pH was adjusted to 6 with 1 M hydrochloric acid at 0 °C. The reaction was extracted with dichloromethane / methanol (10:1, 200 mL x 3). The organic phase was combined, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography to give 510 mg of 3-(2-amino-5-bromophenoxy)propanoic acid.

[0625] MS (ESI) M / Z: 261.7 [M+H] + .

[0626] Step D: To a solution of 3-(2-amino-5-bromophenoxy)propanoic acid (390 mg, 1.5 mmol) in DMF (10 mL) was added tetramethylchloro uric phosphate (550 mg, 1.95 mmol) and N-methylimidazole (250 mg, 3.01 mmol). The reaction was stirred at room temperature for 2 h under nitrogen protection.

[0627] LCMS was used to monitor the reaction. The reaction solution was diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 3). The organic phase was combined, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to give 220 mg of 8-bromo-2,3-dihydrobenzo[b][l,4]oxazepin-4(5H)-one.

[0628] MS (ESI) M / Z: 242.0 [M+H] + .

[0629] Step E: To a solution of 8-bromo-2,3-dihydrobenzo[b][l,4]oxazepin-4(5H)-one (100 mg, 0.41 mmol) in DMF (5 mL) was added sodium hydride (60% dispersion in oil, 25 mg, 0.62 mmol) at 0 °C. After stirring for 10 min, 3-(bromomethyl)-l-methyl-lH-pyrazole (79 mg, 0.45 mmol) was added. The reaction was stirred at 0 °C for 30 min.

[0630] LCMS was used to monitor the reaction. The reaction solution was diluted with water (30 mL) and extracted with ethyl acetate (30 mL x 3). The organic phase was combined, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by TLC preparation plate to give 23 mg of 8-bromo-5-((l-methyl-lH-pyrazol-3-yl)methyl)-2,3-dihydrobenzo[b][l,4]oxazepin-4(5H)-one.

[0631] MS (ESI) M / Z: 337.7 [M+H] + .

[0632] Step F: To a solution of 8-bromo-5-((l-methyl-lH-pyrazol-3-yl)methyl)-2,3- dihydrobenzo[b][l,4]oxazepin-4(5H)-one (23 mg, 0.07 mmol) in 1,4-dioxane (5 mL) and water (0.5 mL) was added INT-2 (39 mg, 0.11 mmol), potassium carbonate (19 mg, 0.14 mmol) and (l,l'-bis(diphenylphosphino)ferrocene)dichloropalladium(ll) (6 mg, 7 μmol). The reaction was stirred at 90 °C for 2 h under nitrogen.

[0633] LCMS monitoring reaction was complete. The reaction solution was diluted with water (10 mL) and extracted with dichloromethane (10 mL x 3). The organic phase was combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by preparative high performance liquid chromatography to give 10.99 mg of 3-(2-chloro-3-(5-((1-methyl-1H-pyrazol-3-yl)methyl)-4-oxo-2,3,4-5- tetrahydrobenzo[b][1,4]oxazepin-8-yl)phenyl)piperidine-2,6-dione.

[0634] MS (ESI) M / Z: 479.0 [M+H] + .

[0635] 1 H NMR (400 MHz, DMSO-d6) δ 10.92 (s, 1H), 7.59 (d, J = 8.4 Hz, 1H), 7.55 (d, J = 2.0 Hz, 1H), 7.40 - 7.32 (m, 3H), 7.29 - 7.25 (m, 1H), 7.17 (d, J = 2.0 Hz, 1H), 6.06 (d, J = 2.0 Hz, 1H), 4.91 (s, 2H), 4.54 (t, J = 6.6 Hz, 2H), 4.40 - 4.28 (m, 1H), 3.76 (s, 3H), 2.85 - 2.74 (m, 1H), 2.63 (t, J = 6.6 Hz, 2H), 2.58 - 2.52 (m, 1H), 2.39 - 2.27 (m, 1H), 2.09 - 1.99 (m, 1H).

[0636] Example 19: 3-(3-chloro-4-(4-(2-oxopyridin-1(2H)-yl)phenyl)thiophen-2-yl)piperidine- 2,6-dione

[0637] Reaction Scheme:

[0638] Procedure:

[0639] Step A: 3-chlorothiophene-2-carboxylic acid methyl ester (3.0 g, 17.04 mmol) was dissolved in dichloromethane (50 mL), and aluminum trichloride (10.29 g, 68.16 mmol), iron tribromide (502 mg, 1.70 mmol) and liquid bromine (2.72 g, 17.04 mmol) were added at room temperature, and the mixture was replaced with nitrogen three times, and the reaction was carried out at room temperature for 16 hours.

[0640] LCMS monitoring showed the disappearance of raw materials, water (100 mL) was added to quench, ethyl acetate (100 mL x 3) was extracted, the organic phase was combined, saturated brine (50 mL x 2) was washed, anhydrous sodium sulfate was dried, filtered, and the filtrate was concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography to obtain 5.1 g of methyl 4-bromo-3-chlorothiophene-2-carboxylate.

[0641] MS (ESI) M / Z: 254.2 [M+H] + .

[0642] Step B: Methyl 4-bromo-3-chlorothiophene-2-carboxylate (1.0 g, 3.94 mmol) was dissolved in tetrahydrofuran (10 mL), diisobutylaluminum hydride (7.87 mL, 7.87 mmol) was added, and the reaction was carried out at room temperature for 2 hours.

[0643] LCMS monitoring showed the disappearance of raw materials, water (50 mL) was added to quench, ethyl acetate (50 mL x 3) was extracted, the organic phase was combined, saturated brine (50 mL x 2) was washed, anhydrous sodium sulfate was dried, filtered, and the filtrate was concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography to obtain 810 mg of (4-bromo-3-chlorothiophen-2-yl)methanol.

[0644] MS (ESI) M / Z: 227.1 [M+H] + .

[0645] Step C: (4-bromo-3-chlorothiophen-2-yl)methanol (810 mg, 3.58 mmol) was dissolved in dichloromethane (5 mL), triphenylphosphine (1.4 g, 5.37 mmol) and carbon tetrabromide (1.77 g, 5.37 mmol) were added, and the reaction was carried out at room temperature for 3 hours.

[0646] LCMS monitoring showed the disappearance of raw materials, water (50 mL) was added to quench, ethyl acetate (30 mL x 3) was extracted, the organic phase was combined, saturated brine (30 mL x 2) was washed, anhydrous sodium sulfate was dried, filtered, and the filtrate was concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography to obtain 800 mg of 4-bromo-2-(bromomethyl)-3-chlorothiophene.

[0647] MS (ESI) M / Z: 289.2 [M+H] + .

[0648] Step D: 4-bromo-2-(bromomethyl)-3-chlorothiophene (800 mg, 2.77 mmol) was dissolved in dichloromethane (5 mL), trimethylsilyl cyanide (412 mg, 4.16 mmol) and tetrabutylammonium bromide (4.16 mL, 4.16 mmol) were added, and the reaction was carried out at room temperature for 3 hours.

[0649] LCMS monitoring showed the disappearance of raw materials, water (30 mL) was added to quench, ethyl acetate (30 mL x 3) was extracted, the organic phase was combined, saturated brine (30 mL x 2) was washed, anhydrous sodium sulfate was dried, filtered, and the filtrate was concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography to obtain 620 mg of 2-(4-bromo-3-chlorothiophen-2-yl)acetonitrile.

[0650] MS (ESI) M / Z: 236.2 [M+H] + .

[0651] Step E: 2-(4-bromo-3-chlorothiophen-2-yl)acetonitrile (620 mg, 2.63 mmol) was dissolved in tetrahydrofuran (10 mL), tert-butyl acrylate (506 mg, 3.95 mmol) and sodium methoxide (28 mg, 0.53 mmol) were added, and the reaction was carried out at room temperature for 2 hours.

[0652] LCMS monitoring showed the disappearance of raw materials, water (30 mL) was added to quench, ethyl acetate (30 mL x 3) was extracted, the organic phase was combined, saturated brine (30 mL x 2) was washed, anhydrous sodium sulfate was dried, filtered, and the filtrate was concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography to obtain 620 mg of 2-(4-bromo-3-chlorothiophen-2-yl)acetonitrile.

[0653] MS (ESI) M / Z: 363.2 [M+H] + .

[0654] Step F: tert-butyl-4-(4-bromo-3-chlorothiophen-2-yl)-4-cyanobutanoate (800 mg, 2.2 mmol) was dissolved in acetic acid (5 mL), sulfuric acid (1.08 g, 11 mmol) was added, and the reaction was carried out at 90°C for 4 hours.

[0655] LCMS monitoring showed the disappearance of raw materials, water (30 mL) was added to quench, ethyl acetate (30 mL x 3) was extracted, the organic phase was combined, saturated brine (30 mL x 2) was washed, anhydrous sodium sulfate was dried, filtered, and the filtrate was concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography to obtain 620 mg of 2-(4-bromo-3-chlorothiophen-2-yl)acetonitrile.

[0656] MS (ESI) M / Z: 307.2 [M+H] + .

[0657] Step G: Dissolve 3-(4-bromo-3-chlorothiophen-2-yl)piperidine-2,6-dione (170 mg, 0.55 mmol), l,l'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (41 mg, 0.055 mmol) in 1,4-dioxane (10 mL) and water (2 mL), add potassium carbonate (151 mg, 1.1 mmol) and INT-2 (163 mg, 0.55 mmol) to the reaction, stir at 100 °C for 3 hours.

[0658] LCMS monitoring showed the disappearance of starting material, the reaction was concentrated under reduced pressure. The resulting residue was purified by preparative high performance liquid chromatography to give 48.8 mg of 3-(3-chloro-4-(4-(2-oxopyridin-l(2H)-yl)phenyl)thiophen-2-yl)piperidine-2,6-dione.

[0659] MS (ESI) M / Z: 339.1 [M+H] + .

[0660] 1 H NMR (400 MHz, DMSO-d6) δ 10.99 (s, 1H), 7.79 (s, 1H), 7.71 (dd, J = 6.9, 1.7 Hz, 1H), 7.68 - 7.61 (m, 2H), 7.56 - 7.47 (m, 3H), 6.51 (d, J = 9.1 Hz, 1H), 6.34 (td, J = 6.7, 1.2 Hz, 1H), 4.44 (dd, J = 12.4, 5.3 Hz, 1H), 2.93 - 2.76 (m, 1H), 2.58 (dt, J = 17.1, 3.4 Hz, 1H), 2.29 - 2.13 (m, 2H).

[0661] Example 20: 3-(2-Ethynyl-4'-(2-oxopyridin-l(2H)-yl)-(l,l'-biphenyl)-3-yl)piperidine-2,6-dione

[0662] Scheme:

[0663] Procedure:

[0664] Step A: Dissolve INT-5 (120 mg, 0.41 mmol) in a mixture of 1,4-dioxane (5 mL) and water (1 mL), add INT-4 (122 mg, 0.41 mmol), (1,1'-bis(ditert-butylphosphino)ferrocene)palladium(II) dichloride (26 mg, 0.041 mmol) and potassium carbonate (169 mg, 1.23 mmol), replace with nitrogen three times, react at 70 °C for 3 hours.

[0665] LCMS monitoring showed the disappearance of raw materials, quenching by adding water (20 mL), extracting with ethyl acetate (20 mL x 3), washing the combined organic phase with saturated brine (20 mL x 2), drying over anhydrous sodium sulfate, filtering, and concentrating the filtrate under reduced pressure. The resulting residue was purified by preparative high performance liquid chromatography to obtain 14.35 mg of 3-(2-ethynyl-4'-(2-oxopyridin-1(2H)-yl)-(1,1'-biphenyl)-3-yl)piperidine-2,6-dione.

[0666] MS (ESI) M / Z: 383.1 [M+H] + .

[0667] 1 H NMR (400 MHz, DMSO-d6) δ 10.92 (s, 1H), 7.75-7.65 (m, 3H), 7.58-7.44 (m, 4H), 7.36 (dd, J = 13.4, 7.3 Hz, 2H), 6.51 (d, J = 9.1 Hz, 1H), 6.34 (td, J = 6.7, 1.1 Hz, 1H), 4.40 (s, 1H), 4.34 (dd, J = 11.9, 4.8 Hz, 1H), 2.83-2.69 (m, 1H), 2.56 (d, J = 3.8 Hz, 1H), 2.36 (dd, J = 23.4, 7.2 Hz, 1H), 2.14-2.01 (m, 1H).

[0668] Example 21: 3-(2-Bromo-4'-(2-oxopyridin-1(2H)-yl)-(1,1'-biphenyl)-3-yl)piperidine-2,6-dione

[0669] Reference to other embodiments of the application, 20.04 mg of 3-(2-bromo-4'-(2-oxopyridin-1(2H)-yl)-(1,1'-biphenyl)-3-yl)piperidine-2,6-dione was prepared.

[0670] MS (ESI) M / Z: 325.2 [M+H] + .

[0671] 1H NMR (400 MHz, DMSO-d6) δ 10.95 (s, 1H), 7.72 (d, J = 6.2 Hz, 1H), 7.59 - 7.44 (m, 6H), 7.34 (dd, J = 17.5, 7.2 Hz, 2H), 6.52 (d, J = 9.1 Hz, 1H), 6.34 (t, J = 6.7 Hz, 1H), 4.40 (dd, J = 12.1, 4.7 Hz, 1H), 2.80 (td, J = 12.5, 6.3 Hz, 1H), 2.58 (s, 1H), 2.34 (d, J = 8.0 Hz, 1H), 2.13 - 2.02 (m, 1H).

[0672] Example 22: 3-(2-chloro-3-(4-(2-oxopyridin-1(2H)-yl)-2,3-dihydrofuran-7-yl)phenyl)piperidine- 2,6-dione

[0673] Reference to other examples of the application, 2.43 mg of 3-(2-chloro-3-(4-(2-oxopyridin-1(2H)-yl)-2,3-dihydrofuran-7-yl)phenyl)piperidine-2,6-dione was prepared.

[0674] MS (ESI) M / Z: 435.0 [M+H] + .

[0675] 1 H NMR (400 MHz, DMSO-d6) δ 10.91 (s, 1H), 8.20 (dd, J = 5.0, 2.0 Hz, 1H), 7.93 - 7.84 (m, 1H), 7.41 - 7.28 (m, 3H), 7.16 (dd, J = 7.2, 5.0 Hz, 1H), 7.09 (dd, J = 8.3, 4.4 Hz, 2H), 6.67 (d, J = 8.3 Hz, 1H), 4.51 (t, J = 8.7 Hz, 2H), 4.34 (dd, J = 12.2, 5.1 Hz, 1H), 2.99 (t, J = 8.7 Hz, 2H), 2.84 - 2.75 (m, 2H), 2.56 (d, J = 3.9 Hz, 1H), 2.13 - 2.01 (m, 1H).

[0676] Example 23: 3-(2-chloro-3-(1-methyl-2-oxo-2',3',5',6'-tetrahydrospiro(indoline-3,4'-pyran)-6-yl)phenyl)piperidine-2,6-dione

[0677] Procedure:

[0678] Step A: Dissolve 6-bromoindolin-2-one (0.3 g, 1.41 mmol) in tetrahydrofuran (5 mL), add lithium bis(trimethylsilyl)amide (7.1 mL, 7.1 mmol) at -78 °C, react for 1 hour at -78 °C, add 2,2'-dibromo-diethyl ether (0.49 g, 2.11 mmol), slowly raise to room temperature after dropwise addition is complete, and react for half an hour at 70 °C.

[0679] LCMS monitoring shows that the starting material disappears, quench with water (50 mL), extract with ethyl acetate (50 mL x 3), combine the organic phases, wash with saturated brine (50 mL x 2), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. Purify the resulting crude product by silica gel column chromatography to obtain 160 mg of 6-bromo-2',3',5',6'-tetrahydrospiro(indolin-3,4'-pyran)-2-one.

[0680] MS (ESI) M / Z: 282.2 [M+H] + .

[0681] Step B: Dissolve 6-bromo-2',3',5',6'-tetrahydrospiro(indolin-3,4'-pyran)-2-one (160 mg, 0.57 mmol) in N,N-dimethylformamide (3 mL), add sodium hydride (45.6 mg, 1.14 mmol), and react at room temperature for 2 hours.

[0682] LCMS monitoring shows that the starting material disappears, quench with water (30 mL), extract with ethyl acetate (30 mL x 3), combine the organic phases, wash with saturated brine (30 mL x 2), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. Purify the resulting crude product by silica gel column chromatography to obtain 150 mg of 6-bromo-1-methyl-2',3',5',6'-tetrahydrospiro(indolin-3,4'-pyran)-2-one.

[0683] MS (ESI) M / Z: 296.1 [M+H] + .

[0684] Step C: Dissolve 6-bromo-1-methyl-2',3',5',6'-tetrahydrospiro(indolin-3,4'-pyran)-2-one (150 mg, 0.51 mmol) in 1,4-dioxane (5 mL), add potassium acetate (0.1 g, 1.02 mmol), 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (37 mg, 0.051 mmol), and react at 90 °C for 3 hours.

[0685] LCMS monitoring showed the disappearance of starting material, quenched by adding water (30 mL), extracted with ethyl acetate (30 mL x 3), the organic phase was combined, washed with saturated brine (30 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography to obtain 130 mg of 1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2',3',5',6'- tetrahydrospiro[indoline-3,4'-pyran]-2-one.

[0686] MS (ESI) M / Z: 344.2 [M+H] + .

[0687] Step D: 1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2',3',5',6'- tetrahydrospiro[indoline-3,4'-pyran]-2-one (50 mg, 0.146 mmol) was dissolved in 1,4- dioxane (5 mL) and water (1 mL), potassium carbonate (40 mg, 0.29 mmol) and 1,1'- bis(diphenylphosphino)ferrocenedichloropalladium (II) (10 mg, 0.015 mmol) were added, and the reaction was carried out at 80 °C for 1 hour.

[0688] LCMS monitoring showed the disappearance of starting material, the reaction solution was concentrated under reduced pressure. The obtained residue was purified by preparative high performance liquid chromatography to obtain 26.1 mg of 3-(2-chloro-3-(1-methyl-2-oxo-2',3',5',6'- tetrahydrospiro(indoline-3,4'-pyran)-6-yl)phenyl)piperidine-2,6-dione.

[0689] MS (ESI) M / Z: 439.1 [M+H] + .

[0690] 1 H NMR (400 MHz, DMSO-d6) δ 10.92 (s, 1H), 7.64 (d, J = 7.5 Hz, 1H), 7.45-7.31 (m, 3H), 7.12-7.03 (m, 2H), 4.36 (dd, J = 12.2, 5.1 Hz, 1H), 4.13-4.02 (m, 2H), 3.90-3.80 (m, 2H), 3.15 (s, 3H), 2.86-2.74 (m, 1H), 2.60-2.53 (m, 1H), 2.40-2.27 (m, 1H), 2.11-2.01 (m, 1H), 1.78 (t, J = 5.4 Hz, 4H).

[0691] Example 24: 3-(2-chloro-3-(4-methyl-5-oxo-2,3,4-δ-tetrahydrobenzo[f][l,4]oxazepin-8- yl)phenyl)piperidine-2,6-dione

[0692] Reference to other examples of the application, 64 mg of 3-(2-chloro-3-(4-methyl-5-oxo-2,3,4-δ-tetrahydrobenzo[f][l,4]oxazepin-8-yl)phenyl)piperidine-2,6-dione was prepared.

[0693] MS (ESI) M / Z: 398.9 [M+H] + .

[0694] 1 H NMR (400 MHz, DMSO-d6) δ 10.93 (s, 1H), 7.74 (d, J = 8.4 Hz, 1H), 7.44 - 7.37 (m, 2H), 7.35 - 7.32 (m, 1H), 7.20 (dd, J = 8.0, 1.6 Hz, 1H), 7.03 (d, J = 1.6 Hz, 1H), 4.40 (t, J = 4.8 Hz, 2H), 4.37 - 4.32 (m, 1H), 3.60 (t, J = 4.8 Hz, 2H), 3.11 (s, 3H), 2.86 - 2.73 (m, 1H), 2.58 - 2.51 (m, 1H), 2.38 - 2.29 (m, 1H), 2.10 - 1.99 (m, 1H).

[0695] Example 25 and Example 26: 3-(2-chloro-3-(l,2,3,4-tetrahydrobenzo[4,5]imidazo[l,2- a]pyridin-7-yl)phenyl)piperidine-2,6-dione and 3-(2-chloro-3-(l,2,3,4-tetrahydrobenzo[4,5]imidazo[l,2- a]pyridin-8-yl)phenyl)piperidine-2,6-dione

[0696] Reaction Scheme:

[0697] Procedure:

[0698] Step A: 4-Bromo-o-phenylenediamine (1.87 g, 10.0 mmol) and δ-valerolactone (6.01 g, 60.0 mmol) were dissolved in hydrochloric acid (4 M aqueous solution, 40 mL) and refluxed overnight.

[0699] LCMS was used to monitor the reaction. The reaction was diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The organic phase was combined, washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel and then purified by preparative high performance liquid chromatography. The separation conditions were as follows: preparative column: SunFire: C18 19*250mm, 5μm, mobile phase: 0.05% TFA in water / CH3CN, flow rate: 20 mL / min, gradient: 7%-17%, detection wavelength: 214 nm / 254 nm, retention time: 13.5 min. 150 mg of 7-bromo-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridine (denoted as compound 1) and 130 mg of 8-bromo-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridine (denoted as compound 2) were obtained.

[0700] MS (ESI) M / Z: 270.8 [M+H] + .

[0701] 1 H NMR (400 MHz, CDCl3) δ 7.68 (s, 1H), 7.41-7.39 (m, 1H), 7.33-7.31 (m, 1H), 3.74 (t, J = 6.0 Hz, 2H), 2.98 (t, J = 7.2 Hz, 2H), 2.05-1.95 (m, 2H), 1.75-1.63 (m, 2H).

[0702] Step B: To a solution of 4-(5-bromo-1H-benzo[d]imidazol-2-yl)butan-1-ol (440 mg, 1.63 mmol) in tetrahydrofuran (10 mL) was added triphenylphosphine (641 mg, 2.44 mmol) and diethyl azodicarboxylate (494 mg, 2.44 mmol). It was stirred at room temperature overnight.

[0703] LCMS was used to monitor the reaction. The reaction was diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The organic phase was combined, washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel and then purified by preparative high performance liquid chromatography. The separation conditions were as follows: preparative column: SunFire: C18 19*250mm, 5μm, mobile phase: 0.05% TFA in water / CH3CN, flow rate: 20 mL / min, gradient: 7%-17%, detection wavelength: 214 nm / 254 nm, retention time: 13.5 min. 150 mg of 7-bromo-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridine (denoted as compound 1) and 130 mg of 8-bromo-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridine (denoted as compound 2) were obtained.

[0704] Compound 1: 1H NMR (400 MHz, CDC13) δ 7.82 (d, J = 8.8 Hz, 1H), 7.66 (d, J = 1.6 Hz, 1H), 7.61 (dd, J = 8.8, 1.6 Hz, 1H), 4.21 (t, J = 6.0 Hz, 2H), 3.42 (t, J = 6.0 Hz, 2H), 2.29-2.23 (m, 2H), 2.14-2.11 (m, 2H).

[0705] Compound 2: 1 H NMR (400 MHz, CDC13) δ 7.82 (d, J = 8.8 Hz, 1H), 7.66 (d, J = 1.6 Hz, 1H), 7.61 (dd, J = 8.8, 1.6 Hz, 1H), 4.21 (t, J = 6.0 Hz, 2H), 3.42 (t, J = 6.0 Hz, 2H), 2.29-2.23 (m, 2H), 2.14-2.11 (m, 2H).

[0706] Step C: To a solution of 7-bromo-l,2,3,4-tetrahydrobenzo[4,5]imidazo[l,2- a]pyridine (100 mg, 0.27 mmol) in 1,4-dioxane (5 mL) and water (0.5 mL) was added INT-2 (122 mg, 0.35 mmol), potassium carbonate (112 mg, 0.81 mmol) and (l,l'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride (20 mg, 0.027 mmol). Nitrogen was purged for three times. The reaction was stirred at 90 °C for 2 hours.

[0707] LCMS was used to monitor the reaction completion. The reaction was diluted with water (10 mL) and extracted with dichloromethane (10 mL x 3). The organic phase was combined, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The crude product was purified by preparative high performance liquid chromatography. Separation condition: preparative column: SunFire: C18 19*250mm, 10μm, mobile phase: 0.1% FA in water / CH3CN, flow rate: 20 mL / min, gradient: 16%-26%, detection wavelength: 214nm / 254nm, retention time: 7.5 min. 13.03 mg of 3-(2-chloro-3-(l,2,3,4-tetrahydrobenzo[4,5]imidazo[l,2-a]pyridin-7-yl)phenyl)piperidine-2,6-dione (Example 25) was obtained.

[0708] MS (ESI) M / Z: 394.0 [M+H] + .

[0709] 1H NMR (400 MHz, DMSO-d6) δ 10.92 (s, 1H), 7.57 (d, J = 8.0 Hz, 1H), 7.47 (d, J = 1.2 Hz, 1H), 7.43-7.38 (m, 1H), 7.37-7.33 (m, 2H), 7.20-7.15 (m, 1H), 4.41-4.29 (m, 1H), 4.11 (t, J = 6.0 Hz, 2H), 2.98 (t, J = 6.2 Hz, 2H), 2.86-2.74 (m, 1H), 2.59-2.52 (m, 1H), 2.37-2.33 (m, 1H), 2.10-2.02 (m, 3H), 1.99-1.91 (m, 2H).

[0710] Step D: To a solution of 8-bromo-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2- a]pyridine (100 mg, 0.27 mmol) in 1,4-dioxane (5 mL) and water (0.5 mL) was added INT-2 (122 mg, 0.35 mmol), potassium carbonate (112 mg, 0.81 mmol) and (1,1'- bis(diphenylphosphino)ferrocene)palladium(II) dichloride (20 mg, 0.027 mmol). Nitrogen was purged for three times. The reaction was stirred at 90 °C for 2 h.

[0711] LCMS was used to monitor the reaction completion. The reaction was diluted with water (10 mL) and extracted with dichloromethane (10 mL x 3). The organic phase was combined, dried over sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The crude product was purified by preparative high performance liquid chromatography to give 12.66 mg of 3-(2-chloro-3-(1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2- a]pyridin-8-yl)phenyl)piperidine-2,6-dione (Example 26).

[0712] MS (ESI) M / Z: 393.9 [M+H] + .

[0713] 1 H NMR (400 MHz, DMSO-d6) δ 10.92 (s, 1H), 7.51 (d, J = 8.4 Hz, 2H), 7.43-7.31 (m, 3H), 7.23-7.17 (m, 1H), 4.42-4.28 (m, 1H), 4.13 (t, J = 6.0 Hz, 2H), 2.98 (t, J = 6.4 Hz, 2H), 2.85-2.73 (m, 1H), 2.59-2.55 (m, 1H), 2.39-2.32 (m, 1H), 2.12-2.02 (m, 3H), 2.00-1.91 (m, 2H).

[0714] Example 27: 3-(2-chloro-3-(5-pyridinecarboxylate-2,3,4-5- tetrahydrobenzo[b][l,4]oxazepin-8-yl)phenyl)piperidine-2,6-dione

[0715] Reference to the preparation method of other embodiments of the application obtained 26 mg of 3-(2-chloro-3-(5-pyridinecarboxylate-2,3,4-5- tetrahydrobenzo[b][l,4]oxazepin-8-yl)phenyl)piperidine-2,6-dione.

[0716] MS (ESI) M / Z: 476.0 [M+H] + .

[0717] 1 H NMR (400 MHz, DMSO-d6) δ 10.90 (s, 1H), 8.29 (d, J = 4.4 Hz, 1H), 7.75 (t, J = 7.4 Hz, 1H), 7.44 (d, J = 7.6 Hz, 1H), 7.37 - 7.32 (m, 2H), 7.29 - 7.24 (m, 1H), 7.20 (d, J = 6.4 Hz, 1H), 7.00 (s, 1H), 6.69 (d, J = 8.0 Hz, 2H), 4.31 - 4.27 (m, 2H), 4.16 (s, 1H), 2.94 - 2.26 (m, 2H), 2.55 (s, 1H), 2.34 - 2.25 (m, 1H), 2.23 - 1.75 (m, 4H).

[0718] Example 28: 2'-chloro-3'-(2,6-dioxopiperidin-3-yl)-[l,l'-biphenyl]-4- ylpyrrolidine-l-carboxylate

[0719] Reference to the preparation method of other embodiments of the application obtained 53 mg of 2'-chloro-3'-(2,6-dioxopiperidin-3-yl)-[l,l'-biphenyl]-4- ylpyrrolidine-l-carboxylate.

[0720] MS (ESI) M / Z: 413.0 [M+H] + .

[0721] 1H NMR (400 MHz, DMSO-d6) δ 10.92 (s, 1H), 7.44 - 7.30 (m, 5H), 7.21 (d, J = 8.4 Hz, 2H), 4.37 - 4.33 (m, 1H), 3.52 (t, J = 6.4 Hz, 2H), 3.36 (t, J = 6.6 Hz, 2H), 2.90 - 2.66 (m, 1H), 2.56 (d, J = 3.6 Hz, 1H), 2.39 - 2.28 (m, 1H), 2.07 - 2.04 (m, 1H), 1.94 - 1.86 (m, 4H).

[0722] Example 29: 3-(2-chloro-3-(1'-((1-methyl-1H-pyrazol-3-yl)methyl)spiro[cyclopropane-1,3'- indolin]-5'-yl)phenyl)piperidine-2,6-dione

[0723] Reaction Scheme:

[0724] Procedure:

[0725] Step A: 5'-Bromospiro[cyclopropane-1,3'-indoline] (0.2 g, 0.90 mmol) was dissolved in dichloromethane (5 mL), 1-methyl-1H-pyrazole-3-carboxaldehyde (197 mg, 1.79 mmol) and acetic acid (0.2 mL) were added, the reaction was carried out for half an hour, sodium triacetoxyborohydride (0.76 g, 3.58 mmol) was added, and the reaction was carried out at room temperature for 2 hours.

[0726] LCMS monitoring showed that the raw material disappeared, water (30 mL) was added to quench, ethyl acetate (30 mL x 3) was extracted, washed with saturated brine (30 mL x 3), the combined organic layer was dried over anhydrous sodium sulfate, filtered, rotary evaporated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography to obtain 160 mg of 5'-bromo-1'-((1-methyl-1H-pyrazol-3-yl)methyl)spiro[cyclopropane-1,3'-indoline].

[0727] MS (ESI) M / Z: 318.2 [M+H] + .

[0728] Step B: 5'-Bromo-1'-((1-methyl-1H-pyrazol-3-yl)methyl)spiro[cyclopropane-1,3'-indoline (100 mg, 0.31 mmol)

[0729] Dissolved in 1,4-dioxane (5 mL) and water (1 mL), added potassium carbonate (40 mg, 0.29 mmol), 1,1'-bis(di-tert-butylphosphino)ferrocene palladium dichloride (20 mg, 0.031 mmol) and INT-2 (0.11 g, 0.314 mmol), replaced with nitrogen for three times, reacted at 70 °C for 1 hour. LCMS monitoring showed that the starting material disappeared, and the reaction solution was concentrated under reduced pressure. The obtained residue was purified by preparative high performance liquid chromatography to obtain 3.3 mg of 3-(2-chloro-3-(1'-((1-methyl-1H-pyrazol-3-yl)methyl)spiro[cyclopropane-1,3'-indolin]-5'-yl)phenyl)piperidine-2,6-dione.

[0730] MS (ESI) M / Z: 461.1 [M+H] + .

[0731] 1 H NMR (400 MHz, DMSO-d6) δ 10.89 (s, 1H), 7.60 (d, J = 2.1 Hz, 1H), 7.34-7.28 (m, 1H), 7.26-7.20 (m, 2H), 7.00 (dd, J = 8.0, 1.8 Hz, 1H), 6.67 (d, J = 8.1 Hz, 1H), 6.60 (d, J = 1.8 Hz, 1H), 6.15 (d, J = 2.1 Hz, 1H), 4.34-4.25 (m, 3H), 3.79 (s, 3H), 3.43 (s, 2H), 2.84-2.70 (m, 1H), 2.57-2.52 (m, 1H), 2.37-2.26 (m, 1H), 2.07-1.96 (m, 1H), 0.93 (s, 4H).

