Selective degradation agent compound for signal transduction and transcriptional activation protein 6

Abstract

The invention relates to an STAT6 selective degradation agent compound shown in a formula (I) or a stereoisomer or pharmaceutically acceptable salt thereof, a pharmaceutical composition containing the STAT6 selective degradation agent compound or the stereoisomer or the pharmaceutically acceptable salt thereof, and application of the STAT6 selective degradation agent compound or the stereoisomer or the pharmaceutically acceptable salt in preparation of drugs for preventing or treating STAT6-mediated diseases.

Description

[0001] Cross-references

[0002] This disclosure claims priority and benefits to Chinese Patent Application No. 202410740269.7, filed on June 7, 2024, and Chinese Patent Application No. 202510351694.1, filed on March 24, 2025, the contents of which are incorporated herein by reference. Technical Field

[0003] This disclosure pertains to the pharmaceutical field and relates to a signal transduction and transcription activator (STAT) selective degrader compound or a pharmaceutically acceptable salt thereof, pharmaceutical compositions containing the same, and their use as STAT selective degraders in the prevention or treatment of related diseases. Background Technology

[0004] IL-4 and IL-13 are key cytokines for inducing and maintaining 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 allergies. STAT6 signaling is essential for IL-4 and IL-13-induced diseases. Upon binding of IL-4 or IL-13 to its receptors (IL-4Rα / γc or IL-4Rα / IL-13Rα1), the tyrosine residues of IL-4Rα on the receptor are phosphorylated by JAK1, JAK3, or Tyk2, subsequently recruiting STAT6 to phosphotyrosine residues and phosphorylating Tyr641 on STAT6. Phosphorylated STAT6 dimers through the SH2 domain-pTyr641 interaction and then translocates to the nucleus, where signals are transferred from the cytoplasm and transmitted to the nucleus, activating the expression of downstream related genes. The expression of these genes is crucial for maintaining 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 that 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, inhibitors that selectively target STAT6 have stronger targeting and fewer side effects, and are considered to have better safety.

[0007] Protein degradation-targeting chimeras (PROTACs) are an important method for selectively inducing protein degradation using the ubiquitin-proteasome pathway (UPP). A PROTAC is a bifunctional molecule, consisting of a small-molecule inhibitor recognizing the target protein at one end and an E3 ubiquitin ligase ligand recognizing E3 ubiquitin ligase at the other, linked by a linker. The PROTAC recruits the target protein at one end and binds to the E3 ubiquitin ligase at the other, forming a ternary complex. After ubiquitination of the target protein, it is degraded in vivo via the UPP. While optimizing the affinity and selectivity of STAT6 small-molecule inhibitors is challenging, STAT6 PROTACs can degrade intracellular STAT6, more thoroughly inhibiting the release of STAT6-mediated downstream inflammatory factors, and exhibiting better selectivity. Therefore, developing novel STAT6 PROTAC drugs could be used to treat various STAT6-related type 2 inflammatory diseases and tumors. Summary of the Invention

[0008] This disclosure relates to compounds of formula (I) or their stereoisomers or pharmaceutically acceptable salts.

[0009]

[0010] in:

[0011] L is the divalent part that connects STAT to LBM;

[0012] LBM is the E3 ubiquitin ligase binding site;

[0013] STAT is the portion that can bind to STAT6, and STAT is a group as described below:

[0014]

[0015] -Q- is selected from -NH-C(O)- and 5-10-membered heteroaryl groups, wherein the 5-10-membered heteroaryl group is optionally surrounded by one or more R groups. q replace;

[0016] Ring A is selected from 3-12 member subheterocyclic groups, wherein the 3-12 member subheterocyclic group is optionally surrounded by one or more R groups. Aa replace;

[0017] Ring D is selected from 4-5 membered heterocyclic groups, 7-12 membered heterocyclic groups, and C6-C. 10 arylene and 5-10 heteroarylene, wherein the 4-5 heterocyclic, 7-12 heterocyclic, C6-C 10 arylene and 5-10 heteroarylene compounds are optionally enclosed by one or more R...Dd replace;

[0018] Ring C is selected from C3-C 12 Cycloalkyl, 3-10 membered heterocyclic, C6-C 10 Aryl and 5-10 heteroaryl, the C3-C 12 Cycloalkyl, 3-10 membered heterocyclic, C6-C 10 Aryl and 5-10 heteroaryl groups are optionally coated with one or more R groups. Cc replace;

[0019] 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) T y)[NH(AA)C(O)OR T ] or -P(O)(OR 1b )[NH(AA)C(O)OR T The substituted 8-10 heteroaryl group, wherein the 8-10 heteroaryl group is optionally substituted with an amino, halogen, cyano, C1-C4 alkyl, or C1-C4 alkoxy group; or 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) T y)[NH(AA)C(O)OR T ] or -P(O)(OR 1b )[NH(AA)C(O)OR T The substituted 8-10 membered heterocyclic group, wherein the 8-10 membered heterocyclic group is optionally substituted with an amino, halogen, cyano, C1-C4 alkyl, or C1-C4 alkoxy group; or substituted with -CR 1a R 2a P(O)(OR 1b OR 2b -CR 1a R2a P(O)(OR 1b )[NH(AA)C(O)OR T ]、-P(O)(OR 1b OR 2b -P(O)(NHR) T y)[NH(AA)C(O)OR T ] or -P(O)(OR 1b )[NH(AA)C(O)OR T Replacement of C6-C 10 Aryl, the C6-C 10 The aryl group may also be optionally substituted with a cyano group, a C1-C4 alkoxy group, or a halogen; -C1-C4 alkylene group C6-C 10 aryl, the -C1-C4 alkylene C6-C 10 aryl aryl-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) T y)[NH(AA)C(O)OR T ] or -P(O)(OR 1b )[NH(AA)C(O)OR T Substitution; -C2-C4 alkenyl C6-C 10 Aryl, the -C2-C4 alkenyl C6-C 10 The aryl group of aryl is further divided 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) T y)[NH(AA)C(O)OR T ] or -P(O)(OR 1b )[NH(AA)C(O)OR T ]replace;

[0020] Each R1a 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;

[0021] each R 1b and R 2b are independently selected from hydrogen, C1-C4alkyl, C1-C4haloalkyl, -(C1-C4alkylene)-OC(O)-(C1-C6alkyl), -(C1-C4alkylene)-C(O)O-(C1-C6alkyl), -(C1-C4alkylene)-O-(C1-C6alkyl), -(C1-C4alkylene)-OC(O)-[(C1-C6)haloalkyl], -(C1-C4alkylene)-OC(O)O-(3-7 membered heterocyclyl), -(C1-C4alkylene)-OC(O)(3-7 membered heterocyclyl), -(C1-C4alkylene)-OC(O)-(C3-C6cycloalkyl), -(C1-C4alkylene)-OC(O)-(C1-C6alkylene)-OH, -(C1-C4alkylene)-OC(O)-(C1-C4alkylene)-O-(C1-C6alkyl), -(C1-C4alkylene)-OC(O)O-(C1-C6alkyl), -(C1-C4alkylene)-OC(O)O-[(C1-C6)haloalkyl], -(C1-C4alkylene)-OC(O)O-(C1-C6alkylene)-OH, -(C1-C4alkylene)-OC(O)O-(C1-C4alkylene)-O-(C1-C6alkyl), -(C1-C4alkylene)-SC(O)-(C1-C6alkyl), -(C1-C4alkylene)-SC(O)-[(C1-C6)haloalkyl], -(C1-C4alkylene)-SC(O)-(3-7 membered heterocyclyl), -(C1-C4alkylene)-SC(O)-(C3-C6cycloalkyl), -(C1-C4alkylene)-SC(O)-(C1-C6alkylene)-OH, -(C1-C4alkylene)-SC(O)-(C1-C4alkylene)-O-(C1-C6alkyl), -(C1-C4alkylene)-OC(O)NH(C1-C6alkyl)], -(C1-C4alkylene)-OC(O)N(C1-C6alkyl)2, C6-C 10 aryl and 5-6 membered heteroaryl, said C6-C 10 aryl and 5-6 membered heteroaryl are optionally substituted with halogen, cyano, or C1-C4alkyl, said 5-7 membered heterocyclyl is optionally substituted with 1 or more C(O)OR h substituents;

[0022] R 2 and R3 independently selected from hydrogen, halogen, hydroxyl, cyano, amino, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, C6-C10aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl, said C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, C6-C10aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl being optionally substituted with 1 or more R 10 independently selected from hydrogen, halogen, hydroxyl, cyano, amino, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, C6-C 10 independently selected from hydrogen, halogen, hydroxyl, cyano, amino, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, C6-C10aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl, said C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, C6-C10aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl being optionally substituted with 1 or more R S substituted;

[0023] or, R 2 and R 3 and the atom to which they are attached together form a C3-C 10 saturated carbocyclic, 4-8 membered heterocyclic, or 5-6 membered heteroaromatic ring, said C3-C 10 saturated carbocyclic, 4-8 membered heterocyclic, or 5-6 membered heteroaromatic ring being optionally substituted with halogen, cyano, amino, or C1-C4alkyl;

[0024] R 4 is selected from hydrogen, C1-C6alkyl, C2-C6alkenyl, and C2-C6alkynyl, said C1-C6alkyl, C2-C6alkenyl, and C2-C6alkynyl being optionally substituted with 1 or more halogen, cyano, hydroxyl, or amino;

[0025] each AA is a residue of an alpha or beta natural or unnatural amino acid;

[0026] each R Aa , R Dd , and R Cc is independently selected from halogen, hydroxyl, cyano, amino, =O, and C1-C4alkyl, said hydroxyl, amino, and C1-C4alkyl being optionally substituted with 1 or more R F substituted;

[0027] each R T , and R Ty is independently selected from C1-C4alkyl, benzyl, and phenyl, said benzyl and phenyl being optionally substituted with halogen, C1-C4alkyl, or C1-C4haloalkyl;

[0028] each R q , R F , and R S is independently selected from halogen, cyano, hydroxyl, amino, thiol, C1-C4alkyl, C3-C6cycloalkyl, C1-C4haloalkyl, C1-C4alkoxy, and C1-C4hydroxy-substituted alkyl;

[0029] each R hindependently selected from hydrogen, C1-C4alkyl, C2-C4alkynyl, -C1-C4alkylphenyl, phenyl, C3-C6cycloalkyl, 4-6 membered heterocycloalkyl, and 5-6 membered heteroaryl, said C1-C4alkyl optionally substituted with halogen, cyano, hydroxyl, or amino, said phenyl, C3-C6cycloalkyl, 4-6 membered heterocycloalkyl, and 5-6 membered heteroaryl optionally substituted with halogen, cyano, C1-C4alkyl, C1-C4haloalkyl, C1-C4alkoxy, C1-C4haloalkoxy, hydroxyl, phenyl, or benzyl;

[0030] one or more hydrogen atoms of the compound are optionally deuterium.

[0031] In some embodiments, -Q- is selected from -NH-C(O)-.

[0032] In some embodiments, -Q- is selected from -NH-C(O)-*, wherein * indicates attachment to R 1 .

[0033] In some embodiments, -Q- is selected from 5-10 membered heteroarylene, said 5-10 membered heteroarylene optionally substituted with 1 or more R q .

[0034] In some embodiments, -Q- is selected from 5-7 membered heteroarylene, said 5-7 membered heteroarylene optionally substituted with 1 or more R q .

[0035] In some embodiments, -Q- is selected from 5 membered heteroarylene, said 5 membered heteroarylene optionally substituted with 1 or more R q .

[0036] In some embodiments, -Q- is selected from isoxazolene, said isoxazolene optionally substituted with 1 or more R q .

[0037] In some embodiments, R q is selected from halogen and C1-C4alkyl.

[0038] In some embodiments, -Q- is selected from -NH-C(O)- and

[0039] In some embodiments, ring A is selected from 3-7 membered heterocycloalkylene, said 3-7 membered heterocycloalkylene optionally substituted with 1 or more R Aa .

[0040] In some embodiments, ring A is selected from 5-7 membered heterocycloalkylene, said 5-7 membered heterocycloalkylene optionally substituted with 1 or more R Aa .

[0041] In some embodiments, ring A is selected from pyrrole alkyl groups, The pyrrole alkyl, Optional by one or more R Aa replace.

[0042] In some implementations, ring A is selected from one or more Rs. Aa Substituted pyrrolidinyl alkyl group.

