STAT6-selective degrader compound and use thereof

Abstract

A compound of formula (I) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, a pharmaceutical composition containing same, and a use thereof in preparation of a drug for preventing or treating STAT6-mediated diseases.

Description

STAT6 selective degrader compounds and uses thereof

[0001] Cross-reference to Related Applications

[0002] This disclosure claims priority to and the benefit of Chinese Patent Application No. 202410459150.2, filed on April 16, 2024, Chinese Patent Application No. 202411000309.0, filed on July 24, 2024, Chinese Patent Application No. 202411377135.X, filed on September 30, 2024, Chinese Patent Application No. 202411954847.3, filed on December 27, 2024, and Chinese Patent Application No. 202510236485.2, filed on February 28, 2025, the contents of all of the above applications are incorporated herein by reference. TECHNICAL FIELD

[0003] The present disclosure belongs to the field of medicine, and relates to a signal transduction and activator of transcription (STAT) selective degrader compound or a pharmaceutically acceptable salt thereof, a pharmaceutical composition containing the same, and use thereof as a STAT selective degrader in the prevention or treatment of related diseases. BACKGROUND

[0004] IL-4 and IL-13 are key cytokines that induce and maintain type 2 inflammatory responses, and are associated with a variety of allergic diseases, such as atopic dermatitis, asthma, chronic obstructive pulmonary disease (COPD), and food allergy. STAT6 signaling is essential for IL-4 and IL-13-induced diseases. After IL-4 or IL-13 binds to the receptor (IL-4Rα / γc or IL-4Rα / IL-13Rα1), the tyrosine residues of IL-4Rα on the receptor are phosphorylated by JAK1, JAK3 or Tyk2, and then STAT6 is recruited to the phosphorylated tyrosine residues and phosphorylates Tyr641 on STAT6. Phosphorylated STAT6 dimerizes through SH2 domain-pTyr641 interaction, and then translocates to the nucleus, transferring and transmitting the signal from the cytoplasm to the nucleus, and activating the expression of downstream related genes. The expression of these genes is crucial for the balance between host immune defense and allergic inflammatory responses.

[0005] STAT6 is a key factor in the IL-4 / IL-13 / STAT6 signaling pathway. STAT6 plays a crucial role in the pathogenesis of allergic asthma. Studies have found that the level of STAT6 in the bronchial epithelium of asthma patients is elevated. STAT6 knockout mice do not produce airway hyperresponsiveness (AHR) or lung pathology associated with asthma, including Th2 cell accumulation, chemokine production, airway eosinophilia, peribronchial inflammation, and epithelial mucus metaplasia. In addition, gain-of-function mutations in STAT6 lead to severe allergic disorders, characterized by atopic dermatitis, eosinophilia, and elevated IgE. About 40% of diffuse large B-cell lymphoma (DLBCL) patients will relapse after first-line treatment. Studies have shown that STAT6 D419 mutations are enriched in relapsed / refractory DLBCL (rrDLBCL) samples, and STAT6 D419 mutations lead to changes in cell autonomy, enhanced signaling, and changes in tumor microenvironment composition, thereby improving the survival of DLBCL. Therefore, STAT6 inhibitors also have potential therapeutic effects on these tumor patients. Inhibiting the activity of STAT6 is expected to become a new model for the treatment of type 2 inflammatory diseases and tumors.

[0006] Currently, several therapies targeting the IL-4 / IL-13 signaling pathway are being studied, including anti-IL-13 monoclonal antibodies and IL-4 receptor antagonists. Among them, Dupixent is a monoclonal antibody targeting IL-4R, which has been approved by the FDA for the treatment of type 2 inflammatory diseases including atopic dermatitis, asthma, chronic sinusitis with nasal polyps, nodular prurigo, and eosinophilic esophagitis. Lebrikizumab is a monoclonal antibody against IL-13, which can bind to soluble IL-13 with high affinity, thereby blocking IL-13 signal transduction. Lebrikizumab has been approved in the European Union for the treatment of moderate-to-severe atopic dermatitis, but it has performed poorly in phase III clinical trials for asthma. As a key node transcription factor, STAT6 selectively mediates the downstream signals of IL-4 and IL-13, and is not utilized by other cytokines or growth factors. Therefore, selective inhibitors targeting STAT6 have stronger targeting and fewer side effects, and are considered to have better safety.

[0007] Proteolysis targeting chimera (PROTAC) is an important method for selectively inducing protein degradation by ubiquitin proteasome pathway (UPP). PROTAC is a bifunctional molecule, one end is a small molecule inhibitor that recognizes the target protein, the other end is an E3 ubiquitin ligase ligand that can recognize E3 ubiquitin ligase, connected by a linker. PROTAC recruits target proteins on one end and binds E3 ubiquitin ligase on the other end, forming a ternary complex, ubiquitinating the target protein, and degrading the target protein in vivo through UPP. STAT6 small molecule inhibitors are difficult to optimize in terms of affinity and selectivity, while STAT6 PROTAC can degrade intracellular STAT6, more completely inhibit the release of downstream inflammatory factors mediated by STAT6, and has better selectivity. Therefore, developing new STAT6 PROTAC drugs can be used for the treatment of various type 2 inflammatory diseases and tumors related to STAT6. SUMMARY

[0008] The present disclosure relates to a compound of Formula (I) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof,

[0009] wherein:

[0010] L is a bivalent moiety linking STAT to LBM;

[0011] LBM is an E3 ubiquitin ligase binding moiety;

[0012] STAT is a moiety capable of binding to STAT6, and STAT is a group as described below:

[0013] q is 0 or 1;

[0014] t is 0, 1 or 2;

[0015] p is 1 or 2;

[0016] n is selected from any natural number from 1-8;

[0017] X is selected from CH2, O, S, SO2, S(O), -C(=O)-NR 10 and NR 8 ;

[0018] Ring A is selected from C3-C 12 saturated carbocyclic and 4-8 membered heterocyclic ring;

[0019] R 1 is selected from -CR 1a R2a P(O)OR 1b OR 2b , -CR 1a R 2a P(O)OR 1b NHR 2b , -CR 1a R 2a P(O)[OR 1b ][NH(AA)C(O)OR T ], -P(O)OR 1b OR 2b , -[P(O)[NHR Ty ][NH(AA)C(O)OR T ] or -P(O)[OR 1b ][NH(AA)C(O)OR T ] substituted 8-10 membered heteroaryl, said 8-10 membered heteroaryl being additionally optionally substituted with amino, halogen, cyano, C1-C4 alkyl or C1-C4 alkoxy; -CR 1a R 2a P(O)OR 1b OR 2b , -CR 1a R 2a P(O)OR 1b NHR 2b , -CR 1a R 2a P(O)[OR 1b ][NH(AA)C(O)OR T ], -P(O)OR 1b OR 2b , -[P(O)[NHR Ty ][NH(AA)C(O)OR T ] or -P(O)[OR 1b ][NH(AA)C(O)OR T ] substituted 8-10 membered heterocyclyl, said 8-10 membered heterocyclyl being additionally optionally substituted with amino, halogen, cyano, C1-C4 alkyl or C1-C4 alkoxy; -CR 1a R 2a P(O)OR 1b OR 2b , -CR 1a R 2a P(O)OR 1b NHR 2b , -CR 1a R 2a P(O)[OR 1b ][NH(AA)C(O)OR T-P(O)OR 1b OR 2b -P(O)[OR Ty ][NH(AA)C(O)OR T ] or -P(O)[OR 1b ][NH(AA)C(O)OR T ] substituted C6-C 10 aryl, said C6-C 10 aryl being additionally optionally substituted by cyano, C1-C4alkoxy or halo; -C1-C4alkyleneC6-C 10 aryl, said -C1-C4alkyleneC6-C 10 aryl of said -C1-C4alkyleneC6-C 1a R 2a P(O)OR 1b OR 2b -CR 1a R 2a P(O)OR 1b NHR 2b -CR 1a R 2a P(O)[OR 1b ][NH(AA)C(O)OR T ], -P(O)OR 1b OR 2b -[P(O)[NHR Ty ][NH(AA)C(O)OR T ] or -P(O)[OR 1b ][NH(AA)C(O)OR T ] substituted; -C2-C4alkenylC6-C 10 aryl, said -C2-C4alkenylC6-C 10 aryl of said -C2-C4alkenylC6-C 1a R 2a P(O)OR 1b OR 2b -CR 1a R 2a P(O)OR 1b NHR 2b -CR 1a R 2a P(O)[OR 1b ][NH(AA)C(O)OR T ], -P(O)OR 1b OR 2b -[P(O)[NHR Ty ][NH(AA)C(O)OR T ] or -P(O)[OR 1b][NH(AA)C(O)OR T ] substituted;

[0020] R 1a and R 2a are independently selected from the group consisting of hydrogen, halogen, cyano, C1-C4alkyl, C1-C4haloalkyl, and C1-C4hydroxyalkyl, or R 1a and R 2a are taken together to form =O;

[0021] R 1b and R 2b are independently selected from the group consisting of hydrogen, C1-C4alkyl, C1-C4haloalkyl, -(C1-C4alkylene)-OC(O)-(C1-C4alkyl), -(C1-C4alkylene)-C(O)O-(C1-C4alkyl), -(C1-C4alkylene)-O-(C1-C4alkyl), -(C1-C4alkylene)-OC(O)-[C1-C4haloalkyl], -(C1-C4alkylene)-OC(O)O-[5-7 membered heterocyclyl], -(C1-C4alkylene)-OC(O)-[5-7 membered heterocyclyl], -(C1-C4alkylene)-OC(O)-(C1-C4alkylene)-OH, -(C1-C4alkylene)-OC(O)-(C1-C4alkylene)-O-(C1-C4alkyl), -(C1-C4alkylene)-OC(O)O-(C1-C4alkyl), -(C1-C4alkylene)-OC(O)O-[C1-C4haloalkyl], -(C1-C4alkylene)-OC(O)O-(C1-C4alkylene)-OH, -(C1-C4alkylene)-OC(O)O-(C1-C4alkylene)-O-(C1-C4alkyl), -(C1-C4alkylene)-SC(O)-(C1-C6alkyl), -(C1-C4alkylene)-C(O)S-(C1-C4alkyl), -(C1-C4alkylene)-SC(O)-[C1-C4haloalkyl], -(C1-C4alkylene)-C(O)S-[C1-C4haloalkyl], -(C1-C4alkylene)-SC(O)-(C1-C4alkylene)-OH, -(C1-C4alkylene)-C(O)S-(C1-C4alkylene)-OH, -(C1-C4alkylene)-SC(O)-(C1-C4alkylene)-O-(C1-C4alkyl), -(C1-C4alkylene)-C(O)S-(C1-C4alkylene)-O-(C1-C4alkyl), -(C1-C4alkylene)-OC(O)NH(C1-C4alkyl)], -(C1-C4alkylene)-OC(O)N(C1-C4alkyl)2, C6-C 10 aryl and 5-6 membered heteroaryl, said C6-C 10R is selected from hydrogen, halogen, COOH, hydroxyl, cyano, C1-C4alkyl, C1-C4alkoxy, C1-C4haloalkoxy, C1-C4haloalkyl, and C1-C4hydroxyalkyl; h substituted;

[0022] R 2 is selected from hydrogen, halogen, COOH, hydroxyl, cyano, C1-C4alkyl, C1-C4alkoxy, C1-C4haloalkoxy, C1-C4haloalkyl, and C1-C4hydroxyalkyl;

[0023] R 3 and R 4 are independently selected from hydrogen, halogen, hydroxyl, cyano, C1-C4alkyl, C1-C4haloalkyl, C1-C4hydroxyalkyl, -C1-C4alkylene phenyl, C1-C4alkoxy, C1-C4haloalkoxy, -C1-C4alkylene C1-C4alkoxy, NR a R b , C3-C6cycloalkyl, C6-C 10 aryl, 5-10 membered heteroaryl, and 4-10 membered heterocyclyl, the C3-C6cycloalkyl, C6-C 10 aryl, 5-10 membered heteroaryl, and 4-10 membered heterocyclyl are optionally substituted with R S ;

[0024] or, R 3 and R 4 and the atom to which they are attached together form a C3-C6saturated carbocyclic ring, 4-8 membered heterocyclic ring, or 5-6 membered heteroaromatic ring, the 3-6 membered saturated carbocyclic ring, 4-8 membered heterocyclic ring, and 5-6 membered heteroaromatic ring are optionally substituted with halogen, cyano, amino, or C1-C4alkyl;

[0025] or, R 2 and R 3 and the atom to which they are attached together form a C4-C6saturated carbocyclic ring, 4-8 membered heterocyclic ring, C6-C 10 aromatic ring, or 5-6 membered heteroaromatic ring, the C4-C6saturated carbocyclic ring, 4-8 membered heterocyclic ring, C6-C 10 aromatic ring, or 5-6 membered heteroaromatic ring are optionally substituted with halogen, cyano, amino, or C1-C4alkyl;

[0026] R 5 is selected from hydrogen, phenyl, and C1-C4alkyl;

[0027] R 6 and R 7 are independently selected from halogen, cyano, hydroxyl, phenyl, C2-C4alkenyl, C1-C4alkyl, C1-C4alkoxy, C1-C4haloalkoxy, 4-9 membered heterocyclyl, 5-10 membered heteroaryl, C3-C6cycloalkyl, =0, imine (i.e., imino), -OR e-C(O)R g -C(O)OR e -NR c C(O)R e -C(O)NR c R d -NR a R b -S(O)R e R f -S(O)2R f -S(O)(=NH)(C1-C4alkyl), -S(O)NR e R f and -S(O)2NR e R f , said C2-C4alkenyl, C1-C4alkyl optionally substituted with R M , said phenyl, 5-10 membered heteroaryl, C3-C6cycloalkyl and 4-9 membered heterocyclyl optionally substituted with R F ;

[0028] R 8 is selected from the group consisting of a bond, hydrogen, -SO2R 8a , C2-C4alkenyl, C1-C4alkyl, C2-C4alkynyl, C1-C4alkoxy, C3-C6cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 aryl and 5-10 membered heteroaryl, said C2-C4alkenyl, C1-C4alkyl, C2-C4alkynyl, C1-C4alkoxy, C3-C6cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 aryl and 5-10 membered heteroaryl optionally substituted with R 8a ;

[0029] or, when X is NR 8 , R 3 and the C attached thereto together with R 8 and the N attached thereto form a 4-8 membered heterocyclic ring or a 5-6 membered heteroaromatic ring, said 4-8 membered heterocyclic ring and 5-6 membered heteroaromatic ring optionally substituted with halogen, cyano, amino or C1-C4alkyl;

[0030] R 8a is selected from the group consisting of hydroxyl, halogen, cyano, amino, C1-C4alkyl, -C(O)C1-C4alkyl, C3-C6cycloalkyl, 4-10 membered heterocyclyl and =O, said hydroxyl, amino, C1-C4alkyl, -C(O)C1-C4alkyl, C3-C6cycloalkyl, 4-10 membered heterocyclyl optionally substituted with halogen, cyano, hydroxyl, C1-C4alkyl, C1-C4alkoxy and C1-C4haloalkyl;

[0031] R 9haloalkyl, C3-C6cycloalkyl, 4-9 membered heterocyclyl, C6-C10aryl, 5-10 membered heteroaryl, -OR 10 aryl and 5-10 membered heteroaryl;

[0032] R 10 haloalkyl, C3-C6cycloalkyl, 4-9 membered heterocyclyl, C6-C 10 aryl and 5-10 membered heteroaryl;

[0033] AA is a residue of an alpha or beta natural or unnatural amino acid;

[0034] R T and R Ty are independently selected from the group consisting of C1-C 10 alkyl, C3-C 10 cycloalkyl, 3-10 membered heterocyclyl, benzyl, and phenyl, said C1-C 10 alkyl, C3-C 10 cycloalkyl, 3-10 membered heterocyclyl, benzyl, and phenyl are optionally substituted with halo, C1-C4alkyl, C1-C4haloalkyl, C1-C4alkoxy, or 3-6 membered heterocyclyl;

[0035] R F , R S and R X are independently selected from the group consisting of halo, cyano, C1-C4alkyl, C3-C6cycloalkyl, C1-C4haloalkyl, -C1-C4alkyleneC(O)NR e R f , -C1-C4alkyleneC1-C4alkoxy, C1-C4hydroxyalkyl, -C1-C4alkylenephenyl, -C1-C4alkyleneheteroaryl, C2-C4alkenyl, C2-C4haloalkenyl, C2-C4alkynyl, C2-C4haloalkynyl, C1-C4alkoxy, C1-C4haloalkoxy, -OR e , =O, imine (i.e., imino), phenyl, 4-6 membered heterocyclyl, 5-6 membered heteroaryl, -S(O)R e R f , -S(O)2R f , -S(O)(=NH)(C1-C4alkyl), -S(O)NR e R f , -S(O)2NR e R f , -C(O)OR e , -NR c C(O)R e , -(C1-C4alkyl)C(O)Rg -C(O)R g -(C1-C4alkyl)C(O)NR c R d -C(O)NR c R d -NO2and -NR a R b , said C1-C4alkyl is optionally substituted with cyano, said phenyl, 4-6 membered heterocyclyl, 5-6 membered heteroaryl, phenyl is optionally substituted with halogen, cyano, =O, C1-C 10 alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl, C1-C 10 haloalkyl, C1-C 10 alkoxy or C1-C 10 haloalkoxy, said C1-C 10 alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl is optionally substituted with 5-10 membered heteroaryl or 4-10 membered heterocyclyl, said 4-10 membered heterocyclyl is optionally substituted with oxo;

[0036] R M is independently selected from the group consisting of halogen, C1-C4alkyl, C1-C4alkoxy, C1-C4haloalkoxy, cyano, -C(O)R g , -C(O)OR e , -NHC(O)R e , -C(O)NR c R d , -NR a R b , -S(O)R e R f , -S(O)2R f , -S(O)NR e R f , -S(O)(=NH)(C1-C4alkyl), -S(O)2NR e R f , hydroxy, phenyl, 4-6 membered heterocyclyl and 5-10 membered heteroaryl, said phenyl, 4-6 membered heterocyclyl and 5-10 membered heteroaryl is optionally substituted with R X ;

[0037] R a , R b , R c , R d , R e , R f , R g and R hindependently selected from hydrogen, C1-C4alkyl, C2-C4alkynyl, -C1-C4alkylphenyl, phenyl, C3-C6cycloalkyl, 4-6 membered cycloalkyl, 4-6 membered heterocyclyl, and 5-6 membered heteroaryl, said C1-C4alkyl optionally substituted with halogen, cyano, hydroxyl, or amino, said phenyl, C3-C6cycloalkyl, 4-6 membered cycloalkyl, 4-6 membered heterocyclyl, and 5-6 membered heteroaryl optionally substituted with halogen, cyano, C1-C4alkyl, C1-C4haloalkyl, C1-C4alkoxy, C1-C4haloalkoxy, hydroxyl, phenyl, or benzyl; for example, R a , R b , R c , R d , R e , R f , R g , and R h are independently selected from hydrogen, C1-C4alkyl, C2-C4alkynyl, -C1-C4alkylphenyl, phenyl, C3-C6cycloalkyl, 4-6 membered cycloalkyl, 4-6 membered heterocyclyl, and 5-6 membered heteroaryl, said C1-C4alkyl optionally substituted with halogen, cyano, hydroxyl, or amino, said phenyl, C3-C6cycloalkyl, 4-6 membered cycloalkyl, 4-6 membered heterocyclyl, and 5-6 membered heteroaryl optionally substituted with halogen, cyano, C1-C4alkyl, C1-C4haloalkyl, C1-C4alkoxy, C1-C4haloalkoxy, hydroxyl, phenyl, or benzyl;

[0038] one or more hydrogen atoms of the compound are optionally deuterium atoms.

[0039] The compound of Formula (I) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof is selected from a compound of Formula (I-1) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof,

[0040] wherein:

[0041] L is a bivalent moiety linking STAT to LBM;

[0042] LBM is selected from

[0043] STAT is a moiety capable of binding to STAT6, and STAT is a group as described below:

[0044] q is 0 or 1;

[0045] t is 0, 1, or 2;

[0046] p is 1 or 2;

[0047] n is selected from any natural number from 1-8;

[0048] X is selected from CH2, O, S, SO2, S(O), -C(=O)-NR 10 - and NR 8 ;

[0049] Ring A is selected from C3-C 12 saturated carbocyclic and 4-8 membered heterocyclic rings;

[0050] R 1 selected from -CR 1a R 2a P(O)OR 1b OR 2b , -CR 1a R 2a P(O)[OR 1b ][NH(AA)C(O)OR T ], -P(O)OR 1b OR 2b , -[P(O)[NHR Ty ][NH(AA)C(O)OR T ] or -P(O)[OR 1b ][NH(AA)C(O)OR T ] substituted 8-10 membered heteroaryl, said 8-10 membered heteroaryl being additionally optionally substituted with amino, halogen, cyano, C1-C4 alkyl or C1-C4 alkoxy; -CR 1a R 2a P(O)OR 1b OR 2b , -CR 1a R 2a P(O)[OR 1b ][NH(AA)C(O)OR T ], -P(O)OR 1b OR 2b , -[P(O)[NHR Ty ][NH(AA)C(O)OR T ] or -P(O)[OR 1b ][NH(AA)C(O)OR T ] substituted 8-10 membered heterocyclyl, said 8-10 membered heterocyclyl being additionally optionally substituted with amino, halogen, cyano, C1-C4 alkyl or C1-C4 alkoxy; -CR 1a R 2a P(O)OR 1b OR 2b , -CR 1a R 2a P(O)[OR 1b ][NH(AA)C(O)OR T ], -P(O)OR 1b OR2b , -P(O)[NHR Ty ][NH(AA)C(O)OR T ] or -P(O)[OR 1b ][NH(AA)C(O)OR T ] substituted C6-C 10 aryl, said C6-C 10 aryl being additionally optionally substituted by cyano, C1-C4alkoxy or halogen; -C1-C4alkyleneC6-C 10 aryl, said -C1-C4alkyleneC6-C 10 aryl of said -C1-C4alkyleneC6-C 1a R 2a P(O)OR 1b OR 2b , -CR 1a R 2a P(O)[OR 1b ][NH(AA)C(O)OR T ], -P(O)OR 1b OR 2b , -[P(O)[NHR Ty ][NH(AA)C(O)OR T ] or -P(O)[OR 1b ][NH(AA)C(O)OR T ] substituted; -C2-C4alkenylC6-C 10 aryl, said -C2-C4alkenylC6-C 10 aryl of said -C2-C4alkenylC6-C 1a R 2a P(O)OR 1b OR 2b , -CR 1a R 2a P(O)[OR 1b ][NH(AA)C(O)OR T ], -P(O)OR 1b OR 2b , -[P(O)[NHR Ty ][NH(AA)C(O)OR T ] or -P(O)[OR 1b ][NH(AA)C(O)OR T ] substituted;

[0051] R 1a and R 2a are independently selected from hydrogen, halogen, cyano, C1-C4alkyl, C1-C4haloalkyl and C1-C4hydroxyalkyl, or R 1a and R 2aTogether form = O;

[0052] R 1b and R 2b independently selected from hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, -(C1-C4 alkylene)-OC(O)-(C1-C4 alkyl), -(C1-C4 alkylene)-C(O)O-(C1-C4 alkyl), -(C1-C4 alkylene)-O-(C1-C4 alkyl), -(C1-C4 alkylene)-OC(O)-[C1-C4 haloalkyl], -(C1-C4 alkylene)-OC (O)O-[5-7 membered heterocyclyl], -(C1-C4 alkylene)-OC(O)-[5-7 membered heterocyclyl], -(C1-C4 alkylene)-OC(O)-(C1-C4 alkylene)-OH, -(C1-C4 alkylene)-OC(O)-(C1-C4 alkylene)-O-(C1-C4 alkyl), -(C1-C4 alkylene)-OC(O)O-(C1-C4 alkyl), -(C1-C4 alkylene)-OC(O)O-(C1-C4 alkyl), -(C1-C4 alkylene)-OC(O)O-[C1-C4 haloalkyl], -(C1-C4 alkylene)-OC(O)O-(C1-C4 alkylene)-OH, -(C1-C4 alkylene)-OC(O)O-(C1-C4 alkylene)-O-(C1-C4 alkyl), -(C1-C4 alkylene)-SC(O)-(C1-C4 alkyl), -(C1-C4 alkylene)-SC(O) -[C1-C4 haloalkyl], -(C1-C4 alkylene)-SC(O)-(C1-C4 alkylene)-OH, -(C1-C4 alkylene)-SC(O)-(C1-C4 alkylene)-O-(C1-C4 alkyl), -(C1-C4 alkylene)-OC(O)NH(C1-C4 alkyl)], -(C1-C4 alkylene)-OC(O)N(C1-C4 alkyl)2, C6-C 10 Aryl and 5-6 membered heteroaryl, the C6-C 10 The aryl and 5-6 membered heteroaryl groups are optionally substituted with halogen, cyano or C1-C4 alkyl, and the 5-7 membered heterocyclic group is optionally substituted with C(O)OR h replace;

[0053] R 2 is selected from the group consisting of hydrogen, halogen, COOH, hydroxy, cyano, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 haloalkyl and C1-C4 hydroxyalkyl;

[0054] R 3 and R 4independently selected from hydrogen, halogen, hydroxyl, cyano, C1-C4alkyl, C1-C4haloalkyl, C1-C4hydroxyalkyl, -C1-C4alkylene phenyl, C1-C4alkoxy, C1-C4haloalkoxy, -C1-C4alkylene C1-C4alkoxy, NR a R b , C3-C6cycloalkyl, C6-C 10 aryl, 5-10 membered heteroaryl, and 4-10 membered heterocyclyl, said C3-C6cycloalkyl, C6-C 10 aryl, 5-10 membered heteroaryl, and 4-10 membered heterocyclyl is optionally substituted with R S ;

[0055] or, R 3 and R 4 , together with the atom to which they are attached, form a C3-C6saturated carbocyclic ring, 4-8 membered heterocyclic ring, or 5-6 membered heteroaromatic ring, said 3-6 membered saturated carbocyclic ring, 4-8 membered heterocyclic ring, and 5-6 membered heteroaromatic ring is optionally substituted with halogen, cyano, amino, or C1-C4alkyl;

[0056] or, R 2 and R 3 , together with the atom to which they are attached, form a C4-C6saturated carbocyclic ring, 4-8 membered heterocyclic ring, C6-C 10 aromatic ring, or 5-6 membered heteroaromatic ring, said C4-C6saturated carbocyclic ring, 4-8 membered heterocyclic ring, C6-C 10 aromatic ring, or 5-6 membered heteroaromatic ring is optionally substituted with halogen, cyano, amino, or C1-C4alkyl;

[0057] R 5 is selected from hydrogen, phenyl, and C1-C4alkyl;

[0058] R 6 and R 7 are independently selected from halogen, cyano, hydroxyl, phenyl, C2-C4alkenyl, C1-C4alkyl, C1-C4alkoxy, C1-C4haloalkoxy, 4-9 membered heterocyclyl, 5-10 membered heteroaryl, C3-C6cycloalkyl, =O, imine (i.e., imino), -OR e , -C(O)R g , -C(O)OR e , -NR c C(O)R e , -C(O)NR c R d , -NR a R b , -S(O)R e R f , -S(O)2R f, -S(O)(=NH)(C1-C4alkyl), -S(O)NR e R f and -S(O)2NR e R f , said C2-C4alkenyl, C1-C4alkyl are optionally substituted with R M , said phenyl, 5-10 membered heteroaryl, C3-C6cycloalkyl and 4-9 membered heterocyclyl are optionally substituted with R F ;

[0059] R 8 is selected from the group consisting of a bond, hydrogen, -SO2R 8a , C2-C4alkenyl, C1-C4alkyl, C2-C4alkynyl, C1-C4alkoxy, C3-C6cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 aryl and 5-10 membered heteroaryl, said C2-C4alkenyl, C1-C4alkyl, C2-C4alkynyl, C1-C4alkoxy, C3-C6cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 aryl and 5-10 membered heteroaryl are optionally substituted with R 8a ;

[0060] or, when X is NR 8 , R 3 and the C attached thereto together with R 8 and the N attached thereto form a 4-8 membered heterocyclic or 5-6 membered heteroaromatic ring, said 4-8 membered heterocyclic and 5-6 membered heteroaromatic ring are optionally substituted with halogen, cyano, amino or C1-C4alkyl;

[0061] R 8a is selected from the group consisting of halogen, cyano, amino, C1-C4alkyl, -C(O)C1-C4alkyl, C3-C6cycloalkyl, 4-10 membered heterocyclyl and =O, said amino, C1-C4alkyl, -C(O)C1-C4alkyl, C3-C6cycloalkyl, 4-10 membered heterocyclyl are optionally substituted with halogen, cyano, hydroxy, C1-C4alkyl, C1-C4alkoxy and C1-C4haloalkyl;

[0062] R 9 is selected from the group consisting of hydrogen, -C(O)C1-C4alkyl, C1-C4alkyl, C1-C4cyanoalkyl, C1-C4haloalkyl, C3-C6cycloalkyl, 4-9 membered heterocyclyl, C6-C 10 aryl and 5-10 membered heteroaryl;

[0063] R 10 is selected from the group consisting of hydrogen, C1-C4alkyl, C1-C4cyanoalkyl, C1-C4haloalkyl, C3-C6cycloalkyl, 4-9 membered heterocyclyl, C6-C 10 aryl and 5-10 membered heteroaryl;

[0064] AA is a residue of an alpha or beta natural or unnatural amino acid;

[0065] R T and R Ty are independently selected from the group consisting of C1-C6alkyl, benzyl and phenyl, said C1-C6alkyl, benzyl and phenyl being optionally substituted with halogen, C1-C4alkyl or C1-C4haloalkyl;

[0066] R F , R S and R X are independently selected from the group consisting of halogen, cyano, C1-C4alkyl, C3-C6cycloalkyl, C1-C4haloalkyl, -C1-C4alkyleneC(O)NR e R f , -C1-C4alkyleneC1-C4alkoxy, C1-C4hydroxyalkyl, -C1-C4alkylenephenyl, -C1-C4alkyleneheteroaryl, C2-C4alkenyl, C2-C4haloalkenyl, C2-C4alkynyl, C2-C4haloalkynyl, C1-C4alkoxy, C1-C4haloalkoxy, -OR e , =O, imine (i.e., imino), phenyl, 4-6 membered heterocyclyl, 5-6 membered heteroaryl, -S(O)R e R f , -S(O)2R f , -S(O)(=NH)(C1-C4alkyl), -S(O)NR e R f , -S(O)2NR e R f , -C(O)OR e , -NR c C(O)R e , -(C1-C4alkyl)C(O)R g , -C(O)R g , -(C1-C4alkyl)C(O)NR c R d , -C(O)NR c R d , -NO2and -NR a R b , said C1-C4alkyl being optionally substituted with cyano, said phenyl, 4-6 membered heterocyclyl, 5-6 membered heteroaryl, phenyl being optionally substituted with halogen, cyano, =O, C1-C 10 alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl, C1-C 10 haloalkyl, C1-C 10 alkoxy or C1-C 10haloalkoxy-substituted, said C1-C 10 alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl is optionally substituted with 5-10 membered heteroaryl or 4-10 membered heterocyclyl, said 4-10 membered heterocyclyl is optionally substituted with oxo;

[0067] R M is independently selected from the group consisting of halogen, C1-C4alkyl, C1-C4alkoxy, C1-C4haloalkoxy, cyano, -C(O)R g , -C(O)OR e , -NHC(O)R e , -C(O)NR c R d , -NR a R b , -S(O)R e R f , -S(O)2R f , -S(O)NR e R f , -S(O)(=NH)(C1-C4alkyl), -S(O)2NR e R f , hydroxy, phenyl, 4-6 membered heterocyclyl, and 5-10 membered heteroaryl, said phenyl, 4-6 membered heterocyclyl, and 5-10 membered heteroaryl are optionally substituted with R X ;

[0068] R a , R b , R c , R d , R e , R f , R g , and R h are independently selected from the group consisting of hydrogen, C1-C4alkyl, C2-C4alkynyl, -C1-C4alkylphenyl, phenyl, C3-C6cycloalkyl, 4-6 membered heterocyclyl, and 5-6 membered heteroaryl, said C1-C4alkyl is optionally substituted with halogen, cyano, hydroxy, or amino, said phenyl, C3-C6cycloalkyl, 4-6 membered heterocyclyl, and 5-6 membered heteroaryl are optionally substituted with halogen, cyano, C1-C4alkyl, C1-C4haloalkyl, C1-C4alkoxy, C1-C4haloalkoxy, hydroxy, phenyl, or benzyl; for example, R a , R b , R c , R d , R e , R f , R g , and R hindependently selected from hydrogen, C1-C4alkyl, C2-C4alkynyl, -C1-C4alkylphenyl, phenyl, C3-C6cycloalkyl, 4-6 membered heterocycloalkyl, 4-6 membered heterocyclyl, and 5-6 membered heteroaryl, said C1-C4alkyl optionally substituted with halogen, cyano, hydroxyl, or amino, said phenyl, C3-C6cycloalkyl, 4-6 membered heterocycloalkyl, 4-6 membered heterocyclyl, and 5-6 membered heteroaryl optionally substituted with halogen, cyano, C1-C4alkyl, C1-C4haloalkyl, C1-C4alkoxy, C1-C4haloalkoxy, hydroxyl, phenyl, or benzyl;

[0069] one or more hydrogen atoms of the compound are optionally deuterium atoms.

[0070] In some embodiments, the compound of Formula (I), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, is not a compound selected from:

[0071] In some embodiments, p is 1.

[0072] In some embodiments, t is 1 or 2.

[0073] In some embodiments, t is 1.

[0074] In some embodiments, t is 2.

[0075] In some embodiments, q is 0.

[0076] In some embodiments, q is 1.

[0077] In some embodiments, n is 1.

[0078] In some embodiments, X is selected from CH2, S, S(O), SO, -C(=O)-NR 10 -, SO2, and NR 8 .

[0079] In some embodiments, X is selected from CH2, S, SO2, , and NR 8 .

[0080] In some embodiments, X is selected from S, S(O), SO, -C(=O)-NR 10 -,

[0081] In some embodiments, X is selected from CH2 and NR 8 .

[0082] In some embodiments, R 8 selected from a bond, hydrogen, C2-C4 alkenyl, C1-C4 alkyl, C2-C4 alkynyl, C1-C4 alkoxy, C3-C6 cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 Aryl and 5-10 membered heteroaryl, the C2-C4 alkenyl, C1-C4 alkyl, C2-C4 alkynyl, C1-C4 alkoxy, C3-C6 cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 Aryl and 5-10 membered heteroaryl are optionally replaced by R 8a replace.

[0083] In some embodiments, R 8 Selected from hydrogen, -SO2R 8a , C1-C4 alkyl and 4-6 membered heterocyclic group, wherein the C1-C4 alkyl and 4-6 membered heterocyclic group are optionally replaced by R 8a replace.

[0084] In some embodiments, R 8 is selected from hydrogen, C1-C4 alkyl and 4-6 membered heterocyclic group, wherein the C1-C4 alkyl and 4-6 membered heterocyclic group are optionally replaced by R 8a replace.

[0085] In some embodiments, R 8 is selected from hydrogen, C1-C4 alkyl and 4-membered heterocyclic group, wherein the C1-C4 alkyl and 4-membered heterocyclic group are optionally replaced by R 8a replace.

[0086] In some embodiments, R 8 Selected from hydrogen, -SO2R 8a , methyl, ethyl, Oxetanyl, azetidinyl, thietanyl and thietanyl-1,1-dioxide, the methyl, ethyl, Oxetanyl, azetidinyl, thietanyl and thietanyl-1,1-dioxide are optionally replaced by R 8a replace.

[0087] In some embodiments, R 8 is selected from hydrogen, ethyl, oxetanyl, azetidinyl, thietanyl and thietanyl-1,1-dioxide, wherein the oxetanyl, azetidinyl, thietanyl and thietanyl-1,1-dioxide are optionally replaced by R 8a replace.

[0088] In some embodiments, R 8ahalogen, cyano, amino, hydroxyl, C1-C4alkyl, -C(O)C1-C4alkyl, C3-C6cycloalkyl, 4-10 membered heterocyclyl, and =O, said amino, C1-C4alkyl, -C(O)C1-C4alkyl, C3-C6cycloalkyl, 4-10 membered heterocyclyl are optionally substituted with halogen, cyano, hydroxyl, C1-C4alkyl, C1-C4alkoxy, and C1-C4haloalkyl.

[0089] In some embodiments, R 8a halogen, cyano, amino, hydroxyl, C1-C4alkyl, -C(O)C1-C4alkyl, C3-C6cycloalkyl, 4-10 membered heterocyclyl, and =O, said amino, C1-C4alkyl, -C(O)C1-C4alkyl, C3-C6cycloalkyl, 4-10 membered heterocyclyl are optionally substituted with halogen, cyano, hydroxyl, C1-C4alkyl, C1-C4alkoxy, and C1-C4haloalkyl.

[0090] In some embodiments, R 8a hydroxyl, halogen, cyano, amino, C1-C4alkyl, -C(O)C1-C4alkyl, and =O.

[0091] In some embodiments, R 8a halogen, =O, C1-C4alkyl, C3-C6cycloalkyl, and -C(O)C1-C4alkyl, said C1-C4alkyl, C3-C6cycloalkyl, and -C(O)C1-C4alkyl are optionally substituted with halogen, cyano, hydroxyl, C1-C4alkyl, C1-C4alkoxy, and C1-C4haloalkyl.

[0092] In some embodiments, R 8a =O, C1-C4alkyl, and -C(O)C1-C4alkyl.

[0093] In some embodiments, R 8a halogen, =O, cyclopropyl, methyl, and said cyclopropyl, methyl, and are optionally substituted with halogen.

[0094] In some embodiments, R 8 hydrogen, methyl, -C(O)CH3, -CH2CHF2, oxetanyl, cyclopropylcarbonyl, methylsulfonyl,

[0095] In some embodiments, R 8 hydrogen, methyl, -C(O)CH3, -CH2CHF2, oxetanyl, cyclopropylcarbonyl, methylsulfonyl,

[0096] In some embodiments, R 8 is selected from hydrogen, -C(O)CH3, oxetanyl.

[0097] In some embodiments, R 9 is hydrogen.

[0098] In some embodiments, R 10 is hydrogen.

[0099] In some embodiments, R 1 is selected from -CR 1a R 2a P(O)OR 1b OR 2b , -CR 1a R 2a P(O)[OR 1b ][NH(AA)C(O)OR T ], -P(O)OR 1b OR 2b , -[P(O)[NHR Ty ][NH(AA)C(O)OR T ], or -P(O)[OR 1b ][NH(AA)C(O)OR T ]; 1a R 2a P(O)OR 1b OR 2b , -CR 1a R 2a P(O)[OR 1b ][NH(AA)C(O)OR T ], -P(O)OR 1b OR 2b , -[P(O)[NHR Ty ][NH(AA)C(O)OR T ], or -P(O)[OR 1b ][NH(AA)C(O)OR T ]; 1a R 2a P(O)OR 1b OR 2b , -CR 1a R 2a P(O)[OR1b ][NH(AA)C(O)OR T ] or -P(O)OR 1b OR 2b , -[P(O)[NHR Ty ][NH(AA)C(O)OR T ] or -P(O)[OR 1b ][NH(AA)C(O)OR T ] substituted C6-C 10 aryl, said C6-C 10 aryl is additionally optionally substituted with cyano, C1-C4alkoxy or halo; -C1-C4alkyleneC6-C 10 aryl, said -C1-C4alkyleneC6-C 10 aryl of said -C1-C4alkyleneC6-C 1a R 2a P(O)OR 1b OR 2b , -CR 1a R 2a P(O)[OR 1b ][NH(AA)C(O)OR T ] or -P(O)OR 1b OR 2b , -[P(O)[NHR Ty ][NH(AA)C(O)OR T ] or -P(O)[OR 1b ][NH(AA)C(O)OR T ] substituted; -C2-C4alkenylC6-C 10 aryl, said -C2-C4alkenylC6-C 10 aryl of said -C2-C4alkenylC6-C 1a R 2a P(O)OR 1b OR 2b , -CR 1a R 2a P(O)[OR 1b ][NH(AA)C(O)OR T ] or -P(O)OR 1b OR 2b , -[P(O)[NHR Ty ][NH(AA)C(O)OR T ] or -P(O)[OR 1b ][NH(AA)C(O)OR T ] substituted.

[0100] In some embodiments, R 1 is selected from -CR 1aR 2a P(O)OR 1b OR 2b , -CR 1a R 2a P(O)OR 1b NHR 2b , -CR 1a R 2a P(O)[OR 1b ][NH(AA)C(O)OR T ], -P(O)OR 1b OR 2b , -[P(O)[NHR Ty ][NH(AA)C(O)OR T ] or -P(O)[OR 1b ][NH(AA)C(O)OR T ] substituted 8-10 membered heteroaryl, which 8-10 membered heteroaryl is additionally optionally substituted with amino, halogen, cyano, C1-C4 alkyl or C1-C4 alkoxy; or -CR 1a R 2a P(O)OR 1b OR 2b , -CR 1a R 2a P(O)OR 1b NHR 2b , -CR 1a R 2a P(O)[OR 1b ][NH(AA)C(O)OR T ], -P(O)OR 1b OR 2b , -[P(O)[NHR Ty ][NH(AA)C(O)OR T ] or -P(O)[OR 1b ][NH(AA)C(O)OR T ] substituted 8-10 membered heterocyclyl, which 8-10 membered heterocyclyl is additionally optionally substituted with amino, halogen, cyano, C1-C4 alkyl or C1-C4 alkoxy; or -CR 1a R 2a P(O)OR 1b OR 2b , -CR 1a R 2a P(O)OR 1b NHR 2b , -CR 1a R 2a P(O)[OR 1b ][NH(AA)C(O)OR T-P(O)OR 1b OR 2b -P(O)[OR Ty ][NH(AA)C(O)OR T ] or -P(O)[OR 1b ][NH(AA)C(O)OR T ] substituted C6-C 10 aryl, which C6-C 10 aryl is additionally optionally substituted with cyano, C1-C4alkoxy or halo.

[0101] In some embodiments, R 1 is selected from -CR 1a R 2a P(O)OR 1b OR 2b -CR 1a R 2a P(O)OR 1b NHR 2b -CR 1a R 2a P(O)[OR 1b ][NH(AA)C(O)OR T ], -P(O)OR 1b OR 2b -[P(O)[NHR Ty ][NH(AA)C(O)OR T ] or -P(O)[OR 1b ][NH(AA)C(O)OR T ] substituted 8-10 membered heteroaryl; C6-C 1a R 2a P(O)OR 1b OR 2b -CR 1a R 2a P(O)OR 1b NHR 2b -CR 1a R 2a P(O)[OR 1b ][NH(AA)C(O)OR T ], -P(O)OR 1b OR 2b -[P(O)[NHR Ty ][NH(AA)C(O)OR T ] or -P(O)[OR 1b ][NH(AA)C(O)OR T ] substituted C6-C 10 aryl or -CR1a R 2a P(O)OR 1b OR 2b , -CR 1a R 2a P(O)OR 1b NHR 2b , -CR 1a R 2a P(O)[OR 1b ][NH(AA)C(O)OR T ], -P(O)OR 1b OR 2b , -[P(O)[NHR Ty ][NH(AA)C(O)OR T ] or -P(O)[OR 1b ][NH(AA)C(O)OR T ] substituted 8-10 membered heterocyclyl.

[0102] In some embodiments, R 1 is selected from

[0103] In some embodiments, R 1 is selected from

[0104] In some embodiments, R 1 is selected from

[0105] In some embodiments, R 1 is selected from

[0106] In some embodiments, R 1 is selected from

[0107] In some embodiments, R 1b and R 2bindependently selected from hydrogen, C1-C4alkyl, C1-C4haloalkyl, -(C1-C4alkylene)-OC(O)-(C1-C4alkyl), -(C1-C4alkylene)-C(O)O-(C1-C4alkyl), -(C1-C4alkylene)-O-(C1-C4alkyl), -(C1-C4alkylene)-OC(O)-[C1-C4haloalkyl], -(C1-C4alkylene)-OC(O)O-[5-7 membered heterocyclyl], -(C1-C4alkylene)-OC(O)-[5-7 membered heterocyclyl], -(C1-C4alkylene)-OC(O)-(C1-C4alkylene)-OH, -(C1-C4alkylene)-OC(O)-(C1-C4alkylene)-O-(C1-C4alkyl), -(C1-C4alkylene)-OC(O)O-(C1-C4alkyl), -(C1-C4alkylene)-OC(O)O-[C1-C4haloalkyl], -(C1-C4alkylene)-OC(O)O-(C1-C4alkylene)-OH, -(C1-C4alkylene)-OC(O)O-(C1-C4alkylene)-O-(C1-C4alkyl), -(C1-C4alkylene)-SC(O)-(C1-C4alkyl), -(C1-C4alkylene)-SC(O)-[C1-C4haloalkyl], -(C1-C4alkylene)-SC(O)-(C1-C4alkylene)-OH, -(C1-C4alkylene)-SC(O)-(C1-C4alkylene)-O-(C1-C4alkyl), -(C1-C4alkylene)-OC(O)NH(C1-C4alkyl)], -(C1-C4alkylene)-OC(O)N(C1-C4alkyl)2, C6-C10aryl, and 5-6 membered heteroaryl, wherein the C6-C10aryl and 5-6 membered heteroaryl are optionally substituted with halo, cyano, or C1-C4alkyl. 10 C6-C10aryl and 5-6 membered heteroaryl, wherein the C6-C10aryl and 5-6 membered heteroaryl are optionally substituted with halo, cyano, or C1-C4alkyl. 10 C6-C10aryl and 5-6 membered heteroaryl, wherein the C6-C10aryl and 5-6 membered heteroaryl are optionally substituted with halo, cyano, or C1-C4alkyl. h substituted.

[0108] In some embodiments, R 1b and R 2bis independently selected from the group consisting of hydrogen, C1-C4alkyl, -(C1-C4alkylene)-OC(O)-(C1-C4alkyl), -(C1-C4alkylene)-OC(O)-[5-7 membered heterocyclyl], -(C1-C4alkylene)-SC(O)-(C1-C4alkyl), -(C1-C4alkylene)-OC(O)O-(C1-C4alkyl), -(C1-C4alkylene)-OC(O)N(C1-C4alkyl)2, -(C1-C4alkylene)-SC(O)-(C1-C6alkyl), -(C1-C4alkylene)-OC(O)O-(C1-C4alkylene)-O-(C1-C4alkyl), -(C1-C4alkylene)-SC(O)-(C1-C4alkylene)-OH, and -(C1-C4alkylene)-C(O)S-(C1-C4alkyl), said 5-7 membered heterocyclyl being optionally substituted with C(O)OR h substituted.

[0109] In some embodiments, R h is selected from C1-C4alkyl, preferably methyl.

[0110] In some embodiments, -CR 1a R 2a P(O)OR 1b OR 2b is selected from

[0111] In some embodiments, -CR 1a R 2a P(O)OR 1b OR 2b is selected from

[0112] In some embodiments, -CR 1a R 2a P(O)OR 1b OR 2b is

[0113] In some embodiments, -CR 1a R 2a P(O)OR 1b OR 2b is

[0114] In some embodiments, -CR 1a R2a P(O)OR 1b OR 2b is

[0115] In some embodiments, R 1 is selected from

[0116] In some embodiments, R T and R Ty are independently selected from C1-C6alkyl, benzyl and phenyl, said C1-C6alkyl, benzyl and phenyl being optionally substituted with halo, C1-C4alkyl or C1-C4haloalkyl;

[0117] In some embodiments, R T and R Ty are independently selected from C1-C4alkyl, benzyl and phenyl, said benzyl and phenyl being optionally substituted with halo, C1-C4alkyl or C1-C4haloalkyl.

[0118] In some embodiments, R T is selected from C1-C6alkyl, benzyl and C3-C6cycloalkyl, said C1-C6alkyl, benzyl and C3-C6cycloalkyl being optionally substituted with halo, C1-C4alkyl, C1-C4alkoxy or 3-6 membered heterocyclyl.

[0119] In some embodiments, -CR 1a R 2a P(O)[OR 1b ][NH(AA)C(O)OR T ] is selected from

[0120] In some embodiments, -CR 1a R 2a P(O)[OR 1b ][NH(AA)C(O)OR T ] is

[0121] In some embodiments, -CR 1a R 2a P(O)OR 1b NHR 2b is selected from

[0122] In some embodiments, R 2 is hydrogen.

[0123] In some embodiments, R 3 is hydrogen.