[0732] Example 30: 3-(2-chloro-3-(5-(2-oxopyridin-1(2H)-yl)benzofuran-2-yl)phenyl)piperidine-2,6-dione

[0733] Reference to the preparation method of other embodiments of the application obtained 16.64 mg of 3-(2-chloro-3-(2-(2-oxopyridin-1(2H)-yl)benzofuran-5-yl)phenyl)piperidine-2,6-dione.

[0734] MS (ESI) M / Z: 432.9 [M+H] + .

[0735] 1H NMR (400 MHz, DMSO-d6) δ 10.97 (s, 1H), 8.02 - 7.88 (m, 1H), 7.81 - 7.75 (m, 2H), 7.72 (d, J = 6.0 Hz, 1H), 7.61 (s, 1H), 7.58 - 7.46 (m, 3H), 7.40 - 7.34 (m, 1H), 6.51 (d, J = 9.2 Hz, 1H), 6.33 (t, J = 6.4 Hz, 1H), 4.48 - 4.39 (m, 1H), 2.90 - 2.76 (m, 1H), 2.62 - 2.52 (m, 1H), 2.44 - 2.30 (m, 1H), 2.12 - 2.01 (m, 1H).

[0736] Example 31 : 3-(2-chloro-3-(4-oxo-5-(pyrimidin-2-ylmethyl)-2,3,4- 5-tetrahydrobenzo[b][l,4]oxazepin-8-yl)phenyl)piperidine-2,6-dione

[0737] Reference to the procedure of other examples of the application resulted in 13.03 mg of 3-(2-chloro-3-(4-oxo-5-(pyrimidin-2-ylmethyl)-2,3,4- 5-tetrahydrobenzo[b][l,4]oxazepin-8-yl)phenyl)piperidine-2,6-dione.

[0738] MS (ESI) M / Z: 476.9 [M+H] + .

[0739] 1 H NMR (400 MHz, DMSO-d6) δ 10.92 (s, 1H), 8.80 (d, J = 5.2 Hz, 2H), 7.46 - 7.32 (m, 5H), 7.26 - 7.17 (m, 2H), 5.11 (s, 2H), 4.58 (t, J = 6.4 Hz, 2H), 4.44 - 4.27 (m, 1H), 2.85 - 2.73 (m, 1H), 2.68 (t, J = 6.4 Hz, 2H), 2.60 - 2.54 (m, 1H), 2.38 - 2.27 (m, 1H), 2.10 - 2.00 (m, 1H).

[0740] Example 32: 3-(2-chloro-3-(2,3,4,5-tetrahydrobenzo[b][l,4]oxazepin-8- yl)phenyl)piperidine-2,6-dione

[0741] Reference to the preparation method of other embodiments of the application obtained 7 mg 3-(2-chloro-3-(2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-8-yl)phenyl)piperidine-2,6-dione.

[0742] MS (ESI) M / Z: 370.9 [M+H] + .

[0743] 1 H NMR (400 MHz, DMSO-d6) δ 10.90 (s, 1H), 7.35-7.31 (m, 1H), 7.29-7.22 (m, 2H), 6.85 (s, 3H), 5.57 (s, 1H), 4.34-4.29 (m, 1H), 4.06-3.99 (m, 2H), 3.15 (s, 2H), 2.84-2.71 (m, 1H), 2.39-2.21 (m, 2H), 2.07-2.02 (m, 1H), 1.90-1.89 (m, 2H).

[0744] Example 33: 3-(2-chloro-3-(4-oxo-2,3,4-5-tetrahydrobenzo[b][1,4]oxazepin-8-yl)phenyl)piperidine-2,6-dione

[0745] Reference to the preparation method of other embodiments of the application obtained 31.89 mg 3-(2-chloro-3-(4-oxo-2,3,4-5-tetrahydrobenzo[b][1,4]oxazepin-8-yl)phenyl)piperidine-2,6-dione.

[0746] MS (ESI) M / Z: 385.0 [M+H] + .

[0747] 1 H NMR (400 MHz, DMSO-d6) δ 10.92 (s, 1H), 9.87 (s, 1H), 7.42-7.27 (m, 3H), 7.14 (d, J=8.2 Hz, 1H), 7.09-7.00 (m, 2H), 4.39 (t, J=5.6 Hz, 2H), 4.36-4.30 (m, 1H), 2.83-2.73 (m, 3H), 2.58-2.54 (m, 1H), 2.36-2.29 (m, 1H), 2.13-1.99 (m, 1H).

[0748] Example 34: 3-(2-chloro-3-(4-(1-methyl-1H-pyrazol-3-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazin-7-yl)phenyl)piperidine-2,6-dione

[0749] Reference to the procedure described in other embodiments of the application resulted in 29 mg of 3-(2-chloro-3-(3-((1-methyl-1H-pyrazol-3-yl)methyl)-2-oxo-2,3- dihydrobenzo[d]thiazol-6-yl)phenyl)piperidine-2,6-dione.

[0750] MS (ESI) M / Z: 481.0 [M+H] + .

[0751] 1 H NMR (400 MHz, DMSO-d6) δ 10.92 (s, 1H), 7.60 (d, J = 2.0 Hz, 1H), 7.49 - 7.26 (m, 6H), 6.08 (d, J = 2.4 Hz, 1H), 5.08 (s, 2H), 4.36 - 4.31 (m, 1H), 3.79 (s, 3H), 3.64 (s, 2H), 2.83 - 2.74 (m, 1H), 2.60 - 2.52 (m, 1H), 2.38 - 2.28 (m, 1H), 2.10 - 1.96 (m, 1H).

[0752] Example 35: 3-(2-chloro-3-(3-((1-methyl-1H-pyrazol-3-yl)methyl)-2-oxo-2,3- dihydrobenzo[d]thiazol-6-yl)phenyl)piperidine-2,6-dione

[0753] Reference to the procedure described in other embodiments of the application resulted in 29 mg of 3-(2-chloro-3-(3-((1-methyl-1H-pyrazol-3-yl)methyl)-2-oxo-2,3- dihydrobenzo[d]thiazol-6-yl)phenyl)piperidine-2,6-dione.

[0754] MS (ESI) M / Z: 467.0 [M+H] + .

[0755] 1 H NMR (400 MHz, DMSO-d6) δ 10.92 (s, 1H), 7.72 (d, J = 1.6 Hz, 1H), 7.63 (d, J = 2.0 Hz, 1H), 7.44 - 7.29 (m, 5H), 6.18 (d, J = 2.4 Hz, 1H), 5.11 (s, 2H), 4.36 - 4.32 (m, 1H), 3.78 (s, 3H), 2.87 - 2.71 (m, 1H), 2.59 - 2.53 (m, 1H), 2.38 - 2.27 (m, 1H), 2.09 - 1.98 (m, 1H).

[0756] Example 36: 3-(2-chloro-3-(4-(l-methyl-lH-pyrazol-3-yl)methyl)-3-oxo-3,4- dihydro-2H-benzo[b][l,4]oxazin-7-yl)phenyl)piperidine-2,6-dione

[0757] Reference to the procedure for preparing the other examples of the application resulted in 14 mg of 3-(2-chloro-3-(4-(l-methyl-lH-pyrazol-3-yl)methyl)-3-oxo-3,4- dihydro-2H-benzo[b][l,4]oxazin-7-yl)phenyl)piperidine-2,6-dione.

[0758] MS (ESI) M / Z: 465.0 [M+H] + .

[0759] 1 H NMR (400 MHz, DMSO-d6) δ 10.91 (s, 1H), 7.61 (d, J = 2.4 Hz, 1H), 7.41 - 7.32 (m, 2H), 7.31 - 7.25 (m, 2H), 7.06 - 7.02 (m, 2H), 6.13 (d, J = 2.4 Hz, 1H), 5.06 (s, 2H), 4.77 (s, 2H), 4.35 - 4.31 (m, 1H), 3.79 (s, 3H), 2.84 - 2.72 (m, 1H), 2.59 - 2.52 (m, 1H), 2.37 - 2.26 (m, 1H), 2.09 - 1.99 (m, 1H).

[0760] Example 37: 3-(2-chloro-3-(5-((5-methyl-lH-pyrazol-3-yl)methyl)-4-oxo-2,3,4- 5-tetrahydrobenzo[b][l,4]oxazepin-8-yl)phenyl)piperidine-2,6-dione

[0761] Reaction Scheme:

[0762] Procedure:

[0763] Reference is made to the procedure of Example 18 for the preparation of 8-bromo-2,3- dihydrobenzo[b][l,4]oxazepin-4(5H)-one.

[0764] Step A: To a solution of methyl 5-methyl-lH-pyrazole-3-carboxylate (1.0 g, 7.14 mmol) in N,N-dimethylformamide (20 mL) was added sodium hydride (60% dispersion in oil, 371 mg, 9.28 mmol) at 0 °C. After stirring the reaction at 0 °C for 30 minutes, 2-(trimethylsilyl)ethoxymethyl chloride (1.54 g, 9.28 mmol) was added. Stirring was continued at room temperature for 2 hours.

[0765] LCMS monitor the reaction complete. The reaction solution was diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 3), the organic phase was combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography to give 800 mg of methyl 5-methyl-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrazole-3-carboxylate.

[0766] MS (ESI) M / Z: 271.1 [M+H] + .

[0767] Step B: To a solution of methyl 5-methyl-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrazole-3-carboxylate (0.8 g, 2.96 mmol) in tetrahydrofuran (10 mL) was added lithium aluminum hydride (2.0 M, 8.9 mL, 4.45 mmol) in tetrahydrofuran dropwise at 0 °C. The reaction was stirred at room temperature for 1 hour.

[0768] LCMS monitor the reaction complete. To the reaction solution was added water (1 mL) and sodium hydroxide solution (1.0 M, 1 mL) dropwise to quench. The crude product was filtered through celite, and the filter cake was washed with ethyl acetate (10 mL). The combined filtrate was diluted with water (30 mL) and extracted with ethyl acetate (30 mL x 3), the organic phase was combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 600 mg of (5-methyl-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrazol-3-yl)methanol.

[0769] MS (ESI) M / Z: 243.1 [M+H] + .

[0770] Step C: To a solution of (5-methyl-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrazol-3-yl)methanol (600 mg, 2.48 mmol) in dichloromethane (10 mL) was added phosphorus tribromide (1.0 g, 3.72 mmol) at 0 °C. The reaction was stirred at room temperature for 16 hours.

[0771] LCMS monitor the reaction complete. The reaction solution was poured into water (30 mL), and the pH was adjusted to about 8 with potassium carbonate, extracted with ethyl acetate (30 mL x 3), the organic phase was combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography to give 380 mg of 3-(bromomethyl)-5-methyl-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrazole.

[0772] MS (ESI) M / Z: 305.0 [M+H] + .

[0773] Step D: To a solution of 8-bromo-2,3-dihydrobenzo[b][l,4]oxazepin-4(5H)-one (200 mg, 0.83 mmol) in N,N-dimethylformamide (10 mL) was added sodium hydride (60% dispersion in oil, 40 mg, 1.00 mmol) at 0 °C. After stirring at 0 °C for 30 min, 3-(bromomethyl)-5-methyl-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrazole (280 mg, 0.92 mmol) was added. The reaction mixture was stirred at room temperature for 1 h.

[0774] LCMS was used to monitor the reaction completion. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to give 280 mg of 8-bromo-5-((5-methyl-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrazol-3-yl)methyl)-2,3-dihydrobenzo[b][l,4]oxazepin-4(5H)-one.

[0775] MS (ESI) M / Z: 468.0 [M+H] + .

[0776] Step E: To a solution of 8-bromo-5-((5-methyl-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrazol-3-yl)methyl)-2,3-dihydrobenzo[b][l,4]oxazepin-4(5H)-one (280 mg, 20.6 mmol) in dichloromethane (3 mL) was added trifluoroacetic acid (1 mL). The reaction mixture was stirred at room temperature for 2 h.

[0777] LCMS was used to monitor the reaction completion. The reaction mixture was diluted with saturated sodium bicarbonate solution (30 mL) and extracted with a mixture of dichloromethane and methanol (10: 1, 30 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography to give 160 mg of 8-bromo-5-((5-methyl-lH-pyrazol-3-yl)methyl)-2,3-dihydrobenzo[b][l,4]oxazepin-4(5H)-one.

[0778] MS (ESI) M / Z: 336.0 [M+H] + .

[0779] Step F: To a solution of 8-bromo-5-((5-methyl-lH-pyrazol-3-yl)methyl)-2,3- dihydrobenzo[b][l,4]oxazepin-4(5H)-one (50 mg, 0.15 mmol) in 1,4-dioxane (3 mL) and water (0.3 mL) was added INT-2 (83 mg, 0.24 mmol), potassium carbonate (45 mg, 0.32 mmol) and (l,l'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride (14 mg, 0.02 mmol). The air was replaced by nitrogen for three times. The reaction was stirred at 90 °C for 2 h.

[0780] LCMS was used to monitor the reaction completion. The reaction solution was diluted with water (20 mL) and extracted with dichloromethane (20 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained crude product was purified by preparative high performance liquid chromatography to give 16 mg of 3-(2-chloro-3-(5-((5-methyl-lH-pyrazol-3-yl)methyl)-4-oxo-2,3,4- 5-tetrahydrobenzo[b][l,4]oxazepin-8-yl)phenyl)piperidine-2,6-dione.

[0781] MS (ESI) M / Z: 479.1 [M+H] + .

[0782] 1 H NMR (400 MHz, DMSO-d6) δ 12.25 (s, 1H), 10.92 (s, 1H), 7.56 (s, 1H), 7.43 - 7.31 (m, 3H), 7.27 - 7.25 (m, 1H), 7.16 (d, J=2.0 Hz, 1H), 5.86 (s, 1H), 4.87 (s, 2H), 4.54 (t, J=8.0 Hz, 2H), 4.36 - 4.32 (m, 1H), 2.86 - 2.72 (m, 1H), 2.64 - 2.61 (m, 2H), 2.57 - 2.55 (m, 1H), 2.36 - 2.30 (m, 1H), 2.15 (s, 3H), 2.09 - 1.99 (m, 1H).

[0783] Example 38: 3-(2-chloro-3-(2-oxo-l-(pyrimidin-2-ylmethyl)-l,2-dihydropyridin-4- yl)phenyl)piperidine-2,6-dione

[0784] Reference to the preparation method of other embodiments of the application, 8.45 mg of 3-(2-chloro-3-(2-oxo-l-(pyrimidin-2-ylmethyl)-l,2-dihydropyridin-4- yl)phenyl)piperidine-2,6-dione was obtained.

[0785] MS (ESI) M / Z: 409.2 [M+H] + .

[0786] 1 H NMR (400 MHz, DMSO-d6) δ 10.94 (s, 1H), 8.79 (d, J = 4.9 Hz, 2H), 7.86 (d, J = 6.9 Hz, 1H), 7.47 - 7.42 (m, 3H), 7.41 - 7.35 (m, 1H), 6.39 (d, J = 1.9 Hz, 1H), 6.35 (dd, J = 7.0, 2.0 Hz, 1H), 5.34 (s, 2H), 4.36 (dd, J = 12.2, 5.0 Hz, 1H), 2.90 - 2.74 (m, 2H), 2.57 (d, J = 3.7 Hz, 1H), 2.08 - 2.00 (m, 1H).

[0787] Example 39: 3-(2-chloro-3-(4-(pyrimidin-2-ylmethoxy)-2,5-dihydrobenzo[b][l,4]oxazinan-8- yl)phenyl)piperidine-2,6-dione

[0788] Reference to the procedure of other examples of the application resulted in 10.6 mg of 3-(2-chloro-3-(4-(pyrimidin-2-ylmethoxy)-2,5-dihydrobenzo[b][l,4]oxazinan-8- yl)phenyl)piperidine-2,6-dione.

[0789] MS (ESI) M / Z: 476.9 [M+H] + .

[0790] 1 H NMR (400 MHz, DMSO-d6) δ 10.91 (s, 1H), 9.73 (s, 1H), 8.85 (d, J = 4.8 Hz, 2H), 8.21 (d, J = 8.4 Hz, 1H), 7.47 (t, J = 4.8 Hz, 1H), 7.39 - 7.30 (m, 2H), 7.29 - 7.23 (m, 1H), 7.07 (d, J = 1.6 Hz, 1H), 7.01 - 6.96 (m, 1H), 6.82 - 6.65 (m, 1H), 6.37 - 6.24 (m, 1H), 5.87 - 5.74 (m, 1H), 5.45 (s, 2H), 4.35 - 4.25 (m, 1H), 2.82 - 2.73 (m, 1H), 2.55 (s, 1H), 2.32 (dd, J = 6.3, 3.0 Hz, 1H), 2.08 - 1.96 (m, 1H).

[0791] Example 40: 3-(2-chloro-3-(3-ethyl-1-((1-methyl-1H-pyrazol-3-yl)methyl)-1H- indol-5-yl)phenyl)piperidine-2,6-dione

[0792] Reference to the procedure for preparing other embodiments of the application resulted in 10.2 mg of 3-(2-chloro-3-(3-ethyl-1-((1-methyl-1H-pyrazol-3-yl)methyl)-1H- indol-5-yl)phenyl)piperidine-2,6-dione.

[0793] MS (ESI) M / Z: 461.1 [M+H] + .

[0794] 1 H NMR (400 MHz, DMSO-d6) δ 10.91 (s, 1H), 7.60 - 7.47 (m, 3H), 7.41 - 7.30 (m, 3H), 7.23 (s, 1H), 7.14 (d, J=8.4 Hz, 1H), 6.13 (d, J=2.0 Hz, 1H), 5.26 (s, 2H), 4.34 (dd, J=12.1, 5.0 Hz, 1H), 3.79 (s, 3H), 2.77 (dd, J=12.4, 4.9 Hz, 1H), 2.70 (dd, J=15.0, 7.6 Hz, 2H), 2.56 (d, J=3.6 Hz, 1H), 2.39 - 2.26 (m, 1H), 2.11 - 2.00 (m, 1H), 1.25 (t, J=7.5 Hz, 3H).

[0795] Example 41: 3-(2-chloro-3-(1'-((1-methyl-1H-pyrazol-3-yl)methyl)-2'- oxospiro[cyclopropane-1,3'-indolin]-5'-yl)phenyl)piperidine-2,6-dione

[0796] Reference to the procedure for preparing other embodiments of the application resulted in 39 mg of 3-(2-chloro-3-(1'-((1-methyl-1H-pyrazol-3-yl)methyl)-2'- oxospiro[cyclopropane-1,3'-indolin]-5'-yl)phenyl)piperidine-2,6-dione.

[0797] MS (ESI) M / Z: 475.0 [M+H] + .

[0798] 1H NMR (400 MHz, DMSO-d6) δ 10.91 (s, 1H), 7.60 (d, J = 2.0 Hz, 1H), 7.40 - 7.20 (m, 4H), 7.11 (d, J = 8.0 Hz, 1H), 7.07 (d, J = 1.6 Hz, 1H), 6.14 (d, J = 2.4 Hz, 1H), 4.90 (s, 2H), 4.32 (dd, J = 12.0, 5.0 Hz, 1H), 3.79 (s, 3H), 2.84 - 2.71 (m, 1H), 2.56 - 2.54 (m, 1H), 2.34 - 2.30 (m, 1H), 2.07 - 1.97 (m, 1H), 1.70 - 1.67 (m, 2H), 1.58 - 1.56 (m, 2H)

[0799] Example 42: 3-(2-chloro-3-(5-((1-methyl-1H-imidazol-4-yl)methyl)-4-oxo- 2,3,4-5-tetrahydrobenzo[b][1,4]oxazepin-8-yl)phenyl)piperidine-2,6-dione

[0800] Reaction Scheme:

[0801] Reference to the method of preparation of other embodiments of the application resulted in 5 mg of 3-(2-chloro-3-(5-((1-methyl-1H-imidazol-4-yl)methyl)-4-oxo- 2,3,4-5-tetrahydrobenzo[b][1,4]oxazepin-8-yl)phenyl)piperidine-2,6-dione.

[0802] MS (ESI) M / Z: 479.0 [M+H] + .

[0803] 1 H NMR (400 MHz, DMSO-d6) δ 10.92 (s, 1H), 7.86 (d, J = 8.4 Hz, 1H), 7.50 (s, 1H), 7.43 - 7.33 (m, 3H), 7.28 (dd, J = 8.4, 2.0 Hz, 1H), 7.17 (d, J = 2.0 Hz, 1H), 6.96 (s, 1H), 4.77 (s, 2H), 4.54 (t, J = 6.4 Hz, 2H), 4.35 (dd, J = 12.4, 5.0 Hz, 1H), 3.59 (s, 3H), 2.84 - 2.76 (m, 1H), 2.61 - 2.55 (m, 3H), 2.34 - 2.32 (m, 1H), 2.07 - 2.01 (m, 1H).

[0804] Example 43: 3-(2-chloro-3-(1-oxo-1,5-dihydro-7H-benzo[e]pyriddo[2,1-c][1,4]oxazolidin-9- yl)phenyl)piperidine-2,6-dione

[0805] Reaction Scheme:

[0806] Procedure:

[0807] Step A: To a solution of (5-bromo-2-iodophenyl)methanol (980 mg, 3.13 mmol) in DMF (20 mL) was added sodium hydride (60% dispersion in oil, 376 mg, 6.26 mmol) at 0 °C. After stirring for 10 min, 2-chloro-6-(chloromethyl)pyridine (605 mg, 3.76 mmol) and tetrabutylammonium iodide (232 mg, 0.62 mmol) were added. The mixture was stirred at 0 °C for 2 h.

[0808] LCMS was used to monitor the completion of the reaction. The reaction was diluted with water (30 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting crude product was purified by column chromatography on silica gel to give 1.2 g of 2-(((5-bromo-2-iodobenzyl)oxy)methyl)-6-chloropyridine.

[0809] MS (ESI) M / Z: 437.8 [M+H] + .

[0810] Step B: To a solution of 2-(((5-bromo-2-iodobenzyl)oxy)methyl)-6-chloropyridine (1.2 g, 2.75 mmol) in DMSO (60 mL) was added sodium hydroxide (1.1 g, 27.5 mmol) and acetoxyhydroxamic acid (2.06 g, 27.5 mmol). The mixture was stirred at 100 °C for 5 h.

[0811] LCMS was used to monitor the completion of the reaction. The reaction was diluted with water (30 mL) and extracted with dichloromethane (30 mL x 3). The combined organic layers were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting crude product was purified by column chromatography on silica gel to give 1.0 g of 6-(((5-bromo-2-iodobenzyl)oxy)methyl)pyridin-2(1H)-one.

[0812] MS (ESI) M / Z: 419.9 [M+H] + .

[0813] Step C: To a solution of 6-(((5-bromo-2-iodobenzyl)oxy)methyl)pyridin-2(lH)-one (200 mg, 0.47 mmol) in DMSO (10 mL) was added (IR, 2S)-N1,N2-dimethylcyclohexane-l,2-diamine (28 mg, o.19 mmol), copper iodide (45 mg, 0.23 mmol) and potassium phosphate (303 mg, 1.41 mmol). Stirring at 85 °C for 2 h.

[0814] LCMS was used to monitor the completion of the reaction. The reaction solution was diluted with water (10 mL) and extracted with dichloromethane (10 mL x 3). The combined organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained crude product was purified by column chromatography on silica gel to give 110 mg of 9-bromo-7H-benzo[e]pyrido[2,l-c][l,4]oxazin-l(5H)-one.

[0815] MS (ESI) M / Z: 292.0 [M+H] + .

[0816] Step D: To a solution of 9-bromo-7H-benzo[e]pyrido[2,l-c][l,4]oxazin-l(5H)-one (80 mg, 0.27 mmol) in 1,4-dioxane (5 mL) and water (0.5 mL) was added INT-2 (144 mg, 0.41 mmol), potassium carbonate (76 mg, 0.54 mmol) and (l,l'-bis(diphenylphosphino)ferrocene)dichloropalladium(ll) (10 mg, 0.013 mmol). The air was replaced by nitrogen for three times and stirred at 90 °C for 2 h.

[0817] LCMS was used to monitor the completion of the reaction. The reaction solution was diluted with water (10 mL) and extracted with dichloromethane (10 mL x 3). The combined organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained crude product was purified by preparative high performance liquid chromatography to give 16 mg of 3-(2-chloro-3-(l-oxo-l,5-dihydro-7H-benzo[e]pyrido[2,l-c][l,4]oxazinan-9-yl)phenyl)piperidine-2,6-dione.

[0818] MS (ESI) M / Z: 434.9 [M+H] + .

[0819] 1H NMR (400 MHz, DMSO-d6) δ 10.94 (s, 1H), 7.74 (d, J = 8.4 Hz, 1H), 7.62-7.53 (m, 3H), 7.47-7.38 (m, 3H), 6.63-6.61 (m, 1H), 6.54-6.52 (m, 1H), 4.68 (d, J = 11.6 Hz, 1H), 4.48 (d, J = 12.4 Hz, 1H), 4.39-4.36 (m, 2H), 3.87 (d, J = 12.4 Hz, 1H), 2.87-2.76 (m, 1H), 2.58-2.54 (m, 1H), 2.41-2.30 (m, 1H), 2.09-2.06 (m, 1H).

[0820] Example 44: 3-(2-chloro-3-(l l-oxo-7, l l-dihydro-6H-benzo[b]pyriddo[l,2- d][l,4]oxazepin-3-yl)phenyl)piperidine-2,6-dione

[0821] Reaction Scheme:

[0822] Reference to the preparation method of other embodiments of the application, 16 mg of 3-(2-chloro-3-(l l-oxo-7, l l-dihydro-6H-benzo[b]pyriddo[l,2- d][l,4]oxazepin-3-yl)phenyl)piperidine-2,6-dione was obtained.

[0823] MS (ESI) M / Z: 434.9 [M+H] + .

[0824] 1 H NMR (400 MHz, DMSO-d6) δ 10.94 (s, 1H), 7.74 (d, J = 8.4 Hz, 1H), 7.62-7.53 (m, 3H), 7.47-7.38 (m, 3H), 6.63-6.61 (m, 1H), 6.54-6.52 (m, 1H), 4.68 (d, J = 11.6 Hz, 1H), 4.48 (d, J = 12.4 Hz, 1H), 4.39-4.36 (m, 2H), 3.87 (d, J = 12.4 Hz, 1H), 2.87-2.76 (m, 1H), 2.58-2.54 (m, 1H), 2.41-2.30 (m, 1H), 2.09-2.06 (m, 1H).

[0825] Example 45: 3-(2-chloro-3-(l-((l-methyl-lH-pyrazol-3-yl)methyl)-2-oxo- 1,2,3,5-tetrahydrobenzo[e][l,4]oxazepin-7-yl)phenyl)piperidine-2,6-dione

[0826] Reference to the preparation method of other embodiments of the present application to obtain 11.29 mg of 3-(2-chloro-3-(1-((1-methyl-1H-pyrazol-3-yl)methyl)-2-oxo-1,2,3,5-tetrahydrobenzo[e][1,4]oxazepin-7-yl)phenyl)piperazine-2,6-dione.

[0827] MS (ESI) M / Z: 479.2 [M+H] + .

[0828] 1 H NMR (400 MHz, DMSO-d6) δ 10.90 (s, 1H), 7.64 (s, 1H), 7.59 - 7.47 (m, 3H), 7.45 - 7.30 (m, 3H), 6.10 (d, J=2.2 Hz, 1H), 5.02 (s, 2H), 4.64 (s, 2H), 4.35 (dd, J=12.1, 5.0 Hz, 1H), 3.92 (s, 2H), 3.75 (s, 3H), 2.84 - 2.74 (m, 1H), 2.56 (d, J=4.0 Hz, 1H), 2.34 (d, J=10.9 Hz, 1H), 2.09 - 2.02 (m, 1H).

[0829] Example 46: 3-(2-ethyl-4'-(6-methyl-2-oxopyridin-1(2H)-yl)-(1,1'-biphenyl)-3-yl)piperazine-2,6-dione

[0830] Reference to the preparation method of other embodiments of the present application to obtain 11.29 mg of 3-(2-chloro-3-(1-((1-methyl-1H-pyrazol-3-yl)methyl)-2-oxo-1,2,3,5-tetrahydrobenzo[e][1,4]oxazepin-7-yl)phenyl)piperazine-2,6-dione.

[0831] MS (ESI) M / Z: 397.1 [M+H] + .

[0832] 1H NMR (400 MHz, DMSO-d6) δ 10.92 (s, 1H), 7.68 (d, J = 8.6 Hz, 2H), 7.53 - 7.36 (m, 3H), 7.33 (dd, J = 7.6, 4.1 Hz, 3H), 6.36 (d, J = 9.1 Hz, 1H), 6.26 (d, J = 6.8 Hz, 1H), 4.40 (s, 1H), 4.34 (dd, J = 11.9, 5.0 Hz, 1H), 2.74 (dd, J = 12.4, 5.1 Hz, 1H), 2.56 (d, J = 3.8 Hz, 1H), 2.38 (d, J = 9.9 Hz, 1H), 2.12 - 2.03 (m, 1H), 1.95 (s, 3H).

[0833] Example 47: 3-(4'-(6-(difluoromethyl)-2-oxopyridin-1(2H)-yl)-2-ethynyl-(1,1'- biphenyl)-3-yl)piperidine-2,6-dione

[0834] Reference to the procedure of other examples of the application resulted in 13.5 mg of 3-(4'-(6-(difluoromethyl)-2-oxopyridin-1(2H)-yl)-2-ethynyl-(1,1'- biphenyl)-3-yl)piperidine-2,6-dione.

[0835] MS (ESI) M / Z: 433.1 [M+H] + .

[0836] 1 H NMR (400 MHz, DMSO-d6) δ 10.92 (s, 1H), 7.68 (d, J = 8.6 Hz, 2H), 7.53 - 7.36 (m, 3H), 7.33 (dd, J = 7.6, 4.1 Hz, 3H), 6.36 (d, J = 9.1 Hz, 1H), 6.26 (d, J = 6.8 Hz, 1H), 4.40 (s, 1H), 4.34 (dd, J = 11.9, 5.0 Hz, 1H), 2.74 (dd, J = 12.4, 5.1 Hz, 1H), 2.56 (d, J = 3.8 Hz, 1H), 2.38 (d, J = 9.9 Hz, 1H), 2.12 - 2.03 (m, 1H), 1.95 (s, 3H).

[0837] Example 48: 3-(2-ethynyl-4'-(6-(hydroxymethyl)-2-oxopyridin-1(2H)-yl)-(1,1'- biphenyl)-3-yl)piperidine-2,6-dione

[0838] Reference to the preparation method of other embodiments of the present application to obtain 7.6 mg of 3-(2-ethynyl-4'-(6-(hydroxymethyl)-2-oxopyridin-1(2H)-yl)-(1,1'-biphenyl)-3-yl)piperidine-2,6-dione.

[0839] MS (ESI) M / Z: 413.1 [M+H] + .

[0840] 1 H NMR (400 MHz, DMSO-d6) δ 10.92 (s, 1H), 7.68 (d, J = 8.6 Hz, 2H), 7.59 - 7.46 (m, 2H), 7.40 (d, J = 6.8 Hz, 1H), 7.33 (t, J = 7.5 Hz, 3H), 6.43 (dd, J = 19.2, 8.0 Hz, 2H), 5.51 (s, 1H), 4.41 (s, 1H), 4.34 (dd, J = 11.4, 4.8 Hz, 1H), 3.93 (d, J = 4.5 Hz, 2H), 2.84 - 2.70 (m, 1H), 2.56 (d, J = 4.0 Hz, 1H), 2.39 (d, J = 12.7 Hz, 1H), 2.13 - 2.00 (m, 1H).