[0043] In some implementation schemes, each R Aa Independently selected from halogens, =O and C1-C4 alkyl groups, wherein the C1-C4 alkyl group is optionally surrounded by one or more R atoms. F replace.

[0044] In some implementation schemes, each R Aa Independently selected from halogens, =O and methyl, wherein the methyl group is optionally surrounded by one or more R F replace.

[0045] In some implementation schemes, each R F It is independently selected from halogen, cyano, hydroxyl and amino groups.

[0046] In some implementation schemes, each R Aa The halogen is independently selected from halogens, =O and methyl, with F being the preferred halogen.

[0047] In some implementations, ring A is selected from...

[0048] In some implementations, ring A is

[0049] In some embodiments, ring D is selected from 4-5 membered heterocyclic groups and 7-12 membered heterocyclic groups, wherein the 4-5 membered heterocyclic group and the 7-12 membered heterocyclic group are optionally surrounded by one or more R groups. Dd replace.

[0050] In some embodiments, ring D is selected from 4-5 member subheterocyclic groups, which are optionally surrounded by one or more R groups. Dd replace.

[0051] In some embodiments, ring D is selected from pyrroloalkyl groups, which are optionally surrounded by one or more R groups. Dd replace.

[0052] In some implementation schemes, each R Dd It is independently selected from halogen, hydroxyl, cyano and amino groups.

[0053] In some implementation schemes, R Dd It is a cyano group.

[0054] In some embodiments, ring D is selected from

[0055] In some embodiments, R 4 is selected from C1-C6 alkyl, preferably methyl. In some embodiments, R 4 is methyl.

[0056] In some embodiments, ring C is selected from C6-C 10 aryl and 5-10 membered heteroaryl, said C6-C 10 aryl and 5-10 membered heteroaryl are optionally substituted with 1 or more R Cc substituents.

[0057] In some embodiments, ring C is selected from phenyl and 5-7 membered heteroaryl, said phenyl and 5-7 membered heteroaryl are optionally substituted with 1 or more R Cc substituents.

[0058] In some embodiments, ring C is selected from phenyl, pyridyl, isothiazolyl and thienyl, said phenyl, pyridyl, isothiazolyl and thienyl are optionally substituted with 1 or more R Cc substituents.

[0059] In some embodiments, R Cc is independently selected from hydroxyl and amino.

[0060] In some embodiments, ring C is selected from phenyl, pyridyl, isothiazolyl and thienyl. In some embodiments, ring C is phenyl.

[0061] 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 T y)[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 is additionally optionally substituted with amino, halogen, cyano, C1-C4 alkyl or C1-C4 alkoxy; -CR 1a R 2a P(O)(OR1b )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 T y)[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 T y)[NH(AA)C(O)OR T ], or -P(O)(OR 1b )[NH(AA)C(O)OR T ]; 10 C6-C 10 aryl optionally substituted with cyano, C1-C4alkoxy, or halo.

[0062] 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 T y)[NH(AA)C(O)OR T ], or -P(O)(OR 1b )[NH(AA)C(O)OR T ;substituted 8-10 membered heteroaryl; C6-Ci0aryl or 8-10 membered heterocyclyl 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 T y)[NH(AA)C(O)OR T ], or -P(O)(OR 1b )[NH(AA)C(O)OR T ]; 10 C6-Ci0aryl or 8-10 membered heterocyclyl 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 T y)[NH(AA)C(O)OR T ], or -P(O)(OR 1b )[NH(AA)C(O)OR T ];

[0063] In some embodiments, R 1 is selected from

[0064] In some embodiments, R 1 is selected from

[0065] In some embodiments, R 1 is selected from In some embodiments, -CR 1a R 2a P(O)(OR 1b )OR 2b is selected from

[0066] In some embodiments, -CR 1a R 2a P(O)(OR1b )OR 2b is

[0067] In some embodiments, -CR 1a R 2a P(O)(OR 1b )OR 2b is selected from In some embodiments, -CR 1a R 2a P(O)(OR 1b )OR 2b is In some embodiments, R 1 is selected from

[0068] In some embodiments, -CR 1a R 2a P(O)(OR 1b )[NH(AA)C(O)OR T ] is

[0069] In some embodiments, R 1 is selected from

[0070] In some embodiments, R 1 is selected from

[0071] In some embodiments, R 2 and R 3 are independently selected from hydrogen, halogen, hydroxyl, cyano, amino, C1-C6alkyl, C3-C6cycloalkyl, and 3-10 membered heterocyclyl, said hydroxyl, amino, C1-C6alkyl, C3-C6cycloalkyl, and 3-10 membered heterocyclyl optionally substituted with 1 or more R S .

[0072] In some embodiments, R 2 and R 3 are independently selected from hydrogen, C1-C6alkyl, C3-C6cycloalkyl, and 3-10 membered heterocyclyl, said C1-C6alkyl, C3-C6cycloalkyl, and 3-10 membered heterocyclyl optionally substituted with 1 or more R S .

[0073] In some embodiments, R 2 and R 3 are independently selected from hydrogen, C1-C4alkyl, C3-C6cycloalkyl, and 3-6 membered heterocyclyl, said C1-C4alkyl, C3-C6cycloalkyl, and 3-6 membered heterocyclyl optionally substituted with 1 or more RS replace.

[0074] In some implementation schemes, R 2 For H, R 3 Selected from C1-C4 alkyl, C3-C6 cycloalkyl, and 3-6 membered heterocyclic groups, wherein the C1-C4 alkyl, C3-C6 cycloalkyl, and 3-6 membered heterocyclic groups are optionally surrounded by one or more R groups. S replace.

[0075] In some implementation schemes, R 2 For H, R 3 Selected from C1-C4 alkyl groups.

[0076] In some implementation schemes, R 2 and R 3 The radicals are independently selected from hydrogen, methyl, isopropyl, tert-butyl, cyclopropyl, and epoxyethyl, wherein the methyl, tert-butyl, cyclopropyl, and epoxyethyl groups are optionally surrounded by one or more R groups. S replace.

[0077] In some implementation schemes, each R S It is independently selected from halogen, cyano, hydroxy, amino, mercapto and C1-C4 alkyl groups.

[0078] In some implementation schemes, R S It is a cyano group.

[0079] In some implementation schemes, R 2 For hydrogen, R 3 It is selected from tert-butyl, isopropyl, cyanomethyl, cyclopropyl and epoxyethyl.

[0080] In some implementation schemes, R 2 For hydrogen, R 3 It is tert-butyl.

[0081] In some implementation schemes, R 2 and R 3 Together with the atoms they connect, they form C3-C 10 Saturated carbon rings and 4-8 membered heterocycles, the C3-C 10 The saturated carbide ring and 4-8 membered heterocycles may be optionally substituted with halogen, cyano, amino or C1-C4 alkyl groups.

[0082] In some implementation schemes, R 2 and R 3 Together with the atoms they are connected to form a C3-C6 saturated carbon ring and a 4-6 membered heterocycle, wherein the C3-C6 saturated carbon ring and the 4-6 membered heterocycle may optionally be substituted with halogen, cyano, amino or C1-C4 alkyl.

[0083] In some implementation schemes, R 2 and R3 and the atoms bound thereto collectively form an oxetane, a cyclobutane, a cyclopentane, and a cyclohexane.

[0084] In some embodiments, the STAT is

[0085] In some embodiments, the STAT is connected to L via ring C, i.e., the STAT is In some embodiments, the STAT is connected to L via ring A, i.e., the STAT is In some embodiments, the STAT is further selected from the group consisting of:

[0086]

[0087] wherein Q, R 1 , R 2 , R 3 , R Dd , ring A and ring C are as defined above.

[0088] In some embodiments, the STAT is further selected from the group consisting of:

[0089]

[0090] wherein Q, R 1 , R 2 , R 3 , ring A and ring C are as defined above.

[0091] In some embodiments, the STAT is further selected from the group consisting of:

[0092]

[0093] wherein R 1 , R 2 , R 3 , R Dd , ring A and ring C are as defined above.

[0094] In some embodiments, the STAT is further selected from the group consisting of:

[0095]

[0096] wherein R 1 , R 2 , R 3 , ring A and ring C are as defined above.

[0097] In some embodiments, the STAT is further selected from the group consisting of:

[0098]

[0100] wherein Q, R 1 , R 2 , R 3 , R Dd , ring A and ring C are as defined above.

[0101] In some embodiments, the STAT is further selected from the group consisting of:

[0102]

[0103] wherein Q, R 1 , R 2 , R 3 , R 1 , ring A and ring C are as defined above.

[0104] In some embodiments, the STAT is further selected from the group consisting of:

[0105]

[0106] wherein R 2 , R 3 , R Dd , R 1 , ring A and ring C are as defined above.

[0107] In some embodiments, the STAT is further selected from the group consisting of:

[0108]

[0109] wherein R 2 , R 3 , ring A and ring C are as defined above.

[0110] In some embodiments, the STAT is further selected from the group consisting of:

[0111]

[0112] wherein R 1 , R 2 , R 3 , R 4 , ring A and ring C are as defined above.

[0113] In some embodiments, the STAT is further selected from the group consisting of:

[0114]

[0115] wherein R 1 , R 2 , R 3 , R 4 and ring C are as defined above.

[0116] In some embodiments, the STAT is further selected from the group consisting of:

[0117]

[0118] wherein R 1 , R 2 , R 3 and ring C are as defined above.

[0119] In some embodiments, in some embodiments, the L is selected from the group consisting of -L A -, -L B -, -R 1L -, -R 2L -, -Q 1 -, -Q 2 -,

[0120] wherein: -L A -, -L B - are independently of 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’ -;

[0121] R 1L and R 2L are independently of each other selected from 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, haloalkyl, OH, hydroxyalkyl, CN, NH2, =O, cycloalkyl, heterocyclyl, aryl, heteroaryl;

[0122] Q 1 , Q 2 , Q 3 and Q 4 are independently of each other selected from cycloalkyl, heterocyclyl, aryl, heteroaryl or cycloalkenyl, wherein said cycloalkyl, heterocyclyl, aryl, heteroaryl and cycloalkenyl are each independently optionally substituted with a group selected from halogen, alkyl, alkoxy, haloalkyl, OH, hydroxyalkyl, CN, NH2, =O, cycloalkyl, heterocyclyl, aryl, heteroaryl;

[0123] R 3’ Selected from H, alkyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl;

[0124] R 4’ and R 5’ Each is independently selected from H, halogen, alkyl, alkoxy, haloalkyl, OH, hydroxyalkyl, CN, NH2, =O, cycloalkyl, heterocyclic, aryl or heteroaryl;

[0125] R 6’ It is selected from H, alkyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclic, aryl or heteroaryl.

[0126] In some implementations, L is selected from...

[0127] In some implementations, L is selected from...

[0128] In some implementations, the L is selected from -R 1L -and

[0129] In some implementations, the -L A -、-L B - is independently selected from the bonds -O-, -C(O)-, -NH- and -C(O)NH-.

[0130] In some implementations, the -L A -、-L B - Independently selected from -NH- and -C(O)NH-.

[0131] In some implementations, the R 1L and R 2L Independently selected from C1-C 10 Alkylene and C2-C 10 Imyynyl group, the C1-C 10 Alkylene and C2-C 10 Each ethynyl group is independently chosen to be =O, C3-C. 10 Cycloalkyl and 3-10 membered heterocyclic groups are substituted.

[0132] In some implementations, the R 1L and R 2L Independently selected from C1-C 10 Alkylene and C2-C 10 Alynyl group.

[0133] In some implementations, the R 1L and R 2Lis independently selected from the group consisting of C1-C4alkylene and C2-C4alkynylene.

[0134] In some embodiments, the Q 1 and Q 2 is independently selected from the group consisting of C3-C 10 cycloalkyl, 3-10 membered heterocyclyl, and 5-10 membered heteroaryl, each of which is independently optionally substituted with C1-C4alkyl. 10 cycloalkyl, 3-10 membered heterocyclyl, and 5-10 membered heteroaryl, each of which is independently optionally substituted with C1-C4alkyl.

[0135] In some embodiments, the Q 1 and Q 2 is independently selected from the group consisting of 3-10 membered heterocyclyl, each of which is independently optionally substituted with C1-C4alkyl.