[0124] In some embodiments, R 2 and R 3 and the atom to which they are attached collectively form a C6-C 10 aromatic ring, which is optionally substituted with halogen, cyano, amino, or C1-C4alkyl. 10

[0125] In some embodiments, R 2 and R 3 and the atom to which they are attached collectively form a phenyl ring, which is optionally substituted with halogen, cyano, amino, or C1-C4alkyl.

[0126] In some embodiments, R 2 and R 3 and the atom to which they are attached collectively form a phenyl ring.

[0127] In some embodiments, is selected from

[0128] In some embodiments, R 4 is hydrogen.

[0129] In some embodiments, R 5 is hydrogen.

[0130] In some embodiments, ring A is selected from 4-8 membered heterocyclic rings.

[0131] In some embodiments, ring A is selected from 4-8 membered nitrogen-containing heterocyclic rings.

[0132] In some embodiments, ring A is selected from 5 membered nitrogen-containing heterocyclic rings.

[0133] In some embodiments, ring A is selected from tetrahydropyrrole rings.

[0134] In some embodiments, ring A is

[0135] In some embodiments, ring A is and morpholine rings.

[0136] In some embodiments, is selected from

[0137] In some embodiments, is selected from

[0138] In some embodiments, is selected from

[0139] ​In some embodiments, R 6 Selected from =0, halogen, cyano, hydroxy, phenyl and C1-C4 alkyl.

[0140] In some embodiments, R 6 Selected from halogen, cyano, hydroxy, phenyl and C1-C4 alkyl.

[0141] In some embodiments, R 6 is cyano or =O.

[0142] In some embodiments, R 6 It is a cyano group.

[0143] In some embodiments, R 7 is selected from phenyl, 4-9 membered heterocyclic group, 5-10 membered heteroaryl and C3-C6 cycloalkyl, wherein the phenyl, 4-9 membered heterocyclic group, 5-10 membered heteroaryl and C3-C6 cycloalkyl are optionally replaced by R F replace.

[0144] In some embodiments, R 7 Selected from phenyl, pyrazolyl, pyrimidinyl, piperidinyl, morpholinyl, pyranyl, piperazinyl and pyridinyl, the phenyl, pyrazolyl, pyrimidinyl, piperidinyl, morpholinyl, Pyranyl, piperazinyl and pyridinyl are optionally replaced by R F replace.

[0145] In some embodiments, R 7 Selected from phenyl, pyrazolyl, pyrimidinyl, piperidinyl, morpholinyl, pyranyl, and pyridinyl, the phenyl, pyrazolyl, pyrimidinyl, piperidinyl, morpholinyl, Pyranyl, and pyridinyl are optionally replaced by R F replace.

[0146] In some embodiments, R 7 is phenyl, the phenyl group is optionally replaced by R F replace.

[0147] In some embodiments, each R F Independently selected from halogen, cyano, =O, -OR e 、-C(O)OR e , C1-C4 alkyl and -NR a R b .

[0148] In some embodiments, each R F Independently selected from halogen, cyano, -OR e , C1-C4 alkyl and -NR a Rb .

[0149] In some embodiments, R a , R b are each hydrogen.

[0150] In some embodiments, each R e is independently selected from the group consisting of H and C1-C4 alkyl.

[0151] In some embodiments, each R F is independently selected from the group consisting of amino, =0, methoxy, methylamino, methyl, carboxyl, and hydroxyl.

[0152] In some embodiments, each R F is independently selected from the group consisting of amino, =0, methoxy, methylamino, carboxyl, and hydroxyl.

[0153] In some embodiments, each R F is independently selected from the group consisting of amino and hydroxyl.

[0154] In some embodiments, R 7 is selected from the group consisting of phenyl, pyrazolyl, pyrimidinyl, piperidinyl, morpholinyl, pyranyl, piperazinyl, and pyridyl.

[0155] In some embodiments, R 7 is selected from the group consisting of phenyl, pyrazolyl, pyridyl, aminopyridyl, aminophenyl, and hydroxyphenyl.

[0156] In some embodiments, R 7 is selected from the group consisting of phenyl, pyrazolyl, aminopyridyl, aminophenyl, and hydroxyphenyl.

[0157] In some embodiments, R 7 is selected from the group consisting of phenyl, aminophenyl, and hydroxyphenyl.

[0158] In some embodiments, the STAT is linked to L via R 8 , i.e., the STAT is

[0159] In some embodiments, the STAT is linked to L via R 8 , and R 8 is a bond, i.e., the STAT is

[0160] In some embodiments, the STAT is linked to L via R 7 , i.e., the STAT is

[0161] In some embodiments, the STAT is linked to L via R3 STAT is linked to L, i.e. the STAT is

[0162] In some embodiments, the STAT is further selected from the group consisting of:

[0163] wherein q, t, p, n, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and ring A are as defined above.

[0164] In some embodiments, the STAT is further selected from the group consisting of:

[0165] wherein n, R 1 , R 5 , R 6 , R 7 , R 8 and ring A are as defined above.

[0166] In some embodiments, the STAT is further selected from the group consisting of:

[0167] wherein R 1 , R 5 , R 6 , R 7 and R 8 are as defined above.

[0168] In some embodiments, the STAT is further selected from the group consisting of:

[0169] wherein q, t, p, n, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and ring A are as defined above.

[0170] In some embodiments, the STAT is further selected from the group consisting of:

[0171] wherein n, R 1 , R 5 , R6 , R 7 and ring A are as defined above.

[0172] In some embodiments, the STAT is further selected from the group consisting of:

[0173] wherein R 1 , R 5 , R 6 and R 7 are as defined above.

[0174] In some embodiments, the STAT is further selected from the group consisting of:

[0175] wherein n, R 1 , R 5 , R 6 , R 7 , R 8 and ring A are as defined above.

[0176] In some embodiments, the STAT is further selected from the group consisting of:

[0177] wherein R 1 , R 5 , R 6 , R 7 and R 8 are as defined above.

[0178] In some embodiments, the L is selected from the group consisting of -L A -, -L B -, -R 1L -, -R 2L -, -Q 1 -, -Q 2 -,

[0179] wherein: -L A -, -L B - are independently of each other selected from the group consisting of a bond, -O-, -S-, -NR 3’ -, -CR 4’ R 5’ -, -C(O)-, -S(O)-, -S(O)2-, -C(S)-, -C(O)O- or -C(O)NR 6’ -;

[0180] R 1L and R 2Lindependently of each other selected from the group consisting of a bond, alkylene, heteroalkylene, alkenylene and alkynylene, wherein said alkylene, heteroalkylene, alkenylene and alkynylene are optionally substituted with a member selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, OH, hydroxyalkyl, CN, NH2, =0, cycloalkyl, heterocyclyl, aryl, heteroaryl; for example, R 1L and R 2L independently of each other selected from the group consisting of a bond, C1-C 10 alkylene, 2-10 membered heteroalkylene, C2-C 10 alkenylene and C2-C 10 alkynylene, wherein said C1-C 10 alkylene, 2-10 membered heteroalkylene, C2-C 10 alkenylene and C2-C 10 alkynylene are optionally substituted with a member selected from the group consisting of halogen, C1-C 10 alkyl, C1-C 10 alkoxy, C1-C 10 haloalkyl, OH, C1-C 10 hydroxyalkyl, CN, NH2, =0, C3-C 10 cycloalkyl, 3-10 membered heterocyclyl, C6-C 10 aryl, 5-10 membered heteroaryl;

[0181] Q 1 , Q 2 , Q 3 and Q 4 independently of each other selected from the group consisting of cycloalkylene, heterocyclylene, arylene, heteroarylene or cycloalkenylene, wherein said cycloalkylene, heterocyclylene, arylene, heteroarylene and cycloalkenylene are each independently optionally substituted with a member selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, OH, hydroxyalkyl, CN, NH2, =0, cycloalkyl, heterocyclyl, aryl, heteroaryl; for example, Q 1 , Q 2 , Q 3 and Q 4 independently of each other selected from the group consisting of C3-C 10 cycloalkylene, 3-12 membered heterocyclylene, C6-C 10 arylene, 5-10 membered heteroarylene or C3-C 12 cycloalkenylene, wherein said C3-C 10 cycloalkylene, 3-12 membered heterocyclylene, C6-C 10 arylene, 5-10 membered heteroarylene and C3-C 12 cycloalkenylene are each independently optionally substituted with a member selected from the group consisting of halogen, C1-C 10 alkyl, C1-C 10 alkoxy, C1-C 10haloalkyl, OH, C1-C 10 hydroxyalkyl, CN, NH2, =O, C3-C 10 cycloalkyl, 3-10 membered heterocyclyl, C6-C 10 aryl, 5-10 membered heteroaryl;

[0182] R 3’ is selected from H, alkyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; for example, R 3’ is selected from H, C1-C 10 alkyl, 2-10 membered heteroalkyl, C1-C 10 haloalkyl, C3-C 10 cycloalkyl, 3-10 membered heterocyclyl, C6-C 10 aryl, and 5-10 membered heteroaryl;

[0183] R 4’ and R 5’ are each independently selected from H, halogen, alkyl, alkoxy, haloalkyl, OH, hydroxyalkyl, CN, NH2, =O, cycloalkyl, heterocyclyl, aryl, or heteroaryl; for example, R 4’ and R 5’ are each independently selected from H, halogen, C1-C 10 alkyl, C1-C 10 alkoxy, C1-C 10 haloalkyl, OH, C1-C 10 hydroxyalkyl, CN, NH2, =O, C3-C 10 cycloalkyl, 3-10 membered heterocyclyl, C6-C 10 aryl, or 5-10 membered heteroaryl;

[0184] R 6’ is selected from H, alkyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; for example R 6’ is selected from H, C1-C 10 alkyl, 2-10 membered heteroalkyl, C1-C 10 haloalkyl, C3-C 10 cycloalkyl, 3-10 membered heterocyclyl, C6-C 10 aryl, or 5-10 membered heteroaryl.

[0185] In some embodiments, the L is selected from -L A -, 1 -, 1L -,

[0186] In some embodiments, the L is selected from -L A -, 1- R 1L -,

[0187] In some embodiments, the L is selected from -R 1L -,

[0188] In some embodiments, the L is selected from -R 1L -,

[0189] In some embodiments, the L is selected from -R 1L -,

[0190] In some embodiments, the R 1L and R 2L are independently selected from a bond, C1-C4 alkylene, C2-C4 alkenylene, and C2-C8 alkynylene, each independently optionally substituted with halo. 10 In some embodiments, the R 10 and R 10 are independently selected from a bond, C1-C4 alkylene, C2-C4 alkenylene, and C2-C8 alkynylene, each independently optionally substituted with =0, C3-C6 cycloalkyl, and 3-10 membered heterocyclyl. 10 In some embodiments, the R 10 and R 10 are independently selected from a bond, C1-C4 alkylene, C2-C4 alkenylene, and C2-C8 alkynylene, each independently optionally substituted with halo.

[0191] In some embodiments, the R 1L is selected from C1-C4 alkylene and C2-C8 alkynylene, each independently optionally substituted with =0, C3-C6 cycloalkyl, and 3-10 membered heterocyclyl. 10 In some embodiments, the R 10 is selected from C1-C4 alkylene and C2-C8 alkynylene, each independently optionally substituted with =0, C3-C6 cycloalkyl, and 3-10 membered heterocyclyl. 10 In some embodiments, the R 10 and R 10 are independently selected from a bond, C1-C4 alkylene, C2-C4 alkenylene, and C2-C8 alkynylene, each independently optionally substituted with halo.

[0192] In some embodiments, the R 1L and R 2L are independently selected from a bond, C1-C4 alkylene, C2-C4 alkenylene, and C2-C8 alkynylene, each independently optionally substituted with halo.

[0193] In some embodiments, the L A or L B is independently selected from a bond, -0-, -S-, -NR 3’ -, -CR 4’ R 5’ -, -C(O)-, -S(O)-, -S(O)2-, -C(S)-, -C(O)O-, or -C(O)NR 6’ -.

[0194] In some embodiments, R 3’ and R 6’ are independently selected from H and C1-C4 alkyl.

[0195] In some embodiments, R 4’ and R 5’ are independently selected from H, halogen, and C1-C4 alkyl.

[0196] In some embodiments, the Q 1 , Q 2 , or Q 3 is independently selected from a bond, C3-C 10 cycloalkylene, 3-12 membered heterocyclylene, and 5-10 membered heteroarylene, each independently optionally substituted with C1-C4 alkyl, halogen, and hydroxyl. 10 cycloalkylene, 3-12 membered heterocyclylene, and 5-10 membered heteroarylene, each independently optionally substituted with C1-C4 alkyl, halogen, and hydroxyl.

[0197] In some embodiments, the Q 2 is selected from C3-C 10 cycloalkylene, 3-10 membered heterocyclylene, and 5-10 membered heteroarylene, each independently optionally substituted with C1-C4 alkyl. 10 cycloalkylene, 3-10 membered heterocyclylene, and 5-10 membered heteroarylene, each independently optionally substituted with C1-C4 alkyl.

[0198] In some embodiments, the L is selected from the following structures:

[0199] methylene, piperidinylene, pyrrolidinylene,

[0200] In some embodiments, the L is selected from the following structures:

[0201] In some embodiments, the LBM is selected from a VHL ligand, i.e., a binding moiety that binds a Von Hippel-Lindau type E3 ubiquitin ligase; or a CRBN ligand, i.e., a binding moiety that binds a cereblon type E3 ubiquitin ligase.

[0202] In some embodiments, the LBM is selected from a CRBN ligand.

[0203] In some embodiments, the LBM is selected from a structure represented by Formula (LBM-1) or (LBM-2):

[0204] wherein:

[0205] is selected from

[0206] Y is a bond or Y is selected from Y A , O, NH, NR E , C(O)O, C(O)NR E , NR E C(O), Y A -NH, Y A -NR E , Y A -C(O), Y A -C(O)O, Y A -OC(O), Y A -C(O)NR E , or Y A -NR E C(O), wherein said Y A is selected from C1-C6alkylene, C2-C6alkenylene or C2-C6alkynylene;

[0207] X' is selected from C(O) or C(R A )2; X A -X B is selected from C(R A )=N or C(R A )2-C(R A )2;

[0208] each R A is independently selected from H or C1-C3alkyl, said C1-C3alkyl being optionally substituted with C6-C 10 aryl or 5-10 membered heteroaryl;

[0209] each R A is independently selected from C1-C3alkyl;

[0210] each R B is independently selected from H or C1-C3alkyl, or two R B together with the atom to which they are attached form C(O), C3-C6cycloalkyl, C3-C6cycloalkenyl or 4-6 membered heterocyclyl;

[0211] R C is selected from H, halogen or C1-C3alkyl;

[0212] each R D is independently selected from halogen, NO2, NH2, OH, COOH, C1-C6alkyl or C1-C6alkoxy;

[0213] each R Eindependently selected from C1-C6 alkyl, C2-C6 alkenyl, C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl, C(O)-C1-C6 alkyl, C(O)-C2-C6 alkenyl, C(O)-C3-C8 cycloalkyl or C(O)-3-8 membered heterocycloalkyl, wherein R E Optionally substituted by a group selected from the group consisting of halogen, N(R a )2、NHC(O)R a 、NHC(O)OR a , OR b , C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl, C6-C 10 aryl or 5-10 membered heteroaryl, wherein the C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl, C6-C 10 The aryl or 5-10 membered heteroaryl is optionally further substituted by a group selected from the group consisting of halogen, NH2, CN, NO2, OH, COOH, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy or C1-C6 haloalkoxy;

[0214] R E ' is selected from H, C1-C6 alkyl, C2-C6 alkenyl, C3-C8 cycloalkyl or 3-8 membered heterocycloalkyl, wherein the C1-C6 alkyl, C2-C6 alkenyl, C3-C8 cycloalkyl or 3-8 membered heterocycloalkyl is optionally substituted by a group selected from the following: halogen, N (R a )2、NHC(O)R a 、NHC(O)OR a , OR b , C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl, C6-C 10 aryl or 5-10 membered heteroaryl, wherein the C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl, C6-C 10 The aryl or 5-10 membered heteroaryl is optionally further substituted by a group selected from the group consisting of halogen, NH2, CN, NO2, OH, COOH, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy or C1-C6 haloalkoxy;

[0215] Every R a Independently selected from H or C1-C6 alkyl;

[0216] R b Selected from H or p-toluenesulfonyl;

[0217] r is selected from 0 or 1;

[0218] m is selected from 0, 1, 2 or 3;

[0219] o is selected from 0, 1 or 2.

[0220] In some embodiments, the LBM is further selected from the structure of Formula (LBM-3):

[0221] wherein the ring B, Y, R A , R A , R B , R C , R D , m and o are as defined above.

[0222] In some embodiments, the LBM is further selected from the structure of Formula (LBM-4):

[0223] wherein the Y, X’, R A , R A , R B , R C , R D , m and o are as defined above.

[0224] In some embodiments, the LBM is selected from the structure of Formula (LBM-5):

[0225] wherein:

[0226] X C is selected from a bond, -CH2-, -CHCF3-, -SO2-, -S(O)-, -P(O)R’-, -P(O)OR’-, -P(O)NR’2-, -C(O)-, -C(S)-, or

[0227] X D is selected from C, N, or Si;

[0228] X E is selected from a bond, -CR’2-, -NR’-, -O-, -S-, or -SiR’2-;

[0229] R F is absent, or R F is selected from H, deuterium, halogen, CN, -OR’, -SR’, -S(O)R’, -S(O)2R’, -NR’2, -P(O)(OR’)2, -P(O)(NR’2)OR’, -P(O)(NR’2)2, -Si(OH)2R’, -Si(OH)R’2, -SiR’3, or C1-C4 alkyl;

[0230] each R G is independently selected from H, deuterium, R Hhalogen, CN, -N02, -OR', -SR', -NR'2, -SiR'3, -S(0)2R', -S(0)2NR'2, -S(0)R', -C(0)R', -C(0)OR', -C(0)NR'2, -C(0)N(R')OR', -C(R')2N(R')C(0)R', -C(R')2N(R')C(0)NR'2, -OC(0)R', -OC(0)NR'2, -OP(0)R'2, -OP(0)(OR')2, -OP(0)(OR')NR'2, -OP(0)(NR'2)2, -N(R')C(0)OR', -N(R')C(0)R', -N(R')C(0)NR'2, -N(R')S(0)2R', -N(R')P(0)R'2, -N(R')P(0)(OR')2, -N(R')P(0)(OR')NR'2, or -N(R')P(0)(NR'2)2;

[0231] each R H is independently selected from C1-C6alkyl, phenyl, 4-7 membered heterocyclyl, or 5-6 membered heteroaryl;

[0232] Ring E, Ring F, Ring G are each independently selected from phenyl, 6 membered heteroaryl, C5-C7cycloalkyl, C5-C7cycloalkenyl, 5-7 membered heterocyclyl, or 5-6 membered heteroaryl, wherein each of Ring E, Ring F, and Ring G is optionally further substituted with =0;

[0233] L 1 is selected from a bond, C1-C3alkylene, C2-C3alkenylene, or C2-C3alkynylene, wherein any 1 or 2 methylene groups of said C1-C3alkylene, C2-C3alkenylene, or C2-C3alkynylene are optionally replaced with -0-, -C(O)-, -C(S)-, -C(R')2-, -CH(R')-, -C(F)2-, -N(R')-, -S-, or -S(0)2-;

[0234] each R' is independently selected from H, C1-C6alkyl, phenyl, 4-7 membered heterocyclyl, or 5-6 membered heteroaryl, or two R' together with the atom to which they are attached form a 4-7 membered heterocyclyl or 5-6 membered heteroaryl;

[0235] g is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16.

[0236] In some embodiments, the LBM is selected from a structure represented by Formula (LBM-5'):

[0237] wherein said X C , RF G g, ring E, ring F, and ring G are as defined in formula (LBM-5).

[0238] In some embodiments, the LBM is selected from a structure represented by formula (LBM-6):

[0239] wherein: ring H is selected from C5-C9 cycloalkyl, C5-C9 cycloalkenyl, 5-9 membered heterocyclyl, and 5-9 membered heteroaryl, said C5-C9 cycloalkyl, C5-C9 cycloalkenyl, and 5-9 membered heterocyclyl being optionally substituted with =0; k is selected from 0, 1, 2, 3, or 4; X C D E F G 1 and ring E is as defined in formula (LBM-5).

[0240] In some embodiments, the LBM is selected from a structure represented by (LBM-6'):

[0241] wherein X C F G k, ring E, and ring H are as defined in formula (LBM-6).

[0242] In some embodiments, the LBM is selected from a structure represented by formula (LBM-7):

[0243] wherein X C D E F G 1 ring E and k are as defined in formula (DIM-6).

[0244] In some embodiments, the DIM is selected from a structure represented by (LBM-7'):

[0245] wherein X C F G ring E and k are as defined in formula (DIM-7).

[0246] In some embodiments, the LBM is selected from a VHL ligand.

[0247] In some embodiments, the LBM is selected from a structure: ​​​​​​​​​​​​​​​

[0248] In some embodiments, the LBM is selected from the following structures:

[0249] In some embodiments, the LBM is selected from the following structures:

[0250] In some embodiments, the LBM is selected from the following structures:

[0251] In some embodiments, the LBM is selected from

[0252] In some embodiments, the compound of the disclosure, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, is selected from the following compounds, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0253] In another aspect, the present disclosure provides a pharmaceutical composition comprising a compound of Formula (I) of the present disclosure, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0254] In another aspect, the present disclosure provides a method of treating a disease mediated by STAT6 in a subject (e.g., a mammal), comprising administering to a subject (e.g., a mammal, preferably a human) in need of such treatment a therapeutically effective amount of a compound of Formula (I), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In some embodiments, the present disclosure provides a method of treating a disease mediated by STAT6 in a subject (e.g., a mammal), comprising administering to a subject (e.g., a mammal, preferably a human) in need of such treatment a compound of Formula (I), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0255] In another aspect, the present disclosure provides use of a compound of Formula (I), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the manufacture of a medicament for preventing or treating a disease mediated by STAT6.

[0256] In another aspect, the present disclosure provides use of a compound of Formula (I), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in preventing or treating a disease mediated by STAT6.

[0257] In another aspect, the present disclosure provides a compound of Formula (I), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in preventing or treating a disease mediated by STAT6.

[0258] In some embodiments, the disease mediated by STAT6 is asthma, atopic dermatitis, or chronic obstructive pulmonary disease.

[0259] Definitions and explanations of terms

[0260] Unless otherwise indicated, the terms used in the present disclosure have the following meanings. The definitions of groups and terms recited in the present disclosure, including the definitions as examples, exemplary definitions, preferred definitions, definitions recited in tables, definitions of specific compounds in examples, etc., can be arbitrarily combined and incorporated with each other. A particular term should not be considered indefinite or unclear without a specific definition, but should be understood according to the ordinary meaning in the art. When a trade name appears herein, it is intended to refer to the corresponding product or active ingredient thereof.

[0261] Herein represents a point of attachment. For herein When ​When not connected to a fixed ring or atom, it means that it can be connected to a group after losing the hydrogen atom at any position in the molecule enclosed by "[]" (including hydrogen atoms directly connected to ring atoms, hydrogen atoms on non-hydrogen substituents of ring atoms, and hydrogen atoms in further substituents on substituents), for example middle The connection positions include but are not limited to X, R 7 and X, R 7 Substituents on , etc.

[0262] The term "[NH(AA)C(O)OR T ]", where NH and C(O)O are both part of the amino acid residue, NH represents the amino terminus, and C(O)O represents the carboxyl terminus.

[0263] The term "capable of binding" means capable of measurably binding to a target (eg, a ligand of an E3 ubiquitin ligase is capable of forming a covalent bond with a cysteine ​​of an E3 ubiquitin ligase, etc.).

[0264] The diagrammatic representations of racemates or enantiomerically pure compounds herein are from Maehr, J. Chem. Ed. 1985, 62: 114-120. Unless otherwise indicated, the solid and imaginary bonds are wedge-shaped. To express the absolute configuration of a stereocenter, use direct real bonds and direct virtual bonds. Indicates the relative configuration of a stereocenter (such as the cis-trans configuration of an alicyclic compound). represent mixture.

[0265] When one of the variables is selected from a chemical bond or does not exist, it means that the two groups it connects are directly connected. For example, when L in ALZ represents a bond, it means that the structure is actually AZ.

[0266] The compounds of the present disclosure can have asymmetric atoms such as carbon atoms, sulfur atoms, nitrogen atoms, phosphorus atoms, or asymmetric double bonds, and thus the compounds of the present disclosure can exist in particular geometric or stereoisomeric forms. The particular geometric or stereoisomeric forms can be cis and trans isomers, E and Z geometric isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)- isomers, (L)-isomers, as well as racemic mixtures or other mixtures thereof, such as those that contain one enantiomeric or diastereomeric excess, all of which are within the scope of the compounds of the present disclosure. Additional asymmetric carbon atoms, asymmetric sulfur atoms, asymmetric nitrogen atoms, or asymmetric phosphorus atoms can be present in a substituent group, and all such isomers and mixtures thereof are included within the scope of the compounds of the present disclosure. Compounds of the present disclosure containing an asymmetric atom can be isolated in optically active form or as racemic mixtures, and the optically active forms can be obtained, for example, by resolution of a racemic form or by synthesis from optically active raw materials.

[0267] The term "substituted" means that any one or more hydrogen atoms on the particular atom is replaced with a substituent group, provided that the valence of the particular atom is not exceeded, and that the substituted compound is stable. When the substituent is oxo (i.e., =0), it means that two hydrogen atoms are replaced by the oxo group. Oxos are not present on aromatic groups.

[0268] The term "optionally" or "optional" means that the subsequently described event or circumstance can or can not occur, and this description includes instances where the event or circumstance occurs and instances where it does not. For example, an ethyl group "optionally" substituted with one or more halogens means that the ethyl group can be unsubstituted (CH2CH3), mono-substituted (CH2CH2F, CH2CH2C1, etc.), poly-substituted (CHFCH2F, CH2CHF2, CHFCH2C1, CH2CHC12, etc.), or fully substituted (CF2CF3, CF2CC13, CC12CC13, etc.). One skilled in the art will appreciate that for any given group containing one or more substituents, no substitution or substitution pattern is introduced that is not spatially possible and / or synthetically feasible.

[0269] When any variable (e.g., R a , R b ) occurs more than one time in a compound, its definition in each occurrence is independent of its definition at every other occurrence. For example, if a group is substituted with 2 R b groups, then each R b is selected independently.

[0270] When the number of a linking group is 0, such as -(CH2)0-, it means that the linking group is a bond.

[0271] C in this document m -C n means having an integer number of carbon atoms in the range m-n. For example "Ci-C6alkyl" means that the group can have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, 6 carbon atoms, or 7 carbon atoms. 10

[0272] When a linking group is referred to herein without specifying the direction of the linkage, the direction of the linkage is arbitrary. For example, when L in structural unit 1 is selected from "Ci-C3alkylene-O", then L 1 may either link ring Q and R 1 to form "ring Q-Ci-C3alkylene-O-R 1 " in the direction from left to right, or link ring Q and R 1 to form "ring Q-O-Ci-C3alkylene-R 1 " in the direction from right to left.

[0273] When a bond of a substituent crosses over to connect to two atoms of a ring, the substituent can be bonded to either atom of the ring. For example, structural unit 5 indicates that R n may be substituted at any position on the phenyl ring.

[0274] The term "alkyl" refers to a hydrocarbon group of formula C 2n+1 H 10 ​​​"Alkyl" can be understood to mean a straight-chained or branched saturated hydrocarbon group having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. Particular examples of said alkyl groups include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1 -methylbutyl, 1 -ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1 -dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1 -methylpentyl, 2-ethylbutyl, 1 -ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1 -dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl or 1,2-dimethylbutyl and the like; the term "Ci-C6alkyl" can be understood to mean an alkyl group having 1 to 6 carbon atoms, particular examples including, but not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 1 -methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, hexyl, 2-methylpentyl and the like. The term "Ci-C4alkyl" can be understood to mean a straight-chained or branched saturated alkyl group having 1 to 4 carbon atoms. The term "Ci-C3alkyl" can be understood to mean a straight-chained or branched saturated alkyl group having 1 to 3 carbon atoms. Said "Ci-C 10 "Alkyl" can include the ranges "Ci-C6alkyl", "Ci-C4alkyl" or "Ci-C3alkyl" and the like, said "Ci-C6alkyl" can further include "Ci-C4alkyl" or "Ci-C3alkyl". The term "alkylene" refers to a straight-chained or branched divalent hydrocarbon chain linking the rest of the molecule to a group, consisting solely of carbon and hydrogen atoms and being saturated. The term "haloalkyl" is intended to include mono-haloalkyl and poly-haloalkyl groups. For example, the term "Ci-C 10 "Alkyl" can include the ranges "Ci-C6alkyl", "Ci-C4alkyl" or "Ci-C3alkyl" and the like, said "Ci-C6alkyl" can further include "Ci-C4alkyl" or "Ci-C3alkyl". The term "alkylene" refers to a straight-chained or branched divalent hydrocarbon chain linking the rest of the molecule to a group, consisting solely of carbon and hydrogen atoms and being saturated. The term "haloalkyl" is intended to include mono-haloalkyl and poly-haloalkyl groups. For example, the term "Ci-C 10 haloalkyl" means a Ci-C6alkyl group as defined above substituted by one or more halogen atoms. Particular examples include, but are not limited to, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, trichloromethyl, pentafluoroethyl and pentachloroethyl and the like.

[0275] The term "alkoxy" refers to a straight-chained or branched alkoxy group, which can be understood as "alkyloxy" or "alkyl-O-". The term "Ci-C 10 "Alkoxy" can include the ranges "Ci-C6alkoxy", "Ci-C4alkoxy" or "Ci-C3alkoxy" and the like, said "Ci-C6alkoxy" can further include "Ci-C4alkoxy" or "Ci-C3alkoxy". The term "alkyloxy" is intended to include mono-alkyloxy and poly-alkyloxy groups. For example, the term "Ci-C 10 "Alkoxy" can include the ranges "Ci-C6alkoxy", "Ci-C4alkoxy" or "Ci-C3alkoxy" and the like, said "Ci-C6alkoxy" can further include "Ci-C4alkoxy" or "Ci-C3alkoxy". The term "alkyloxy" is intended to include mono-alkyloxy and poly-alkyloxy groups. For example, the term "Ci-C 10 "Alkoxy" can include the ranges "Ci-C6alkoxy", "Ci-C4alkoxy" or "Ci-C3alkoxy" and the like, said "Ci-C6alkoxy" can further include "Ci-C4alkoxy" or "Ci-C3alkoxy". The term "alkyloxy" is intended to include mono-alkyloxy and poly-alkyloxy groups. For example, the term "Ci-C 10 "Alkoxy" can include the ranges "Ci-C6alkoxy", "Ci-C4alkoxy" or "Ci-C3alkoxy" and the like, said "Ci-C6alkoxy" can further include "Ci-C4alkoxy" or "Ci-C3alkoxy". The term "alkyloxy" is intended to include mono-alkyloxy and poly-alkyloxy groups. For example, the term "Ci-C

[0276] The term "alkenyl" refers to a linear or branched unsaturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms and having at least one double bond. 10 "Alkenyl" is understood to mean a linear or branched unsaturated hydrocarbon radical containing one or more double bonds and having 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, "C2-C 10 The term "alkenyl" may include "C2-C6 alkenyl", "C2-C4 alkenyl", C2 or C3 alkenyl. It will be understood that when the alkenyl contains more than one double bond, the double bonds may be separated or conjugated. Specific examples of the alkenyl include, but are not limited to, vinyl, allyl, (E)-2-methylvinyl, (Z)-2-methylvinyl, (E)-but-2-enyl, (Z)-but-2-enyl, (E)-but-1-enyl, (Z)-but-1-enyl, isopropenyl, 2-methylprop-2-enyl, 1-methylprop-2-enyl, 2-methylprop-1-enyl, (E)-1-methylprop-1-enyl or (Z)-1-methylprop-1-enyl, etc. The term "alkenylene" refers to a divalent alkenyl disclosed herein.

[0277] The term "alkynyl" refers to a straight or branched unsaturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms and having at least one triple bond. 10 "Alkynyl" is understood to mean a linear or branched unsaturated hydrocarbon radical containing one or more triple bonds and having 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. "C2-C 10 Examples of "alkynyl" include, but are not limited to, ethynyl (-C≡CH), propynyl (-C≡CCH 3、 -CH2C≡CH), but-1-ynyl, but-2-ynyl or but-3-ynyl. "C2-C 10 The term "alkynyl" may include "C2-C3 alkynyl". Examples of "C2-C3 alkynyl" include ethynyl (-C≡CH), prop-1-ynyl (-C≡CCH3), and prop-2-ynyl (-CH2C≡CH). The term "alkynylene" refers to a divalent alkynyl group disclosed herein.

[0278] The term "cycloalkyl" refers to a fully saturated carbocyclic group that exists in the form of a monocyclic, fused, bridged, or spirocyclic ring. Unless otherwise indicated, the carbocyclic ring is typically a 3- to 20-membered ring. The term "C3-C 10 The term "cycloalkyl" refers to a cycloalkyl group having 3, 4, 5, 6, 7, 8, 9 or 10 ring carbon atoms. The term "C3-C6 cycloalkyl" refers to a cycloalkyl group having 3, 4, 5 or 6 ring carbon atoms. The term "cycloalkylene" refers to a divalent cycloalkyl group disclosed herein.

[0279] The term "heterocycle" or "heterocyclyl" refers to a monocyclic, fused ring, spiro, or bridged ring radical, which is completely saturated or partially saturated (not an aromatic heteroaromatic overall), which contains from 1 to 5 (e.g., 1 to 3 or 1 to 2) heteroatoms or groups of heteroatoms (i.e., groups of atoms containing heteroatoms) in its ring atom count, including but not limited to nitrogen (N), oxygen (O), sulfur (S), phosphorus (P), boron (B), -S(=0)2-, -S(=0)-, -P(=0)2-, -P(=0)-, -NH-, -S(=0)(=NH)-, -C(=0)NH-, or -NHC(=0)NH-, and the like, in its ring atoms. The term "4-10 membered heterocyclyl" refers to a heterocyclyl radical having a ring atom count of 4, 5, 6, 7, 8, 9, or 10, and which contains from 1 to 5 heteroatoms or groups of heteroatoms independently selected from those described above in its ring atoms. A "4-10 membered heterocyclyl" can include a "4-7 membered heterocyclyl." The term "4-7 membered heterocyclyl" refers to a heterocyclyl radical having a ring atom count of 4, 5, 6, or 7, and which contains from 1, 2, 3, 4, or 5 heteroatoms or groups of heteroatoms independently selected from those described above in its ring atoms. Specific examples of 4-membered heterocyclyl groups include, but are not limited to, azetidinyl or oxetanyl; specific examples of 5-membered heterocyclyl groups include, but are not limited to, tetrahydrofuranyl, dioxolyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl, 4,5-dihydrooxazolyl, or 2,5-dihydro-lH-pyrrolyl; specific examples of 6-membered heterocyclyl groups include, but are not limited to, tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, trithianyl, tetrahydropyridinyl, or 4H-[l,3,4]thiadiazinyl; specific examples of 7-membered heterocyclyl groups include, but are not limited to, diazepanyl. The heterocyclyl radical can also be a bicyclic radical, where specific examples of 5,5 membered bicyclic radicals include, but are not limited to, hexahydrocyclopenta[c]pyrrol-2(lH)-yl; specific examples of 5,6 membered bicyclic radicals include, but are not limited to, hexahydropyrrolo[l,2-a]pyrazin-2(lH)-yl, 5,6,7,8-tetrahydro-[l,2,4]triazolo[4,3-a]pyrazinyl, or 5,6,7,8-tetrahydroimidazo[l,5-a]pyrazinyl. Optionally, the heterocyclyl radical can be a benzo-fused ring radical of the aforementioned 4-7 membered heterocyclyl groups, specific examples include, but are not limited to, dihydroisoquinolinyl, and the like. A "4-10 membered heterocyclyl" can include a "5-10 membered heterocyclyl," a "4-7 membered heterocyclyl," a "5-6 membered heterocyclyl," a "6-8 membered heterocyclyl," a "4-10 membered heterocycloalkyl," a "5-10 membered heterocycloalkyl," a "4-7 membered heterocycloalkyl," a "5-6 membered heterocycloalkyl," a "6-8 membered heterocycloalkyl," and the like. A "4-7 membered heterocyclyl" can further include a "4-6 membered heterocyclyl," a "5-6 membered heterocyclyl," a "4-7 membered heterocycloalkyl," a "4-6 membered heterocycloalkyl," a "5-6 membered heterocycloalkyl," and the like.Although some bicyclic heterocyclyl moieties in the present disclosure contain a benzene ring or a heteroaromatic ring partially, the heterocyclyl is still non-aromatic as a whole. The term "heterocycloalkylene" or "heterocyclylene" refers to a divalent heterocycle or heterocyclyl group disclosed herein.

[0280] The term "heterocycloalkyl" refers to a fully saturated cyclic group that exists in a single ring, fused rings, bridged rings, or spiro rings, etc., with 1-5 heteroatoms or heteroatom groups (i.e., an atom group containing a heteroatom) in the ring atoms of the ring, which "heteroatoms or heteroatom groups" include, but are not limited to, a nitrogen atom (N), an oxygen atom (O), a sulfur atom (S), a phosphorus atom (P), a boron atom (B), -S(=O)2-, -S(=O)-, -NH-, -S(=O)(=NH)-, -C(=O)NH-, or -NHC(=O)NH-, etc. The term "4-10 membered heterocycloalkyl" refers to a heterocycloalkyl group with 4, 5, 6, 7, 8, 9, or 10 ring atoms, and with 1-5 ring atoms independently selected from the above-mentioned heteroatoms or heteroatom groups. The term "5-10 membered heterocycloalkyl" refers to a heterocycloalkyl group with 5, 6, 7, 8, 9, or 10 ring atoms, and with 1-5 ring atoms independently selected from the above-mentioned heteroatoms or heteroatom groups. "4-10 membered heterocycloalkyl" and "5-10 membered heterocycloalkyl" include "4-7 membered heterocycloalkyl", wherein specific examples of 4-membered heterocycloalkyl groups include, but are not limited to, azetidinyl, oxetanyl, or thietanyl; specific examples of 5-membered heterocycloalkyl groups include, but are not limited to, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, isoxazolidinyl, oxazolidinyl, isothiazolidinyl, thiazolidinyl, imidazolidinyl, or tetrahydropyrazolyl; specific examples of 6-membered heterocycloalkyl groups include, but are not limited to, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, piperazinyl, 1,4-thioxinanyl, 1,4-dioxanyl, thiomorpholinyl, 1,3-dithianyl, or 1,4-dithianyl; and specific examples of 7-membered heterocycloalkyl groups include, but are not limited to, azepanyl, oxepanyl, or thiepanyl.

[0281] The term "aryl" refers to an all-carbon monocyclic or fused ring polycyclic ring system that is aromatic and has a conjugated π-electron system. The aryl group can have 6-20 carbon atoms, 6-14 carbon atoms, or 6-12 carbon atoms. The term "C6-C 10 The term "aryl" can be understood as an aryl group having 6 to 10 carbon atoms. For example, a ring having 6 carbon atoms ("C6 aryl"), such as phenyl; or a ring having 9 carbon atoms ("C9 aryl"), such as indanyl or indenyl; or a ring having 10 carbon atoms ("C 10 The term "arylene" refers to a divalent aryl group disclosed herein.

[0282] The term "heteroaryl" refers to a monocyclic or fused polycyclic ring system having aromaticity, which contains at least one ring atom selected from N, O, S, the remaining ring atoms being C. The term "5-10 membered heteroaryl" is understood to include monocyclic or bicyclic aromatic ring systems having 5, 6, 7, 8, 9, or 10 ring atoms, e.g., 5 or 6 or 9 or 10 ring atoms, and which contain 1-5, e.g., 1-3, heteroatoms independently selected from N, O, and S. In particular, the heteroaryl group is selected from thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, or thiadiazolyl, and the like, as well as benzo derivatives thereof, e.g., benzofuranyl, benzothienyl, benzothiazolyl, benzoxazolyl, benzoisoxazolyl, benzoimidazolyl, benzotriazolyl, indazolyl, indolyl, or isoindolyl, and the like; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, or triazinyl, and the like, as well as benzo derivatives thereof, e.g., quinolinyl, quinazolinyl, or isoquinolinyl, and the like; or azocinyl, indolizinyl, purinyl, and the like, as well as benzo derivatives thereof; or cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenoxazinyl, phenothiazinyl, or phenoxazinyl, and the like. The term "6-10 membered heteroaryl" is understood to include monocyclic or bicyclic aromatic ring systems having 6, 7, 8, 9, or 10 ring atoms, e.g., 6 or 9 or 10 ring atoms, and which contain 1-5, e.g., 1-3, heteroatoms independently selected from N, O, and S. The term "5-6 membered heteroaryl" refers to aromatic ring systems having 5 or 6 ring atoms, and which contain 1-3, e.g., 1-2, heteroatoms independently selected from N, O, and S. The term "heteroarylene" refers to a divalent heteroaryl group as disclosed herein.

[0283] The term "cycloalkenyl" refers to a monovalent unsaturated monocyclic or bicyclic hydrocarbon ring. The term "C3-C12 cycloalkenyl" is understood to include unsaturated monocyclic or bicyclic hydrocarbon rings containing 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 carbon atoms. 12 The term "cycloalkenyl" refers to a monovalent unsaturated monocyclic or bicyclic hydrocarbon ring. The term "C3-C12 cycloalkenyl" is understood to include unsaturated monocyclic or bicyclic hydrocarbon rings containing 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 carbon atoms. 12 Examples of cycloalkenyl groups include, but are not limited to, bicyclo[2.2.1]hept-2- enyl or bicyclo[2.2.2]oct-2-enyl.

[0284] The term "cycloalkenyl" refers to a monovalent unsaturated monocyclic or bicyclic hydrocarbon ring. The term "C3-C12 cycloalkenyl" is understood to include unsaturated monocyclic or bicyclic hydrocarbon rings containing 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 carbon atoms.

[0285] The term "halo" or "halogen" refers to fluoro, chloro, bromo, or iodo.

[0286] The term "hydroxy" refers to an -OH group.

[0287] The term "cyano" refers to a -CN group.

[0288] The term "amino" refers to the -NH2group.

[0289] The term "nitro" refers to the -NO2group.

[0290] The term "treatment" means the administration of a compound or formulation described herein to improve or eliminate a disease or one or more symptoms associated with the disease, and includes:

[0291] (i) inhibiting the disease or condition, i.e., arresting its development;

[0292] (ii) relieving the disease or condition, i.e., causing regression of the disease or condition.

[0293] The term "therapeutically effective amount" means an amount of a compound of the disclosure that (i) treats a particular disease, condition, or disorder, (ii) reduces, ameliorates, or eliminates one or more symptoms of a particular disease, condition, or disorder. The amount of a compound of the disclosure that constitutes a "therapeutically effective amount" will vary depending on the compound, the disease state and its severity, the manner of administration, and the age of the mammal to be treated, but can be determined routinely by the skilled practitioner as a matter of routine.

[0294] The term "prevention" means the administration of a compound or formulation described herein to prevent a disease or one or more symptoms associated with the disease, and includes preventing the disease or condition from occurring in an individual (e.g., a mammal), particularly when such individual (e.g., a mammal) is predisposed to the disease state but has not yet been diagnosed as having it.

[0295] The term "individual" includes mammals and non-mammals. Examples of mammals include, but are not limited to, any member of the mammalian class: humans, non-human primates (e.g., chimpanzees and other apes and monkeys); farm animals such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice and guinea pigs, and the like. Examples of non-human mammals include, but are not limited to, birds and fish, and the like. In one embodiment of the methods and compositions provided herein, the mammal is a human. The terms "patient" and "individual" are used interchangeably.

[0296] The term "pharmaceutically acceptable" in reference to 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 humans and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0297] The term "pharmaceutically acceptable salt" means a salt of a pharmaceutically acceptable acid or base, including salts of inorganic acids or organic acids, and salts of inorganic bases or organic bases, with which the compounds are formulated.

[0298] The term "pharmaceutical composition" means a mixture of one or more compounds of the disclosure or salts thereof with a pharmaceutically acceptable excipient. The purpose of a pharmaceutical composition is to facilitate administration of a compound of the disclosure to an organism.

[0299] The term "pharmaceutically acceptable excipient" means an excipient that is not biologically or otherwise undesirable, i.e., the excipient can be administered to an organism without causing any undesirable biological effects or interacting in a deleterious manner with any of the other components of the pharmaceutical composition in which it is contained. The presence of an excipient in a composition does not interfere with any of the biological activity or properties of the active compound.

[0300] The words "comprise" or "comprising" and variations thereof such as "comprises" or "comprising", when used in this document, can be understood to encompass the terms "consisting of" or "consisting of".

[0301] The present disclosure also includes isotopically-labeled compounds of the present disclosure which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be present in compounds of the disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulphur, fluorine, iodine, and chlorine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 123 I, 125 I, and 36 Cl, and the like.

[0302] Certain isotopically-labeled compounds of the disclosure (for example, those 3 H and 14 C) can be used in compound and / or substrate tissue distribution analysis. Tritiated (i.e., 3 H) and carbon-14 (i.e., 14 C) isotopes are particularly preferred for their ease of preparation and detectability. Positron emitting isotopes such as 15 O,13 N, 11 C and 18 F can be used in positron emission tomography (PET) studies to determine substrate occupancy. Isotopically-labeled compounds of the present disclosure can generally be prepared by substituting a readily available isotopically-labeled reagent for a non-isotopically labeled reagent in a

[0303] The pharmaceutical compositions of the present disclosure can be prepared by combining a compound of the present disclosure with suitable pharmaceutically acceptable excipients, e.g., can be formulated into solid, semi-solid, liquid, or gaseous dosage forms, such as tablets, pills, capsules, powders, granules, ointments, creams, lotions, suppositories, injections, inhalers, gels, microspheres, aerosols, and the like.

[0304] Typical routes of administering a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, intravenous administration.

[0305] The pharmaceutical compositions of the present disclosure can be manufactured in a manner appropriate for the route of administration, e.g., by conventional methods such as those described in Remington: The Science and Practice of Pharmacy, 22nd Edition, Philadelphia, PA: Mack Publishing Company, 2012, incorporated herein by reference.

[0306] In some embodiments, the pharmaceutical composition is in oral form. For oral administration, the pharmaceutical composition can be formulated by combining the active compound with a pharmaceutically acceptable excipient well known in the art. These excipients enable the compounds of the present disclosure to be formulated as tablets, pills, lozenges, dragees, capsules, liquids, gels, slurries, suspensions, and the like, for oral administration to a patient.

[0307] Solid oral compositions can be prepared by conventional mixing, encapsulation, or by confectionary methods. For example, the active compound can be mixed with a solid excipient to form a stable and free-flowing dispersion for tabletting or filling a capsule. Suitable excipients include, but are not limited to, binders, diluents, disintegrants, lubricants, glidants, or flavoring agents.

[0308] The pharmaceutical composition can also be suitable for parenteral administration, such as sterile solutions, suspensions, or lyophilized products in appropriate unit dosage forms.

[0309] The dosage administered will depend on factors such as the particular compound, the disease condition and its severity, the identity of the subject or host to be treated (e.g., body weight, sex), and the particular formulation to be used, the route of administration, the condition being treated, and the subject or host being treated.

[0310] In all methods of administration of the compounds of general formula (I) described herein, the daily dosage for oral administration is from 0.01 mg / kg to 100 mg / kg of body weight, in single or divided doses. The daily and unit doses vary according to many variables, including but not limited to the activity of the compound used, the disease or condition to be treated, the mode of administration, the requirements of the individual subject, the severity of the disease or condition treated, and the judgment of the practitioner.

[0311] 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 other chemical synthetic methods, and equivalents thereof as appreciated by those skilled in the art, preferred embodiments including but not limited to the examples of the present disclosure.

[0312] The chemical reactions of the specific embodiments of the present disclosure are performed in solvents appropriate to the reaction step and the reagents and materials used therein. In order to obtain compounds of the present disclosure, it is sometimes necessary to modify or select the synthetic steps or reaction sequences based on the skill of the person skilled in the art from the embodiments provided.