[0841] Example 49: 3-(2-ethynyl-4'-(6-(methoxymethyl)-2-oxopyridin-1(2H)-yl)-(1,1'-biphenyl)-3-yl)piperidine-2,6-dione

[0842] Reference to the preparation method of other embodiments of the present application to obtain 7.6 mg of 3-(2-ethynyl-4'-(6-(hydroxymethyl)-2-oxopyridin-1(2H)-yl)-(1,1'-biphenyl)-3-yl)piperidine-2,6-dione.

[0843] MS (ESI) M / Z: 413.1 [M+H] + .

[0844] 1H NMR (400 MHz, DMSO-d6) δ 10.92 (s, 1H), 7.66 (d, J = 8.4 Hz, 2H), 7.57 - 7.46 (m, 2H), 7.40 (d, J = 7.4 Hz, 1H), 7.34 (dd, J = 8.4, 2.5 Hz, 3H), 6.47 (d, J = 9.2 Hz, 1H), 6.40 (d, J = 6.7 Hz, 1H), 4.40 (s, 1H), 4.34 (dd, J = 11.7, 4.9 Hz, 1H), 3.92 (s, 2H), 3.06 (s, 3H), 2.82 - 2.70 (m, 1H), 2.56 (d, J = 3.7 Hz, 1H), 2.39 (d, J = 11.9 Hz, 1H), 2.14 - 2.02 (m, 1H).

[0845] Example 50: 3-(2-chloro-3-(4-((1-methyl-1H-pyrazol-3-yl)methyl)-3,4- dihydrospiro(benzo[b][1,4]oxazine-2,1 '-cyclopropan)-7-yl)phenyl)piperidine-2,6-dione

[0846] Reaction Scheme:

[0847] Reference to the preparation method of other embodiments of the application, 12 mg of 3-(2-chloro-3-(4-((1-methyl-1H-pyrazol-3-yl)methyl)-3,4- dihydrospiro(benzo[b][1,4]oxazine-2,1 '-cyclopropan)-7-yl)phenyl)piperidine-2,6-dione was obtained.

[0848] MS (ESI) M / Z: 477.1 [M+H] + .

[0849] 1 H NMR (400 MHz, DMSO-d6) δ 10.90 (s, 1H), 7.59 (d, J = 2.0 Hz, 1H), 7.34 - 7.28 (m, 1H), 7.27 - 7.21 (m, 2H), 6.94 (d, J = 8.4 Hz, 1H), 6.83 - 6.81 (m, 1H), 6.66 (d, J = 2.0 Hz, 1H), 6.16 (d, J = 2.0 Hz, 1H), 4.43 (s, 2H), 4.30 (dd, J = 12.0, 5.0 Hz, 1H), 3.79 (s, 3H), 3.40 (s, 2H), 2.82 - 2.71 (m, 1H), 2.56 - 2.53 (m, 1H), 2.37 - 2.24 (m, 1H), 2.05 - 2.01 (m, 1H), 0.92 (t, J = 6.0 Hz, 2H), 0.73 (t, J = 6.4 Hz, 2H).

[0850] Example 51: 2'-chloro-3'-(2,6-dioxopiperidin-3-yl)-3-methyl-[1,1'-biphenyl]-4- ylpyrrolidine-1-carboxylate

[0851] Reaction Scheme:

[0852] Procedure:

[0853] Step A: 4-bromo-2-methylphenol (100 mg, 0.53 mmol) was dissolved in acetonitrile (2 mL), pyrrolidine-1-carboxylic acid chloride (85.5 mg, 0.64 mmol) and potassium carbonate (111 mg, 0.80 mmol) were added, the reaction was stirred at 80 °C for 6 hours.

[0854] LCMS monitoring showed the disappearance of the starting material, water (30 mL) was added to quench, extracted with ethyl acetate (20 mL x 3), the organic phase was combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, the obtained crude was purified by column chromatography to give 110 mg of 4-bromo-2-methylphenyl pyrrolidine-1-carboxylate.

[0855] MS (ESI) M / Z: 284.0 [M+H] + .

[0856] Step B: 4-bromo-2-methylphenyl pyrrolidine-1-carboxylate (45 mg, 0.16 mmol) was dissolved in 1,4-dioxane (1 mL) and water (0.2 mL), INT-2 (61 mg, 0.17 mmol), (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride (12 mg, 0.02 mmol) and potassium carbonate (55 mg, 0.40 mmol) were added, replaced with nitrogen three times, reacted under microwave conditions at 90 °C for half an hour.

[0857] LCMS monitoring showed the disappearance of the starting material, water (30 mL) was added to quench, extracted with ethyl acetate (20 mL x 3), the organic phase was combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, the obtained crude was purified by high performance liquid chromatography to give 26.46 mg of 2'-chloro-3'-(2,6-dioxopiperidin-3-yl)-3-methyl-(1,1'-biphenyl)-4-ylpyrrolidine-1-carboxylate.

[0858] MS (ESI) M / Z: 427.2 [M+H] + .

[0859] 1H NMR (400 MHz, DMSO-d6) δ 10.92 (s, 1H), 7.47 - 7.33 (m, 2H), 7.33 - 7.27 (m, 2H), 7.23 (dd, J = 8.3, 2.2 Hz, 1H), 7.15 (d, J = 8.2 Hz, 1H), 4.34 (dd, J = 12.2, 5.1 Hz, 1H), 3.58 - 3.52 (m, 2H), 3.39 - 3.33 (m, 2H), 2.84 - 2.74 (m, 1H), 2.58 - 2.54 (m, 1H), 2.41 - 2.26 (m, 1H), 2.20 (s, 3H), 2.09 - 2.01 (m, 1H), 1.99 - 1.82 (m, 4H).

[0860] Example 52: 3-(2-chloro-4'-(2-oxopiperidin-1-yl)-(1,1'-biphenyl)-3-yl)piperidine- 2,6-dione

[0861] Reference to the procedure of other examples of the application resulted in 281 mg of 3-(2-chloro-4'-(2-oxopiperidin-1-yl)-(1,1'-biphenyl)-3-yl)piperidine-2,6-dione.

[0862] MS (ESI) M / Z: 397.1 [M+H] + .

[0863] 1 H NMR (400 MHz, DMSO-d6) δ 10.92 (s, 1H), 7.45 - 7.31 (m, 7H), 4.35 (dd, J = 12.0, 5.0 Hz, 1H), 3.68 - 3.65 (m, 2H), 2.86 - 2.74 (m, 1H), 2.60 - 2.53 (m, 1H), 2.42 (t, J = 6.4 Hz, 2H), 2.38 - 2.29 (m, 1H), 2.10 - 2.00 (m, 1H), 1.94 - 1.80 (m, 4H).

[0864] Example 53: 3-(3-(3-acetyl-1a,2,3,7b-tetrahydro-1H-cyclopropa[c]quinolin-6-yl)-2- chlorophenyl)piperidine-2,6-dione

[0865] Scheme:

[0866] Procedure:

[0867] Step A: To a solution of 6-bromo-l,2-dihydroquinolin-2-one (2.0 g, 8.93 mmol) in N,N-dimethylformamide (20 mL) was added sodium hydride (60% dispersion in oil, 0.53 g, 13.39 mmol) at 0 °C under nitrogen atmosphere. After stirring for 10 min, l-(chloromethyl)-4-methoxybenzene (1.68 g, 10.72 mmol) was added. The reaction mixture was stirred at room temperature overnight.

[0868] LCMS monitoring showed the disappearance of starting material, the reaction mixture was diluted with water (50 mL) to quench the reaction, solid precipitated, filtered, the filter cake was slurry with (petroleum ether: ethyl acetate = 10: 1) at room temperature for 30 min, to get 2.4 g of 6-bromo-l-(4-methoxybenzyl)quinolin-2(lH)-one.

[0869] LC-MS (ESI) m / z: 346.0 [M+H] + .

[0870] Step B: To a solution of sodium hydride (60% dispersion in oil, 87 mg, 2.17 mmol) in dimethyl sulfoxide (10 mL) was added 6-bromo-l-(4-methoxybenzyl)quinolin-2(lH)-one (500 mg, 1.45 mmol) and trimethylsulfoxonium iodide (479 mg, 2.17 mmol) at room temperature. The reaction mixture was heated to 45 °C and stirred overnight.

[0871] LCMS monitoring showed the disappearance of starting material, the reaction mixture was diluted with water (30 mL) to quench the reaction, extracted with ethyl acetate (20 mL x 3), the combined organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, the obtained residue was purified by silica gel column chromatography to give 270 mg of 6-bromo-3-(4-methoxybenzyl)-l,la,3,7b-tetrahydro-2H- cyclopropa[c]quinolin-2-one.

[0872] MS (ESI) M / Z: 358.1 [M+H] + .

[0873] 1 H NMR (400 MHz, CDC13) δ 7.47 (d, J = 2.2 Hz, 1H), 7.17-7.14 (m, 1H), 7.08 (d, J = 8.5 Hz, 2H), 6.82 (d, J = 8.6 Hz, 2H), 6.70 (d, J = 8.8 Hz, 1H), 5.25-4.87 (m, 2H), 3.76 (s, 3H), 2.56-2.33 (m, 2H), 1.69-1.63 (m, 1H), 0.69 (q, J = 4.8 Hz, 1H).

[0874] Step C: 6-Bromo-3-(4-methoxybenzyl)-l,la,3,7b-tetrahydro-2H- cyclopropa[c]quinolin-2-one (200 mg, 0.56 mmol) was dissolved in trifluoroacetic acid (10 mL). The reaction was heated to 70 °C and stirred overnight.

[0875] LCMS monitoring showed the disappearance of starting material, the reaction was concentrated under reduced pressure. The obtained residue was adjusted to pH about 8 with saturated sodium bicarbonate, extracted with dichloromethane (10 mL x 3), the organic phase was combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 120 mg of 6-bromo-l,la,3,7b-tetrahydro-2H- cyclopropa[c]quinolin-2-one.

[0876] MS (ESI) M / Z: 238.0 [M+H] + .

[0877] Step D: To a solution of 6-bromo-l,la,3,7b-tetrahydro-2H- cyclopropa[c]quinolin-2-one (1.9 g, 7.98 mmol) (product from multiple batches) in tetrahydrofuran (20 mL) was added borane dimethyl sulfide (10 M, 3.9 mL, 39.90 mmol). It was stirred at 60 °C for 2 hours.

[0878] LCMS monitoring showed the disappearance of starting material, the reaction was quenched by pouring into methanol (20 mL), and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography to give 1.4 g of 6-bromo-la,2,3,7b-tetrahydro-lH-cyclopropa[c]quinoline.

[0879] LC-MS (ESI) m / z: 224.0 [M+H] + .

[0880] Step E: To a solution of 6-bromo-la,2,3,7b-tetrahydro-lH- cyclopropa[c]quinoline (500 mg, 2.23 mmol) and diisopropylethylamine (865 mg, 6.69 mmol) in dichloromethane (10 mL) was added acetyl chloride (865 mg, 6.69 mmol) dropwise at 0 °C. After the addition was completed, it was stirred at room temperature for 3 hours.

[0881] LCMS monitoring showed the disappearance of starting material, the reaction was diluted with water (30 mL), extracted with ethyl acetate (20 mL x 3), the organic phase was combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography to give 570 mg of l-(6-bromo-l,la,2,7b-tetrahydro-3H- cyclopropa[c]quinolin-3-yl)ethan-l-one.

[0882] MS (ESI) M / Z: 266.0 [M+H] + .

[0883] Step F: To a solution of 1-(6-bromo-1,1a,2,7b-tetrahydro-3H-cyclopropane[c]quinolin-3- yl)ethan-1-one (50 mg, 0.19 mmol) and INT-2 (100 mg, 0.29 mmol) in 1,4-dioxane (10 mL) and water (1 mL) was added (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride (14 mg, 0.019 mmol) and potassium carbonate (79 mg, 0.57 mmol). The air was replaced by nitrogen for three times and heated to 90 °C with stirring for 2 h.

[0884] LCMS monitoring showed the disappearance of starting material, the reaction solution was diluted with water (10 mL) and extracted with dichloromethane (10 mL x 3), the organic phase was combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained crude product was purified by C18 column chromatography to give 21 mg of 3-(3-(3-acetyl-1a,2,3,7b-tetrahydro-1H-cyclopropane[c]quinolin-6-yl)-2-chlorophenyl)piperidine-2,6-dione.

[0885] MS (ESI) M / Z: 409.1 [M+H] + .

[0886] 1 H NMR (400 MHz, DMSO-d6) δ 10.92 (s, 1H), 7.55-7.26 (m, 5H), 7.18 (d, J = 7.6 Hz, 1H), 4.89 (s, 1H), 4.37-4.33 (m, 1H), 2.88-2.74 (m, 1H), 2.59-2.52 (m, 2H), 2.41-2.26 (m, 1H), 2.21-2.01 (m, 5H), 1.95 (s, 1H), 1.06-0.99 (m, 1H), 0.59-0.54 (m, 1H).

[0887] Example 54: 3-(2-chloro-3-(4-oxo-4,5-dihydro-2H-spiro[benzo[b][1,4]oxazepine-3,1'- cyclopropane]-8-yl)phenyl)piperidine-2,6-dione

[0888] Reference to the preparation method of other embodiments of the application, 52.1 mg of 3-(2-chloro-3-(4-oxo-4,5-dihydro-2H-spiro[benzo[b][1,4]oxazepine-3,1'-cyclopropane]-8- yl)phenyl)piperidine-2,6-dione was obtained.

[0889] MS (ESI) M / Z: 411.0 [M+H] +.

[0890] 1 H NMR (400 MHz, DMSO-d6) δ 10.91 (s, 1H), 10.05 (s, 1H), 7.40-7.27 (m, 3H), 7.23 (d, J = 8.0 Hz, 1H), 7.02-6.98 (m, 1H), 6.96 (d, J = 2.0 Hz, 1H), 4.38-4.28 (m, 1H), 4.08 (s, 2H), 2.84-2.73 (m, 1H), 2.58-2.52 (m, 1H), 2.38-2.26 (m, 1H), 2.09-1.99 (m, 1H), 1.29-1.23 (m, 2H), 0.99-0.92 (m, 2H).

[0891] Example 55: 2'-chloro-3'-(2,6-dioxopiperidin-3-yl)-(1,1'-biphenyl)-4- yl dimethylformamide

[0892] Reaction Scheme:

[0893] Procedure:

[0894] Step A: 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (200 mg, 0.91 mmol) was dissolved in acetonitrile (2 mL), dimethylcarbamoyl chloride (293 mg, 2.73 mmol) and potassium carbonate (627 mg, 4.55 mmol) were added, and the reaction was stirred at 80 °C for 6 hours.

[0895] LCMS monitoring showed that the starting material was consumed, water (30 mL) was added to quench, extracted with ethyl acetate (30 mL x 3), the combined organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the obtained crude was purified by silica gel column chromatography to give 210 mg of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl dimethylformamide.

[0896] MS (ESI) M / Z: 292.2 [M+H] + .

[0897] Step B: Dissolve 3-(3-bromo-2-chlorophenyl)piperidine-2,6-dione (50 mg, 0.17 mmol) in 1,4-dioxane (1 mL) and water (0.2 mL), add INT-1 (58 mg, 0.20 mmol), (1,1'- bis(diphenylphosphino)ferrocene)palladium(II) dichloride (12 mg, 0.02 mmol) and potassium carbonate (57 mg, 0.41 mmol), replace with nitrogen for three times, microwave at 90 °C for half an hour.

[0898] LCMS monitoring shows the disappearance of starting material, quench with water (20 mL), extract with ethyl acetate (30 mL x 3), wash the combined organic phase with saturated brine (30 mL x 2), dry over anhydrous sodium sulfate, filter, concentrate under reduced pressure, purify the obtained crude product by high performance liquid chromatography to obtain 15.22 mg of 2'-chloro-3'-(2,6-dioxopiperidin-3-yl)-(1,1'-biphenyl)-4- yl dimethylcarboxamide.

[0899] MS (ESI) M / Z: 387.2 [M+H] + .

[0900] 1 H NMR (400 MHz, DMSO-d6) δ 10.92 (s, 1H), 7.51 - 7.29 (m, 5H), 7.26 - 6.95 (m, 2H), 4.35 (dd, J = 12.2, 5.1 Hz, 1H), 3.07 (s, 3H), 2.93 (s, 3H), 2.84 - 2.74 (m, 1H), 2.56 (d, J = 3.9 Hz, 1H), 2.33 (d, J = 2.1 Hz, 1H), 2.10 - 2.00 (m, 1H).

[0901] Example 56: 2'-chloro-3'-(2,6-dioxopiperidin-3-yl)-3-fluoro-(1,1'-biphenyl)-4- yl pyrrolidine-1-carboxylate

[0902] Reference to the preparation method of other embodiments of the application, 22.63 mg of 2'-chloro-3'-(2,6-dioxopiperidin-3-yl)-3-fluoro-(1,1'-biphenyl)-4-yl pyrrolidine-1- carboxylate is obtained.

[0903] MS (ESI) M / Z: 431.2 [M+H] + .

[0904] 1H NMR (400 MHz, DMSO-d6) δ 10.93 (s, 1H), 7.46 - 7.32 (m, 5H), 7.24 (d, J = 8.5 Hz, 1H), 4.35 (dd, J = 12.2, 5.1 Hz, 1H), 3.58 - 3.50 (m, 2H), 2.91 - 2.72 (m, 1H), 2.56 (s, 3H), 2.34 (d, J = 11.7 Hz, 1H), 2.04 (d, J = 12.9 Hz, 1H), 1.98 - 1.82 (m, 4H).

[0905] Example 57: 3-(2-chloro-3-(1-(1-methyl-1H-pyrazol-3-yl)methyl)-2-oxo-2,3,4- 5-tetrahydro-1H-benzo[d][1,3]diazepin-7-yl)phenyl)piperidine-2,6-dione

[0906] Reference to the procedure for preparing the other examples of the application resulted in 34.24 mg of 3-(2-chloro-3-(1-(1-methyl-1H-pyrazol-3-yl)methyl)-2-oxo-2,3,4- 5-tetrahydro-1H-benzo[d][1,3]diazepin-7-yl)phenyl)piperidine-2,6-dione.

[0907] MS (ESI) M / Z: 478.2 [M+H] + .

[0908] 1 H NMR (400 MHz, DMSO-d6) δ 10.91 (s, 1H), 7.52 (d, J = 2.2 Hz, 1H), 7.44 - 7.28 (m, 4H), 7.24 (d, J = 6.5 Hz, 2H), 6.27 (d, J = 3.1 Hz, 1H), 6.05 (d, J = 2.2 Hz, 1H), 4.91 (s, 2H), 4.33 (dd, J = 12.2, 5.0 Hz, 1H), 3.74 (s, 3H), 3.35 (d, J = 8.2 Hz, 2H), 2.96 (t, J = 5.9 Hz, 2H), 2.79 (ddd, J = 17.5, 12.8, 5.3 Hz, 1H), 2.55 (d, J = 3.7 Hz, 1H), 2.37 - 2.26 (m, 1H), 2.13 - 1.93 (m, 1H).

[0909] Example 58: 8-(2-chloro-3-(2,6-dioxopiperidin-3-yl)phenyl)-3,4-dihydrobenzo[b][1,4]oxazepine-5(2H)-carboxylic acid methyl ester

[0910] Procedure:

[0911] 8-Bromo-2,3,4,5-tetrahydrobenzo[b][l,4]oxazepine was prepared according to Reference Example 13.

[0912] Step A: To a solution of 8-bromo-2,3,4,5-tetrahydrobenzo[b][l,4]oxazepine (150 mg, 0.66 mmol) in N,N-dimethylformamide (6 mL) was added potassium carbonate (183 mg, 1.32 mmol) and methyl chloroformate (310 mg, 3.3 mmol) at 0 °C. The reaction was stirred at 80 °C for 2 h.

[0913] LCMS monitoring showed the disappearance of starting material. The reaction was diluted with water (50 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography to give 140 mg of 8-bromo-3,4-dihydrobenzo[b][l,4]oxazepine-5(2H)-carboxylic acid methyl ester.

[0914] MS (ESI) M / Z: 286.1 [M+H] + .

[0915] Step B: To a solution of 8-bromo-3,4-dihydrobenzo[b][l,4]oxazepine-5(2H)-carboxylic acid methyl ester (40 mg, 0.14 mmol) in 1,4-dioxane (5 mL) and water (0.5 mL) was added INT-2 (74 mg, 0.21 mmol), sodium bicarbonate (24 mg, 0.28 mmol) and (l,l’-bis(diphenylphosphino)ferrocene)palladium(II) dichloride (15 mg, 0.02 mmol). The air was replaced by nitrogen for three times. It was stirred at 90 °C for 4 h.

[0916] LCMS monitoring showed the reaction was complete. The reaction was diluted with water (10 mL) and extracted with dichloromethane (10 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained crude product was purified by high performance liquid chromatography to give 12.86 mg of 8-(2-chloro-3-(2,6-dioxopiperidin-3-yl)phenyl)-3,4-dihydrobenzo[b][l,4]oxazepine-5(2H)-carboxylic acid methyl ester.

[0917] MS (ESI) M / Z: 429.0 [M+H] + .

[0918] 1H NMR (400 MHz, DMSO-d6) δ 10.93 (s, 1H), 7.42-7.31 (m, 4H), 7.12-7.07 (m, 1H), 7.06 (s, 1H), 4.45-4.28 (m, 1H), 4.09 (s, 2H), 3.80-3.55 (m, 5H), 2.87-2.74 (m, 1H), 2.59-2.53 (m, 1H), 2.41-2.26 (m, 1H), 2.10-1.93 (m, 3H).

[0919] Example 59: 3-(4'-(l,4-dimethyl-2-oxo-l,2-dihydropyridin-3-yl)-2-ethynyl- [l,l'-biphenyl]-3-yl)piperidine-2,6-dione

[0920] Reference to the procedure of other examples of the application resulted in 29 mg of 3-(4'-(l,4-dimethyl-2-oxo-l,2-dihydropyridin-3-yl)-2-ethynyl- [l,l'-biphenyl]-3-yl)piperidine-2,6-dione.

[0921] MS (ESI) M / Z: 411.1 [M+H] + .

[0922] 1 H NMR (400 MHz, DMSO-d6) δ 10.91 (s, 1H), 7.61 (d, J=6.9 Hz, 1H), 7.58-7.54 (m, 2H), 7.47 (t, J=7.7 Hz, 1H), 7.38-7.36 (m, 1H), 7.32-7.25 (m, 3H), 6.22 (d, J=7.0 Hz, 1H), 4.37 (s, 1H), 4.35-4.31 (m, 1H), 3.44 (s, 3H), 2.82-2.70 (m, 1H), 2.53 (d, J=6.8 Hz, 1H), 2.44-2.30 (m, 1H), 2.11-2.05 (m, 1H), 2.03 (s, 3H).

[0923] Example 60: 2'-chloro-3'-(2,6-dioxopiperidin-3-yl)-[l,l'-biphenyl]-4-yl-(2S)-2- methylpyrrolidine-l-carboxylate

[0924] Reference to the procedure of other examples of the application resulted in 2.80 mg of 2'-chloro-3'-(2,6-dioxopiperidin-3-yl)-[l,l'-biphenyl]-4-yl-(2S)-2- methylpyrrolidine-l-carboxylate.

[0925] MS (ESI) M / Z: 427.2 [M+H] + .

[0926] 1 H NMR (400 MHz, DMSO-d6) δ 10.92 (s, 1H), 7.48 - 7.28 (m, 5H), 7.26 - 7.16 (m, 2H), 4.35 (dd, J = 12.2, 5.1 Hz, 1H), 4.10 - 3.92 (s, 1H), 3.54 (d, J = 9.2 Hz, 1H), 3.38 (q, J = 8.4, 7.2 Hz, 1H), 2.84 - 2.74 (m, 1H), 2.56 (d, J = 3.8 Hz, 1H), 2.41 - 2.33 (m, 1H), 2.24 - 1.76 (m, 4H), 1.61 (s, 1H), 1.23 (dd, J = 31.5, 6.3 Hz, 3H).

[0927] Example 61: 2'-chloro-3'-(2,6-dioxopiperidin-3-yl)-[1,1'-biphenyl]-4-yl 4- azaspiro[2.4]heptane-4-carboxylate

[0928] Reference to the procedure of other examples of the application resulted in 27 mg of 2'-chloro-3'-(2,6-dioxopiperidin-3-yl)-[1,1'-biphenyl]-4-yl 4- azaspiro[2.4]heptane-4-carboxylate.

[0929] MS (ESI) M / Z: 439.0 [M+H] + .

[0930] 1 H NMR (400 MHz, DMSO-d6) δ 10.92 (s, 1H), 7.42 - 7.35 (m, 4H), 7.32 - 7.29 (m, 1H), 7.18 - 7.16 (m, 2H), 4.36 - 4.32 (m, 1H), 3.72 (s, 2H), 2.85 - 2.73 (m, 1H), 2.57 - 2.55 (m, 1H), 2.38 - 2.29 (m, 1H), 2.09 - 2.01 (m, 1H), 1.95 - 1.92 (m, 4H), 1.56 (s, 2H), 0.55 (s, 2H).

[0931] Example 62: 3-(2-chloro-3-(4-(1-methyl-1H-pyrazol-3-yl)methyl)-3-oxo-3,4- dihydrospiro[benzo[b][1,4]oxazine-2,1'-cyclopropane]-7-yl)phenyl)piperidine-2,6- dione

[0932] Reference to the preparation method of other embodiments of the application obtained 38 mg 3-(2-chloro-3-(4-(1-methyl-1H-pyrazol-3-yl)methyl)-3-oxo-3,4-dihydrospiro[benzo[b][1,4]oxazine-2,1'-cyclopropan]-7-yl)phenyl)piperidine-2,6-dione.

[0933] MS (ESI) M / Z: 491.0 [M+H] + .

[0934] 1 H NMR (400 MHz, DMSO-d6) δ 10.91 (s, 1H), 7.61 (d, J = 2.0 Hz, 1H), 7.41 - 7.24 (m, 4H), 7.10 - 7.08 (m, 1H), 6.96 (d, J = 8.4 Hz, 1H), 6.09 (d, J = 2.0 Hz, 1H), 5.08 (s, 2H), 4.32 (dd, J = 12.0, 4.9 Hz, 1H), 3.80 (s, 3H), 2.84 - 2.72 (m, 1H), 2.57 - 2.54 (m, 1H), 2.36 - 2.27 (m, 1H), 2.08 - 1.97 (m, 1H), 1.35 - 1.31 (m, 2H), 1.27 - 1.24 (m, 2H).

[0935] Example 63: 2'-chloro-3'-(2,6-dioxopiperidin-3-yl)-3-methyl-[1,1'-biphenyl]-4-yl-(2S)-2-(hydroxymethyl)pyrrolidine-1-carboxylate

[0936] Reference to the preparation method of other embodiments of the application obtained 9.44 mg 2'-chloro-3'-(2,6-dioxopiperidin-3-yl)-3-methyl-[1,1'-biphenyl]-4-yl-(2S)-2-(hydroxymethyl)pyrrolidine-1-carboxylate.

[0937] MS (ESI) M / Z: 457.2 [M+H] + .

[0938] 1H NMR (400 MHz, DMSO-d6) δ 10.91 (s, 1H), 7.50-7.27 (m, 4H), 7.23 (dd, J = 8.2, 2.3 Hz, 1H), 7.19-7.12 (m, 1H), 4.90-4.78 (m, 1H), 4.34 (dd, J = 12.2, 5.0 Hz, 1H), 3.91 (d, J = 77.8 Hz, 1H), 3.70-3.60 (m, 1H), 3.60-3.50 (m, 1H), 3.50-3.45 (m, 1H), 3.44-3.35 (m, 1H), 2.84-2.74 (m, 1H), 2.58-2.54 (m, 1H), 2.42-2.27 (m, 1H), 2.20 (d, J = 3.8 Hz, 3H), 2.11-1.81 (m, 5H).

[0939] Example 64: 2'-Chloro-3'-(2,6-dioxopiperidin-3-yl)-3-methyl-[1,1'-biphenyl]-4-yl-(2R)-2-(hydroxymethyl)pyrrolidine-1-carboxylate

[0940] Reference to the procedure of other examples of the application resulted in 3.37 mg of 2'-chloro-3'-(2,6-dioxopiperidin-3-yl)-3-methyl-[1,1'-biphenyl]-4-yl-(2R)-2-(hydroxymethyl)pyrrolidine-1-carboxylate.

[0941] MS (ESI) M / Z: 457.2 [M+H] + .

[0942] 1 H NMR (400 MHz, DMSO-d6) δ 10.91 (s, 1H), 7.42-7.28 (m, 4H), 7.25-7.21 (m, 1H), 7.15 (d, J = 8.2 Hz, 1H), 4.92-4.73 (m, 1H), 4.34 (dd, J = 12.2, 5.1 Hz, 1H), 4.10-3.75 (m, 1.5H), 3.70-3.35 (m, 3.5H), 2.85-2.73 (m, 1H), 2.61-2.53 (m, 1H), 2.41-2.33 (m, 1H), 2.24-2.16 (m, 3H), 2.11-1.78 (m, 5H).

[0943] Example 65: 2'-Chloro-3'-(2,6-dioxopiperidin-3-yl)-3-methyl-[1,1'-biphenyl]-4- yldimethylformamide

[0944] Reaction Scheme:

[0945] Procedure:

[0946] Step A: 2-methyl-4-(4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2-yl) phenol (150 mg, 0.64 mmol) was dissolved in acetonitrile (2 mL), dimethylcarbamoyl chloride (206 mg, 1.92 mmol) and potassium carbonate (442 mg, 3.20 mmol) were added under ice water bath condition, stirred at 80 °C for 6 hours.

[0947] LCMS monitoring showed the disappearance of starting material, quenched by water (20 mL), extracted by ethyl acetate (20 mL x 3), combined organic phase, washed by saturated brine (30 mL), dried by anhydrous sodium sulfate, filtered, concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography to give 160 mg of 2-methyl-4-(4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2-yl) phenyl dimethylformamide.

[0948] MS (ESI) M / Z: 306.2 [M+H] + .

[0949] Step B: INT-1 (50 mg, 0.17 mmol) was dissolved in 1, 4-dioxane (1 mL) and water (0.2 mL), 2-methyl-4-(4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2-yl) phenyl dimethylformamide (61 mg, 0.20 mmol), (1, l'-bis(diphenylphosphino) ferrocene) dichloropalladium (II) (12 mg, 0.02 mmol) and potassium carbonate (57 mg, 0.41 mmol) were added, replaced by nitrogen for three times, reacted for half an hour under microwave condition at 90 °C.

[0950] LCMS monitoring showed the disappearance of starting material, quenched by water (20 mL), extracted by ethyl acetate (20 mL x 3), combined organic phase, washed by saturated brine (30 mL x 2), dried by anhydrous sodium sulfate, filtered, concentrated under reduced pressure. The obtained crude product was purified by high performance liquid chromatography to give 38.58 mg of 2'-chloro-3'-(2, 6-dioxopiperidin-3-yl)-3-methyl-[l,l'-bi- nyl]-4-yl dimethylformamide.

[0951] MS (ESI) M / Z: 401.1 [M+H] + .

[0952] 1H NMR (400 MHz, DMSO-d6) δ 10.91 (s, 1H), 7.43 - 7.34 (m, 2H), 7.33 - 7.28 (m, 2H), 7.23 (dd, J = 8.2, 2.3 Hz, 1H), 7.13 (d, J = 8.3 Hz, 1H), 4.40 - 4.30 (m, 1H), 3.10 (s, 3H), 2.94 (s, 3H), 2.84 - 2.74 (m, 1H), 2.56 (d, J = 3.9 Hz, 1H), 2.39 - 2.32 (m, 1H), 2.18 (s, 3H), 2.08 - 2.00 (m, 1H).