[0136] In some embodiments, the L is selected from the following structures:

[0137]

[0138] In some embodiments, the L is selected from

[0139] In some embodiments, the L is selected from

[0140] In some embodiments, the L is selected from

[0141] In some embodiments, the LBM is selected from a VHL ligand, i.e., a binding moiety that binds to a Von Hippel-Lindau type E3 ubiquitin ligase; or a CRBN ligand, i.e., a binding moiety that binds to a cereblon type E3 ubiquitin ligase.

[0142] In some embodiments, the LBM is selected from a CRBN ligand.

[0143] In some embodiments, the LBM is selected from a structure represented by Formula (LBM-1) or (LBM-2):

[0144]

[0145] wherein:

[0146] is selected from

[0147] Y is a bond, or Y is selected from the group consisting of Y A , O, NH, NR E , C(O)O, C(O)NRE ', 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;

[0148] 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;

[0149] 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;

[0150] each R A ' is independently selected from C1-C3alkyl;

[0151] 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;

[0152] R C is selected from H, halogen or C1-C3alkyl;

[0153] each R D is independently selected from halogen, NO2, NH2, OH, COOH, C1-C6alkyl or C1-C6alkoxy;

[0154] each R E is independently selected from C1-C6alkyl, C2-C6alkenyl, C3-C8cycloalkyl, 3-8 membered heterocycloalkyl, C(O)-C1-C6alkyl, C(O)-C2-C6alkenyl, C(O)-C3-C8cycloalkyl or C(O)-3-8 membered heterocycloalkyl, said R E being optionally substituted with a group selected from halogen, N(Ra )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;

[0155] R E ' is selected from H, C1-C6alkyl, C2-C6alkenyl, C3-C8cycloalkyl, or 3-8 membered heterocycloalkyl, said C1-C6alkyl, C2-C6alkenyl, C3-C8cycloalkyl, or 3-8 membered heterocycloalkyl is 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;

[0156] each R a is independently selected from H or C1-C6alkyl;

[0157] R b is selected from H or p-toluenesulfonyl;

[0158] r is selected from 0 or 1;

[0159] m is selected from 0, 1, 2, or 3;

[0160] o is selected from 0, 1, or 2.

[0161] In some embodiments, the LBM is further selected from a structure represented by Formula (LBM-3):

[0162]

[0163] wherein the ring B, Y, R A , R AR B R C R D m and o are as defined above.

[0164] In some embodiments, the LBM is further selected from a structure represented by Formula (LBM-4):

[0165]

[0166] wherein Y, X’, R A R A R B R C R D m and o are as defined above.

[0167] In some embodiments, the LBM is selected from a structure represented by Formula (LBM-5):

[0168]

[0169] wherein:

[0170] 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

[0171] X D is selected from C, N, or Si;

[0172] X E is selected from a bond, -CR’2-, -NR’-, -O-, -S-, or -SiR’2-;

[0173] 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;

[0174] each R G is independently selected from H, deuterium, R Hhalogen, 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', -NP(O)R'2, -N(R')P(O)(OR')2, -N(R')P(O)(OR')NR'2, or -N(R')P(O)(NR'2)2;

[0175] each R H is independently selected from C1-C6alkyl, phenyl, 4-7 membered heterocyclyl, or 5-6 membered heteroaryl;

[0176] 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 =O;

[0177] 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 is optionally replaced with -O-, -C(O)-, -C(S)-, -C(R')2-, -CH(R')-, -C(F)2-, -N(R')-, -S-, or -S(O)2-;

[0178] 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;

[0179] g is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16.

[0180] In some embodiments, the LBM is selected from a structure represented by Formula (LBM-5'):

[0181]

[0182] wherein the XC , R F , R G , g, ring E, ring F, and ring G are as defined in formula (LBM-5).

[0183] In some embodiments, the LBM is selected from a structure represented by formula (LBM-6):

[0184]

[0185] 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 , X D , X E , R F , R G , L 1 and ring E are as defined in formula (LBM-5).

[0186] In some embodiments, the LBM is selected from a structure represented by formula (LBM-6):

[0187]

[0188] wherein: X C , R F , R G , k, ring E, and ring H are as defined in formula (LBM-6).

[0189] In some embodiments, the LBM is selected from a structure represented by formula (LBM-7):

[0190]

[0191] wherein: X C , X D , X E , R F , R G , L 1 , ring E, and k are as defined in formula (DIM-6).

[0192] In some embodiments, the DIM is selected from a structure represented by formula (LBM-7):

[0193]

[0194] wherein: X C , R F , R G , ring E, and k are as defined in formula (DIM-7).

[0195] In some embodiments, the LBM is selected from a VHL ligand.

[0196] In some embodiments, the LBM is selected from the following structure:

[0197]

[0198]

[0199] In some embodiments, the LBM is selected from the following structure:

[0200] In some embodiments, the compound of the present 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:

[0201]

[0202]

[0203]

[0204]

[0205] 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.

[0206] 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.

[0207] In another aspect, the present disclosure provides the 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.

[0208] In another aspect, the present disclosure provides the 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.

[0209] 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.

[0210] In some embodiments, the STAT6-mediated disease is asthma, atopic dermatitis, or chronic obstructive pulmonary disease.

[0211] The compounds of Formula (I) of the present disclosure, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, have good, even excellent degradation effect on STAT6.

[0212] Definitions and explanations of terms

[0213] 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 combined and integrated with each other arbitrarily. A specific term should not be considered as 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 its corresponding product or active ingredient thereof.

[0214] Herein represents a connection site. For herein of when not connected to a fixed ring or atom, represents a group that can be connected to any site in the molecule within "[]", which contains a hydrogen atom that can be substituted, including a hydrogen atom directly connected to a ring atom, a hydrogen atom on a non-hydrogen substituent of a ring atom, and a hydrogen atom in a further substituent on a substituent, after losing the hydrogen atom, for example in the connection site of

[0215] The term "[NH(AA)C(O)OR T ]", wherein NH and C(O)O are both part of an amino acid residue, NH represents the amino terminus, and C(O)O represents the carboxyl terminus.

[0216] The term "capable of binding" means capable of measurably binding to a target (e.g., a ligand of an E3 ubiquitin ligase is capable of forming a covalent bond with a cysteine of the E3 ubiquitin ligase, etc.).

[0217] The graphical representation of racemates or enantiomerically pure compounds herein is from Maehr, J. Chem. Ed. 1985, 62: 114-120. Unless otherwise indicated, a wedge solid bond and a wedge dashed bond represents the absolute configuration of a stereocenter, with a straight solid bond and a straight dashed bond represents the relative configuration of a stereocenter (e.g., the syn or anti configuration of an alicyclic compound).

[0218] When one of the variables is selected from a bond or is absent, it means that the two groups to which it is attached are directly connected, such as L represents a bond in A-L-Z means that the structure is actually A-Z.

[0219] 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 examples of enantiomeric or diastereomeric mixtures that are richer in one enantiomer or diastereomer than the other. All such isomers, as well as mixtures thereof, are intended to be 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, as well as mixtures thereof, are included in the definition of the compounds of the present disclosure. The 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 by separation from the racemic mixtures or by using chiral starting materials or chiral reagents in the synthetic sequence.

[0220] The term "substituted" means that any one or more hydrogen atoms on the particular atom is replaced with a substituent group, provided that the valency 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 cannot be present on an aromatic group.

[0221] The term "optionally" or "optional" means that the subsequently described event or circumstance can or can not occur, and this description includes instances where said 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 understand that for any group containing one or more substituents, no substitution or substitution pattern is introduced that is not spatially possible and / or synthetically feasible.

[0222] When any variable (e.g., R a , R b ) occurs more than one time in a compound, its definition in each instance is independent of the other occurrences. For example, if a group is substituted with 2 R bReplaced, then each R b Each has its own independent options.

[0223] When the number of a linking group is 0, such as -(CH2)0-, it indicates that the linking group is a bond.

[0224] C in this article m -C n It refers to having an integer number of carbon atoms in the range mn. For example, "C1-C 10 "" means that the group can have 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms.

[0225] If the linking group mentioned in this article does not specify its linking direction, then its linking direction is arbitrary. For example, when the structural unit... L in 1 When selected from "C1-C3 alkylene-O", L 1 Both loops Q and R can be connected in a left-to-right direction. 1 Composed of "cyclo-Q-C1-C3 alkylene-OR" 1 Alternatively, rings Q and R can be connected from right to left. 1 Composed of "cyclo-QO-C1-C3 alkylene-R" 1 ".

[0226] When a substituent is cross-bonded to two atoms on a ring, it can bond to any atom on that ring. For example, structural units. R represents 5 Substitution can occur at any position on the benzene ring.

[0227] The term "alkyl" refers to a compound with the general formula C10. n H 2n+1 The alkyl group can be straight-chain or branched. The term "C1-C" refers to a hydrocarbon group. 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 "Ci-C6alkyl" can further comprise "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-C 10 alkyl group as defined above substituted by one or more halogen, including but not limited to trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, trichloromethyl, pentafluoroethyl and pentachloroethyl and the like.

[0228] The term "alkoxy" refers to a straight-chained or branched alcohols group losing a hydrogen atom on the hydroxyl group resulting in a group, which can be understood as "alkyloxy" or "alkyl-O-". The term "Ci-C 10 alkoxy" can be understood as "Ci-C 10 alkyloxy" or "Ci-C 10 alkyl-O-"; the term "Ci-C6alkoxy" can be understood as "Ci-C6alkyloxy" or "Ci-C6alkyl-O-". Said "Ci-C 10 alkoxy" can comprise the ranges "Ci-C6alkoxy" and "Ci-C3alkoxy", said "Ci-C6alkoxy" can further comprise "Ci-C3alkoxy".

[0229] The term "alkenyl" refers to an unsaturated aliphatic hydrocarbon group consisting of a straight or branched chain of carbon and hydrogen atoms and having at least one double bond. The term "C2-C"... 10 "Alkenyl" can be understood as representing a straight-chain or branched unsaturated hydrocarbon group containing one or more double bonds and having 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms, "C2-C". 10 "Alkenyl" can include "C2-C6 alkenyl", "C2-C4 alkenyl", C2 or C3 alkenyl. It is understood that when the alkenyl group contains more than one double bond, the double bonds can be separable or conjugated. Specific examples of alkenyl groups 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.

[0230] The term "alkynyl" refers to a straight-chain or branched unsaturated aliphatic hydrocarbon group consisting of carbon and hydrogen atoms and having at least one triple bond. The term "C2-C"... 10 "Alkyne" can be understood as representing a straight-chain or branched unsaturated hydrocarbon group 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≡CCH3, -CH2C≡CH), buty-1-alkynyl, buty-2-alkynyl, or buty-3-alkynyl. "C2-C 10 "Alynyl" can include "C2-C3 alkynyl", and examples of "C2-C3 alkynyl" include ethynyl (-C≡CH), propynyl-1-alkynyl (-C≡CCH3), and propynyl-2-alkynyl (-CH2C≡CH).

[0231] 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" is also used. 10 "Cycloalkyl" refers to a cycloalkyl group having 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms in the ring. The term "C3-C6 cycloalkyl" refers to a cycloalkyl group having 3, 4, 5, or 6 carbon atoms in the ring.

[0232] 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 heterocyclic groups in this disclosure partially contain a benzene ring or a heteroaromatic ring, the heterocyclic group as a whole remains non-aromatic. The term "subheterocyclic group" refers to a residue derived by further removing a hydrogen atom from a heterocyclic group.

[0233] The term "heterocyclic alkyl" refers to a fully saturated cyclic group existing in the form of a monocyclic, fused, bridged, or spirocyclic ring, wherein the ring atoms contain 1-5 heteroatoms or heteroatom groups (i.e., atomic groups containing heteroatoms). These "heteroatoms or heteroatom groups" include, but are not limited to, nitrogen (N), oxygen (O), sulfur (S), phosphorus (P), boron (B), -S(=O)2-, -S(=O)-, -NH-, -S(=O)(=NH)-, -C(=O)NH-, or -NHC(=O)NH-. The term "4-10 membered heterocyclic alkyl" refers to a heterocyclic alkyl group with 4, 5, 6, 7, 8, 9, or 10 ring atoms, and its ring atoms contain 1-5 independently selected heteroatoms or heteroatom groups as described above. The term "5-10 membered heterocyclic alkyl" refers to a heterocyclic alkyl group with 5, 6, 7, 8, 9 or 10 ring atoms, and whose ring atoms contain 1 to 5 independent heteroatoms or heterogroups selected from those described above. "4-10-membered heterocyclic alkyl" and "5-10-membered heterocyclic alkyl" include "4-7-membered heterocyclic alkyl", wherein specific examples of 4-membered heterocyclic alkyl include, but are not limited to, acridine, oxadiazolyl, or thiobutylcycloyl; specific examples of 5-membered heterocyclic alkyl include, but are not limited to, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, imidazolyl, or tetrahydropyrazolyl; specific examples of 6-membered heterocyclic alkyl include, but are not limited to, piperidinyl, tetrahydropyranyl, tetrahydrothiaranyl, morpholinyl, piperazine, 1,4-thiaoxalyl, 1,4-dioxane, thiomorpholinyl, 1,3-dithiaalkyl, or 1,4-dithiaalkyl; and specific examples of 7-membered heterocyclic alkyl include, but are not limited to, azirheptanyl, oxaheptanyl, or thioheptanyl.