[0313] The following abbreviations are used in the present disclosure:

[0314] THF stands for tetrahydrofuran; CAN stands for acetonitrile; FmocOSu stands for (9H-fluoren-9-yl)methyl (2,5-dioxopyrrolidin-1-yl) carbonate; Bn stands for benzyl; DMF stands for N,N-dimethylformamide; DCM stands for dichloromethane; TFA stands for trifluoroacetic acid; DMK stands for dimethyl ketone; DIEA stands for N,N-diisopropylethylamine; HATU stands for O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; MeOH stands for methanol; Dioxane stands for 1,4-dioxane; Pd(dppf)Cl2 stands for [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II); Pd(PPh3)4 stands for tetrakis(triphenylphosphine)palladium; Bestmann reagent stands for (1-diazo-2-oxopropyl)dimethyl phosphonate; BH3-Me2S stands for borane dimethyl sulfide complex; DMP stands for Dess-Martin reagent; EDCI stands for 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride; DMAP stands for 4-dimethylaminopyridine; ISiMe3 stands for trimethylsilyl iodide; TEA / NEt3 stands for triethylamine; PPh3 stands for triphenylphosphine; NIS stands for N-iodosuccinimide; IRC 120 Na+ stands for Amberlite IR120, Na resin ion exchange resin; AcOH stands for acetic acid; STAB stands for sodium triacetoxyborohydride; NaOAc stands for sodium acetate; Pd-PEPPSI-IPent-Cl stands for (SP-4-1)-[1,3-bis[2,6-bis(1- ethylpropyl)phenyl]-4,5-dichloro-1,3-dihydro-2H-imidazol-2-ylidene]dichloro(3- chloropyridine-KN)palladium; Pd-PEPPSI-IHept-Cl stands for (SP-4-1)-[1,3-bis[2,6-bis(1- propylbutyl)phenyl]-4,5-dichloro-1,3-dihydro-2H-imidazol-2-ylidene]dichloro(3- chloropyridine-KN)palladium; tBuOK stands for potassium tert-butoxide; NBS stands for N-bromosuccinimide; AIBN stands for azobisisobutyronitrile; Et stands for ethyl; P(OEt)3 stands for triethyl phosphite; LiHMDS stands for lithium bis(trimethylsilyl)amide; NFSI stands for N-fluorobenzenesulfonimide; TMSI stands for trimethylsilyl iodide; BSTFA stands for N,O-bistrimethylsilyltrifluoroacetamide; t-BuONa stands for sodium tert-butoxide; NMP stands for N-methylpyrrolidone; tBu stands for tert-butyl; Pd2(dba)3 stands for tris[dibenzylideneacetone]dipalladium; XPhos stands for 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl; HOBT stands for 1-hydroxybenzotriazole; Cbz stands for benzyloxycarbonyl; CMPI stands for 2-chloro-1-methylpyridinium iodide; PyBop stands for 1H-benzotriazol-1-yl oxytripyrrolidinophosphonium hexafluorophosphate;TMIS stands for trimethyl iodosilane; PE stands for petroleum ether; EA stands for ethyl acetate; TMS stands for trimethylsilyl; TMSCHN2 stands for trimethylsilylated diazomethane; DCE stands for 1,2-dichloroethane; Ph3PCHCOOtBu stands for tert-butyl triphenylphosphinoacetate; TsCI stands for p-toluenesulfonyl chloride; TFE stands for trifluoroethanol; DMAC stands for N,N-dimethylacetamide; Troc-Cl stands for 2,2,2-trichloroethyl chloroformate; Py stands for pyridine; (Boc)2O stands for di-tert-butyl dicarbonate; (HCHO); n stands for paraformaldehyde; tBuOH stands for tert-butyl alcohol; XantPhos stands for 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; FA stands for formic acid; LC-MS stands for liquid chromatography-mass spectrometry; MS stands for mass spectrometry; 1 H NMR stands for proton nuclear magnetic resonance; ESI stands for electrospray ionization; HPLC stands for high-performance liquid chromatography; DMSO stands for dimethyl sulfoxide; PBS stands for phosphate-buffered saline; DC 50 represents the half-maximal degradation concentration of the compound. BRIEF DESCRIPTION OF THE DRAWINGS

[0315] Figure 1 Ellipsoid diagram of the three-dimensional structure of intermediate M

[0316] Figure 2. Intermediate M unit cell structure stacking diagram DETAILED DESCRIPTION

[0317] 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 listed herein, embodiments formed by combining them with other chemical synthesis methods, and equivalent substitutions well known to those skilled in the art. Preferred embodiments include but are not limited to the examples of the present disclosure.

[0318] The present disclosure is described in detail below by way of examples, but this is not intended to limit the present disclosure in any way. While the present disclosure has been described in detail herein, including specific embodiments thereof, it will be apparent to those skilled in the art that various changes and modifications can be made to the specific embodiments without departing from the spirit and scope of the present disclosure. All reagents used in the present disclosure are commercially available and can be used without further purification.

[0319] Unless otherwise specified, the ratios expressed for mixed solvents are volume ratios.

[0320] Unless otherwise specified, % refers to weight %.

[0321] Compounds are manually or Software naming, commercially available compounds use supplier catalog names.

[0322] The structure of the compound is determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). The unit of NMR shift is 10 -6 (ppm). The solvent for NMR determination is deuterated dimethyl sulfoxide, deuterated chloroform, deuterated methanol, etc., and the internal standard is tetramethylsilane (TMS);

[0323] The eluent or mobile phase can be a mixed eluent or mobile phase composed of two or more solvents in a ratio of volume ratio of each solvent.

[0324] Preparation Example:

[0325] Synthesis of intermediate A: tert-butyl ((5S,8S,10aR)-8-((trans)-3-cyano-4-phenylpyrrolidine-1-carbonyl)-6-oxododecahydro pyrrolo[1,2-a][1,5]diazocin-5-yl)carbamate

[0326] Step 1: Synthesis of (5S,8S,10aR)-5-((tert-butoxycarbonyl)amino)-6-oxododecahydropyrrolo[1,2-a][1,5]diazocin-8-carboxylic acid (A-2)

[0327] Dissolve the starting material (A-1, 500 mg, 1.46 mmol) in a mixed solvent of tetrahydrofuran (5 mL) and water (0.5 mL), add lithium hydroxide monohydrate (156 mg, 3.73 mmol), and react at room temperature overnight. After LC-MS detection shows that the reaction is complete, adjust the pH to 6 with dilute hydrochloric acid (2M), and concentrate to dryness under reduced pressure to obtain the crude title compound, which is directly subjected to the next step.

[0328] MS m / z (ESI): 328.1 [M+H] +

[0329] Step 2: Synthesis of (5S,8S,10aR)-3-(((9H-fluoren-9-yl)methoxy)carbonyl)-5-((tert-butoxycarbonyl)amino)-6-oxododecahydropyrrolo[1,2-a][1,5]diazocin-8-carboxylic acid (A-3)

[0330] To a solution of (5S,8S,10aR)-5-((tert-butoxycarbonyl)amino)-6- oxododecahydropyrrolo[l,2-a][l,5]diazocin-8-carboxylic acid crude (A-2, 713 mg) in tetrahydrofuran (5 mL) and water (1 mL) was added (9H-fluoren-9-yl)methyl (2,5-dioxopyrrolidin-l- yl) carbonate (628 mg, 1.86 mmol) and sodium bicarbonate (209 mg, 2.48 mmol) and the reaction mixture was stirred at room temperature for 2 hours. LC-MS analysis showed the reaction was complete. The reaction mixture was adjusted to pH = 6 with dilute hydrochloric acid, and then partitioned between ethyl acetate (10 mL) and saturated brine (10 mL). The aqueous phase was extracted with ethyl acetate (10 mL x 3), and the combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to dryness. The residue was purified by silica gel column chromatography (methanol / dichloromethane = 0-10% gradient elution) to give the title compound (613 mg).

[0331] MS m / z (ESI): 450.2 [M+H-Boc] +

[0332] Step 3: Synthesis of (9H-fluoren-9-yl)methyl (5S,8S,10aR)-5-((tert- butoxycarbonyl)amino)-8-((trans)-3-cyano-4-phenylpyrrolidine-l-carbonyl)-6- oxooctahydropyrrolo[l,2-a][l,5]diazocin-3(4H)-carboxylate (A-4)

[0333] To a solution of (5S,8S,10aR)-3-(((9H-fluoren-9-yl)methoxy)carbonyl)-5-((tert- butoxycarbonyl)amino)-6-oxododecahydropyrrolo[l,2-a][l,5]diazocin-8-carboxylic acid (A-3, 400 mg, 728 μmol) in N,N-dimethylformamide (1 mL) was added O-(7-azabenzotriazol-l-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (329 mg, 873 μmol) and N,N-diisopropylethylamine (113 mg, 873 μmol), and the reaction mixture was stirred at room temperature for 30 minutes. Then, trans-4-phenylpyrrolidine-3-carbonitrile (138 mg, 801 μmol) was added and the reaction mixture was stirred at room temperature for 1 hour. LC-MS analysis showed the reaction was complete. The reaction mixture was concentrated under reduced pressure to dryness. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 30-70% gradient elution) to give the title compound (501 mg).

[0334] MS m / z (ESI): 604.3 [M+H-Boc] +

[0335] Step 4: Synthesis of tert-butyl ((5S,8S,10aR)-8-((trans)-3-cyano-4-phenylpyrrolidine-1- carbonyl)-6-oxododecahydro pyrrolo[1,2-a][1,5]diazocin-5-yl)carbamate (Intermediate A)

[0336] (9H-fluoren-9-yl)methyl (5S,8S,10aR)-5-((tert-butoxycarbonyl)amino)-8-((trans)-3- cyano-4-phenylpyrrolidine-1-carbonyl)-6-oxooctahydro pyrrolo[1,2-a][1,5]diazocin-3(4H)- carboxylate (A-4, 500 mg, 710 μmol) was dissolved in acetonitrile (5 mL), piperidine (302 mg, 3.55 mmol) was added and the reaction was stirred at room temperature for 1 h. LC-MS indicated the reaction was complete. The reaction was concentrated to dryness under reduced pressure and the residue was purified by silica gel column chromatography (methanol / methylene chloride = 0-10% gradient elution) to give the title compound (328 mg).

[0337] MS m / z (ESI): 482.3 [M+H] +

[0338] Step 4: Synthesis of tert-butyl ((5S,8S,10aR)-8-((trans)-3-cyano-4-phenylpyrrolidine-1- carbonyl)-6-oxododecahydro pyrrolo[1,2-a][1,5]diazocin-5-yl)carbamate (Intermediate A)

[0339] Step 1: Synthesis of tert-butyl ((3S,6S,10aS)-3-((trans)-3-cyano-4-(4-nitrophenyl)pyrrolidine-1- carbonyl)-5-oxododecahydro pyrrolo[1,2-a]azocin-6-yl)carbamate (B-2)

[0340] (3S,6S,10aS)-6-((tert-butoxycarbonyl)amino)-5-oxododecahydro pyrrolo[1,2-a]azocin-3- carboxylic acid (B-1, 150 mg, 460 μmol) was dissolved in N,N-dimethylformamide (2 mL), N,N-diisopropylethylamine (119 mg, 921 μmol) and O-(7-azabenzotriazol-1-yl)-N,N,N',N'- tetramethyluronium hexafluorophosphate (261 mg, 690 μmol) were added and the reaction was stirred at room temperature for 30 min. (trans)-4-(4-nitrophenyl)pyrrolidine-3-carbonitrile (100 mg, 460 μmol) was added and the reaction was continued overnight. LC-MS indicated the reaction was complete. The reaction was concentrated to dryness under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0-60% gradient elution) to give the title compound (233 mg).

[0341] MS m / z (ESI): 470.2 [M+H-tBu] +

[0342] Step 2: Synthesis of tert-butyl ((3S,6S,10aS)-3-((trans)-3-cyano-4-(4- nitrophenyl)pyrrolidine-1-carbonyl)-5-oxododecahydropyrrolo[1,2-a]azocin-6- yl)carbamate (Intermediate B)

[0343] tert-Butyl ((3S,6S,10aS)-3-((trans)-3-cyano-4-(4-nitrophenyl)pyrrolidine-1- carbonyl)-5-oxododecahydropyrrolo[1,2-a]azocin-6-yl)carbamate (B-2, 230 mg, 438 μmol) was dissolved in methanol (5 mL), palladium on carbon (10% palladium, 20 mg) was added and the reaction was stirred under hydrogen atmosphere overnight. LC-MS indicated the reaction was complete, the reaction mixture was diluted with methanol (10 mL) and filtered. The filtrate was concentrated to dryness under reduced pressure to give the title compound as a crude (210 mg).

[0344] MS m / z (ESI): = 496.2 [M+H] + .

[0345] Synthesis of 2-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1- yl)acetic acid (Intermediate C)

[0346] Step 1: Synthesis of 2-(2,6-dioxopiperidin-3-yl)-5-(piperazin-1-yl)isoindoline-1,3- dione (C-2)

[0347] tert-Butyl 4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl]piperazine-1- carboxylate (C-1, 100 mg, 226.01 μmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (26 mg, 226.01 μmol, 1 mL) was added and the mixture was stirred at room temperature for 30 minutes. The reaction was monitored by LC-MS and upon completion, the solvent was removed under reduced pressure to give the title compound as a crude which was used directly in the next step without further purification.

[0348] MS m / z (ESI): 343 [M+H] +

[0349] Step 2: Synthesis of tert-butyl 2-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5- yl)piperazin-1-yl)acetate (C-3)

[0350] 2-(2,6-dioxopiperidin-3-yl)-5-(piperazin-l-yl)isoindoline-l,3-dione (C-2, 130 mg, 379.73 μmol) was dissolved in acetone (2 mL), after stirring evenly, tert-butyl bromoformate (96 mg, 493.65 μmol) was added, and the temperature was raised to 60 °C and stirred for 2 hours. The reaction was monitored by LC-MS, and after the reaction was completed, the solvent was removed by reduced pressure concentration, and the residue was separated and purified by silica gel column chromatography (dichloromethane / methanol system = 50 / 1) to obtain the title compound (105 mg).

[0351] MS m / z (ESI): 457 [M+H] +

[0352] Step 3: Synthesis of 2-(4-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)piperazin-l- yl)acetic acid (Intermediate C)

[0353] 2-(4-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)piperazin-l-yl)acetic acid tert-butyl ester (C-3, 105 mg, 230.02 μmol) was dissolved in dichloromethane (5 mL), after stirring evenly, trifluoroacetic acid (1 mL) was added, and stirred at room temperature for 30 minutes. The reaction was monitored by LC-MS, and after the reaction was completed, the solvent was removed by reduced pressure concentration to obtain the title compound crude product, which was directly used in the subsequent reaction without further purification.

[0354] MS m / z (ESI): 401.0 [M+H] +

[0355] Synthesis of 2-(4-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperazin-l-yl)acetic acid (Intermediate E)

[0356] Step 1: Synthesis of 2-(4-(5-iodopyridin-2-yl)piperazin-l-yl)acetic acid tert-butyl ester (E-2)

[0357] 2-fluoro-5-iodopyridine (E-l, 2.0 g, 8.97 mmol) and 2-(piperazin-l-yl)acetic acid tert-butyl ester (1.98 g, 9.87 mmol) were dissolved in dimethyl sulfoxide (20 mL), after adding N,N-diisopropylethylamine (2.32 g, 17.94 mmol), the temperature was raised to 80 °C and reacted overnight. LC-MS detection showed that the reaction was complete. After the reaction solution was cooled to room temperature, it was diluted with ethyl acetate (30 mL), then washed with saturated brine (20 mL x 3), and the organic phase was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to obtain the title compound (2.5 g).

[0358] MS m / z (ESI): 404.0 [M+H] +

[0359] Step 2: Synthesis of tert-butyl 2-(4-(2',6'-bis(benzyloxy)-[3,3'-bipyridinyl]-6- yl)piperazin-1-yl)acetate (E-3)

[0360] Tert-butyl 2-(4-(5-iodopyridin-2-yl)piperazin-1-yl)acetate (E-2, 2.2 g, 5.46 mmol) and 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (2.5 g, 6.00 mmol) were dissolved in a mixed solvent of 1,4-dioxane (10 mL) and water (2 mL), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (396 mg, 545.6 μmol) and potassium carbonate (1.51 g, 10.9 mmol) were added, and the system was heated to 100 °C under argon protection overnight. The reaction was monitored by LC-MS, and after the reaction was completed, the system was cooled to room temperature, diluted with ethyl acetate (10 mL) and filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate system = 2 / 1) to give the title compound (2.03 g).

[0361] MS m / z (ESI): 567.2 [M+H] +

[0362] Step 3: Synthesis of tert-butyl 2-(4-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperazin-1- yl)acetate (E-4)

[0363] Tert-butyl 2-(4-(2',6'-bis(benzyloxy)-[3,3'-bipyridinyl]-6-yl)piperazin-1-yl)acetate (E-3, 2.0 g, 3.53 mmol) was dissolved in ethyl acetate (20 mL), palladium on carbon (palladium content 10%, 2 g) was added, and the system was stirred at room temperature under a hydrogen atmosphere overnight. LC-MS detection showed that the reaction was complete, the reaction solution was diluted with ethyl acetate (10 mL) and filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 10:1) to give the title compound (790 mg).

[0364] MS m / z (ESI): 389.2 [M+H] +

[0365] Step 4: Synthesis of 2-(4-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperazin-1-yl)acetic acid (Intermediate E)

[0366] Dissolve 2-(4-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperazin-1-yl)acetic acid tert-butyl ester (E-4, 560 mg, 1.44 mmol) in dichloromethane (5 mL), add trifluoroacetic acid (1 mL) and continue the reaction at room temperature for 3 hours. LC-MS detection shows the reaction is complete, concentrate the reaction solution under reduced pressure to get the title compound crude, which is directly used in the next step without further purification.

[0367] MS m / z (ESI): 333.1 [M+H] +

[0368] Synthesis of intermediate F: 4-(2-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H- benzo[d]imidazol-5-yl)ethyl)cyclohexane-1-carboxylic acid

[0369] Step 1: Synthesis of methyl 4-(hydroxymethyl)cyclohexane-1-carboxylate (F-2)

[0370] Dissolve 4-(methoxycarbonyl)cyclohexane-1-carboxylic acid (F-1, 5.0 g, 26.8 mmol) in tetrahydrofuran (50 mL), cool to 0 °C under argon protection, then add borane dimethyl sulfide complex (10 M, 5.4 mL) dropwise, remove from ice bath and continue the reaction overnight. TLC detection shows the reaction is complete, cool the reaction solution to 0 °C, then quench with methanol slowly dropwise, then concentrate to dryness under reduced pressure, the residue is purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0-50% gradient elution) to give the title compound (3.5 g).

[0371] 1 H NMR (400 MHz, CDCl3) δ 3.68 (d, J = 5.1 Hz, 3H), 3.52-3.42 (m, 2H), 2.63-2.53 (m, 1H), 2.32-2.19 (m, 1H), 2.08-1.95 (m, 2H), 1.93-1.82 (m, 2H), 1.69-1.35 (m, 3H), 1.36-1.22 (m, 1H), 1.07-0.91 (m, 1H).

[0372] Step 2: Synthesis of methyl 4-formylcyclohexane-1-carboxylate (F-3)

[0373] Methyl 4-(hydroxymethyl)cyclohexane-l-carboxylate (F-2, 3.5 g, 20.3 mmol) was dissolved in dichloromethane (50 mL), and Dess-Martin reagent (10.3 g, 24.4 mmol) was added at room temperature for 4 h. TLC detection showed that the reaction was complete, the reaction solution was filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0-20% gradient elution) to give the title compound (1.9 g).

[0374] 1 H NMR (400 MHz, CDC13) δ 9.68-9.63 (m, 1H), 3.69-3.66 (m, 3H), 2.51-2.17 (m, 2H), 2.16-2.02 (m, 2H), 2.02-1.90 (m, 1H), 1.80-1.63 (m, 3H), 1.58-1.42 (m, 1H), 1.39-1.23 (m, 1H).

[0375] Step 3: Synthesis of methyl 4-ethynylcyclohexane-l-carboxylate (F-4)

[0376] Methyl 4-formylcyclohexane-l-carboxylate (F-3, 1.8 g, 10.6 mmol) and potassium carbonate (2.2 g, 15.6 mmol) were dissolved in methanol (20 mL), and dimethyl (l-diazo-2-oxopropyl)phosphonate (3.1 g, 15.9 mmol) was added at room temperature overnight. TLC detection showed that the reaction was complete, the reaction solution was diluted with ethyl acetate (20 mL), washed with saturated ammonium chloride solution (15 mL x 3), and then dried over anhydrous sodium sulfate. The organic phase was filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0-20% gradient elution) to give the title compound (1.4 g).

[0377] 1 H NMR (400 MHz, CDC13) δ 3.69-3.65 (d, J = 6.7 Hz, 3H), 2.39-2.21 (m, 1H), 2.11-1.93 (m, 4H), 1.97-1.79 (m, 1H), 1.83-1.70 (m, 1H), 1.63-1.44 (m, 1H), 1.47-1.31 (m, 3H).

[0378] Step 4: Synthesis of 4-ethynylcyclohexane-l-carboxylic acid (F-5)

[0379] Methyl 4-ethynylcyclohexane-1-carboxylate (F-4, 1.4 g, 8.4 mmol) was dissolved in a mixture solvent of tetrahydrofuran (10 mL) and water (5 mL), and lithium hydroxide monohydrate (707 mg, 16.9 mmol) was added. The reaction was carried out at room temperature for 2 hours. TLC detection showed that the reaction was complete. After adjusting the pH to 4 with dilute hydrochloric acid (2 M), ethyl acetate (10 mL x 5) was added for extraction. The organic phase was combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to dryness. The residue was swirled with petroleum ether (10 mL) and filtered to obtain the title compound (360 mg).

[0380] 1 H NMR (400 MHz, DMSO-d6) δ 12.08 (s, 1H), 2.87-2.85 (m, 1H), 2.34-2.11 (m, 2H), 2.00-1.76 (m, 4H), 1.45-1.22 (m, 4H).

[0381] Step 5: Synthesis of 4-((1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H- benzo[d]imidazol-5-yl)ethynyl)cyclohexane-1-carboxylic acid (F-6)

[0382] Methyl 4-ethynylcyclohexane-1-carboxylate (F-4, 1.4 g, 8.4 mmol) was dissolved in a mixture solvent of tetrahydrofuran (10 mL) and water (5 mL), and lithium hydroxide monohydrate (707 mg, 16.9 mmol) was added. The reaction was carried out at room temperature for 2 hours. TLC detection showed that the reaction was complete. After adjusting the pH to 4 with dilute hydrochloric acid (2 M), ethyl acetate (10 mL x 5) was added for extraction. The organic phase was combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to dryness. The residue was swirled with petroleum ether (10 mL) and filtered to obtain the title compound (360 mg).

[0383] MS m / z (ESI): 410.2 [M+H] +

[0384] Step 6: Synthesis of 4-(2-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H- benzo[d]imidazol-5-yl)ethyl)cyclohexane-1-carboxylic acid (Intermediate F)

[0385] Dissolve 4-((1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H- benzo[d]imidazol-5-yl)ethynyl)cyclohexane-1-carboxylic acid (F-6, 67 mg, 164 pmol) in methanol (5 mL), add palladium on carbon (palladium content 10%, 20 mg), and react overnight under a hydrogen atmosphere. After LC-MS detection of complete reaction, the reaction solution is diluted with methanol (10 mL) and filtered. The filtrate is concentrated to dryness under reduced pressure to give the title compound (57 mg).

[0386] MS m / z (ESI): = 414.2 [M+H] +

[0387] Synthesis of intermediate G: 2-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)- 2-azaspiro[3.5]nonane-7-carbaldehyde

[0388] Step 1: Synthesis of (2-azaspiro[3.5]nonan-7-yl)methanol (G-2)

[0389] Dissolve 7-(hydroxymethyl)-2-azaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (G-1, 800 mg, 3.13 mmol) in dichloromethane (4 mL) at room temperature. Add hydrochloric acid dioxane solution (2 mL, 4 N) dropwise at room temperature and stir for 2 hours at room temperature. Concentrate the solvent under vacuum to give the crude title compound which is used directly in the next step.

[0390] Step 2: Synthesis of 2-(2,6-dioxopiperidin-3-yl)-5-(7-(hydroxymethyl)-2- azaspiro[3.5]nonan-2-yl)isoindoline-1,3-dione (G-3)

[0391] Dissolve 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (864.6 mg, 3.13 mmol), (2-azaspiro[3.5]nonan-7-yl)methanol (G-2, crude, 3.13 mmol), and N,N- diisopropylethylamine (2.02 g, 15.65 mmol) in dimethyl sulfoxide (5 mL), and raise the temperature to 100 °C. Stir the reaction mixture at 100 °C for 4 hours. After the reaction is complete, cool the reaction solution to room temperature, dilute with water (100 mL), filter, collect the filter cake, and separate it by silica gel column chromatography (dichloromethane / methanol = 100 / 1 to 100 / 2) to give the title compound (1.20 g).

[0392] MS m / z (ESI): 412.2 [M+H] +

[0393] Step 3: Synthesis of 2-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)-2- azaspiro[3.5]nonane-7-carbaldehyde (Intermediate G)

[0394] To a solution of 2-(2,6-dioxopiperidin-3-yl)-5-(7-(hydroxymethyl)-2- azaspiro[3.5]nonan-2-yl)isoindoline-l,3-dione (G-3, 500.0 mg, 1.22 mmol) in dichloromethane (10 mL) was added Dess-Martin Oxidizing Reagent (776.2 mg, 1.83 mmol) slowly at ice-bath temperature. The reaction mixture was stirred at 0 °C for 1 h, then warmed to room temperature and stirred for 2 h. After completion of the reaction, it was concentrated and purified by silica gel column chromatography (dichloromethane / methanol = 100 / 1-100 / 2) to give the title compound (450.0 mg).

[0395] MS m / z (ESI): 410.1 [M+H] +

[0396] 1 H NMR (400 MHz, DMSO-d6) δ 11.06 (s, 1H), 9.59 (s, 1H), 7.63 (d, J = 8.4 Hz, 1H), 6.76 (d, J = 2.0 Hz, 1H), 6.63 (dd, J1= 2.0 Hz, J2= 8.0 Hz, 1H), 5.05 (dd, J1= 5.6 Hz, J2= 12.8 Hz, 1H), 3.72 (s, 4H), 2.93-2.83 (m, 1H), 2.60-2.47 (m, 2H), 2.35-2.29 (m, 1H), 2.03-1.97 (m, 1H), 1.91-1.80 (m, 4H), 1.63-1.47 (m, 2H), 1.43-1.34 (m, 2H).

[0397] Intermediate I: Synthesis of (difluoro(2-((perfluorophenoxy)carbonyl)benzo[b]thiophen-5- yl)methyl)phosphonic acid

[0398] Step 1: Synthesis of 5-((diethoxyphosphoryl)difluoromethyl)benzo[b]thiophene-2- carboxylic acid (perfluorophenyl ester) (I-2)

[0399] 5-((diethoxyphosphoryl)difluoromethyl)benzo[b]thiophene-2-carboxylic acid (perfluorophenol ester) (I-2, 220 mg, 0.41 mmol) was added to a reaction flask, N,O-bis(trimethylsilyl)trifluoroacetamide (534 mg, 2.07 mmol) and anhydrous dichloromethane (2.5 mL) were added, then an argon balloon was installed, the gas was replaced three times, and then the gas was protected, then it was cooled in an ice bath, trimethylsilyl iodide (332 mg, 1.66 mmol) was added, and the ice bath was maintained for 15 minutes, then it was removed to room temperature and reacted for 15 minutes. LC-MS monitoring showed that the reaction was complete. A mixture solution of 3 mL of water and acetonitrile (water: acetonitrile = 2:1, containing 0.1% trifluoroacetic acid) was added to quench, and stirred at room temperature for 15 minutes. The mixture was transferred to a round-bottom flask, and the dichloromethane in the system was removed by concentration under reduced pressure, then an appropriate amount of water and acetonitrile were added and freeze-dried to obtain the title compound (178 mg).

[0400] MS m / z (ESI): 531.0 [M+H] +

[0401] 1 H NMR (400 MHz, CDCl3) δ 8.44-8.35 (m, 1H), 8.27-8.21 (m, 1H), 8.07-7.99 (m, 1H), 7.83-7.74 (m, 1H), 4.34-4.15 (m, 4H), 1.34 (t, J = 7.1 Hz, 6H).

[0402] Step 2: Synthesis of (difluoro(2-((perfluorophenoxy)carbonyl)benzo[b]thiophen-5-yl)methyl)phosphonic acid (intermediate I)

[0403] 5-((diethoxyphosphoryl)difluoromethyl)benzo[b]thiophene-2-carboxylic acid (perfluorophenol ester) (I-2, 220 mg, 0.41 mmol) was added to a reaction flask, N,O-bis(trimethylsilyl)trifluoroacetamide (534 mg, 2.07 mmol) and anhydrous dichloromethane (2.5 mL) were added, then an argon balloon was installed, the gas was replaced three times, and then the gas was protected, then it was cooled in an ice bath, trimethylsilyl iodide (332 mg, 1.66 mmol) was added, and the ice bath was maintained for 15 minutes, then it was removed to room temperature and reacted for 15 minutes. LC-MS monitoring showed that the reaction was complete. A mixture solution of 3 mL of water and acetonitrile (water: acetonitrile = 2:1, containing 0.1% trifluoroacetic acid) was added to quench, and stirred at room temperature for 15 minutes. The mixture was transferred to a round-bottom flask, and the dichloromethane in the system was removed by concentration under reduced pressure, then an appropriate amount of water and acetonitrile were added and freeze-dried to obtain the title compound (178 mg).

[0404] MS m / z (ESI): 472.9 [M-H] -

[0405] 1H NMR (400 MHz, DMSO-d6) δ 8.80 (s, 1H), 8.35 - 8.27 (m, 2H), 7.78 - 7.71 (m, 1H).

[0406] Synthesis of Intermediate J: 5-((bis(2-((3-methylbutanoyl)thio)ethoxy) phosphoryl)difluoromethyl)benzo[b]thiophene-2-carboxylic acid perfluorophenyl ester

[0407] Step 1: Synthesis of S-(2-hydroxyethyl)-3-methylbutanoic acid thioester (J-2)

[0408] Into a reaction flask was placed 3-methylbutanoyl chloride (6.24 mL, 51.19 mmol), triethylamine (7.15 mL, 51.19 mmol), dichloromethane (50 mL), and the gas was replaced with argon three times. 2-Mercaptoethanol (J-1, 4 g, 51.19 mmol) was added slowly at -78 °C, and the reaction solution was stirred at -78 °C for 1 hour under gas protection. Then the reaction solution was moved to room temperature and stirred for another 1 hour. Then saturated aqueous ammonium chloride solution was added for quenching, and extracted with dichloromethane three times (200 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (silica, petroleum ether / ethyl acetate = 10 / 1) to give the title compound (4.81 g).

[0409] 1 H NMR (400 MHz, CDCl3) δ 3.67 (t, J = 6.2 Hz, 2H), 3.01 (t, J = 6.2 Hz, 2H), 2.65 (s, 1H), 2.39 (d, J = 7.1 Hz, 2H), 2.17 - 2.02 (m, 1H), 0.89 (d, J = 6.7 Hz, 6H).

[0410] Step 2: Synthesis of S-(2-iodoethyl)-3-methylbutanoic acid thioester (J-3)

[0411] Into a reaction flask was placed S-(2-hydroxyethyl)-3-methylbutanoic acid thioester (J-2, 1 g, 6.16 mmol), triphenylphosphine (1.62 g, 6.16 mmol), dichloromethane (20 mL), and N-iodosuccinimide (1.39 g, 6.16 mmol) was added at 0 °C. The reaction solution was stirred at room temperature for 1 hour. Then saturated sodium bicarbonate was added for quenching, and extracted with ethyl acetate three times (50 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (silica, petroleum ether) to give the title compound (1.41 g).

[0412] 1H NMR (400 MHz, CDC13) δ 3.30 - 3.23 (m, 2H), 3.23 - 3.12 (m, 2H), 2.38 (d, J = 7.2 Hz, 2H), 2.17 - 2.02 (m, 1H), 0.89 (d, J = 6.7 Hz, 6H).

[0413] Step 3: Synthesis of (difluoro(2-((perfluorophenoxy)carbonyl)benzo[b]thiophen-5- yl)methyl)phosphonic acid disilver salt (J-4)

[0414] To a reaction flask was added (difluoro(2-((perfluorophenoxy)carbonyl)benzo[b]thiophen-5- yl)methyl)phosphonic acid (Intermediate I, 400 mg, 843.45 pmol), tetrahydrofuran (2.5 mL) and deionized water (5 mL) were added, followed by Amberlite IR120, Na resin ion exchange resin (2.63 g, 8.43 mmol), the resulting reaction was stirred at room temperature overnight, filtered, the filter cake was washed with a small amount of deionized water, the mother liquor was collected, then silver nitrate (315.21 mg, 1.86 mmol) aqueous solution (1 mL) was added, the resulting reaction was stirred at room temperature for 1 hour, a large amount of white solid was precipitated, filtered, the filter cake was collected and dried under vacuum to give the title compound (523 mg).

[0415] Step 4: Synthesis of perfluorophenyl 5-((bis(2-((3-methylbutanoyl)thio)ethoxy)phosphoryl)difluoromethyl)benzo[b]thiophene-2-carboxylate (Intermediate J)

[0416] To a reaction flask was added (difluoro(2-((perfluorophenoxy)carbonyl)benzo[b]thiophen-5- yl)methyl)phosphonic acid disilver salt (J-4, 600 mg, 872.14 pmol), super dry toluene (6 mL) was added, then S-(2-iodoethyl)-3-methylbutanoic thioester (J-3, 712.05 mg, 2.62 mmol) was added, stirred at room temperature overnight under argon protection. The reaction was concentrated under reduced pressure, then purified by column chromatography (silica, petroleum ether / ethyl acetate = 4 / 1) to give the title compound (237 mg).

[0417] 1 H NMR (400 MHz, CDC13) δ 8.47 - 8.38 (m, 1H), 8.28 - 8.21 (m, 1H), 8.08 - 7.99 (m, 1H), 7.82 - 7.75 (m, 1H), 4.33 - 4.15 (m, 4H), 3.24 - 3.08 (m, 4H), 2.43 (d, J = 7.2 Hz, 4H), 2.19 - 2.08 (m, 2H), 0.94 (d, J = 6.7 Hz, 12H).

[0418] Synthesis of Intermediate K: (((difluoro(2-((perfluorophenoxy)carbonyl)benzo[b]thiophen-5-yl)methyl)phosphoryl)bis(oxy))bis(methylene)bis(2,2-dimethylpropanoate)

[0419] Intermediate K was prepared according to the procedure described for the synthesis of Intermediate J, substituting iodo methyl pivalate for Intermediate J-3.

[0420] 1 H NMR (400 MHz, CDC13) δ 8.36 (s, 1H), 8.22 (s, 1H), 8.02 (d, J = 8.4 Hz, 1H), 7.75 (d, J = 8.8 Hz, 1H), 5.75 (dd, J = 4.8 Hz, 12.4 Hz, 2H), 5.67 (dd, J = 4.8 Hz, 12.0 Hz, 2H), 1.19 (s, 18H).

[0421] Synthesis of Intermediate L: l-(l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH- benzo[d]imidazol-5-yl)piperidine-4-carbaldehyde

[0422] Step 1: Synthesis of 3-(5-(4-(dimethoxymethyl)piperidin-l-yl)-3-methyl-2-oxo-2,3-dihydro-lH- benzo[d]imidazol-l-yl)piperidine-2,6-dione (L-2)

[0423] Under nitrogen protection, 3-(5-bromo-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-l- yl)piperidine-2,6-dione (L-l, 500 mg, 1.48 mmol) and 4-(dimethoxymethyl)piperidine (470.86 mg, 2.96 mmol) were dissolved in dioxane (6 mL), to which (SP-4-1)-[l,3-bis[2,6-bis(l- ethylpropyl)phenyl]-4,5-dichloro-l,3-dihydro-2H-imidazol-2-ylidene]palladium(127 mg, 148.0 μmol) and cesium carbonate (2.41 g, 7.39 mmol) were added, and the reaction was stirred at 100 °C for 6 hours. LC-MS showed the reaction was complete. Ethyl acetate (10 x 2 mL) and water (10 mL) were added to extract, and the organic phase was combined, dried, filtered, and the filtrate was concentrated to give the title compound (20 mg).

[0424] Step 2: Synthesis of l-(l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH- benzo[d]imidazol-5-yl)piperidine-4-carbaldehyde (Intermediate L)

[0425] To a solution of 3-(5-(4-(dimethoxymethyl)piperidin-l-yl)-3-methyl-2-oxo-2,3- dihydro-lH-benzo[d]imidazol-l-yl)piperidine-2,6-dione (L-2, 18 mg, 43.22 pmol) in a mixture of tetrahydrofuran (2 mL) and water (0.4 mL) was added hydrochloric acid (2 M, 216.10 pL) and the reaction mixture was stirred at 60 °C for 3 h. The solvent was removed by concentration under reduced pressure and the residue was lyophilized from acetonitrile and water. The title compound (15 mg) was obtained.

[0426] MS m / z (ESI): 371.00 [M+H] +

[0427] Synthesis of (3R,4S)-4-(4-nitrophenyl)pyrrolidine-3-carbonitrile and (3S,4R)-4-(4- nitrophenyl)pyrrolidine-3-carbonitrile hydrochloride (Intermediate M & N)

[0428] Step 1: Synthesis of (E)-3-(4-nitrophenyl)acrylonitrile (M-2)

[0429] To a solution of potassium tert-butoxide in tetrahydrofuran (1 M, 7 mL) was added diethyl (cyanomethyl)phosphonate (1.17 g, 6.62 mmol) dropwise at 0 °C under argon. After 30 min, 4-nitrobenzaldehyde (M-l, 1.00 g, 6.62 mmol) was added and the reaction mixture was allowed to warm to room temperature and stirred overnight. TLC analysis indicated that the reaction was complete. The reaction mixture was diluted with ethyl acetate (20 mL) and washed with saturated brine (10 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (100% dichloromethane) to give the title compound (495 mg).

[0430] 1 H NMR (400 MHz, CDC13) δ 8.28 (d, J = 8.8 Hz, 2H), 7.63 (d, J = 8.8 Hz, 2H), 7.47 (d, J = 16.7 Hz, 1H), 6.05 (d, J = 16.7 Hz, 1H).

[0431] Step 2: Synthesis of trans-l-benzyl-4-(4-nitrophenyl)pyrrolidine-3-carbonitrile (M-3)

[0432] (E)-3-(4-nitrophenyl)acrylonitrile (M-2, 495 mg, 2.84 mmol) was dissolved in dichloromethane (5 mL) and cooled to 0 °C after addition of trifluoroacetic acid (32 mg, 284 pmol). N-benzyl-1-methoxy-N-((trimethylsilyl)methyl)methanamine (1.35 g, 5.68 mmol) was added dropwise and the reaction was allowed to warm to room temperature overnight. LC-MS indicated complete reaction and the reaction was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0-20% gradient elution) to give the title compound (834 mg).

[0433] MS m / z (ESI): = 308.1 [M+H] + .

[0434] Step 3: Synthesis of (3S,4R)-1-benzyl-4-(4-nitrophenyl)pyrrolidine-3-carbonitrile and (3R,4S)-1-benzyl-4-(4-nitrophenyl)pyrrolidine-3-carbonitrile (intermediate M-3P1 and M-3P2)

[0435] The chiral separation of trans-1-benzyl-4-(4-nitrophenyl)pyrrolidine-3-carbonitrile intermediate (M-3) to give single configuration (3S,4R)-1-benzyl-4-(4-nitrophenyl)pyrrolidine-3-carbonitrile and (3R,4S)-1-benzyl-4-(4-nitrophenyl)pyrrolidine-3-carbonitrile (M-3P1 and M-3P2) Chiral separation method: Column: Daicel CHIRALPAK IF_3, 3.0*150mm, 3um; Mobile phase: Mobile phase A: Supercritical CO2; Mobile phase B: MeOH (0.1% DEA); Elution gradient: 5% B to 40% B; Flow rate: 1.5 mL / min; Detector: PDA; Column temperature: 37 °C. M-3P1 retention time: 1.455 min, M-3P2 retention time: 1.626 min.

[0436] Step 4: Synthesis of (3S,4R)-4-(4-nitrophenyl)pyrrolidine-3-carbonitrile hydrochloride and (3R,4S)-4-(4-nitrophenyl)pyrrolidine-3-carbonitrile hydrochloride (intermediate M and intermediate N)

[0437] Dissolve intermediate M-3P1(or intermediate M-3P2)(75 mg, 0.24 mmol) in 1,2-dichloroethane (0.5 mL) and cool to 0 °C. Then dissolve 1-chloroethyl chloroformate (348 mg, 2.40 mmol) in 1,2-dichloroethane (0.5 mL) and drop into the above solution. After 30 minutes at this temperature, warm to 80 °C and react for 1 hour. Cool to room temperature and concentrate the reaction mixture to dryness under reduced pressure. Dissolve the residue in methanol (1 mL) and heat to 80 °C for 1 hour. LC-MS detection shows that the reaction is substantially complete. Concentrate the reaction mixture to dryness under reduced pressure to obtain intermediate M (or intermediate N), which is used directly in the next step without purification.

[0438] Intermediate M is prepared from intermediate M-3P1, and intermediate N is prepared from intermediate M-3P2. MS m / z (ESI): = 218.1 [M+H] + .

[0439] After single crystal cultivation, intermediate M is identified as (3S,4R)-4-(4-nitrophenyl)pyrrolidine-3-carbonitrile, as follows:

[0440] Single crystal cultivation method: weigh 10 mg of intermediate M (hydrochloride form) into a 1.5 mL centrifuge tube, add 500 μL of methanol, sonicate to dissolve, then seal with a sealing film, prick three small holes on the sealing film with a needle, and slowly evaporate at 30 °C. After 3 days, rod-shaped crystals are obtained, which are single crystals of the compound.

[0441] The obtained single crystal sample is subjected to X-ray analysis, and the test results are shown in Table 1 and Figure 1.

[0442] Test power 70 W, test voltage 50 kV, test current 1.4 mA.

[0443] Table 1 Single crystal sample and crystal data of intermediate M

[0444] Through the above X-ray crystal diffraction experiment, the chemical structure and absolute configuration of intermediate M can be determined, and it is identified as (3S,4R)-4-(4-nitrophenyl)pyrrolidine-3-carbonitrile hydrochloride.

[0445] Synthesis of Intermediate O and Intermediate P: tert-butyl ((3S,6S,10aS)-3-((3R,4S)-3-(4-aminophenyl)-4- (iminomethyl)pyrrolidine-1-carbonyl)-5-oxodecahydropyrrolo[1,2-a]azocin-6-yl)carbamate and tert-butyl ((3S,6S,10aS)-3-((3S,4R)-3-(4-aminophenyl)-4- (iminomethyl)pyrrolidine-1-carbonyl)-5-oxodecahydropyrrolo[1,2-a]azocin-6-yl)carbamate

[0446] Referring to the synthesis method of Intermediate B, replace (trans)-4-(4- nitrophenyl)pyrrolidine-3-carbonitrile in the method with Intermediate M (or Intermediate N), and Intermediate O (or Intermediate P) is prepared in the same manner.

[0447] Intermediate M is prepared to obtain Intermediate O, and Intermediate N is prepared to obtain Intermediate P.

[0448] Synthesis of Intermediate Q: 5-(fluoro((((S)-1-oxo-1-propyloxypropan-2-yl)amino) (phenoxy)phosphoryl)methyl)benzo[b]thiophene-2-carboxylic acid

[0449] Step 1: Synthesis of ethyl 5-methylbenzo[b]thiophene-2-carboxylate (Q-2)

[0450] To a solution of 2-fluoro-5-methylbenzaldehyde (Q-1, 100 g, 0.72 mol) in N,N- dimethylformamide (1 L) was added ethyl mercaptoacetate (91.34 g, 0.76 mol) and potassium carbonate (200.10 g, 1.45 mol) at room temperature, and the resulting mixture was stirred at 80 °C for 6 hours. After the reaction was completed, the reaction solution was cooled to room temperature, poured into ice water, stirred for 1 hour, filtered, and the filter cake was washed once with water and dried to obtain the crude product of the title compound (120 g), which was used directly in the next step without further purification.

[0451] MS m / z (ESI): 221.1 [M+H] +

[0452] Step 2: Synthesis of 5-methylbenzo[b]thiophene-2-carboxylic acid (Q-3)

[0453] A solution of sodium hydroxide (43.58 g, 1.09 mol) in water (600 mL) was added dropwise to a solution of ethyl 5-methylbenzo[b]thiophene-2-carboxylate (Q-2, 120 g, 0.54 mol) in methanol (600 mL) and tetrahydrofuran (600 mL) at room temperature. The resulting reaction solution was stirred at room temperature for 1 hour. After completion of the reaction, the organic solvent was removed by concentration under reduced pressure, and the solution was diluted with water (300 mL). The pH was adjusted to 3 with dilute hydrochloric acid (2 N), and the solution was extracted with ethyl acetate (800 mL x 2). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was washed with petroleum ether twice and dried to obtain the title compound (58.0 g).

[0454] MS m / z (ESI): 193.1 [M+H] +

[0455] Step 3: Synthesis of benzyl 5-methylbenzo[b]thiophene-2-carboxylate (Q-4)

[0456] To a solution of 5-methylbenzo[b]thiophene-2-carboxylic acid (Q-3, 58 g, 0.30 mol) in N,N-dimethylformamide (500 mL) were added benzyl bromide (61.92 g, 0.36 mol) and cesium carbonate (127.80 g, 0.39 mol) at room temperature. The resulting reaction solution was stirred at 30°C for 2 hours. After completion of the reaction, the reaction solution was cooled to room temperature, poured into ice water, and extracted with ethyl acetate (400 mL x 2). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was washed with petroleum ether twice and dried to obtain the title compound (75 g).

[0457] MS m / z (ESI): 283.1 [M+H] +

[0458] Step 4: Synthesis of benzyl 5-(bromomethyl)benzo[b]thiophene-2-carboxylate (Q-5)

[0459] Benzyl 5-methylbenzo[b]thiophene-2-carboxylate (Q-4, 75 g, 0.266 mol) was dissolved in 1,2-dichloroethane (1.2 L) at room temperature, and N-bromosuccinimide (51.64 g, 0.29 mol) and azobisisobutyronitrile (8.66 g, 0.053 mol) were added. The resulting mixture was warmed to 80°C and stirred for 16 hours. After completion of the reaction, the reaction solution was cooled to room temperature, diluted with water (500 mL), and extracted with dichloromethane (500 mL x 3). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was separated and purified by column chromatography on silica gel (petroleum ether / dichloromethane = 3 / 1) to obtain the title compound (40 g).

[0460] MS m / z (ESI): 383.0 [M+Na] +

[0461] Step 5: Synthesis of benzyl 5-((diethoxyphosphoryl)methyl)benzo[b]thiophene-2- carboxylate (Q-6)

[0462] Benzyl 5-(bromomethyl)benzo[b]thiophene-2-carboxylate (Q-5, 40 g, 0.11 mol) was dissolved in toluene (400 mL) at room temperature, and triethyl phosphite (400 mL) was added. The resulting reaction solution was warmed to 110°C and stirred for 16 hours. After the reaction was completed, the reaction solution was reduced to room temperature, and concentrated under reduced pressure to obtain a residue, which was separated and purified by silica gel column chromatography (ethyl acetate: dichloromethane = 1:2) to obtain the title compound (37 g).

[0463] MS m / z (ESI): 419.1 [M+H] +

[0464] Step 6: Synthesis of benzyl 5-((diethoxyphosphoryl)fluoromethyl)benzo[b]thiophene-2- carboxylate (Q-7)

[0465] Benzyl 5-((diethoxyphosphoryl)methyl)benzo[b]thiophene-2-carboxylate (Q-6, 27 g, 64.53 mmol) was dissolved in tetrahydrofuran (200 mL) at room temperature, and nitrogen gas was replaced 3 times, and cooled to -70°C. Lithium bis(trimethylsilyl)amide (71 mL, 70.98 mmol, 1M) was slowly added dropwise under a nitrogen atmosphere, and then a solution of N-fluorobenzenesulfonimide (20.96 g, 66.46 mmol) in tetrahydrofuran (200 mL) was slowly added dropwise. After the addition was completed, stirring was performed at -70°C for 1 hour. After the reaction was completed, saturated ammonium chloride solution (50 mL) was added at -70°C to quench the reaction, filtered, diluted with water (200 mL), extracted with ethyl acetate (300 mL x 3), and the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain the title compound (18 g).

[0466] MS m / z (ESI): 437.1 [M+H] +

[0467] 1H NMR (400 MHz, DMSO-d6) δ 8.03 (s, 1H), 7.91 (s, 1H), 7.82 (d, J = 8.0 Hz, 1H), 7.51 (d, J = 8.0 Hz, 1H), 7.40 - 7.30 (m, 5H), 5.73 (dd, J = 8.0 Hz, 44.0 Hz, 1H), 5.33 (s, 2H), 4.11 - 3.94 (m, 4H), 1.23 - 1.17 (m, 6H).