[0953] Example 67: 2-(8-(2-chloro-3-(2,6-dioxopiperidin-3-yl)phenyl)-4-oxo- 3,4-dihydrobenzo[b][l,4]oxazepin-5(2H)-yl)-N-methylacetamide

[0954] Reference to the procedure of other examples of the application resulted in 52.61 mg of 2-(8-(2-chloro-3-(2,6-dioxopiperidin-3-yl)phenyl)-4-oxo- 3,4-dihydrobenzo[b][l,4]oxazepin-5(2H)-yl)-N-methylacetamide.

[0955] MS (ESI) M / Z: 445.9 [M+H] + .

[0956] 1 H NMR (400 MHz, DMSO-d6) δ 10.93 (s, 1H), 8.13 - 7.91 (m, 1H), 7.44 - 7.32 (m, 4H), 7.30 - 7.26 (m, 1H), 7.18 (d, J = 2.0 Hz, 1H), 4.53 (t, J = 6.4 Hz, 2H), 4.39 - 4.32 (m, 1H), 4.28 (s, 2H), 2.87 - 2.73 (m, 1H), 2.69 - 2.62 (m, 5H), 2.58 - 2.52 (m, 1H), 2.41 - 2.26 (m, 1H), 2.11 - 1.98 (m, 1H).

[0957] Example 69: 3-(2-ethynyl-4'-(4-(methoxymethyl)-l-methyl-2-oxo- 1,2-dihydropyridin-3-yl)-[l,l'-biphenyl]-3-yl)piperidine-2,6-dione

[0958] Reference to the preparation method of other embodiments of the present application obtained 19 mg of 3-(2-ethynyl-4'-(4-(methoxymethyl)-1-methyl-2-oxo-1,2-dihydro- pyridin-3-yl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione.

[0959] MS (ESI) M / Z: 441.4 [M+H] + .

[0960] 1 H NMR (400 MHz, DMSO-d6) δ 10.91 (s, 1H), 7.73 (d, J = 6.8 Hz, 1H), 7.57 (d, J = 8.4 Hz, 2H), 7.49-7.46 (m, 1H), 7.40-7.36 (m, 1H), 7.32-7.27 (m, 3H), 6.39 (d, J = 7.2 Hz, 1H), 4.37 (s, 1H), 4.36-4.31 (m, 1H), 4.13 (s, 2H), 3.47 (s, 3H), 3.21 (s, 3H), 2.82-2.70 (m, 1H), 2.57-2.52 (m, 1H), 2.42-2.33 (m, 1H), 2.11-2.03 (m, 1H).

[0961] Example 70: 3-(2-chloro-3-(5-(1-methyl-1H-pyrazole-3-carbonyl)-2,3,4- 5-tetrahydrobenzo[b][1,4]oxazepin-8-yl)phenyl)piperidine-2,6-dione

[0962] Reference to the preparation method of other embodiments of the present application obtained 24 mg of 3-(2-chloro-3-(5-(1-methyl-1H-pyrazole-3-carbonyl)-2,3,4- 5-tetrahydrobenzo[b][1,4]oxazepin-8-yl)phenyl)piperidine-2,6-dione.

[0963] MS (ESI) M / Z: 479.0 [M+H] + .

[0964] 1 H NMR (400 MHz, CDCl3) δ 7.97 (s, 1H), 7.36-7.28 (m, 2H), 7.26-7.15 (m, 2H), 7.10 (s, 1H), 6.90 (s, 2H), 5.81 (s, 1H), 4.67-3.55 (m, 6H), 3.30-1.65 (m, 8H).

[0965] Example 71: 3-(3-(5-acetyl-2,3,4-5-tetrahydrobenzo[b][l,4]oxazepin-8-yl)-2- chlorophenyl)piperidine-2,6-dione

[0966] Reference to the procedure for preparing other embodiments of the application resulted in 24 mg of 3-(3-(5-acetyl-2,3,4-5-tetrahydrobenzo[b][l,4]oxazepin-8-yl)-2- chlorophenyl)piperidine-2,6-dione.

[0967] MS (ESI) M / Z: 413.0 [M+H] + .

[0968] 1 H NMR (400 MHz, DMSO-d6) δ 10.93 (s, 1H), 7.49 - 7.26 (m, 4H), 7.20 - 7.02 (m, 2H), 4.77 - 4.50 (m, 1H), 4.37 - 4.33 (m, 1H), 3.95 - 3.67 (m, 1H), 2.92 - 2.64 (m, 2H), 2.61 - 2.51 (m, 3H), 2.39 - 2.28 (m, 1H), 2.13 - 1.95 (m, 2H), 1.87 (s, 3H).

[0969] Example 72: 3-(3-(4-acetyl-3,4-dihydro-2H-benzo[b][l,4]thiazin-7-yl)-2-chlorophenyl)piperidine- 2,6-dione

[0970] Reference to the procedure for preparing other embodiments of the application resulted in 43 mg of 3-(3-(4-acetyl-3,4-dihydro-2H-benzo[b][l,4]thiazin-7-yl)-2-chlorophenyl)piperidine- 2,6-dione.

[0971] MS (ESI) M / Z: 415.0 [M+H] + .

[0972] 1H NMR (400 MHz, DMSO-d6) δ 10.92 (s, 1H), 7.47 (d, J = 8.3 Hz, 1H), 7.42 - 7.30 (m, 3H), 7.24 (s, 1H), 7.14 (d, J = 8.5 Hz, 1H), 4.34 (dd, J = 12.2, 5.0 Hz, 1H), 3.98 - 3.84 (m, 2H), 3.25 (s, 2H), 2.86 - 2.73 (m, 1H), 2.59 - 2.53 (m, 1H), 2.38 - 2.27 (m, 1H), 2.17 (s, 3H), 2.09 - 2.00 (m, 1H).

[0973] Example 73: 3-(2-chloro-4'-(5-cyclopropyloxy-2-oxopyridin-l(2H)-yl)-[l,l'-biphenyl]-3-yl)piperidine-2,6-dione

[0974] Reference to the procedure of other examples of the invention resulted in 51 mg of 3-(2-chloro-4'-(5-cyclopropyloxy-2-oxopyridin-l(2H)-yl)-[l,l'-biphenyl]-3-yl)piperidine-2,6-dione.

[0975] MS (ESI) M / Z: 448.9 [M+H] + .

[0976] 1 H NMR (400 MHz, DMSO-d6) δ 10.94 (s, 1H), 7.58 - 7.53 (m, 4H), 7.49 - 7.33 (m, 5H), 6.50 (d, J = 9.7 Hz, 1H), 4.39 - 4.35 (m, 1H), 3.88 - 3.75 (m, 1H), 2.86 - 2.73 (m, 1H), 2.57 - 2.49 (m, 1H), 2.43 - 2.28 (m, 1H), 2.09 - 2.05 (m, 1H), 0.72 - 0.67 (m, 4H).

[0977] Example 74: 3-(4'-(6-(dimethylamino)methyl)-2-oxopyridin-l(2H)-yl)-2-ethynyl-[l,l'-biphenyl]-3-yl)piperidine-2,6-dione (formate salt)

[0978] Reference to the procedure of other examples of the invention resulted in 39.68 mg of the formate salt of 3-(4'-(6-(dimethylamino)methyl)-2-oxopyridin-l(2H)-yl)-2-ethynyl-[l,l'-biphenyl]-3-yl)piperidine-2,6-dione.

[0979] MS (ESI) M / Z: 440.1 [M+H] + .

[0980] 1 H NMR (400 MHz, DMSO-d6) δ 10.91 (s, 1H), 8.22 (s, 1H), 7.63 (d, J = 7.9 Hz, 2H), 7.55-7.45 (m, 2H), 7.43-7.23 (m, 4H), 6.43 (d, J = 9.2 Hz, 1H), 6.36 (d, J = 6.8 Hz, 1H), 4.35 (d, J = 18.2 Hz, 2H), 2.83-2.70 (m, 1H), 2.61-2.53 (m, 1H), 2.44-2.30 (m, 1H), 2.14-2.03 (m, 1H), 1.99 (s, 6H).

[0981] Example 75: 8-(2-chloro-3-(2,6-dioxopiperidin-3-yl)phenyl)-N-methyl-3,4- dihydrobenzo[b][l,4]oxazepine-5(2H)-carboxamide

[0982] Reaction Scheme:

[0983] Procedure:

[0984] The method for preparing 8-bromo-2,3,4,5-tetrahydrobenzo[b][l,4]oxazepine is Reference Example 13.

[0985] Step A: To a solution of 8-bromo-2,3,4,5-tetrahydrobenzo[b][l,4]oxazepine (150 mg, 0.66 mmol) in tetrahydrofuran (6 mL) was added triphosgene (137 mg, 0.46 mmol) and N,N-diisopropylethylamine (256 mg, 1.98 mmol) at 0 °C. After 1 hour of reaction at 0 °C, methylamine in tetrahydrofuran (2 M, 1 mL) was added slowly. Stirring at room temperature for 2 hours.

[0986] LCMS monitoring showed the disappearance of the starting material. The reaction solution was diluted with water (50 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give 130 mg of 8-bromo-N-methyl-3,4-dihydrobenzo[b][l,4]oxazepine-5(2H)-carboxamide.

[0987] MS (ESI) M / Z: 440.1 [M+H] + .

[0988] Step B: To a solution of 8-bromo-N-methyl-3,4-dihydrobenzo[b][l,4]oxazepine-5(2H)- carboxamide (80 mg, 0.28 mmol) in 1,4-dioxane (10 mL) and water (1 mL), was added INT-2 (148 mg, 0.42 mmol), sodium bicarbonate (48 mg, 0.56 mmol) and (l,l'-bis(diphenylphosphino) ferrocene)palladium(II) dichloride (22 mg, 0.03 mmol). The air was replaced by nitrogen three times. It was heated to 90 °C and stirred for 5 h.

[0989] LCMS was used to monitor the completion of the reaction. The reaction was diluted with water (10 mL) and extracted with dichloromethane (10 mL x 3). The organic phase was combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting crude product was purified by high performance liquid chromatography to give 41.57 mg of 8-(2-chloro-3-(2,6-dioxopiperidin-3-yl)phenyl)-N-methyl-3,4- dihydrobenzo[b][l,4]oxazepine-5(2H)-carboxamide.

[0990] MS (ESI) M / Z: 428.0 [M+H] + .

[0991] 1 H NMR (400 MHz, DMSO-d6) δ 10.92 (s, 1H), 7.44 - 7.23 (m, 4H), 7.12 - 7.03 (m, 2H), 6.12 - 5.89 (m, 1H), 4.40 - 4.28 (m, 1H), 4.12 - 3.98 (m, 2H), 3.68 (s, 2H), 2.86 - 2.72 (m, 1H), 2.59 (d, J=4.4 Hz, 3H), 2.57 - 2.52 (m, 1H), 2.41 - 2.27 (m, 1H), 2.13 - 2.00 (m, 1H), 2.00 - 1.86 (m, 2H).

[0992] Example 76: 8-(2-chloro-3-(2,6-dioxopiperidin-3-yl)phenyl)-N-ethyl-3,4- dihydrobenzo[b][l,4]oxazepine-5(2H)-carboxamide

[0993] Reference to the preparation method of other embodiments of the application gave 45 mg of 8-(2-chloro-3-(2,6-dioxopiperidin-3-yl)phenyl)-N-ethyl-3,4- dihydrobenzo[b][l,4]oxazepine-5(2H)-carboxamide.

[0994] MS (ESI) M / Z: 442.0 [M+H] + .

[0995] 1 H NMR (400 MHz, DMSO-d6) δ 10.92 (s, 1H), 7.43-7.29 (m, 3H), 7.25 (d, J = 8.0 Hz, 1H), 7.10-7.02 (m, 2H), 6.14 (t, J = 5.6 Hz, 1H), 4.35 (dd, J = 12.0, 4.9 Hz, 1H), 4.08-4.06 (m, 2H), 3.68 (s, 2H), 3.14-2.99 (m, 2H), 2.86-2.71 (m, 1H), 2.61-2.53 (m, 1H), 2.38-2.29 (m, 1H), 2.10-2.00 (m, 1H), 1.98-1.88 (m, 2H), 1.01 (t, J = 7.2 Hz, 3H).

[0996] Example 77: 3-(2-chloro-3-(3-methyl-l-((l-methyl-lH-pyrazol-3-yl)methyl)-2- oxo-2,3,4,5-tetrahydro-lH-benzo[d][l,3]diazepin-7-yl)phenyl)piperidine-2,6-dione

[0997] Reference to the procedure of other examples of the application resulted in 17.88 mg of 3-(2-chloro-3-(3-methyl-l-((l-methyl-lH-pyrazol-3-yl)methyl)-2- oxo-2,3,4,5-tetrahydro-lH-benzo[d][l,3]diazepin-7-yl)phenyl)piperidine-2,6-dione.

[0998] MS (ESI) M / Z: 492.2 [M+H] + .

[0999] 1 H NMR (400 MHz, DMSO-d6) δ 10.91 (s, 1H), 7.51 (d, J = 2.2 Hz, 1H), 7.427.21 (m, 6H), 6.04 (d, J = 2.2 Hz, 1H), 4.91 (s, 2H), 4.33 (dd, J = 12.2, 5.0 Hz, 1H), 3.73 (s, 3H), 3.39 (t, J = 6.4 Hz, 2H), 2.99 (t, J = 6.3 Hz, 2H), 2.84-2.74 (m, 1H), 2.62 (s, 3H), 2.58-2.54 (m, 1H), 2.37-2.26 (m, 1H), 2.13-1.99 (m, 1H).

[1000] Example 78: 3-(2-chloro-3-(3-methyl-2-oxo-2,3,4,5-tetrahydro-lH- benzo[d][l,3]diazepin-7-yl)phenyl)piperidine-2,6-dione

[1001] Reference to the preparation method of other embodiments of the application, 22.78 mg of 3-(2-chloro-3-(3-methyl-2-oxo-2,3,4,5-tetrahydro-1H benzo[d][1,3]diazepin-7-yl) phenyl) piperidine-2,6-dione was prepared.

[1002] MS (ESI) M / Z: 398.2 [M+H] + .

[1003] 1 H NMR (400 MHz, DMSO-d6) δ 10.90 (s, 1H), 8.68 (s, 1H), 7.46-7.21 (m, 3H), 7.17-6.96 (m, 3H), 4.32 (dd, J = 12.1, 5.0 Hz, 1H), 3.56-3.41 (m, 2H), 3.07-2.96 (m, 2H), 2.92 (s, 3H), 2.84-2.74 (m, 1H), 2.55 (d, J = 3.6 Hz, 1H), 2.30 (d, J = 4.2 Hz, 1H), 2.20-1.76 (m, 1H). J = 3.6 Hz, 1H), 2.30 (d, J = 4.2 Hz, 1H), 2.20-1.76 (m, 1H).

[1004] Example 79: 3-(2-chloro-4'-(3-(difluoromethoxy)-2-oxopyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl) piperidine-2,6-dione

[1005] Reaction Scheme:

[1006] Operation Steps:

[1007] Step A: To a solution of 2-chloropyridin-3-ol (2.0 g, 15.4 mmol) in N,N-dimethylformamide (40 mL) and water (5 mL), potassium carbonate (2.56 g, 18.5 mmol) and sodium 2-chloro-2,2-difluoroacetate (4.71 g, 30.8 mmol) were added, stirred at 100 °C for 2 hours.

[1008] LCMS monitoring showed that the raw material was disappeared, diluted with water (100 mL), extracted with ethyl acetate (50 mL x 3), the combined organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give 1.9 g of 2-chloro-3-(difluoromethoxy)pyridine.

[1009] MS (ESI) M / Z: 180.0 [M+H] + .

[1010] Step B: To a solution of 2-chloro-3-(difluoromethoxy)pyridine (1.9 g, 10.61 mmol) and acetoxy hydroxamic acid (7.96 g, 106.1 mmol) in dimethyl sulfoxide (30 mL) and water (6 mL) was added sodium hydroxide (4.24 g, 106.1 mmol). The air was replaced by nitrogen three times. It was stirred at 100 °C for 16 h.

[1011] LCMS was used to monitor the reaction completion. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by C18 column to give 1.2 g of 3-(difluoromethoxy)pyridine-2(lH)-one.

[1012] MS (ESI) M / Z: 162.2 [M+H] + .

[1013] Step C: To a solution of 3-(difluoromethoxy)pyridine-2(lH)-one (300 mg, 1.86 mmol) and 4-bromobenzenboronic acid (372.7 mg, 1.86 mmol) in dichloromethane (10 mL) was added copper acetate (337.3 mg, 1.86 mmol) and triethylamine (564.6 mg, 5.58 mmol). The air was replaced by nitrogen three times. It was stirred at room temperature for 16 h.

[1014] LCMS was used to monitor the reaction completion. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 260 mg of l-(4-bromophenyl)-3-(difluoromethoxy)pyridine-2(lH)-one.

[1015] MS (ESI) M / Z: 318.0 [M+H] + .

[1016] Step D: To a solution of l-(4-bromophenyl)-3-(difluoromethoxy)pyridine-2(lH)-one (90 mg, 0.28 mmol) and INT-2 (150 mg, 0.42 mmol) in 1,4-dioxane (10 mL) and water (1 mL) was added (l,l'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride (11 mg, 14 μmol) and potassium carbonate (79 mg, 0.56 mmol). The air was replaced by nitrogen three times. It was stirred at 90 °C for 2 h.

[1017] LCMS was used to monitor the reaction completion. The reaction was diluted with water (10 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by high performance liquid chromatography to give 64 mg of 3-(2-chloro-4'-(3-(difluoromethoxy)-2-oxopyridin-l(2H)-yl)-[l,l'-biphenyl]-3-yl)piperidine-2,6-dione

[1018] MS (ESI) M / Z: 458.9 [M+H] + .

[1019] 1 H NMR (400 MHz, DMSO-d6) δ 10.94 (s, 1H), 7.72-7.70 (m, 1H), 7.60-7.52 (m, 4H), 7.48-7.01 (m, 5H), 6.36 (t, J = 7.2 Hz, 1H), 4.40-4.35 (m, 1H), 2.86-2.75 (m, 1H), 2.58-2.52 (m, 1H), 2.41-2.30 (m, 1H), 2.09-2.05 (m, 1H).

[1020] Example 80: 3-(2-chloro-3-(1'-methyl-2'-oxo-2H-spiro[benzofuran-3,3'-pyrrolin]-6- yl)phenyl)piperidine-2,6-dione

[1021] Reference to the method of preparation of other embodiments of the application resulted in 5.34 mg of 3-(2-chloro-3-(1'-methyl-2'-oxo-2H-spiro[benzofuran-3,3'-pyrrolin]-6- yl)phenyl)piperidine-2,6-dione.

[1022] MS (ESI) M / Z: 425.1 [M+H] + .

[1023] 1 H NMR (400 MHz, DMSO-d6) δ 10.91 (s, 1H), 7.43-7.33 (m, 2H), 7.29 (dd, J = 7.0, 2.3 Hz, 1H), 7.23 (d, J = 7.7 Hz, 1H), 6.88 (d, J = 7.8 Hz, 1H), 6.82 (s, 1H), 4.70 (d, J = 9.1 Hz, 1H), 4.50 (d, J = 9.2 Hz, 1H), 4.34 (dd, J = 12.2, 5.1 Hz, 1H), 3.70-3.59 (m, 1H), 3.46-3.38 (m, 1H), 2.91-2.73 (m, 4H), 2.56 (s, 1H), 2.35-2.27 (m, 3H), 2.05 (s, 1H).

[1024] Example 81: 2'-chloro-3'-(2,6-dioxopiperidin-3-yl)-[1,1'-biphenyl]-4-yl-(3R)-3- fluoropyrrolidine-1-carboxylate

[1025] Reaction Scheme:

[1026] Reference to the preparation method of other embodiments of the application resulted in 19.91 mg of 2'-chloro-3'-(2,6-dioxopiperidin-3-yl)-[1,1'-biphenyl]-4-yl-(3R)-3- fluoropyrrolidine-1-carboxylate.

[1027] MS (ESI) M / Z: 431.0 [M+H] + .

[1028] 1 H NMR (400 MHz, DMSO-d6) δ 10.85 (s, 1H), 7.45 - 7.29 (m, 5H), 7.24 (d, J=8.2 Hz, 2H), 5.39 (dd, J=52.9, 12.1 Hz, 1H), 4.34 (dd, J=12.1, 5.1 Hz, 1H), 3.89 - 3.71 (m, 1H), 3.60 (dd, J=23.6, 12.1 Hz, 2H), 3.49 - 3.38 (m, 1H), 2.83 - 2.73 (m, 1H), 2.58 - 2.50 (m, 2H), 2.41 - 2.32 (m, 1H), 2.29 - 2.12 (m, 1H), 2.10 - 2.02 (m, 1H).

[1029] Example 82: 2'-chloro-3'-(2,6-dioxopiperidin-3-yl)-[1,1'-biphenyl]-4-yl-(3S)-3- fluoropyrrolidine-1-carboxylate

[1030] Reference to the preparation method of other embodiments of the application resulted in 19.91 mg of 2'-chloro-3'-(2,6-dioxopiperidin-3-yl)-[1,1'-biphenyl]-4-yl-(3R)-3- fluoropyrrolidine-1-carboxylate.

[1031] MS (ESI) M / Z: 431.0 [M+H] + .

[1032] 1H NMR (400 MHz, DMSO-d6) δ 10.85 (s, 1H), 7.45 - 7.30 (m, 5H), 7.24 (d, J = 8.2 Hz, 2H), 5.39 (dd, J = 52.9, 12.1 Hz, 1H), 4.34 (dd, J = 12.1, 5.1 Hz, 1H), 3.80 (dd, J = 17.4, 7.6 Hz, 1H), 3.60 (dd, J = 23.6, 12.1 Hz, 2H), 3.54 - 3.37 (m, 1H), 2.83 - 2.73 (m, 1H), 2.58 - 2.50 (m, 1H), 2.39 - 2.32 (m, 1H), 2.30 - 2.14 (m, 2H), 2.10 - 2.02 (m, 1H).

[1033] Example 83: 2'-Chloro-3'-(2,6-dioxopiperidin-3-yl)-[1,1'-biphenyl]-4-yl-(2S)-2- (hydroxymethyl)pyrrolidine-1-carboxylate

[1034] Reference to the procedure of other examples of the application resulted in 10.29 mg of 2'-Chloro-3'-(2,6-dioxopiperidin-3-yl)-[1,1'-biphenyl]-4-yl-(2S)-2- (hydroxymethyl)pyrrolidine-1-carboxylate.

[1035] MS (ESI) M / Z: 443.0 [M+H] + .

[1036] 1 H NMR (400 MHz, DMSO-d6) δ 10.90 (s, 1H), 7.45 - 7.30 (m, 5H), 7.22 (d, J = 8.6 Hz, 2H), 4.82 (d, J = 33.8 Hz, 1H), 4.35 (dd, J = 12.2, 5.0 Hz, 1H), 3.90 (d, J = 68.2 Hz, 1H), 3.65 - 3.50 (s, 2H), 3.50 - 3.34 (m, 2H), 2.84 - 2.74 (m, 1H), 2.58 - 2.54 (m, 1H), 2.40 - 2.30 (m, 1H), 2.13 - 1.76 (m, 5H).

[1037] Example 84: 2'-Chloro-3'-(2,6-dioxopiperidin-3-yl)-[1,1'-biphenyl]-4-yl-(2R)-2- (hydroxymethyl)pyrrolidine-1-carboxylate

[1038] Reference to the preparation method of other embodiments of the application obtained 6.63 mg of 2'-chloro-3'-(2,6-dioxopiperidin-3-yl)-[1,1'-biphenyl]-4-yl-(2R)-2- (hydroxymethyl)pyrrolidine-1-carboxylate.

[1039] MS (ESI) M / Z: 443.0 [M+H] + .

[1040] 1 H NMR (400 MHz, DMSO-d6) δ 10.91 (s, 1H), 7.59-7.57 (m, 2H), 7.47 (t, J = 7.6 Hz, 1H), 7.36-7.30 (m, 2H), 7.21-7.19 (m, 2H), 4.37-4.29 (m, 4H), 3.89 (s, 2H), 2.77-2.71 (m, 1H), 2.56-2.49 (m, 1H), 2.42-2.33 (m, 1H), 2.08-2.03 (m, 1H), 0.78 (t, J = 6.3 Hz, 2H), 0.58 (t, J = 6.3 Hz, 2H).

[1041] Example 85: 3-(2-ethynyl-4'-(5-oxo-7-oxa-4-azaspiro[2.5]oct-4-yl)-[1,1'-biphenyl]-3-yl)piperidine- 2,6-dione

[1042] Reaction Scheme:

[1043] Reference to the preparation method of other embodiments of the application obtained 17.93 mg of 3-(2-ethynyl-4'-(5-oxo-7-oxa-4-azaspiro[2.5]oct-4-yl)-[1,1'-biphenyl]-3-yl)piperidine- 2,6-dione.

[1044] MS (ESI) M / Z: 415.0 [M+H] + .

[1045] 1 H NMR (400 MHz, DMSO-d6) δ 10.91 (s, 1H), 7.59-7.57 (m, 2H), 7.47 (t, J = 7.6 Hz, 1H), 7.36-7.30 (m, 2H), 7.21-7.19 (m, 2H), 4.37-4.29 (m, 4H), 3.89 (s, 2H), 2.77-2.71 (m, 1H), 2.56-2.49 (m, 1H), 2.42-2.33 (m, 1H), 2.08-2.03 (m, 1H), 0.78 (t, J = 6.3 Hz, 2H), 0.58 (t, J = 6.3 Hz, 2H).

[1046] Example 86: 3-(2-chloro-3-(10-oxo-6,7,7a,8,9,10-hexahydrobenzo[b]pyrrolo[l,2- d][l,4]oxazepin-3-yl)phenyl)piperidine-2,6-dione

[1047] Reference to the procedure for preparing other embodiments of the application resulted in 19 mg of 3-(2-chloro-3-(10-oxo-6,7,7a,8,9,10-hexahydrobenzo[b]pyrrolo[l,2- d][l,4]oxazepin-3-yl)phenyl)piperidine-2,6-dione.

[1048] MS (ESI) M / Z: 425.1 [M+H] + .

[1049] 1 H NMR (400 MHz, DMSO-d6) δ 10.92 (s, 1H), 7.47 (d, J = 8.2 Hz, 1H), 7.43 - 7.27 (m, 3H), 7.13 - 7.11 (m, 1H), 7.09 - 7.02 (m, 1H), 4.45 - 4.21 (m, 2H), 4.00 - 3.70 (m, 2H), 2.89 - 2.72 (m, 1H), 2.72 - 2.55 (m, 2H), 2.44 - 2.25 (m, 3H), 2.06 - 2.02 (m, 3H), 1.87 - 1.80 (m, 1H).

[1050] Example 87: 2-(2'-chloro-3'-(2,6-dioxopiperidin-3-yl)-[l,l'-biphenyl]-4-yl)pyridine 1-oxide

[1051] Reaction Scheme:

[1052] Reference to the procedure for preparing other embodiments of the application resulted in 19 mg of 3-(2-chloro-3-(10-oxo-6,7,7a,8,9,10-hexahydrobenzo[b]pyrrolo[l,2- d][l,4]oxazepin-3-yl)phenyl)piperidine-2,6-dione.

[1053] MS (ESI) M / Z: 392.9 [M+H] + .

[1054] 1H NMR (400 MHz, DMSO-d6) δ 10.94 (s, 1H), 8.39-8.35 (m, 1H), 7.95-7.93 (m, 2H), 7.74-7.70 (m, 1H), 7.54-7.52 (m, 2H), 7.46-7.36 (m, 5H), 4.39-4.35 (m, 1H), 2.86-2.76 (m, 1H), 2.59-2.53 (m, 1H), 2.41-2.30 (m, 1H), 2.11-2.05 (m, 1H).

[1055] Example 88: 3-(2-chloro-3-(5-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)- 2,3,4-5-tetrahy drobenzo [b] [1,4] oxazepin-8-yl)phenyl)piperidine-2,6-dione

[1056] Reaction Scheme:

[1057] Operation Steps:

[1058] Step A: To a solution of 3-amino-1-methylpyridin-2(1H)-one (1.0 g, 8.06 mmol) in 1,4-dioxane (20 mL), 4-bromo-1-iodo-2-methoxybenzene (3.3 g, 10.48 mmol), cesium carbonate (4.2 g, 12.90 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (467 mg, 0.81 mmol) and tris(dibenzylideneacetone)dipalladium (370 mg, 0.40 mmol) were added. The air was replaced by nitrogen for three times. Stirring at 100 °C for 2 h.

[1059] LCMS was used to monitor the reaction completion. The reaction solution was diluted with water (50 mL) and extracted with ethyl acetate (30 mL x 3). The organic phase was combined, washed with saturated brine (30 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography to give 2.2 g of 3-((4-bromo-2-methoxyphenyl)amino)-1-methylpyridin-2(1H)-one.

[1060] MS (ESI) M / Z: 311.0 [M+H] + .

[1061] Step B: To a solution of 3-((4-bromo-2-methoxyphenyl)amino)-1-methylpyridin-2(1H)-one (2.2 g, 7.12 mmol) in dichloromethane (20 mL), boron tribromide (2.0 M, 7.2 mL, 14.4 mmol) in dichloromethane was added at 0 °C. The air was replaced by nitrogen for three times. Stirring at room temperature for 2 h.

[1062] LCMS monitoring showed the reaction was complete. The reaction solution was quenched with saturated sodium bicarbonate solution (20 mL), extracted with dichloromethane (30 mL x 3), the organic phase was combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography to give 1.9 g of 3-((4-bromo-2-hydroxyphenyl)amino)-1-methylpyridin-2(1H)-one.

[1063] MS (ESI) M / Z: 297.0 [M+H] + .

[1064] Step C: To a solution of 3-((4-bromo-2-hydroxyphenyl)amino)-1-methylpyridin-2(1H)-one (1.9 g, 6.44 mmol) in toluene (30 mL) was added 3-((tert-butyldimethylsilyl)oxy)propan-1-ol (2.45 g, 12.88 mmol) and cyanomethylidene tri-n-butylphosphonium (4.66 g, 19.32 mmol). The air was replaced by nitrogen for three times. It was stirred at 100 °C for 2 h.

[1065] LCMS monitoring showed the reaction was complete. The reaction solution was quenched with saturated sodium bicarbonate solution (20 mL), extracted with dichloromethane (30 mL x 3), the organic phase was combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography to give 1.9 g of 3-((4-bromo-2-hydroxyphenyl)amino)-1-methylpyridin-2(1H)-one.

[1066] MS (ESI) M / Z: 469.1 [M+H] + .

[1067] Step D: To a solution of 3-((4-bromo-2-(3-(tert-butyldimethylsilyl)oxy)propoxy)phenyl)amino)-1-methylpyridin-2(1H)-one (1.7 g, 3.64 mmol) in tetrahydrofuran (20 mL) was added tetrabutylammonium fluoride (1.0 M, 7.3 mL, 7.3 mmol) in tetrahydrofuran at 0 °C. The air was replaced by nitrogen for three times. It was stirred at room temperature for 2 h.

[1068] LCMS monitoring showed the reaction was complete. The reaction solution was quenched with saturated sodium bicarbonate solution (20 mL), extracted with dichloromethane (30 mL x 3), the organic phase was combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography to give 1.9 g of 3-((4-bromo-2-hydroxyphenyl)amino)-1-methylpyridin-2(1H)-one.

[1069] MS (ESI) M / Z: 354.8 [M+H] + .

[1070] Step E: To a solution of 3-((4-bromo-2-(3-hydroxypropoxy)phenyl)amino)-1- methylpyridin-2(1H)-one (500 mg, 1.42 mmol) in toluene (30 mL), cyanomethylidene tri-n-butylphosphonium (1.03 g, 4.26 mmol) was added. The reaction was stirred at 100 °C for 6 h after purging with nitrogen three times.

[1071] LCMS monitoring showed the reaction was complete. The reaction solution was concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography to give 300 mg of 3-(8-bromo-3,4-dihydrobenzo[b][1,4]oxazepin-5(2H)-yl)-1- methylpyridin-2(1H)-one.

[1072] MS (ESI) M / Z: 337.0 [M+H] + .