[0234] The term "aryl" refers to an aromatic ring group consisting of an all-carbon monocyclic or fused polycyclic aromatic cyclic group with a conjugated π-electron system. Aryl groups can have 6-20, 6-14, or 6-12 carbon atoms. The term "C6-C"... 10 "Aryl" can be understood as an aryl group having 6 to 10 carbon atoms. Examples include a ring with 6 carbon atoms ("C6 aryl"), such as phenyl; or a ring with 9 carbon atoms ("C9 aryl"), such as indenyl or indenyl; or a ring with 10 carbon atoms ("C9 aryl"). 10 Aryl), such as tetrahydronaphthyl, dihydronaphthyl, or naphthyl. The term "aryl" refers to a residue derived from an aryl group by further removing a hydrogen atom.

[0235] 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 and their benzo derivatives, 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 and their benzo derivatives, e.g. quinolinyl, quinazolinyl or isoquinolinyl and the like; or azocinyl, indolizinyl, purinyl and the like and their benzo derivatives; 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" is a residue derived from a heteroaryl group by further removal of one hydrogen.

[0236] The term "halo" or "halogen" refers to fluoro, chloro, bromo or iodo.

[0237] The term "hydroxy" refers to the -OH group.

[0238] The term "cyano" refers to the -CN group.

[0239] The term "amino" refers to the -NH2 group.

[0240] The term "nitro" refers to the -NO2 group.

[0241] 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:

[0242] (i) inhibiting the disease or condition, i.e., arresting its development;

[0243] (ii) relieving the disease or condition, i.e., causing regression of the disease or condition.

[0244] The term "therapeutically effective amount" means an amount of a compound of the disclosure that (i) treats a particular disease, condition, or disorder, (ii) alleviates, ameliorates, or eliminates one or more symptoms of a particular disease, condition, or disorder. The amount of a compound of the disclosure that will constitute 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 by a consideration of the factors relevant to the choice of an appropriate dose of a therapeutic agent.

[0245] The term "prevent" means administering 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 disease state 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.

[0246] 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 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.

[0247] The term "pharmaceutically acceptable" refers to those compounds, materials, compositions, and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0248] The term "pharmaceutically acceptable salt" refers to pharmaceutically acceptable salts of acids or bases that are included in the disclosure, including salts of compounds with inorganic or organic acids, and salts of compounds with inorganic or organic bases.

[0249] The term "pharmaceutical composition" refers to 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.

[0250] The term "pharmaceutically acceptable excipient" refers to those excipients that are not biologically or otherwise undesirable, and that do not interfere with the biological activity of the active compound. Suitable excipients are well known to those skilled in the art, e.g., carbohydrates, waxes, water soluble and / or swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, and the like.

[0251] The word "comprise" or "comprising" and variations such as "comprises" or "comprising", will be understood to imply the inclusion of a stated step or element but not the exclusion of any other steps or elements.

[0252] The present disclosure also includes isotopically-labelled 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 present 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.

[0253] Certain isotopically-labelled compounds of the present 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, are useful in positron emission tomography (PET) studies for measurement of substrate occupancy. Isotopically-labelled compounds of the present disclosure can generally be prepared by

[0254] The pharmaceutical compositions of the present disclosure can be manufactured by combining a compound of the present disclosure with suitable pharmaceutically acceptable excipients, and can be formulated into preparations in solid, semi-solid, liquid or gaseous forms, such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres, aerosols and the like.

[0255] Typical routes of administering the compounds of the disclosure, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, include, but are not limited to, oral, rectal, topical, inhalant, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, intravenous administration.

[0256] The pharmaceutical compositions of the present disclosure can be manufactured in a manner standard to the art, such as by conventional mixing, dissolving, granulating, emulsifying, re- freezing drying, or lyophilizing processes.

[0257] In some embodiments, the pharmaceutical composition is in oral form. For oral administration, the pharmaceutical composition can be formulated by combining the active compounds with pharmaceutically acceptable excipients well known in the art. These excipients enable the compounds of the present disclosure to be formulated as tablets, pills, dragees, sugar-coated tablets, capsules, liquids, gels, slurries, suspensions, and the like, for oral administration to a patient.

[0258] Solid oral compositions can be prepared by conventional mixing or compaction methods. For example, the active compounds can be mixed with a solid excipient, optionally ground, and if necessary, with other suitable excipients, and then processed into granules or a core for tablets or sugar-coated tablets. Suitable excipients include, but are not limited to, binders, diluents, disintegrants, lubricants, glidants, or flavorings.

[0259] The pharmaceutical composition can also be suitable for parenteral administration, such as sterile solutions, suspensions or lyophilized products in suitable unit dosage forms.

[0260] The dosage administered will depend on such factors 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 judgment of the treating physician, including, for example, the particular composition to be administered, the mode of administration, the disorder to be treated, and the subject or host to be treated.

[0261] In all methods of administration of the compounds of general formula (I) described herein, the daily dosage for oral administration is in the range of 0.01 mg / kg to 100 mg / kg body weight, in single or divided doses. The daily dose and unit dose are varied according to many variables, including but not limited to the activity of the compound used, the disease or disorder to be treated, the mode of administration, the requirements of the individual subject, the severity of the disease or disorder to be treated, and the judgment of the practitioner.

[0262] The compounds of the present disclosure can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments set forth below, embodiments formed by a combination of the other chemical synthetic methods well known to those skilled in the art, and equivalents thereof well known to those skilled in the art, preferred embodiments including but not limited to the examples of the present disclosure.

[0263] The chemical reactions of the specific embodiments of the present disclosure are performed in solvents appropriate to the reactants and reagents used and appropriate to the desired transformation. These reactions are performed at temperatures appropriate to the solvents and reagents used and appropriate to the transformation. The reagents and solvents used in the synthesis of the compounds of the present disclosure are either commercially available or are readily prepared by standard synthetic methods known to the skilled artisan.

[0264] The following abbreviations have been used in the present disclosure:

[0265] THF represents tetrahydrofuran; HOBt represents 1-hydroxybenzotriazole; DCM represents dichloromethane; TFA represents trifluoroacetic acid; DIEA represents N,N-diisopropylethylamine; MeOH represents methanol; EtOH represents ethanol; Dioxane represents 1,4-dioxane; EDCI represents l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride; DMAP represents 4-dimethylaminopyridine; ISiMe3 represents trimethylsilyl iodide; NaOAc represents sodium acetate; Pd-PEPPSI-IPent-Cl represents (SP-4-1)-[l,3-bis[2,6-bis(l- ethylpropyl)phenyl]-4,5-dichloro-l,3-dihydro-2H-imidazol-2-ylidene]dichloro(3- chloropyridine-KN)palladium; tBuOK represents potassium tert-butoxide; TMS represents trimethylsilyl; DCE represents 1,2-dichloroethane; DMA represents N,N- dimethylacetamide; Py represents pyridine; HOBT represents 1-hydroxybenzotriazole; LC-MS represents liquid chromatography-mass spectrometry; MS represents mass spectrometry; 1 H NMR represents proton nuclear magnetic resonance; ESI represents electrospray ionization; HPLC represents high performance liquid chromatography; DMSO represents dimethylsulfoxide; PBS represents phosphate buffered saline; DC 50 represents the half maximal inhibitory concentration of a compound. BRIEF DESCRIPTION OF DRAWINGS

[0266] Figure 1 Stereoscopic ellipsoidal plot of intermediate A

[0267] Figure 2 Cell structure packing plot of intermediate A DETAILED DESCRIPTION

[0268] The compounds of the present disclosure can be prepared by a variety of synthetic methods known to those skilled in the art, including the specific embodiments set forth herein, embodiments formed by the combination of the specific embodiments set forth herein with other chemical synthetic methods, and equivalents thereof known to those skilled in the art, preferred embodiments including but not limited to the examples of the present disclosure.

[0269] The present disclosure is described in detail below with reference to embodiments, but this does not imply any adverse limitation thereof. 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 of the present disclosure without departing from the spirit and scope thereof. All reagents used in this disclosure are commercially available and can be used without further purification.

[0270] Unless otherwise stated, the proportions of mixed solvents are volume-based.

[0271] Unless otherwise stated, % refers to weight percentage (wt%).

[0272] Compounds are processed manually or Software naming conventions are used; commercially available compounds use supplier catalog names.

[0273] The structure of the compound was determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts are measured in units of 10⁻⁶. -6 (ppm). The solvents used for NMR determination were deuterated dimethyl sulfoxide, deuterated chloroform, deuterated methanol, etc., and the internal standard was tetramethylsilane (TMS).

[0274] The eluent or mobile phase may be a mixture of two or more solvents, with the ratio being the volume ratio of each solvent.

[0275] Preparation example:

[0276] Synthesis of Intermediates A & B: (3R,4S)-4-(4-nitrophenyl)pyrrolidine-3-onitrile hydrochloride and (3S,4R)-4-(4-nitrophenyl)pyrrolidine-3-onitrile hydrochloride

[0277] Step 1: Synthesis of (E)-3-(4-nitrophenyl)acrylonitrile (A-2)

[0278] A 1M, 7mL solution of potassium tert-butoxide in tetrahydrofuran was added to 10mL of tetrahydrofuran. The mixture was cooled to 0°C under an argon atmosphere. Diethyl(cyanomethyl)phosphonate (1.17g, 6.62mmol) was added dropwise, and the reaction was carried out for 30 minutes. Then, 4-nitrobenzaldehyde (A-1, 1.00g, 6.62mmol) was added, and the reaction was continued for another 30 minutes. The mixture was then allowed to react overnight at room temperature. TLC analysis showed that the reaction was complete. The reaction solution was diluted with 20mL of ethyl acetate, washed with saturated brine (10mL × 3), 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 (100% dichloromethane) to give the title compound A-2 (495mg).

[0279] 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).

[0280] Step 2: Synthesis of trans-1-benzyl-4-(4-nitrophenyl)pyrrolidine-3-carbonitrile (A-3)

[0281] (E)-3-(4-nitrophenyl)acrylonitrile (A-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-l-methoxy-N-((trimethylsilyl)methyl)methanamine (1.35 g, 5.68 mmol) was added dropwise, followed by moving to room temperature for overnight reaction. LC-MS detection showed that the reaction was complete, the reaction solution was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0-20% gradient elution) to give the title compound A-3 (834 mg).

[0282] MS m / z (ESI): = 308.1 [M+H] + .

[0283] Step 3: Synthesis of (3R,4S)-1-benzyl-4-(4-nitrophenyl)pyrrolidine-3-carbonitrile and (3S,4R)-1-benzyl-4-(4-nitrophenyl)pyrrolidine-3-carbonitrile (A-3P1 and A-3P2)

[0284] The trans-1-benzyl-4-(4-nitrophenyl)pyrrolidine-3-carbonitrile intermediate (A-3) was resolved by chiral SFC 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 (A-3P1 and A-3P2)

[0285] Chiral analysis 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. A-3P1 retention time: 1.455 min, A-3P2 retention time: 1.626 min.