[0468] Step 7: Synthesis of ((2-((benzyloxy)carbonyl)benzo[b]thiophen-5-yl)fluoromethyl)phosphonic acid (Q-8)

[0469] Benzyl 5-((diethoxyphosphoryl)fluoromethyl)benzo[b]thiophene-2-carboxylate (Q-7, 2.18 g, 5.00 mmol) was dissolved in dichloromethane (20 mL) under ice bath, trimethylsilyl iodide (3.00 g, 14.99 mmol) and N,O-bistrimethylsilyltrifluoroacetamide (3.21 g, 12.47 mmol) were added, and stirred for 1 hour. After the reaction was completed, 0.05% trifluoroacetic acid-acetonitrile aqueous solution (acetonitrile: water = 1:2) (1.5 mL) was added to the reaction solution and stirred for 15 minutes, dichloromethane was removed by concentration under reduced pressure, and an appropriate amount of water and acetonitrile were added, and lyophilized to obtain the title compound (1.88 g).

[0470] MS m / z (ESI): 379.1 [M-H] -

[0471] Step 8: Synthesis of benzyl 5-(fluoro((((S)-1-oxo-1-propoxypropan-2-yl)amino)(phenoxy)phosphoryl)methyl)benzo[b]thiophene-2-carboxylate (Q-9)

[0472] ((2-((benzyloxy)carbonyl)benzo[b]thiophen-5-yl)fluoromethyl)phosphonic acid (Q-8, 200 mg, 0.53 mmol) was dissolved in dichloromethane (10 mL) at room temperature, and oxalyl chloride (200 mg, 1.58 mmol) and N,N-dimethylformamide (38 mg, 0.53 mmol) were added. The reaction was stirred at 40 °C for 2 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain an intermediate phosphorus oxychloride as a yellow solid. The intermediate phosphorus oxychloride was dissolved in dichloromethane (10 mL), and anhydrous triethylamine (160 mg, 1.58 mmol) was added at 0 °C. A solution of dry phenol (45 mg, 0.473 mmol) in dichloromethane (2 mL) and a solution of free L-alanine propyl ester (83 mg, 0.63 mmol) in dichloromethane (2 mL) were added dropwise, and the mixture was stirred at 0 °C for 1 h. After the reaction was completed, the reaction solution was diluted with water (20 mL) and extracted with dichloromethane (20 mL x 3). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated and purified by column chromatography on silica gel (petroleum ether: ethyl acetate = 3:1) to obtain the title compound (110 mg).

[0473] MS m / z (ESI): 570.2 [M+H] +

[0474] Step 9: Synthesis of 5-(fluoro((((S)-1-oxo-1-propyloxypropan-2-yl)amino)(phenoxy)phosphoryl)methyl)benzo[b]thiophene-2-carboxylic acid (Intermediate Q)

[0475] Benzyl 5-(fluoro((((S)-1-oxo-1-propyloxypropan-2-yl)amino)(phenoxy)phosphoryl)methyl)benzo[b]thiophene-2-carboxylate (Q-9, 230 mg, 0.403 mmol) was dissolved in tetrahydrofuran (25 mL) at room temperature, and palladium on carbon (palladium content 10%, 75 mg) and palladium hydroxide on carbon (palladium hydroxide content 10%, 85 mg) were added. The reaction was replaced with hydrogen three times, and stirred at room temperature for 16 h under a hydrogen atmosphere. After the reaction was completed, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound (165 mg).

[0476] MS m / z (ESI): 480.1 [M+H] +

[0477] Synthesis of 1-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)piperidine-4-carboxylic acid (Intermediate S)

[0478] Step 1: Synthesis of tert-butyl 1-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3- dihydro-1H-benzo[d]imidazol-4-yl)piperidine-4-carboxylate (S-1)

[0479] At room temperature, 3-(4-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1- yl)piperidine-2,6-dione (AC-1, 1 g, 2.97 mmol), tert-butyl piperidin-4-ylcarboxylate (1.10 g, 5.94 mmol) and sodium tert-butoxide (856 mg, 8.91 mmol) were dissolved in N,N- dimethylformamide (15 mL). After replaced with nitrogen, (SP-4-1)-[1,3-bis[2,6-bis(1- ethylpropyl)phenyl]-4,5-dichloro-1,3-dihydro-2H-imidazol-2-ylidene]dichloro(palladium-2- methylpyridine) (249 mg, 0.297 mmol) was added. The reaction mixture was stirred at 100 °C for 16 hours. After the reaction was completed, the reaction solution was cooled to room temperature, adjusted to pH 6 with diluted acetic acid, and extracted with dichloromethane (30 mL x 3). The 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 residue was separated and purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to obtain the title compound (490 mg).

[0480] MS m / z (ESI): = 443.2 [M+H] +

[0481] Step 2: Synthesis of 1-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H- benzo[d]imidazol-4-yl)piperidine-4-carboxylic acid (Intermediate S)

[0482] At room temperature, tert-butyl 1-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3- dihydro-1H-benzo[d]imidazol-4-yl)piperidine-4-carboxylate (S-1, 490 mg, 1.11 mmol) was dissolved in dichloromethane (12 mL), followed by the addition of trifluoroacetic acid (3 mL), and the obtained reaction mixture was stirred at room temperature for 16 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the obtained residue was separated and purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to obtain 1-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H- benzo[d]imidazol-4-yl)piperidine-4-carboxylic acid (246 mg).

[0483] MS m / z (ESI): = 387.1 [M+H] +

[0484] 1 H NMR (400 MHz, DMSO-d6) δ 12.24 (s, 1H), 11.08 (s, 1H), 6.97 (t, J = 8.0 Hz, 1H), 6.88 (t, J = 7.6 Hz, 2H), 5.34 (dd, J = 5.2 Hz, 12.4 Hz, 1H), 3.62 (s, 3H), 3.17 - 3.11 (m, 2H), 2.91 - 2.84 (m, 1H), 2.74 - 2.59 (m, 4H), 2.39 - 2.28 (m, 1H), 2.00 - 1.92 (m, 3H), 1.75 - 1.72 (m, 2H).

[0485] Synthesis of Intermediate T: 2-(1-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H- benzo[d]imidazol-4-yl)piperidin-4-yl)acetic acid

[0486] Intermediate T was prepared according to the procedure described for the synthesis of Intermediate S, replacing 4-piperidinecarboxylic acid tert-butyl ester with 2-(piperidin-4-yl)acetic acid tert-butyl ester.

[0487] MS m / z (ESI): = 401.1 [M+H] +

[0488] 1 H NMR (400 MHz, DMSO-d6) δ 12.08 (s, 1H), 11.08 (s, 1H), 6.99 - 6.85 (m, 3H), 5.34 (dd, J = 5.2 Hz, 12.8 Hz, 1H), 3.61 (s, 3H), 3.10 - 3.07 (m, 2H), 2.94 - 2.84 (m, 1H), 2.73 - 2.50 (m, 4H), 2.23 (d, J = 5.6 Hz, 2H), 2.01 - 1.96 (m, 1H), 1.79 - 1.77 (m, 3H), 1.46 - 1.37 (m, 2H).

[0489] Synthesis of Intermediate W: 2-(2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-2,7- diazaspiro[3.5]nonan-7-yl)acetic acid

[0490] Step 1: Synthesis of tert-butyl 2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-2,7- diazaspiro[3.5]nonane-7-carboxylate (W-2)

[0491] Compound 3-(5-bromo-l-oxoisoindolin-2-yl)piperidine-2,6-dione (W-l, 1.1 g, 3.40 mmol), tert-butyl 2,7-diazaspiro[3.5]nonane-7-carboxylate (770 mg, 3.40 mmol) and cesium carbonate (3.33 g, 10.21 mmol) were dissolved in 1,4-dioxane (50 mL) at room temperature, and after addition of (SP-4-1)-[l,3-bis[2,6-bis(l-ethylpropyl)phenyl]-4,5-dichloro-l,3-dihydro-2H-imidazol-2- ylidene]dichloropalladium (286 mg, 0.34 mmol), the reaction mixture was purged with nitrogen and the temperature was raised to 100°C, and the reaction mixture was stirred at 100°C for 16 hours. After completion of the reaction, the reaction solution was cooled to room temperature, diluted with dichloromethane (30 mL), and the pH was adjusted to about 7 with a 5% acetic acid solution. The organic phase was extracted with dichloromethane (40 mL x 3), washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was separated by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to obtain the title compound (419 mg).

[0492] MS m / z (ESI): = 469.1 [M+H] +

[0493] 1 H NMR (400 MHz, DMSO-d6) δ 10.92 (s, 1H), 7.49 (d, J = 8.4 Hz, 1H), 6.50-6.45 (m, 2H), 5.03 (dd, Ji = 5.2, J2 = 13.2 Hz, 1H), 4.27 (dd, Ji = 16.8, J2 = 50.0 Hz, 2H), 3.66 (s, 4H), 3.31 (s, 4H), 2.94-2.84 (m, 1H), 2.59-2.55 (m, 1H), 2.39-2.30 (m, 1H), 1.97-1.92 (m, 1H), 1.69 (t, J = 5.6 Hz, 4H), 1.40 (s, 9H).

[0494] Step 2: Synthesis of 3-(l-oxo-5-(2,7-diazaspiro[3.5]nonan-2-yl)isoindolin-2- yl)piperidine-2,6-dione (W-3)

[0495] 2-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-5-yl)-2,7-diazaspiro[3.5]nonane-7- carboxylic acid tert-butyl ester (W-2, 419 mg, 894 pmol) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (102 mg, 894 pmol, 1 mL) was added to the mixture, which was stirred at room temperature for 30 minutes. The reaction was monitored by LC-MS, and after the reaction was completed, the solvent was removed by concentration under reduced pressure to obtain the crude product of the title compound, which was used directly in the subsequent reaction without further purification.

[0496] Step 3: Synthesis of 2-(2-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-5-yl)-2,7- diazaspiro[3.5]nonan-7-yl)acetic acid tert-butyl ester (W-4)

[0497] 3-(l-oxo-5-(2,7-diazaspiro[3.5]nonan-2-yl)isoindolin-2-yl)piperidine-2,6-dione (W-3, 140 mg, 379.99 pmol) was dissolved in dichloromethane (1.78 mL), and triethylamine (192.26 mg, 1.90 mmol, 265.00 pL) and tert-butyl 2-bromoacetate (222.36 mg, 1.14 mmol) were added, and the mixture was heated to 40 °C overnight. LC-MS monitoring showed that the reaction was complete. The reaction was concentrated under reduced pressure, and the title compound (111 mg) was obtained by purification on a silica gel column (petroleum ether / ethyl acetate = 1 / 1).

[0498] MS m / z (ESI): = 483.4 [M+H] +

[0499] Step 4: Synthesis of 2-(2-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-5-yl)-2,7- diazaspiro[3.5]nonan-7-yl)acetic acid (Intermediate W)

[0500] Tert-butyl 2-(2-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-5-yl)-2,7- diazaspiro[3.5]nonan-7-yl)acetate (W-4, 100 mg, 207.22 pmol) was dissolved in dichloromethane (5 mL), and 0.4 mL of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 1 hour. LC-MS monitoring showed that the reaction was complete. The reaction was concentrated to dryness under reduced pressure to obtain the crude product of the title compound (135 mg), which was directly used in the next step.

[0501] MS m / z (ESI): = 427.4 [M+H] +

[0502] Synthesis of intermediate Z: 1-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidine-4- carboxaldehyde

[0503] Step 1: Synthesis of 2,6-bis(benzyloxy)-6'-fluoro-3,3'-bipyridine (Z-2)

[0504] Dissolve 2-fluoro-5-iodopyridine (Z-1, 3 g, 13.5 mmol) and 2,6-bis(benzyloxy)-3-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (8.46 g, 20.3 mmol) in 1,4-dioxane (80 mL), then add water (20 mL), add [1,1 '-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (495 mg, 0.68 mmol) and cesium carbonate (6.60 g, 20.27 mmol), stir at 90 °C. After LC-MS shows the reaction is complete, add water (200 mL), extract with ethyl acetate (40 mL x 3), combine the organic phases and dry over anhydrous sodium sulfate, filter and concentrate the filtrate under reduced pressure, the residue is purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 5 / 1) to give the title compound (3.5 g).

[0505] MS m / z [ESI]: 387.10 [M+H] +

[0506] Step 2: Synthesis of 3-(6-fluoropyridin-3-yl)piperidine-2,6-dione (Z-3)

[0507] Dissolve 2,6-bis(benzyloxy)-6'-fluoro-3,3'-bipyridine (Z-2, 3.5 g, 9.06 mmol) in ethyl acetate (100 mL), add palladium on carbon (palladium content 10%, 2.0 g), stir under hydrogen atmosphere. Stir the reaction at 50 °C for 12 hours. After LC-MS shows the reaction is complete, filter and concentrate the filtrate under reduced pressure to give the title compound crude (1.8 g), which is used directly in the next step without purification.

[0508] MS m / z [ESI]: 209.1 [M+H] +

[0509] Step 3: Synthesis of 3-(6-(4-(dimethoxymethyl)piperidin-1-yl)pyridin-3-yl)piperidine-2,6- dione (Z-4)

[0510] Dissolve 3-(6-fluoropyridin-3-yl)piperidine-2,6-dione (Z-3, 450 mg, 2.16 mmol) and 4-(dimethoxymethyl)piperidine (1.03 mg, 6.48 mmol) in dimethyl sulfoxide (5 mL), add N,N-diisopropylethylamine (558.70 mg, 4.32 mmol), and warm to 120 °C for 2.5 hours under microwave. After LC-MS shows the reaction is complete, dilute with 100 mL of ethyl acetate, wash the organic phase with water (30 mL) and saturated brine (30 mL), dry using anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. Purify the residue by silica gel column chromatography (dichloromethane / ethyl acetate = 1 / 1) to give the title compound (340 mg).

[0511] MS m / z (ESI): 348.2 [M+H] +

[0512] Step 4: Synthesis of 1-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidine-4- carboxaldehyde (Intermediate Z)

[0513] Dissolve 3-(6-(4-(dimethoxymethyl)piperidin-1-yl)pyridin-3-yl)piperidine-2,6-dione (Z-4, 40 mg, 115.14 µmol) in tetrahydrofuran (2 mL), add dilute hydrochloric acid (2 N, 575 µL), and warm to 60 °C for 2 hours. After the reaction is complete, directly lyophilize the reaction solution to give the title compound (40.0 mg).

[0514] MS m / z (ESI): 302.1 [M+H] + .

[0515] Synthesis of 2-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)-2-azaspiro[3.5]nonane-7- carboxaldehyde (Intermediate AA)

[0516] Step 1: Synthesis of (2-azaspiro[3.5]nonan-7-yl)methanol hydrochloride (AA-2)

[0517] Dissolve compound 7-(hydroxymethyl)-2-azaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (AA-1, 1.04 g, 4.07 mmol) and hydrochloric acid-1,4-dioxane (3 mL) in dichloromethane (9 mL), and stir the reaction mixture at room temperature for 3 hours. After the reaction is complete, concentrate the reaction solution under reduced pressure to give the crude compound (2-azaspiro[3.5]nonan-7-yl)methanol hydrochloride (0.56 g).

[0518] Step 2: Synthesis of 3-(6-(7-(hydroxymethyl)-2-azaspiro[3.5]nonan-2-yl)pyridin-3- yl)piperidine-2,6-dione (AA-3)

[0519] In a microwave tube, compound 3-(6-fluoropyridin-3-yl)piperidine-2,6-dione (Z-3, 0.53 g, 2.55 mmol), (2-azaspiro[3.5]nonan-7-yl)methanol hydrochloride (AA-2, 0.56 g, 2.95 mmol) were dissolved in N-methylpyrrolidine (1.5 mL) at room temperature, the temperature was raised to 130 °C and stirred for 1 h. After the reaction was completed, the reaction solution was reduced to room temperature, diluted with water (30 mL), and extracted with ethyl acetate (30 mL x 3). The organic phase was washed with saturated brine (20 mL x 2), separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was separated by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to obtain the title compound (0.19 g).

[0520] MS m / z (ESI): 344.2 [M+H] +

[0521] Step 3: Synthesis of 2-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)-2-azaspiro[3.5]nonane-7- carbaldehyde (Intermediate AA)

[0522] In an ice bath, 3-(6-(7-(hydroxymethyl)-2-azaspiro[3.5]nonan-2-yl)pyridin-3-yl)piperidine- 2,6-dione (AA-3, 0.18 g, 0.52 mmol) was dissolved in dichloromethane (4 mL), followed by the addition of Dess-Martin oxidant (0.33 g, 0.79 mmol), and the reaction mixture was stirred at room temperature for 4 h. After the reaction was completed, saturated aqueous sodium thiosulfate solution was added to quench, and extracted with ethyl acetate (30 mL x 3). The organic phase was washed with saturated brine (20 mL x 2), separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was separated by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to obtain the title compound (0.11 g).

[0523] MS m / z (ESI): 342.1 [M+H] +

[0524] 1H NMR (400 MHz, DMSO-d6) δ 10.78 (s, 1H), 9.59 (d, J = 0.8 Hz, 1H), 7.88 (d, J = 2.4 Hz, 1H), 7.36-7.34 (m, 1H), 6.33 (d, J = 0.8 Hz, 1H), 3.74-3.69 (m, 1H), 3.59 (s, 4H), 2.67-2.62 (m, 1H), 2.52 (s, 1H), 2.33-2.30 (m, 1H), 2.18-2.15 (m, 1H), 1.98-1.94 (m, 1H), 1.86-1.80 (m, 4H), 1.60-1.54 (m, 2H), 1.42-1.37 (m, 2H).

[0525] Synthesis of intermediate AC: 5-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3- dihydro-1H-benzo[d]imidazol-4-yl)pent-4-ynoic acid

[0526] Intermediate AC: 5-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H- benzo[d]imidazol-4-yl)pent-4-ynoic acid

[0527] MS m / z (ESI): = 356.1 [M+H] +

[0528] Synthesis of intermediate AD: 5-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3- dihydro-1H-benzo[d]imidazol-5-yl)pent-4-ynoic acid

[0529] Intermediate AD was prepared according to the procedure described for the synthesis of intermediate AC, by replacing compound AC-1 with L-1.

[0530] Synthesis of intermediate AE: tert-butyl ((5S,8S,10aR)-8-((trans)-3-(4- aminophenyl)-4-cyanopyrrolidine-1-carbonyl)-3-(oxetan-3-yl)-6-oxodecahydropyrrolo[1,2- a][1,5]diazocin-5-yl)carbamate

[0531] Step 1: Synthesis of methyl (5S,8S,10aR)-5-((tert-butoxycarbonyl)amino)-3-(oxetan-3-yl)- 6-oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxylate (AE-1)

[0532] Methyl (5S,8S,10aR)-5-((tert-butoxycarbonyl)amino)-6-oxodecahydropyrrolo[1,2- a][1,5]diazocine-8-carboxylate (A-1, 2g, 5.86 mmol), 3-oxetanone (844.31 mg, 11.72 mmol) were added to a reaction flask, dissolved with anhydrous dichloromethane (29 mL), sodium triacetoxyborohydride (2.48 g, 11.72 mmol) and acetic acid (527.68 mg, 8.79 mmol) were added, the resulting reaction solution was stirred at room temperature overnight. LC-MS showed that the reaction was complete. The reaction solution was poured into water, extracted with dichloromethane three times, the organic phase was combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under pressure, and purified by column chromatography (silica, petroleum ether / ethyl acetate = 2 / 3) to give the title compound (2.29 g).

[0533] MS m / z (ESI): = 398.2 [M+H] +

[0534] 1 H NMR (400 MHz, CDCl3) δ 5.67 (d, J = 7.1 Hz, 1H), 4.71 - 4.39 (m, 7H), 4.03 - 3.95 (m, 1H), 3.76 (s, 3H), 2.95 - 2.73 (m, 3H), 2.53 - 2.44 (m, 1H), 2.39 - 2.29 (m, 1H), 2.21 - 2.08 (m, 1H), 2.04 - 1.95 (m, 1H), 1.85 - 1.77 (m, 1H), 1.76 - 1.63 (m, 2H), 1.42 (s, 9H).

[0535] Step 2: Synthesis of (5S,8S,10aR)-5-((tert-butoxycarbonyl)amino)-3-(oxetan-3-yl)-6- oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxylic acid (AE-2)

[0536] Methyl (5S,8S,10aR)-5-((tert-butoxycarbonyl)amino)-3-(oxetan-3-yl)-6- oxodecahydropyrrolo[l,2-a][l,5]diazocin-8-carboxylate (AE-1, 100 mg, 0.252 mmol) was added to a reaction vial, dissolved in methanol (1.2 mL), followed by water (0.3 mL) and lithium hydroxide monohydrate (31.67 mg, 0.755 mmol), and the resulting reaction was stirred at room temperature overnight. LC-MS showed the reaction was complete. The reaction was concentrated under reduced pressure to dryness to give the title compound crude (132 mg), which was used directly in the next step without purification.

[0537] MS m / z (ESI): = 384.2 [M+H] +

[0538] Step 3: Synthesis of tert-butyl ((5S,8S,10aR)-8-((trans)-3-cyano-4-(4- nitrophenyl)pyrrolidine-l-carbonyl)-3-(oxetan-3-yl)-6-oxodecahydropyrrolo[l,2- a][l,5]diazocin-5-yl)carbamate (AE-3)

[0539] (5S,8S,10aR)-5-((tert-butoxycarbonyl)amino)-3-(oxetan-3-yl)-6-oxodecahydropyrrolo[l,2-a][l,5]diazocin-8-carboxylic acid (AE-2, 230 mg, 599 μmol) was dissolved in N,N-dimethylformamide (2 mL), O-(7-azabenzotriazol-l-yl)-N,N,N',N'- tetramethyluronium hexafluorophosphate (272 mg, 720 μmol) and N,N- diisopropylethylamine (155 mg, 1.20 mmol) were added, and the reaction was stirred at room temperature for 30 minutes, followed by the addition of trans-4-(4- nitrophenyl)pyrrolidine-3-carbonitrile (130 mg, 599 μmol) and the reaction was continued for 1 hour. LC-MS showed the reaction was complete, and the reaction was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (methanol / dichloromethane = 0-10% gradient elution) to give the title compound (259 mg).

[0540] MS m / z (ESI): = 583.3 [M+H] +

[0541] Step 4: Synthesis of tert-butyl ((5S,8S,10aR)-8-((trans)-3-(4-aminophenyl)-4- cyanopyrrolidine-l-carbonyl)-3-(oxetan-3-yl)-6-oxodecahydropyrrolo[l,2- a][l,5]diazocin-5-yl)carbamate (Intermediate AE)

[0542] tert-Butyl (((5S,8S,10aR)-8-((trans)-3-cyano-4-(4-nitrophenyl)pyrrolidine-1 - carbonyl)-3-(oxetan-3-yl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocin-5- yl)amino)carboxylate (250 mg, 429 μmol) was dissolved in methanol (5 mL) and palladium on carbon (10% palladium, 25 mg) was added. The reaction was stirred at room temperature under an atmosphere of hydrogen overnight. LC-MS indicated complete conversion. The reaction was diluted with methanol (10 mL) and filtered. The filtrate was concentrated to dryness under reduced pressure to give the crude title compound (220 mg).

[0543] MS m / z (ESI): = 553.3 [M+H] +

[0544] Synthesis of intermediate AF: 2-(2-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5- yl)-2,7-diazaspiro[3.5]non-7-yl)acetic acid

[0545] Intermediate AF was prepared according to the procedure described for the synthesis of intermediate W by replacing intermediate W-1 with 5-bromo-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione.

[0546] Synthesis of intermediate AG: 2-(2-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)-2,7- diazaspiro[3.5]nonan-7-yl)acetic acid

[0547] Intermediate AG was prepared according to the procedure described for the synthesis of intermediate W by replacing intermediate W-1 with intermediate Z-3.

[0548] MS m / z (ESI): = 373.1 [M+H] +

[0549] Synthesis of intermediate AI: tert-butyl ((5S,8S,10aR)-6-oxo-8-((S)-3- phenylpyrrolidine-1 -carbonyl)decahydropyrrolo[1,2-a][1,5]diazocin-5-yl)carbamate

[0550] Intermediate AI was prepared according to the procedure described for the synthesis of intermediate A by replacing trans-4-phenylpyrrolidine-3-carbonitrile with (3S)-3- phenylpyrrolidine.

[0551] MS m / z (ESI): = 456.9 [M+H] +

[0552] Synthesis of intermediate AJ: tert-butyl ((5S,8S,10aR)-6-oxo-8-((R)-3- phenylpyrrolidine-1-carbonyl)decahydropyrrolo[1,2-a][1,5]diazocin-5-yl)carbamate

[0553] Intermediate AJ was prepared according to the procedure described for the synthesis of intermediate A by replacing trans-4-phenylpyrrolidine-3-carbonitrile with (3R)-3- phenylpyrrolidine.

[0554] MS m / z (ESI): = 456.9 [M+H] +

[0555] Synthesis of intermediate AK: 2-(4-(4-((2,6-dioxopiperidin-3-yl)carbamoyl)-3- fluorophenyl)piperazin-1-yl)acetic acid

[0556] Step 1: Synthesis of methyl 4-(4-(2-(tert-butoxy)-2-oxoethyl)piperazin-1-yl)-2- fluorobenzoate (AK-2)

[0557] To a reaction flask was added tert-butyl 2-(piperazin-1-yl)acetate (AK-1, 1 g, 4.99 mmol), methyl 4-bromo-2-fluorobenzoate (1.12 g, 4.81 mmol), tris(dibenzylideneacetone)dipalladium (0.36 g, 0.39 mmol), 2-dicylohexylphosphino-2',4',6'-triisopropylbiphenyl (0.51 g, 1.07 mmol), cesium carbonate (4.19 g, 12.87 mmol), and the flask was purged with argon three times before 1,4-dioxane (10 mL) was added. The reaction was stirred at 90 °C for 16 h. TLC showed the reaction was complete and the reaction mixture was extracted with ethyl acetate (100 mL) three times. The organic phase was combined and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (silica, petroleum ether / ethyl acetate = 90 / 10) to give the title compound (0.8 g).

[0558] Step 2: Synthesis of 4-(4-(2-(tert-butoxy)-2-oxoethyl)piperazin-1-yl)-2- fluorobenzoic acid (AK-3)

[0559] Methyl 4-(4-(2-(tert-butoxy)-2-oxoethyl)piperazin-1-yl)-2- fluorobenzoate (AK-2, 400 mg, 1.14 mmol), lithium hydroxide monohydrate (119.1 mg, 2.84 mmol), methanol (5 mL) and water (2 mL) were added into a reaction flask, stirred at room temperature for 16 hours. LC-MS showed the reaction was completed, the reaction solution was concentrated under reduced pressure to give the title compound crude (380 mg), which was used directly in the next step.

[0560] MS m / z (ESI): = 339.1 [M+H] +

[0561] Step 3: Synthesis of tert-butyl 2-(4-(4-((2,6-dioxopiperidin-3-yl)carbamoyl)-3- fluorophenyl)piperazin-1-yl)acetate (AK-4)

[0562] 4-(4-(2-(tert-butoxy)-2-oxoethyl)piperazin-1-yl)-2-fluorobenzoic acid (AK-3, 380 mg, 1.12 mmol), 3-aminopiperidine-2,6-dione (172.7 mg, 1.35 mmol), diisopropylethylamine (978 μί, 5.62 mmol), N,N-dimethylformamide (5 mL) were added into a reaction flask, stirred at room temperature for 20 minutes, then O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (1.69 g, 4.49 mmol) was added, the reaction solution was stirred at room temperature for 2 hours. TLC showed the reaction was completed, quenched by water, extracted with ethyl acetate for three times (50 mL), the organic phase was combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, then purified by column chromatography (silica, petroleum ether / ethyl acetate = 40 / 60) to give the title compound (260 mg).

[0563] MS m / z (ESI): = 449.2 [M+H] +

[0564] Step 4: Synthesis of 2-(4-(4-((2,6-dioxopiperidin-3-yl)carbamoyl)-3- fluorophenyl)piperazin-1-yl)acetic acid (Intermediate AK)

[0565] Tert-butyl 2-(4-(4-((2,6-dioxopiperidin-3-yl)carbamoyl)-3-fluorophenyl)piperazin-1- yl)acetate (AK-4, 20 mg, 44.59 μmol), dichloromethane (0.5 mL) were added into a reaction flask, then trifluoroacetic acid (1 mL) was added, the reaction solution was stirred at room temperature for 2 hours. Then the reaction solution was concentrated under reduced pressure to give the title compound (17.5 mg), which was used directly in the next step without further purification.

[0566] MS m / z (ESI): = 393.1 [M+H] +

[0567] Synthesis of intermediate AL: 4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3- dihydro-1H-benzo[d]imidazol-4-yl)but-3-ynoic acid

[0568] Intermediate AL was prepared according to the procedure described for the synthesis of intermediate AC, replacing pent-4-ynoic acid by 3-butynoic acid.

[0569] MS m / z (ESI): = 342.1 [M+H] +

[0570] Synthesis of intermediate AM: 2-(4-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5- yl)piperazin-1-yl)acetic acid

[0571] Intermediate AM was prepared according to the procedure described for the synthesis of intermediate C, replacing intermediate C-1 by tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5- yl)piperazine-1-carboxylate.

[0572] MS m / z (ESI): = 387.1 [M+H] + .

[0573] Synthesis of intermediate AP: tert-butyl ((5S,8S,10aR)-8-((3R,4S)-3-(4- aminophenyl)-4-cyanopyrrolidine-1-carbonyl)-3-(2,2-difluoroethyl)-6-oxodecahydropyrrolo[1,2- a][1,5]diazocin-5-yl)carbamate

[0574] Step 1: Synthesis of tert-butyl ((5S,8S,10aR)-8-((3S,4R)-3-cyano-4-(4-nitrophenyl)pyrrolidine- 1-carbonyl)-3-(2,2-difluoroethyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)carbamate (AP-2)

[0575] (Intermediate M) (96 mg, 0.44 mmol), 1-hydroxybenzotriazole (81 mg, 0.60 mmol), 1-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (115 mg, 0.60 mmol) and N,N- diisopropylethylamine (155 mg, 1.20 mmol) were added, and the mixture was stirred at room temperature for 16 hours. After the reaction was completed, the reaction solution was diluted with water (10 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated and purified by silica gel column (petroleum ether / ethyl acetate = 1 / 1) to obtain the title compound AP-2 (165 mg).

[0576] MS-ESI: m / z = 591.3 [M+H] +

[0577] Step 2: Synthesis of tert-butyl ((5S,8S,10aR)-8-((3R,4S)-3-(4-aminophenyl)-4- cyanopyrrolidine-1-carbonyl)-3-(2,2-difluoroethyl)-6-oxodecahydropyrrolo[1,2-a][1,5] diazocin-5-yl)carbamate (Intermediate AP)

[0578] The compound AP-2 (165 mg, 0.28 mmol) was dissolved in a mixed solution of tetrahydrofuran (3 mL), ethanol (3 mL) and water (1 mL) at room temperature, and then iron powder (156 mg, 2.80 mmol) and ammonium chloride (150 mg, 2.80 mmol) were added, and the mixture was stirred at 80°C for 2 hours. After the reaction was completed, the reaction solution was cooled to room temperature, diluted with water (10 mL), extracted with ethyl acetate (20 mL x 2), and the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated and purified by silica gel column (petroleum ether / ethyl acetate = 1 / 1) to obtain the intermediate AP (140 mg).

[0579] MS-ESI: m / z = 561.3 [M+H] +

[0580] Synthesis of 5-(fluoro((((S)-1-oxo-1-propyloxypropan-2-yl)amino)(phenoxy) phosphoryl)methyl)benzo[b]thiophene-2-carboxylic acid perfluorophenyl ester (Intermediate AQ)

[0581] Intermediate AQ: tert-butyl ((5S,8S,10aR)-3-acetyl-8-((3R,4S)-3-(4- aminophenyl)-4-cyanopyrrolidine-1-carbonyl)-6-oxodecahydropyrrolo[1,2-a][1,5] diazocin-5- yl)carbamate

[0582] MS-ESI: m / z = 646.1 [M+H] +

[0583] Synthesis of Intermediate AR: tert-butyl ((5S,8S,10aR)-3-acetyl-8-((3R,4S)-3-(4- aminophenyl)-4-cyanopyrrolidine-1-carbonyl)-6-oxodecahydropyrrolo[1,2-a][1,5] diazocin-5- yl)carbamate

[0584] Intermediate AR: tert-butyl ((5S,8S,10aR)-3-acetyl-8-((3R,4S)-3-(4- aminophenyl)-4-cyanopyrrolidine-1-carbonyl)-6-oxodecahydropyrrolo[1,2-a][1,5] diazocin-5- yl)carbamate was prepared according to the procedures described for the synthesis of Intermediate AP by replacing (5S,8S,10aR)-5-((tert-butoxycarbonyl)amino)-3-(2,2- difluoroethyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocin-8-carboxylic acid (AP-1) with (5S,8S,10aR)-3-acetyl-5-((tert-butoxycarbonyl)amino)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocin-8-carboxylic acid.

[0585] MS-ESI: m / z = 439.2 [M-Boc+H] +

[0586] Synthesis of Intermediate AS: tert-butyl ((5R,8S,10aR)-8-((3R,4S)-3-(4- aminophenyl)-4-cyanopyrrolidine-1-carbonyl)-6-oxooctahydro-4H-pyrrolo[2,1-d][1,5]thiazin-5- yl)carbamate

[0587] Reference to the synthesis method of intermediate AP, replace (5S,8S,10aR)-5-((tert-butoxycarbonyl)amino)-3-(2,2-difluoroethyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocin-8-carboxylic acid (AP-1) in it with (5R,8S,10aR)-5-((tert-butoxycarbonyl)amino)-6-oxooctahydro-4H-pyrrolo[2,1-d][1,5]thiazocin-8-carboxylic acid, the same method to prepare intermediate AS.

[0588] MS-ESI: m / z = 536.2 [M+Na] +

[0589] Synthesis of intermediate AT: tert-butyl ((5S,8S,10aR)-8-((3R,4S)-3-(4-aminophenyl)-4- cyanopyrrolidine-1-carbonyl)-2,6-dioxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)carbamate

[0590] Step 1: synthesis of 2-((5S)-1-(tert-butoxycarbonyl)-5-(methoxycarbonyl)pyrrolidin-2-yl)acetic acid (AT-2)

[0591] Under ice-bath, 1-(tert-butyl)-2-methyl (2S)-5-allyl pyrrolidine-1,2-dicarboxylate (AT-1, 2.9 g, 10.77 mmol) was dissolved in a mixed solvent of tetrahydrofuran (15 mL), ethyl acetate (15 mL) and water (15 mL), potassium osmate (792 mg, 2.15 mmol) and sodium periodate (3.83 g, 17.89 mmol) were added, stirred at room temperature for 12 hours, extracted with ethyl acetate (15 mL x 3), the organic phase was collected, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain an intermediate aldehyde compound. Under ice-bath, the intermediate aldehyde compound was dissolved in acetone (18 mL), and the prepared Jones reagent was slowly added dropwise. After the solution changed from orange yellow to dark green and then to orange yellow, the reaction was complete. Methanol (10 mL) was added, the solution changed from orange yellow to dark green, diluted with water (50 mL), extracted with ethyl acetate (50 mL x 3), the organic phase was collected, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain the title compound (3 g).

[0592] MS-ESI: m / z = 286.1 [M-H] -

[0593] Step 2: synthesis of 1-(tert-butyl)-2-methyl (2S)-5-(2-(benzyloxy)-2-oxoethyl)pyrrolidine-1,2-dicarboxylate (AT-3)

[0594] AT-2, 3g, 10.44 mmol) was dissolved in N, N-dimethylformamide (30 mL), potassium carbonate (2.886 g, 20.88 mmol) and benzyl bromide (2.68 g, 15.66 mmol) were added, stirred at room temperature for 1 hour, after the reaction was completed, diluted with water (50 mL), extracted with ethyl acetate (50 mL x 3), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, the obtained residue was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain the title compound (2.94 g).

[0595] MS-ESI: m / z = 378.1 [M+H] +

[0596] Step 3: Synthesis of methyl (2S)-5-(2-benzyloxy-2-oxoethyl)pyrrolidine-2- carboxylate (AT-4)

[0597] AT-3, 2.44 g, 6.46 mmol) was dissolved in dichloromethane (20 mL), hydrochloric acid dioxane solution (10 mL, 4M) was added dropwise, and stirring was continued for 1 hour. After the reaction was completed, it was concentrated under reduced pressure to obtain the title compound. Without further purification, it was directly used in the next step.

[0598] MS-ESI: m / z = 278.1 [M+H] +

[0599] Step 4: Synthesis of methyl (2S, 5R)-5-(2-benzyloxy-2-oxoethyl)-1-((S)-3- (((benzyloxy)carbonyl)amino)-2-((tert-butoxy)carbonylamino)propanoyl)pyrrolidine- 2-carboxylate (AT-5)

[0600] Methyl (2S)-5-(2-benzyloxy-2-oxoethyl)pyrrolidine-2-carboxylate (AT-4, 1.79 g, 6.45 mmol) and triethylamine (1.96 g, 19.36 mmol) were dissolved in dichloromethane (60 mL) at room temperature, (S)-3-(((benzyloxy)carbonyl)amino)-2-((tert- butoxycarbonyl)amino)propanoic acid (2.62 g, 7.75 mmol) and 2-chloro-1-methylpyridine iodide (1.81 g, 7.10 mmol) were added, and stirring was performed at 30°C for 1 hour. After the reaction was completed, the mixture was concentrated under reduced pressure, and the obtained residue was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain a crude product, which was further purified by reverse phase column chromatography (acetonitrile / water from 0 to 40%) to obtain the title compound (3.8 g).

[0601] MS-ESI: m / z = 498.2 [M-Boc+H] +

[0602] Step 5: Synthesis of 2-((2R,5S)-1-((S)-3-amino-2-((tert-butoxycarbonyl)amino)propanoyl)-5- (methoxycarbonyl)pyrrolidin-2-yl)acetic acid (AT-6)

[0603] Methyl (2S,5R)-5-(2-benzyloxy-2-oxoethyl)-1-((S)-3-(((benzyloxy)carbonyl)amino)-2- ((tert-butoxycarbonyl)amino)propanoyl)pyrrolidine-2-carboxylate (AT-5, 3.8 g, 6.36 mmol) was dissolved in ethyl acetate (50 mL) at room temperature, 1,1,2-trichloroethane (2.54 g, 19.07 mmol), palladium on carbon (palladium content 10%, 1.02 g), and palladium hydroxide on carbon (palladium hydroxide content 20%, 1.34 g) were added, and hydrogen gas was replaced three times, and stirring was performed under a hydrogen atmosphere for 36 hours. After the reaction was completed, the mixture was filtered with celite and washed with ethyl acetate, and the filtrate was concentrated under reduced pressure to obtain the title compound (2.1 g).

[0604] MS-ESI: m / z = 374.1 [M+H] +

[0605] Step 6: Synthesis of methyl (5S,8S,10aR)-5-((tert-butoxycarbonyl)amino)-2,6-dioxodecahydropyrrolo[1,2- a][1,5]diazocin-8-carboxylate (AT-7)

[0606] To a solution of (5S,8S,10aR)-5-((tert-butoxycarbonyl)amino)-2,6-dioxo-decahydropyrrolo[l,2- a] [ 1,5 ] diazocin-8-carboxylic acid (AT-8, 80 mg, 0.22 mmol) in tetrahydrofuran (2 mL) was added 2-(aminomethyl)pyridine hydrochloride (AT-9, 40 mg, 0.26 mmol) and triethylamine (0.1 mL, 0.73 mmol) at room temperature. The reaction mixture was stirred at room temperature for 12 hours. The reaction was complete. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (10 mL) and washed with water (10 mL x 3). The organic phase was collected, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was separated and purified by column chromatography on silica gel (dichloromethane / methanol = 15 / 1) to give the product as a colorless oil. The product was further separated and purified by reverse phase column chromatography (acetonitrile / water from 0 to 30%) to give the title compound (AT-10, 60 mg).

[0607] MS-ESI: m / z = 378.2 [M+Na] +

[0608] Step 7: Synthesis of (5S,8S,10aR)-5-((tert-butoxycarbonyl)amino)-2,6-dioxo- decahydropyrrolo[l,2-a][l,5]diazocin-8-carboxylic acid (AT-8)

[0609] To a solution of methyl (5S,8S,10aR)-5-((tert-butoxycarbonyl)amino)-2,6-dioxo- decahydropyrrolo[l,2-a][l,5]diazocin-8-carboxylate (AT-7, 150 mg, 0.42 mmol) in tetrahydrofuran (4 mL), water (2 mL) and ethanol (2 mL) was added lithium hydroxide monohydrate (17.6 mg, 0.42 mmol) at room temperature. The reaction mixture was stirred at room temperature for 12 hours. The reaction was complete. The reaction mixture was adjusted to pH 6 by adding dilute hydrochloric acid (IN) dropwise. The reaction mixture was extracted with ethyl acetate (10 mL x 3). The organic phase was collected, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (80 mg) which was used directly in the next step.

[0610] MS-ESI: m / z = 360.2 [M+H3O + ]

[0611] Steps 8 and 9 were performed according to the synthesis method of Intermediate AP, with (5S,8S,10aR)-5-((tert-butoxycarbonyl)amino)-3-(2,2-difluoroethyl)-6-oxo- decahydropyrrolo[l,2-a][l,5]diazocin-8-carboxylic acid (AP-1) replaced by (5S,8S,10aR)-5-((tert-butoxycarbonyl)amino)-2,6-dioxo-decahydropyrrolo[l,2- a][ 1,5 ] diazocin-8-carboxylic acid (AT-8) to give Intermediate AT.

[0612] MS-ESI: m / z = 511.3 [M+H] +

[0613] Synthesis of intermediate AV: 1-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1- methyl-1H-indazol-7-yl)piperidine-4-carboxylic acid

[0614] Step 1: Synthesis of tert-butyl 1-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1- methyl-1H-indazol-7-yl)piperidine-4-carboxylate (AV-2)

[0615] Compound 1-(7-bromo-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)- dione (AV-1, 2.10 g, 6.50 mmol), tert-butyl piperidine-4-carboxylate (2.41 g, 13.00 mmol), (SP-4-1)-[1,3-bis[2,6-bis(1-ethylpropyl)phenyl]-4,5-dichloro-1,3-dihydro-2H-imidazol-2- ylidene]dichloro(2-methylpyridine)palladium (55 mg, 0.065 mmol) and cesium carbonate (6.35 g, 19.50 mmol) were dissolved in 1,4-dioxane (20 mL) at room temperature, replaced with N2, the temperature was raised to 100 °C, and the reaction mixture was stirred at 100 °C for 16 hours. After the reaction was completed, the reaction liquid was reduced to room temperature, diluted with water (30 mL), and extracted with ethyl acetate (30 mL x 3). The combined organic phase was washed with saturated brine (20 mL x 2), separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain the title compound (1.03 g).

[0616] MS-ESI: m / z = 428.2 [M+H] +

[0617] Step 2: Synthesis of 1-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H- indazol-7-yl)piperidine-4-carboxylic acid (intermediate AV)

[0618] Tert-butyl 1-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-7- yl)piperidine-4-carboxylate (AV-2, 930 mg, 2.18 mmol) was dissolved in trifluoroacetic acid (7 mL) and dichloromethane (7 mL) at room temperature, and the reaction mixture was stirred at room temperature for 16 hours. After the reaction was completed, the reaction liquid was concentrated under reduced pressure, diluted with water (10 mL) and ethyl acetate (10 mL), filtered, and the filter cake was concentrated under reduced pressure to obtain the title compound (693 mg).

[0619] MS-ESI: m / z = 372.2 [M+H] +

[0620] 1 H NMR (400 MHz, DMSO-d6) δ 12.28 (d, J = 5.6 Hz, 1H), 10.54 (s, 1H), 7.30 (dd, J = 2.4, 6.4 Hz, 1H), 7.02 - 6.99 (m, 2H), 4.23 (s, 3H), 3.88 (t, J = 6.8 Hz, 2H), 3.36 - 3.25 (m, 2H), 2.77 - 2.70 (m, 4H), 2.39 - 2.33 (m, 1H), 2.00 (d, J = 10.8 Hz, 2H), 1.80 (d, J = 11.2 Hz, 2H).

[0621] Synthesis of Intermediate AX: tert-butyl ((3S,6S)-6-((3R,4S)-3-(4- aminophenyl)-4-cyanopyrrolidine-1-carbonyl)-4-oxo-1,2,3,4,6,7-hexahydroazepino[3,2,1- hi]indol-3-yl)carbamate

[0622] Intermediate AX was prepared according to the procedure described for the synthesis of Intermediate AP by replacing (5S,8S,10aR)-5-((tert-butoxycarbonyl)amino)-3-(2,2- difluoroethyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazepine-8-carboxylic acid (AP-1) with (3S,6S)-3-((tert-butoxycarbonyl)amino)-4-oxo-1,2,3,4,6,7-hexahydroazepino[3,2,1- hi]indole-6-carboxylic acid.

[0623] MS m / z (ESI): = 416.2 [M+H-Boc] +

[0624] Synthesis of Intermediate AX: tert-butyl ((3S,6S)-6-((3R,4S)-3-(4- aminophenyl)-4-cyanopyrrolidine-1-carbonyl)-4-oxo-1,2,3,4,6,7-hexahydroazepino[3,2,1- hi]indol-3-yl)carbamate

[0625] Intermediate AX was prepared according to the procedure described for the synthesis of Intermediate AP by replacing (5S,8S,10aR)-5-((tert-butoxycarbonyl)amino)-3-(2,2- difluoroethyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazepine-8-carboxylic acid (AP-1) with (3S,6S)-3-((tert-butoxycarbonyl)amino)-4-oxo-1,2,3,4,6,7-hexahydroazepino[3,2,1- hi]indole-6-carboxylic acid.

[0626] MS (ESI) m / z = 358.1 [M+H]+

[0627] 1 H NMR (400 MHz, DMSO-d6) δ 12.24 (s, 1H), 10.39 (s, 1H), 7.99 (s, 1H), 7.84 (s, 1H), 7.46 (d, J = 9.2 Hz, 1H), 7.25 (dd, J = 1.2 Hz, 10.0 Hz, 1H), 3.75 (t, J = 6.4 Hz, 2H), 3.51 (d, J = 12.0 Hz, 2H), 2.77-2.67 (m, 4H), 2.39-2.35 (m, 1H), 1.95-1.93 (m, 2H), 1.75-1.65 (m, 2H).

[0628] Synthesis of intermediate AZ: 3-(2,6-difluoro-4-(3-(hydroxymethyl)azetidin-1- yl)phenyl)piperidine-2,6-dione

[0629] Step 1: Synthesis of (1-(4-bromo-3,5-difluorophenyl)azetidin-3-yl)methanol (AZ-2)

[0630] To a solution of 2-bromo-1,3-difluoro-5-iodobenzene (AZ-1, 5 g, 15.68 mmol), azetidin-3-ylmethanol hydrochloride (1.94 g, 15.70 mmol), potassium carbonate (10.84 g, 78.43 mmol), cuprous iodide (597 mg, 3.13 mmol), L-proline (722 mg, 6.27 mmol) in dimethyl sulfoxide (48 mL) was added at room temperature. The reaction mixture was stirred at 90 °C for 12 h. After completion of the reaction, the reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (60 mL x 3). The combined organic phase was washed with saturated brine (30 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 5 / 1) to give the title compound (2.80 g).

[0631] MS-ESI: m / z = 278.0 [M+H] +

[0632] Step 2: Synthesis of (1-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-3,5-difluorophenyl)azetidin-3- yl)methanol (AZ-3)

[0633] Compound (1-(4-bromo-3,5-difluorophenyl)azetidin-3-yl)methanol (AZ-2, 2.8 g, 10.07 mmol), 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (6.30 g, 15.10 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (737 mg, 1.01 mmol) and cesium carbonate (9.84 g, 30.20 mmol) were dissolved in dioxane (24 mL), the reaction system was replaced with nitrogen for three times, and the reaction mixture was stirred at 100 °C for 14 hours. After the reaction was completed, the reaction liquid was reduced to room temperature, diluted with water (30 mL), extracted with ethyl acetate (70 mL x 3), the 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 residue was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain the title compound (1.70 g).