[1073] Step F: To a solution of 3-(8-bromo-3,4-dihydrobenzo[b][1,4]oxazepin-5(2H)-yl)-1- methylpyridin-2(1H)-one (70 mg, 0.21 mmol) and INT-2 (110 mg, 0.32 mmol) in 1,4- dioxane (10 mL) and water (1 mL), (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride (8 mg, 0.011 mmol) and sodium bicarbonate (35 mg, 0.42 mmol) were added. The reaction was stirred at 90 °C for 2 h after purging with nitrogen three times.

[1074] LCMS monitoring showed the starting material was consumed, quenched by adding water (10 mL), extracted with ethyl acetate (10 mL x 3), the organic phase was combined, washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained crude product was purified by high performance liquid chromatography, separation condition: preparative column: SunFire: C18 19*250mm, 10μm, mobile phase: 0.1% FA in water / CH3CN, flow rate: 10 mL / min, gradient: 40%-46%, detection wavelength: 214nm / 254nm, retention time: 9.83 min. 57 mg of 3-(2-chloro-3-(5-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-2,3,4- 5-tetrahydrobenzo[b][1,4]oxazepin-8-yl)phenyl)piperidine-2,6-dione was obtained.

[1075] MS (ESI) M / Z: 477.9 [M+H] + .

[1076] 1H NMR (400 MHz, DMSO-d6) δ 10.91 (s, 1H), 7.50-7.48 (m, 1H), 7.38-7.27 (m, 3H), 7.15-7.13 (m, 1H), 6.92-6.91 (m, 1H), 6.85-6.83 (m, 1H), 6.60-6.58 (m, 1H), 6.20 (t, J = 7.0 Hz, 1H), 4.35-4.31 (m, 1H), 4.27 (t, J = 5.8 Hz, 2H), 3.92 (t, J = 5.8 Hz, 2H), 3.48 (s, 3H), 2.83-2.74 (m, 1H), 2.57-2.55 (m, 1H), 2.37-2.27 (m, 1H), 2.07-2.02 (m, 1H), 1.93-1.87 (m, 2H).

[1077] Example 89: Methyl (2'-chloro-3'-(2,6-dioxopiperidin-3-yl)-3-methyl-[1,1'-biphenyl]-4-yl)carbamate

[1078] Reference to the procedure of other examples of the application resulted in 38 mg of methyl (2'-chloro-3'-(2,6-dioxopiperidin-3-yl)-3-methyl-[1,1'-biphenyl]-4-yl)carbamate.

[1079] MS (ESI) M / Z: 387.1 [M+H] + .

[1080] 1 H NMR (400 MHz, DMSO-d6) δ 10.91 (s, 1H), 8.93 (s, 1H), 7.45 (d, J = 8.0 Hz, 1H), 7.41-7.27 (m, 3H), 7.24-7.16 (m, 2H), 4.33 (dd, J = 12.0, 5.0 Hz, 1H), 3.67 (s, 3H), 2.84-2.73 (m, 1H), 2.58-2.53 (m, 1H), 2.35-2.31 (m, 1H), 2.25 (s, 3H), 2.09-1.99 (m, 1H).

[1081] Example 90: 2'-chloro-3'-(2,6-dioxopiperidin-3-yl)-3-methyl-[1,1'-biphenyl]-4-yl-(2-hydroxyethyl)(methyl)carbamate

[1082] Reference to the preparation method of other embodiments of the application to obtain 37.16 mg of 2'-chloro-3'-(2,6-dioxopiperidin-3-yl)-3-methyl-[1,1'-biphenyl]-4-yl-(2-hydroxyethyl)(methyl)carbamate.

[1083] MS (ESI) M / Z: 431.0 [M+H] + .

[1084] 1 H NMR (400 MHz, DMSO-d6) δ 10.92 (s, 1H), 7.44-7.26 (m, 4H), 7.23 (d, J = 8.4 Hz, 1H), 7.13 (t, J = 7.6 Hz, 1H), 4.88-4.74 (m, 1H), 4.34 (dd, J = 12.1, 5.0 Hz, 1H), 3.76-3.70 (m, J = 5.7 Hz, 1H), 3.62-3.54 (m, 1H), 3.54-3.46 (m, 1H), 3.40-3.32 (m, 1H), 3.05 (d, J = 62.9 Hz, 3H), 2.84-2.70 (m, 1H), 2.59-2.53 (m, 1H), 2.40-2.32 (m, 1H), 2.19 (s, 3H), 2.09-2.00 (m, 1H).

[1085] Example 91: 2'-chloro-3-(difluoromethyl)-3'-(2,6-dioxopiperidin-3-yl)-[1,1'-biphenyl]-4- yldimethylcarbamate

[1086] Reference to the preparation method of other embodiments of the application to obtain 17.14 mg of 2'-chloro-3-(difluoromethyl)-3'-(2,6-dioxopiperidin-3-yl)-[1,1'-biphenyl]-4- yldimethylcarbamate.

[1087] MS (ESI) M / Z: 437.1 [M+H] + .

[1088] 1 H NMR (400 MHz, DMSO-d6) δ 10.88 (s, 1H), 7.62-7.58 (m, 2H), 7.47-7.33 (m, 4H), 7.14 (t, J = 54.5 Hz, 1H), 4.35 (dd, J = 12.2, 5.1 Hz, 1H), 3.09 (s, 3H), 2.95 (s, 3H), 2.84-2.74 (m, 1H), 2.61-2.53 (m, 1H), 2.36 (d, J = 4.2 Hz, 1H), 2.10-2.02 (m, 1H).

[1089] Example 92: 2'-Chloro-3'-(2,6-dioxopiperidin-3-yl)-3-methyl-[1,1'-biphenyl]-4-yl (2S)-2-(hydroxymethyl)azetidine-1-carboxylate

[1090] Reference to the procedure for preparing the other examples of the application resulted in 62 mg of 2'-Chloro-3'-(2,6-dioxopiperidin-3-yl)-3-methyl-[1,1'-biphenyl]-4-yl (2S)-2-(hydroxymethyl)azetidine-1-carboxylate.

[1091] MS (ESI) M / Z: 443.1 [M+H] + .

[1092] 1 H NMR (400 MHz, DMSO-d6) δ 10.92 (s, 1H), 7.42 - 7.33 (m, 2H), 7.33 - 7.26 (m, 2H), 7.22 (dd, J=8.4, 2.0 Hz, 1H), 7.14 (d, J=8.4 Hz, 1H), 5.01 - 4.89 (m, 1H), 4.59 - 4.25 (m, 2H), 4.04 - 3.59 (m, 4H), 2.88 - 2.71 (m, 1H), 2.58 - 2.53 (m, 1H), 2.38 - 2.27 (m, 2H), 2.25 - 2.16 (m, 4H), 2.09 - 2.00 (m, 1H).

[1093] Example 93: 2'-Chloro-3'-(2,6-dioxopiperidin-3-yl)-3-methyl-[1,1'-biphenyl]-4-yl (2R)-2-(hydroxymethyl)azetidine-1-carboxylate

[1094] Reference to the procedure for preparing the other examples of the application resulted in 72 mg of 2'-Chloro-3'-(2,6-dioxopiperidin-3-yl)-3-methyl-[1,1'-biphenyl]-4-yl (2R)-2-(hydroxymethyl)azetidine-1-carboxylate.

[1095] MS (ESI) M / Z: 443.1 [M+H] + .

[1096] 1H NMR (400 MHz, DMSO-d6) δ 10.92 (s, 1H), 7.42-7.33 (m, 2H), 7.33-7.26 (m, 2H), 7.22 (dd, J = 8.4, 1.9 Hz, 1H), 7.14 (d, J = 8.4 Hz, 1H), 5.01-4.90 (m, 1H), 4.57-4.27 (m, 2H), 4.04-3.59 (m, 4H), 2.85-2.73 (m, 1H), 2.58-2.55 (m, 1H), 2.37-2.28 (m, 2H), 2.25-2.16 (m, 4H), 2.06-2.03 (m, 1H).

[1097] Example 94: 3-(2'-chloro-3'-(2,6-dioxopiperidin-3-yl)-3-methyl-[1,1'-biphenyl]-4-yl)-1,1- dimethylurea

[1098] Reaction Scheme:

[1099] Procedure:

[1100] Step A: To a solution of 4-bromo-2-methylaniline (600 mg, 3.22 mmol) in N,N- dimethylformamide (10 mL) was added potassium carbonate (1.33 g, 9.66 mmol) and dimethylcarbamoyl chloride (1.73 g, 16.1 mmol). The air was replaced by nitrogen for three times. Stirring at 80 °C for 16 hours.

[1101] LCMS was used to monitor the completion of the reaction. The reaction solution was diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The organic phase was combined, washed with saturated brine (20 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography to give 100 mg of 3-(4-bromo-2-methylphenyl)-1,1-dimethylurea.

[1102] MS (ESI) M / Z: 257.0 [M+H] + .

[1103] Step B: To a solution of 3-(4-bromo-2-methylphenyl)-1,1-dimethylurea (90 mg, 0.35 mmol) in 1,4-dioxane (5 mL) and water (0.5 mL) was added INT-2 (183 mg, 0.53 mmol), potassium carbonate (97 mg, 0.70 mmol) and (1,1'- bis(diphenylphosphino)ferrocene)palladium(II) dichloride (12.8 mg, 18 μmol). The air was replaced by nitrogen for three times. Stirring at 90 °C for 2 hours.

[1104] LCMS monitoring showed the disappearance of the starting material, diluted with water (20 mL), extracted with dichloromethane (20 mL x 3), the combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained crude product was purified by high performance liquid chromatography to obtain 55 mg of 3-(2'-chloro-3'-(2,6-dioxopiperidin-3-yl)-3-methyl-[1,1'-biphenyl]-4-yl)-1,1-dimethylurea.

[1105] MS (ESI) M / Z: 399.9 [M+H] + .

[1106] 1 H NMR (400 MHz, DMSO-d6) δ 10.91 (s, 1H), 7.79 (s, 1H), 7.40-7.28 (m, 4H), 7.20-7.14 (m, 2H), 4.35-4.31 (m, 1H), 2.95 (s, 6H), 2.83-2.74 (m, 1H), 2.56-2.52 (m, 1H), 2.39-2.29 (m, 1H), 2.22 (s, 3H), 2.07-2.03 (m, 1H).

[1107] Example 94A and Example 94B: (R)-3-(2'-chloro-3'-(2,6-dioxopiperidin-3-yl)-3-methyl-[1,1'-biphenyl]-4-yl)-1,1-dimethylurea and (S)-3-(2'-chloro-3'-(2,6-dioxopiperidin-3-yl)-3-methyl-[1,1'-biphenyl]-4-yl)-1,1-dimethylurea

[1108] 3-(2'-chloro-3'-(2,6-dioxopiperidin-3-yl)-3-methyl-[1,1'-biphenyl]-4-yl)-1,1-dimethylurea (50 mg, 0.125 mmol) was separated by SFC, separation conditions: preparative column: 250*30 mm 10 mm, mobile phase: Mobile Phase A: Supercritical CO2, Mobile Phase B: MeOH, flow rate: 140 mL / min, gradient: A / B = 70 / 30, detection wavelength: 214 nm, column temperature: room temperature. 21 mg of Example 94A (elution time 3.232 min) and 22 mg of Example 94B (elution time 4.188 min) were obtained.

[1109] Example 94A:

[1110] MS (ESI) M / Z: 400.1 [M+H] + .

[1111] 1 H NMR (400 MHz, DMSO-d6) δ 10.91 (s, 1H), 7.79 (s, 1H), 7.40 - 7.29 (m, 4H), 7.20 - 7.13 (m, 2H), 4.35 - 4.31 (m, 4H), 2.95 (s, 6H), 2.83 - 2.74 (m, 1H), 2.57 - 2.50 (m, 1H), 2.39 - 2.27 (m, 1H), 2.22 (s, 3H), 2.06 - 2.02 (m, 1H).

[1112] Example 94B:

[1113] MS (ESI) M / Z: 400.1 [M+H] + .

[1114] 1 H NMR (400 MHz, DMSO-d6) δ 10.91 (s, 1H), 7.79 (s, 1H), 7.40 - 7.29 (m, 4H), 7.20 - 7.13 (m, 2H), 4.35 - 4.31 (m, 4H), 2.95 (s, 6H), 2.83 - 2.74 (m, 1H), 2.57 - 2.50 (m, 1H), 2.39 - 2.27 (m, 1H), 2.22 (s, 3H), 2.06 - 2.02 (m, 1H).

[1115] Example 95: (2S)-N-(2'-chloro-3'-(2,6-dioxopiperidin-3-yl)-3-methyl-[l,l'-biphenyl]-4-yl)-2- (methoxymethyl)pyrrolidine-l-carboxamide

[1116] Reaction Scheme:

[1117] Procedure:

[1118] Step A: To a solution of 4-bromo-2-methylaniline (200 mg, 1.08 mmol) in tetrahydrofuran (15 mL) was added triphosgene (225 mg, 0.76 mmol) and N,N-diisopropylethylamine (418 mg, 3.24 mmol) at 0 °C. After stirring at 0 °C for 1 h, (S)-2-(methoxymethyl)pyrrolidine (373 mg, 3.24 mmol) was added slowly. Stirring at room temperature for 2 h.

[1119] LCMS monitoring showed the starting material disappeared, diluted with water (10 mL), extracted with dichloromethane (10 mL x 3), dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure, the obtained crude was purified by high performance liquid chromatography to obtain 60.89 mg of (2S)-N-(2'-chloro-3'-(2,6-dioxopiperidin-3-yl)-3-methyl-[l,r-biphenyl]-4-yl)-2- (methoxymethyl)pyrrolidine-l-carboxamide.

[1120] MS (ESI) M / Z: 328.9 [M+H] + .

[1121] Step B: To a solution of (S)-N-(4-bromo-2-methylphenyl)-2- (methoxymethyl)pyrrolidine-l-carboxamide (100 mg, 0.31 mmol) in 1,4-dioxane (10 mL) and water (1 mL), INT-2 (161 mg, 0.46 mmol), potassium carbonate (86 mg, 0.62 mmol) and (l,l'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride (22 mg, 0.03 mmol) were added. The air was replaced by nitrogen for three times. Stirring at 90 °C for 2 hours.

[1122] LCMS monitoring showed the starting material disappeared, diluted with water (10 mL), extracted with dichloromethane (10 mL x 3), dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure, the obtained crude was purified by high performance liquid chromatography to obtain 60.89 mg of (2S)-N-(2'-chloro-3'-(2,6-dioxopiperidin-3-yl)-3-methyl-[l,r-biphenyl]-4-yl)-2- (methoxymethyl)pyrrolidine-l-carboxamide.

[1123] MS (ESI) M / Z: 470.1 [M+H] + .

[1124] 1 H NMR (400 MHz, DMSO-d6) δ 10.91 (s, 1H), 7.92 (s, 1H), 7.62 (d, J = 8.0 Hz, 1H), 7.41 - 7.26 (m, 3H), 7.19 (s, 1H), 7.17 - 7.12 (m, 1H), 4.41 - 4.24 (m, 1H), 4.07 (d, J = 6.3 Hz, 1H), 3.54 - 3.46 (m, 1H), 3.44 - 3.36 (m, 3H), 3.34 (s, 3H), 2.88 - 2.71 (m, 1H), 2.58 - 2.54 (m, 1H), 2.40 - 2.28 (m, 1H), 2.23 (s, 3H), 2.10_2.00 (m, 1H), 2.00 - 1.80 (m, 3H), 1.79 - 1.70 (m, 1H).

[1125] Example 96: (3R)-N-(2'-chloro-3'-(2,6-dioxopiperidin-3-yl)-3-methyl-[l,l'-biphenyl]-4-yl)-3- (methoxymethyl)morpholine-4-carboxamide

[1126] Reaction Scheme:

[1127] Reference to the preparation method of other embodiments of the present application obtained 51 mg of (3R)-N-(2'-chloro-3'-(2,6-dioxopiperidin-3-yl)-3-methyl-[l,l'-biphenyl]-4-yl)-3- (methoxymethyl)morpholine-4-carboxamide.

[1128] MS (ESI) M / Z: 486.1 [M+H] + .

[1129] 1 H NMR (400 MHz, DMSO-d6) δ 10.91 (s, 1H), 8.01 (s, 1H), 7.44 - 7.26 (m, 4H), 7.22 - 7.12 (m, 2H), 4.35 - 4.31 (m, 1H), 4.23 - 4.05 (m, 1H), 3.85 (d, J=11.6 Hz, 2H), 3.78 (d, J=13.4 Hz, 1H), 3.70 - 3.60 (m, 1H), 3.60 - 3.47 (m, 2H), 3.45 - 3.39 (m, 1H), 3.33 (s, 3H), 3.13 - 3.06 (m, 1H), 2.88 - 2.72 (m, 1H), 2.60 - 2.53 (m, 1H), 2.38 - 2.29 (m, 1H), 2.21 (s, 3H), 2.11 - 1.95 (m, 1H).

[1130] Example 97: l-(2'-chloro-3'-(2,6-dioxopiperidin-3-yl)-[l,l'-biphenyl]-4-yl)-l,3-dimethylurea

[1131] Reference to the preparation method of other embodiments of the present application obtained 49 mg of l-(2'-chloro-3'-(2,6-dioxopiperidin-3-yl)-[l,l'-biphenyl]-4-yl)-l,3-dimethylurea.

[1132] MS (ESI) M / Z: 386.0 [M+H] + .

[1133] 1H NMR (400 MHz, DMSO-d6) δ 10.92 (s, 1H), 7.42-7.30 (m, 7H), 6.19-6.16 (m, 1H), 4.37-4.33 (m, 1H), 3.20 (s, 3H), 2.85-2.75 (m, 1H), 2.60 (d, J = 4.4 Hz, 3H), 2.58-2.52 (m, 1H), 2.39-2.30 (m, 1H), 2.07-2.03 (m, 1H).

[1134] Example 98: 2'-chloro-3'-(2,6-dioxopiperidin-3-yl)-3-methoxy-[1,1'-biphenyl]-4- yl dimethylformamide

[1135] Reference to the procedure of other examples of the application resulted in 33.64 mg of 2'-chloro-3'-(2,6-dioxopiperidin-3-yl)-3-methoxy-[1,1'-biphenyl]-4- yl dimethylformamide.

[1136] MS (ESI) M / Z: 417.1 [M+H] + .

[1137] 1 H NMR (400 MHz, DMSO-d6) δ 10.92 (s, 1H), 7.42-7.30 (m, 7H), 6.19-6.16 (m, 1H), 4.37-4.33 (m, 1H), 3.20 (s, 3H), 2.85-2.75 (m, 1H), 2.60 (d, J = 4.4 Hz, 3H), 2.58-2.52 (m, 1H), 2.39-2.30 (m, 1H), 2.07-2.03 (m, 1H).

[1138] Example 99: 3-(2-chloro-4'-(5-(difluoromethoxy)-2-oxopyridin-1(2H)-yl)-[1,1'- biphenyl]-3-yl)piperidine-2,6-dione

[1139] Reference to the procedure of other examples of the application resulted in 69 mg of 3-(2-chloro-4'-(5-(difluoromethoxy)-2-oxopyridin-1(2H)-yl)-[1,1'- biphenyl]-3-yl)piperidine-2,6-dione.

[1140] MS (ESI) M / Z: 458.9 [M+H] + .

[1141] 1H NMR (400 MHz, DMSO-d6) δ 10.94 (s, 1H), 7.87 (d, J = 3.2 Hz, 1H), 7.60-7.53 (m, 5H), 7.47-6.89 (m, 4H), 6.57 (d, J = 10.0 Hz, 1H), 4.40-4.36 (m, 1H), 2.86-2.76 (m, 1H), 2.59-2.53 (m, 1H), 2.40-2.31 (m, 1H), 2.09-2.05 (m, 1H).

[1142] Example 100: 2'-chloro-3'-(2,6-dioxopiperidin-3-yl)-3-methyl-[1,1'-biphenyl]-4-yl- morpholine-4-carboxylate

[1143] Reference to the procedure of other examples of the application resulted in 24.08 mg of 2'-chloro-3'-(2,6-dioxopiperidin-3-yl)-3-methyl-[1,1'-biphenyl]-4-yl- morpholine-4-carboxylate.

[1144] MS (ESI) M / Z: 443.2 [M+H] + .

[1145] 1 H NMR (400 MHz, DMSO-d6) δ 10.92 (s, 1H), 7.51-7.32 (m, 4H), 7.24 (dd, J = 8.2, 2.2 Hz, 1H), 7.16 (d, J = 8.3 Hz, 1H), 4.34 (dd, J = 12.2, 5.0 Hz, 1H), 3.81-3.56 (m, 6H), 3.52-3.37 (m, 2H), 2.84-2.72 (m, 1H), 2.59-2.53 (m, 1H), 2.40-2.26 (m, 1H), 2.19 (s, 3H), 2.10-1.87 (m, 1H).

[1146] Example 101: 2'-chloro-3'-(2,6-dioxopiperidin-3-yl)-3-methyl-[1,1'-biphenyl]-4-yl- 3-hydroxyazetidine-1-carboxylate

[1147] Reference to the procedure of other examples of the application resulted in 27.88 mg of 2'-chloro-3'-(2,6-dioxopiperidin-3-yl)-3-methyl-[1,1'-biphenyl]-4-yl- 3-hydroxyazetidine-1-carboxylate.

[1148] MS (ESI) M / Z: 429.0 [M+H] + .

[1149] 1 H NMR (400 MHz, DMSO-d6) δ 10.91 (s, 1H), 7.45 - 7.29 (m, 4H), 7.26 - 7.01 (m, 2H), 5.82 (d, J = 6.4 Hz, 1H), 4.60 - 4.50 (m, 1H), 4.44 - 4.30 (m, 2H), 4.26 - 4.12 (m, 1H), 4.10 - 3.88 (m, 1H), 3.82 - 3.70 (m, 1H), 2.84 - 2.74 (m, 1H), 2.60 - 2.50 (m, 1H), 2.40 - 2.33 (m, 1H), 2.19 (s, 3H), 2.08 - 1.84 (m, 1H).

[1150] Example 102: 2'-chloro-3'-(2,6-dioxopiperidin-3-yl)-3-methyl-[1,1'-biphenyl]-4-yl (2-methoxyethyl)(methyl)carbamate

[1151] Reference to the procedure of other examples of the application resulted in 35.19 mg of 2'-chloro-3'-(2,6-dioxopiperidin-3-yl)-3-methyl-[1,1'-biphenyl]-4-yl (2-methoxyethyl)(methyl)carbamate.

[1152] MS (ESI) M / Z: 445.0 [M+H] + .

[1153] 1 H NMR (400 MHz, DMSO-d6) δ 10.92 (s, 1H), 7.44 - 7.27 (m, 4H), 7.26 - 7.20 (m, 1H), 7.12 (t, J = 8.0 Hz, 1H), 4.34 (dd, J = 12.2, 5.1 Hz, 1H), 3.65 - 3.57 (m, 2H), 3.54 - 3.44 (m, 2H), 3.32 - 3.26 (m, 3H), 3.12 (s, 1.5H), 2.96 (s, 1.5H), 2.84 - 2.74 (m, 1H), 2.57 - 2.53 (m, 1H), 2.35 (d, J = 4.2 Hz, 1H), 2.18 (s, 3H), 2.09 - 2.00 (m, 1H).

[1154] Example 103: 2'-chloro-3'-(2,6-dioxopiperidin-3-yl)-3-methyl-[1,1'-biphenyl]-4-yl-(3R)-3-hydroxypiperidine-1-carboxylate

[1155] Scheme:

[1156] Reference to the preparation method of other embodiments of the application resulted in 27.94 mg of 2'-chloro-3'-(2,6-dioxopiperidin-3-yl)-3-methyl-[1,1'-biphenyl]-4-yl-(3R)-3-hydroxypiperidine-1-carboxylate.

[1157] MS (ESI) M / Z: 443.0 [M+H] + .

[1158] 1 H NMR (400 MHz, DMSO-d6) δ 10.92 (s, 1H), 7.44 - 7.27 (m, 4H), 7.25 - 7.13 (m, 2H), 5.06 (dd, J=11.6, 3.3 Hz, 1H), 4.39 - 4.30 (m, 2H), 3.71 - 3.57 (m, 1H), 3.49 - 3.39 (m, 2H), 3.28 (d, J=12.5 Hz, 1H), 2.84 - 2.54 (m, 1H), 2.56 (d, J=3.8 Hz, 1H), 2.40 - 2.26 (m, 1H), 2.19 (d, J=2.5 Hz, 3H), 2.11 - 1.92 (m, 2H), 1.92 - 1.78 (m, 1H).

[1159] Example 104: 2'-chloro-3'-(2,6-dioxopiperidin-3-yl)-3-methyl-[1,1'-biphenyl]-4-yl-(3S)-3-hydroxypiperidine-1-carboxylate

[1160] Reaction Scheme:

[1161] Reference to the preparation method of other embodiments of the application resulted in 27.94 mg of 2'-chloro-3'-(2,6-dioxopiperidin-3-yl)-3-methyl-[1,1'-biphenyl]-4-yl-(3R)-3-hydroxypiperidine-1-carboxylate.

[1162] MS (ESI) M / Z: 443.0 [M+H] + .

[1163] 1H NMR (400 MHz, DMSO-d6) δ 10.92 (s, 1H), 7.44 - 7.27 (m, 4H), 7.25 - 7.07 (m, 2H), 5.05 (dd, J = 11.6, 3.5 Hz, 1H), 4.39 - 4.30 (m, 2H), 3.72 - 3.61 (m, 1H), 3.50 - 3.40 (m, 2H), 3.35 - 3.25 (m, 1H), 2.85 - 2.73 (m, 1H), 2.60 - 2.54 (m, 1H), 2.44 - 2.26 (d, J = 3.8 Hz, 1H), 2.19 (d, J = 2.5 Hz, 3H), 2.13 - 1.93 (m, 2H), 1.92 - 1.74 (m, 1H).

[1164] Example 105: 2'-chloro-3'-(2,6-dioxopiperidin-3-yl)-3-methyl-[1,1'-biphenyl]-4-yl thiomorpholine-4-carboxylate-1,1-dioxide

[1165] Reference to the procedure of other examples of the application resulted in 45.3 mg of 2'-chloro-3'-(2,6-dioxopiperidin-3-yl)-3-methyl-[1,1'-biphenyl]-4-yl thiomorpholine-4-carboxylate-1,1-dioxide.

[1166] MS (ESI) M / Z: 491.1 [M+H] + .

[1167] 1 H NMR (400 MHz, DMSO-d6) δ 10.92 (s, 1H), 7.44 - 7.27 (m, 4H), 7.25 - 7.07 (m, 2H), 5.05 (dd, J = 11.6, 3.5 Hz, 1H), 4.39 - 4.30 (m, 2H), 3.72 - 3.61 (m, 1H), 3.50 - 3.40 (m, 2H), 3.35 - 3.25 (m, 1H), 2.85 - 2.73 (m, 1H), 2.60 - 2.54 (m, 1H), 2.44 - 2.26 (d, J = 3.8 Hz, 1H), 2.19 (d, J = 2.5 Hz, 3H), 2.13 - 1.93 (m, 2H), 1.92 - 1.74 (m, 1H).

[1168] Example 106: 2'-chloro-3'-(2,6-dioxopiperidin-3-yl)-3-methyl-[1,1'-biphenyl]-4-yl-(3R)-3-(dimethylamino)pyrrolidine-1-carboxylate

[1169] Reference to the preparation method of other embodiments of the application obtained 35.3 mg of 2'-chloro-3'-(2,6-dioxopiperidin-3-yl)-3-methyl-[1,1'-biphenyl]-4-yl-(3R)-3-(dimethylamino)pyrrolidine-1-carboxylate.

[1170] MS (ESI) M / Z: 470.1 [M+H] + .

[1171] 1 H NMR (400 MHz, Methanol-d4) δ 7.41 - 7.27 (m, 4H), 7.26 - 7.20 (m, 1H), 7.12 (d, J=8.2 Hz, 1H), 4.38 (dd, J=11.9, 5.2 Hz, 1H), 4.05 - 4.01 (m, 0.5H), 3.93 - 3.80 (m, 1H), 3.75 - 3.62 (m 1H), 3.53 - 3.43 (m, 1H), 3.37 - 3.35 (d, J=8.0 Hz, 0.5H), 3.23 - 3.21 (m, 1H), 2.87 - 2.63 (m, 2H), 2.51 (s, 6H), 2.48 - 2.15 (m, 6H), 2.10 - 1.90 (m, 1H).

[1172] Example 107: 2'-chloro-3'-(2,6-dioxopiperidin-3-yl)-3-methyl-[1,1'-biphenyl]-4-yl-(3S)-3-(dimethylamino)pyrrolidine-1-carboxylate

[1173] Reference to the preparation method of other embodiments of the application obtained 12.68 mg of 2'-chloro-3'-(2,6-dioxopiperidin-3-yl)-3-methyl-[1,1'-biphenyl]-4-yl-(3R)-3-(dimethylamino)pyrrolidine-1-carboxylate.

[1174] MS (ESI) M / Z: 470.1 [M+H] + .

[1175] 1H NMR (400 MHz, Methanol-d4) δ 7.41-7.27 (m, 4H), 7.24 (dd, J = 8.3, 2.2 Hz, 1H), 7.12 (d, J = 8.3 Hz, 1H), 4.38 (dd, J = 11.8, 5.2 Hz, 1H), 4.05-4.01 (m, 0.5H), 3.93-3.80 (m, 1H), 3.75-3.62 (m 1H), 3.53-3.41 (m, 1H), 3.37-3.33 (m, 0.5H), 3.24-3.22 (d, J = 7.7 Hz, 1H), 2.87-2.63 (m, 2H), 2.52 (s, 6H), 2.45-2.12 (m, 6H), 2.10-1.90 (m, 1H).

[1176] Example 108: (2R)-N-(2'-chloro-3'-(2,6-dioxopiperidin-3-yl)-3-methyl-[l,l'-biphenyl]-4-yl)-2- (methoxymethyl)pyrrolidine-1-carboxamide

[1177] Reaction Scheme:

[1178] Procedure:

[1179] Step A: To a solution of 4-bromo-2-methylaniline (200 mg, 1.08 mmol) in tetrahydrofuran (15 mL) was added triphosgene (225 mg, 0.76 mmol) and N,N-diisopropylethylamine (418 mg, 3.24 mmol) at 0 °C. After stirring at 0 °C for 1 h, (R)-2-(methoxymethyl)pyrrolidine (373 mg, 3.24 mmol) was added slowly. The mixture was stirred at room temperature for 2 h.

[1180] The reaction was monitored by LCMS. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The organic phase was combined, washed with saturated brine (20 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography to give 300 mg of (R)-N-(4-bromo-2-methylphenyl)-2-(methoxymethyl)pyrrolidine-1-carboxamide.

[1181] MS (ESI) M / Z: 328.9 [M+H] + .

[1182] Step B: To a solution of (R)-N-(4-bromo-2-methylphenyl)-2- (methoxymethyl)pyrrolidine-l-carboxamide (100 mg, 0.31 mmol) in 1,4- dioxane (10 mL) and water (1 mL), was added INT-2 (161 mg, 0.46 mmol), potassium carbonate (86 mg, 0.62 mmol) and (l,l'-bis(diphenylphosphino) ferrocene)palladium(II) dichloride (22 mg, 0.03 mmol). The air was replaced by nitrogen three times. It was heated to 90 °C with stirring for 2 hours.

[1183] LCMS monitoring showed the disappearance of the starting material, diluted with water (10 mL), extracted with dichloromethane (10 mL x 3), the combined organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, the obtained crude was purified by high performance liquid chromatography to obtain 57.05 mg of (2R)-N-(2'-chloro-3'-(2,6-dioxopiperidin-3-yl)-3-methyl-[l,l'-biphenyl]-4-yl)-2- (methoxymethyl)pyrrolidine-l-carboxamide.

[1184] MS (ESI) M / Z: 470.1 [M+H] + .