[0286] Step 4: Synthesis of (3S,4R)-4-(4-nitrophenyl)pyrrolidine-3-carbonitrile hydrochloride and (3R,4S)-4-(4-nitrophenyl)pyrrolidine-3-carbonitrile hydrochloride (Intermediate A and Intermediate B)

[0287] Intermediate A-3P1(or Intermediate A-3P2)(75 mg, 0.24 mmol) was dissolved in 1,2-dichloroethane (0.5 mL) and cooled to 0 °C. Then 1-chloroethyl chloroformate (348 mg, 2.40 mmol) was dissolved in 1,2-dichloroethane (0.5 mL) and added dropwise to the above solution. After 30 minutes at this temperature, the reaction was warmed to 80 °C for 1 hour, cooled to room temperature, and the reaction was concentrated to dryness under reduced pressure. The residue was dissolved in methanol (1 mL) and heated to 80 °C for 1 hour. LC-MS analysis showed that the reaction was essentially complete, and the reaction was concentrated to dryness under reduced pressure to give Intermediate A (or Intermediate B), which was used directly in the next step without purification.

[0288] Intermediate A-3P1 was prepared to obtain Intermediate A, and Intermediate A-3P2 was prepared to obtain Intermediate B.

[0289] MS m / z (ESI): = 218.1 [M+H] +

[0290] After single crystal cultivation, Intermediate A was identified as (3S,4R)-4-(4- nitrophenyl)pyrrolidine-3-carbonitrile, by the following method:

[0291] Single crystal cultivation method: 10 mg of Intermediate A (hydrochloride form) was weighed into a 1.5 mL centrifuge tube, 500 μL of methanol was added, and after ultrasonic dissolution, the tube was sealed with a sealing film, three small holes were punched in the sealing film with a needle, and the tube was slowly evaporated at 30 °C. After 3 days, a rod-shaped crystal was obtained, which was the single crystal of the compound.

[0292] The obtained single crystal sample was subjected to X-ray analysis, and the test results are shown in Table 1 and Figure 1 .

[0293] The test power was 70 W, the test voltage was 50 kV, and the test current was 1.4 mA.

[0294] Table 1 Single crystal sample and crystal data of Intermediate A

[0295]

[0296] Through the above X-ray crystal diffraction experiment, the chemical structure and absolute configuration of Intermediate A were determined, and it was identified as (3S,4R)-4-(4- nitrophenyl)pyrrolidine-3-carbonitrile monohydrochloride.

[0297] Synthesis of Intermediate C

[0298]

[0299] Step 1: Synthesis of ((S)-2-((tert-butoxycarbonyl)amino)-3,3-dimethylbutanoyl)-L- proline methyl ester (C-2)

[0300] (S)-2-((tert-butoxycarbonyl)amino)-3,3-dimethylbutanoic acid (C-1, 3.00 g, 12.97 mmol) was dissolved in dichloromethane (60 mL), then L-proline methyl ester hydrochloride (2.51 g, 15.16 mmol), 1-hydroxybenzotriazole (2.63 g, 19.46 mmol), N-(3- dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (3.73 g, 19.46 mmol) and N,N- diisopropylethylamine (3.35 g, 25.94 mmol) were added, and the resulting mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the resulting residue was separated and purified by silica gel column (petroleum ether / ethyl acetate = 3 / 2) to obtain the title compound C-2 (4.20 g).

[0301] MS m / z (ESI): 343.2 [M+H] +

[0302] Step 2: Synthesis of ((S)-2-((tert-butoxycarbonyl)amino)-3,3-dimethylbutanoyl)-L- proline (C-3)

[0303] ((S)-2-((tert-butoxycarbonyl)amino)-3,3-dimethylbutanoyl)-L-proline methyl ester (C-2, 4.20 g, 12.27 mmol) was dissolved in methanol (60 mL) and water (60 mL), then lithium hydroxide (587 mg, 24.53 mmol) was added, and the resulting mixture was stirred at room temperature overnight. After the reaction was completed, the organic phase was removed by concentrating the reaction solution under reduced pressure, then the pH was adjusted to 5 with 1N aqueous hydrochloric acid solution, extracted with ethyl acetate (3 x 60 mL), and the combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound C-3 (3.70 g).

[0304] MS m / z (ESI): 329.2 [M+H] +

[0305] Step 3: Synthesis of compound C-4

[0306] ((S)-2-((tert-butoxycarbonyl)amino)-3,3-dimethylbutanoyl)-L-proline (C-3, 528 mg, 1.61 mmol) was dissolved in dichloromethane (5 mL) at room temperature, then (3S,4R)-4-(4-nitrophenyl)pyrrolidine-3-carbonitrile hydrochloride (intermediate A, 408 mg, 1.61 mmol), 1-hydroxybenzotriazole (327 mg, 2.42 mol), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (472 mg, 2.42 mol) and N,N-diisopropylethylamine (623 mg, 4.83 mmol) were added, and the resulting mixture was stirred at room temperature for 2 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the resulting residue was separated and purified by silica gel column (petroleum ether / ethyl acetate = 3 / 2) to obtain the title compound (780 mg).

[0307] MS m / z (ESI): 550.2 [M+Na] +

[0308] Step 4: Synthesis of intermediate C

[0309] Intermediate C-4 (760 mg, 1.44 mmol) was dissolved in ethanol (12 mL) and water (3 mL) at room temperature, then reduced iron powder (402 mg, 7.20 mmol) and ammonium chloride (370 mg, 7.20 mmol) were added, and the resulting mixture was stirred at 80°C for 2 hours. After completion of the reaction, water (10 mL) was added to the reaction solution to dilute, extracted with ethyl acetate (30 mL x 3), and the combined organic phase was 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 (methanol / dichloromethane = 1 / 20) to obtain the title compound (680 mg).

[0310] MS m / z (ESI): 498.3 [M+H] +

[0311] Synthesis of intermediate D: (difluoro(2-((perfluorophenoxy)carbonyl)benzo[b]thiophen-5-yl)methyl)phosphonic acid

[0312]

[0313] Step 1: Synthesis of 5-((diethoxyphosphoryl)difluoromethyl)benzo[b]thiophene-2-carboxylic acid (perfluorophenyl ester) (D-2)

[0314] 5-((diethoxyphosphoryl)difluoromethyl)benzo[b]thiophene-2-carboxylic acid (D-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).

[0315] MS m / z (ESI): 531.0 [M+H] +

[0316] 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).

[0317] Step 2: Synthesis of (difluoro(2-((perfluorophenoxy)carbonyl)benzo[b]thiophen-5-yl)methyl)phosphonic acid (Intermediate D)

[0318] 5-((diethoxyphosphoryl)difluoromethyl)benzo[b]thiophene-2-carboxylic acid (D-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).

[0319] MS m / z (ESI): 472.9 [M-H] -

[0320] 1H NMR (400 MHz, DMSO-d6) δ 8.80 (s, 1H), 8.35 - 8.27 (m, 2H), 7.78 - 7.71 (m, 1H).

[0321] Synthesis of intermediate E: 1-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3- dihydro-1H-benzo[d]imidazol-5-yl)piperidine-4-carbaldehyde

[0322]

[0323] Step 1: Synthesis of 3-(5-(4-(dimethoxymethyl)piperidin-1-yl)-3-methyl-2-oxo-2,3- dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (E-2)

[0324] Under nitrogen protection, 3-(5-bromo-3-methyl-2-oxo-2,3-dihydro-1H- benzo[d]imidazol-1-yl)piperidine-2,6-dione (E-1, 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)-[1,3-bis[2,6-bis(1-ethylpropyl)phenyl]-4,5-dichloro-1,3-dihydro-2H- imidazol-2-ylidene]dichloropalladium (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. LCMS showed that the reaction was complete. Ethyl acetate (10 mL) and water (10 mL x 2) were added for extraction, the organic phase was combined, dried, filtered, and the filtrate was concentrated to give the title compound (20 mg).

[0325] Step 2: Synthesis of 1-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H- benzo[d]imidazol-5-yl)piperidine-4-carbaldehyde (intermediate E)

[0326] 3-(5-(4-(dimethoxymethyl)piperidin-1-yl)-3-methyl-2-oxo-2,3-dihydro-1H- benzo[d]imidazol-1-yl)piperidine-2,6-dione (E-2, 18 mg, 43.22 μmol) was dissolved in a mixed solution of tetrahydrofuran (2 mL) and water (0.4 mL), hydrochloric acid (2 M, 216.10 μL) was added, and the reaction was carried out at 60 °C for 3 hours. The solvent was removed by concentration under reduced pressure, and an appropriate amount of acetonitrile and water were added for lyophilization to give the title compound (15 mg).

[0327] MS m / z (ESI): 371.1 [M+H]+

[0328] Synthesis of Intermediate H: 5-((bis(2-((3-methylbutanoyl)thio)ethoxy) phosphoryl)difluoromethyl)benzo[b]thiophene-2-carboxylic acid perfluorophenyl ester

[0329]

[0330] Step 1: Synthesis of S-(2-hydroxyethyl)-3-methylbutanoic acid thioester (H-2)

[0331] 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), the gas was replaced with argon for three times, 2-mercaptoethanol (H-1, 4 g, 51.19 mmol) was added slowly at -78 °C, the reaction solution was stirred at -78 °C for 1 hour under the protection of argon. Then the reaction solution was moved to room temperature, and the stirring was continued for 1 hour. Then saturated aqueous ammonium chloride solution was added for quenching, extracted with dichloromethane for three times (200 mL), the organic phase was combined and dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and then purified by column chromatography (silica, petroleum ether / ethyl acetate = 10 / 1) to give the title compound (4.81 g).

[0332] 1 H NMR (400 MHz, CDC13) 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).

[0333] Step 2: Synthesis of S-(2-iodoethyl)-3-methylbutanoic acid thioester (H-3)

[0334] Into a reaction flask was placed S-(2-hydroxyethyl)-3-methylbutanoic acid thioester (H-2, 1 g, 6.16 mmol), triphenylphosphine (1.62 g, 6.16 mmol), dichloromethane (20 mL), then 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, 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, and then purified by column chromatography (silica, petroleum ether) to give the title compound (1.41 g).

[0335] 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).

[0336] Step 3: Synthesis of (difluoro(2-((perfluorophenoxy)carbonyl)benzo[b]thiophen-5- yl)methyl)phosphonic acid disilver salt (H-4)

[0337] To a reaction flask was added (difluoro(2-((perfluorophenoxy)carbonyl)benzo[b]thiophen-5- yl)methyl)phosphonic acid (Intermediate D, 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).

[0338] Step 4: Synthesis of perfluorophenyl 5-((bis(2-((3-methylbutanoyl)thio)ethoxy)phosphoryl)difluoromethyl)benzo[b]thiophene-2-carboxylate (Intermediate H)

[0339] To a reaction flask was added (difluoro(2-((perfluorophenoxy)carbonyl)benzo[b]thiophen-5- yl)methyl)phosphonic acid disilver salt (H-4, 600 mg, 872.14 pmol), super dry toluene (6 mL) was added, then S-(2-iodoethyl)-3-methylbutanoic thioester (H-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).

[0340] 1 H 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).

[0341] Synthesis of intermediate I: 5-(fluoro((((S)-1-oxo-1- propyloxypropan-2-yl)amino)(phenoxy)phosphoryl)methyl)benzo[b]thiophene-2- carboxylic acid

[0342]

[0343] Step 1: Synthesis of ethyl 5-methylbenzo[b]thiophene-2-carboxylate (I-2)

[0344] To a solution of 2-fluoro-5-methylbenzaldehyde (I-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 h. After completion of the reaction, the reaction mixture was cooled to room temperature, poured into ice water, stirred for 1 h, filtered, the filter cake was washed once with water, and dried to give the title compound as a crude product (120 g), which was used directly in the next step without further purification.

[0345] MS m / z (ESI): 221.1 [M+H] +

[0346] Step 2: Synthesis of 5-methylbenzo[b]thiophene-2-carboxylic acid (I-3)

[0347] 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 crude (I-2, 120 g, 0.54 mol) in methanol (600 mL) and tetrahydrofuran (600 mL) at room temperature, and the resulting reaction mixture was stirred at room temperature for 1 h. After completion of the reaction, the organic solvents were removed by concentration under reduced pressure, diluted with water (300 mL), adjusted to pH 3 with dilute hydrochloric acid (2 N), 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 give a crude product, which was washed twice with petroleum ether and dried to give the title compound (58.0 g).

[0348] MS m / z (ESI): 193.1 [M+H] +

[0349] Step 3: Synthesis of benzyl 5-methylbenzo[b]thiophene-2-carboxylate (I-4)

[0350] To 5-methylbenzo[b]thiophene-2-carboxylic acid (I-3, 58 g, 0.30 mol) in N,N- dimethylformamide (500 mL) was 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 h. 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 give a crude product, which was dried by washing with petroleum ether twice to give the title compound (75 g).