[0634] MS-ESI: m / z = 489.2 [M+H] +

[0635] Step 3: Synthesis of 3-(2,6-difluoro-4-(3-(hydroxymethyl)azetidin-1-yl)phenyl)piperidine- 2,6-dione (Intermediate AZ-4)

[0636] (1-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)methanol (AZ-3, 1.7 g, 3.48 mmol) was dissolved in tetrahydrofuran (17 mL) at room temperature, followed by the addition of palladium on carbon (palladium content 10%, 122 mg) and palladium hydroxide on carbon (palladium hydroxide content 20%, 122 mg), the reaction system was replaced with hydrogen for three times, and the reaction mixture was stirred at room temperature under hydrogen atmosphere for 12 hours. After the reaction was completed, the reaction liquid was filtered through diatomite, the filter cake was washed with ethyl acetate (30 mL), the filtrate was concentrated under reduced pressure to obtain the title compound (834 mg).

[0637] MS-ESI: m / z = 311.1 [M+H] +

[0638] 1H NMR (400 MHz, DMSO-d6) δ 10.85 (s, 1H), 6.08 (d, J = 11.2 Hz, 2H), 4.78 (t, J = 5.2 Hz, 1H), 4.04-4.00 (m, 1H), 3.86-3.82 (m, 2H), 3.55 (t, J = 6.0 Hz, 4H), 2.82-2.73 (m, 2H), 2.49-2.47 (m, 1H), 2.09-1.92 (m, 2H).

[0639] Step 4: Synthesis of 1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidine-3- carboxaldehyde (Intermediate AZ)

[0640] 3-(2,6-difluoro-4-(3-(hydroxymethyl)azetidin-1-yl)phenyl)piperidine-2,6-dione (AZ-4, 50 mg, 161.14 μmol) was dissolved in dichloromethane (2.5 mL), then Dess-Martin oxidant (68.34 mg, 161.14 μmol) was added, and the reaction was stirred at room temperature overnight. LC-MS detection showed that the reaction was complete, the reaction solution was added to saturated aqueous sodium carbonate solution (50 mL), extracted with dichloromethane (30 mL x 3), the organic phases were combined and dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give the title compound (45 mg).

[0641] MS m / z (ESI): 309.1 [M+H] +

[0642] Synthesis of 5-(difluoro((((S)-1-oxo-1-propyloxypropan-2-yl)amino)(phenoxy) phosphoryl)methyl)benzo[b]thiophene-2-carboxylic acid (Intermediate BC)

[0643] Step 1: Synthesis of allyl 5-((diethoxyphosphoryl)difluoromethyl)benzo[b]thiophene-2- carboxylate (BC-2)

[0644] Into a reaction vial was placed 5-((diethoxyphosphoryl)difluoromethyl)benzo[b]thiophene-2-carboxylic acid (BC-1, 3.0 g, 8.23 mmol), sodium carbonate (1.74 g, 16.46 mmol), N,N-dimethylformamide (20 mL), stirred at room temperature for 0.5 h, then allyl bromide (1.42 mL, 16.46 mmol) was added, the reaction was continued to stir at room temperature for 14 h. LC-MS showed the reaction was completed, quenched by water, extracted with ethyl acetate for three times (90 mL), the organic phase was combined and dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, then purified by column chromatography (silica, petroleum ether / ethyl acetate = 90 / 10) to give the title compound (2.5 g).

[0645] MS m / z (ESI): = 405.0 [M+H] + .

[0646] Step 2: Synthesis of ((2-((allyloxy)carbonyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphonic acid (BC-3)

[0647] Into a reaction vial was placed 5-((diethoxyphosphoryl)difluoromethyl)benzo[b]thiophene-2-carboxylic acid allyl ester (BC-2, 2.3 g, 5.69 mmol), trimethylsilyl bromide (15 mL, 113.76 mmol), dichloromethane (15 mL), the reaction was stirred at room temperature for 6 h. LC-MS showed the reaction was completed, quenched by water, then the reaction was concentrated under reduced pressure, then freeze-dried to give the title compound (1.6 g).

[0648] MS m / z (ESI): = 347.0 [M-H] - .

[0649] Step 3: Synthesis of 5-((dichlorophosphoryl)difluoromethyl)benzo[b]thiophene-2-carboxylic acid allyl ester (BC-4)

[0650] Into a reaction vial was placed ((2-((allyloxy)carbonyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphonic acid (BC-3, 1.0 g, 2.87 mmol), N,N-dimethylformamide (22 μL, 0.29 mmol), dichloromethane (5 mL), stirred at 0 °C for 10 min after purging with argon for three times, then oxalyl chloride (0.73 mL, 8.61 mmol) was added, the reaction was continued to stir at 0 °C for 20 min, then transferred to 40 °C for 1 h. LC-MS showed the reaction was completed, the reaction was concentrated under reduced pressure to give the title compound (1.1 g). No further purification, used directly in the next step.

[0651] Step 4: Synthesis of allyl 5-(difluoro((((S)-1-oxo-1- propyloxypropan-2-yl)amino)(phenyloxy)phosphoryl)methyl)benzo[b]thiophene-2- carboxylate (BC-5)

[0652] Allyl 5-((difluorophosphoryl)difluoromethyl)benzo[b]thiophene-2-carboxylate (BC-4, 1.1 g, 2.87 mmol), sodium phenolate (333 mg, 2.87 mmol), dichloromethane (5 mL) were added into a reaction flask, after purging with argon for three times, stirred at 0 °C for 10 minutes, then added N,N-diisopropylethylamine (1.5 mL, 8.61 mmol), the reaction solution was stirred at 0 °C for 20 minutes, then added L-alanine propyl ester (0.376 g, 2.87 mmol) dissolved in toluene (0.8 mL), the reaction solution was stirred at 0 °C for 30 minutes, then transferred to room temperature and stirred for 2 hours. After LC-MS showed that the reaction was completed, water was added to quench, extracted with dichloromethane three times (20 mL), the organic phase was combined and dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, then purified by column chromatography (silica, petroleum ether / ethyl acetate = 85 / 15) to give the title compound (0.45 g).

[0653] MS m / z (ESI): = 538.1 [M+H] + .

[0654] 1 H NMR (400 MHz, CDC13) δ 8.17 (s, 1H), 8.11 (s, 1H), 7.96 - 7.90 (m, 1H), 7.78 - 7.70 (m, 1H), 7.31 - 7.23 (m, 2H), 7.18 - 7.06 (m, 3H), 6.11 - 5.96 (m, 1H), 5.52 - 5.40 (m, 1H), 5.38 - 5.28 (m, 1H), 4.86 (d, J = 5.7 Hz, 2H), 4.24 - 4.11 (m, 1H), 4.10 - 4.02 (m, 2H), 3.89 - 3.75 (m, 1H), 1.67 - 1.59 (m, 2H), 1.37 - 1.31 (m, 3H), 0.95 - 0.88 (m, 3H).

[0655] Step 5: Synthesis of 5-(difluoro((((S)-1-oxo-1- propyloxypropan-2-yl)amino)(phenyloxy)phosphoryl)methyl)benzo[b]thiophene-2- carboxylic acid (Intermediate BC)

[0656] Allyl 5-(difluoro((((S)-1-oxo-1-(propyloxy)propan-2-yl)amino)(phenoxy) phosphoryl)methyl)benzo[b]thiophene-2-carboxylate (BC-5, 0.45 g, 837.19 pmol), tetrakis(triphenylphosphine)palladium (96.7 mg, 83.72 pmol), morpholine (366 pL, 4.19 mmol), tetrahydrofuran (3 mL) were added into a reaction flask, which was purged with argon for three times, and the reaction was stirred at room temperature for 1 hour. After LC-MS showed the reaction was completed, water was added to quench the reaction, and the pH was adjusted to 3-5. The mixture was extracted with ethyl acetate for three times (20 mL), and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica, dichloromethane / methanol = 92 / 8) to give the title compound (0.25 g).

[0657] MS m / z (ESI): = 498.1 [M+H] + .

[0658] Synthesis of Intermediate BD: 5-((bis(2-(butanoylthio)ethoxy) phosphoryl)difluoromethyl)benzo[b]thiophene-2-carboxylic acid perfluorophenyl ester

[0659] Intermediate BD was prepared according to the procedure described for the synthesis of Intermediate J by replacing 3-methylbutanoyl chloride with n-valeroyl chloride.

[0660] MS-ESI: m / z = 757.0 [M+Na] +

[0661] 1 H NMR (400 MHz, CDC13) δ = 8.34 (s, 1H), 8.17 (s, 1H), 7.96 (d, J = 8.8, 1H), 7.71 (d, J = 8.4, 1H), 4.21-4.10 (m, 4H), 3.13-3.04 (m, 4H), 2.46 (t, J = 7.6, 4H), 1.66-1.57 (m, 4H), 0.88 (t, J = 7.6, 6H).

[0662] Intermediate BE: 5-((bis(2-(neopentanoylthio)ethoxy) phosphoryl)difluoromethyl)benzo[b]thiophene-2-carboxylic acid perfluorophenyl ester

[0663] Intermediate BE was prepared according to the procedure described for the synthesis of Intermediate J by replacing 3-methylbutanoyl chloride with neopentanoyl chloride.

[0664] 1H NMR (400 MHz, CDC13) δ 8.44 - 8.40 (m, 1H), 8.25 (s, 1H), 8.07 - 8.00 (m, 1H), 7.82 - 7.75 (m, 1H), 4.32 - 4.15 (m, 4H), 3.21 - 3.07 (m, 4H), 2.43 (s, 4H), 1.02 (s, 18H).

[0665] Synthesis of Intermediate BF: 5-((bis(2-((3,3-dimethylbutanoyl)thio)ethoxy) phosphoryl)difluoromethyl)benzo[b]thiophene-2-carboxylic acid perfluorophenyl ester

[0666] Intermediate BF was prepared by the same method as the synthesis of Intermediate J, replacing 3-methylbutanoyl chloride with 3,3-dimethylbutanoyl chloride.

[0667] 1 H NMR (400 MHz, CDC13) δ 8.44 - 8.40 (m, 1H), 8.25 (s, 1H), 8.07 - 8.00 (m, 1H), 7.82 - 7.75 (m, 1H), 4.32 - 4.15 (m, 4H), 3.21 - 3.07 (m, 4H), 2.43 (s, 4H), 1.02 (s, 18H).

[0668] Synthesis of Intermediate BG:

[0669] Intermediate BG was prepared by the same method as the synthesis of Intermediate Q, Steps 8-9, replacing Q-8 with ((2-((benzyloxy)carbonyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphonic acid, and replacing L-alanine propyl ester with L-alanine isopropyl ester.

[0670] MS-ESI: m / z = 498.0 [M+H] +

[0671] 1 H NMR (400 MHz, DMSO-d6) δ = 8.29 - 8.19 (m, 3H), 7.77 (d, J = 8.4, 1H), 7.38 - 7.33 (m, 2H), 7.21 - 7.12 (m, 3H), 6.81 - 6.73 (m, 1H), 4.87 - 4.77 (m, 1H), 3.82 - 3.71 (m, 1H), 1.22 - 1.06 (m, 9H).

[0672] Synthesis of intermediate BH: tert-butyl ((3S,6S,10aS)-3-((trans)-3-(5- aminopyridin-2-yl)-4-cyanopyrrolidine-1-carbonyl)-5-oxodecahydropyrrolo[1,2- a]azocin-6-yl)carbamate

[0673] Step 1: Synthesis of (E)-3-(5-nitropyridin-2-yl)acrylonitrile (BH-2)

[0674] Compound BH-1 (2 g, 13.15 mmol) was dissolved in tetrahydrofuran (20 mL), to which 2-(triphenylphosphoranyl)acetonitrile (4.75 g, 15.78 mmol) was added. The reaction was stirred at 100 °C for 16 hours. The reaction was filtered and concentrated under reduced pressure, and purified by column chromatography (silica, petroleum ether / ethyl acetate = 1 / 1) to give the title compound (0.6 g).

[0675] MS m / z (ESI): = 176.1 [M+H] + .

[0676] Step 2: Synthesis of (trans)-1-benzyl-4-(5-nitropyridin-2-yl)pyrrolidine-3-carbonitrile (BH-3)

[0677] (E)-3-(5-nitropyridin-2-yl)acrylonitrile (BH-2, 600 mg, 3.43 mmol) was dissolved in dichloromethane (10 mL), and after cooling to 0 °C, N-benzyl-1-methoxy-N- ((trimethylsilyl)methyl)methanamine (1.22 g, 5.14 mmol) was added dropwise, followed by warming to room temperature overnight. The reaction was concentrated under reduced pressure, and purified by column chromatography (silica, petroleum ether / ethyl acetate = 10 / 1) to give the title compound (0.7 g).

[0678] MS m / z (ESI): = 309.1 [M+H] + .

[0679] Step 3: Synthesis of (trans)-3-cyano-4-(5-nitropyridin-2-yl)pyrrolidine-1-carboxylic acid 1- chloroethyl ester (BH-4)

[0680] (Trans)-l-benzyl-4-(5-nitropyridin-2-yl)pyrrolidine-3-carbonitrile (BH-3, 650 mg, 2.11 mmol) was dissolved in 1,2-dichloroethane (10 mL) to which was added l-chloroethyl chloroformate (3.01 g, 21.08 mmol). The mixture was stirred at 100 °C for 16 hours. The mixture was extracted with dichloromethane, water, dried over anhydrous sodium sulfate, filtered and concentrated to dryness. Purification by column chromatography (silica, petroleum ether / ethyl acetate = 2 / 1) gave the title compound (0.4 g).

[0681] MS m / z (ESI): = 325.0 [M+H] + .

[0682] Step 4: Synthesis of (trans)-4-(5-nitropyridin-2-yl)pyrrolidine-3-carbonitrile (BH-5)

[0683] (Trans)-3-cyano-4-(5-nitropyridin-2-yl)pyrrolidine-l-carboxylic acid l- chloroethyl ester (BH-4, 25 mg, 76.99 pmol) was dissolved in methanol (1 mL). The mixture was stirred at 40 °C for 16 hours. The mixture was concentrated to dryness to give the title compound (20 mg).

[0684] MS m / z (ESI): = 219.0 [M+H] + .

[0685] Step 5: Synthesis of ((3S,6S,10aS)-3-((trans)-3-cyano-4-(5-nitropyridin-2- yl)pyrrolidine-l-carbonyl)-5-oxodecahydropyrrolo[l,2-a]azocin-6-yl)carbamic acid tert-butyl ester (BH-6)

[0686] (Trans)-4-(5-nitropyridin-2-yl)pyrrolidine-3-carbonitrile (BH-5, 182.52 mg, 836.43 pmol) and (3S,6S,10aS)-6-((tert-butoxycarbonyl)amino)-5-oxododecahydropyrrolo[l,2- a]azocin-3-carboxylic acid (B-l, 273 mg, 836.43 pmol) were dissolved in N,N- dimethylformamide (5 mL) to which was added O-(7-azabenzotriazol-l-yl)-N,N,N',N'- tetramethyluronium hexafluorophosphate (349.63 mg, 920.07 pmol) and triethylamine (253.91 mg, 2.51 mmol). The mixture was stirred at 25 °C for 16 hours. Water was added to the mixture, which was extracted with ethyl acetate, dried over anhydrous sodium sulfate and concentrated to dryness. The residue was purified by flash silica gel chromatography (silica, dichloromethane:methanol = 20: 1) to give the title compound (230 mg).

[0687] MS m / z (ESI): = 527.2 [M+H] + .

[0688] Step 6: Synthesis of tert-butyl ((3S,6S,10aS)-3-((trans)-3-(5-aminopyridin-2-yl)-4- cyanopyrrolidine-1-carbonyl)-5-oxodecahydropyrrolo[1,2-a]azocin-6-yl)carbamate (Intermediate BH)

[0689] Tert-butyl ((3S,6S,10aS)-3-((trans)-3-cyano-4-(5-nitropyridin-2-yl)pyrrolidine-1- carbonyl)-5-oxodecahydropyrrolo[1,2-a]azocin-6-yl)carbamate (BH-6, 200 mg, 379.81 pmol) was dissolved in ethanol (10 mL) and water (2 mL), to which iron powder (106 mg, 1.90 mmol) and ammonium chloride (737.62 mg, 3.80 mmol) were added. The mixture was stirred at 60 °C for 3 h. The mixture was filtered and concentrated to dryness. The residue was purified by flash silica gel chromatography (silica, petroleum ether: ethyl acetate = 1:2) to give the title compound (70 mg).

[0690] MS m / z (ESI): = 497.3 [M+H] + .

[0691] Synthesis of tert-butyl ((5S,8S,10aR)-8-((3R,4S)-3-(4-aminophenyl)-4-cyanopyrrolidine-1- carbonyl)-3-(oxetan-3-yl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)carbamate (Intermediate BI)

[0692] Intermediate BI was prepared according to the procedure described for the synthesis of Intermediate AE, replacing trans-4-(4-nitrophenyl)pyrrolidine-3-carbonitrile with Intermediate M.

[0693] Synthesis of (fluoro(2-((perfluorophenoxy)carbonyl)benzo[b]thiophen-5-yl)methyl)phosphonic acid (Intermediate BK)

[0694] Step 1: Synthesis of 5-((diethoxyphosphoryl)fluoromethyl)benzo[b]thiophene-2-carboxylic acid (BK-2)

[0695] ​Benzyl 5-((diethoxyphosphoryl)fluoromethyl)benzo[b]thiophene-2-carboxylate (BK-1, 325 mg, 0.74 mmol) was dissolved in tetrahydrofuran (25 mL) at room temperature, palladium on carbon (palladium content 10%, 150 mg) and palladium hydroxide on carbon (palladium hydroxide content 20%, 150 mg) were added, replaced with hydrogen gas for 3 times, stirred for 16 hours under hydrogen atmosphere. After the reaction was completed, it was filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound (270 mg).

[0696] MS-ESI: m / z = 345.0 [M-H] -

[0697] Step 2: Synthesis of perfluorophenyl 5-((diethoxyphosphoryl)fluoromethyl)benzo[b]thiophene-2-carboxylate (BK-3)

[0698] Benzyl 5-((diethoxyphosphoryl)fluoromethyl)benzo[b]thiophene-2-carboxylate (BK-1, 325 mg, 0.74 mmol) was dissolved in tetrahydrofuran (25 mL) at room temperature, palladium on carbon (palladium content 10%, 150 mg) and palladium hydroxide on carbon (palladium hydroxide content 20%, 150 mg) were added, replaced with hydrogen gas for 3 times, stirred for 16 hours under hydrogen atmosphere. After the reaction was completed, it was filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound (270 mg).

[0699] MS-ESI: m / z = 513.0 [M+H] +

[0700] Step 3: Synthesis of (fluoro(2-((perfluorophenoxy)carbonyl)benzo[b]thiophen-5-yl)methyl)phosphonic acid (intermediate BK)

[0701] Perfluorophenyl 5-((diethoxyphosphoryl)fluoromethyl)benzo[b]thiophene-2-carboxylate (BK-3, 78 mg, 0.15 mmol) was dissolved in dichloromethane (5 mL) under ice bath, N,O-bistrimethylsilyltrifluoroacetamide (98 mg, 0.38 mmol) and trimethylsilyl iodide (92 mg, 0.46 mmol) were added, stirred for 1 hour at 0 °C. After the reaction was completed, the prepared acetonitrile aqueous solution of trifluoroacetic acid (0.1%, 1.5 mL, acetonitrile: water = 3: 1) was used to quench the reaction, most of the solvent was concentrated under reduced pressure, a small amount of water was added and freeze-dried to obtain the title compound (60 mg)

[0702] MS-ESI: m / z = 454.9 [M-H] -

[0703] Synthesis of intermediate BL: 2-(1-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-7- yl)piperidin-4-yl)acetic acid

[0704] Step 1 : Synthesis of tert-butyl 2-(1-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-1-methyl-1H- indazol-7-yl)piperidin-4-yl)acetate (BL-2)

[0705] To a solution of 3-(2,6-bis(benzyloxy)pyridin-3-yl)-7-bromo-1-methyl-1H-indazole (BL-1, 190 mg, 379.71 pmol), tert-butyl 2-(piperidin-4-yl)acetate (227.01 mg, 1.14 mmol), cesium carbonate (494.86 mg, 1.52 mmol) and (SP-4-1)-[1,3-bis[2,6-bis(1- propylbutyl)phenyl]-4,5-dichloro-1,3-dihydro-2H-imidazol-2-ylidene]dichloro(3- chloropyridine-KN)palladium (Pd-PEPPSI-Ihept-Cl) (36.94 mg, 37.97 pmol) in dioxane (6 mL) was purged with argon three times and stirred at 100 °C overnight under argon atmosphere. LC-MS showed the reaction was complete. The reaction mixture was concentrated under reduced pressure and purified by column chromatography (silica, petroleum ether / ethyl acetate = 97% / 3%) to give the title compound (160 mg).

[0706] MS m / z (ESI): = 619.3 [M+H] +

[0707] Step 2: Synthesis of tert-butyl 2-(1-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-7- yl)piperidin-4-yl)acetate (BL-3)

[0708] To a solution of tert-butyl 2-(1-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-1-methyl-1H-indazol-7- yl)piperidin-4-yl)acetate (BL-2, 160 mg, 258.58 pmol) in methanol (4.2 mL) and tetrahydrofuran (2.1 mL) was added palladium on carbon (10% palladium, 32 mg) and palladium hydroxide on carbon (20% palladium hydroxide, 32 mg) and purged with hydrogen three times. The reaction mixture was stirred at room temperature under hydrogen atmosphere for 4 hours. LC-MS showed the reaction was complete. The reaction mixture was diluted with DCM, and the solution was filtered through celite. The filter cake was washed with DCM and the filtrate was purified by column chromatography (PE:EA = 0:100) to give the title compound (99 mg).

[0709] MS m / z (ESI): = 441.24 [M+H]+

[0710] Step 3: Synthesis of 2-(l-(3-(2,6-dioxopiperidin-3-yl)-l-methyl-lH-indol-7- yl)piperidin-4-yl)acetic acid (Intermediate BL)

[0711] tert-Butyl 2-(l-(3-(2,6-dioxopiperidin-3-yl)-l-methyl-lH-indol-7-yl)piperidin-4- yl)acetate (BL-3, 35 mg, 79.45 pmol) was added to dichloromethane (0.5 mL) and trifluoroacetic acid (0.5 mL) was added last. The reaction was stirred at room temperature for 1 h. LC-MS indicated the reaction was complete. The solvent was removed directly by rotary evaporation and used in the next step.

[0712] MS m / z (ESI): = 385.18 [M+H] +

[0713] Synthesis of 5-((bis(2-((3,3-dimethylbutanoyl)thio)ethoxy)phosphoryl)fluoromethyl)benzo[b]thiophene-2-carboxylic acid perfluorophenyl ester (Intermediate BM)

[0714] Intermediate BM was prepared according to the procedure for the synthesis of Intermediate J by replacing Intermediate I with Intermediate BK and 3-methylbutanoyl chloride with 3,3-dimethylbutanoyl chloride.

[0715] MS (ESI) m / z = 795.0 [M+Na] +

[0716] 1 H NMR (400 MHz, CDC13) δ 8.30 (s, 1H), 8.02 (s, 1H), 7.91 (d, J = 8.4 Hz, 1H), 7.60 (d, J = 8.4 Hz, 1H), 5.80 (dd, J = 7.6 Hz, 44.4 Hz, 1H), 4.12 - 3.99 (m, 4H), 3.04 - 2.99 (m, 4H), 2.36 (s, 4H), 0.96 - 0.94 (m, 18H).

[0717] Synthesis of 5-((bis(2-(neopentanoylthio)ethoxy)phosphoryl)fluoromethyl)benzo[b]thiophene-2-carboxylic acid perfluorophenyl ester (Intermediate BN)

[0718] Intermediate BN was prepared according to the procedure for the synthesis of Intermediate J by replacing Intermediate I with Intermediate BK and 3-methylbutanoyl chloride with neopentanoyl chloride.

[0719] MS (ESI) m / z = 767.0 [M+Na] +

[0720] Synthesis of intermediate BP: 1-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-1H-indazol-5- yl)piperidine-4-carbaldehyde

[0721] Step 1: Synthesis of tert-butyl 5-(4-(dimethoxymethyl)piperidin-1-yl)-3-methyl-1H- indazole-1-carboxylate (BP-2)

[0722] Tert-butyl 5-bromo-3-methyl-1H-indazole-1-carboxylate (BP-1, 400 mg, 1.29 mmol) and 4-(dimethoxymethyl)piperidine (409 mg, 2.57 mmol) were dissolved in 1,4-dioxane (5 mL), and methane sulfonic acid (2-dicyclohexylphosphino-2',4',6'-tri- isopropyl-1,1'-biphenyl) (2'-amino-1,1'-biphenyl-2-yl)palladium(II) (109 mg, 129 μmol) and cesium carbonate (828 mg, 2.57 mmol) were added. The reaction was heated to 100 °C under argon overnight. LC-MS showed the reaction was complete. The reaction was cooled to room temperature, diluted with ethyl acetate and filtered. The filtrate was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0-50% gradient elution) to give the title compound (315 mg).

[0723] MS m / z (ESI): = 390.2 [M+H] + .

[0724] Step 2: Synthesis of 5-(4-(dimethoxymethyl)piperidin-1-yl)-3-methyl-1H-indazole (BP-3)

[0725] Tert-butyl 5-(4-(dimethoxymethyl)piperidin-1-yl)-3-methyl-1H-indazole-1-carboxylate (BP-2, 315 mg, 809 mmol) was dissolved in methanol (5 mL), and potassium carbonate (56 mg, 404 μmol) was added. The reaction was stirred at room temperature overnight. LC-MS showed the reaction was complete. The reaction was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (methanol / dichloromethane = 0-5% gradient elution) to give the title compound (103 mg).

[0726] MS m / z (ESI): = 290.2 [M+H] + .

[0727] Step 3: Synthesis of 3-(5-(4-(dimethoxymethyl)piperidin-l-yl)-3-methyl-lH- indazol-l-yl)piperidine-2,6-dione (BP-4)

[0728] Dissolve 5-(4-(dimethoxymethyl)piperidin-l-yl)-3-methyl-lH-indazole (BP-3, 70 mg, 242 μmol) in tetrahydrofuran (1 mL), add sodium hydride (60%, 19 mg, 484 μmol) at 0 °C, after 30 min at this temperature add 3-bromopiperidine-2,6-dione (93 mg, 484 μmol) and move to room temperature to continue the reaction overnight. LC-MS detection shows that the reaction is complete, pour the reaction into ice saturated ammonium chloride solution (5 mL), then extract with ethyl acetate (10 mL x 3), combine the organic phase, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to dryness. The residue is purified by silica gel column chromatography (methanol / methylene chloride = 0-10% gradient elution) to give the title compound (71 mg).

[0729] MS m / z (ESI): = 401.2 [M+H] + .

[0730] Step 4: Synthesis of l-(l-(2,6-dioxopiperidin-3-yl)-3-methyl-lH-indazol-5-yl)piperidine- 4-carbaldehyde (Intermediate BP)

[0731] Dissolve 3-(5-(4-(dimethoxymethyl)piperidin-l-yl)-3-methyl-lH-indazol-l-yl)piperidine- 2,6-dione (BP-4, 60 mg, 150 μmol) in tetrahydrofuran (10 mL), add dilute hydrochloric acid (2 M, 750 μL) and react at room temperature for 6 h. LC-MS detection shows that the reaction is complete, and the reaction is concentrated under reduced pressure to dryness to give the title compound (64 mg) which is directly used in the next step.

[0732] MS m / z (ESI): = 355.1 [M+H] + .

[0733] Synthesis of Intermediate BQ: 5-(fluoro((((S)-l-isopropoxy-l-oxopropan-2-yl)amino)(phenoxy)phosphoryl)methyl)benzo[b]thiophene-2-carboxylic acid

[0734] Referring to the synthesis method of Intermediate Q, Steps 8 to 9, replace L-alanine propyl ester with L-alanine isopropyl ester to give Intermediate BQ in the same manner.

[0735] MS-ESI: m / z = 480.1 [M+H] +

[0736] 1 H NMR (400 MHz, DMSO-d6) δ 8.02-7.96 (m, 1H), 7.83-7.82 (m, 1H), 7.64-7.54 (m, 2H), 7.38-7.31 (m, 2H), 7.21-7.12 (m, 3H), 6.18-6.03 (m, 2H), 5.36-5.23 (m, 1H), 3.43-3.41 (m, 1H), 1.16-0.91 (m, 9H).

[0737] Synthesis of Intermediate BR: 5-(fluoro((((S)-1-isobutoxy-1-oxopropan-2-yl)amino)(phenoxy)phosphoryl)methyl)benzo[b]thiophene-2-carboxylic acid

[0738] Following the procedure for the synthesis of Intermediate Q, Steps 8-9, replacing L-alanine propyl ester with L-alanine isobutyl ester, Intermediate BR was prepared in the same manner.

[0739] MS-ESI: m / z = 494.1 [M+H] +

[0740] 1 H NMR (400 MHz, DMSO-d6) δ 8.01-7.95 (m, 2H), 7.79 (s, 1H), 7.55-7.53 (m, 1H), 7.37-7.31 (m, 2H), 7.21-7.11 (m, 3H), 6.23-6.03 (m, 2H), 3.94-3.87 (m, 3H), 1.81-1.74 (m, 1H), 1.35 (d, J = 6.8 Hz, 3H), 0.90 (d, J = 6.8 Hz, 6H).

[0741] Synthesis of Intermediate BS: 5-(((((S)-1-(2-ethylbutoxy)-1-oxopropan-2-yl)amino)(phenoxy)phosphoryl)fluoromethyl)benzo[b]thiophene-2-carboxylic acid

[0742] Following the procedure for the synthesis of Intermediate Q, Steps 8-9, replacing L-alanine propyl ester with L-alanine 2-ethylbutyl ester, Intermediate BS was prepared in the same manner.

[0743] MS-ESI: m / z = 522.1 [M+H] +

[0744] 1H NMR (400 MHz, DMSO-d6) δ 8.01 - 7.91 (m, 1H), 7.79 (s, 1H), 7.64 - 7.52 (m, 2H), 7.47 - 7.31 (m, 2H), 7.21 - 6.75 (m, 3H), 6.22 - 5.88 (m, 2H), 5.37 - 5.24 (m, 1H), 3.44 (d, J = 6.8 Hz, 2H), 1.34 - 1.08 (m, 8H), 0.84 - 0.80 (m, 6H).

[0745] Synthesis of Intermediate BT: 5-(fluoro((((S)-1-(neopentyloxy)-1- oxopropan-2-yl)amino)(phenoxy)phosphoryl)methyl)benzo[b]thiophene-2- carboxylic acid

[0746] Following the procedure for the synthesis of Intermediate Q, Steps 8 to 9, replacing L-alanine propyl ester with neopentyl L-alaninate, Intermediate BT was prepared in the same manner.

[0747] MS-ESI: m / z = 508.1 [M+H] +

[0748] 1 H NMR (400 MHz, DMSO-d6) δ 8.04 - 7.89 (m, 2H), 7.83 - 7.49 (m, 2H), 7.40 - 7.12 (m, 5H), 6.27 - 5.88 (m, 2H), 5.43 - 5.30 (m, 1H), 3.00 (s, 2H), 1.30 - 1.11 (m, 3H), 0.99 - 0.80 (m, 9H).

[0749] Synthesis of Intermediate BU: 5-((bis(2-((3-methylbutanoyl)thio)ethoxy) phosphoryl)fluoromethyl)benzo[b]thiophene-2-carboxylic acid perfluorophenyl ester

[0750] Following the procedure for the synthesis of Intermediate J, replacing Intermediate I with Intermediate BK, Intermediate BU was prepared in the same manner.

[0751] MS (ESI) m / z = 767.0 [M+Na] +

[0752] 1H NMR (400 MHz, CDC13) δ 8.36 (s, 1H), 8.09 (s, 1H), 7.98 (d, J = 8.4 Hz, 1H), 7.67 (d, J = 8.8 Hz, 1H), 5.87 (dd, J = 7.6 Hz, 44.0 Hz, 1H), 4.21 - 4.06 (m, 4H), 3.17 - 3.08 (m, 4H), 2.42 (d, J = 7.2 Hz, 4H), 2.19 - 2.08 (m, 2H), 0.94 (d, J = 6.4 Hz, 12H).

[0753] Synthesis of Intermediate BV: 2-(2-(l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3- dihydro-lH-benzo[d]imidazol-4-yl)-2,7-diazaspiro[3.5]non-7-yl)acetic acid

[0754] Intermediate BV: 2-(2-(l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3- dihydro-lH-benzo[d]imidazol-4-yl)-2,7-diazaspiro[3.5]non-7-yl)acetic acid

[0755] MS-ESI: m / z = 442.2 [M+H] +

[0756] 1 H NMR (400 MHz, DMSO-d6) δ 11.09 (s, 1H), 6.97 - 6.93 (m, 1H), 6.74 - 6.66 (m, 2H), 5.32 (dd, J = 5.2, 12.8 Hz, 1H), 3.60 - 3.56 (m, 9H), 3.17 (s, 2H), 2.83 - 2.80 (m, 3H), 2.69 - 2.58 (m, 2H), 2.00 - 1.90 (m, 5H).

[0757] Synthesis of Intermediate BW: 2-(2-(l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3- dihydro-lH-benzo[d]imidazol-5-yl)-2,7-diazaspiro[3.5]non-7-yl)acetic acid

[0758] Reference to the synthetic method of intermediate BV, replace BV-1 therein with 3-(3-methyl-2-oxo-5-(2,7-diazaspiro[3.5]nonan-2-yl)-2,3-dihydro-1H- benzo[d]imidazol-1-yl)piperidine-2,6-dione, to give intermediate BW.

[0759] MS-ESI: m / z = 442.2 [M+H] +

[0760] 1 H NMR (400 MHz, DMSO-d6) δ 11.05 (s, 1H), 6.90 (d, J = 8.4 Hz, 1H), 6.29 (d, J = 2.0 Hz, 1H), 6.10 (dd, J = 1.6, 8.4 Hz, 1H), 5.27 (dd, J = 5.2, 12.8 Hz, 1H), 3.54 (s, 4H), 3.28 (s, 3H), 3.20 (s, 2H), 2.92 - 2.84 (m, 1H), 2.79 (s, 4H), 2.68 - 2.58 (m, 2H), 1.98 - 1.95 (m, 1H), 1.86 (s, 4H).

[0761] Synthesis of intermediate BX: 1-((1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3- dihydro-1H-benzo[d]imidazol-4-yl)methyl)piperidine-4-carboxylic acid

[0762] Compound BX-1 (287 mg, 1.00 mmol), piperidine-4-carboxylic acid (194 mg, 1.50 mmol), sodium cyanoborohydride (189 mg, 3.00 mmol) and zinc chloride (680 mg, 5.00 mmol) were dissolved in N,N-dimethylformamide (10 mL) at room temperature, and stirred at 50 °C for 16 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The obtained residue was purified by reverse phase preparative separation to give the title compound (297 mg).

[0763] MS-ESI: m / z = 401.1 [M+H] +

[0764] 1H NMR (400 MHz, DMSO-d6) δ 12.12 (s, 1H), 11.09 (s, 1H), 7.08-7.06 (m, 1H), 6.97-6.92 (m, 1H), 6.88-6.85 (m, 1H), 5.37 (dd, J = 4.8, 12.4 Hz, 1H), 3.66 (s, 3H), 3.62-3.59 (m, 2H), 2.93-2.58 (m, 1H), 2.75-2.60 (m, 4H), 2.26-2.17 (m, 1H), 2.09-1.95 (m, 3H), 1.79-1.76 (m, 2H), 1.51-1.46 (m, 2H).

[0765] Synthesis of intermediate CA: 4-(2-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2- oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)ethyl)cyclohexane-1-carboxylic acid

[0766] Following the procedure for the synthesis of intermediate F, replacing 3-(5-bromo-3- methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione in intermediate F with 3-(4-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6- dione (AC-1), intermediate CA was prepared in the same manner.

[0767] MS m / z (ESI): = 414.2 [M+H] +

[0768] Synthesis of intermediate CC: 2-(1-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5- yl)piperidin-4-yl)acetic acid

[0769] Following the procedure for the synthesis of intermediate S, replacing tert-butyl 4- piperidinecarboxylate in intermediate S with tert-butyl 2-(piperidin-4-yl)acetate, replacing intermediate AC-1 with intermediate W-1, intermediate CC was prepared in the same manner.

[0770] MS m / z (ESI): = 386.1 [M+H] +

[0771] Synthesis of intermediate CE: 4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3- dihydro-1H-benzo[d]imidazol-4-yl)butanoic acid

[0772] Dissolve 4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H- benzo[d]imidazol-4-yl)but-3-ynoic acid (Intermediate AL, 70 mg, 208 pmol) in methanol (10 mL), add palladium on carbon (10% palladium, 20 mg) and stir at room temperature under a hydrogen balloon overnight. LC-MS indicates the reaction is complete. Filter the reaction and concentrate the filtrate to dryness under reduced pressure to give the title compound (70 mg).

[0773] MS m / z (ESI): = 346.1 [M+H] +

[0774] Synthesis of Intermediate CF: 5-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3- dihydro-1H-benzo[d]imidazol-4-yl)pentanoic acid (Intermediate 2)

[0775] Refer to the synthesis of Intermediate CE, replace Intermediate AL with Intermediate AC, and prepare Intermediate CF in the same manner.

[0776] MS m / z (ESI): = 360.2 [M+H] +

[0777] Synthesis of Intermediate CI: 5-(((((S)-1-(benzyloxy)-1-oxopropan-2-yl)amino)(phenoxy) phosphoryl)fluoromethyl)benzo[b]thiophene-2-carboxylic acid

[0778] Refer to the synthesis of Intermediate Q, Steps 8 to 9, replace L-alanine propyl ester with L-alanine benzyl ester, and prepare Intermediate CI in the same manner.

[0779] MS-ESI: m / z = 528.1 [M+H] +

[0780] 1 H NMR (400 MHz, DMSO-d6) δ 8.06 - 7.98 (m, 2H), 7.63 - 7.09 (m, 12H), 6.29 - 6.06 (m, 2H), 5.09 - 4.98 (m, 2H), 3.95 - 3.72 (m, 1H), 1.30 - 1.15 (m, 3H).

[0781] Synthesis of Intermediate CL: 2-(4-((1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3- dihydro-1H-benzo[d]imidazol-5-yl)methyl)cyclohexyl)acetic acid

[0782] Step 1 : Synthesis of tert-butyl 2-(4-methylene cyclohexyl)acetate (CL-2)

[0783] Methyltriphenylphosphonium bromide (2.52 g, 7.07 mmol) was added to a three necked flask, fitted with an argon balloon, the gas was replaced three times, anhydrous tetrahydrofuran (8.5 mL) was added under a gas blanket, then cooled in an ice bath, a solution of potassium tert-butoxide in tetrahydrofuran (1 M, 7.07 mL) was added, the ice bath was maintained for 30 minutes, then tert-butyl 2-(4-oxocyclohexyl)acetate (CL-1, 1 g, 4.71 mmol) was added, the reaction was allowed to warm to room temperature for 2.5 hours. The reaction was quenched by the addition of water to the system, then extracted twice with ethyl acetate, the organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure and purified by column chromatography (silica, petroleum ether = 100%) to give the title compound (700 mg).

[0784] 1 H NMR (400 MHz, CDC13) δ 4.64 - 4.56 (m, 2H), 2.33 - 2.25 (m, 2H), 2.15 - 2.10 (m, 2H), 2.10 - 2.01 (m, 2H), 1.96 - 1.86 (m, 1H), 1.86 - 1.79 (m, 2H), 1.45 (s, 9H), 1.14 - 1.01 (m, 2H).

[0785] Step 2: Synthesis of tert-butyl 2-(4-((1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3- dihydro-1H-benzo[d]imidazol-5-yl)methyl)cyclohexyl)acetate (CL-3)

[0786] L-1 (85 mg, 251.36 μmol), tert-butyl 2-(4-methylene cyclohexyl)acetate (CL-2, 264.32 mg, 1.26 mmol), [1,1'-bis(ditert-butylphosphino)ferrocene]dichloropalladium (16.38 mg, 25.14 μmol), triethylamine (76.31 mg, 754.09 μmol) were added to a reaction vial, N,N-dimethylacetamide (2 mL) was added, then an argon balloon was fitted, the gas was replaced three times, the reaction was placed in a 100 °C heating module under a gas blanket and left to react overnight. The reaction was cooled, poured into water, extracted three times with ethyl acetate, the organic phases were combined and washed with water, saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure and purified by column chromatography (silica, dichloromethane / methanol = 98 / 2) to give the title compound (100 mg).

[0787] MS m / z (ESI): = 468.2 [M+H] + .

[0788] Step 3: Synthesis of tert-butyl 2-(4-((l-(2,6-dioxopiperidin-3-yl)-3-methyl-2- oxo-2,3-dihydro-lH-benzo[d]imidazol-5-yl)methyl)cyclohexyl)acetate (CL-4)

[0789] Tert-butyl 2-(4-((l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH- benzo[d]imidazol-5-yl)methyl)cyclohexyl)acetate (CL-4, 78 mg, 166.11 pmol) was dissolved in dichloromethane (0.5 mL), trifluoroacetic acid (0.5 mL) was added with stirring at room temperature, and the resulting reaction solution was allowed to react for 1 hour at room temperature. The reaction solution was concentrated under reduced pressure to give the title compound, which was used directly in the next reaction without purification.

[0790] MS m / z (ESI): = 414.2 [M+H] t Bu+2H] + .

[0791] Step 4: Synthesis of 2-(4-((l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro- lH-benzo[d]imidazol-5-yl)methyl)cyclohexyl)acetic acid (Intermediate CL)

[0792] Tert-butyl 2-(4-((l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH- benzo[d]imidazol-5-yl)methyl)cyclohexyl)acetate (CL-4, 78 mg, 166.11 pmol) was dissolved in dichloromethane (0.5 mL), trifluoroacetic acid (0.5 mL) was added with stirring at room temperature, and the resulting reaction solution was allowed to react for 1 hour at room temperature. The reaction solution was concentrated under reduced pressure to give the title compound, which was used directly in the next reaction without purification.

[0793] MS m / z (ESI): = 414.2 [M+H] + .

[0794] Synthesis of Intermediate CM: l-(l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3- dihydro-lH-benzo[d]imidazol-5-yl)methyl)piperidine-4-carbaldehyde

[0795] Step 1 : Synthesis of 3-(5-((4-(dimethoxymethyl)piperidin-1 -yl)methyl)-3-methyl- 2-oxo-2,3-dihydro-1 H-benzo[d]imidazol-1 -yl)piperidine-2,6-dione (CM-2)

[0796] To a reaction vial was added 1 -(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3- dihydro-1 H-benzo[d]imidazole-5-carbaldehyde (CM-1, 30 mg, 104.43 pmol), 4- (dimethoxymethyl)piperidine (33.26 mg, 208.86 pmol), anhydrous dichloromethane (2 mL) and sodium triacetoxyborohydride (28.77 mg, 135.76 pmol). The resulting reaction was warmed to 40 °C for 6 h. The reaction was filtered and the filtrate was concentrated under reduced pressure and purified by column chromatography (silica, dichloromethane / methanol = 10 / 1 ) to give the title compound (32 mg).

[0797] MS m / z (ESI): = 431.2 [M+H] + .

[0798] Step 2: Synthesis of 1 -(1 -(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1 H- benzo[d]imidazol-5-yl)methyl)piperidine-4-carbaldehyde (Intermediate CM)

[0799] To a reaction vial was added 3-(5-((4-(dimethoxymethyl)piperidin-1 -yl)methyl)-3- methyl-2-oxo-2,3-dihydro-1 H-benzo[d]imidazol-1 -yl)piperidine-2,6-dione (CM-2, 32 mg, 74.33 pmol), dichloromethane (0.8 mL) and hydrogen chloride in 1,4- dioxane (4 M, 0.56 mL). The resulting reaction was stirred at room temperature overnight. The reaction was concentrated under reduced pressure to give the title compound which was used directly in the next step without purification.

[0800] MS m / z (ESI): = 385.1 [M+H] + .

[0801] Intermediate CN: Synthesis of 1 -(3-(2,4-dioxotetrahydropyrimidin-1 (2H)-yl)pyrazolo[1,5- a]pyridin-6-yl)piperidine-4-carbaldehyde

[0802] Step 1 : Synthesis of 1 -(6-(4-(dimethoxymethyl)piperidin-1 -yl)pyrazolo[1,5-a]pyridin-3- yl)dihydropyrimidine-2,4(1 H,3H)-dione (CN-1 )

[0803] To a reaction flask was placed 1-(6-bromopyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine- 2,4(1H,3H)-dione (AY-1, 120 mg, 0.39 mmol), 4-(dimethoxymethyl)piperidine (92.7 mg, 0.58 mmol), anhydrous 1,4-dioxane (50 mL), ((SP-4-1)-[1,3-bis[2,6-bis(1- ethylpropyl)phenyl]-4,5-dichloro-1,3-dihydro-2H-imidazol-2-ylidene]dichloro(3- chloropyridine-KN)palladium (33.41 mg, 38.82 μmol), cesium carbonate (252.9 mg, 776.9 mmol), and the resulting reaction mixture was heated at 100 °C for 12 h. The reaction mixture was added to water (10 mL) and extracted with ethyl acetate (15 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by column chromatography (silica, dichloromethane / methanol = 95 / 5) to give the title compound (70 mg).

[0804] MS m / z (ESI): = 388.2 [M+H] + .

[0805] Step 2: Synthesis of 1-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyrazolo[1,5- a]pyridin-6-yl)piperidine-4-carbaldehyde (Intermediate CN)

[0806] To a reaction flask was placed 1-(6-(4-(dimethoxymethyl)piperidin-1-yl)pyrazolo[1,5- a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (CN-1, 30 mg, 77.43 μmol), diluted with dilute hydrochloric acid (2 N) (1 mL), and heated at 60 °C for 1 h. The reaction mixture was adjusted to pH 8 with saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate, and the organic phase was dried and concentrated in vacuo to give the title compound. The crude product was used directly in the next reaction without purification.

[0807] MS m / z (ESI): = 342.1 [M+H] + .

[0808] Synthesis of Intermediate CO: 1-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3- dihydro-1H-benzo[d]imidazole-5-carbonyl)piperidine-4-carbaldehyde

[0809] Step 1: Synthesis of 1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H- benzo[d]imidazole-5-carboxylic acid (CO-1)

[0810] In room temperature, 1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H- benzo[d]imidazole-5-carboxaldehyde (CM-1, 230 mg, 0.80 mmol) was dissolved in acetonitrile (5 mL), sodium chlorite (724 mg, 8.00 mmol) and sodium phosphate monobasic (960 mg, 8.00 mmol) were dissolved in water (3 mL) and added into the reaction solution, followed by the addition of hydrogen peroxide (0.5 mL), the reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, 2N HCl was added to make the pH of the reaction solution 5-6, extracted with ethyl acetate (60 mL x 3), the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure to obtain the title compound (240 mg).

[0811] MS-ESI: m / z = 304.1 [M+H] +

[0812] Step 2: Synthesis of 3-(5-(4-(dimethoxymethyl)piperidine-1-carbonyl)-3-methyl-2-oxo- 2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (CO-2)

[0813] In room temperature, 1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H- benzo[d]imidazole-5-carboxaldehyde (CM-1, 230 mg, 0.80 mmol) was dissolved in acetonitrile (5 mL), sodium chlorite (724 mg, 8.00 mmol) and sodium phosphate monobasic (960 mg, 8.00 mmol) were dissolved in water (3 mL) and added into the reaction solution, followed by the addition of hydrogen peroxide (0.5 mL), the reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, 2N HCl was added to make the pH of the reaction solution 5-6, extracted with ethyl acetate (60 mL x 3), the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure to obtain the title compound (240 mg).

[0814] MS-ESI: m / z = 304.1 [M+H] +

[0815] 1H NMR (400 MHz, DMSO-d6) δ 11.13 (s, 1H), 7.23 (d, J = 1.2 Hz, 1H), 7.16 (d, J = 8.0 Hz, 1H), 7.06 (dd, J = 1.2, 8.0 Hz, 1H), 5.41 (dd, J = 5.2, 12.8 Hz, 1H), 4.08 (d, J = 6.8 Hz, 1H), 3.36 (s, 3H), 3.26 (s, 6H), 2.95 - 2.86 (m, 1H), 2.77 - 2.61 (m, 2H), 2.51 - 2.49 (m, 4H), 2.06 - 2.01 (m, 1H), 1.91 - 1.83 (m, 1H), 1.68 - 1.60 (m, 2H), 1.26 - 1.14 (m, 2H).

[0816] Step 3: Synthesis of 1-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H- benzo[d]imidazole-5-carbonyl)piperidine-4-carbaldehyde (Intermediate CO)

[0817] Intermediate CO: 1-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H- benzo[d]imidazole-5-carbonyl)piperidine-4-carbaldehyde

[0818] MS m / z (ESI): = 399.1 [M+H] + .