[1185] 1 H NMR (400 MHz, DMSO-d6) δ 10.91 (s, 1H), 7.92 (s, 1H), 7.62 (d, J = 8.4 Hz, 1H), 7.42 - 7.26 (m, 3H), 7.19 (s, 1H), 7.17 - 7.12 (m, 1H), 4.41 - 4.24 (m, 1H), 4.13 - 4.00 (m, 1H), 3.54 - 3.47 (m, 1H), 3.46 - 3.36 (m, 3H), 3.34 (s, 3H), 2.87 - 2.72 (m, 1H), 2.58 - 2.54 (m, 1H), 2.40 - 2.30 (m, 1H), 2.23 (s, 3H), 2.10 - 1.80 (m, 4H), 1.79 - 1.70 (m, 1H).

[1186] Example 109: (2R)-N-(2'-chloro-3'-(2,6-dioxopiperidin-3-yl)-3-methyl-[l,l'-biphenyl]-4-yl)-2- (methoxymethyl)azetidine-l-carboxamide

[1187] Reference to the preparation method of other embodiments of the application obtained 52.86 mg of (2R)-N-(2'-chloro-3'-(2,6-dioxopiperidin-3-yl)-3-methyl-[l,l'-biphenyl]-4-yl)-2- (methoxymethyl)azetidine-l-carboxamide.

[1188] MS (ESI) M / Z: 456.0 [M+H] + .

[1189] 1 H NMR (400 MHz, DMSO-d6) δ 10.91 (s, 1H), 7.91 (s, 1H), 7.86 (d, J = 8.4 Hz, 1H), 7.39 - 7.26 (m, 3H), 7.19 (s, 1H), 7.18 - 7.14 (m, 1H), 4.55 - 4.44 (m, 1H), 4.37 - 4.28 (m, 1H), 3.98 - 3.86 (m, 1H), 3.74 - 3.61 (m, 3H), 3.42 (s, 3H), 2.85 - 2.73 (m, 1H), 2.58 - 2.52 (m, 1H), 2.39 - 2.24 (m, 2H), 2.22 (s, 3H), 2.09 - 2.00 (m, 1H), 1.98 - 1.88 (m, 1H).

[1190] Example 110: (2S)-N-(2'-chloro-3'-(2,6-dioxopiperidin-3-yl)-3-methyl-[1,1'-biphenyl]-4-yl)-2- (methoxymethyl)azetidine-1-carboxamide

[1191] Reference to the preparation method of other embodiments of the application, 65.44 mg (2S)-N-(2'-chloro-3'-(2,6-dioxopiperidin-3-yl)-3-methyl-[1,1'-biphenyl]-4-yl)-2- (methoxymethyl)azetidine-1-carboxamide was obtained.

[1192] MS (ESI) M / Z: 456.1 [M+H] + .

[1193] 1 H NMR (400 MHz, DMSO-d6) δ 10.91 (s, 1H), 7.91 (s, 1H), 7.86 (d, J = 8.4 Hz, 1H), 7.39 - 7.26 (m, 3H), 7.19 (s, 1H), 7.18 - 7.14 (m, 1H), 4.55 - 4.44 (m, 1H), 4.37 - 4.28 (m, 1H), 3.98 - 3.86 (m, 1H), 3.74 - 3.61 (m, 3H), 3.42 (s, 3H), 2.85 - 2.73 (m, 1H), 2.58 - 2.52 (m, 1H), 2.39 - 2.24 (m, 2H), 2.22 (s, 3H), 2.09 - 2.00 (m, 1H), 1.98 - 1.88 (m, 1H).

[1194] Example 111: 2'-chloro-3'-(2,6-dioxopiperidin-3-yl)-3-methyl-[1,1'-biphenyl]-4-yl ((S)- tetrahydrofuran-3-yl)carbamate

[1195] Reference to the procedure for preparing other embodiments of the application resulted in 45 mg of 2'-chloro-3'-(2,6-dioxopiperidin-3-yl)-3-methyl-[1,1'-biphenyl]-4-yl ((S)- tetrahydrofuran-3-yl)carbamate.

[1196] MS (ESI) M / Z: 442.9 [M+H] + .

[1197] 1 H NMR (400 MHz, DMSO-d6) δ 10.92 (s, 1H), 8.13 (d, J = 6.4 Hz, 1H), 7.41 - 7.29 (m, 4H), 7.24 - 7.22 (m, 1H), 7.13 (d, J = 8.4 Hz, 1H), 4.37 - 4.32 (m, 1H), 4.13 - 4.11 (m, 1H), 3.86 - 3.78 (m, 2H), 3.73 - 3.68 (m, 1H), 3.59 - 3.56 (m, 1H), 2.84 - 2.75 (m, 1H), 2.57 - 2.53 (m, 1H), 2.39 - 2.28 (m, 1H), 2.19 (s, 3H), 2.15 - 2.03 (m, 2H), 1.89 - 1.82 (m, 1H).

[1198] Example 112: 2'-chloro-3'-(2,6-dioxopiperidin-3-yl)-3-methyl-[1,1'-biphenyl]-4-yl ((R)- tetrahydrofuran-3-yl)carbamate

[1199] Reference to the procedure for preparing other embodiments of the application resulted in 95 mg of 2'-chloro-3'-(2,6-dioxopiperidin-3-yl)-3-methyl-[1,1'-biphenyl]-4-yl ((R)- tetrahydrofuran-3-yl)carbamate.

[1200] MS (ESI) M / Z: 442.9 [M+H] + .

[1201] 1H NMR (400 MHz, DMSO-d6) δ 10.92 (s, 1 H), 8.13 (d, J = 6.8 Hz, 1 H), 7.41 - 7.29 (m, 4 H), 7.24 - 7.22 (m, 1 H), 7.13 (d, J = 8.0 Hz, 1 H), 4.37 - 4.32 (m, 1 H), 4.15 - 4.10 (m, 1 H), 3.86 - 3.78 (m, 2 H), 3.73 - 3.68 (m, 1 H), 3.59 - 3.56 (m, 1 H), 2.84 - 2.75 (m, 1 H), 2.58 - 2.52 (m, 1 H), 2.39 - 2.28 (m, 1 H), 2.19 (s, 3 H), 2.15 - 2.03 (m, 2 H), 1.89 - 1.82 (m, 1 H).

[1202] Example 113: 3-(2'-chloro-3'-(2,6-dioxopiperidin-3-yl)-[1,1'-biphenyl]-4-yl)-1-(2- methoxyethyl)-1-methylurea

[1203] Reference to the procedure of other examples of the application resulted in 67.27 mg of 3-(2'-chloro-3'-(2,6-dioxopiperidin-3-yl)-[1,1'-biphenyl]-4-yl)-1-(2- methoxyethyl)-1-methylurea.

[1204] MS (ESI) M / Z: 430.0 [M+H] + .

[1205] 1 H NMR (400 MHz, DMSO-d6) δ 10.91 (s, 1 H), 8.37 (s, 1 H), 7.57 - 7.50 (m, 2 H), 7.40 - 7.24 (m, 5 H), 4.38 - 4.28 (m, 1 H), 3.50 (s, 4 H), 3.29 (s, 3 H), 2.99 (s, 3 H), 2.85 - 2.73 (m, 1 H), 2.59 - 2.52 (m, 1 H), 2.41 - 2.26 (m, 1 H), 2.09 - 1.99 (m, 1 H).

[1206] Example 114: (3S)-N-(2'-chloro-3'-(2,6-dioxopiperidin-3-yl)-3-methyl-[1,1'-biphenyl]-4- yl)-3-(methoxymethyl)morpholine-4-carboxamide

[1207] Reference to the preparation method of other embodiments of the application obtained 57 mg (3S)-N-(2'-chloro-3'-(2,6-dioxopiperidin-3-yl)-3-methyl-[1,1'-biphenyl]-4-yl)-3- (methoxymethyl)morpholine-4-carboxamide.

[1208] MS (ESI) M / Z: 486.2 [M+H] + .

[1209] 1 H NMR (400 MHz, DMSO-d6) δ 10.91 (s, 1H), 8.01 (s, 1H), 7.45-7.24 (m, 4H), 7.24-7.08 (m, 2H), 4.35-4.14 (m, 1H), 4.25-4.10 (m, 1H), 3.85 (d, J=11.6 Hz, 2H), 3.78 (d, J=11.3 Hz, 1H), 3.70-3.61 (m, 1H), 3.60-3.48 (m, 2H), 3.43-3.32 (m, 1H), 3.33 (s, 3H), 3.14-3.06 (m, 1H), 2.86-2.72 (m, 1H), 2.60-2.53 (m, 1H), 2.51-2.49 (m, 1H), 2.21 (s, 3H), 2.11-1.95 (m, 1H).

[1210] Example 115: 1-(2'-chloro-3'-(2,6-dioxopiperidin-3-yl)-3-methyl-[1,1'-biphenyl]-4-yl)-1-(2- hydroxyethyl)-3-methylurea

[1211] Reference to the preparation method of other embodiments of the application obtained 23 mg 1-(2'-chloro-3'-(2,6-dioxopiperidin-3-yl)-3-methyl-[1,1'-biphenyl]-4-yl)-1-(2- hydroxyethyl)-3-methylurea.

[1212] MS (ESI) M / Z: 430.0 [M+H] + .

[1213] 1H NMR (400 MHz, DMSO-d6) δ 10.90 (s, 1H), 7.36 - 7.29 (m, 1H), 7.28 - 7.20 (m, 2H), 7.13 - 6.99 (m, 3H), 6.65 (d, J = 8.4 Hz, 1H), 5.09 (t, J = 5.6 Hz, 1H), 4.31 (dd, J = 12.0, 5.0 Hz, 1H), 4.15 (t, J = 6.0 Hz, 2H), 3.34 (dd, J = 10.8, 5.0 Hz, 2H), 2.84 - 2.70 (m, 1H), 2.58 (d, J = 4.8 Hz, 3H), 2.57 - 2.53 (m, 1H), 2.36 - 2.27 (m, 1H), 2.11 (s, 3H), 2.08 - 1.99 (m, 1H).

[1214] Example 116: Methyl (2'-chloro-3'-(2,6-dioxopiperidin-3-yl)-3-methyl-[1,1'-biphenyl]-4-yl)(2- hydroxyethyl)carbamate

[1215] Reference to the procedure of other examples of the application resulted in 44 mg of methyl (2'-chloro-3'-(2,6-dioxopiperidin-3-yl)-3-methyl-[1,1'-biphenyl]-4-yl)(2- hydroxyethyl)carbamate.

[1216] MS (ESI) M / Z: 431.1 [M+H] + .

[1217] 1 H NMR (400 MHz, DMSO-d6) δ 10.92 (s, 1H), 7.53 - 7.08 (m, 6H), 4.74 (s, 1H), 4.35 (dd, J = 12.0, 5.0 Hz, 1H), 3.82 - 3.37 (m, 7H), 2.85 - 2.73 (m, 1H), 2.58 - 2.56 (m, 1H), 2.38 - 2.29 (m, 1H), 2.19 (s, 3H), 2.10 - 1.99 (m, 1H).

[1218] Example 117: (S)-Tetrahydrofuran-3-yl (2'-chloro-3'-(2,6-dioxopiperidin-3-yl)-3-methyl- [1,1'-biphenyl]-4-yl)carbamate

[1219] Reference to the procedure of other examples of the application resulted in 53 mg of (S)- tetrahydrofuran-3-yl (2'-chloro-3'-(2,6-dioxopiperidin-3-yl)-3-methyl-[1,1'-biphenyl]-4- yl)carbamate.

[1220] MS (ESI) M / Z: 442.9 [M+H] + .

[1221] 1 H NMR (400 MHz, DMSO-d6) δ 10.91 (s, 1H), 9.02 (s, 1H), 7.55 - 7.24 (m, 4H), 7.25 - 7.05 (m, 2H), 5.29 - 5.17 (m, 1H), 4.34 - 4.31 (m, 1H), 3.93 - 3.68 (m, 4H), 2.83 - 2.73 (m, 1H), 2.51 - 2.50 (m, 1H), 2.38 - 2.33 (m, 1H), 2.25 (s, 3H), 2.23 - 2.13 (m, 1H), 2.09 - 1.91 (m, 2H).

[1222] Example 118: (R)-Tetrahydrofuran-3-yl (2'-chloro-3'-(2,6-dioxopiperidin-3-yl)-3-methyl-[1,1'-biphenyl]-4-yl)carbamate

[1223] Reference to the procedure of other examples of the application resulted in 53 mg of (R)-Tetrahydrofuran-3-yl (2'-chloro-3'-(2,6-dioxopiperidin-3-yl)-3-methyl-[1,1'-biphenyl]-4-yl)carbamate.

[1224] MS (ESI) M / Z: 442.9 [M+H] + .

[1225] 1 H NMR (400 MHz, DMSO-d6) δ 10.91 (s, 1H), 9.02 (s, 1H), 7.55 - 7.24 (m, 4H), 7.25 - 7.05 (m, 2H), 5.29 - 5.17 (m, 1H), 4.34 - 4.31 (m, 1H), 3.93 - 3.68 (m, 4H), 2.83 - 2.73 (m, 1H), 2.51 - 2.50 (m, 1H), 2.38 - 2.33 (m, 1H), 2.25 (s, 3H), 2.23 - 2.13 (m, 1H), 2.09 - 1.91 (m, 2H).

[1226] Example 119: 2'-Chloro-3'-(2,6-dioxopiperidin-3-yl)-3-methyl-[1,1'-biphenyl]-4-yl (3S)-3-(hydroxymethyl)morpholine-4-carboxylate

[1227] Reference to the preparation method of other embodiments of the application to obtain 50.3 mg of 2'-chloro-3'-(2,6-dioxopiperidin-3-yl)-3-methyl-[1,1'-biphenyl]-4-yl (3S)-3-(hydroxymethyl)morpholine-4-carboxylate.

[1228] MS (ESI) M / Z: 473.1 [M+H] + .

[1229] 1 H NMR (400 MHz, Methanol-d4) δ 7.36 - 7.32 (m, 1H), 7.32 - 7.27 (m, 3H), 7.23 (dd, J = 8.2, 2.3 Hz, 1H), 7.12 (d, J = 8.3 Hz, 1H), 4.38 (dd, J = 11.9, 5.2 Hz, 1H), 4.26 (dd, J = 11.9, 5.2 Hz, 1H), 4.12 - 3.81 (m, 5H), 3.60 (dd, J = 29.1, 17.3 Hz, 2H), 3.46 (d, J = 14.9 Hz, 1H), 2.83 - 2.74 (m, 1H), 2.69 (dt, J = 13.1, 4.3 Hz, 1H), 2.46 - 2.35 (m, 1H), 2.31 - 2.15 (m, 4H).

[1230] Example 120: 2'-chloro-3'-(2,6-dioxopiperidin-3-yl)-3-methyl-[1,1'-biphenyl]-4-yl (3R)-3-(hydroxymethyl)morpholine-4-carboxylate

[1231] Reference to the preparation method of other embodiments of the application to obtain 50.3 mg of 2'-chloro-3'-(2,6-dioxopiperidin-3-yl)-3-methyl-[1,1'-biphenyl]-4-yl (3R)-3-(hydroxymethyl)morpholine-4-carboxylate.

[1232] MS (ESI) M / Z: 473.1 [M+H] + .

[1233] 1H NMR (400 MHz, Methanol-d4) δ 7.39 - 7.27 (m, 4H), 7.23 (dd, J = 8.2, 2.3 Hz, 1H), 7.12 (d, J = 8.2 Hz, 1H), 4.38 (dd, J = 11.9, 5.2 Hz, 1H), 4.31 - 3.79 (m, 6H), 3.61 (dd, J = 29.1, 17.1 Hz, 2H), 3.45 (s, 1H), 2.86 - 2.62 (m, 2H), 2.46 - 2.35 (m, 1H), 2.31 - 2.15 (m, 4H).

[1234] Example 121 : 2'-chloro-3'-(2,6-dioxopiperidin-3-yl)-3-methyl-[1,1'-biphenyl]-4- methylpiperazine-1-carboxylate

[1235] Reference to the procedure of other examples of the application resulted in 22.45 mg of 2'-chloro-3'-(2,6-dioxopiperidin-3-yl)-3-methyl-[1,1'-biphenyl]-4- methylpiperazine-1-carboxylate.

[1236] MS (ESI) M / Z: 456.2 [M+H] + .

[1237] 1 H NMR (400 MHz, DMSO-d6) δ 10.92 (s, 1H), 7.44 - 7.28 (m, 4H), 7.24 (d, J = 2.3 Hz, 1H), 7.14 (d, J = 8.3 Hz, 1H), 4.34 (dd, J = 12.2, 5.0 Hz, 1H), 3.68 - 3.58 (m, 2H), 3.52 - 3.42 (m, 2H), 2.84 - 2.74 (m, 1H), 2.60 - 2.56 (m, 1H), 2.43 - 2.28 (m, 5H), 2.25 (s, 3H), 2.18 (s, 3H), 2.10 - 2.02 (m, 1H).

[1238] Example 122: 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylazetidine-1- carboxylate

[1239] Reference to the procedure of other examples of the application resulted in 49.60 mg of 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylazetidine-1- carboxylate.

[1240] MS (ESI) M / Z: 413.0 [M+H] + .

[1241] 1 H NMR (400 MHz, DMSO-d6) δ 10.92 (s, 1H), 7.47 - 7.33 (m, 2H), 7.33 - 7.26 (m, 2H), 7.23 (dd, J = 8.3, 2.2 Hz, 1H), 7.14 (d, J = 8.3 Hz, 1H), 4.34 (dd, J = 12.2, 5.0 Hz, 1H), 4.25 - 4.15 (m, 2H), 4.05 - 3.95 (m, 2H), 2.84 - 2.72 (m, 1H), 2.56 (t, J = 3.7 Hz, 1H), 2.40 - 2.23 (m, 3H), 2.19 (s, 3H), 2.09 - 2.01 (m, 1H).

[1242] Example 123: 2'-Chloro-3-(difluoromethyl)-3'-(2,6-dioxopiperidin-3-yl)-[1,1'- biphenyl]-4-ylpyrrolidine-1-carboxylate

[1243] Reference to the procedure of other examples of the application resulted in 20.39 mg of 2'-Chloro-3-(difluoromethyl)-3'-(2,6-dioxopiperidin-3-yl)-[1,1'- biphenyl]-4-ylpyrrolidine-1-carboxylate.

[1244] MS (ESI) M / Z: 463.1 [M+H] + .

[1245] 1 H NMR (400 MHz, DMSO-d6) δ 10.93 (s, 1H), 7.61 (d, J = 6.2 Hz, 2H), 7.50 - 7.35 (m, 4H), 7.17 (t, J = 54.4 Hz, 1H), 4.36 (dd, J = 12.3, 5.0 Hz, 1H), 3.55 (t, J = 6.6 Hz, 2H), 3.37 (t, J = 6.6 Hz, 2H), 2.88 - 2.75 (m, 1H), 2.60 - 2.54 (m, 1H), 2.44 - 2.28 (m, 1H), 2.12 - 2.00 (m, 1H), 1.98 - 1.84 (m, 4H).

[1246] Example 124: 2'-Chloro-3'-(2,6-dioxopiperidin-3-yl)-3-methyl-[1,1'-biphenyl]-4- yl(methyl(prop-2-yn-1-yl)carbamate

[1247] Reference to the preparation method of other embodiments of the application obtained 23.19 mg of 2'-chloro-3'-(2,6-dioxopiperidin-3-yl)-3-methyl-[1,1'-biphenyl]-4- ylmethyl(prop-2-yn-1-yl)carbamate.

[1248] MS (ESI) M / Z: 466.4 [M+MeCN+H] + .

[1249] 1 H NMR (400 MHz, DMSO-d6) δ 10.92 (s, 1H), 7.41-7.35 (m, 4H), 7.25-7.23 (m, 1H), 7.16-7.12 (m, 1H), 4.41-4.25 (m, 2H), 4.16 (s, 1H), 3.38 (s, 1H), 3.13-2.97 (m, 3H), 2.84-2.74 (m, 1H), 2.60-2.55 (m, 1H), 2.38-2.29 (m, 1H), 2.19 (s, 3H), 2.11-2.00 (m, 1H).

[1250] Example 125: 1-(2'-chloro-3'-(2,6-dioxopiperidin-3-yl)-3-methyl-[1,1'-biphenyl]-4-yl)-3- methoxyurea

[1251] Reference to the preparation method of other embodiments of the application obtained 23.23 mg of 1-(2'-chloro-3'-(2,6-dioxopiperidin-3-yl)-3-methyl-[1,1'-biphenyl]-4-yl)-3- methoxyurea.

[1252] MS (ESI) M / Z: 402.3 [M+H] + .

[1253] 1 H NMR (400 MHz, DMSO-d6) δ 10.91 (s, 1H), 9.62 (s, 1H), 8.34 (s, 1H), 7.55 (d, J = 8.0 Hz, 1H), 7.41-7.29 (m, 3H), 7.24 (s, 1H), 7.19 (d, J = 8.0 Hz, 1H), 4.35-4.31 (m, 1H), 3.67 (s, 3H), 2.82-2.74 (m, 1H), 2.58-2.55 (m, 1H), 2.35-2.31 (m, 1H), 2.26 (s, 3H), 2.09-2.01 (m, 1H).

[1254] Example 126: Methyl (2'-chloro-3'-(2,6-dioxopiperidin-3-yl)-[1,1'-biphenyl]-4-yl)(isopropyl)carbamate

[1255] Reference to the procedure of other examples of the invention resulted in 61 mg of methyl (2'-chloro-3'-(2,6-dioxopiperidin-3-yl)-[1,1'-biphenyl]-4-yl)(isopropyl)carbamate.

[1256] MS (ESI) M / Z: 415.1 [M+H] + .

[1257] 1 H NMR (400 MHz, DMSO-d6) δ 10.93 (s, 1H), 7.39 (m, 5H), 7.24 (d, J = 8.4 Hz, 2H), 4.48 - 4.34 (m, 2H), 3.55 (s, 3H), 2.84 - 2.76 (m, 1H), 2.58 - 2.55 (m, 1H), 2.39 - 2.29 (m, 1H), 2.08 - 2.04 (m, 1H), 1.10 (d, J = 6.8 Hz, 6H).

[1258] Example 127: 1-(2'-chloro-3'-(2,6-dioxopiperidin-3-yl)-[1,1'-biphenyl]-4-yl)-1-(cyclopropylmethyl)-3-methylurea

[1259] Reference to the procedure of other examples of the invention resulted in 82 mg of 1-(2'-chloro-3'-(2,6-dioxopiperidin-3-yl)-[1,1'-biphenyl]-4-yl)-1-(cyclopropylmethyl)-3-methylurea.

[1260] MS (ESI) M / Z: 426.0 [M+H] + .

[1261] 1 H NMR (400 MHz, DMSO-d6) δ 10.93 (s, 1H), 7.45 - 7.32 (m, 7H), 5.71 - 5.67 (m, 1H), 4.38 - 4.34 (m, 1H), 3.48 (d, J = 6.8 Hz, 2H), 2.84 - 2.75 (m, 1H), 2.56 (d, J = 4.4 Hz, 3H), 2.54 - 2.53 (m, 1H), 2.40 - 2.29 (m, 1H), 2.08 - 2.04 (m, 1H), 0.98 - 0.88 (m, 1H), 0.39 - 0.34 (m, 2H), 0.09 - 0.05 (m, 2H).

[1262] Example 128: 1 -(2'-chloro-3'-(2,6-dioxopiperidin-3-yl)-[1, 1 '-biphenyl]-4-yl)-1 - cyclopropyl-3-methylurea

[1263] Reference to the preparation method of other embodiments of the present application obtained 30 mg of 1 -(2'-chloro-3'-(2,6-dioxopiperidin-3-yl)-[1, 1 '-biphenyl]-4-yl)-1 - cyclopropyl-3-methylurea.

[1264] MS (ESI) M / Z: 412.1 [M+H] + .

[1265] 1 H NMR (400 MHz, DMSO-d6) δ 10.92 (s, 1 H), 7.58 - 7.18 (m, 7H), 6.56 (d, J=4.4 Hz, 1 H), 4.35 (dd, J=12.0, 5.0 Hz, 1 H), 2.97 - 2.92 (m, 1 H), 2.83 - 2.74 (m, 1 H), 2.68 (d, J=4.4 Hz, 3H), 2.59 - 2.54 (m, 1 H), 2.39 - 2.28 (m, 1 H), 2.16 - 1.96 (m, 1 H), 0.97 - 0.92 (m, 2H), 0.61 - 0.39 (m, 2H).

[1266] Example 129: 1 -(2'-chloro-3'-(2,6-dioxopiperidin-3-yl)-[1, 1 '-biphenyl]-4-yl)-1 - cyclobutyl-3-methylurea

[1267] Reference to the preparation method of other embodiments of the present application obtained 89 mg of 1 -(2'-chloro-3'-(2,6-dioxopiperidin-3-yl)-[1, 1 '-biphenyl]-4-yl)-1 - cyclobutyl-3-methylurea.

[1268] MS (ESI) M / Z: 426.0 [M+H] + .

[1269] 1H NMR (400 MHz, DMSO-d6) δ 10.93 (s, 1H), 7.50-7.48 (m, 2H), 7.45-7.34 (m, 3H), 7.20-7.17 (m, 2H), 5.40-5.36 (m, 1H), 4.79-4.70 (m, 1H), 4.39-4.35 (m, 1H), 2.85-2.76 (m, 1H), 2.58-2.56 (m, 1H), 2.53 (d, J = 4.4 Hz, 3H), 2.40-2.29 (m, 1H), 2.07-2.02 (m, 3H), 1.74-1.64 (m, 2H), 1.56-1.38 (m, 2H).

[1270] Example 130: 2'-chloro-3'-(2,6-dioxopiperidin-3-yl)-3-methyl-[1,1'-biphenyl]-4-yl ((S)-1- hydroxypropan-2-yl)(methyl)carbamate

[1271] Reference to the procedure of other examples of the application resulted in 61.72 mg of 2'-chloro-3'-(2,6-dioxopiperidin-3-yl)-3-methyl-[1,1'-biphenyl]-4-yl ((S)-1- hydroxypropan-2-yl)(methyl)carbamate.

[1272] MS (ESI) M / Z: 445.1 [M+H] + .

[1273] 1 H NMR (400 MHz, DMSO-d6) δ 10.92 (s, 1H), 7.43-7.26 (m, 4H), 7.26-7.19 (m, 1H), 7.16-7.08 (m, 1H), 4.95-4.72 (m, 1H), 4.43-4.05 (m, 2H), 3.57-3.38 (m, 2H), 2.99-2.74 (m, 4H), 2.58-2.54 (m, 1H), 2.39-2.28 (m, 1H), 2.19 (s, 3H), 2.10-1.99 (m, 1H), 1.21-1.00 (m, 3H).

[1274] Example 131: 2'-chloro-3'-(2,6-dioxopiperidin-3-yl)-3-methyl-[1,1'-biphenyl]-4-yl ((R)-1- hydroxypropan-2-yl)(methyl)carbamate

[1275] Reference to the preparation method of other embodiments of the application to obtain 47.26 mg of 2'-chloro-3'-(2,6-dioxopiperidin-3-yl)-3-methyl-[1,1'-biphenyl]-4-yl((R)-1- hydroxypropan-2-yl)(methyl)carbamate.

[1276] MS (ESI) M / Z: 445.1 [M+H] + .

[1277] 1 H NMR (400 MHz, DMSO-d6) δ 10.92 (s, 1H), 7.44 - 7.26 (m, 4H), 7.25 - 7.19 (m, 1H), 7.15 - 7.08 (m, 1H), 4.96 - 4.70 (m, 1H), 4.43 - 4.06 (m, 2H), 3.58 - 3.36 (m, 2H), 2.98 - 2.75 (m, 4H), 2.59 - 2.54 (m, 1H), 2.40 - 2.27 (m, 1H), 2.19 (s, 3H), 2.10 - 2.00 (m, 1H), 1.21 - 1.05 (m, 3H).

[1278] Example 132: N-(2'-chloro-3'-(2,6-dioxopiperidin-3-yl)-3-methyl-[1,1'-biphenyl]-4- yl)azetidine-1-carboxamide

[1279] Reference to the preparation method of other embodiments of the application to obtain 44 mg of N-(2'-chloro-3'-(2,6-dioxopiperidin-3-yl)-3-methyl-[1,1'-biphenyl]-4-yl)azetidine-1- carboxamide.

[1280] MS (ESI) M / Z: 412.3 [M+H] + .

[1281] 1 H NMR (400 MHz, DMSO-d6) δ 10.91 (s, 1H), 7.72 (s, 1H), 7.46 - 7.26 (m, 4H), 7.23 - 7.11 (m, 2H), 4.35 - 4.31 (m, 1H), 3.97 - 3.94 (m, 4H), 2.88 - 2.72 (m, 1H), 2.56 (d, J=3.7 Hz, 1H), 2.41 - 2.29 (m, 1H), 2.27 - 2.14 (m, 5H), 2.11 - 1.98 (m, 1H).

[1282] Example 133: N-(2'-chloro-3'-(2,6-dioxopiperidin-3-yl)-3-methyl-[1,1'-biphenyl]-4-yl)-3- cyanohomocyclobutane-1-carboxamide

[1283] Reference to the preparation method of other embodiments of the application, 55 mg of N-(2'-chloro-3'-(2,6-dioxopiperidin-3-yl)-3-methyl-[1,1'-biphenyl]-4-yl)-3- cyanohomocyclobutane-1-carboxamide was obtained.

[1284] MS (ESI) M / Z: 437.3 [M+H] + .

[1285] 1 H NMR (400 MHz, DMSO-d6) δ 10.91 (s, 1H), 8.09 (s, 1H), 7.43-7.27 (m, 4H), 7.24-7.03 (m, 2H), 4.35-4.31 (m, 1H), 4.27-4.23 (m, 2H), 4.11-4.08 (m, 2H), 3.81-3.73 (m, 1H), 2.83-2.68 (m, 1H), 2.55 (d, J = 10.5 Hz, 1H), 2.35-2.29 (m, 1H), 2.24 (s, 3H), 2.07-2.03 (m, 1H).

[1286] Example 134: 1-(2'-chloro-3'-(2,6-dioxopiperidin-3-yl)-3-methyl-[1,1'-biphenyl]-4-yl)-3- methylurea

[1287] Reaction Scheme:

[1288] Operation Steps:

[1289] Step A: 4-bromo-2-methylaniline (0.3 g, 1.62 mmol) was dissolved in N,N-dimethylformamide (5 mL), potassium carbonate (671 mg, 4.86 mmol) and methylcarbamoyl chloride (451 mg, 4.86 mmol) were added. Stirring at 80°C for 3 hours.

[1290] LCMS was used to monitor the completion of the reaction. The reaction solution was quenched with water (20 mL), extracted with ethyl acetate (20 mL x 3), the combined organic phase was washed with saturated brine (30 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography to obtain 150 mg of 1-(4-bromo-2-methylphenyl)-3-methylurea.

[1291] MS (ESI) m / z: 243.1 [M+H]+ .

[1292] Step B: To a solution of 1-(4-bromo-2-methylphenyl)-3-methylurea (110 mg, 0.456 mmol) and INT-2 (80 mg, 0.228 mmol) in 1,4-dioxane (5 mL) and water (1 mL) was added (1,1'- bis(diphenylphosphino)ferrocene)palladium(II) dichloride (17 mg, 23 μmol) and sodium bicarbonate (38 mg, 0.46 mmol). The air was replaced by nitrogen three times. It was heated to 80 °C and stirred for 20 min.

[1293] LCMS monitoring showed the disappearance of starting material. The reaction was concentrated under reduced pressure. The resulting crude product was purified by high performance liquid chromatography to give 17.6 mg of 1-(2'-chloro-3'-(2,6-dioxopiperidin-3-yl)-3-methyl-[1,1'-biphenyl]-4-yl)-3-methylurea.

[1294] MS (ESI) M / Z: 386.1 [M+H] + .