[0351] MS m / z (ESI): 283.1 [M+H] +

[0352] Step 4: Synthesis of benzyl 5-(bromomethyl)benzo[b]thiophene-2-carboxylate (I-5)

[0353] To benzyl 5-methylbenzo[b]thiophene-2-carboxylate (I-4, 75 g, 0.266 mol) in 1,2- dichloroethane (1.2 L) was added N-bromosuccinimide (51.64 g, 0.29 mol) and azobisisobutyronitrile (8.66 g, 0.053 mol) at room temperature. The resulting mixture was warmed to 80 °C and stirred for 16 h. After completion of the reaction, the reaction solution was cooled to room temperature, diluted with water (500 mL), 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 residue was purified by column chromatography on silica gel (petroleum ether / dichloromethane = 3 / 1) to give the title compound (40 g).

[0354] MS m / z (ESI): 383.0 [M+Na] +

[0355] Step 5: Synthesis of benzyl 5-((diethoxyphosphoryl)methyl)benzo[b]thiophene-2- carboxylate (I-6)

[0356] To benzyl 5-(bromomethyl)benzo[b]thiophene-2-carboxylate (I-5, 40 g, 0.11 mol) in toluene (400 mL) was added triethyl phosphite (400 mL) at room temperature. The resulting reaction solution was warmed to 110 °C and stirred for 16 h. After completion of the reaction, the reaction solution was cooled to room temperature and concentrated under reduced pressure to give a residue, which was purified by column chromatography on silica gel (ethyl acetate / dichloromethane = 1:2) to give the title compound (37 g).

[0357] MS m / z (ESI): 419.1 [M+H] +

[0358] Step 6: Synthesis of benzyl 5-((diethoxyphosphoryl)fluoromethyl)benzo[b]thiophene-2-carboxylate (I-7)

[0359] Benzyl 5-((diethoxyphosphoryl)methyl)benzo[b]thiophene-2-carboxylate (I-6, 27 g, 64.53 mmol) was dissolved in tetrahydrofuran (200 mL) at room temperature, replaced with nitrogen for 3 times, cooled to -70 °C, slowly added dropwise with lithium bis(trimethylsilyl)amide (71 mL, 70.98 mmol, 1 M) under nitrogen atmosphere, then slowly added dropwise with a solution of N-fluorobenzenesulfonimide (20.96 g, 66.46 mmol) in tetrahydrofuran (200 mL), kept stirring at -70 °C for 1 hour after dropwise addition was completed. 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), the combined organic phase was washed with saturated brine, 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 = 1 / 1) to obtain the title compound (18 g).

[0360] MS m / z (ESI): 437.1 [M+H] +

[0361] 1 H 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).

[0362] Step 7: Synthesis of ((2-((benzyloxy)carbonyl)benzo[b]thiophen-5-yl)fluoromethyl)phosphonic acid (I-8)

[0363] Benzyl 5-((diethoxyphosphoryl)fluoromethyl)benzo[b]thiophene-2-carboxylate (I-7, 2.18 g, 5.00 mmol) was dissolved in dichloromethane (20 mL) under ice bath, added with trimethylsilyl iodide (3.00 g, 14.99 mmol) and N,O-bistrimethylsilyltrifluoroacetamide (3.21 g, 12.47 mmol), 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, added with appropriate amount of water and acetonitrile, and freeze-dried to obtain the title compound (1.88 g).

[0364] MS m / z (ESI): 379.1 [M-H] -

[0365] Step 8: Synthesis of benzyl 5-(fluoro((((S)-1-oxo-1- propoxypropan-2-yl)amino)(phenoxy)phosphoryl)methyl)benzo[b]thiophene-2- carboxylate (I-9)

[0366] ((2-((benzyloxy)carbonyl)benzo[b]thiophen-5-yl)fluoromethyl)phosphonic acid (I-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 the 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).

[0367] MS m / z (ESI): 570.2 [M+H] +

[0368] Step 9: Synthesis of 5-(fluoro((((S)-1-oxo-1-propoxypropan-2-yl)amino)(phenoxy)phosphoryl)methyl)benzo[b]thiophene-2-carboxylic acid (Intermediate I)

[0369] Benzyl 5-(fluoro((((S)-1-oxo-1-propoxypropan-2-yl)amino)(phenoxy)phosphoryl)methyl)benzo[b]thiophene-2-carboxylate (I-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 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).

[0370] MS m / z (ESI): 480.1 [M+H]+

[0371] Synthesis of Intermediate J: Perfluorophenyl 5-(fluoro((((S)-1-oxo-1- propyloxypropan-2-yl)amino)(phenoxy)phosphoryl)methyl)benzo[b]thiophene-2- carboxylate

[0372]

[0373] Intermediate J: Perfluorophenyl 5-(fluoro((((S)-1-oxo-1- propyloxypropan-2-yl)amino)(phenoxy)phosphoryl)methyl)benzo[b]thiophene-2- carboxylate

[0374] MS-ESI: m / z = 646.1 [M+H] +

[0375] Synthesis of Intermediate K: tert-Butyl ((S)-1-((S)-2-((4- aminophenyl)(methyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1- oxobutan-2-yl)carbamate

[0376]

[0377] Step 1: Synthesis of tert-butyl (S)-2-(methyl(4-nitrophenyl)carbamoyl)pyrrolidine-1- carboxylate (K-2)

[0378] tert-Butyl (S)-2-(methyl(4-nitrophenyl)carbamoyl)pyrrolidine-1-carboxylate (K-2) was prepared according to the procedure described in WO2016 / 175 1 1 1, except that (tert- butoxycarbonyl)-L-proline (K-1, 2.0 g, 9.29 mmol), N-methyl-4-nitroaniline (2.12 g, 13.94 mmol), and phosphorus oxychloride (4.27 g, 27.88 mmol) were dissolved in dichloromethane (20 mL) at room temperature. The temperature was lowered to 0 °C and dry pyridine (7.35 g, 92.92 mmol) was added dropwise. The reaction was stirred for 10 min at 0 °C and then allowed to warm to room temperature. The reaction was stirred for 16 h at room temperature. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (dichloromethane / methanol = 50 / 1 ) to give the title compound (1.1 g).

[0379] MS-ESI: m / z = 372.2 [M+Na] +

[0380] Step 2: Synthesis of (S)-N-methyl-N-(4-nitrophenyl)pyrrolidine-2-carboxamide (K-3)

[0381] (S)-2-(methyl(4-nitrophenyl)carbamoyl)pyrrolidine-1-carboxylic acid tert-butyl ester (K-2, 379 mg, 1.08 mmol) was dissolved in dichloromethane (4 mL) at room temperature, hydrochloric acid-dioxane solution (1 mL, 4 M) was added, stirred at room temperature for 30 minutes. After the reaction was completed, the reaction was concentrated under reduced pressure to obtain the title compound (270 mg) which was directly used in the next step.

[0382] MS-ESI: m / z = 250.1 [M+H] +

[0383] Step 3: Synthesis of tert-butyl ((S)-3,3-dimethyl-1-((S)-2-(methyl(4- nitrophenyl)carbamoyl)pyrrolidin-1-yl)-1-oxobutan-2-yl)carbamate (K-4)

[0384] (S)-N-methyl-N-(4-nitrophenyl)pyrrolidine-2-carboxamide (K-3, 204 mg, 0.82 mmol), (S)-2-((tert-butoxycarbonyl)amino)-3,3-dimethylbutanoic acid (190 mg, 0.82 mmol) were dissolved in dichloromethane (8 mL) at room temperature, 1-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (236 mg, 1.23 mmol), N,N- diisopropylethylamine (531 mg, 4.11 mmol) and 1-hydroxybenzotriazole (167 mg, 1.23 mmol) were added. Stirred at room temperature for 12 hours. After the reaction was completed, concentrated, the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain the title compound (350 mg).

[0385] MS-ESI: m / z = 485.2 [M+Na] +

[0386] Step 4: Synthesis of tert-butyl ((S)-1-((S)-2-((4-aminophenyl)(methyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)carbamate (Intermediate K)

[0387] To a solution of (S)-3,3-dimethyl-l-((S)-2-(methyl(4- nitrophenyl)carbamoyl)pyrrolidin-l-yl)-l-oxobutan-2-yl)carbamic acid tert-butyl ester (K-4, 200 mg, 0.43 mmol), ammonium chloride (116 mg, 2.16 mmol), iron powder (121 mg, 2.16 mmol) in tetrahydrofuran (4 mL), water (4 mL) and ethanol (2 mL) was added at room temperature. The reaction was stirred at 70 °C for 5 hours. After completion of the reaction, it was filtered, the filtrate was diluted with ethyl acetate (50 mL), washed with saturated brine and dried over anhydrous sodium sulfate. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 15 / 1) to give the title compound (169 mg).

[0388] MS-ESI: m / z = 433.3 [M+H] +

[0389] Synthesis of intermediate L: 2-(4-(l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3- dihydro-lH-benzo[d]imidazol-5-yl)piperazin-l-yl)acetic acid

[0390]

[0391] To a solution of 3-(3-methyl-2-oxo-5-(piperazin-l-yl)-2,3-dihydro-lH- benzo[d]imidazol-l-yl)piperidine-2,6-dione (309 mg, 0.9 mmol) in methanol (1 mL) / dichloromethane (4 mL) was added N,N-diisopropylethylamine (233 mg, 1.81 mmol) and glyoxylic acid (67 mg, 0.9 mmol) at room temperature. After stirring for half an hour at room temperature, sodium cyanoborohydride (114 mg, 1.81 mmol) was added and stirred at room temperature overnight. After completion of the reaction, it was concentrated under reduced pressure and the crude product was purified by reverse phase column chromatography (acetonitrile / water (0.1% formic acid) from 0-10%) to give the title compound (150 mg).

[0392] MS-ESI: m / z = 402.2 [M+H] +

[0393] 1H NMR (400 MHz, DMSO-d6) d = 11.06 (s, 1H), 6.94 (d, J = 8.6 Hz, 1H), 6.85 (s, 1H), 6.62 (d, J = 2.1 Hz, 1H), 5.31-5.26 (m, 1H), 3.28 (s, 3H), 3.23 (s, 2H), 3.12 (s, 4H), 2.89-2.85 (m, 1H), 2.75 (s, 4H), 2.66-2.58 (m, 2H), 1.99-1.96 (m, 1H).

[0394] Example 1: Synthesis of compound 1

[0395]

[0396] Step 1: Synthesis of compound 1a

[0397] To a solution of ((S)-1-((S)-2-((3R,4S)-3-(4-aminophenyl)-4-cyanopyrrolidine-1- carbonyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)carbamic acid tert-butyl ester (Intermediate C, 60 mg, 0.12 mmol) in dimethyl sulfoxide (5 mL) and tetrahydrofuran (5 mL) was added 1-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H- benzimidazol-5-yl)piperidine-4-carbaldehyde (Intermediate E, 45 mg, 0.12 mmol) and sodium cyanoborohydride (30 mg, 0.48 mol) at room temperature. The resulting mixture was adjusted to pH 5 with glacial acetic acid (0.1 mL) and stirred at 60 °C overnight. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to remove tetrahydrofuran. The resulting residue was separated and purified by reverse phase column chromatography (acetonitrile: water = 0-45%) to give the title compound (76 mg).

[0398] MS m / z (ESI): 852.4 [M+H] +

[0399] Step 2: Synthesis of compound 1b

[0400] To a solution of compound 1a (39 mg, 0.046 mmol) in dichloromethane (4 mL) was added trifluoroacetic acid (1 mL) dropwise at room temperature. The resulting mixture was stirred at room temperature for 3 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The resulting residue was dissolved in dichloromethane and concentrated under reduced pressure again. This process was repeated three times to give the title compound (34 mg).

[0401] MS m / z (ESI): 752.4 [M+H] +

[0402] Step 3: synthesis of compound 1

[0403] Compound 1b (34 mg, 0.05 mmol) was dissolved in N,N-dimethylacetamide (6 mL) at room temperature, then (difluoro(2-((perfluorophenoxy)carbonyl)benzo[b]thiophen-5-yl)methyl)phosphonic acid (Intermediate D, 24 mg, 0.05 mmol) and N,N-diisopropylethylamine (23 mg, 0.18 mmol) were added, and the mixture was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was filtered, and the filtrate was separated and purified by high performance liquid chromatography preparation (ammonium bicarbonate / acetonitrile / water system, column: Xbridge prep c18 10um OBD 19*150mm; mobile phase: water (containing 0.1% NH4HCO3), acetonitrile; gradient ratio: acetonitrile phase (0-8 min, 10-20%); flow rate: 30 mL / min; column temperature: room temperature) to obtain the title compound (16.4 mg).