[0819] Intermediate CP: 1-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H- benzo[d]imidazole-4-carbonyl)piperidine-4-carbaldehyde

[0820] Intermediate CP was prepared according to the procedure for the synthesis of Intermediate CO, by replacing Intermediate CM-1 with Intermediate BX-1.

[0821] MS m / z (ESI): = 399.1 [M+H] + .

[0822] Intermediate CR: (trans)-4-(3-nitrophenyl)pyrrolidine-3-carbonitrile

[0823] Intermediate CR was prepared according to the procedure described for the synthesis of Intermediate B, replacing (trans)-4-(4-nitrophenyl)pyrrolidine-3-carbonitrile with Intermediate CR.

[0824] MS m / z (ESI): = 218.1 [M+H] + .

[0825] Synthesis of Intermediate CS: tert-butyl (3S,6S,10aS)-3-((trans)-3-(3- aminophenyl)-4-cyanopyrrolidine-1-carbonyl)-5-oxodecahydropyrrolo[1,2- a]azocin-6-yl)carbamate

[0826] Intermediate CS was prepared according to the procedure described for the synthesis of Intermediate B, replacing (trans)-4-(4-nitrophenyl)pyrrolidine-3-carbonitrile with Intermediate CR.

[0827] MS m / z (ESI): = 496.2 [M+H] + .

[0828] Synthesis of Intermediate CT: 2-(1-(2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-5-yl)piperidin-4-yl)acetic acid

[0829] Intermediate CT was prepared according to the procedure described for the synthesis of Intermediate S, replacing tert-butyl 4-piperidinecarboxylate with tert-butyl 2-(piperidin-4-yl)acetate and Intermediate AC-1 with 3-(4-bromo-1- oxoisoindolin-2-yl)piperidine-2,6-dione (CT-1).

[0830] MS m / z (ESI): = 386.1 [M+H] +

[0831] Synthesis of Intermediate CU: 7-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2- oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)hept-6-ynoic acid

[0832] Intermediate CU was prepared according to the procedure described for the synthesis of Intermediate AC, replacing pent-4-ynoic acid with hept-6-ynoic acid.

[0833] MS m / z (ESI): = 384.2 [M+H] + .

[0834] Synthesis of Intermediate CW: tert-butyl ((3S,6S,10aS)-3-(6-(4-aminophenyl)-5,7-dioxo- 4,6-diazaspiro[2.4]heptan-4-ylcarbonyl)-5-oxodecahydropyrrolo[l,2-a]azepin-6-yl)carbamate

[0835] Step 1: Synthesis of ethyl 1-(3-(4-nitrophenyl)ureido)cyclopropane-1-carboxylate (CW-2).

[0836] Ethyl 1-amino cyclopropane-1-carboxylate hydrochloride (1.21 g, 7.31 mmol) was dissolved in toluene (10 mL), triethylamine (1.85 g, 18.28 mmol) and 1-isocyanate-4-nitrobenzene (CW-1, 1.00 g, 6.09 mmol) were added, and the reaction mixture was warmed to 100 °C overnight. LC-MS indicated the reaction was complete, and the reaction mixture was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (methanol / dichloromethane = 0-5% gradient elution) to give the title compound (1.59 g).

[0837] MS m / z (ESI): = 294.1 [M+H] +

[0838] Step 2: Synthesis of 6-(4-nitrophenyl)-4,6-diazaspiro[2.4]heptane-5,7-dione (CW-3)

[0839] Ethyl 1-(3-(4-nitrophenyl)ureido)cyclopropane-1-carboxylate (CW-2, 1.22 g, 4.16 mmol) was dissolved in anhydrous ethanol (15 mL), followed by the addition of sodium ethoxide in ethanol (1 M, 6.14 mL), and the reaction mixture was allowed to react at room temperature overnight. LC-MS indicated the reaction was complete, and the reaction mixture was poured into saturated ammonium chloride solution (10 mL), extracted with ethyl acetate (10 mL x 3), and the combined organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (methanol / dichloromethane = 0-5% gradient elution) to give the title compound (1.03 g).

[0840] MS m / z (ESI): = 248.0 [M+H] + .

[0841] Step 3 & 4: Synthesis of tert-butyl ((3S,6S,10aS)-3-(6-(4-aminophenyl)-5,7-dioxo-4,6- diazaspiro[2.4]heptan-4-ylcarbonyl)-5-oxodecahydropyrrolo[l,2-a]azepin-6-yl)carbamate (Intermediate CW)

[0842] Following the procedure for the synthesis of Intermediate B, replacing (trans)-4- (4-nitrophenyl)pyrrolidine-3-carbonitrile with CW-3, Intermediate CW was prepared in the same manner.

[0843] MS m / z (ESI): = 526.2 [M+H] + .

[0844] Intermediate CX: trans-6-(4-aminophenyl)-7-cyano-4-azaspiro[2.4]heptane-4- carboxylic acid tert-butyl ester

[0845] Step 1: Synthesis of trans-6-(4-nitrophenyl)-4-azaspiro[2.4]heptane-7-carbonitrile (CX-2)

[0846] trans-6-phenyl-4-azaspiro[2.4]heptane-7-carbonitrile (CX-1, 300 mg, 1.51 mmol), concentrated sulfuric acid (1 mL) were added into a reaction flask, stirred for 10 minutes at 0 degree, then concentrated nitric acid (0.4 mL, 6.05 mmol, 68% wt) was added slowly, the reaction solution was stirred at 0 °C for 1 hour. LCMS showed the reaction was completed, quenched by saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate for three times (20 mL), the organic phase was combined and dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, then purified by column chromatography (silica, dichloromethane / methanol = 98 / 2) to give the title compound (310 mg).

[0847] MS m / z (ESI): = 244.1 [M+H] + .

[0848] Step 2: Synthesis of trans-7-cyano-6-(4-nitrophenyl)-4-azaspiro[2.4]heptane-4- carboxylic acid tert-butyl ester (CX-3)

[0849] trans-6-(4-nitrophenyl)-4-azaspiro[2.4]heptane-7-carbonitrile (CX-2, 560 mg, 2.30 mmol), di-tert-butyl dicarbonate (502.4 mg, 2.30 mmol), sodium bicarbonate (193.4 mg, 2.30 mmol), tetrahydrofuran (2 mL), water (2 mL) were added into a reaction flask, the reaction solution was stirred at room temperature for 16 hours. TLC showed the reaction was completed, extracted with ethyl acetate for three times (50 mL), the organic phase was combined and dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, then purified by column chromatography (silica, petroleum ether / ethyl acetate = 90:10) to give the title compound (600 mg).

[0850] MS m / z (ESI): = 366.1 [M+Na] + .

[0851] Step 3: Synthesis of trans-tert-butyl 6-(4-aminophenyl)-7-cyano-4- azaspiro[2.4]heptane-4-carboxylate (Intermediate CX)

[0852] trans-tert-butyl 7-cyano-6-(4-nitrophenyl)-4-azaspiro[2.4]heptane-4- carboxylate (CX-3, 600 mg, 1.75 mmol), palladium on carbon (10% palladium, 0.3 g), methanol (2 mL) were added to a reaction flask, purged with hydrogen gas three times, and the reaction was stirred at room temperature for 16 hours. LC-MS showed the reaction was complete, the reaction was filtered, the filtrate was concentrated under reduced pressure, and purified by Prep-HPLC [YMC TAR-C18 column, 30 mm diameter, 150 mm length, using a mixture of water (with 0.5% formic acid) and acetonitrile (acetonitrile content: 57-70%) as eluent] to give the title compound (120 mg).

[0853] MS m / z (ESI): = 258.1 [M- t Bu+2H] + .

[0854] 1 H NMR (400 MHz, Chloroform-d) δ 7.10 (d, J = 8.4 Hz, 2H), 6.68 (d, J = 8.4 Hz, 2H), 4.02 - 3.91 (m, 1H), 3.59 - 3.47 (m, 2H), 3.34 - 3.23 (m, 1H), 2.05 - 1.97 (m, 1H), 1.55 - 1.48 (m, 1H), 1.44 (s, 9H), 1.06 - 0.97 (m, 1H), 0.71 - 0.62 (m, 1H).

[0855] Step 4: Synthesis of tert-butyl (3R,4S)-6-(4-aminophenyl)-7-cyano-4- azaspiro[2.4]heptane-4-carboxylate and tert-butyl (3S,4R)-6-(4-aminophenyl)-7- cyano-4-azaspiro[2.4]heptane-4-carboxylate (Intermediate CX-P1 and CX-P2)

[0856] tert-butyl trans-6-(4-aminophenyl)-7-cyano-4-azaspiro[2.4]heptane-4- carboxylate (Intermediate CX) was resolved by chiral SFC to give single configuration tert-butyl (3R,4S)-6-(4-aminophenyl)-7-cyano-4-azaspiro[2.4]heptane-4- carboxylate and tert-butyl (3S,4R)-6-(4-aminophenyl)-7-cyano-4-azaspiro[2.4]heptane-4- carboxylate (Intermediate CX-P1 and CX-P2).

[0857] Chiral resolution method: apparatus: supercritical fluid chromatograph SFC-80; column: Daicel CHIRALCEL IC, 250 mm x 30 mm I.D., 10 pm; mobile phase: CO2 / MeOH [0.2% NH3(7 M solution in MeOH)] = 60 / 40; flow rate: 80 g / min; wavelength: UV 214 nm; column temperature: 35 °C. CX-P1 retention time: 1.11 min, CX-P2 retention time: 2.21 min.

[0858] Synthesis of intermediate CY: 2-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H- benzo[d]imidazol-4-yl)methyl)cyclohexyl)acetic acid

[0859] Intermediate CY was prepared by the same method as for the synthesis of intermediate CL, replacing L-1 with AC-1.

[0860] MS m / z (ESI): = 414.2 [M+H] + .

[0861] Synthesis of intermediate CZ: 1-((1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H- benzo[d]imidazol-4-yl)methyl)piperidine-4-carbaldehyde

[0862] Intermediate CZ was prepared by the same method as for the synthesis of intermediate CM, replacing CM-1 with BX-1.

[0863] MS m / z (ESI): = 385.1 [M+H] + .

[0864] Synthesis of intermediate DA: 3-(5-(4-(aminomethyl)piperidin-1-yl)-3-methyl-2-oxo-2,3-dihydro-1H- benzo[d]imidazol-1-yl)piperidine-2,6-dione

[0865] Step 1: Synthesis of 3-(5-(4-((benzylamino)methyl)piperidin-1-yl)-3-methyl-2-oxo-2,3-dihydro-1H- benzo[d]imidazol-1-yl)piperidine-2,6-dione (DA-1)

[0866] Intermediate L (150 mg, 404.97 pmol), benzylamine (45.56 mg, 425.21 pmol) were added into a reaction vial, followed by dichloromethane (3.8 mL) and sodium triacetoxyborohydride (111.58 mg, 526.46 pmol), the resulting reaction was stirred at room temperature for 3 hours. The reaction was filtered, the filtrate was concentrated under reduced pressure and purified by column chromatography (silica, dichloromethane / methanol = 9 / 1) to give the title compound (183 mg).

[0867] MS m / z (ESI): = 462.2 [M+H] + .

[0868] Step 2: Synthesis of 3-(5-(4-(aminomethyl)piperidin-l-yl)-3-methyl-2-oxo-2,3- dihydro-lH-benzo[d]imidazol-l-yl)piperidine-2,6-dione (Intermediate DA)

[0869] Intermediate DA-1 (182 mg, 394.32 pmol) was dissolved with methanol (3.8 mL), palladium on carbon (palladium content 10%, 50 mg) and palladium hydroxide on carbon (palladium hydroxide content 10%, 50 mg) were added, then a hydrogen balloon was attached, the gas was replaced for three times, and the reaction was stirred at room temperature for 3 hours under hydrogen atmosphere. The reaction was filtered, the filtrate was concentrated under reduced pressure, and then freeze-dried with appropriate amount of water and acetonitrile to give the title compound (141 mg), which was used directly in the next step without purification.

[0870] MS m / z (ESI): = 372.2 [M+H] + .

[0871] Synthesis of trans-3-cyano-4-(6-fluoropyridin-3-yl)pyrrolidine-l- carboxylic acid tert-butyl ester (Intermediate DB)

[0872] Steps 1 to 2: Synthesis of trans-4-(6-fluoropyridin-3-yl)pyrrolidine-3-carbonitrile (DB-3)

[0873] Referring to the synthesis method of Intermediate M & N (step 2 and step 4), (E)-3-(6- fluoropyridin-3-yl)acrylonitrile was used instead of (E)-3-(4-nitrophenyl)acrylonitrile (M-2), and Intermediate DB-3 was prepared by the same method.

[0874] MS m / z (ESI): = 192.1 [M+H] + .

[0875] Step 3: Synthesis of trans-3-cyano-4-(6-fluoropyridin-3-yl)pyrrolidine-l- carboxylic acid tert-butyl ester (Intermediate DB)

[0876] DB-3 (655 mg, 3.43 mmol) was dissolved in tetrahydrofuran (8 mL), water (4 mL) was added, sodium carbonate (1.09 g, 10.28 mmol) and di-tert-butyl dicarbonate (1.12 g, 5.14 mmol) were added and the resulting reaction was stirred at room temperature overnight. The reaction was poured into water and extracted three times with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure and purified by column chromatography (silica, petroleum ether / ethyl acetate = 4 / 1) to give the title compound (837 mg).

[0877] MS m / z (ESI): = 236.1 [M+2H - H2O] t Bu] + .

[0878] 1 H NMR (400 MHz, CDC13) δ 8.24 - 8.18 (m, 1H), 7.78 - 7.70 (m, 1H), 7.02 - 6.95 (m, 1H), 4.03 - 3.92 (m, 2H), 3.73 - 3.60 (m, 2H), 3.52 - 3.41 (m, 1H), 3.16 - 3.05 (m, 1H), 1.49 (s, 9H).

[0879] Synthesis of intermediate DC: trans-3-cyano-4-(6-(piperidin-4-ylmethoxy)pyridin-3- yl)pyrrolidine-1-carboxylic acid tert-butyl ester

[0880] Step 1: Synthesis of benzyl 4-(((5-(trans-1-(tert-butoxycarbonyl)-4-cyanopyrrolidin-3- yl)pyridin-2-yl)oxy)methyl)piperidine-1-carboxylate (DC-1)

[0881] N-benzyloxycarbonyl-4-piperidinemethanol (718.85 mg, 2.88 mmol) was added to a three-necked flask, dissolved in anhydrous tetrahydrofuran (5 mL), then an argon balloon was attached to replace the gas three times, and then cooled in an ice bath under gas protection, then sodium hydride (173.01 mg, 4.33 mmol, 60% purity) was added, and the reaction was maintained in the ice bath for 10 minutes, then a tetrahydrofuran (4 mL) solution of intermediate DB (420 mg, 1.44 mmol) was added, and the resulting reaction was gradually warmed to room temperature and stirred overnight. The reaction was quenched by adding water, then extracted three times with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (silica, petroleum ether / ethyl acetate = 7 / 3) to give the title compound (456 mg).

[0882] MS m / z (ESI): = 521.3 [M+H] + .

[0883] Step 2: Synthesis of trans-3-cyano-4-(6-(piperidin-4-ylmethoxy)pyridin-3- yl)pyrrolidine-1-carboxylic acid tert-butyl ester (Intermediate DC)

[0884] Intermediate DC-1 (368 mg, 706.85 μmol) was added to a reaction flask, mixed solvent tetrahydrofuran (3 mL) and methanol (3 mL) was added, then palladium on carbon (palladium content 10%, 73.60 mg) was added, a hydrogen balloon was attached and the gas was replaced three times, the reaction was stirred at room temperature under hydrogen atmosphere for 2 hours. The reaction was filtered, the filtrate was concentrated under reduced pressure and purified by column chromatography (silica, dichloromethane / methanol = 94 / 6) to give the title compound (218 mg).

[0885] MS m / z (ESI): = 387.2 [M+H] + .

[0886] 1 H NMR (400 MHz, CDC13) δ 8.09 (d, J = 2.6 Hz, 1H), 7.54 - 7.42 (m, 1H), 6.76 (d, J = 8.6 Hz, 1H), 4.14 (d, J = 6.5 Hz, 2H), 4.03 - 3.84 (m, 2H), 3.69 - 3.61 (m, 1H), 3.59 - 3.50 (m, 1H), 3.45 - 3.35 (m, 1H), 3.17 - 3.01 (m, 3H), 2.71 - 2.60 (m, 2H), 1.95 - 1.89 (m, 1H), 1.86 - 1.77 (m, 2H), 1.48 (s, 9H), 1.38 - 1.22 (m, 3H).

[0887] Synthesis of Intermediate DD: trans-3-(4-bromophenyl)-4-cyanopyrrolidine-1- carboxylic acid tert-butyl ester

[0888] Intermediate DD was prepared according to the procedure described for the synthesis of Intermediate DB, replacing DB-1 with (E)-3-(4-bromophenyl)acrylonitrile.

[0889] MS m / z (ESI): = 295.00 [M+2H- t Bu] + .

[0890] 1H NMR (400 MHz, DMSO-d6) δ 7.62 - 7.57 (m, 2H), 7.42 - 7.37 (m, 2H), 3.91 - 3.82 (m, 1H), 3.78 - 3.63 (m, 3H), 3.54 - 3.43 (m, 1H), 3.28 - 3.19 (m, 1H), 1.48 - 1.35 (m, 9H).

[0891] Synthesis of intermediate DE: tert-butyl (trans)-3-cyano-4-(4-(4-formylpiperidin-1- yl)phenyl)pyrrolidine-1-carboxylate

[0892] Step 1: Synthesis of tert-butyl (trans)-3-cyano-4-(4-(4-(hydroxymethyl)piperidin-1- yl)phenyl)pyrrolidine-1-carboxylate (DE-1)

[0893] Step 1: Synthesis of tert-butyl (trans)-3-cyano-4-(4-(4-(hydroxymethyl)piperidin-1- yl)phenyl)pyrrolidine-1-carboxylate (DE-1)

[0894] MS-ESI: m / z = 386.2 [M+H] +

[0895] Step 2: Synthesis of tert-butyl (trans)-3-cyano-4-(4-(4-formylpiperidin-1-yl)phenyl)pyrrolidine-1- carboxylate (intermediate DE)

[0896] Under ice, tert-butyl (trans)-3-cyano-4-(4-(4-(hydroxymethyl)piperidin-1-yl)phenyl)pyrrolidine-1-carboxylate (DE-1, 187 mg, 0.486 mmol) and Dess-Martin periodinane (309 mg, 0.729 mmol) were dissolved in dichloromethane (8 mL). The reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction, the mixture was extracted with dichloromethane (10 mL x 3). The combined organic phases were washed with saturated brine (10 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was isolated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain the title compound (74 mg).

[0897] MS-ESI: m / z = 384.2 [M+H] +

[0898] Intermediate DF: Synthesis of tert-butyl ((5R,8S,10aR)-8-((3R,4S)-3-(4-aminophenyl)-4-cyanopyrrolidine-1-carbonyl)-3,3-dioxido-6-oxooctahydro-4H-pyrrolo[2,1-d][1,5]thiazolin-5-yl)carbamate

[0899] Referring to the synthesis method of intermediate AP, (5S,8S,10aR)-5-((tert-butoxycarbonyl)amino)-3-(2,2-difluoroethyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazepine-8-carboxylic acid (AP-1) was replaced with (5R,8S,10aR)-5-((tert-butoxycarbonyl)amino)-6-oxooctahydro-4H-pyrrolo[2,1-d][1,5]thiazepine-8-carboxylic acid 3,3-dioxide, and intermediate DF was prepared by the same method.

[0900] MS-ESI: m / z = 490.1 [M- t Bu+2H] +

[0901] Intermediate DG: Synthesis of tert-butyl (trans)-3-cyano-4-(4-(7-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl)-2,7-diazaspiro[3.5]nonan-2-yl)phenyl)pyrrolidine-1-carboxylate

[0902] Step 1: Synthesis of tert-butyl 7-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-1-methyl-1H-indazol-6-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (DG-2)

[0903] At room temperature, compound 3-(2,6-di(benzyloxy)pyridin-3-yl)-6-bromo-1-methyl-1H-indazole (DG-1, 2.00 g, 4.00 mmol), tert-butyl 2,7-diazaspiro[3.5]nonane-2-carboxylate (1.81 g, 8.00 mmol), cesium carbonate (3.91 g, 12.00 mmol), 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl (373 mg, 0.80 mmol) and methanesulfonic acid (2-dicyclohexylphosphino-2',6'-di-isopropoxy-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (334 mg, 0.4 mmol) were dissolved in 1,4-dioxane (20 mL), the reaction system was replaced with nitrogen three times, and the reaction mixture was stirred at 100 ° C for 16 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, diluted with water (30 mL), and extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to obtain the title compound (1.91 g).

[0904] MS-ESI: m / z = 646.3 [M+H] +

[0905] Step 2: Synthesis of tert-butyl 7-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (DG-3)

[0906] At room temperature, tert-butyl 7-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-1-methyl-1H-indazol-6-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (DG-2, 2 g, 3.10 mmol) was dissolved in tetrahydrofuran (50 mL), followed by the addition of palladium / carbon (10% palladium content, 200 mg) and palladium hydroxide / carbon (20% palladium hydroxide content, 200 mg). The reaction system was purged with hydrogen three times, and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was filtered through a pad of celite, the filter cake was rinsed with ethyl acetate (70 mL), and the filtrate was concentrated under reduced pressure to give the title compound (827 mg).

[0907] MS-ESI: m / z = 468.2 [M+H] +

[0908] 1H NMR (400 MHz, DMSO-d6) δ 10.84 (s, 1H), 7.48 (d, J = 8.8 Hz, 1H), 6.91 (dd, J = 1.2, 9.2 Hz, 1H), 6.85 (s, 1H), 4.25 (dd, J = 5.2, 9.2 Hz, 1H), 3.88 (s, 3H), 3.60 (s, 4H), 3.19 (s, 4H), 2.64 - 2.56 (m, 2H), 2.32 - 2.26 (m, 1H), 2.17 - 2.13 (m, 1H), 1.80 (t, J = 5.2 Hz, 4H), 1.39 (s, 9H).

[0909] Step 3: Synthesis of 3-(1-methyl-6-(2,7-diazaspiro[3.5]nonan-7-yl)-1H-indazol-3- yl)piperidine-2,6-dione (DG-4)

[0910] tert-Butyl 7-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl)-2,7- diazaspiro[3.5]nonane-2-carboxylate (DG-3, 200 mg, 0.428 mmol) was dissolved in dichloromethane (4 mL) at room temperature, trifluoroacetic acid (1 mL) was added, and the resulting mixture was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was concentrated under reduced pressure, the resulting residue was dissolved in acetonitrile, and was concentrated under reduced pressure again, which was repeated three times to obtain the title compound (157 mg), which was used directly in the next reaction.

[0911] MS-ESI: m / z = 368.1 [M+H] +

[0912] Step 4: Synthesis of (trans)-tert-butyl 3-cyano-4-(4-(7-(3-(2,6-dioxopiperidin-3-yl)-1- methyl-1H-indazol-6-yl)-2,7-diazaspiro[3.5]nonan-2-yl)phenyl)pyrrolidine-1-carboxylate (Intermediate DG)

[0913] DG-4 (157 mg, 0.427 mmol) and (trans)-3-(4-bromophenyl)-4-cyanopyrrolidine-1- carboxylate tert-butyl ester (Intermediate DD, 150 mg, 0.427 mmol) were dissolved in dioxane (10 mL) at room temperature, cesium carbonate (696 mg, 2.135 mmol) and (SP-4-1)-[1,3-bis[2,6-bis(1- ethylpropyl)phenyl]-4,5-dichloro-1,3-dihydro-2H-imidazol-2-ylidene]dichloro(2- methylpyridine)palladium (36 mg, 0.043 mmol) were added, the reaction system was replaced with nitrogen for three times, the reaction mixture was stirred at 90 °C for 16 hours. After the reaction was completed, it was diluted with dichloromethane (50 mL), 5% acetic acid solution was added to adjust pH = 6-7, the mixture was diluted with water (30 mL), extracted with dichloromethane (40 mL x 2), the combined organic phase was washed with saturated brine (10 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give a crude product, which was separated by column chromatography (petroleum ether / ethyl acetate = 2 / 1, v / v) to give the title compound (70 mg).

[0914] MS-ESI: m / z = 638.3 [M+H] +

[0915] Synthesis of Intermediate DH: (trans)-3-cyano-4-(4-(7-(3-(2,6-dioxopiperidin-3-yl)-1- methyl-1H-indazol-7-yl)-2,7-diazaspiro[3.5]nonan-2-yl)phenyl)pyrrolidine-1-carboxylic acid tert-butyl ester

[0916] Referring to the synthetic method of Intermediate DG, replace DG-1 with 3-(2,6-bis(benzyloxy)pyridin-3-yl)-7-bromo-1-methyl-1H-indazole (DH-1), and the same method was used to prepare Intermediate DH.

[0917] MS-ESI: m / z = 638.3 [M+H] +

[0918] Synthesis of Intermediate DI: ((2-((perfluorophenoxy)carbonyl)benzo[b]thiophen-5-yl)methyl) phosphonic acid

[0919] Referring to the synthetic method of Intermediate I, replace I-1 with 5-((diethoxyphosphoryl)methyl)benzo[b]thiophene-2-carboxylic acid, and the same method was used to prepare Intermediate DI.

[0920] MS-ESI: m / z = 397.1 [M-Boc+H] +

[0921] Synthesis of intermediate DJ: tert-butyl (trans)-3-cyano-4-(4-(4-((3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)prop-2-yn-1-yl)oxy)piperidin-1-yl)phenyl)pyrrolidine-1-carboxylate

[0922] Step 1: Synthesis of tert-butyl 4-((3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)prop-2-yn-1-yl)oxy)piperidine-1-carboxylate (DJ-2)

[0923] To a solution of 3-(4-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (AC-1, 3.0 g, 8.87 mmol), tert-butyl 4-(prop-2-yn-1-yloxy)piperidine-1-carboxylate (DJ-1, 3.18 g, 13.31 mmol), cesium carbonate (11.56 g, 35.48 mmol), cuprous iodide (337.9 mg, 1.77 mmol) and dichlorobis(triphenylphosphine)palladium (622.6 mg, 0.89 mmol) in N,N-dimethylformamide (150 mL) was purged with nitrogen for 3 times, then the reaction mixture was heated to 80 °C and stirred for 6 h. After the reaction was completed, the reaction mixture was cooled to room temperature, poured into water (300 mL), and then extracted with ethyl acetate (200 mL x 3). The organic phase was collected, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by silica gel column chromatography (dichloromethane / methanol = 15 / 1) to give the title compound (2.79 g).

[0924] MS-ESI: m / z = 397.1 [M-Boc+H] + .

[0925] Step 2: Synthesis of 3-(3-methyl-2-oxo-4-(3-(piperidin-4-yloxy)prop-1-yn-1-yl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (DJ-3)

[0926] tert-Butyl 4-((3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H- benzo[d]imidazol-4-yl)prop-2-yn-1-yl)oxy)piperidine-1-carboxylate (DJ-2, 1.8 g, 3.62 mmol) was dissolved in dichloromethane (20 mL), trifluoroacetic acid (5 mL) was added, and the reaction was stirred at room temperature for 1 hour. After the reaction was completed, it was concentrated under reduced pressure to obtain the title compound (1.44 g), which was used directly in the next step.

[0927] MS-ESI: m / z = 397.2 [M+H] + .

[0928] Step 3: Synthesis of tert-butyl (trans)-3-cyano-4-(4-(4-((3-(1-(2,6-dioxopiperidin-3-yl)-3- methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)prop-2-yn-1-yl)oxy)piperidin-1- yl)phenyl)pyrrolidine-1-carboxylate (Intermediate DJ)

[0929] DJ-3 (460 mg, 1.16 mmol), Intermediate DD (407 mg, 1.16 mmol) were dissolved in DMA (24 mL), cesium carbonate (1.13 g, 3.48 mmol) and (SP-4-1)-[1,3-bis[2,6-bis(1- ethylpropyl)phenyl]-4,5-dichloro-1,3-dihydro-2H-imidazol-2-ylidene]dichloropalladium (2- methylpyridine) (92 mg, 0.11 mmol) were added, the reaction system was replaced with nitrogen three times, and the reaction mixture was stirred at 100 °C for 16 hours. After the reaction was completed, it was diluted with ethyl acetate (20 mL), 5% acetic acid solution was added to adjust pH = 6-7, water (20 mL) was added to dilute the mixture, and it was extracted with ethyl acetate (20 mL x 2), the organic phases were combined, washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product, which was separated by column chromatography (dichloromethane / methanol = 15 / 1, v / v) to obtain the title compound (226 mg).

[0930] MS-ESI: m / z = 667.2 [M+H] +

[0931] Intermediate DK: Synthesis of tert-butyl (trans)-3-cyano-4-(4-(4-((3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)prop-2-yn-1-yl)oxy)piperidin-1-yl)phenyl)pyrrolidine-1-carboxylate

[0932] Intermediate DK was prepared by the same method as that for the synthesis of intermediate DJ, replacing AC-1 with L-1.

[0933] MS-ESI: m / z = 667.2 [M+H] +

[0934] Synthesis of Intermediate DL: trans-3-cyano-4-(4-(2-(1-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl)piperidin-4-yl)ethyl)phenyl)pyrrolidine-1-carboxylic acid tert-butyl ester

[0935] Step 1: Synthesis of benzyl 4-((E)-4-(trans-1-(tert-butoxycarbonyl)-4-cyanopyrrolidin-3-yl)styryl)piperidine-1-carboxylate (DL-1)

[0936] Intermediate DD (110 mg, 313.18 μmol), benzyl 4-vinylpiperidine-1-carboxylate (384.14 mg, 1.57 mmol) were added into a reaction flask, N,N-dimethylacetamide (2.5 mL), [1,1'-bis(ditert-butylphosphine)ferrocene]palladium dichloride (20.41 mg, 31.32 μmol) and triethylamine (95.07 mg, 939.54 μmol) were added, then an argon balloon was attached and the gas was replaced for three times, and the flask was put into a 100 °C oil bath overnight under the protection of argon. The reaction solution was poured into water, extracted with ethyl acetate for three times, the organic phase was combined and washed with water, saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (silica, petroleum ether / ethyl acetate = 7 / 3) to give the title compound (148.8 mg).

[0937] MS m / z (ESI): = 416.2 [M+H-Boc] + .

[0938] Step 2: Synthesis of trans-3-cyano-4-(4-(2-(piperidin-4-yl)ethyl)phenyl)pyrrolidine-1-carboxylic acid tert-butyl ester (DL-2)

[0939] Intermediate DL-1 (148 mg, 287.02 μmol) was dissolved in a mixed solvent of methanol (2.8 mL) and tetrahydrofuran (2.8 mL), then palladium on carbon (palladium content 10%, 60 mg) was added, an argon balloon was attached and the gas was replaced for three times, and the flask was put into a hydrogen atmosphere at room temperature for 2 hours. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, dissolved in a mixed solvent of water and acetonitrile, and lyophilized to give the title compound (90 mg).

[0940] MS m / z (ESI): = 384.3 [M+H] + .

[0941] Step 3: Synthesis of trans-3-(4-(2-(1-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-1- methyl-1H-indazol-6-yl)piperidin-4-yl)ethyl)phenyl)-4-cyanopyrrolidine-1-carboxylic acid tert-butyl ester (DL-3)

[0942] Intermediate DG-1 (90 mg, 179.86 pmol), DL-2 (89.68 mg, 233.82 pmol), cesium carbonate (175.81 mg, 539.58 pmol), Pd-PEPPSI-IPent (CAS: 1158652-41-5) (14.23 mg, 17.99 pmol) were added to a reaction vial, 1,4-dioxane (2.3 mL) was added, then the gas was replaced with an argon balloon for three times, and then it was put into a 100 °C reaction for 10 hours under the protection of gas. The reaction solution was concentrated under reduced pressure, and then purified by column chromatography (silica, petroleum ether / ethyl acetate = 6 / 4) to give the title compound (61.5 mg).

[0943] MS m / z (ESI): = 803.5 [M+H] + .

[0944] Step 4: Synthesis of trans-3-cyano-4-(4-(2-(1-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H- indazol-6-yl)piperidin-4-yl)ethyl)phenyl)pyrrolidine-1-carboxylic acid tert-butyl ester (Intermediate DL)

[0945] Intermediate DL-3 (61.5 mg, 76.59 pmol) was dissolved in a mixture solvent of methanol (1 mL) and tetrahydrofuran (0.5 mL), palladium on carbon (palladium content 10%, 20 mg) and palladium hydroxide on carbon (palladium hydroxide content 10%, 20 mg) were added, then a hydrogen balloon was installed, the gas was replaced for three times, and then it was reacted under the atmosphere of hydrogen at room temperature for 8 hours. The reaction solution was concentrated under reduced pressure, and then purified by column chromatography (silica, petroleum ether / ethyl acetate = 3 / 7) to give the title compound (14 mg).

[0946] MS m / z (ESI): = 625.4 [M+H] + .

[0947] Synthesis of Intermediate DM: 5-((bis(((S)-1-oxo-1-propyloxypropan-2-yl)amino) phosphoryl)fluoromethyl)benzo[b]thiophene-2-carboxylic acid

[0948] Step 1: Synthesis of 2,2'-((((2-((benzyloxy)carbonyl)benzo[b]thiophen-5-yl)fluoromethyl) phosphoryl)bis(azanediyl))(2S,2'S)-dipropionic acid dipropyl ester (DM-1)

[0949] ((2-((benzyloxy)carbonyl)benzo[b]thiophen-5-yl)fluoromethyl)phosphonic acid (Q-8, 1.50 g, 3.94 mmol) and N,N-dimethylformamide (3 drops) were dissolved in dichloromethane (30 mL) at room temperature, the temperature was lowered to 0 °C, oxalyl chloride (1.50 g, 11.82 mmol) was added dropwise, stirred for 10 minutes, then the temperature was raised to 40 °C and the reaction was stirred for 2 hours. After the reaction was completed, it was concentrated under reduced pressure. The residue was dissolved in dichloromethane (30 mL), replaced with nitrogen 3 times, the temperature was lowered to 0 °C, triethylamine (1.99 g, 19.70 mmol) was added, then L-alanine propyl ester (1.29 g, 9.85 mmol) was dissolved in dichloromethane (5 mL) and slowly added to the reaction solution, the temperature was raised to room temperature and the reaction was stirred for 30 minutes. After the reaction was completed, it was diluted with water (50 mL), extracted with dichloromethane (50 mL x 3), the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to obtain the title compound (1.30 g).

[0950] MS-ESI: m / z = 607.2 [M+H] +

[0951] Step 2: Synthesis of 5-((bis(((S)-1-oxo-1-propoxypropan-2-yl)amino) phosphoryl)fluoromethyl)benzo[b]thiophene-2-carboxylic acid (Intermediate DM)

[0952] 2,2'-((((2-((benzyloxy)carbonyl)benzo[b]thiophen-5-yl)fluoromethyl) phosphoryl)bis(azanediyl))(2S,2'S)-dipropionic acid dipropyl ester (DM-1, 1.30 g, 2.14 mmol) was dissolved in tetrahydrofuran (40 mL) at room temperature, palladium on carbon (palladium content 10%, 150 mg) was added, replaced with hydrogen 3 times, and the reaction was stirred under a hydrogen atmosphere at room temperature for 16 hours. After the reaction was completed, it was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to obtain the title compound (365 mg).

[0953] MS-ESI: m / z = 517.1 [M+H] +

[0954] 1H NMR (400 MHz, DMSO-d6) δ 8.12 (d, J = 2.0 Hz, 1H), 8.07-8.00 (m, 2H), 7.56 (t, J = 8.4 Hz, 1H), 5.96-5.81 (m, 1H), 5.03-4.95 (m, 1H), 4.84 (dd, J = 11.2 Hz, 23.6 Hz, 1H), 4.03-3.83 (m, 4H), 3.75-3.68 (m, 2H), 1.61-1.45 (m, 4H), 1.28-1.13 (m, 6H), 0.90-0.81 (m, 6H).

[0955] Synthesis of intermediate DN: 5-((bis(((S)-1-oxo-1- propyloxypropan-2-yl)amino)phosphoryl)difluoromethyl)benzo[b]thiophene-2- carboxylic acid

[0956] Intermediate DN was prepared according to the procedure for the synthesis of intermediate DM, replacing Q-8 with ((2-((benzyloxy)carbonyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphonic acid.

[0957] MS-ESI: m / z = 535.1 [M+H] +

[0958] 1 H NMR (400 MHz, DMSO-d6) δ 8.58 (s, 1H), 8.04-8.00 (m, 3H), 4.35-4.29 (m, 2H), 4.05-3.96 (m, 6H), 1.63-1.53 (m, 4H), 1.32-1.22 (m, 6H), 0.89-0.83 (m, 6H).

[0959] Synthesis of intermediate DO: 1-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3- dihydro-1H-benzo[d]imidazole-4-carbonyl)piperidine-4-carboxylic acid (Intermediate DO)

[0960] Step 1: Synthesis of 1-(2,6-bis(benzyloxy)pyridin-3-yl)-3-methyl-2-oxo-2,3-dihydro- 1H-benzo[d]imidazole-4-carboxylic acid (DO-2)

[0961] Dissolve 1-(2,6-bis(benzyloxy)pyridin-3-yl)-4-bromo-3-methyl-1,3-dihydro-2H- benzo[d]imidazol-2-one (DO-1, 100 mg, 193.65 μmol) in 1,4-dioxane (5 mL), add tert-butyl alcohol (28.71 mg, 387.31 μmol), acetic anhydride (39.54 mg, 387.31 μmol), palladium acetate (4.35 mg, 19.37 μmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (22.41 mg, 38.73 μmol), formic acid (18.61 mg, 387.31 μmol), triethylamine (39.19 mg, 387.31 μmol, 54.02 μL), evacuate and purge with nitrogen, heat to 100 °C for 5 h. LCMS monitoring shows the reaction is complete. Add the reaction to 10 mL water, extract with ethyl acetate, combine the organic phase, dry over anhydrous sodium sulfate, concentrate under reduced pressure to give the title compound (116 mg) which is used directly for the next step.

[0962] MS m / z (ESI): = 481.9 [M+H] + .

[0963] Step 2: Synthesis of tert-butyl 1-(1-(2,6-bis(benzyloxy)pyridin-3-yl)-3-methyl-2-oxo- 2,3-dihydro-1H-benzo[d]imidazole-4-carbonyl)piperidine-4-carboxylate (DO-3)

[0964] Dissolve 1-(2,6-bis(benzyloxy)pyridin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H- benzo[d]imidazole-4-carboxylic acid (DO-2, 75 mg, 155.76 μmol) and tert-butyl piperidine-4- carboxylate (34.63 mg, 186.92 μmol) in N,N-dimethylformamide (5 mL), add O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (88.84 mg, 233.65 μmol), N,N-diisopropylethylamine (100.65 mg, 778.82 μmol, 135.65 μL), and react at room temperature overnight. LCMS monitoring shows the reaction is complete. Add the reaction to 20 mL water, extract with ethyl acetate (20 mL x 3), combine the organic phase, wash with saturated brine three times, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and purify by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to give the title compound (72.6 mg)

[0965] MS m / z (ESI): = 648.9 [M+H] + .

[0966] Step 3: Synthesis of tert-butyl 1-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3- dihydro-1H-benzo[d]imidazole-4-carbonyl)piperidine-4-carboxylate (DO-4)

[0967] tert-Butyl 1-(1-(2,6-bis(benzyloxy)pyridin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H- benzo[d]imidazole-4-carbonyl)piperidine-4-carboxylate (DO-3, 72 mg, 110.98 pmol) was dissolved in tetrahydrofuran (1.25 mL) and ethanol (1.25 mL), palladium hydroxide on carbon (10% palladium hydroxide, 15.59 mg) and palladium on carbon (10% palladium, 13.48 mg) were added, heated to 50 °C under hydrogen atmosphere, and stirred overnight. LCMS monitoring showed the reaction was complete. The reaction was filtered using celite, the filtrate was collected, concentrated to dryness under reduced pressure, and purified using silica gel column chromatography (dichloromethane / methanol = 20 / 1) to give the title compound (24 mg).

[0968] MS m / z (ESI): = 471.0 [M+H] + .

[0969] Step 4: Synthesis of 1-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H- benzo[d]imidazole-4-carbonyl)piperidine-4-carboxylic acid (Intermediate DO)

[0970] tert-Butyl 1-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole- 4-carbonyl)piperidine-4-carboxylate (DO-4, 24 mg, 51.01 pmol) was dissolved in dichloromethane (3 mL), trifluoroacetic acid (5.82 mg, 51.01 pmol) was added, and the reaction was stirred at room temperature for 2 hours. LCMS monitoring showed the reaction was complete. The reaction was concentrated to dryness under reduced pressure to give the title compound as a crude product (20 mg), which was used directly in the next step.

[0971] MS m / z (ESI): = 415.0 [M+H] + .

[0972] Intermediate DP: Synthesis of tert-butyl (trans)-3-cyano-4-(4-(4-(3-(1-(2,6-dioxopiperidin-3- yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)prop-2-yn-1-yl)piperidin-1- yl)phenyl)pyrrolidine-1-carboxylate

[0973] Following the procedure for the synthesis of intermediate DJ, replacing DJ-1 with 4- (prop-2-yn-1-yl)piperidine-1-carboxylic acid tert-butyl ester, intermediate DP was prepared.

[0974] MS-ESI: m / z = 651.3 [M+H] +

[0975] Synthesis of intermediate DQ: (trans)-3-cyano-4-(4-(4-(2-(1-(2,6-dioxopiperidin-3-yl)- 3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)ethyl)piperidin-1-yl)phenyl)pyrrolidine- 1-carboxylic acid tert-butyl ester

[0976] Step 1: Synthesis of tert-butyl 4-((1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3- dihydro-1H-benzo[d]imidazol-4-yl)ethynyl)piperidine-1-carboxylate (DQ-2)

[0977] Following the procedure for the synthesis of intermediate DJ, Step 1, replacing DJ-1 with tert-butyl 4-ethynylpiperidine-1-carboxylate (DQ-1), DQ-2 was prepared.

[0978] MS-ESI: m / z = 467.2 [M+H] +

[0979] Step 2: Synthesis of tert-butyl 4-(2-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3- dihydro-1H-benzo[d]imidazol-4-yl)ethyl)piperidine-1-carboxylate (DQ-3)

[0980] Tert-butyl 4-((1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H- benzo[d]imidazol-4-yl)ethynyl)piperidine-1-carboxylate (DQ-2, 614 mg, 1.32 mmol) was dissolved in trifluoroethanol (10 mL) with palladium on carbon (130 mg, 10% palladium content) at room temperature. After three times of hydrogen replacement, the reaction mixture was stirred at 25 °C for 16 hours. After the reaction was completed, the reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The obtained residue was the title compound (570 mg).

[0981] MS-ESI: m / z = 471.2 [M+H] +

[0982] Step 3 & 4: Synthesis of (trans)-3-cyano-4-(4-(4-(2-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)ethyl)piperidin-1-yl)phenyl)pyrrolidine-1-carboxylic acid tert-butyl ester (Intermediate DQ)

[0983] Referring to the procedure for the synthesis of Intermediate DJ, Steps 2 to 3, replace DJ-2 therein with 4-(2-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H- benzo[d]imidazol-4-yl)ethyl)piperidine-1-carboxylic acid tert-butyl ester (DQ-3), to give the title compound.

[0984] MS-ESI: m / z = 641.3 [M+H] +

[0985] Synthesis of Intermediate DR: 5-(((((S)-1-(tert-butoxy)-1-oxopropan-2-yl)amino)(phenoxy)phosphoryl)fluoromethyl)benzo[b]thiophene-2-carboxylic acid

[0986] Referring to the procedure for the synthesis of Intermediate Q, Steps 8 to 9, replace L-alanine propyl ester therein with L-alanine tert-butyl ester, to give Intermediate DR.

[0987] MS-ESI: m / z = 438.1 [M- t Bu+2H] +

[0988] Synthesis of Intermediate DS: 5-(((((S)-1-cyclopropoxy-1-oxopropan-2-yl)amino)(phenoxy)phosphoryl)fluoromethyl)benzo[b]thiophene-2-carboxylic acid

[0989] Referring to the procedure for the synthesis of Intermediate Q, Steps 8 to 9, replace L-alanine propyl ester therein with L-alanine cyclopropyl ester, to give Intermediate DS.

[0990] MS-ESI: m / z = 478.1 [M+H] +

[0991] Synthesis of Intermediate DT: 5-(((((S)-1-(2-ethylbutoxy)-1-oxopropan-2-yl)amino)(4-fluorophenoxy)phosphoryl)fluoromethyl)benzo[b]thiophene-2-carboxylic acid

[0992] Referring to steps 8 to 9 of the synthesis method of intermediate Q, the phenol was replaced by 4-fluorophenol, and the L-alanine propyl ester was replaced by L-alanine 2-ethylbutyl ester, and the intermediate DT was prepared in the same manner.

[0993] MS-ESI: m / z = 540.1 [M+H] +

[0994] Intermediate DU: Synthesis of 5-(fluoro((((S)-1-oxo-1-(propylthio)propan-2-yl)amino)(phenoxy)phosphoryl)methyl)benzo[b]thiophene-2-carboxylic acid

[0995] Referring to steps 8 to 9 of the synthesis method of intermediate Q, the intermediate DU was prepared by replacing L-alanine propyl ester with S-propyl (S)-2-aminothiopropionic acid propyl ester.

[0996] MS-ESI: m / z = 496.1 [M+H] +

[0997] Intermediate DV: Synthesis of Perfluorophenyl 5-((Bis(2-(Butyrylthio)ethoxy)phosphoryl)fluoromethyl)benzo[b]thiophene-2-carboxylate

[0998] Referring to the synthetic method of intermediate J, intermediate I was replaced by intermediate BK, and 3-methylbutyryl chloride was replaced by n-butyryl chloride, and intermediate DV was prepared in the same manner.

[0999] 1 H NMR (400MHz, CDCl3) δ8.36(s,1H),8.09(s,1H),8.02-7.97(m,1H),7.66(d,J=8.4Hz,1H),5.88(dd,J=7.6,44.4 Hz,1H),4.20-4.07(m,4H),3.14-3.10(m,4H),2.53(t,J=7.6Hz,4H),1.71-1.633(m,4H),0.94(t,J=7.2Hz,6H).

[1000] Intermediate DW: Synthesis of (((fluoro(2-((perfluorophenoxy)carbonyl)benzo[b]thiophen-5-yl)methyl)phosphoryl)bis(oxy))bis(methylene)bis(2,2-dimethylpropionate)

[1001] Referring to the synthesis method of step 3 to step 4 of intermediate J, intermediate I was replaced by intermediate BK, and intermediate J-3 was replaced by iodomethyl pivalate, and intermediate DW was prepared in the same manner.

[1002] MS-ESI: m / z = 707.1 [M+Na] +

[1003] Synthesis of intermediate DX: 2-(1-(1-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2- oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)azetidin-3-yl)piperidin-4-yl)acetic acid

[1004] Step 1: Synthesis of tert-butyl 2-(1-(1-benzhydrylazetidin-3-yl)piperidin-4-yl)acetate (DX-2)

[1005] tert-Butyl 2-(piperidin-4-yl)acetate (DX-1, 5.00 g, 25.09 mmol), 1-benzhydrylazetidin- 3-ylmethanesulfonate (6.37 g, 20.07 mmol) and triethylamine (5.08 g, 50.18 mmol) were dissolved in acetonitrile (50 mL) at room temperature, warmed to 80 °C and stirred for 16 h. After completion of the reaction, the temperature was lowered to room temperature and concentrated under reduced pressure. The residue was separated by column chromatography on silica gel (petroleum ether / ethyl acetate = 5 / 1) to give the title compound (4.90 g).

[1006] MS-ESI: m / z = 421.3 [M+H] +

[1007] Step 2: Synthesis of tert-butyl 2-(1-(azetidin-3-yl)piperidin-4-yl)acetate (DX-3)

[1008] tert-Butyl 2-(1-(1-benzhydrylazetidin-3-yl)piperidin-4-yl)acetate (DX-2, 5.10 g, 12.13 mmol) and palladium hydroxide on carbon (500 mg, 10% palladium hydroxide) were dissolved in acetic acid (50 mL) at room temperature, purged with hydrogen three times and stirred for 16 h under a hydrogen atmosphere at room temperature. After completion of the reaction, the mixture was filtered and concentrated under reduced pressure to give the title compound (3.08 g), which was used directly in the next reaction.