[1295] 1 H NMR (400 MHz, DMSO-d6) δ 10.90 (s, 1H), 7.89 (d, J = 8.3 Hz, 1H), 7.74 (s, 1H), 7.40 - 7.22 (m, 3H), 7.20 - 7.09 (m, 2H), 6.48 (q, J = 4.6 Hz, 1H), 4.33 (dd, J = 12.2, 5.0 Hz, 1H), 2.83 - 2.68 (m, 1H), 2.67 (d, J = 4.5 Hz, 3H), 2.58 - 2.52 (m, 1H), 2.37 - 2.30 (m, 1H), 2.22 (s, 3H), 2.10 - 1.98 (m, 1H).

[1296] Example 135: 2-Methoxyethyl (2'-chloro-3'-(2,6-dioxopiperidin-3-yl)-3-methyl-[1'- biphenyl]-4-yl)carbamate

[1297] Reference to the preparation method of other embodiments of the application gave 14.1 mg of 2-methoxyethyl (2'-chloro-3'-(2,6-dioxopiperidin-3-yl)-3-methyl-[1'- biphenyl]-4-yl)carbamate.

[1298] MS (ESI) M / Z: 431.1 [M+H] + .

[1299] 1H NMR (400 MHz, DMSO-d6) δ 10.91 (s, 1H), 9.03 (s, 1H), 7.47 - 7.26 (m, 4H), 7.24 - 7.14 (m, 2H), 4.33 (dd, J = 12.3, 5.0 Hz, 1H), 4.20 (t, J = 4.6 Hz, 2H), 3.58 (t, J = 4.6 Hz, 2H), 3.30 (s, 3H), 2.87 - 2.70 (m, 1H), 2.56 (d, J = 3.8 Hz, 1H), 2.37 - 2.30 (m, 1H), 2.25 (s, 3H), 2.14 - 1.97 (m, 1H).

[1300] Example 136: 2-Methoxyethyl N-(4-(2-chloro-3-(2,6-dioxopiperidin-3-yl)phenyl)-2- methylphenyl)carbamate

[1301] Reaction Scheme:

[1302] Procedure:

[1303] Step A: To a solution of 4-bromo-2-methylaniline (250 mg, 1.34 mmol) and N,N- diisopropylethylamine (0.52 g, 4.03 mmol) in tetrahydrofuran (5 mL) was added to a solution of 3-(4-bromo-2-methoxyphenyl)-l-(2-methoxyethyl)-l-methylurea (250 mg, 0.68 mmol) in tetrahydrofuran (5 mL) was added triphosgene (280 mg, 0.94 mmol) and stirred at room temperature for 10 min. Then (2-methoxyethyl)(methyl)amine (240 mg, 2.68 mmol) was added. Stirred at room temperature for 2 h.

[1304] LCMS was used to monitor the reaction. The reaction was diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with saturated brine (30 mL x 2), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to give 3-(4-bromo-2-methoxyphenyl)-l-(2-methoxyethyl)-l- methylurea (250 mg, 0.68 mmol).

[1305] MS (ESI) m / z: 300.1 [M+H] + .

[1306] Step B: To a solution of 3-(4-bromo-2-methoxyphenyl)-l-(2-methoxyethyl)-l- methylurea (136 mg, 0.46 mmol) and INT-2 (80 mg, 0.228 mmol) in 1,4-dioxane (5 mL) and water (1 mL) was added (l,l'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride (17 mg, 23 μmol) and sodium bicarbonate (38 mg, 0.46 mmol). The air was replaced by nitrogen for three times. Heated to 80 °C and stirred for 20 min.

[1307] LCMS monitoring showed the disappearance of the starting material, diluted with water (10 mL), extracted with dichloromethane (10 mL x 3), the combined organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, the obtained crude was purified by high performance liquid chromatography to give 30.9 mg of 2-methoxyethyl N-(4-(2-chloro-3-(2,6-dioxopiperidin-3-yl)phenyl)-2- methylphenyl)carbamate.

[1308] MS (ESI) M / Z: 444.1 [M+H] + .

[1309] 1 H NMR (400 MHz, DMSO-d6) δ 10.91 (s, 1H), 7.82 (s, 1H), 7.45 (d, J = 8.2 Hz, 1H), 7.41 - 7.25 (m, 3H), 7.23 - 7.11 (m, 2H), 4.33 (dd, J = 12.1, 5.0 Hz, 1H), 3.61 - 3.40 (m, 4H), 3.32 (s, 3H), 2.96 (s, 3H), 2.87 - 2.70 (m, 1H), 2.61 - 2.52 (m, 1H), 2.37 - 2.30 (m, 1H), 2.09 - 1.99 (m, 1H).

[1310] Example 137: 2'-chloro-3'-(2,6-dioxopiperidin-3-yl)-3-methyl-[1'-biphenyl]-4-yl-(2- (dimethylamino)ethyl)(methyl)carbamate

[1311] Reference to the preparation method of other embodiments of the application gave 1.84 mg of 2'-chloro-3'-(2,6-dioxopiperidin-3-yl)-3-methyl-[1'-biphenyl]-4-yl-(2- (dimethylamino)ethyl)(methyl)carbamate hydrochloride.

[1312] MS (ESI) M / Z: 458.2 [M+H] + .

[1313] 1H NMR (400 MHz, DMSO-d6) δ 10.92 (s, 1H), 9.85 (d, J = 44.4 Hz, 2H), 7.45 - 7.34 (m, 2H), 7.34 - 7.28 (m, 2H), 7.28 - 7.21 (m, 2H), 4.34 (dd, J = 12.2, 5.0 Hz, 1H), 3.88 - 3.80 (m, 1H), 3.73 - 3.65 (m, 1H), 3.40 - 3.28 (m, 2H), 3.14 - 3.10 (m, 2H), 3.00 - 2.06 (m, 1H), 2.85 (m, 6H), 2.81 - 2.73 (m, 1H), 2.61 - 2.53 (m, 1H), 2.39 - 2.33 (m, 1H), 2.21 (s, 3H), 2.08 - 2.00 (m, 1H).

[1314] Example 138: Methyl (2'-chloro-3'-(2,6-dioxopiperidin-3-yl)-[1,1'-biphenyl]-4-yl)(cyclopropyl)carbamate

[1315] Reference to the procedures of other examples herein resulted in 2.0 mg of methyl (2'-chloro-3'-(2,6-dioxopiperidin-3-yl)-[1,1'-biphenyl]-4-yl)(cyclopropyl)carbamate.

[1316] MS (ESI) M / Z: 413.2 [M+H] + .

[1317] 1 H NMR (400 MHz, DMSO-d6) δ 10.92 (s, 1H), 7.42 - 7.31 (m, 7H), 4.37 - 4.33 (m, 1H), 3.65 (s, 3H), 3.32 - 3.07 (m, 1H), 2.83 - 2.75 (m, 1H), 2.57 - 2.50 (m, 1H), 2.34 - 2.29 (m, 1H), 2.07 - 2.02 (m, 1H), 0.84 - 0.79 (m, 2H), 0.40 - 0.46 (m, 2H).

[1318] Example 139: (R)-Tetrahydrofuran-3-yl (2'-chloro-3'-(2,6-dioxopiperidin-3-yl)-3-methyl-[1,1'-biphenyl]-4-yl)carbamate

[1319] Reference to the procedures of other examples herein resulted in 53 mg of (R)-tetrahydrofuran-3-yl (2'-chloro-3'-(2,6-dioxopiperidin-3-yl)-3-methyl-[1,1'-biphenyl]-4-yl)carbamate.

[1320] MS (ESI) M / Z: 443.0 [M+H] + .

[1321] 1 H NMR (400 MHz, DMSO-d6) δ 10.91 (s, 1H), 9.02 (s, 1H), 7.68 - 7.25 (m, 4H), 7.21 - 7.17 (m, 2H), 5.44 - 4.88 (m, 1H), 4.35 - 4.31 (m, 1H), 3.96 - 3.62 (m, 4H), 2.86 - 2.72 (m, 1H), 2.59 - 2.51 (m, 1H), 2.39 - 2.30 (m, 1H), 2.25 (s, 3H), 2.18 - 2.14 (m, 1H), 2.09 - 1.92 (m, 2H).

[1322] Example 140: l-(2'-chloro-3'-(2,6-dioxopiperidin-3-yl)-[l,l'-biphenyl]-4-yl)-3-methyl- 1-( 1 -methylcyclopropyl) urea

[1323] Reference to the procedure of other examples of the application resulted in 33 mg of l-(2'-chloro-3'-(2,6-dioxopiperidin-3-yl)-[l,l'-biphenyl]-4-yl)-3-methyl- 1-( 1 -methylcyclopropyl) urea.

[1324] MS (ESI) m / z: 425.9 [M+H] + .

[1325] 1 H NMR (400 MHz, DMSO-d6) δ 10.92 (s, 1H), 7.47 - 7.30 (m, 5H), 7.24 (d, J=8.4 Hz, 2H), 6.14 (d, J=4.4 Hz, 1H), 4.37 - 4.33 (m, 1H), 2.84 - 2.75 (m, 1H), 2.67 (d, J=4.4 Hz, 3H), 2.56 - 2.50 (m, 1H), 2.43 - 2.24 (m, 1H), 2.07 - 2.02 (m, 1H), 1.47 (s, 3H), 0.81 - 0.75 (m, 4H).

[1326] Example 141: l-(2'-chloro-3'-(2,6-dioxopiperidin-3-yl)-[l,l'-biphenyl]-4-yl)-l- (cyclopropylmethyl)-3-methyl urea

[1327] Reference to the preparation method of other embodiments of the application to obtain 82 mg of 1-(2'-chloro-3'-(2,6-dioxopiperidin-3-yl)-[1,1'-biphenyl]-4-yl)-1- (cyclopropylmethyl)-3-methylurea.

[1328] MS (ESI) M / Z: 426.0 [M+H] + .

[1329] 1 H NMR (400 MHz, DMSO-d6) δ 10.93 (s, 1H), 7.45-7.32 (m, 7H), 5.71-5.67 (m, 1H), 4.38-4.34 (m, 1H), 3.48 (d, J = 6.8 Hz, 2H), 2.84-2.75 (m, 1H), 2.56 (d, J = 4.4 Hz, 3H), 2.54-2.53 (m, 1H), 2.40-2.29 (m, 1H), 2.08-2.04 (m, 1H), 0.98-0.88 (m, 1H), 0.39-0.34 (m, 2H), 0.09-0.05 (m, 2H).

[1330] Example 143: 1-(2'-chloro-3'-(2,6-dioxopiperidin-3-yl)-[1,1'-biphenyl]-4-yl)-1- cyclobutyl-3-methylurea

[1331] Reference to the preparation method of other embodiments of the application to obtain 82 mg of 1-(2'-chloro-3'-(2,6-dioxopiperidin-3-yl)-[1,1'-biphenyl]-4-yl)-1- (cyclopropylmethyl)-3-methylurea.

[1332] MS (ESI) M / Z: 426.0 [M+H] + .

[1333] 1 H NMR (400 MHz, DMSO-d6) δ 10.93 (s, 1H), 7.45-7.32 (m, 7H), 5.71-5.67 (m, 1H), 4.38-4.34 (m, 1H), 3.48 (d, J = 6.8 Hz, 2H), 2.84-2.75 (m, 1H), 2.56 (d, J = 4.4 Hz, 3H), 2.54-2.53 (m, 1H), 2.40-2.29 (m, 1H), 2.08-2.04 (m, 1H), 0.98-0.88 (m, 1H), 0.39-0.34 (m, 2H), 0.09-0.05 (m, 2H).

[1334] Example 144: 1 -Methylazetidin-3-yl (2'-chloro-3'-(2,6-dioxopiperidin-3-yl)-3- methyl-[1, 1 '-biphenyl]-4-yl)carbamate formate salt

[1335] Reference to the procedure for preparing the other examples of the invention gave 60.21 mg of 1 -methylazetidin-3-yl (2'-chloro-3'-(2,6-dioxopiperidin-3-yl)-3- methyl-[1, 1 '-biphenyl]-4-yl)carbamate formate salt.

[1336] MS (ESI) M / Z: 442.3 [M+H] + .

[1337] 1 H NMR (400 MHz, DMSO-d6) δ 10.92 (s, 1H), 9.10 (s, 1H), 8.18 (s, 1H), 7.43-7.40 (m, 1H), 7.39-7.32 (m, 2H), 7.30-7.27 (m, 1H), 7.25-7.16 (m, 2H), 5.03-4.91 (m, 1H), 4.35-4.31 (m, 1H), 3.75-3.63 (m, 2H), 3.17-3.08 (m, 2H), 2.85-2.73 (m, 1H), 2.56-2.54 (m, 1H), 2.34 (s, 3H), 2.32-2.29 (m, 1H), 2.25 (s, 3H), 2.10-1.98 (m, 1H).

[1338] Example 145: 2'-chloro-3'-(2,6-dioxopiperidin-3-yl)-3-methyl-[1, 1 '-biphenyl]-4-yl (1- (hydroxymethyl)cyclopropyl)(methyl)carbamate

[1339] Reference to the procedure for preparing the other examples of the invention gave 100 mg of 2'-chloro-3'-(2,6-dioxopiperidin-3-yl)-3-methyl-[1, 1 '-biphenyl]-4-yl (1- (hydroxymethyl)cyclopropyl)(methyl)carbamate.

[1340] MS (ESI) M / Z: 457.0 [M+H] + .

[1341] 1H NMR (400 MHz, DMSO-d6) δ 10.92 (s, 1H), 7.42-7.34 (m, 2H), 7.32-7.29 (m, 2H), 7.24-7.22 (m, 1H), 7.13 (d, J = 8.0 Hz, 1H), 4.94-4.93 (m, 1H), 4.36-4.32 (m, 1H), 3.59-3.50 (m, 2H), 3.05 (d, J = 60.8 Hz, 3H), 2.84-2.75 (m, 1H), 2.57-2.53 (m, 1H), 2.39-2.29 (m, 1H), 2.19 (d, J = 10.4 Hz, 3H), 2.07-2.03 (m, 1H), 0.99-0.81 (m, 4H).

[1342] Example 146: N-(2'-chloro-3'-(2,6-dioxopiperidin-3-yl)-3-methyl-[1,1'-biphenyl]-4-yl)-3- (methylsulfonyl)azetidine-1-carboxamide

[1343] Reference to the procedure of other examples of the application resulted in 101.54 mg of N-(2'-chloro-3'-(2,6-dioxopiperidin-3-yl)-3-methyl-[1,1'-biphenyl]-4-yl)-3-(methylsulfonyl)azetidine-1- carboxamide.

[1344] MS (ESI) M / Z: 490.1 [M+H] + .

[1345] 1 H NMR (400 MHz, DMSO-d6) δ 10.91 (s, 1H), 8.11 (s, 1H), 7.42-7.27 (m, 4H), 7.24-7.20 (m, 1H), 7.17 (m, J = 8.2, 1.8 Hz, 1H), 4.38-4.21 (m, 4H), 4.19-4.10 (m, 2H), 3.04 (s, 3H), 2.85-2.72 (m, 1H), 2.59-2.54 (m, 1H), 2.39-2.30 (m, 1H), 2.24 (s, 3H), 2.10-2.00 (m, 1H).

[1346] Example 147: (3R)-N-(2'-chloro-3'-(2,6-dioxopiperidin-3-yl)-3-methyl-[1,1'-biphenyl]-4-yl)-3- hydroxypyrrolidine-1-carboxamide

[1347] Reference to the preparation method of other embodiments of the application obtained 28.85 mg (3R)-N-(2'-chloro-3'-(2,6-dioxopiperidin-3-yl)-3-methyl-[1,1'-biphenyl]-4-yl)-3- hydroxypyrrolidine-1-carboxamide.

[1348] MS (ESI) M / Z: 442.0 [M+H] + .

[1349] 1 H NMR (400 MHz, DMSO-d6) δ 10.91 (s, 1H), 7.54 (s, 1H), 7.45 - 7.26 (m, 4H), 7.20 (d, J=2.0 Hz, 1H), 7.18 - 7.12 (m, 1H), 4.97 (d, J=3.6 Hz, 1H), 4.37 - 4.25 (m, 2H), 3.53 - 3.40 (m, 3H), 3.29 (s, 1H), 2.86 - 2.72 (m, 1H), 2.58 - 2.53 (m, 1H), 2.39 - 2.30 (m, 1H), 2.25 (s, 3H), 2.09 - 1.90 (m, 2H), 1.88 - 1.77 (m, 1H).

[1350] Example 148: 1-(4-(2-chloro-3-(2,6-dioxopiperidin-3-yl)phenyl)-2-methylphenyl)-3-(2- methoxyethyl)urea

[1351] Reference to the preparation method of other embodiments of the application obtained 36.81 mg 1-(4-(2-chloro-3-(2,6-dioxopiperidin-3-yl)phenyl)-2-methylphenyl)-3-(2- methoxyethyl)urea.

[1352] MS (ESI) M / Z: 430.1 [M+H] + .

[1353] 1H NMR (400 MHz, DMSO-d6) δ 10.90 (s, 1H), 7.95 (d, J = 8.4 Hz, 1H), 7.82 (s, 1H), 7.42 - 7.24 (m, 3H), 7.21 - 7.06 (m, 2H), 6.76 (t, J = 5.5 Hz, 1H), 4.32 (dd, J = 12.2, 5.0 Hz, 1H), 3.41 (t, J = 5.3 Hz, 2H), 3.30 (s, 3H), 3.28 (d, J = 5.4 Hz, 2H), 2.86 - 2.72 (m, 1H), 2.58 - 2.53 (m, 1H), 2.36 - 2.30 (m, 1H), 2.22 (s, 3H), 2.10 - 1.98 (m, 1H).

[1354] Example 149: 3-(2'-chloro-3'-(2,6-dioxopiperidin-3-yl)-3-methyl-[1,1'-biphenyl]-4-yl)-1-(2-(dimethylamino)ethyl)-1-methylurea (formate salt)

[1355] Reference to the procedure of other examples of the application resulted in 19.03 mg of 3-(2'-chloro-3'-(2,6-dioxopiperidin-3-yl)-3-methyl-[1,1'-biphenyl]-4-yl)-1-(2-(dimethylamino)ethyl)-1-methylurea.

[1356] MS (ESI) M / Z: 457.1 [M+H] + .

[1357] 1 H NMR (400 MHz, DMSO-d6) δ 10.91 (s, 1H), 8.47 (s, 1H), 8.20 (d, J = 3.7 Hz, 1H), 7.44 - 7.27 (m, 4H), 7.23 - 7.07 (m, 2H), 4.33 (dd, J = 12.1, 5.0 Hz, 1H), 3.41 (t, J = 5.9 Hz, 2H), 2.94 (s, 3H), 2.86 - 2.70 (m, 1H), 2.56 (t, J = 3.7 Hz, 1H), 2.47 (s, 2H), 2.39 - 2.29 (m, 1H), 2.29 - 2.16 (m, 9H), 2.09 - 1.99 (m, 1H).

[1358] Example 150: 2'-chloro-3-cyclopropyl-3'-(2,6-dioxopiperidin-3-yl)-[1,1'-biphenyl]-4-yl-(2-hydroxyethyl)(methyl)carbamate

[1359] Reference to the preparation method of other embodiments of the application to obtain 24.69 mg of 2'-chloro-3-cyclopropyl-3'-(2,6-dioxopiperidin-3-yl)-[1,1'-biphenyl]-4-yl-(2-hydroxyethyl)(methyl)carbamate.

[1360] MS (ESI) M / Z: 457.2 [M+H] + .

[1361] 1 H NMR (400 MHz, DMSO-d6) δ 10.92 (s, 1H), 7.43 - 7.28 (m, 3H), 7.20 (d, J = 7.7 Hz, 1H), 7.11 (t, J = 7.4 Hz, 1H), 7.02 - 6.87 (m, 1H), 4.82 (dt, J = 34.6, 5.4 Hz, 1H), 4.34 (dd, J = 12.2, 5.0 Hz, 1H), 3.66 (t, J = 5.7 Hz, 1H), 3.58 (d, J = 5.7 Hz, 1H), 3.52 (t, J = 5.8 Hz, 1H), 3.36 (t, J = 6.0 Hz, 1H), 3.07 (d, J = 67.3 Hz, 3H), 2.84 - 2.74 (m, 1H), 2.56 (d, J = 3.9 Hz, 1H), 2.37 - 2.26 (m, 1H), 2.08 - 2.00 (m, 1H), 2.00 - 1.88 (m, 1H), 0.96 - 0.87 (m, 2H), 0.72 - 0.64 (m, 2H).

[1362] Example 151 : 7-(2-chloro-3-(2,6-dioxopiperidin-3-yl)phenyl)-N-ethyl-2,3- dihydrobenzo[e][1,4]oxazepine-1(5H)-carboxamide

[1363] Reference to the preparation method of other embodiments of the application to obtain 39.54 mg of 7-(2-chloro-3-(2,6-dioxopiperidin-3-yl)phenyl)-N-ethyl-2,3- dihydrobenzo[e][1,4]oxazepine-1(5H)-carboxamide.

[1364] MS (ESI) M / Z: 442.2 [M+H] + .

[1365] 1H NMR (400 MHz, DMSO-d6) δ 10.93 (s, 1H), 7.48 - 7.23 (m, 6H), 6.11 (t, J = 5.6 Hz, 1H), 4.64 - 4.49 (m, 2H), 4.36 (dd, J = 12.2, 5.0 Hz, 1H), 3.74 (s, 2H), 3.14 - 3.02 (m, 2H), 2.90 - 2.72 (m, 1H), 2.56 - 2.54 (m, J = 3.9 Hz, 1H), 2.54 - 2.52 (m, 2H), 2.41 - 2.31 (m, 1H), 2.10 - 2.00 (m, 1H), 1.01 (t, J = 7.1 Hz, 3H).

[1366] Example 152: 2-Hydroxyethyl-7-(2-chloro-3-(2,6-dioxopiperidin-3-yl)phenyl)- 2,3-dihydrobenzo[e][l,4]oxazepine-l(5H)-carboxylate

[1367] Reference to the procedure of other examples of the application resulted in 27.75 mg of 2-hydroxyethyl-7-(2-chloro-3-(2,6-dioxopiperidin-3-yl)phenyl)-2,3- dihydrobenzo[e][l,4]oxazepine-l(5H)-carboxylate.

[1368] MS (ESI) M / Z: 459.2 [M+H] + .

[1369] 1 H NMR (400 MHz, DMSO-d6) δ 10.92 (s, 1H), 7.71 - 6.97 (m, 6H), 4.78 (s, 1H), 4.60 (s, 2H), 4.35 (dd, J = 12.2, 5.0 Hz, 1H), 4.11 (s, 2H), 3.84 (s, 2H), 3.56 (s, 2H), 2.84 - 2.74 (m, 1H), 2.62 - 2.55 (m, 1H), 2.55 - 2.50 (m, 2H), 2.42 - 2.31 (m, 1H), 2.12 - 1.96 (m, 1H).

[1370] Example 153: 3-(2'-chloro-3'-(2,6-dioxopiperidin-3-yl)-3-methyl-[l,l'-biphenyl]-4-yl)- 1-(1-(hydroxymethyl)cyclopropyl)-l-methylurea

[1371] Reference to the preparation method of other embodiments of the application to obtain 48.29 mg of 3-(2'-chloro-3'-(2,6-dioxopiperidin-3-yl)-3-methyl-[1,1'-biphenyl]-4-yl)-1-(1-(hydroxymethyl)cyclopropyl)-1-methylurea.

[1372] MS (ESI) M / Z: 456.3 [M+H] + .

[1373] 1 H NMR (400 MHz, DMSO-d6) δ 10.91 (s, 1H), 8.39 (s, 1H), 7.85 (d, J = 8.4 Hz, 1H), 7.39-7.26 (m, 3H), 7.18-7.12 (m, 2H), 5.75 (s, 1H), 4.34-4.30 (m, 1H), 3.33 (s, 2H), 2.88 (s, 3H), 2.84-2.73 (m, 1H), 2.56-2.49 (m, 1H), 2.39-2.31 (m, 1H), 2.27 (s, 3H), 2.10-1.99 (m, 1H), 0.98 (s, 4H).

[1374] Example 154: N-(4-(2-chloro-3-(2,6-dioxopiperidin-3-yl)phenyl)-2-methylphenyl)-3-(dimethylamino)azetidine-1-carboxamide

[1375] Reference to the preparation method of othe...