[0404] MS m / z (ESI): 1042.3 [M+H] +

[0405] 1 H NMR (400 MHz, DMSO-d6) d 11.03 (s, 1H), 8.49-8.45 (m, 1H), 8.31-8.26 (m, 1H), 8.04-7.97 (m, 2H), 7.61-7.59 (m, 1H), 7.14-7.10 (m, 2H), 6.94-6.91 (m, 2H), 6.85-6.45 (m, 3H), 5.75 (br s, 1H), 5.29-5.26 (m, 1H), 4.77-4.75 (m, 1H), 4.70-4.62 (m, 1H), 4.25-4.13 (m, 1H), 4.13-4.10 (m, 2H), 3.93-3.54 (m, 5H), 3.49-3.46 (m, 3H), 3.12-3.07 (m, 2H), 3.07-2.85 (m, 3H), 2.68-2.55 (m, 2H), 2.44-2.40 (m, 1H), 2.33-2.20 (m, 1H), 2.11-1.98 (m, 7H), 1.87-1.85 (m, 1H), 1.36-1.31 (m, 2H), 1.08 (s, 9H).

[0406] Example 2: synthesis of compound 2

[0407]

[0408] Following the synthetic procedure of Example 1, replacing intermediate E with 1-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H- benzo[d]imidazol-4-yl)piperidine-4-carbaldehyde (Intermediate F, prepared according to patent WO2022266258), compound 2 was prepared in the same manner.

[0409] MS m / z (ESI): 1040.8 [M-H] - .

[0410] 1 H NMR (400 MHz, DMSO-d6) δ 11.09 (s, 1H), 8.49 (s, 1H), 8.31-8.29 (m, 1H), 8.03-7.97 (m, 2H), 7.63-7.61 (m, 1H), 7.22-7.10 (m, 4H), 6.97-6.87 (m, 4H), 6.59 (d, J = 7.2 Hz, 2H), 5.80 (s, 1H), 5.37-5.33 (m, 1H), 5.77 (d, J = 8.8 Hz, 1H), 4.68-4.63 (m, 1H), 4.28-4.12 (m, 1H), 3.93-3.85 (m, 2H), 3.79-3.73 (m, 1H), 3.69-3.63 (m, 1H), 3.58 (s, 3H), 3.53-3.46 (m, 2H), 3.16-3.12 (m, 2H), 3.02-2.97 (m, 2H), 2.89-2.85 (m, 1H), 2.73-2.52 (m, 3H), 2.22-2.09 (m, 1H), 2.00-1.89 (m, 2H), 1.87-1.79 (m, 5H), 1.78-1.68 (m, 1H), 1.41-1.38 (m, 2H), 1.08 (s, 9H).

[0411] Example 3: Synthesis of compound 3

[0412]

[0413] Following the synthetic procedure of Example 1, replacing intermediate E with 3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H- benzo[d]imidazol-5-yl)propynal (Intermediate G, prepared according to patent WO2023076161), compound 3 was prepared in the same manner.

[0414] MS m / z (ESI): 983.6 [M+H] +

[0415] 1H NMR (400 MHz, DMSO-d6) δ 11.10 (s, 1H), 8.52 (s, 1H), 8.36-8.28 (m, 1H), 8.14-7.99 (m, 2H), 7.64-7.54 (m, 1H), 7.25-7.02 (m, 5H), 6.70 (d, J = 8.8 Hz, 2H), 6.12 (br s, 1H), 5.42-5.30 (m, 1H), 4.75 (d, J = 8.8 Hz, 1H), 4.67-4.56 (m, 1H), 4.12 (s, 2H), 3.97-3.60 (m, 4H), 3.59-3.42 (m, 6H), 3.32-3.31 (m, 3H), 2.96-2.80 (m, 1H), 2.20-2.15 (m, 1H), 2.01-1.84 (m, 4H), 1.00 (s, 9H).

[0416] Example 4: Synthesis of compound 4

[0417]

[0418] Compound 4 was prepared by the same method as in reference example 1, replacing intermediate D with intermediate H.

[0419] MS-ESI: m / z = 1330.3 [M+H] +

[0420] 1 H NMR (400 MHz, DMSO-d6) δ 11.06 (s, 1H), 8.54 (s, 1H), 8.43 (d, J = 8.8 Hz, 1H), 8.23-8.19 (m, 1H), 8.11 (s, 1H), 7.60-7.57 (m, 1H), 7.12 (t, J = 8.0 Hz, 2H), 6.93 (s, 1H), 6.82 (s, 1H), 6.64 (s, 1H), 6.59 (d, J = 8.4 Hz, 2H), 5.78 (s, 1H), 5.32-5.27 (m, 1H), 4.77 (d, J = 8.8 Hz, 1H), 4.65-4.59 (m, 1H), 4.25-4.11 (m, 5H), 3.93-3.40 (m, 2H), 3.62-3.58 (m, 6H), 3.13 (t, J = 4.8 Hz, 4H), 2.95-2.85 (m, 3H), 2.68-2.58 (m, 4H), 2.46-2.36 (m, 7H), 2.20-1.64 (m, 11H), 1.39-1.29 (m, 2H), 1.08-1.01 (m, 9H), 0.87-0.85 (m, 12H).

[0421] Example 5: Synthesis of compound 5

[0422]

[0423] Compound 5 was prepared by the similar method as described in Example 1, by replacing intermediate D with intermediate J.

[0424] MS-ESI: m / z = 1213.4 [M+H] +

[0425] 1 H NMR (400 MHz, DMSO-d6) δ 11.05 (s, 1H), 8.51-8.48 (m, 1H), 8.40-8.34 (m, 1H), 8.11-8.04 (m, 2H), 7.63-7.58 (m, 1H), 7.38-7.32 (m, 2H), 7.21-7.09 (m, 5H), 6.91 (d, J = 8.8 Hz, 1H), 6.83 (t, J = 2.4 Hz, 1H), 6.64-6.62 (m, 1H), 6.58 (d, J = 8.8 Hz, 2H), 6.24-6.06 (m, 2H), 5.77 (t, J = 5.2 Hz, 1H), 5.34-5.25 (m, 1H), 4.76 (d, J = 8.4 Hz, 1H), 4.66-4.60 (m, 1H), 3.92-3.39 (m, 9H), 3.29-3.23 (m, 5H), 2.94-2.84 (m, 3H), 2.68-2.58 (m, 3H), 2.12-1.62 (m, 10H), 1.52-1.23 (m, 5H), 1.19-0.71 (m, 15H).

[0426] Example 6: Synthesis of compound 6

[0427]

[0428] Compound 6 was prepared by the similar method as described in Example 1, by replacing intermediate C with intermediate K.

[0429] MS-ESI: m / z = 977.3 [M+H]+

[0430] 1H NMR (400 MHz, DMSO-d6) δ 11.05 (s, 1H), 8.53-8.50 (m, 1H), 8.33 (d, J = 8.8 Hz, 1H), 8.05-8.02 (m, 2H), 7.59 (d, J = 8.0 Hz, 1H), 7.23-6.83 (m, 5H), 6.71-6.56 (m, 3H), 5.30 (dd, J = 4.8 Hz, 12.4 Hz, 1H), 4.76 (d, J = 5.2 Hz, 1H), 4.31 (t, J = 12.8 Hz, 1H), 3.75-3.57 (m, 3H), 3.30-3.28 (m, 5H), 3.07 (s, 3H), 2.92-2.91 (m, 2H), 2.67-2.61 (m, 2H), 1.98-1.65 (m, 12H), 1.37-1.30 (m, 2H), 1.08 (s, 9H).

[0431] Example 7: Synthesis of compound 7

[0432]

[0433] Step 1: Synthesis of compound 7a

[0434] tert-Butyl ((S)-1-((S)-2-((4-aminophenyl)(methyl)carbamoyl)pyrrolidin-1-yl)-3,3- dimethyl-1-oxobutan-2-yl)carbamate (Intermediate K, 45 mg, 0.10 mmol), 2-(4-(1-(2,6- dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)piperazin-1- yl)acetic acid (Intermediate L, 42 mg, 0.10 mmol) were dissolved in N,N- dimethylformamide (5 mL), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (29 mg, 0.15 mmol), N,N-diisopropylethylamine (39 mg, 0.3 mmol) and 1- hydroxybenzotriazole (20 mg, 0.15 mmol) were added. Stirring was carried out at room temperature for 12 hours. After completion of the reaction, it was concentrated and the residue was purified by thin layer chromatography on silica gel (dichloromethane / methanol = 15 / 1) to give the title compound (30 mg).

[0435] MS-ESI: m / z = 816.3 [M+H] +

[0436] Step 2: Synthesis of compound 7b

[0437] Compound 7a (30 mg, 0.037 mmol) was dissolved in dichloromethane (4 mL), trifluoroacetic acid (1 mL) was added, and stirred at room temperature for 1 hour. After the reaction was completed, it was concentrated under reduced pressure to obtain the title compound (26 mg) which was used directly for the next step.

[0438] MS-ESI: m / z = 716.3 [M+H] +

[0439] Step 3: Synthesis of compound 7

[0440] Compound 7b (26 mg, 0.036 mmol), (difluoro(2-((perfluorophenoxy)carbonyl)benzo[b]thiophen-5-yl)methyl)phosphonic acid (intermediate D, 17 mg, 0.036 mmol), and N,N-diisopropylethylamine (23 mg, 0.18 mmol) were dissolved in N,N-dimethylformamide (3 mL) and stirred at room temperature for 2 hours. After the reaction was completed, it was concentrated under reduced pressure, and the obtained residue was separated and purified by high performance liquid chromatography (column: Xbridge prep C18 10 pm OBD 19*150 mm; mobile phase: water (0.1% trifluoroacetic acid), acetonitrile; gradient ratio: acetonitrile phase (0-10 min, 10-20%); flow rate: 25 mL / min; column temperature: room temperature) to obtain the title compound (2.5 mg).

[0441] MS-ESI: m / z = 1006.3 [M+H] +

[0442] 1 H NMR (400 MHz, DMSO-d6) d 11.07 (s, 1H), 10.55 (s, 1H), 8.48 (s, 1H), 8.32 (d, J = 8.8 Hz, 1H), 8.07-8.03 (m, 2H), 7.68-7.38 (m, 5H), 6.98 (d, J = 7.6 Hz, 1H), 6.88 (s, 1H), 6.67 (d, J = 8.4 Hz, 1H), 5.30 (dd, J = 4.8 Hz, 12.4 Hz, 1H), 4.74 (d, J = 8.8 Hz, 1H), 4.21 (t, J = 7.2 Hz, 1H), 3.91-3.76 (m, 4H), 3.30-3.14 (m, 11H), 3.12 (s, 3H), 2.89-2.85 (m, 1H), 2.69-2.63 (m, 2H), 2.01-1.97 (m, 3H), 1.81-1.76 (m, 2H), 1.09 (s, 9H).

[0443] Test Example 1: Western blot (WB) method for detecting the degradation effect of the compound on STAT6 protein in THP-1 cells.