[1009] MS-ESI: m / z = 255.2 [M+H] +

[1010] Step 3 & 4: Synthesis of 2-(1-(1-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3- dihydro-1H-benzo[d]imidazol-4-yl)azetidin-3-yl)piperidin-4-yl)acetic acid (intermediate DX)

[1011] Reference to the synthetic method of intermediate S, replace 4-piperidine-4-carboxylic acid tert-butyl ester in it with 2-(1-(azetidin-3-yl)piperidin-4-yl)acetic acid tert-butyl ester (DX-3), prepared intermediate DX by the same method.

[1012] MS-ESI: m / z = 456.2 [M+H] +

[1013] 1 H NMR (400 MHz, DMSO-d6) δ 12.08 (s, 1H), 11.09 (s, 1H), 6.95 (t, J = 8.0 Hz, 1H), 6.74 (d, J = 8.0 Hz, 1H), 6.66 (d, J = 8.0 Hz, 1H), 5.32 (dd, J = 5.2 Hz, 12.4 Hz, 1H), 3.88 (s, 2H), 3.59-3.56 (m, 5H), 3.15-3.12 (m, 1H), 2.94-2.84 (m, 1H), 2.76-2.59 (m, 4H), 2.10 (d, J = 5.2 Hz, 2H), 1.99-1.97 (m, 1H), 1.83-1.75 (m, 2H), 1.65 (d, J = 9.6 Hz, 3H), 1.16 (dd, J = 12.4 Hz, 22.8 Hz, 2H).

[1014] Synthesis of intermediate DY: 2-(1-(1-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H- benzo[d]imidazol-5-yl)azetidin-3-yl)piperidin-4-yl)acetic acid

[1015] Reference to the synthetic method of intermediate DX, replace AC-1 in it with 3-(5-bromo-3-methyl-2-oxo-2,3-dihydro-1H- benzo[d]imidazol-1-yl)piperidine-2,6-dione (L-1), prepared intermediate DY by the same method.

[1016] MS-ESI: m / z = 456.2 [M+H] +

[1017] 1H NMR (400 MHz, DMSO-d6) δ 12.04 (s, 1H), 11.57 (s, 1H), 6.91 (d, J = 8.8 Hz, 1H), 6.32 (s, 1H), 6.12 (dd, J = 1.2 Hz, 8.4 Hz, 1H), 5.27 (dd, J = 5.6 Hz, 12.8 Hz, 1H), 3.94 (t, J = 6.0 Hz, 2H), 3.54 (s, 2H), 3.28 (s, 3H), 2.92 - 2.84 (m, 3H), 2.72 - 2.58 (m, 3H), 2.14 (d, J = 6.4 Hz, 2H), 1.99 - 1.95 (m, 3H), 1.67 - 1.65 (m, 3H), 1.21 - 1.15 (m, 2H).

[1018] Synthesis of intermediate DZ: 3-(4-(4-(2-chloroacetyl)piperidin-l-yl)-3-methyl-2- oxo-2,3-dihydro-lH-benzo[d]imidazol-l-yl)piperidine-2,6-dione

[1019] Step 1: Synthesis of l-(l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH- benzo[d]imidazol-4-yl)piperidine-4-carboxylic chloride (DZ-1)

[1020] Intermediate S (100 mg, 258.80 μmol) was dissolved in acetonitrile (5 mL) and dichloromethane (5 mL), to which was added N,N-dimethylformamide (1.89 mg, 25.88 μmol) and oxalyl chloride (164.34 mg, 1.29 mmol). The reaction was stirred at room temperature for 2 hours. Concentration gave the title compound (110 mg).

[1021] Step 2: Synthesis of 3-(4-(4-(2-chloroacetyl)piperidin-l-yl)-3-methyl-2-oxo-2,3- dihydro-lH-benzo[d]imidazol-l-yl)piperidine-2,6-dione (Intermediate DZ)

[1022] Intermediate DZ-1 (100 mg, 247.01 pmol) was dissolved in tetrahydrofuran (2.5 mL) and acetonitrile (2.5 mL), to which was added trimethylsilyldiazomethane (2 M, 1.24 mL) at 0 °C and stirred at 0 °C for 2 hours. The reaction solution was concentrated to dryness, dissolved in tetrahydrofuran (2.5 mL) and acetonitrile (2.5 mL), and hydrogen chloride dioxane solution (4 M, 1.24 mL) was added, and stirred at 0 °C for 12 hours. The reaction solution was concentrated to dryness, diluted with dichloromethane, washed with saturated sodium bicarbonate solution and brine, dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product, which was purified by flash silica gel chromatography (silica, dichloromethane / methanol = 20 / 1) to give the title compound (78 mg).

[1023] MS m / z (ESI): = 418.90 [M+H] +

[1024] Synthesis of intermediate EA: 1-((1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3- dihydro-1H-benzo[d]imidazol-5-yl)methyl)piperidine-4-carboxylic acid

[1025] Intermediate EA was prepared according to the procedure described for the synthesis of intermediate BX, by replacing BX-1 with 1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3- dihydro-1H-benzo[d]imidazole-5-carbaldehyde (intermediate CM-1).

[1026] MS-ESI: m / z = 401.1 [M+H] +

[1027] 1 H NMR (400 MHz, DMSO-d6) δ 11.10 (s, 1H), 7.11 (s, 1H), 7.05 (d, J = 8.4 Hz, 1H), 6.97 (d, J = 8.4 Hz, 1H), 5.36 (dd, J = 5.2, 12.4 Hz, 1H), 3.50 (s, 2H), 3.34 (s, 3H), 2.95 - 2.72 (m, 5H), 2.25 - 2.18 (m, 1H), 2.05 - 2.00 (m, 3H), 1.78 (d, J = 10.8 Hz, 2H), 1.60 - 1.51 (m, 2H).

[1028] Synthesis of intermediate EB: 2-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3- dihydro-1H-benzo[d]imidazol-4-yl)piperazin-1-yl)acetic acid

[1029] Referring to the synthesis method of intermediate BV, replace BV-1 in it with 3-(3-methyl-2-oxo-4-(piperazin-1-yl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione, and the intermediate EB is prepared in the same way.

[1030] MS-ESI: m / z = 402.1 [M+H] +

[1031] 1 H NMR (400 MHz, DMSO-d6) δ 11.10 (s, 1H), 7.05-6.94 (m, 3H), 5.37 (dd, J = 5.2 Hz, 12.8 Hz, 1H), 4.07 (s, 2H), 3.63 (s, 3H), 3.46-3.11 (m, 8H), 2.90-2.85 (m, 1H), 2.72-2.60 (m, 2H), 2.01-1.97 (m, 1H).

[1032] Synthesis of intermediate EC: 3-(1-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)piperidin-4-yl)propanoic acid

[1033] Step 1: Synthesis of tert-butyl (E)-3-(1-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)piperidin-4-yl)acrylate (EC-1)

[1034] tert-Butyl (E)-3-(1-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)piperidin-4-yl)acrylate (EC-1) was prepared according to the procedure described in step 1 of the synthesis of intermediate EC, using 1-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)piperidine-4-carbaldehyde (intermediate H, 300 mg, 0.81 mmol) and tert-butyl phosphonic acid triphenyl ester (457.3 mg, 1.21 mmol). LC-MS showed the reaction was completed, the reaction solution was concentrated under reduced pressure, then washed with a small amount of ethyl acetate twice (4 mL), washed with tetrahydrofuran twice (4 mL), and the solid was dried to give the title compound (340 mg).

[1035] MS m / z (ESI): = 469.0 [M+H] + .

[1036] 1H NMR (400 MHz, DMSO-d6) δ 11.09 (s, 1H), 6.98 (t, J = 7.9 Hz, 1H), 6.93 - 6.81 (m, 3H), 5.78 (d, J = 15.7 Hz, 1H), 5.40 - 5.30 (m, 1H), 3.62 (s, 3H), 3.13 (d, J = 11.2 Hz, 2H), 2.92 - 2.84 (m, 1H), 2.77 - 2.74 (m, 1H), 2.72 - 2.56 (m, 3H), 2.35 - 2.24 (m, 1H), 2.02 - 1.98 (m, 1H), 1.81 (d, J = 12.6 Hz, 2H), 1.64 - 1.52 (m, 2H), 1.44 (s, 9H).

[1037] Step 2: Synthesis of tert-butyl 3-(1-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3- dihydro-1H-benzo[d]imidazol-4-yl)piperidin-4-yl)propanoate (EC-2)

[1038] Into a reaction vial was placed tert-butyl (E)-3-(1-(1-(2,6-dioxopiperidin-3-yl)-3-methyl- 2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)piperidin-4-yl)acrylate (EC-1, 30 mg, 64.03 pmol), wet palladium on carbon (6 mg, 10% palladium content), anhydrous methanol (1 mL), N,N- dimethylformamide (3 mL), and the reaction was purged with hydrogen gas three times. The reaction was stirred at room temperature for 5 hours. LC-MS showed the reaction was complete, anhydrous sodium sulfate was added to dry the reaction, then filtered, the filter cake was washed twice with N,N-dimethylformamide (4 mL), twice with ethyl acetate (4 mL), and the filtrate was concentrated under reduced pressure to give the title compound (30 mg).

[1039] MS m / z (ESI): = 471.1 [M+H] + .

[1040] Step 3: Synthesis of 3-(1-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H- benzo[d]imidazol-4-yl)piperidin-4-yl)propanoic acid (Intermediate EC)

[1041] tert-Butyl 3-(1-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H- benzo[d]imidazol-4-yl)piperidin-4-yl)propanoate (EC-2, 30 mg, 63.75 pmol), dichloromethane (0.5 mL) was added to a reaction vial, followed by trifluoroacetic acid (1 mL), and the reaction was stirred at room temperature for 2 hours. The reaction was then concentrated under reduced pressure to give the title compound, which was used directly in the next step without further purification.

[1042] MS m / z (ESI): = 415.0 [M+H] + .

[1043] Synthesis of Intermediate ED: 5-((bis(2-(acetylthio)ethoxy)phosphoryl)difluoromethyl)benzo[b]thiophene-2-carboxylic acid perfluorophenyl ester

[1044] Intermediate ED was prepared according to the procedure for the synthesis of Intermediate J, replacing 3-methylbutanoyl chloride with acetyl chloride.

[1045] MS-ESI: m / z = 701.0 [M+Na] +

[1046] 1 H NMR (400 MHz, CDC13) δ 8.40 (s, 1H), 8.24 (s, 1H), 8.04 (d, J = 8.4, 1H), 7.77 (d, J = 8.8, 1H), 4.31 - 4.16 (m, 4H), 3.22 - 3.10 (m, 4H), 2.35 (s, 6H).

[1047] Synthesis of Intermediate EE: 5-((bis(2-(propionylthio)ethoxy)phosphoryl)difluoromethyl)benzo[b]thiophene-2-carboxylic acid perfluorophenyl ester

[1048] Intermediate EE was prepared according to the procedure for the synthesis of Intermediate J, replacing 3-methylbutanoyl chloride with propionyl chloride.

[1049] MS-ESI: m / z = 729.0 [M+Na] +

[1050] 1H NMR (400 MHz, CDC13) δ = 8.80 (s, 1H), 8.40 (s, 1H), 8.38 (s, 1H), 7.77 (d, J = 8.8, 1H), 4.23-4.13 (m, 4H), 3.16-3.12 (m, 4H), 2.59 (q, J = 7.6, 4H), 1.04 (t, J = 7.2, 6H).

[1051] Synthesis of Intermediate EF: tert-butyl ((5S,8S,10aR)-8-((trans)-7-cyano-6-phenyl-4- azaspiro[2.4]heptane-4-carbonyl)-6-oxodecahydropyrrolo[l,2-a][l,5]diazepin-5- yl)carbamate

[1052] Referring to the synthesis of Intermediate A, replace trans-4-phenylpyrrolidine-3-carbonitrile with (trans)-6-phenyl-4-azaspiro[2.4]heptane-7-carbonitrile (CX-1) in the same manner to give Intermediate EF.

[1053] MS m / z (ESI): = 508.1 [M+H] + .

[1054] Synthesis of Intermediate EG: (E)-3-(l-(l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3- dihydro-lH-benzo[d]imidazol-4-yl)piperidin-4-yl)acrylic acid

[1055] tert-butyl (E)-3-(l-(l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH- benzo[d]imidazol-4-yl)piperidin-4-yl)acrylate (EC-1, 30 mg, 64.03 pmol), dichloromethane (0.5 mL) were added to a reaction vial, followed by trifluoroacetic acid (1 ml), the reaction was stirred at room temperature for 2 hours. Then the reaction was concentrated under reduced pressure to give the title compound (26 mg).

[1056] MS m / z (ESI): = 411.0 [M-H] - .

[1057] Synthesis of Intermediate EH: (trans)-4-(6-methoxypyridin-2-yl)pyrrolidine-3-carbonitrile hydrochloride

[1058] Referring to the synthesis of Intermediate M & N (skip step 3, no separation), replace 4- nitrobenzaldehyde with 6-methoxypyridinecarboxaldehyde in the same manner to give Intermediate EH.

[1059] MS m / z (ESI): = 204.1 [M+H] + .

[1060] Synthesis of Intermediate EI: tert-butyl ((5S,8S,10aR)-8-((trans)-3-cyano-4-(6- methoxypyridin-2-yl)pyrrolidine-1-carbonyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocin-5- yl)carbamate

[1061] Intermediate EI was prepared in analogy to the synthesis of Intermediate A by replacing trans-4-phenylpyrrolidine-3-carbonitrile in Intermediate A with Intermediate EH.

[1062] MS m / z (ESI): = 513.10 [M+H] + .

[1063] Synthesis of Intermediate EJ: tert-butyl ((5S,8S,10aR)-8-((trans)-3-cyano-4-(4- nitrophenyl)pyrrolidine-1-carbonyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)carbamate

[1064] Intermediate EJ was prepared in analogy to the synthesis of Intermediate A by replacing trans-4-phenylpyrrolidine-3-carbonitrile in Intermediate A with (trans)-4-(4- nitrophenyl)pyrrolidine-3-carbonitrile.

[1065] MS m / z (ESI): = 527.2 [M+H] + .

[1066] Synthesis of Intermediate EK: 4-(((1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3- dihydro-1H-benzo[d]imidazol-4-yl)amino)methyl)cyclohexane-1-carboxylic acid

[1067] Step 1: Synthesis of methyl 4-((1-(2,6-bis(benzyloxy)pyridin-3-yl)-3-methyl-2-oxo-2,3- dihydro-1H-benzo[d]imidazol-4-yl)amino)methyl)cyclohexane-1-carboxylate (EK-2)

[1068] Methyl 4-(aminomethyl)cyclohexane-1 -carboxylate hydrochloride (EK-1, 42.44 mg, 204.36 pmol), 1 -(2,6-bis(benzyloxy)pyridin-3-yl)-4-bromo-3-methyl-1,3-dihydro-2H- benzo[d]imidazol-2-one (DO-1, 100 mg, 193.65 pmol) were added to a reaction vial, anhydrous 1,4-dioxane solution (3 mL) was added, (SP-4-1 )-[1,3-bis[2,6-bis(1 - ethylpropyl)phenyl]-4,5-dichloro-1,3-dihydro-2H-imidazol-2-ylidene]dichloropalladium (16.68 mg, 19.37 pmol) and cesium carbonate (189.29 mg, 580.96 pmol) were added, the resulting reaction was stirred at 100 °C for 4 h. The reaction was added to water (5 mL), extracted with ethyl acetate (5 mL), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, the crude was purified by column chromatography (silica, dichloromethane / methanol = 95 / 5) to give the title compound (100 mg).

[1069] MS m / z (ESI): = 607.3 [M+H] + .

[1070] Step 2: Synthesis of 4-((1 -(2,6-bis(benzyloxy)pyridin-3-yl)-3-methyl-2-oxo-2,3- dihydro-1 H-benzo[d]imidazol-4-yl)amino)methyl)cyclohexane-1 -carboxylic acid (EK-3)

[1071] Methyl 4-((1 -(2,6-bis(benzyloxy)pyridin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1 H- benzo[d]imidazol-4-yl)amino)methyl)cyclohexane-1 -carboxylate (EK-2, 65 mg, 107.14 pmol) was added to a reaction vial, tetrahydrofuran solution (0.5 mL), water (0.5 mL) and anhydrous lithium hydroxide (3.85 mg, 160.7 pmol) were added, the resulting reaction was stirred at room temperature for 1 h. The reaction was adjusted to pH about 6 with dilute hydrochloric acid (1 N), extracted with ethyl acetate, the organic phase was dried, concentrated under reduced pressure to give the title compound, the crude was used directly in the next step without purification.

[1072] MS m / z (ESI): = 591.3 [M-H] + .

[1073] Step 3: Synthesis of 4-(((1 -(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1 H- benzo[d]imidazol-4-yl)amino)methyl)cyclohexane-1 -carboxylic acid (Intermediate EK)

[1074] Into a reaction flask was placed 4-((1-(2,6-bis(benzyloxy)pyridin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H- benzo[d]imidazol-4-yl)amino)methyl)cyclohexane-1-carboxylic acid (EK-3, 70 mg, 118.11 pmol), ethanol (5 mL) was added, followed by acetic acid (3.55 mg, 59.05 pmol), palladium on carbon (30 mg, 20% palladium content), palladium hydroxide on carbon (30 mg, 10% palladium hydroxide content), and the resulting reaction mixture was stirred at 60 °C for 12 h. The reaction mixture was concentrated under reduced pressure and purified by column chromatography (silica, dichloromethane / methanol = 95 / 5) to give the title compound (20 mg).

[1075] MS m / z (ESI): = 415.2 [M+H] + .

[1076] Synthesis of intermediate EL: 2-(1-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H- benzo[d]imidazole-4-carbonyl)piperidin-4-yl)acetic acid

[1077] Intermediate EL was prepared according to the procedure described for the synthesis of intermediate DO, replacing piperidine-4-carboxylic acid tert-butyl ester with 2-(piperidin-4-yl)acetic acid tert-butyl ester.

[1078] MS m / z (ESI): = 429.20 [M+H] + .

[1079] Synthesis of intermediate EM: 5-((bis(2-(acetylsulfanyl)ethoxy)phosphoryl)fluoromethyl)benzo[b]thiophene-2- carboxylic acid perfluorophenyl ester

[1080] Intermediate EM was prepared according to the procedure described for the synthesis of intermediate J, replacing intermediate I with intermediate BK and 3-methylbutanoyl chloride with acetyl chloride.

[1081] MS-ESI: m / z = 683.0 [M+Na] +

[1082] Synthesis of intermediate EN: 6-(((1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H- benzo[d]imidazol-4-yl)methyl)amino)benzo[d]isothiazole-3-carboxylic acid

[1083] Step 1: Synthesis of tert-butyl 6-bromobenzo[d]isothiazole-3-carboxylate (EN-2).

[1084] Disperse 6-bromobenzo[d]isothiazole-3-carboxylic acid (EN-1, 500 mg, 1.94 mmol) in tert-butanol (10 mL), add 4-dimethylaminopyridine (24 mg, 194 μmol) and di-tert-butyl dicarbonate (635 mg, 2.91 mmol), and allow to react at room temperature overnight. TLC analysis indicated completion of the reaction. The reaction solution was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (gradient elution with ethyl acetate / petroleum ether = 0-20%) to obtain the title compound (320 mg).

[1085] Step 2: Synthesis of tert-butyl 6-((tert-butoxycarbonyl)amino)benzo[d]isothiazole-3-carboxylate (EN-3).

[1086] EN-2 (140 mg, 446 μmol) and tert-butyl carbamate (78 mg, 668 μmol) were dissolved in 1,4-dioxane (1 mL). Tris(dibenzylideneacetone)dipalladium (41 mg, 45 μmol), 4,5-bis(diphenylphosphino-9,9-dimethylxanthene) (52 mg, 89 μmol), and cesium carbonate (290 mg, 891 μmol) were added. The mixture was heated to 100°C under argon and allowed to react overnight. LC-MS analysis indicated the reaction was complete. The reaction solution was cooled to room temperature, diluted with ethyl acetate (5 mL), and filtered. The filtrate was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (gradient elution: ethyl acetate / petroleum ether = 0-30%) to obtain the title compound (110 mg).

[1087] MS m / z(ESI):=295.0[M+2H-tBu] +

[1088] Step 3: Synthesis of 6-aminobenzo[d]isothiazole-3-carboxylic acid (EN-4).

[1089] Dissolve tert-butyl 6-((tert-Butoxycarbonyl)amino)benzo[d]isothiazole-3-carboxylate (EN-3, 200 mg, 570.7 μmol) in dichloromethane (5 mL). Add trifluoroacetic acid (1 mL) and react at room temperature for 6 hours. LC-MS analysis indicated the reaction was complete. The reaction solution was concentrated to dryness under reduced pressure to obtain the title compound (112 mg), which was directly carried out to the next step.

[1090] MS m / z(ESI):=195.0[M+H] +

[1091] Step 4: Synthesis of 6-(((l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3- dihydro-lH-benzo[d]imidazol-4-yl)methyl)amino)benzo[d]isothiazole-3-carboxylic acid (Intermediate EN)

[1092] Intermediate EN: 6-(((l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3- dihydro-lH-benzo[d]imidazol-4-yl)methyl)amino)benzo[d]isothiazole-3-carboxylic acid was synthesized according to the procedure described in Step 4, substituting 6-aminobenzo[d]isothiazole-3-carboxylic acid (EN-4, 101 mg, 522 μmol) and l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH- benzo[d]imidazole-4-carbaldehyde (BX-1, 100 mg, 348 μmol) for 6-aminobenzo[d]isothiazole-3- carboxylic acid (EN-4, 101 mg, 522 μmol) and l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3- dihydro-lH-benzo[d]imidazole-4-carbaldehyde (BX-1, 100 mg, 348 μmol).

[1093] MS m / z (ESI): = 465.8 [M+H] +

[1094] Intermediate EN: 6-(((l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3- dihydro-lH-benzo[d]imidazol-4-yl)methyl)amino)benzo[d]isothiazole-3-carboxylic acid was synthesized according to the procedure described in Step 4, substituting 6-aminobenzo[d]isothiazole-3-carboxylic acid (EN-4, 101 mg, 522 μmol) and l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH- benzo[d]imidazole-4-carbaldehyde (BX-1, 100 mg, 348 μmol) for 6-aminobenzo[d]isothiazole-3- carboxylic acid (EN-4, 101 mg, 522 μmol) and l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3- dihydro-lH-benzo[d]imidazole-4-carbaldehyde (BX-1, 100 mg, 348 μmol).

[1095] Intermediate EN: 6-(((l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3- dihydro-lH-benzo[d]imidazol-4-yl)methyl)amino)benzo[d]isothiazole-3-carboxylic acid was synthesized according to the procedure described in Step 4, substituting 6-aminobenzo[d]isothiazole-3-carboxylic acid (EN-4, 101 mg, 522 μmol) and l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH- benzo[d]imidazole-4-carbaldehyde (BX-1, 100 mg, 348 μmol) for 6-aminobenzo[d]isothiazole-3- carboxylic acid (EN-4, 101 mg, 522 μmol) and l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3- dihydro-lH-benzo[d]imidazole-4-carbaldehyde (BX-1, 100 mg, 348 μmol).

[1096] MS m / z (ESI): = 465.8 [M+H] +

[1097] Intermediate EN: 6-(((l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3- dihydro-lH-benzo[d]imidazol-4-yl)methyl)amino)benzo[d]isothiazole-3-carboxylic acid was synthesized according to the procedure described in Step 4, substituting 6-aminobenzo[d]isothiazole-3-carboxylic acid (EN-4, 101 mg, 522 μmol) and l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH- benzo[d]imidazole-4-carbaldehyde (BX-1, 100 mg, 348 μmol) for 6-aminobenzo[d]isothiazole-3- carboxylic acid (EN-4, 101 mg, 522 μmol) and l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3- dihydro-lH-benzo[d]imidazole-4-carbaldehyde (BX-1, 100 mg, 348 μmol).

[1098] Intermediate EN: 6-(((l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3- dihydro-lH-benzo[d]imidazol-4-yl)methyl)amino)benzo[d]isothiazole-3-carboxylic acid was synthesized according to the procedure described in Step 4, substituting 6-aminobenzo[d]isothiazole-3-carboxylic acid (EN-4, 101 mg, 522 μmol) and l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH- benzo[d]imidazole-4-carbaldehyde (BX-1, 100 mg, 348 μmol) for 6-aminobenzo[d]isothiazole-3- carboxylic acid (EN-4, 101 mg, 522 μmol) and l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3- dihydro-lH-benzo[d]imidazole-4-carbaldehyde (BX-1, 100 mg, 348 μmol).

[1099] MS m / z (ESI): = 465.8 [M+H] + .

[1100] Synthesis of intermediate EQ: 4-((1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3- dihydro-1H-benzo[d]imidazol-4-yl)oxy)cyclohexane-1-carboxylic acid

[1101] Step 1: Synthesis of tert-butyl 4-(tosyloxy)cyclohexane-1-carboxylate (EQ-2)

[1102] Tert-butyl 4-hydroxycyclohexane-1-carboxylate (EQ-1, 200 mg, 998.63 pmol) was dissolved in tetrahydrofuran (4 mL), N,N-diisopropylethylamine (258.13 mg, 2.00 mmol) and 4-dimethylaminopyridine (12.20 mg, 99.86 pmol) were added, p-toluenesulfonyl chloride (380.77 mg, 2.00 mmol) was slowly added under ice water bath, and the reaction was stirred at 60 °C for 12 h. The reaction was concentrated under reduced pressure to get the crude product, the residue was purified by flash silica gel chromatography (silica, petroleum ether / ethyl acetate = 3 / 1) to give the title compound (30 mg).

[1103] Step 2: Synthesis of tert-butyl 4-((1-(2,6-bis(benzyloxy)pyridin-3-yl)-3-methyl-2-oxo-2,3- dihydro-1H-benzo[d]imidazol-4-yl)oxy)cyclohexane-1-carboxylate (EQ-3)

[1104] Tert-butyl 4-(tosyloxy)cyclohexane-1-carboxylate (EQ-2, 29 mg, 82.69 pmol) and 1-(2,6- bis(benzyloxy)pyridin-3-yl)-4-hydroxy-3-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (25 mg, 55.13 pmol, CAS: 2655646-58-3) were dissolved in N,N-dimethylformamide (0.5 mL), cesium carbonate (36 mg, 110.26 pmol) was added, and the reaction was warmed to 100 °C for 12 h. The reaction was filtered, concentrated under reduced pressure to get the crude product, the residue was purified by flash silica gel chromatography (silica, petroleum ether / ethyl acetate = 3 / 1) to give the title compound (25 mg).

[1105] MS m / z (ESI): = 636.30 [M+H] +

[1106] Step 3: Synthesis of tert-butyl 4-((1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3- dihydro-1H-benzo[d]imidazol-4-yl)oxy)cyclohexane-1-carboxylate (EQ-4)

[1107] tert-Butyl 4-((l-(2,6-bis(benzyloxy)pyridin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH- benzo[d]imidazol-4-yl)oxy)cyclohexane-l -carboxylate (EQ-3, 45 mg, 70.78 pmol) was dissolved in trifluoroethanol (5 mL), palladium hydroxide (45 mg, 10% palladium hydroxide content) was added, and stirred at 60 °C under hydrogen atmosphere for 8 hours. The reaction was filtered, concentrated under reduced pressure to give a crude product, which was purified by preparative HPLC (column: YMC TAR-C18, 30 x 150 mm, 5 pm; mobile phase A: water (5 mmol FA), mobile phase B: acetonitrile; flow rate: 25 mL / min; gradient: 45% B ~ 75% B), and lyophilized to give the title compound (10 mg).

[1108] MS m / z (ESI): = 458.20 [M+H] + .

[1109] Step 4: Synthesis of 4-(l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH- benzo[d]imidazol-4-yl)oxy)cyclohexane-l-carboxylic acid (Intermediate EQ)

[1110] tert-Butyl 4-((l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH- benzo[d]imidazol-4-yl)oxy)cyclohexane-l -carboxylate (EQ-4, 5 mg, 10.93 pmol) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (0.3 mL) was added. Stirred at room temperature for 2 hours. The reaction was concentrated under reduced pressure to give the title compound (4 mg).

[1111] MS m / z (ESI): = 402.10 [M+H] + .

[1112] Synthesis of Intermediate ER: l-(3-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)-4- methylbenzoyl)piperidine-4-carboxylic acid

[1113] Intermediate ER was prepared according to the procedure described for the synthesis of Intermediate ES, by replacing 4-chloro-3-(2,4-dioxotetrahydropyrimidin-l(2H)- yl)benzoic acid (ES-1) with 3-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)-4- methylbenzoic acid (CAS: 2377643-37-1).

[1114] MS m / z (ESI): = 360.1 [M+H] + .

[1115] Synthesis of intermediate ES: 1-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)- yl)benzoyl)piperidine-4-carboxylic acid

[1116] Step 1: Synthesis of tert-butyl 1-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)- yl)benzoyl)piperidine-4-carboxylate (ES-2)

[1117] tert-Butyl piperidine-4-carboxylate (ES-2, 120 mg, 275 pmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (1 mL) was added and the reaction was stirred at room temperature for 4 hours. LC-MS indicated the reaction was complete, the reaction was concentrated to dryness under reduced pressure to give the title compound (100 mg).

[1118] MS m / z (ESI): = 379.9 [M+2H- t Bu] +

[1119] Step 2: Synthesis of 1-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzoyl)piperidine- 4-carboxylic acid (intermediate ES)

[1120] tert-Butyl piperidine-4-carboxylate (ES-2, 120 mg, 275 pmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (1 mL) was added and the reaction was stirred at room temperature for 4 hours. LC-MS indicated the reaction was complete, the reaction was concentrated to dryness under reduced pressure to give the title compound (100 mg).

[1121] MS m / z (ESI): = 380.0 [M+H] +

[1122] Synthesis of intermediate ET: 1-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H- benzo[d]imidazole-5-carbonyl)piperidine-4-carboxylic acid

[1123] Referring to the synthesis method of intermediate DO, replace 1-(2,6-bis(benzyloxy)pyridin-3-yl)-4-bromo-3-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (DO-1) therein with 1-(2,6-bis(benzyloxy)pyridin-3-yl)-5-bromo-3-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one, and the intermediate ET is prepared by the same method.

[1124] MS m / z (ESI): = 415.1 [M+H] +

[1125] Synthesis of intermediate EU: 4-((1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H- benzo[d]imidazol-4-yl)methylidenyl)cyclohexane-1-carboxylic acid

[1126] Step 1: Synthesis of tert-butyl 4-((1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H- benzo[d]imidazol-4-yl)methylidenyl)cyclohexane-1-carboxylate (EU-2)

[1127] tert-Butyl 4-methylene cyclohexane-1-carboxylate (EU-1, 464.37 mg, 2.37 mmol) and 3-(4-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (AC-1, 200 mg, 591.44 µmol) were dissolved in N,N-dimethylacetamide (5 mL), [1,1'-bis(di-tert-butylphosphino)ferrocene] palladium dichloride (38.19 mg, 59.14 µmol) and triethylamine (179.54 mg, 1.77 mmol, 247.48 µL) were added, and the mixture was degassed with nitrogen and heated to 100 °C overnight. LCMS monitoring showed that the reaction was complete. The reaction was quenched by adding 20 mL of water, and then extracted with ethyl acetate (10 mL x 3). The organic phase was combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (dichloromethane / methanol = 50 / 1) to give the title compound (255 mg).

[1128] MS m / z (ESI): = 452.0 [M-H] -

[1129] Step 2: Synthesis of 4-((1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H- benzo[d]imidazol-4-yl)methylidenyl)cyclohexane-1-carboxylic acid (intermediate EU)

[1130] ((1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4- yl)methylene)cyclohexane-1-carboxylic acid tert-butyl ester (EU-2, 40 mg, 88.20 pmol) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (100.57 mg, 881.97 pmol) was added, and the reaction mixture was stirred at room temperature overnight. LCMS monitoring showed the reaction was complete. The reaction was concentrated to dryness under reduced pressure to give the title compound as a crude product, which was directly used for the next step.

[1131] MS m / z (ESI): = 398.0 [M+H] +

[1132] Synthesis of intermediate EV: 2,2,2-trichloroethyl (5S,8S,10aR)-8-((3R,4S)-3-(4- aminophenyl)-4-cyanopyrrolidine-1-carbonyl)-5-((tert-butoxycarbonyl)amino)-6- oxooctahydropyrrolo[1,2-a][1,5]diazocin-3(4H)-carboxylate

[1133] Step 1: Synthesis of 8-methyl-3-(2,2,2-trichloroethyl)(5S,8S,10aR)-5-((tert- butoxycarbonyl)amino)-6-oxooctahydropyrrolo[1,2-a][1,5]diazocin-3,8(4H)-dicarboxylate (EV-1)

[1134] Methyl (5S,8S,10aR)-5-((tert-butoxycarbonyl)amino)-6-oxo-decahydropyrrolo[1,2- a][1,5]diazocin-8-carboxylate (A-1, 300 mg, 0.879 mmol), 2,2,2-trichloroethyl chloroformate (373 mg, 1.76 mmol) and pyridine (209 mg, 2.64 mmol) were dissolved in dichloromethane (10 mL) at room temperature, and the reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, water (5 mL) was added for quenching, and dichloromethane (10 mL x 2) was used for extraction. The combined organic phase was washed with saturated brine (10 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give the title compound (305 mg).

[1135] MS-ESI: m / z = 516.1 [M+H] +

[1136] Step 2: Synthesis of (5S,8S,10aR)-5-((tert-butoxycarbonyl)amino)-6-oxo-3-((2,2,2- trichloroethoxy)carbonyl)decahydropyrrolo[l,2-a][l,5]diazocin-8-carboxylic acid (EV-2)

[1137] To a solution of (5S,8S,10aR)-5-((tert-butoxycarbonyl)amino)-6-oxo-3-((2,2,2- trichloroethoxy)carbonyl)decahydropyrrolo[l,2-a][l,5]diazocin-8-carboxylic acid (EV-2, 284 mg, 0.563 mmol) in tetrahydrofuran (2 mL) was added 3-(aminomethyl)pyrrolidine- 1-carboxylic acid tert-butyl ester (EV-4, 150 mg, 0.563 mmol) and stirred at room temperature for 16 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, and the residue was diluted with water (5 mL) and adjusted to pH 5 with hydrochloric acid (2 N). The mixture was extracted with ethyl acetate (10 mL x 2), and the combined organic phase was washed with saturated brine (10 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (300 mg).

[1138] MS-ESI: m / z = 502.1 [M+H] +

[1139] Step 3: Synthesis of 2,2,2-trichloroethyl (5S,8S,10aR)-5-((tert-butoxycarbonyl)amino)- 8-((3S,4R)-3-cyano-4-(4-nitrophenyl)pyrrolidine-l-carbonyl)-6-oxodecahydropyrrolo[l,2- a][l,5]diazocin-3(4H)-carboxylate (EV-3)

[1140] To a solution of (5S,8S,10aR)-5-((tert-butoxycarbonyl)amino)-6-oxo-3-((2,2,2- trichloroethoxy)carbonyl)decahydropyrrolo[l,2-a][l,5]diazocin-8-carboxylic acid (EV-2, 150 mg, 0.299 mmol), (3S,4R)-4-(4-nitrophenyl)pyrrolidine-3-carbonitrile hydrochloride (76 mg, 0.299 mmol), O-(7-azabenzotriazol-l-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (171 mg, 0.449 mmol) and N,N-diisopropylethylamine (116 mg, 0.897 mmol) in N,N-dimethylformamide (5 mL) was stirred at room temperature for 16 hours. After the reaction was completed, the reaction solution was diluted with water (10 mL) and extracted with dichloromethane (10 mL x 2). The combined organic phase was washed with saturated brine (10 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to obtain the title compound (190 mg).

[1141] MS-ESI: m / z = 701.1 [M+H] +

[1142] Step 4: Synthesis of 2,2,2-trichloroethyl (5S,8S,10aR)-8-((3R,4S)-3-(4- aminophenyl)-4-cyanopyrrolidine-l-carbonyl)-5-((tert-butoxycarbonyl)amino)-6- oxodecahydropyrrolo[l,2-a][l,5]diazocin-3(4H)-carboxylate (Intermediate EV)

[1143] To a solution of 2,2,2-trichloroethyl (5S,8S,10aR)-5-((tert-butoxycarbonyl)amino)-8- ((3S,4R)-3-cyano-4-(4-nitrophenyl)pyrrolidine-l-carbonyl)-6-oxodecahydropyrrolo[l,2- a][l,5]diazocin-3(4H)-carboxylate (EV-3, 190 mg, 0.271 mmol), iron powder (76 mg, 1.36 mmol) and ammonium chloride (73 mg, 1.36 mmol) in ethanol / tetrahydrofuran / water (4 mL / 2 mL / 1 mL) was stirred at 70 °C for 4 hours. After the reaction was completed, it was filtered through celite, and the filtrate was extracted with dichloromethane (10 mL x 2). The combined organic phase was washed with saturated brine (10 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to obtain the title compound (156 mg).

[1144] MS-ESI: m / z = 671.1 [M+H]+

[1145] Synthesis of intermediate EW: tert-butyl (3S,4R)-3-cyano-4-(4- (methylamino)phenyl)pyrrolidine-1-carboxylate

[1146] Step 1: Synthesis of tert-butyl (3S,4R)-3-cyano-4-(4-nitrophenyl)pyrrolidine-1- carboxylate (EW-1)

[1147] To a solution of (3S,4R)-4-(4-nitrophenyl)pyrrolidine-3-carbonitrile monohydrochloride (Intermediate M, 233 mg, 0.921 mmol), di-tert-butyl dicarbonate (301 mg, 1.38 mmol), 4-dimethylaminopyridine (22 mg, 0.184 mmol) and N,N-diisopropylethylamine (178 mg, 1.38 mmol) in dichloromethane (6 mL) was stirred at room temperature for 12 hours. After completion of the reaction, the reaction mixture was diluted with water (5 mL) and extracted with dichloromethane (10 mL x 2). The combined organic phase was washed with saturated brine (10 mL x 2), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was separated and purified by column chromatography on silica gel (dichloromethane / methanol = 50 / 1) to give the title compound (228 mg).

[1148] MS-ESI: m / z = 318.1 [M+H] +

[1149] Step 2: Synthesis of tert-butyl (3R,4S)-3-(4-aminophenyl)-4-cyanopyrrolidine-1- carboxylate (EW-2)

[1150] To a solution of tert-butyl (3S,4R)-3-cyano-4-(4-nitrophenyl)pyrrolidine-1-carboxylate (EW-1, 228 mg, 0.719 mmol), iron powder (201 mg, 3.60 mmol) and ammonium chloride (193 mg, 3.60 mmol) in ethanol / tetrahydrofuran / water (6 mL / 3 mL / 1 mL) was stirred at 80 °C for 4 hours. After completion of the reaction, the reaction mixture was diluted with water (5 mL) and extracted with dichloromethane (10 mL x 2). The combined organic phase was washed with saturated brine (10 mL x 2), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was separated and purified by column chromatography on silica gel (dichloromethane / methanol = 20 / 1) to give the title compound (165 mg).

[1151] MS-ESI: m / z = 310.2 [M+Na] +

[1152] Step 3: Synthesis of tert-butyl (3S,4R)-3-cyano-4-(4-(methylamino)phenyl)pyrrolidine-1- carboxylate (Intermediate EW)

[1153] To a solution of tert-butyl (3R,4S)-3-(4-aminophenyl)-4-cyanopyrrolidine-1-carboxylate (EW-2, 165 mg, 0.575 mmol), paraformaldehyde (17 mg, 0.575 mmol) and sodium cyanoborohydride (109 mg, 1.73 mmol) in dichloromethane / methanol (5 mL / 0.5 mL) was stirred at room temperature for 12 hours. After completion of the reaction, the reaction mixture was diluted with water (5 mL) and extracted with dichloromethane (10 mL x 2). The combined organic phase was washed with saturated brine (10 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 (dichloromethane / methanol = 20 / 1) to give the title compound (35 mg).

[1154] MS-ESI: m / z = 302.1 [M+H] +

[1155] Step 1: Synthesis of tert-butyl (3R,4S)-3-(4-aminophenyl)-4-cyanopyrrolidine-1-carboxylate (EW-2)

[1156] Step 1: Synthesis of tert-butyl (3R,4S)-3-(4-aminophenyl)-4-cyanopyrrolidine-1-carboxylate (EW-2)

[1157] To a solution of tert-butyl (3R,4S)-3-(4-aminophenyl)-4-cyanopyrrolidine-1-carboxylate (EW-2, 165 mg, 0.575 mmol), paraformaldehyde (17 mg, 0.575 mmol) and sodium cyanoborohydride (109 mg, 1.73 mmol) in dichloromethane / methanol (5 mL / 0.5 mL) was stirred at room temperature for 12 hours. After completion of the reaction, the reaction mixture was diluted with water (5 mL) and extracted with dichloromethane (10 mL x 2). The combined organic phase was washed with saturated brine (10 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 (dichloromethane / methanol = 20 / 1) to give the title compound (35 mg).

[1158] MS-ESI: m / z = 302.1 [M+H] +

[1159] Step 2 to Step 4: Synthesis of tert-butyl ((5S,8S,10aR)-8-((3R,4S)-3-(4- aminophenyl)-4-cyanopyrrolidine-1-carbonyl)-3-methyl-6-oxodecahydropyrrolo[1,2- a][1,5]diazocin-5-yl)carbamate (Intermediate EX)

[1160] Referring to the synthesis method of Intermediate EV, replace EV-1 with EX-1 in it, and Intermediate EX is prepared by the same method.

[1161] MS-ESI: m / z = 511.4 [M+H] +

[1162] Synthesis of (3S,4S)-4-(5-nitropyridin-2-yl)pyrrolidine-3-carbonitrile and (3R,4R)-4-(5-nitropyridin-2-yl)pyrrolidine-3-carbonitrile (Intermediate EY & EZ)

[1163] (Trans)-4-(5-nitropyridin-2-yl)pyrrolidine-3-carbonitrile (Intermediate BH-5) was resolved by chiral SFC to give single configuration (3S,4S)-4-(5-nitropyridin-2-yl)pyrrolidine-3-carbonitrile and (3R,4R)-4-(5-nitropyridin-2-yl)pyrrolidine-3-carbonitrile (Intermediate EY and Intermediate EZ). Chiral resolution method: Column: Daicel CHIRALPAK IF_3, 250*30mm, 10μm; Mobile phase: Mobile phase A: Supercritical CO2; Mobile phase B: MeOH [0.2% NH3 (7M in MeOH)]; Elution gradient: A / B = 80 / 60; Flow rate: 80 g / min; Detector: PDA; Column temperature: 35℃. Intermediate EY retention time: 2.481 min, Intermediate EZ retention time: 3.54 min.

[1164] Synthesis of tert-butyl ((3S,6S,10aS)-3-((3S,4S)-3-(5-aminopyridin-2-yl)-4- cyanopyrrolidine-1-carbonyl)-5-oxodecahydropyrrolo[1,2-a]azocin-6-yl)carbamate and tert-butyl ((3S,6S,10aS)-3-((3R,4R)-3-(5-aminopyridin-2-yl)-4-cyanopyrrolidine-1- carbonyl)-5-oxodecahydropyrrolo[1,2-a]azocin-6-yl)carbamate (Intermediate FA & FB)

[1165] Referring to the synthesis method of Intermediate BH Step 5 to Step 6, replace BH-5 with Intermediate EY (or Intermediate EZ) in it, and Interme...