Claims

A compound represented by the following formula (II), a pharmaceutically acceptable salt thereof, an isomer thereof, or a nitroxide thereof, characterized by wherein X is CR 4 or N; Ring A is selected from C 6-10 aryl, 5-10 membered heteroaryl, 5-10 membered heterocyclyl; L1is selected from a chemical bond, C 1-6 alkylene, C 2-6 alkenylene, C 2-6 alkynylene, wherein any methylene unit is optionally replaced by -O-, -C(O)-, -N(R a )-, -S-, -S(O)-, -S(O)2-; Ring B is selected from C 6-10 aryl, 5-10 membered heteroaryl, 5-12 membered heterocyclyl, C 5-12 bridged cycloalkyl, C 5-12 spirocycloalkyl, 5-12 membered bridged heterocyclyl, 5-12 membered spiroheterocyclyl; R is selected from R 2-1 , R 2-2 ; R 1 selected from hydrogen, deuterium, cyano, halogen, oxo, thia, hydroxy, C 1-6 alkyl, haloC 1-6 alkyl, deuteratedC 1-6 alkyl, hydroxyC 1-6 alkyl, cyanoC 1-6 alkyl, C 2-6 alkenyl, haloC 2-6 alkenyl, deuteratedC 2-6 alkenyl, C 2-6 alkynyl, haloC 2-6 alkynyl, deuteratedC 2-6 alkynyl, C 1-6 alkoxy, haloC 1-6 alkoxy, deuteratedC 1-6 alkoxy, (C 1-6 alkyl)2P(O)-, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 1-6 alkyl-S(=O)(=NH)-, (R d )(R e )N-, C 1-6 alkoxy-C 1-6 alkylene-, C 1-6 alkyl-S(O)2-, C 1-6 alkoxy-C(O)-, C 1-6 alkyl-C(O)-, (R d )(R e )N-C(O)-C 1-6 alkylene, C 3-6 cycloalkyl-O-, 3-6 membered heterocyclyl-O-; R 2-1 selected from hydrogen, deuterium, cyano, halogen, oxo, thia, hydroxy, C 1-6 alkyl, halogen-C 1-6 alkyl, hydroxy-C 1-6 alkyl, cyano-C 1-6 alkyl, C 2-6 alkenyl, halogen-C 2-6 alkenyl, deuterated-C 2-6 alkenyl, C 2-6 alkynyl, halogen-C 2-6 alkynyl, deuterated-C 2-6 alkynyl, C 1-6 alkoxy, halogen-C 1-6 alkoxy, (C 1-6 alkyl)2P(O)-, C 1-6 alkyl-S(=O)(=NH)-, (R d )(R e )N-, C 1-6 alkoxy-C 1- 6alkylene-, C 1-6 alkyl-S(O)2-, C 1-6 alkoxy-C(O)-, C 1-6 alkyl-C(O)-, (R d )(R e )N-C(O)-C 1-6 alkylene, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 3-6 cycloalkyl-O-, 3-6 membered heterocyclyl-O-, (R d )(R e )N-C(O)-, (R d )(R e )N-C(O)O-, C 1-6 alkyl-C(O)-NR d -, C 1-6 alkoxy-C(O)-NR d -, C 1-6 alkoxy-C 1-6 alkylene-C(O)-, (R d )(R e )N-C(O)NR d -, (R d )(R e )N-C 1-6 alkylene-C(O)-, C 1-6 alkoxy-C 1-6 alkylene-OC(O)-, hydroxy-C 1-6 alkyl-NR d -, hydroxy-C 1-6 alkoxy-C(O)-, hydroxy-C 1-6 alkyl, haloC d -,(Rd)(Re)N-S(O)2-, 3-6 membered heterocyclyl, 5-6 membered heteroaryl, deuterated C 1-6 alkyl, haloC 1-6 alkyl, haloC 1-6 alkyl, haloC 1-6 alkyl, haloC 1-6 alkyl, haloC 1-6 alkyl, haloC R 2-2 selected from hydrogen, deuterium, cyano, halogen, oxo, thioxo, hydroxy, C 1-6 alkyl, halogenated C 1-6 alkyl, hydroxy C 1-6 alkyl, cyano C 1-6 alkyl, deuterated C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, halogenated C 2-6 alkenyl, deuterated C 2-6 alkenyl, halogenated C 2-6 alkynyl, deuterated C 2-6 alkynyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, deuterated C 1-6 alkoxy, (C 1-6 alkyl)2P(O)-, C 1-6 alkyl-S(=O)(=NH)-, (R d )(R e )N-, C 1-6 alkoxy-C 1-6 alkylene-, C 1-6 alkyl-S(O)2-, C 1-6 alkoxy-C(O)-, C 1- 6alkyl-C(O)-, (R d )(R e )N-C(O)-C 1-6 alkylene, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 3-6 cycloalkyl-O-, 3-6 membered heterocyclyl-O-, (R d )(R e )N-C(O)-, (R d )(R e )N-C(O)O-, C 1-6 alkyl-C(O)-NR d -, C 1-6 alkoxy-C(O)-NR d -, C 1-6 alkoxy-C 1-6 alkylene-C(O)-, (R d )(R e )N-C(O)NR d -, (Rd)(Re)N-C 1-6 alkylene-C(O)-, C 1-6 alkoxy-C 1-6 alkylene-OC(O)-, hydroxy C 1-6 alkyl-NR d -, (R d )(R e )N-S(O)2-, 1-6 alkyl, haloC 1-6 alkyl, haloC d alkyl, haloC 1-6 alkyl, haloC 1-6 alkyl, haloC d alkyl, haloC d alkyl, haloC e alkyl, haloC d alkyl, haloC d alkyl, haloC g alkyl, haloC h alkyl, haloC 3-6 alkyl, haloC 3-6 alkyl, haloC d alkyl, haloC 1-6 alkyl, haloC 1-6 alkyl, haloC 1-6 alkyl, haloC 1-6 alkyl, haloC 1-6 alkyl, haloC 2-6 alkyl, haloC 2-6 alkyl, haloC 2-6 alkyl, haloC 2-6 alkyl, haloC 2-6 alkyl, haloC 2-6 alkyl, haloC 1-6 alkyl, haloC 1-6 alkyl, haloC 1-6 alkyl, haloC L2is selected from a chemical bond, C 1-6 alkylene, *-N(R b )-C 1-6 alkylene, *-N(R b )-C(O)-, -C(O)-, -N(R b )-, -O-, -S-, -S(O)-, -S(O)2-, -S(=O)(=NH)-, -P(O)-, *-OCO-, *-O-C(O)-N(R b )-, *-O-C 1-6 alkylene-, *-N(R b )-C(O)-O-, *-N(R b )-C(O)-N(R b )-; the * indicates the point of attachment to ring B; wherein said C 1-6 alkylene, *-N(R b )-C 1-6 alkylene-, *-O-C 1-6 alkylene- is optionally substituted with one or more halo, hydroxy, cyano, C 1-6 alkyl, hydroxyC 1-6 alkyl; R a , R b are each independently selected from hydrogen, C 1-6 1-6alkyl, haloC 1-6 1-6alkyl, C 1-6 1-6alkoxy, haloC 1-6 1-6alkoxy, C 1-6 1-6alkyl-C(O)-, (R a-1 )(R b-1 )N-C(O)-, C 1-6 1-6alkoxy-C(O)-; R a-1 , R b-1 are each independently selected from hydrogen, C 1-6 alkyl, haloC 1-6 alkyl; Ring C is selected from 5-10 membered aryl, 5-10 membered heteroaryl, 5-12 membered heterocyclyl, C 3-6 cycloalkyl, C 3-6 cycloalkenyl, 8-12 membered fused heteroaryl; R 3 selected from hydrogen, deuterium, cyano, halogen, oxo, thioxo, amino, hydroxy, C 1-6 alkyl, halogenated C 1-6 alkyl, deuterated C 1-6 alkyl, hydroxy C 1-6 alkyl, cyano C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, halogenated C 2-6 alkenyl, halogenated C 2-6 alkynyl, deuterated C 2-6 alkenyl, deuterated C 2-6 alkynyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, deuterated C 1-6 alkoxy, hydroxy C 1-6 alkoxy, (C 1-6 alkyl)2P(O)-, C 1-6 alkyl-S(=O)(=NH)-, (R j )(R k )N-, C 1-6 alkoxy-C 1-6 alkylene-, C 1-6 alkyl-S(O)2-, C 1-6 alkoxy-C(O)-, C 1- 6alkyl-C(O)-, (R j )(R k )N-C(O)-C 1-6 alkylene, =NR f , (R j )(R k )N-C1-6alkylene-, C 1-6 alkoxy-C 1-6 alkylene-O-, halogenated C 1-6 alkoxy-C 1-6 alkylene-, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 3-6 cycloalkyl-O-, 3-6 membered heterocyclyl-O-, 5-6 membered heteroaryl, C 1-6 alkoxy-C(O)N(R j )-C 1-6 alkylene, (R j )(R k )N-C(O)-, (R j )(R k )N-C(O)-O-, (R j )(R k )N-C(O)N(R j )-, deuterium substituted halogenated C 1-6 alkyl, haloC 1-6 alkoxy, 3-6 membered heterocyclyl-O-C(O)-N(R j )-; wherein said C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 3-6 cycloalkyl-O-, 3-6 membered heterocyclyl-O-, 3-6 membered heterocyclyl-O-C(O)-N(R j )-optionally substituted with one or more groups selected from the group consisting of hydroxy, cyano, C 1-6 alkyl, haloC 1-6 alkyl, hydroxyC 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkoxy; R f selected from CN, C 1-6 alkyl, haloC 1-6 alkyl, C 1-6 alkyl-C(O)-; R g , R h are each independently selected from C 1-6 alkyl, haloC 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl; R d , R e , R j , R k are each independently selected from hydrogen, deuterium, cyano, halogen, oxo, thioxo, amino, hydroxy, C 1-6 alkyl, haloC 1-6 alkyl, deuterated C 1-6 alkyl, hydroxyC 1-6 alkyl, cyanoC 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, haloC 2-6 alkenyl, haloC 2-6 alkynyl, deuterated C 2-6 alkenyl, deuterated C 2-6 alkynyl, C 1-6 alkoxy, haloC 1-6 alkoxy, deuterated C 1-6 alkoxy, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 5-8 membered bridged cyclyl, C 1-6 alkoxy-C 1-6 alkylene, (R d-1 )(R e-1 )N-, (R d-1 )(R e-1 )N-C(O)-, (R d- 1 )(R e-2 )N-C 1-6 alkylene, C 3-6 cycloalkyl-C 1-6 alkylene, C 1-6 alkyl-C(O)-, C 1-6 alkoxy-C(O)-, C 1-6 alkyl-S(O)2-, (R d-1 )(R e-2 )N-C(O)-C 1-6 alkylene, 5-6 membered heteroaryl, C 1-6 alkyl-S(O)2-C 1-6 alkylene, haloC 1-6 alkoxy-C 1-6 alkylene, or R d , R e and the N atom to which they are attached collectively form a 3-6 membered heterocyclyl, 3-12 membered spiroheterocyclyl, 6-12 membered fused heterocyclyl, wherein said C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 3-6 cycloalkyl-C 1-6 alkylene, 5-6 membered heteroaryl, 3-12 membered spiroheterocyclyl, 6-12 membered fused heterocyclyl optionally substituted with one or more groups selected from hydroxy, cyano, halo, amino, C 1-6 alkyl, haloC 1-6 alkyl, hydroxyC 1- 6alkyl, cyanoC 1-6 alkyl, deuteratedC 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkoxy, deuteratedC 1-6 alkoxy, (R d-2 )(R e-2 )N-C(O)-C 1-6 alkylene, (R d-1 )(R e-1 )N-, C 1-6 alkoxy-C 1-6 alkylene, haloC 1-6 alkoxy-C 1-6 alkylene, =CH2, C 1-6 alkyl-S(O)2-; R d-1 , R e-1 are each independently selected from H, C 1-6 alkyl, haloC 1-6 alkyl, or R d-1 , R e-1 and the N atom to which they are attached together form a 3-6 membered heterocyclyl; said 3-6 membered heterocyclyl is selected from the group consisting of hydroxy, halo, amino, C 1-6 alkyl, haloC 1-6 alkyl, hydroxyC 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkyl; R d-2 , R e-2 are each independently selected from the group consisting of H, C 1-6 alkyl, haloC 1-6 alkyl; or R 1 and R 2-1 together with the atom to which they are attached form a group selected from 3-6 membered heterocyclyl, C 3-6 cycloalkenyl, C 3-6 cycloalkyl; or R 2-1 and R 3 together with the atom to which they are attached form a ring E, which is selected from the group consisting of 3-8 membered heterocyclyl, C 3-8 cycloalkenyl, C 3-8 cycloalkyl, 5-6 membered heteroaryl; or two R 2-1 with the ring atom to which it is attached to form a group optionally substituted with one or more Rc: C 3-6 C1-6alkyl, C 3-6 C3-6cycloalkyl, 3-6 membered heterocyclyl, or, two R3on the same ring atom, together with the ring atom to which they are attached, form a group optionally substituted with one or more Rc: C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 3-6 cycloalkenyl; R c selected from hydrogen, halogen, oxo, thioxo, C 1-6 alkyl, haloC 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkoxy, C 1-6 alkoxy-C 1-6 alkylene-; R 4 selected from hydrogen, cyano, halogen, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy; m, p, q, t are independently selected from 0, 1, 2, 3, 4, 5. The compound of Formula (II) as claimed in claim 1, a pharmaceutically acceptable salt thereof, an isomer thereof or a nitroxide thereof, characterized in that, The compound of formula (II) is a compound of formula (I): wherein X is CR 4 or N; Ring A is selected from C 6-10 aryl, 5-10 membered heteroaryl, 5-10 membered heterocyclyl; L1is selected from a chemical bond, C 1-6 alkylene, C 2-6 alkenylene, C 2-6 alkynylene, wherein any methylene unit is optionally replaced by -O-, -C(O)-, -N(R a )-, -S-, -S(O)-, -S(O)2-; Ring B is selected from the group consisting of absent, C 6-10 aryl, 5-10 membered heteroaryl, 5-12 membered heterocyclyl, C 5-12 spirocycloalkyl, 5-12 membered spiroheterocyclyl; and 5-12 spirocycloalkyl, 5-12 membered spiroheterocyclyl; and L2is selected from the group consisting of absent, a chemical bond, C 1-6 alkylene, *-N(Rb)-C 1-6 alkylene-, *-N(R b )-C(O)-, -C(O)-, -N(R b )-, -O-, -S-, -S(O)-, -S(O)2-, -S(=O)(=NH)-, -P(O)-, *-OC(O)-, *-O-C(O)-N(Rb)-, *-O-C 1- 6alkylene-, -OC(O)-N(R b )-; the * indicates attachment to ring B; wherein said C 1-6 alkylene, *-N(Rb)-C 1-6 alkylene-, *-O-C 1-6 alkylene- is optionally substituted with one or more halo, hydroxy, cyano, hydroxyC 1-6 alkyl; R a , R b are each independently selected from the group consisting of hydrogen, C 1-6 1-6alkyl, C 1-6 1-6alkyl-C(O)-, (R a-1 )(R b-2 )N-C(O)-, C 1-6 1-6alkoxy-C(O)-; R a-1 , R b-1 are each independently selected from hydrogen, C 1-6 alkyl; Ring C is selected from the group consisting of absent, 5-10 membered heteroaryl, 5-12 membered heterocyclyl, C 3-6 cycloalkyl, C 3-6 cycloalkenyl, 8-12 membered fused heteroaryl; R 1 selected from hydrogen, cyano, halogen, oxo, thia, C 1-6 alkyl, C 2-6 alkenyl, C 1-6 alkynyl, haloC 1-6 alkyl, haloC 1- 6alkoxy, (C 1-6 alkyl)2P(O)-, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 1-6 alkyl-S(=O)(=NH)-, (R d )(R e )N-, C 1-6 alkoxy-C 1-6 alkylene-, hydroxyC 1-6 alkyl, cyanoC 1-6 alkyl, hydroxy, C 1-6 alkyl-S(O)2-, C 1-6 alkoxy-C(O)-, C 1-6 alkyl-C(O)-, (R d )(R e )N-C(O)-C 1-6 alkylene, C 3-6 cycloalkyl-O-, 3-6 membered heterocyclyl-O-, C 2-6 alkenyl, C 2-6 alkynyl, haloC 2-6 alkenyl, haloC 2-6 alkynyl, deuterated C 2-6 alkynyl; R 2 selected from hydrogen, cyano, halogen, oxo, thia, C 1-6 alkyl, deuterated C 1-6 alkyl, C 2-6 alkynyl, C 1-6 alkoxy, halogenated C 1- 6alkyl, halogenated C 1-6 alkoxy, (C 1-6 alkyl)2P(O)-, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 1-6 alkyl-S(=O)(=NH)-, (R d )(R e )N-, C 1-6 alkoxy-C 1-6 alkylene-, hydroxy C 1-6 alkyl, cyano C 1-6 alkyl, hydroxy, C 1-6 alkyl-S(O)2-, C 1-6 alkoxy-C(O)-, C 1-6 alkyl-C(O)-, (R d )(R e )N-C(O)-C 1-6 alkylene, C 3-6 cycloalkyl-O-, 3-6 membered heterocyclyl-O-, C 2-6 alkenyl, halogenated C 2-6 alkenyl, halogenated C 2-6 alkynyl, deuterated C 2-6 alkynyl, (R d )(R e )N-C(O)-, (R d )(R e )N-C(O)O-, (R d )(R e )N-C(O)-C(O)NR d -, C 1-6 alkyl-C(O)-NR d -, C 1-6 alkoxy-C(O)-NR d -, hydroxy C 1-6 alkoxy-C(O)-N(R d )-, C 1-6 alkoxy-C 1-6 alkylene-C(O)-, (R d )(R e )N-C(O)NR d -, (R d )(R e )N-C 1-6 alkylene-C(O)-, C 1-6 alkyl-C(O)-NR 1-6 alkylene-OC(O)-, hydroxy C 1-6 alkyl-NR d -; R 3 selected from hydrogen, cyano, halogen, oxo, thioxo, C 1-6 alkyl, C 2-6 alkynyl, C 1-6 alkoxy, halogenated C 1-6 alkyl, halogenated C 1- alkoxy, deuterated C 1-6 alkoxy, deuterium substituted halogenated C 1-6 alkoxy, (C 1-6 alkyl)2P(O)-, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 1-6 alkyl-S(=O)(=NH)-, (R d )(R e )N-, C 1-6 alkoxy-C 1-6 alkylene-, hydroxy C 1-6 alkyl, cyano C 1-6 alkyl, hydroxy, C 1-6 alkyl-S(O)2-, C 1-6 alkoxy-C(O)-, C 1-6 alkyl-C(O)-, (R d )(R e )N-C(O)-C 1-6 alkylene, C 3-6 cycloalkyl-O-, 3-6 membered heterocyclyl-O-, amino, C 2-6 alkenyl, halogenated C 2-6 alkenyl, halogenated C 2-6 alkynyl, deuterated C 2-6 alkynyl, =NR f , (R d )(R e )N-C 1-6 alkylene-, hydroxy C 1-6 alkoxy, C 1-6 alkoxy-C 1-6 alkylene-O-, halogenated C 1-6 alkoxy-C 1-6 alkylene-, 5-6 membered heteroaryl, C 1-6 alkoxy-C(O)N(R d )-C 1-6 alkylene, (R d )(R e )N-C(O)-; wherein said C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 3- 6cycloalkyl-O-, 3-6 membered heterocyclyl-O- optionally substituted with one or more selected from hydroxy, CN, C 1-6 alkyl, halogenated C 1-6 alkyl, hydroxy C 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 substituted by a group of alkyl, C R f selected from CN, C 1-6 alkyl, C 1-6 alkyl-C(O)-; R d , R e are each independently selected from hydrogen, C 1-6 alkyl, haloC 1-6 alkyl, C 3-6 cycloalkyl, C 5-8 bridged cycloalkyl, deuterated C 1-6 alkyl, 3-6 membered heterocyclyl, hydroxyC 1-6 alkyl, C 1-6 alkoxy-C 1-6 alkylene, C 2-6 alkenyl, C 2-6 alkynyl, (R d-1 )(R e-2 )N-C 1-6 alkylene, C 3-6 cycloalkyl-C 1-6 alkylene, C 1-6 alkoxy, said C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 3-6 cycloalkyl-C 1-6 alkylene is optionally substituted with one or more groups selected from hydroxy, C 1-6 alkyl, haloC 1-6 alkyl, hydroxyC 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkyl; R d-1 , R e-1 are each independently selected from the group consisting of H, C 1-6 alkyl, haloC 1-6 alkyl; or, R 1 and R 2 together with the atom to which they are attached form a 3-6 membered heterocyclyl, C c cycloalkenyl, C 3-6 cycloalkyl group optionally substituted with one or more R 3-6 substituents; Or, R 2 and R 3 Together with the atoms they are attached to, they form an array that is optionally bounded by one or more R atoms. c Substitution of the following groups: 3-8 membered heterocyclic groups, C 3-8 Cycloalkenyl, C 3-8 cycloalkyl, 5-6 membered heteroaryl; or, two R 2 together with the ring atom to which they are attached form an optionally substituted group selected from C c 3-6 C1-6alkyl, C 3-6 C3-6cycloalkyl, C3-6cycloalkenyl, 3-6 membered heterocyclyl,​ or, two R on the same ring atom 3 with the ring atom to which it is attached to form an optionally substituted group: c substituted with one or more R 3-6 C1-6alkyl, C2-6alkenyl, C2-6alkynyl, haloalkyl, cycloalkyl, 3-6 membered 3-6 heterocyclyl, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, haloalkyl, cycloalkyl, 3-6 membered R c selected from hydrogen, halogen, oxo, thioxo, C 1-6 alkyl, haloC 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkoxy, C 1-6 alkoxy-C 1-6 alkylene-; R 4 selected from hydrogen, cyano, halogen, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy; m, n, p, q are independently selected from 0, 1, 2, 3, 4, 5. The compound, pharmaceutically acceptable salt thereof, isomer thereof, or nitrogen oxide thereof according to claim 1, characterized in that, Ring A is selected from phenyl, naphthyl, 5-6 membered heteroaryl, 5-6 membered heterocyclyl; or, R 1 selected from hydrogen, cyano, halogen, oxo, C 2-4 alkynyl, C 3-4 cycloalkyl, 3-4 membered heterocyclyl, deuterated C 2-4 alkynyl; preferably selected from halogen and C 2-4 alkynyl. The compound, the pharmaceutically acceptable salt thereof, the isomer thereof or the nitroxide thereof according to claim 1 or 2, wherein Ring A is selected from phenyl; or, R 1 selected from H, CN, F, CI, I, oxo, ethynyl, cyclopropyl, deuterated ethynyl; preferably selected from CI and ethynyl; Preferably, the structural unit selected from the group consisting of The "*" end indicates the connection with X. The compound, the pharmaceutically acceptable salt thereof, the isomer thereof or the nitroxide thereof according to any one of claims 1 to 4, wherein Ring B is selected from phenyl, 5-9 membered heteroaryl, 5-11 membered heterocyclyl, 5-8 membered bridged cycloalkyl; Preferably, Ring B is selected from phenyl, 5-6 membered heteroaryl, 8-11 membered fused heterocyclyl; Preferably, Ring B is selected from phenyl, benzo 5-7 membered heterocyclyl; Preferably, Ring B is selected from phenyl, benzo 5-7 membered heterocyclyl; wherein the ring B structure contains 1-4 atoms or atom groups selected from N, S(O) 0-2 , O, C(O) in the heterocyclic group; Preferably, ring B is selected from phenyl, wherein ring D is selected from 5-7 membered heterocyclyl, wherein said heterocyclyl contains 1-4 atoms or atom groups selected from N, S(O) 0-2 , O, C(O) and the asterisked end indicates the end attached to L1. The compound, pharmaceutically acceptable salt thereof, isomer thereof, or nitrogen oxide thereof according to any one of claims 1 to 5, wherein Structural unit selected from the group consisting of t-1 is selected from 0, 1, 2, 3, 4; preferably 0, 1, 2, 3. The compound, the pharmaceutically acceptable salt thereof, the isomer thereof or the nitroxide thereof according to any one of claims 1 to 6, wherein R 2-1 selected from hydrogen, deuterium, cyano, halogen, oxo, thia, C 1-4 alkyl, halogenated C 1-4 alkyl, deuterated C 1-4 alkyl, hydroxy C 1- 4alkyl, cyano C 1-4 alkyl, C 2-4 alkenyl, halogenated C 2-4 alkenyl, deuterated C 2-4 alkenyl, C 2-4 alkynyl, halogenated C 2-4 alkynyl, deuterated C 2- 4alkynyl, C 1-4 alkoxy, halogenated C 1-4 alkoxy, deuterated C 1-4 alkoxy, C 3-6 membered cycloalkyl; or two R on the same ring atom 2-1 with the ring atom to which it is attached to form a group 3-6 C1-6alkyl, C 3-6 C3-6cycloalkyl, 3-6 membered Alternatively, two R atoms located on adjacent ring atoms 2-1 Together with the ring atoms to which they are attached, they form the following groups, which may be optionally substituted with one or more Rc groups: C 3-6 Cycloalkyl, C 3-6 Cycloalkenyl, 3-6 membered heterocyclic groups; R is selected from hydrogen, cyano, halogen, C 2-1 alkyl, deuterated C 1-4 alkyl, C 1-4 alkyl, C 1-4 alkoxy; More preferably, R 2-1 selected from halogen, C 1-4 alkyl and deuterated C1-4alkyl. The compound, pharmaceutically acceptable salt thereof, isomer thereof, or nitrogen oxide thereof according to any one of claims 1 to 7, wherein R 2-2 selected from hydrogen, deuterium, cyano, halogen, oxo, thioxo, hydroxy, C 1-4 alkyl, halogenated C 1-4 alkyl, hydroxy C 1-4 alkyl, cyano C 1-4 alkyl, deuterated C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halogenated C 2-4 alkenyl, deuterated C 2-4 alkenyl, halogenated C 2-4 alkynyl, deuterated C 2-4 alkynyl, C 1-4 alkoxy, halogenated C 1-4 alkoxy, deuterated C 1-4 alkoxy, (R d )(R e )N-, (R d )(R e )N-C(O)O-, C 1-4 alkoxy-C 1-4 alkylene-, C 1-4 alkyl-S(O)2-, C 1-4 alkoxy-C(O)-, C 1-4 alkyl-C(O)-, (R d )(R e )N-C(O)-C 1-4 alkylene, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 3-6 cycloalkyl-O-, 3-6 membered heterocyclyl-O-, (R d )(R e )N-C(O)-, (R d )(R e )N-C(O)O-, C 1-4 alkyl-C(O)-NR d -, C 1-4 alkoxy-C(O)-NR d -, C 1-4 alkoxy-C 1-4 alkylene-C(O)-, (R d )(R e )N-C(O)NR d -, (R d )(R e )N-C 1-4 alkylene-C(O)-, C 1-4 alkoxy-C 1-4 alkylene-OC(O)-, hydroxy C 1-4 alkyl-NR d -, (R d )(R e )N-S(O)2-, 1-4 alkyl, haloC 1-4 alkylene-O-C(O)N(R d )-, hydroxyC 1-4 alkyl, haloC 1-4 alkyl, haloC d alkyl, haloC d alkyl, haloC e alkyl, haloC d alkyl, haloC d alkyl, haloC g alkyl, haloC h alkyl, haloC 3-6 alkyl, haloC 3-6 alkyl, haloC d alkyl, haloC 1-4 alkyl, haloC 1-4 alkyl, haloC 1-4 alkyl, haloC 1-4 alkyl, haloC 1-4 alkyl, haloC 2-4 alkyl, haloC 2-4 alkyl, haloC 2-4 alkyl, haloC 2-4 alkyl, haloC 2-4 alkyl, haloC 2-4 alkyl, haloC 1-4 alkyl, haloC 1-4 alkyl, haloC 1-4 alkyl, haloC L2is selected from a chemical bond, C 1-4 alkylene, *-N(R b )-C 1-4 alkylene-, *-N(R b )-C(O)-, *-N(R b )-C(O)-N(R b )-, *-OC(O)-, -C(O)-; R b selected from hydrogen, C 1-4 alkyl, (R a-1 )(R b-2 )N-C(O)-; R a-1 , R b-1 are each independently selected from hydrogen, C 1-4 alkyl, haloC 1-4 alkyl; The ring C is selected from 4-6 membered heterocyclic groups, 5-6 membered heteroaryl groups, and C. 3-6 cycloalkyl; R d , R e are each independently selected from hydrogen, deuterium, cyano, halogen, oxo, thioxo, amino, hydroxy, C 1-4 alkyl, haloC 1-4 alkyl, deuterated C 1-4 alkyl, hydroxyC 1-4 alkyl, cyanoC 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, haloC 2-4 alkenyl, haloC 2-4 alkynyl, deuterated C 2-4 alkenyl, deuterated C 2-4 alkynyl, C 1-4 alkoxy, haloC 1-4 alkoxy, deuterated C 1-4 alkoxy, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 1-4 alkoxy-C 1-4 alkylene, (R d-1 )(R e-1 )N-, (R d-1 )(R e-1 )N-C(O)-, (R d-1 )(R e-2 )N-C 1-4 alkylene, C 3- 6cycloalkyl-C 1-4 alkylene, C 1-4 alkyl-C(O)-, C 1-4 alkoxy-C(O)-, C 1-4 alkyl-S(O)2-, (R d-1 )(R e-1 )N-C(O)-C 1-4 alkylene, 5-6 membered heteroaryl, C 1-4 alkyl-S(O)2-C 1-4 alkylene, haloC 1-4 alkoxy-C 1-4 alkylene, or R d , R e and the N atom to which they are attached together form a 3-6 membered heterocyclyl, 3-8 membered spiroheterocyclyl, 8-12 membered fused heterocyclyl, wherein the C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 3-6 cycloalkyl-C 1-4 alkylene, 5-6 membered heteroaryl, 3-12 membered spiroheterocyclyl, 6-12 membered fused heterocyclyl is optionally substituted with one or more selected from hydroxy, cyano, halogen, amino, C 1-4 alkyl, haloC 1-4 alkyl, hydroxyC 1-4 alkyl, cyano C 1-4 alkyl, deuterated C 1-4 alkyl, C 1-4 alkoxy, halo C 1-4 alkoxy, deuterated C 1-4 alkoxy, (R d-2 )(R e-2 )N-C(O)-C 1-4 alkylene, (R d-2 )(R e- 2 )N-, C 1-4 alkoxy-C 1-4 alkylene, halo C 1-4 alkoxy-C 1-4 alkylene, =CH2, C 1-4 alkyl-S(O)2-; R d-1 , R e-1 are each independently selected from the group consisting of H, C 1-4 alkyl, haloC 1-4 alkyl, or R d-1 , R e-1 and the N atom to which they are attached together form a 3-6 membered heterocyclyl; said 3-6 membered heterocyclyl is selected from the group consisting of hydroxy, halo, amino, C 1-4 alkyl, haloC 1-4 alkyl, hydroxyC 1-4 alkyl, C 1-4 alkoxy, haloC 1-4 alkyl; R d-2 , R e-2 are each independently selected from H, C 1-4 alkyl, haloC 1-4 alkyl; R g , R h are each independently selected from the group consisting of C 1-4 alkyl, C 3-6 cycloalkyl; with the proviso that the following molecules are excluded; Preferably, R 2-2 selected from , C 1-4 alkyl-C(O)-, (R 1-4 )(R d )N-C(O)-, (R e )(R d )N-C(O)O-, e (R d )(R e )N-C(O)-C(O)-N(R d )-, (R d )(R e )N-C(O)NR d - and hydroxyC 1-6 alkyl-C(O)-N(R d )-; R a-1 , R b-1 are each independently selected from hydrogen, C 1-4 alkyl; L2is selected from a chemical bond, *-N(R b )-C(O)- and *-N(R b )-C(O)-N(R b ) R b selected from C 1-4 alkyl; Ring C is selected from 4-6 membered heterocyclyl; R d , R e are each independently selected from the group consisting of hydrogen, C 1-4 alkyl, halo-C 1-4 alkyl, C 3-6 cycloalkyl, deuterated C 1-4 alkyl, C 1-4 alkoxy-C 1-4 alkylene, and C 2-4 alkynyl; More preferably, R d , R e are each independently selected from hydrogen, C 1-4 alkyl, C 3-6 cycloalkyl, deuterated C 1-4 alkyl, and C 2-4 alkynyl. The compound, pharmaceutically acceptable salt thereof, isomer thereof, or nitrogen oxide thereof of any one of claims 1-8, wherein R 3 selected from hydrogen, deuterium, cyano, halogen, oxo, thioxo, amino, hydroxy, C 1-4 alkyl, haloC 1-4 alkyl, deuterated C 1- 6alkyl, C 2-4 alkenyl, C 2-4 alkynyl, haloC 2-4 alkenyl, haloC 2-4 alkynyl, deuterated C 2-4 alkenyl, deuterated C 2-4 alkynyl, C 1-4 alkoxy, haloC 1-4 alkoxy, deuterated C 1-4 alkoxy, deuterium-substituted haloC 1-4 alkyl, deuterium-substituted haloC 1-4 alkoxy, C 3-6 cycloalkyl-O-, (R j )(R k )N-C 1-4 alkylene-, (R j )(R k )N-C(O)N(R j )-, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 3-6 cycloalkyl-O-, 3-6 membered heterocyclyl-O-; wherein said C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 3-6 cycloalkyl-O-, 3-6 membered heterocyclyl-O- are optionally substituted with one or more groups selected from hydroxy, cyano, C 1-4 alkyl, haloC 1-4 alkyl, hydroxyC 1-4 alkyl, C 1-4 alkoxy, haloC 1-4 alkoxy; or, two R groups located on the same ring atom 3 together with the ring atom to which they are attached form an optionally substituted group selected from C c alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl; R g , R h are each independently selected from C 1-4 alkyl, haloC 1-4 alkyl, C 1-4 alkoxy, haloC 1-4 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl; R j , R k are each independently selected from hydrogen, deuterium, cyano, halogen, oxo, thioxido, amino, hydroxy, C 1-4 alkyl, haloC 1-4 alkyl, deuterated C 1-4 alkyl, hydroxyC 1-4 alkyl, cyanoC 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, haloC 2-4 alkenyl, haloC 2-4 alkynyl, deuterated C 2-4 alkenyl, deuterated C 2-4 alkynyl, C 1-4 alkoxy, haloC 1-4 alkoxy, deuterated C 1-4 alkoxy; Or, R 2-1 and R 3 Together with the atoms they are attached to, they form an array that is optionally bounded by one or more R atoms. c The substituted ring E is selected from 3-8 membered heterocyclic groups; R c selected from hydrogen, halogen, oxo, thioxo, C 1-4 alkyl, haloC 1-4 alkyl, C 1-4 alkoxy, haloC 1-4 alkoxy, C 1-4 alkoxy-C 1-4 alkylene-; Preferably, R 3 selected from hydrogen, halogen, oxo, C 1-4 alkyl, C 1-4 alkoxy, halogenated C 1-4 alkoxy, deuterated C 1-4 alkoxy, deuterium-substituted halogenated C 1-4 alkyl, C 1-4 alkoxy-C 1-4 alkylene-, cyano C 1-4 alkyl, hydroxyl and C 3-6 cycloalkyl-O-; More preferably, R 3 selected from hydrogen, oxo, C 1-4 alkoxy, haloC 1-4 alkoxy, deuterated C 1-4 alkoxy, deuterium-substituted haloC 1-4 alkyl or hydroxy. The compound, pharmaceutically acceptable salt thereof, isomer thereof, or nitrogen oxide thereof according to any one of claims 1-9, wherein R 2-1 selected from hydrogen, halogen, C 1-4 alkyl, halogen-C 1-4 alkyl, deuterium-C 1-4 alkyl, C 1-4 alkoxy, halogen-C 1-4 alkoxy, deuterium-C 1-4 alkoxy; R 2-2 selected from (R d )(R e )N-C(O)NR d -; R d , R e are each independently selected from hydrogen, C 1-4 alkyl, haloC 1-4 alkyl, deuterated C 1-4 alkyl, C 1-4 alkoxy, haloC 1-4 alkoxy, deuterated C 1-4 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, haloC 2-4 alkenyl, haloC 2-4 alkynyl, deuterated C 2-4 alkenyl, deuterated C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 5-6 bridged cyclyl; or R d , R e and the N atom to which they are attached together form a 3-6 membered heterocyclyl; wherein said 3-6 membered heterocyclyl is optionally substituted with one or more groups selected from hydroxyl, halogen, C 1-4 alkyl, haloC 1-4 alkyl, deuterated C 1-4 alkyl, cyanoC 1-4 alkyl, C 1-4 alkoxy, haloC 1-4 alkoxy, deuterated C 1-4 alkoxy, C 1-4 alkoxy-C 1-4 alkylene; with the proviso that the following molecules are excluded; The compound, pharmaceutically acceptable salt thereof, isomer thereof, or nitrogen oxide thereof according to any one of claims 1-10, wherein Ring C is selected from Preferably, R 2-1 and R 3 Together with the atoms it is attached to, they form a ring E, which is selected from... Preferably, ring B, R 2-1 , L 2 , ring C, R 3 together form the following structural fragment: The compound, pharmaceutically acceptable salt thereof, isomer thereof, or nitrogen oxide thereof of any one of claims 1-11, wherein R 2-1 selected from H, F, CI, CN, -CH3, -CD3, -OCH3; or two R on the same ring atom are taken together to form a cyclopropyl group; 2-1 together to form a cyclopropyl group; or two R on adjacent ring atoms together are 2-1 together form a cyclopropyl group; R 2-2 selected from H, The compound, the pharmaceutically acceptable salt thereof, the isomer thereof or the nitroxide thereof according to any one of claims 1 to 12, is selected from the structures shown below, wherein t-1 is selected from 0, 1, 2, 3, 4; R 1 , R 2-1 , R 2-2 , L2, ring C, R 3 , ring E, R d , R e , R, ring D, p are as described in any one of claims 1-12. a compound, a pharmaceutically acceptable salt thereof, an isomer thereof, or a nitroxide thereof, selected from, A pharmaceutical preparation comprising a compound, a pharmaceutically acceptable salt, an isomer thereof or a nitroxide thereof of any one of claims 1-14, and a pharmaceutically acceptable carrier(s). Use of a compound, a pharmaceutically acceptable salt, an isomer thereof or a nitroxide thereof of any one of claims 1-14, or a pharmaceutical preparation of claim 15, in the manufacture of a medicament for treating a VAV1-mediated related disease. The use of claim 16, wherein the VAV1-mediated related disease is selected from a disease caused by or associated with a disorder in lymphocyte development or activation, an autoimmune disease or an inflammatory disease, a disorder or a condition caused by or associated with a disorder in T cell receptor signaling, a disorder or a condition caused by or associated with a VAV1 polymorphism. The use of claim 16, wherein the VAV1-mediated related disease is an autoimmune disease selected from multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus, Hashimoto's thyroiditis, myasthenia gravis, type I or type II diabetes and related diseases thereof, vasculitis, pernicious anemia, Sjogren's syndrome, uveitis, psoriasis, Graves' ophthalmopathy, alopecia areata, an allergic disease (e.g., allergic asthma, atopic dermatitis, allergic rhinitis / conjunctivitis, allergic contact dermatitis, an inflammatory disease optionally with underlying abnormal reactions (e.g., inflammatory bowel disease, Crohn's disease or ulcerative colitis, intrinsic asthma, inflammatory lung injury, inflammatory liver injury, inflammatory glomerular injury), atherosclerosis, osteoarthritis, irritant contact dermatitis and further eczematous dermatitis, seborrheic dermatitis, cutaneous manifestations of immune-mediated diseases, inflammatory eye disease, keratoconjunctivitis, myocarditis or hepatitis.

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