Claims

1. A compound of formula (I) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein: L is a bivalent moiety connecting STAT to LBM; LBM is an E3 ubiquitin ligase binding moiety; STAT is a group as described below: q is 0 or 1 ; t is 0, 1 or 2; p is 1 or 2; n is any natural number selected from 1-8; X is selected from CH2, O, S, SO2, S(O), -C(=O)-NR 10 - and NR 8 ; Ring A is selected from C3-C 12 saturated carbocyclic and 4-8 membered heterocyclic rings; R 1 selected from -CR 1a R 2a P(O)OR 1b OR 2b , -CR 1a R 2a P(O)OR 1b NHR 2b , -CR 1a R 2a P(O)[OR 1b ][NH(AA)C(O)OR T ], -P(O)OR 1b OR 2b , -[P(O)[NHR Ty ][NH(AA)C(O)OR T ] or -P(O)[OR 1b ][NH(AA)C(O)OR T ]; 8-10 membered heteroaryl optionally substituted with -CR 1a R 2a P(O)OR 1b OR 2b , -CR 1a R 2a P(O)OR 1b NHR 2b , -CR 1a R 2a P(O)[OR 1b ][NH(AA)C(O)OR T ], -P(O)OR 1b OR 2b , -[P(O)[NHR Ty ][NH(AA)C(O)OR T ] or -P(O)[OR 1b ][NH(AA)C(O)OR T ]; 8-10 membered heterocyclyl optionally substituted with -CR 1a R 2a P(O)OR 1b OR 2b , -CR 1a R 2a P(O)OR 1b NHR 2b , -CR 1a R 2a P(O)[OR 1b ][NH(AA)C(O)OR T ]、-P(O)OR 1b OR 2b 、-[P(O)[NHR Ty ][NH(AA)C(O)OR T ] or -P(O)[OR 1b ][NH(AA)C(O)OR T ] substituted C6-C 10 Aryl, the C6-C 10 Aryl is optionally substituted by cyano, C1-C4 alkoxy or halogen; -C1-C4 alkylene C6-C 10 Aryl, the -C1-C4 alkylene C6-C 10 The aryl group of the aryl group is replaced by -CR 1a R 2a P(O)OR 1b OR 2b 、-CR 1a R 2a P(O)OR 1b NHR 2b 、-CR 1a R 2a P(O)[OR 1b ][NH(AA)C(O)OR T ]、-P(O)OR 1b OR 2b 、-[P(O)[NHR Ty ][NH(AA)C(O)OR T ] or -P(O)[OR 1b ][NH(AA)C(O)OR T ] substituted; -C2-C4 alkenyl C6-C 10 Aryl, the -C2-C4 alkenyl C6-C 10 The aryl group of the aryl group is replaced by -CR 1a R 2a P(O)OR 1b OR 2b 、-CR 1a R 2a P(O)OR 1b NHR 2b 、-CR 1a R 2a P(O)[OR 1b ][NH(AA)C(O)OR T ]、-P(O)OR 1b OR 2b 、-[P(O)[NHR Ty ][NH(AA)C(O)OR T ] or -P(O)[OR 1b ][NH(AA)C(O)OR T ] substituted; R 1a and R 2a are independently selected from hydrogen, halogen, cyano, C1-C4alkyl, C1-C4haloalkyl and C1-C4hydroxyalkyl, or R 1a and R 2a are taken together to form =0; R 1b and R 2b are independently selected from the group consisting of hydrogen, C1-C4alkyl, C1-C4haloalkyl, -(C1-C4alkylene)-OC(O)-(C1-C4alkyl), -(C1-C4alkylene)-C(O)O-(C1-C4alkyl), -(C1-C4alkylene)-O-(C1-C4alkyl), -(C1-C4alkylene)-OC(O)-[C1-C4haloalkyl], -(C1-C4alkylene)-OC(O)O-[5-7 membered heterocyclyl], -(C1-C4alkylene)-OC(O)-[5-7 membered heterocyclyl], -(C1-C4alkylene)-OC(O)-(C1-C4alkylene)-OH, -(C1-C4alkylene)-OC(O)-(C1-C4alkylene)-O-(C1-C4alkyl), -(C1-C4alkylene)-OC(O)O-(C1-C4alkyl), -(C1-C4alkylene)-OC(O)O-[C1-C4haloalkyl], -(C1-C4alkylene)-OC(O)O-(C1-C4alkylene)-OH, -(C1-C4alkylene)-OC(O)O-(C1-C4alkylene)-O-(C1-C4alkyl), -(C1-C4alkylene)-SC(O)-(C1-C6alkyl), -(C1-C4alkylene)-C(O)S-(C1-C4alkyl), -(C1-C4alkylene)-SC(O)-[C1-C4haloalkyl], -(C1-C4alkylene)-C(O)S-[C1-C4haloalkyl], -(C1-C4alkylene)-SC(O)-(C1-C4alkylene)-OH, -(C1-C4alkylene)-C(O)S-(C1-C4alkylene)-OH, -(C1-C4alkylene)-SC(O)-(C1-C4alkylene)-O-(C1-C4alkyl), -(C1-C4alkylene)-C(O)S-(C1-C4alkylene)-O-(C1-C4alkyl), -(C1-C4alkylene)-OC(O)NH(C1-C4alkyl)], -(C1-C4alkylene)-OC(O)N(C1-C4alkyl)2, C6-C 10 aryl and 5-6 membered heteroaryl, said C6-C 10 aryl and 5-6 membered heteroaryl are optionally substituted with halo, cyano or C1-C4alkyl, said 5-7 membered heterocyclyl is optionally substituted with C(O)OR h ; R 2 selected from hydrogen, halogen, COOH, hydroxyl, cyano, C1-C4alkyl, C1-C4alkoxy, C1-C4haloalkoxy, C1-C4haloalkyl, and C1-C4hydroxyalkyl; R 3 and R 4 are independently selected from hydrogen, halogen, hydroxyl, cyano, C1-C4alkyl, C1-C4haloalkyl, C1-C4hydroxyalkyl, -C1-C4alkylene phenyl, C1-C4alkoxy, C1-C4haloalkoxy, -C1-C4alkylene C1-C4alkoxy, NR a R b , C3-C6cycloalkyl, C6-C 10 aryl, 5-10 membered heteroaryl, and 4-10 membered heterocyclyl, said C3-C6cycloalkyl, C6-C 10 aryl, 5-10 membered heteroaryl, and 4-10 membered heterocyclyl are optionally substituted with R S ; or R 3 and the atom to which they are attached together form a C3-C6saturated carbocyclic ring, 4-8 membered heterocyclic ring, or 5-6 membered heteroaromatic ring, which 3-6 membered saturated carbocyclic ring, 4-8 membered heterocyclic ring, and 5-6 membered heteroaromatic ring is optionally substituted with halogen, cyano, amino, or C1-C4alkyl; 4 and the atom to which they are attached together form a C3-C6saturated carbocyclic ring, 4-8 membered heterocyclic ring, or 5-6 membered heteroaromatic ring, which 3-6 membered saturated carbocyclic ring, 4-8 membered heterocyclic ring, and 5-6 membered heteroaromatic ring is optionally substituted with halogen, cyano Or, R 2 and R 3 and the atoms connected thereto together form a C4-C6 saturated carbocyclic ring, a 4-8 membered heterocyclic ring, a C6-C 10 Aromatic ring or 5-6 membered heteroaromatic ring, the C4-C6 saturated carbocyclic ring, 4-8 membered heterocyclic ring, C6-C 10 The aromatic ring or 5-6 membered heteroaromatic ring is optionally substituted by halogen, cyano, amino or C1-C4 alkyl; R 5 selected from hydrogen, phenyl and C1-C4alkyl; R 6 and R 7 are independently selected from the group consisting of halogen, cyano, hydroxyl, phenyl, C2-C4 alkenyl, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, 4-9 membered heterocyclyl, 5-10 membered heteroaryl, C3-C6 cycloalkyl, =0, imino, -OR e , -C(O)R g , -C(O)OR e , -NR c C(O)R e , -C(O)NR c R d , -NR a R b , -S(O)R e R f , -S(O)2R f , -S(O)(=NH)(C1-C4 alkyl), -S(O)NR e R f , and -S(O)2NR e R f , said C2-C4 alkenyl, C1-C4 alkyl are optionally substituted with R M , said phenyl, 5-10 membered heteroaryl, C3-C6 cycloalkyl and 4-9 membered heterocyclyl are optionally substituted with R F ; R 8 selected from the group consisting of a bond, hydrogen, -SO2R 8a , C2-C4alkenyl, C1-C4alkyl, C2-C4alkynyl, C1-C4alkoxy, C3-C6cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 aryl, and 5-10 membered heteroaryl, said C2-C4alkenyl, C1-C4alkyl, C2-C4alkynyl, C1-C4alkoxy, C3-C6cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 aryl, and 5-10 membered heteroaryl are optionally substituted with R 8a ; or, when X is NR 8 R 3 and the C to which it is attached together with R 8 and the N to which it is attached form a 4-8 membered heterocyclic ring or a 5-6 membered heteroaromatic ring, which is optionally substituted with halogen, cyano, amino or C1-C4alkyl; R 8a selected from the group consisting of hydroxy, halogen, cyano, amino, C1-C4alkyl, -C(O)C1-C4alkyl, C3-C6cycloalkyl, 4-10 membered heterocyclyl, and =O, said hydroxy, amino, C1-C4alkyl, -C(O)C1-C4alkyl, C3-C6cycloalkyl, 4-10 membered heterocyclyl are optionally substituted with halogen, cyano, hydroxy, C1-C4alkyl, C1-C4alkoxy, and C1-C4haloalkyl; R 9 selected from hydrogen, -C(O)C1-C4 alkyl, C1-C4 alkyl, C1-C4 cyanoalkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl, 4-9 membered heterocyclyl, C6-C 10 Aryl and 5-10 membered heteroaryl; R 10 selected from hydrogen, C1-C4 alkyl, C1-C4 cyanoalkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl, 4-9 membered heterocyclic group, C6-C 10 Aryl and 5-10 membered heteroaryl; AA is a residue of an alpha or beta natural or unnatural amino acid; R T and R Ty are independently selected from the group consisting of C1-C 10 alkyl, C3-C 10 cycloalkyl, 3-10 membered heterocyclyl, benzyl, and phenyl, said C1-C 10 alkyl, C3-C 10 cycloalkyl, 3-10 membered heterocyclyl, benzyl, and phenyl are optionally substituted with halo, C1-C4alkyl, C1-C4haloalkyl, C1-C4alkoxy, or 3-6 membered heterocyclyl; R F , R S and R X are independently selected from the group consisting of halogen, cyano, C1-C4alkyl, C3-C6cycloalkyl, C1-C4haloalkyl, -C1-C4alkyleneC(O)NR e R f , -C1-C4alkyleneC1-C4alkoxy, C1-C4hydroxyalkyl, -C1-C4alkylenephenyl, -C1-C4alkyleneheteroaryl, C2-C4alkenyl, C2-C4haloalkenyl, C2-C4alkynyl, C2-C4haloalkynyl, C1-C4alkoxy, C1-C4haloalkoxy, -OR e , =O, imine, phenyl, 4-6 membered heterocyclyl, 5-6 membered heteroaryl, -S(O)R e R f , -S(O)2R f , -S(O)(=NH)(C1-C4alkyl), -S(O)NR e R f , -S(O)2NR e R f , -C(O)OR e , -NR c C(O)R e , -(C1-C4alkyl)C(O)R g , -C(O)R g , -(C1-C4alkyl)C(O)NR c R d , -C(O)NR c R d , -NO2and -NR a R b , said C1-C4alkyl is optionally substituted with cyano, said phenyl, 4-6 membered heterocyclyl, 5-6 membered heteroaryl, phenyl is optionally substituted with halogen, cyano, =O, C1-C 10 alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl, C1-C 10 haloalkyl, C1-C 10 alkoxy or C1-C 10 haloalkoxy, said C1-C 10 alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl is optionally substituted with 5-10 membered heteroaryl or 4-10 membered heterocyclyl, said 4-10 membered heterocyclyl is optionally substituted with oxo; R M independently selected from halogen, C1-C4alkyl, C1-C4alkoxy, C1-C4haloalkoxy, cyano, -C(O)R g , -C(O)OR e , -NHC(O)R e , -C(O)NR c R d , -NR a R b , -S(O)R e R f , -S(O)2R f , -S(O)NR e R f , -S(O)(=NH)(C1-C4alkyl), -S(O)2NR e R f , hydroxy, phenyl, 4-6 membered heterocyclyl, and 5-10 membered heteroaryl, which phenyl, 4-6 membered heterocyclyl, and 5-10 membered heteroaryl are optionally substituted with R X ; R a , R b , R c , R d , R e , R f , R g and R h are independently selected from hydrogen, C1-C4alkyl, C2-C4alkynyl, -C1-C4alkylphenyl, phenyl, C3-C6cycloalkyl, 4-6cycloalkyl, 4-6membered heterocycloalkyl, 4-6membered heterocyclyl and 5-6membered heteroaryl, said C1-C4alkyl optionally substituted with halogen, cyano, hydroxyl or amino, said phenyl, C3-C6cycloalkyl, 4-6cycloalkyl, 4-6membered heterocycloalkyl, 4-6membered heterocyclyl and 5-6membered heteroaryl optionally substituted with halogen, cyano, C1-C4alkyl, C1-C4haloalkyl, C1-C4alkoxy, C1-C4haloalkoxy, hydroxyl, phenyl or benzyl; one or more hydrogen atoms of the compound are optionally deuterium atoms.

2. The compound of claim 1 of formula (I) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, selected from the group consisting of a compound of formula (I-1) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein: L is a bivalent moiety connecting STAT to LBM; LBM is selected from STAT is a group as described below: q is 0 or 1 ; t is 0, 1 or 2; p is 1 or 2; n is any natural number selected from 1-8; X is selected from CH2, O, S, SO2, S(O), -C(=O)-NR 10 - and NR 8 ; Ring A is selected from C3-C 12 saturated carbocyclic and 4-8 membered heterocyclic rings; R 1 selected from -CR 1a R 2a P(O)OR 1b OR 2b , -CR 1a R 2a P(O)[OR 1b ][NH(AA)C(O)OR T ], -P(O)OR 1b OR 2b , -[P(O)[NHR Ty ][NH(AA)C(O)OR T ] or -P(O)[OR 1b ][NH(AA)C(O)OR T ]; 8-10 membered heteroaryl optionally substituted with -CR 1a R 2a P(O)OR 1b OR 2b , -CR 1a R 2a P(O)[OR 1b ][NH(AA)C(O)OR T ], -P(O)OR 1b OR 2b , -[P(O)[NHR Ty ][NH(AA)C(O)OR T ] or -P(O)[OR 1b ][NH(AA)C(O)OR T ]; 8-10 membered heterocyclyl optionally substituted with -CR 1a R 2a P(O)OR 1b OR 2b , -CR 1a R 2a P(O)[OR 1b ][NH(AA)C(O)OR T ], -P(O)OR 1b OR 2b , -[P(O)[NHR Ty ][NH(AA)C(O)OR T ] or -P(O)[OR 1b ][NH(AA)C(O)OR T ]; C6-C 10 aryl, said C6-C 10 aryl is additionally optionally substituted by cyano, C1-C4alkoxy or halo; -C1-C4alkyleneC6-C 10 aryl, said -C1-C4alkyleneC6-C 10 aryl of aryl is substituted by -CR 1a R 2a P(O)OR 1b OR 2b , -CR 1a R 2a P(O)[OR 1b ][NH(AA)C(O)OR T ], -P(O)OR 1b OR 2b , -[P(O)[NHR Ty ][NH(AA)C(O)OR T ] or -P(O)[OR 1b ][NH(AA)C(O)OR T ] substituted; -C2-C4alkenylC6-C 10 aryl, said -C2-C4alkenylC6-C 10 aryl of aryl is substituted by -CR 1a R 2a P(O)OR 1b OR 2b , -CR 1a R 2a P(O)[OR 1b ][NH(AA)C(O)OR T ], -P(O)OR 1b OR 2b , -[P(O)[NHR Ty ][NH(AA)C(O)OR T ] or -P(O)[OR 1b ][NH(AA)C(O)OR T ] substituted; R 1a and R 2a are independently selected from hydrogen, halogen, cyano, C1-C4alkyl, C1-C4haloalkyl and C1-C4hydroxyalkyl, or R 1a and R 2a are taken together to form =0; R 1b and R 2b are independently selected from the group consisting of hydrogen, C1-C4alkyl, C1-C4haloalkyl, -(C1-C4alkylene)-OC(O)-(C1-C4alkyl), -(C1-C4alkylene)-C(O)O-(C1-C4alkyl), -(C1-C4alkylene)-O-(C1-C4alkyl), -(C1-C4alkylene)-OC(O)-[C1-C4haloalkyl], -(C1-C4alkylene)-OC(O)O-[5-7 membered heterocyclyl], -(C1-C4alkylene)-OC(O)-[5-7 membered heterocyclyl], -(C1-C4alkylene)-OC(O)-(C1-C4alkylene)-OH, -(C1-C4alkylene)-OC(O)-(C1-C4alkylene)-O-(C1-C4alkyl), -(C1-C4alkylene)-OC(O)O-(C1-C4alkyl), -(C1-C4alkylene)-OC(O)O-[C1-C4haloalkyl], -(C1-C4alkylene)-OC(O)O-(C1-C4alkylene)-OH, -(C1-C4alkylene)-OC(O)O-(C1-C4alkylene)-O-(C1-C4alkyl), -(C1-C4alkylene)-SC(O)-(C1-C4alkyl), -(C1-C4alkylene)-SC(O)-[C1-C4haloalkyl], -(C1-C4alkylene)-SC(O)-(C1-C4alkylene)-OH, -(C1-C4alkylene)-SC(O)-(C1-C4alkylene)-O-(C1-C4alkyl), -(C1-C4alkylene)-OC(O)NH(C1-C4alkyl)], -(C1-C4alkylene)-OC(O)N(C1-C4alkyl)2, C6-C 10 aryl and 5-6 membered heteroaryl, said C6-C 10 aryl and 5-6 membered heteroaryl are optionally substituted with halo, cyano or C1-C4alkyl, said 5-7 membered heterocyclyl is optionally substituted with C(O)OR h ; R 2 selected from hydrogen, halogen, COOH, hydroxyl, cyano, C1-C4alkyl, C1-C4alkoxy, C1-C4haloalkoxy, C1-C4haloalkyl, and C1-C4hydroxyalkyl; R 3 and R 4 are independently selected from hydrogen, halogen, hydroxyl, cyano, C1-C4alkyl, C1-C4haloalkyl, C1-C4hydroxyalkyl, -C1-C4alkylene phenyl, C1-C4alkoxy, C1-C4haloalkoxy, -C1-C4alkylene C1-C4alkoxy, NR a R b , C3-C6cycloalkyl, C6-C 10 aryl, 5-10 membered heteroaryl, and 4-10 membered heterocyclyl, said C3-C6cycloalkyl, C6-C 10 aryl, 5-10 membered heteroaryl, and 4-10 membered heterocyclyl are optionally substituted with R S ; or R 3 and the atom to which they are attached together form a C3-C6saturated carbocyclic ring, 4-8 membered heterocyclic ring, or 5-6 membered heteroaromatic ring, which 3-6 membered saturated carbocyclic ring, 4-8 membered heterocyclic ring, and 5-6 membered heteroaromatic ring is optionally substituted with halogen, cyano, amino, or C1-C4alkyl; 4 and the atom to which they are attached together form a C3-C6saturated carbocyclic ring, 4-8 membered heterocyclic ring, or 5-6 membered heteroaromatic ring, which 3-6 membered saturated carbocyclic ring, 4-8 membered heterocyclic ring, and 5-6 membered heteroaromatic ring is optionally substituted with halogen, cyano Or, R 2 and R 3 and the atoms connected thereto together form a C4-C6 saturated carbocyclic ring, a 4-8 membered heterocyclic ring, a C6-C 10 Aromatic ring or 5-6 membered heteroaromatic ring, the C4-C6 saturated carbocyclic ring, 4-8 membered heterocyclic ring, C6-C 10 The aromatic ring or 5-6 membered heteroaromatic ring is optionally substituted by halogen, cyano, amino or C1-C4 alkyl; R 5 selected from hydrogen, phenyl and C1-C4alkyl; R 6 and R 7 are independently selected from the group consisting of halogen, cyano, hydroxyl, phenyl, C2-C4 alkenyl, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, 4-9 membered heterocyclyl, 5-10 membered heteroaryl, C3-C6 cycloalkyl, =0, imino, -OR e , -C(O)R g , -C(O)OR e , -NR c C(O)R e , -C(O)NR c R d , -NR a R b , -S(O)R e R f , -S(O)2R f , -S(O)(=NH)(C1-C4 alkyl), -S(O)NR e R f , and -S(O)2NR e R f , said C2-C4 alkenyl, C1-C4 alkyl are optionally substituted with R M , said phenyl, 5-10 membered heteroaryl, C3-C6 cycloalkyl and 4-9 membered heterocyclyl are optionally substituted with R F ; R 8 is selected from the group consisting of a bond, hydrogen, -SO2R 8a , C2-C4alkenyl, C1-C4alkyl, C2-C4alkynyl, C1-C4alkoxy, C3-C6cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 aryl, and 5-10 membered heteroaryl, said C2-C4alkenyl, C1-C4alkyl, C2-C4alkynyl, C1-C4alkoxy, C3-C6cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 aryl, and 5-10 membered heteroaryl are optionally substituted with R 8a ; or, when X is NR 8 R 3 and the C to which it is attached together with R 8 and the N to which it is attached form a 4-8 membered heterocyclic ring or a 5-6 membered heteroaromatic ring, which is optionally substituted with halogen, cyano, amino or C1-C4alkyl; R 8a selected from halogen, cyano, amino, Ci-C4alkyl, -C(0)Ci-C4alkyl, C3-C6cycloalkyl, 4-10 membered heterocyclyl, and =0, said amino, Ci-C4alkyl, -C(0)Ci-C4alkyl, C3-C6cycloalkyl, 4-10 membered heterocyclyl optionally substituted with halogen, cyano, hydroxyl, Ci-C4alkyl, Ci-C4alkoxy, and Ci-C4haloalkyl; R 9 selected from hydrogen, -C(O)C1-C4 alkyl, C1-C4 alkyl, C1-C4 cyanoalkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl, 4-9 membered heterocyclyl, C6-C 10 Aryl and 5-10 membered heteroaryl; R 10 selected from hydrogen, C1-C4 alkyl, C1-C4 cyanoalkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl, 4-9 membered heterocyclic group, C6-C 10 Aryl and 5-10 membered heteroaryl; AA is a residue of an alpha or beta natural or unnatural amino acid; R T and R Ty is independently selected from the group consisting of C1-C6alkyl, benzyl, and phenyl, said C1-C6alkyl, benzyl, and phenyl being optionally substituted with halo, C1-C4alkyl, or C1-C4haloalkyl; R F , R S and R X are independently selected from the group consisting of halogen, cyano, C1-C4alkyl, C3-C6cycloalkyl, C1-C4haloalkyl, -C1-C4alkyleneC(O)NR e R f , -C1-C4alkyleneC1-C4alkoxy, C1-C4hydroxyalkyl, -C1-C4alkylenephenyl, -C1-C4alkyleneheteroaryl, C2-C4alkenyl, C2-C4haloalkenyl, C2-C4alkynyl, C2-C4haloalkynyl, C1-C4alkoxy, C1-C4haloalkoxy, -OR e , =O, imine, phenyl, 4-6 membered heterocyclyl, 5-6 membered heteroaryl, -S(O)R e R f , -S(O)2R f , -S(O)(=NH)(C1-C4alkyl), -S(O)NR e R f , -S(O)2NR e R f , -C(O)OR e , -NR c C(O)R e , -(C1-C4alkyl)C(O)R g , -C(O)R g , -(C1-C4alkyl)C(O)NR c R d , -C(O)NR c R d , -NO2and -NR a R b , said C1-C4alkyl is optionally substituted with cyano, said phenyl, 4-6 membered heterocyclyl, 5-6 membered heteroaryl, phenyl is optionally substituted with halogen, cyano, =O, (C1-C 10 )alkyl, (C2-C 10 )alkenyl, (C2-C 10 )alkynyl, (C1-C 10 )haloalkyl, (C1-C 10 )alkoxy or (C1-C 10 )haloalkoxy, said C1-C 10 alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl is optionally substituted with 5-10 membered heteroaryl or 4-10 membered heterocyclyl, said 4-10 membered heterocyclyl is optionally substituted with oxo; R M is independently selected from the group consisting of halogen, C1-C4alkyl, C1-C4alkoxy, C1-C4haloalkoxy, cyano, -C(O)R g , -C(O)OR e , -NHC(O)R e , -C(O)NR c R d , -NR a R b , -S(O)R e R f , -S(O)2R f , -S(O)NR e R f , -S(O)(=NH)(C1-C4alkyl), -S(O)2NR e R f , hydroxy, phenyl, 4-6 membered heterocyclyl and 5-10 membered heteroaryl, said phenyl, 4-6 membered heterocyclyl and 5-10 membered heteroaryl are optionally substituted with R X ; R a , R b , R c , R d , R e , R f , R g and R h are independently selected from hydrogen, C1-C4alkyl, C2-C4alkynyl, -C1-C4alkylphenyl, phenyl, C3-C6cycloalkyl, 4-6cycloalkyl, 4-6membered heterocycloalkyl, 4-6membered heterocyclyl and 5-6membered heteroaryl, said C1-C4alkyl optionally substituted with halogen, cyano, hydroxyl or amino, said phenyl, C3-C6cycloalkyl, 4-6cycloalkyl, 4-6membered heterocycloalkyl, 4-6membered heterocyclyl and 5-6membered heteroaryl optionally substituted with halogen, cyano, C1-C4alkyl, C1-C4haloalkyl, C1-C4alkoxy, C1-C4haloalkoxy, hydroxyl, phenyl or benzyl; one or more hydrogen atoms of the compound are optionally deuterium atoms.

3. The compound of claim 1 of formula (I) or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, The compounds of Formula (I) or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof do not include the following compounds:

4. The compound of any one of claims 1-3 of formula (I) or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, p is 1.

5. The compound of any one of claims 1-4 of formula (I) or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, t is 1 or 2; or t is 1 ; or t is 2.

6. The compound of any one of claims 1-5 of formula (I) or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, q is 0; or q is 1.

7. The compound of any one of claims 1-6 of formula (I) or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, n is 1.

8. The compound of any one of claims 1-7 of Formula (I) or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, X is selected from CH2, S, S(O), -C(=O)-NR 10 -, SO2, and NR 8 ; or X is selected from CH2, S, SO2, and NR 8 ; or X is selected from S, S(O), -C(=O)-NR 10 -, SO2and or X is selected from CH2and NR 8 .

9. The compound of any one of claims 1-8 of Formula (I): or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, R 8 selected from bond, hydrogen, C2-C4alkenyl, C1-C4alkyl, C2-C4alkynyl, C1-C4alkoxy, C3-C6cycloalkyl, 4-10 membered heterocyclyl, C6-C10aryl, and 5-10 membered heteroaryl, said C2-C4alkenyl, C1-C4alkyl, C2-C4alkynyl, C1-C4alkoxy, C3-C6cycloalkyl, 4-10 membered heterocyclyl, C6-C10aryl, and 5-10 membered heteroaryl being optionally substituted with R 10 ; or R 10 is selected from hydrogen, -SO2R 8a , C1-C4alkyl, and 4-6 membered heterocyclyl, said C1-C4alkyl and 4-6 membered heterocyclyl being optionally substituted with R 8 ; or R 8a is selected from hydrogen, -SO2R 8a , C1-C4alkyl, and 4-6 membered heterocyclyl, said C1-C4alkyl and 4-6 membered heterocyclyl being optionally substituted with R 8 ; or R 8a is selected from hydrogen, -SO2R 8 , C1-C4alkyl, and 4-6 membered heterocyclyl, said C1-C4alkyl and 4-6 membered heterocyclyl being optionally substituted with R 8a ; or R 8 is selected from hydrogen, -SO2R 8a , methyl, ethyl, oxetanyl, azetidinyl, thietanyl, and thietanyl-1,1-dioxide, said methyl, ethyl, oxetanyl, azetidinyl, thietanyl, and thietanyl-1,1-dioxide being optionally substituted with R 8a ; or R 8 is selected from hydrogen, ethyl, oxetanyl, azetidinyl, thietanyl, and thietanyl-1,1-dioxide, said oxetanyl, azetidinyl, thietanyl, and thietanyl-1,1-dioxide being optionally substituted with R 8a ; or R 8 is selected from hydrogen, methyl, -C(O)CH3, -CH2CHF2, oxetanyl, cyclopropylcarbonyl, methylsulfonyl, ; or R 8 is selected from hydrogen, -C(O)CH3, oxetanyl.

10. The compound of any one of claims 1-9 of Formula (I): or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, R 8a selected from halogen, cyano, amino, hydroxyl, C1-C4alkyl, -C(O)C1-C4alkyl, C3-C6cycloalkyl, 4-10 membered heterocyclyl, and =O, said amino, C1-C4alkyl, -C(O)C1-C4alkyl, C3-C6cycloalkyl, 4-10 membered heterocyclyl are optionally substituted with halogen, cyano, hydroxyl, C1-C4alkyl, C1-C4alkoxy, and C1-C4haloalkyl; or R 8a selected from hydroxyl, halogen, cyano, amino, C1-C4alkyl, -C(O)C1-C4alkyl, and =O; or R 8a selected from halogen, =O, C1-C4alkyl, C3-C6cycloalkyl, and -C(O)C1-C4alkyl, said C1-C4alkyl, C3-C6cycloalkyl, and -C(O)C1-C4alkyl are optionally substituted with halogen, cyano, hydroxyl, C1-C4alkyl, C1-C4alkoxy, and C1-C4haloalkyl; or R 8a selected from =O, C1-C4alkyl, and -C(O)C1-C4alkyl; or R 8a selected from halogen, =O, cyclopropyl, methyl, and said cyclopropyl, methyl, and are optionally substituted with halogen.

11. The compound of any one of claims 1-10 of Formula (I): or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, R 9 is hydrogen.

12. The compound of any one of claims 1-11 of Formula (I): or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, R 10 is hydrogen.

13. The compound of any one of claims 1-12 of Formula (I): or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, R 1 selected from -CR 1a R 2a P(O)OR 1b OR 2b , -CR 1a R 2a P(O)[OR 1b ][NH(AA)C(O)OR T ], -P(O)OR 1b OR 2b , -[P(O)[NHR Ty ][NH(AA)C(O)OR T ], or -P(O)[OR 1b ][NH(AA)C(O)OR T ]; 8-10 membered heteroaryl optionally substituted with -CR 1a R 2a P(O)OR 1b OR 2b , -CR 1a R 2a P(O)[OR 1b ][NH(AA)C(O)OR T ], -P(O)OR 1b OR 2b , -[P(O)[NHR Ty ][NH(AA)C(O)OR T ], or -P(O)[OR 1b ][NH(AA)C(O)OR T ]; 8-10 membered heterocyclyl optionally substituted with -CR 1a R 2a P(O)OR 1b OR 2b , -CR 1a R 2a P(O)[OR 1b ][NH(AA)C(O)OR T ], -P(O)OR 1b OR 2b , -[P(O)[NHR Ty ][NH(AA)C(O)OR T ], or -P(O)[OR 1b ][NH(AA)C(O)OR T ]; C6-C 10 Aryl, the C6-C 10 Aryl is optionally substituted by cyano, C1-C4 alkoxy or halogen; -C1-C4 alkylene C6-C 10 Aryl, the -C1-C4 alkylene C6-C 10 The aryl group of the aryl group is replaced by -CR 1a R 2a P(O)OR 1b OR 2b 、-CR 1a R 2a P(O)[OR 1b ][NH(AA)C(O)OR T ]、-P(O)OR 1b OR 2b 、-[P(O)[NHR Ty ][NH(AA)C(O)OR T ] or -P(O)[OR 1b ][NH(AA)C(O)OR T ] substituted; -C2-C4 alkenyl C6-C 10 Aryl, the -C2-C4 alkenyl C6-C 10 The aryl group of the aryl group is replaced by -CR 1a R 2a P(O)OR 1b OR 2b 、-CR 1a R 2a P(O)[OR 1b ][NH(AA)C(O)OR T ]、-P(O)OR 1b OR 2b 、-[P(O)[NHR Ty ][NH(AA)C(O)OR T ] or -P(O)[OR 1b ][NH(AA)C(O)OR T ] substituted; or R 1 Selected from CR 1a R 2a P(O)OR 1b OR 2b 、-CR 1a R 2a P(O)OR 1b NHR 2b 、-CR 1a R 2a P(O)[OR 1b ][NH(AA)C(O)OR T ]、-P(O)OR 1b OR 2b , -P(O)[OR Ty ][NH(AA)C(O)OR T ] or -P(O)[OR 1b ][NH(AA)C(O)OR T ] substituted 8-10 membered heteroaryl, said 8-10 membered heteroaryl being additionally optionally substituted with amino, halogen, cyano, C1-C4alkyl or C1-C4alkoxy; or -CR 1a R 2a P(O)OR 1b OR 2b , -CR 1a R 2a P(O)OR 1b NHR 2b , -CR 1a R 2a P(O)[OR 1b ][NH(AA)C(O)OR T ], -P(O)OR 1b OR 2b , -[P(O)[NHR Ty ][NH(AA)C(O)OR T ] or -P(O)[OR 1b ][NH(AA)C(O)OR T ] substituted 8-10 membered heterocyclyl, said 8-10 membered heterocyclyl being additionally optionally substituted with amino, halogen, cyano, C1-C4alkyl or C1-C4alkoxy; or -CR 1a R 2a P(O)OR 1b OR 2b , -CR 1a R 2a P(O)OR 1b NHR 2b , -CR 1a R 2a P(O)[OR 1b ][NH(AA)C(O)OR T ], -P(O)OR 1b OR 2b , -[P(O)[NHR Ty ][NH(AA)C(O)OR T ] or -P(O)[OR 1b ][NH(AA)C(O)OR T ] substituted C6-C 10 aryl, said C6-C 10 aryl being additionally optionally substituted with cyano, C1-C4alkoxy or halogen; or R 1 is selected from -CR 1a R 2a P(O)OR 1b OR 2b 、 -CR 1a R 2a P(O)OR 1b NHR 2b 、 -CR 1a R 2a P(O)[OR 1b [NH(AA)C(O)OR T 、 -P(O)OR 1b OR 2b 、 -[P(O)[NHR Ty [NH(AA)C(O)OR T or -P(O)[OR 1b [NH(AA)C(O)OR T -substituted 8- to 10-membered heteroaryl; -CR 1a R 2a P(O)OR 1b OR 2b 、 -CR 1a R 2a P(O)OR 1b NHR 2b 、 -CR 1a R 2a P(O)[OR 1b [NH(AA)C(O)OR T 、 -P(O)OR 1b OR 2b 、 -[P(O)[NHR Ty [NH(AA)C(O)OR T or -P(O)[OR 1b [NH(AA)C(O)OR T -substituted C6-C 10 aryl or -CR 1a R 2a P(O)OR 1b OR 2b 、 -CR 1a R 2a P(O)OR 1b NHR 2b 、 -CR 1a R 2a P(O)[OR 1b [NH(AA)C(O)OR T 、 -P(O)OR 1b OR 2b 、 -[P(O)[NHR Ty ][NH(AA)C(O)OR T ] or -P(O)[OR 1b ][NH(AA)C(O)OR T ] substituted 8-10 membered heterocyclyl; or R 1 selected from or R 1 selected from or R 1 selected from or R 1 selected from or R 1 selected from or R 1 selected from 14. The compound of any one of claims 1-13 of Formula (I): or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, R 1b and R 2b are independently selected from the group consisting of hydrogen, C1-C4alkyl, C1-C4haloalkyl, -(C1-C4alkylene)-OC(O)-(C1-C4alkyl), -(C1-C4alkylene)-C(O)O-(C1-C4alkyl), -(C1-C4alkylene)-O-(C1-C4alkyl), -(C1-C4alkylene)-OC(O)-[C1-C4haloalkyl], -(C1-C4alkylene)-OC(O)O-[5-7 membered heterocyclyl], -(C1-C4alkylene)-OC(O)-[5-7 membered heterocyclyl], -(C1-C4alkylene)-OC(O)-(C1-C4alkylene)-OH, -(C1-C4alkylene)-OC(O)-(C1-C4alkylene)-O-(C1-C4alkyl), -(C1-C4alkylene)-OC(O)O-(C1-C4alkyl), -(C1-C4alkylene)-OC(O)O-[C1-C4haloalkyl], -(C1-C4alkylene)-OC(O)O-(C1-C4alkylene)-OH, -(C1-C4alkylene)-OC(O)O-(C1-C4alkylene)-O-(C1-C4alkyl), -(C1-C4alkylene)-SC(O)-(C1-C4alkyl), -(C1-C4alkylene)-SC(O)-[C1-C4haloalkyl], -(C1-C4alkylene)-SC(O)-(C1-C4alkylene)-OH, -(C1-C4alkylene)-SC(O)-(C1-C4alkylene)-O-(C1-C4alkyl), -(C1-C4alkylene)-OC(O)NH(C1-C4alkyl)], -(C1-C4alkylene)-OC(O)N(C1-C4alkyl)2, C6-C10aryl, and 5-6 membered heteroaryl, said C6-C10aryl and 5-6 membered heteroaryl being optionally substituted with halo, cyano, or C1-C4alkyl, said 5-7 membered heterocyclyl being optionally substituted with C(O)OR 10 10 h 1b and R 2b ​​​independently selected from the group consisting of hydrogen, C1-C4alkyl, -(C1-C4alkylene)-OC(O)-(C1-C4alkyl), -(C1-C4alkylene)-OC(O)-[5-7 membered heterocyclyl], -(C1-C4alkylene)-SC(O)-(C1-C4alkyl), -(C1-C4alkylene)-OC(O)O-(C1-C4alkyl), -(C1-C4alkylene)-OC(O)N(C1-C4alkyl)2, -(C1-C4alkylene)-SC(O)-(C1-C6alkyl), -(C1-C4alkylene)-OC(O)O-(C1-C4alkylene)-O-(C1-C4alkyl), -(C1-C4alkylene)-SC(O)-(C1-C4alkylene)-OH, and -(C1-C4alkylene)-C(O)S-(C1-C4alkyl), said 5-7 membered heterocyclyl being optionally substituted with C(O)OR h substituted.

15. The compound of any one of claims 1-14 of Formula (I): or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, R h selected from C1-C4 alkyl, preferably methyl.

16. The compound of any one of claims 1-15 of Formula (I): or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, -CR 1a R 2a P(O)OR 1b OR 2b selected from or -CR 1a R 2a P(O)OR 1b OR 2b selected from or -CR 1a R 2a P(O)OR 1b OR 2b is or -CR 1a R 2a P(O)OR 1b OR 2b is or -CR 1a R 2a P(O)OR 1b OR 2b is 17. The compound of any one of claims 1-16 of Formula (I): or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, R T and R Ty are independently selected from the group consisting of C1-C6alkyl, benzyl and phenyl, said C1-C6alkyl, benzyl and phenyl being optionally substituted with halogen, C1-C4alkyl or C1-C4haloalkyl; or R T and R Ty are independently selected from the group consisting of C1-C4alkyl, benzyl and phenyl, said benzyl and phenyl being optionally substituted with halogen, C1-C4alkyl or C1-C4haloalkyl; or R T is selected from the group consisting of C1-C6alkyl, benzyl and C3-C6cycloalkyl, said C1-C6alkyl, benzyl and C3-C6cycloalkyl being optionally substituted with halogen, C1-C4alkyl, C1-C4alkoxy or 3-6 membered heterocyclyl.

18. The compound of any one of claims 1-17 of Formula (I): or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, -CR 1a R 2a P(O)[OR 1b ][NH(AA)C(O)OR T ] is selected from or -CR 1a R 2a P(O)[OR 1b ][NH(AA)C(O)OR T ] is 19. The compound of any one of claims 1-18 of Formula (I): or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, -CR 1a R 2a P(O)OR 1b NHR 2b selected from 20. The compound of any one of claims 1-19 of Formula (I): or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, R 2 is hydrogen.

21. The compound of any one of claims 1-20 of Formula (I): or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, R 3 is hydrogen.

22. The compound of any one of claims 1-21 of Formula (I): or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, R 2 and the atom to which they are attached together form a C6-C 3 aromatic ring, which is optionally substituted with halogen, cyano, amino, or C1-C4alkyl; or R 10 and the atom to which they are attached together form a C6-C 10 aromatic ring, which is optionally substituted with halogen, cyano, amino, or C1-C4alkyl; or R 2 and the atom to which they are attached together form a C6-C 3 aromatic ring, which is optionally substituted with halogen, cyano, amino, or C1-C4alkyl; or R 2 and the atom to which they are attached together form a C6-C 3 aromatic ring.

23. The compound of any one of claims 1-22 of Formula (I): or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, selected from 24. The compound of any one of claims 1-23 of Formula (I): or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, R 4 is hydrogen.

25. The compound of any one of claims 1-24 of Formula (I): or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, R 5 is hydrogen.

26. The compound of any one of claims 1-25 of Formula (I): or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, Ring A is selected from a 4-8 membered heterocyclic ring; or Ring A is selected from a 4-8 membered nitrogen-containing heterocyclic ring; or Ring A is selected from a 5 membered nitrogen-containing heterocyclic ring; or Ring A is selected from a tetrahydropyrrole ring; or Ring A is or Ring A is and morpholine rings.

27. The compound of any one of claims 1-26 of Formula (I): or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, selected from or selected from or selected from 28. The compound of any one of claims 1-27 of Formula (I): or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, R 6 is selected from =0, halogen, cyano, hydroxy, phenyl and C1-C4alkyl; or R 6 is selected from halogen, cyano, hydroxy, phenyl and C1-C4alkyl; or R 6 is cyano or =0; or R 6 is cyano.

29. The compound of any one of claims 1-28 of Formula (I): or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, R 7 is selected from phenyl, 4-9 membered heterocyclic group, 5-10 membered heteroaryl and C3-C6 cycloalkyl, wherein the phenyl, 4-9 membered heterocyclic group, 5-10 membered heteroaryl and C3-C6 cycloalkyl are optionally replaced by R F Replacement; or R 7 Selected from phenyl, pyrazolyl, pyrimidinyl, piperidinyl, morpholinyl, pyranyl, piperazinyl and pyridinyl, the phenyl, pyrazolyl, pyrimidinyl, piperidinyl, morpholinyl, Pyranyl, piperazinyl and pyridinyl are optionally replaced by R F Replacement; or R 7 is phenyl, the phenyl group is optionally replaced by R F Replacement; or R 7 is selected from phenyl, pyrazolyl, pyridyl, aminopyridyl, aminophenyl and hydroxyphenyl; or R 7 is selected from phenyl, pyrazolyl, aminopyridinyl, aminophenyl and hydroxyphenyl; or R 7 Selected from phenyl, aminophenyl and hydroxyphenyl.

30. The compound of any one of claims 1-29 of Formula (I): or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, each R F is independently selected from the group consisting of halogen, cyano, =0, -OR e , -C(O)OR e , C1-C4 alkyl and -NR a R b ; or each R F is independently selected from the group consisting of halogen, cyano, -OR e , C1-C4 alkyl and -NR a R b ; or each R F is independently selected from the group consisting of amino, =0, methoxy, methylamino, methyl, carboxyl and hydroxy; or each R F is independently selected from the group consisting of amino and hydroxy.

31. The compound of any one of claims 1-30 of Formula (I): or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, STAT is attached to L via R 8 and L is attached to the STAT via R or STAT is attached to L via R 8 and L is attached to the STAT via R 8 and L is attached to the STAT via R or STAT is attached to L via R 7 and L is attached to the STAT via R or STAT is attached to L via R 3 and L is attached to the STAT via R 32. The compound of claim 1 or 2 of formula (I): ###0009### or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, The STAT is a group represented by the following formula: wherein q, t, p, n, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and ring A are as defined in claims 1-31.

33. The compound of claim 1 or 2 of formula (I) or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, The STAT is a group represented by the following formula: wherein n, R 1 , R 5 , R 6 , R 7 , R 8 and ring A are as defined in claims 1-31.

34. The compound of claim 1 or 2 of formula (I): ###0009### or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, The STAT is a group represented by the following formula: wherein R 1 , R 5 , R 6 , R 7 and R 8 are as defined in claims 1-31.

35. The compound of claim 1 or 2 of formula (I): ###00010### or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, The STAT is a group represented by the following formula: wherein q, t, p, n, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and ring A are as defined in claims 1-31.

36. The compound of claim 1 or 2 of formula (I): ###00010### or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, The STAT is a group represented by the following formula: wherein n, R 1 , R 5 , R 6 , R 7 and ring A are as defined in claims 1-31.

37. The compound of claim 1 or 2 of formula (I): ###00010### or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, The STAT is a group represented by the following formula: wherein R 1 , R 5 , R 6 and R 7 are as defined in claims 1-31.

38. The compound of claim 1 or 2 of formula (I) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein, The STAT is a group represented by the following formula: wherein n, R 1 , R 5 , R 6 , R 7 , R 8 and ring A are as defined in claims 1-31.

39. The compound of claim 1 or 2 of formula (I) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein, The STAT is a group represented by the following formula: wherein R 1 , R 5 , R 6 , R 7 and R 8 are as defined in claims 1-31.

40. The compound of any one of claims 1-39 of Formula (I): or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, said L is selected from -L A - and -L B - and -R 1L - and -R 2L - and -Q 1 - and -Q 2 -, wherein: -L A - and -L B - are independently from each other selected from a bond, -O-, -S-, -NR 3’ -, -CR 4’ R 5’ -, -C(O)-, -S(O)-, -S(O)2-, -C(S)-, -C(O)O- or -C(O)NR 6’ - ; R 1L and R 2L are independently of each other selected from the group consisting of a bond, alkylene, heteroalkylene, alkenylene and alkynylene, wherein said alkylene, heteroalkylene, alkenylene and alkynylene are optionally substituted with a group selected from halogen, alkyl, alkoxy, halogenalkyl, OH, hydroxyalkyl, CN, NH2, =0, cycloalkyl, heterocyclyl, aryl, heteroaryl; Q 1 , Q 2 , Q 3 and Q 4 are independently of each other selected from cycloalkylene, heterocyclylene, arylene, heteroarylene or cycloalkenylene, wherein each of said cycloalkylene, heterocyclylene, arylene, heteroarylene and cycloalkenylene is independently optionally substituted with a group selected from halogen, alkyl, alkoxy, halogenalkyl, OH, hydroxyalkyl, CN, NH2, =0, cycloalkyl, heterocyclyl, aryl, heteroaryl; R 3’ selected from H, alkyl, heteroalkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; R 4’ and R 5’ each independently is selected from H, halogen, alkyl, alkoxy, haloalkyl, OH, hydroxyalkyl, CN, NH2, =0, cycloalkyl, heterocyclyl, aryl, or heteroaryl; R 6’ is selected from H, alkyl, heteroalkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl.

41. The compound of any one of claims 1, 3-40 of Formula (I): or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein, The LBM is selected from the group consisting of structures shown in Formula LBM-1 or LBM-2: wherein: selected from the group consisting of Y is a bond or Y is selected from Y A , O, NH, NR E , C(O)O, C(O)NR E , NR E C(O), Y A -NH, Y A -NR E , Y A -C(O), Y A -C(O)O, Y A -OC(O), Y A -C(O)NR E , or Y A -NR E C(O), wherein said Y A is selected from C1-C6alkylene, C2-C6alkenylene or C2-C6alkynylene; X' is selected from C(O) or C(R A )2; X A - X B is selected from C(R A )=N or C(R A )2-C(R A )2; Every R A independently selected from H or C1-C3 alkyl, said C1-C3 alkyl being optionally replaced by C6-C 10 substituted with aryl or 5-10 membered heteroaryl; Every R A 'Independently selected from C1-C3 alkyl; each R is independently selected from H or C1-C3alkyl, or two R B are taken together with the atom to which they are attached to form C(O), C3-C6cycloalkyl, C3-C6cycloalkenyl, or 4-6 membered heterocyclyl; B are taken together with the atom to which they are attached to form C(O), C3-C6cycloalkyl, C3-C6cycloalkenyl, or 4-6 membered heterocyclyl; R C selected from H, halogen or C1-C3alkyl; Every R D Independently selected from halogen, NO2, NH2, OH, COOH, C1-C6 alkyl or C1-C6 alkoxy; Every R E independently selected from C1-C6 alkyl, C2-C6 alkenyl, C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl, C(O)-C1-C6 alkyl, C(O)-C2-C6 alkenyl, C(O)-C3-C8 cycloalkyl or C(O)-3-8 membered heterocycloalkyl, wherein R E Optionally substituted by a group selected from the group consisting of halogen, N(R a )2、NHC(O)R a 、NHC(O)OR a , OR b , C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl, C6-C 10 aryl or 5-10 membered heteroaryl, wherein the C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl, C6-C 10 The aryl or 5-10 membered heteroaryl is optionally further substituted by a group selected from the group consisting of halogen, NH2, CN, NO2, OH, COOH, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy or C1-C6 haloalkoxy; R E H, C1-C6alkyl, C2-C6alkenyl, C3-C8cycloalkyl, or 3-8 membered heterocycloalkyl, optionally substituted with a group selected from halogen, N(R a )2, NHC(O)R a , NHC(O)OR a , OR b , C3-C8cycloalkyl, 3-8 membered heterocycloalkyl, C6-C 10 aryl, or 5-10 membered heteroaryl, wherein said C3-C8cycloalkyl, 3-8 membered heterocycloalkyl, C6-C 10 aryl, or 5-10 membered heteroaryl is optionally further substituted with a group selected from halogen, NH2, CN, NO2, OH, COOH, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, or C1-C6haloalkoxy; each R is independently selected from H or C1-C6alkyl; a is independently selected from H or C1-C6alkyl; R b selected from H or p-toluenesulfonyl; r is selected from 0 or 1 ; m is selected from 0, 1, 2 or 3; o is selected from 0, 1 or 2.

42. The compound of any one of claims 1, 3-40 of Formula (I): or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, The LBM is selected from the group consisting of structures represented by Formula LBM-5: wherein: X C is selected from a bond, -CH2-, -CHCF3-, -SO2-, -S(O)-, -P(O)R’-, -P(O)OR’-, -P(O)NR’2-, -C(O)-, -C(S)- or X D is selected from C, N or Si; X E is selected from a bond, -CR'2-, -NR'-, -0-, -S-, or -SiR'2-; R F is absent, or R F is selected from H, deuterium, halogen, CN, -OR', -SR', -S(O)R', -S(O)2R', -NR'2, -P(O)(OR')2, -P(O)(NR'2)OR', -P(O)(NR'2)2, -Si(OH)2R', -Si(OH)R'2, -SiR'3, or C1-C4alkyl; each R is independently selected from H, deuterium, R G is independently selected from H, deuterium, R H halogen, CN, -NO2, -OR', -SR', -NR'2, -SiR'3, -S(O)2R', -S(O)2NR'2, -S(O)R', -C(O)R', -C(O)OR', -C(O)NR'2, -C(O)N(R')OR', -C(R')2N(R')C(O)R', -C(R')2N(R')C(O)NR'2, -OC(O)R', -OC(O)NR'2, -OP(O)R'2, -OP(O)(OR')2, -OP(O)(OR')NR'2, -OP(O)(NR'2)2, -N(R')C(O)OR', -N(R')C(O)R', -N(R')C(O)NR'2, -N(R')S(O)2R', -N(R')P(O)R'2, -N(R')P(O)(OR')2, -N(R')P(O)(OR')NR'2, or -N(R')P(O)(NR'2)2; Every R H Independently selected from C1-C6 alkyl, phenyl, 4-7 membered heterocyclyl or 5-6 membered heteroaryl; ring E, ring F, ring G are independently of each other selected from phenyl, C5-C7 cycloalkyl, C5-C7 cycloalkenyl, 5-7 membered heterocyclyl or 5-6 membered heteroaryl, wherein each of ring E, ring F and ring G is optionally further substituted by =0; L 1 is selected from a bond, C1-C3alkylene, C2-C3alkenylene, or C2-C3alkynylene, wherein any 1 or 2 methylene groups of said C1-C3alkylene, C2-C3alkenylene, or C2-C3alkynylene are optionally replaced with -O-, -C(O)-, -C(S)-, -C(R’)2-, -CH(R’)-, -C(F)2-, -N(R’)-, -S-, or -S(O)2-; each R' is independently selected from H, C1-C6 alkyl, phenyl, 4-7 membered heterocyclyl or 5-6 membered heteroaryl, or two R' together with the atom to which they are attached form a 4-7 membered heterocyclyl or 5-6 membered heteroaryl; g is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1, 12, 13, 14, 15 or 16.

43. The compound of any one of claims 1, 3-40 of Formula (I): or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein, The LBM is selected from the group consisting of structures represented by Formula LBM-6: wherein: ring H is selected from C5-C9cycloalkyl, C5-C9cycloalkenyl, 5-9 membered heterocyclyl, and 5-9 membered heteroaryl, said C5-C9cycloalkyl, C5-C9cycloalkenyl, and 5-9 membered heterocyclyl optionally substituted with =0; k is selected from 0, 1, 2, 3, or 4; X C , X D , X E , R F , R G , L 1 and ring E is as defined in claim 42.

44. The compound of any one of claims 1, 3-40 of Formula (I): or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein, The LBM is selected from the group consisting of structures represented by Formula LBM-7: wherein X C , X D , X E , R F , R G , L 1 , ring E and k are as defined in claims 42-43.

45. The compound of claim 1 of formula (I): ###0009### or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, The LBM is selected from the following structures:

46. A compound selected from the following or a stereoisomer thereof or a pharmaceutically acceptable salt thereof:

47. A pharmaceutical composition comprising a compound of any one of claims 1-46, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

48. Use of a compound of any one of claims 1-46, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 47, for the manufacture of a medicament for the prevention or treatment of a STAT6-mediated disease.

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