[0444] THP-1 medium: RPMI 1640 (Gibco, catalog number 72400120) + 10% fetal bovine serum (FBS) (Gibco, catalog number 10091-148) + 1% penicillin-streptomycin P / S (Gibco, catalog number 15140-122) + β-mercaptoethanol (1×) (Gibco, catalog number 21985-023). The compounds were dissolved in DMSO to prepare a 20 mM stock solution, then serially diluted 10-fold with DMSO to three concentrations (20, 2, and 0.2 mM). Finally, the solutions were diluted 1000-fold with the medium to prepare 20, 2, and 0.2 μM (at which point the final DMSO concentration was 0.1%). THP-1 cells (purchased from the Shanghai Academy of Sciences, catalog number: SCSP-567) were seeded in 24-well flat-bottom plates (Corning, catalog number 3524) at a density of 4 × 10⁵ cells / 500 μL / well. Then, 500 μL / well of the above-mentioned concentration gradient compounds (final concentrations in 1 mL: 10, 1, and 0.1 μM) or a control (0.1% DMSO prepared in the culture medium) were added, mixed well, and incubated at 37°C in a 5% CO₂ incubator for 24 hours. The final concentrations of the compounds in 1 mL were 10, 1, and 0.1 μM, and the final concentration of DMSO was 0.05%. After incubation, cells were collected into 1.5 mL centrifuge tubes and centrifuged at 12,000 rpm for 5 minutes at room temperature. The supernatant was discarded. The cell pellet was washed with PBS and then centrifuged again at 12,000 rpm for 5 minutes at room temperature. The cell pellet was collected. Add 50 μL of RIPA lysis buffer (Thermo, catalog number 89900, containing 1% protease inhibitor mixture (Thermo, catalog number 78430) and 1% phosphatase inhibitor mixture (Thermo, catalog number 78420)) to the cell pellet, mix well, and lyse on ice for 25 minutes. Then centrifuge the cell lysis buffer at 12000g for 15 minutes at 4°C, collect the supernatant, and determine the protein concentration using a BCA protein quantification kit (Thermo, catalog number 23225). Add 5×SDS-PAGE protein loading buffer (Beyotime, catalog number: P0015L) to the lysis supernatant, mix well, and heat at 100°C for 10 minutes to prepare the electrophoresis sample. Use a 10% SurePAGE Bis-Tris gel precast gel (GenScript, catalog number: M00666) and... SDS-PAGE electrophoresis was performed using a Tetra Vertical Electrophoresis Cell (Bio-Rad, catalog number: 1658004) (200V constant voltage, 45 min), with a protein loading of 30 μg per lane. A Mini was used. Module Trans-blot apparatus (Bio-Rad, item number: 1703935) was used to transfer proteins (400 mA, 40 min) to PVDF membranes (Millipore, item number: IPVH00010). The PVDF membranes were placed in a 5% skim milk solution (BBI, item number: A600669) prepared with 1x TBST (Shenguo, item number: C520009) and blocked at room temperature with shaking (80 rpm) for 1 hour. The primary antibody solution was prepared: STAT6 Rabbit mAb (CST, item number: 5397, dilution ratio 1:1000), Beta Actin Mouse Monoclonal antibody (Proteintech, item number: 66009-1-Ig, dilution ratio 1:10000). The PVDF membranes were incubated with the primary antibody solution at 4°C overnight. After the primary antibody incubation, the membranes were washed 3 times with 1x TBST. The secondary antibody solution was prepared: HRP Anti-rabbit IgG (CST, item number: 7074S, dilution ratio 1:3000), HRP Anti-mouse IgG (CST, item number: 7076S, dilution ratio 1:3000). The PVDF membranes were incubated with the secondary antibody solution at room temperature with shaking (80 rpm) for 1 hour. After the secondary antibody incubation, the membranes were washed 3 times with 1x TBST. SuperSignal West Pico PLUS Chemiluminescent Substrate (Thermo Fisher, item number: 34577) was added to the PVDF membranes and incubated at room temperature for 60 seconds. The ChemiDoc XRS+ (Bio-Rad) system was used to image, and Image J software was used to analyze the gray value of the target band. The sample gray value analysis was as follows: sample corrected gray value = sample gray value / internal reference gray value; STAT6 degradation rate % = (1 - drug group gray value / control group gray value) x 100%, the degradation percentage of STAT6 at each concentration and the maximum degradation rate D max were calculated. The internal reference was β-actin. Graphpad Prism 10.0 software was used to perform nonlinear fitting of the compound concentration-STAT6 degradation percentage to obtain the degradation activity curve of the compound, and the half degradation concentration (DC 50 ) of the compound was calculated. The smaller the DC 50 value, the stronger the degradation activity of the compound. The DC 50 values of the tested compounds for STAT6 degradation are shown in Table 1.

[0445] Table 1. DC 50

[0446] Test compounds DC 50 ]]> Compound 1 B

[0447] Note: A represents <100 nM, B represents 100 nM-1000 nM, C represents >1000 nM

[0448] Example 2: HiBiT method to detect the degradation effect of compounds on STAT6 in HEK293-HiBiT-STAT6 overexpression cells

[0449] Construction of HiBiT-STAT6 overexpression HEK293 cells: HiBiT-STAT6 overexpression plasmid (synthesized by Jinsuirui) was transfected into HEK293 cells (source: Chinese Academy of Sciences) by liposome, and stable expression of HiBiT-STAT6 HEK293 cells was obtained by G418 (Melunbio, item number MA0321) pressure screening, and the cell strain was named HiBiT-STAT6 overexpression HEK293.

[0450] HEK293-HiBiT-STAT6 cells were inoculated in 96-well flat-bottom white plates (Corning, item number: 3917) at a seeding density of 1x10 5 cells / 25 μL / well, and the cells were attached overnight. The next day, 25 μL / well of concentration gradient compounds (concentration gradient compound preparation: starting concentration 1 μM, 8-fold gradient dilution, a total of 7 concentrations, diluent is DEME (Gibco, item number 10569-010) + 10% FBS (Gibco, item number 10091-148) + 1% penicillin-streptomycin (Gibco, item number 15140-122) + 400 μg / mL G418) were added, and after mixing, they were incubated at 37°C in a 5% CO2 incubator for 24 hours. The experimental setup groups are as follows: sample treatment group (cells + concentration gradient compounds), solvent control group (cells + solvent control 0.1% DMSO), blank control group (only medium). After incubation, 50 μL of Nano-Glo HiBiT lysis reagent (Promega, item number: N3040) was added, and the mixture was incubated at room temperature with shaking (350 rpm) for 10 minutes. The chemiluminescence value RLU was read by a microplate reader (PE Envision). The degradation rate of the compound on STAT6 was calculated as follows: (1-(sample treatment group RLU value-blank control group RLU value) / (solvent control group RLU value-blank control group RLU value))x100%, and the degradation rate of the compound at each concentration and the maximum degradation rate D max were calculated. The compound degradation activity curve was obtained by three-parameter fitting of compound concentration-degradation rate using Graphpad Prism 9 software, and the half-degradation concentration (DC 50 ) of the compound was calculated. DC 50The smaller the value indicates the stronger degradation activity of the compound. DCs treated with the test compounds 50 The values are shown in Table 2.

[0451] Table 2. Half-degradation concentration DC of the compounds 50

[0452] Test compounds DC 50 ]]> Compound 1 B Compound 2 C Compound 3 C Compound 4 A Compound 5 A Compound 6 A Compound 7 A

[0453] Note: In the table, A represents <100 nM, B represents 100 nM-1000 nM, and C represents >1000 nM.

Claims

1. A compound of Formula (I) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, Formula (I) wherein: L is a bivalent moiety connecting STAT to LBM; LBM is an E3 ubiquitin ligase binding moiety; STAT is a moiety capable of binding to STAT6, and STAT is a group as described below: each AA is a residue of an alpha or beta natural or unnatural amino acid; Q is selected from -NH-C(O)- and 5-10 membered heteroarylene, said 5-10 membered heteroarylene being optionally substituted with 1 or more R q substituents; Ring A is selected from a 3-12 membered heterocyclylene group optionally substituted with 1 or more R Aa substituents; Ring D is selected from 4-5 membered heterocyclylene, 7-12 membered heterocyclylene, C6-C 10 arylene and 5-10 membered heteroarylene, said 4-5 membered heterocyclylene, 7-12 membered heterocyclylene, C6-C 10 arylene and 5-10 membered heteroarylene is optionally substituted with 1 or more R Dd substituents; Ring C is selected from C3-C 12 Cycloalkyl, 3-10 membered heterocyclic, C6-C 10 Aryl and 5-10 heteroaryl, the C3-C 12 Cycloalkyl, 3-10 membered heterocyclic, C6-C 10 Aryl and 5-10 heteroaryl groups are optionally coated with one or more R groups. Cc replace; 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 T y)[NH(AA)C(O)OR T ], or -P(O)(OR 1b )[NH(AA)C(O)OR T ]; 8-10 membered heteroaryl 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 T y)[NH(AA)C(O)OR T ], or -P(O)(OR 1b )[NH(AA)C(O)OR T ]; 8-10 membered heterocyclyl 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 T y)[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 substituted by cyano, C1-C4alkoxy or halogen; -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 T y)[NH(AA)C(O)OR T ] or -P(O)(OR 1b )[NH(AA)C(O)OR T ]; 10 aryl, said -C2-C4alkenylC6-C 10 aryl of aryl is additionally 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 T y)[NH(AA)C(O)OR T ] or -P(O)(OR 1b )[NH(AA)C(O)OR T ]; each R 1a and R 2a is 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 =0; each R 1b and R 2b is independently selected from the group consisting of hydrogen, C1-C4alkyl, C1-C4haloalkyl, -(C1-C4alkylene)-OC(O)-(C1-C6alkyl), -(C1-C4alkylene)-C(O)O-(C1-C6alkyl), -(C1-C4alkylene)-O-(C1-C6alkyl), -(C1-C4alkylene)-OC(O)-[(C1-C6)haloalkyl], -(C1-C4alkylene)-OC(O)O-(3-7 membered heterocyclyl), -(C1-C4alkylene)-OC(O)(3-7 membered heterocyclyl), -(C1-C4alkylene)-OC(O)-(C3-C6cycloalkyl), -(C1-C4alkylene)-OC(O)-(C1-C6alkylene)-OH, -(C1-C4alkylene)-OC(O)-(C1-C4alkylene)-O-(C1-C6alkyl), -(C1-C4alkylene)-OC(O)O-(C1-C6alkyl), -(C1-C4alkylene)-OC(O)O-[(C1-C6)haloalkyl], -(C1-C4alkylene)-OC(O)O-(C1-C6alkylene)-OH, -(C1-C4alkylene)-OC(O)O-(C1-C4alkylene)-O-(C1-C6alkyl), -(C1-C4alkylene)-SC(O)-(C1-C6alkyl), -(C1-C4alkylene)-SC(O)-[(C1-C6)haloalkyl], -(C1-C4alkylene)-SC(O)-(3-7 membered heterocyclyl), -(C1-C4alkylene)-SC(O)-(C3-C6cycloalkyl), -(C1-C4alkylene)-SC(O)-(C1-C6alkylene)-OH, -(C1-C4alkylene)-SC(O)-(C1-C4alkylene)-O-(C1-C6alkyl), -(C1-C4alkylene)-OC(O)NH(C1-C6alkyl)], -(C1-C4alkylene)-OC(O)N(C1-C6alkyl)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 1 or more C(O)OR h ; R 2 and R 3 Independently selected from hydrogen, halogen, hydroxyl, cyano, amino, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C 10 aryl, 5-10 membered heteroaryl and 3-10 membered heterocyclic groups, wherein the hydroxyl, amino, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C 10 Aryl, 5-10 heteroaryl, and 3-10 heterocyclic groups are optionally coupled with one or more R groups. S replace; or R 2 and R 3 together with the atom to which they are attached form a C3-C 10 saturated carbocyclic, 4-8 membered heterocyclic, or 5-6 membered heteroaromatic ring, optionally substituted with halogen, cyano, amino, or C1-C4alkyl; 10 saturated carbocyclic, 4-8 membered heterocyclic, or 5-6 membered heteroaromatic ring, optionally substituted with halogen, cyano, amino, or C1-C4alkyl; R 4 selected from hydrogen, Ci-C6alkyl, C2-C6alkenyl, and C2-C6alkynyl, said Ci-C6alkyl, C2-C6alkenyl, and C2-C6alkynyl groups being optionally substituted with 1 or more halogen, cyano, hydroxyl, or amino; one or more hydrogen atoms of the compound are optionally deuterium atoms. each R Aa , R Dd and R Cc are independently selected from the group consisting of halogen, hydroxy, cyano, amino, =0 and C1-C4alkyl, said hydroxy, amino and C1-C4alkyl groups being optionally substituted with one or more R F ; Each R T and R Ty The components are independently selected from C1-C4 alkyl, benzyl, and phenyl, wherein the benzyl and phenyl are optionally substituted with halogen, C1-C4 alkyl, or C1-C4 haloalkyl; Each R q R F and R S Independently selected from halogen, cyano, hydroxy, amino, mercapto, C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 haloalkyl, C1-C4 alkoxy and C1-C4 hydroxy-substituted alkyl; Each R h The components are independently selected from hydrogen, C1-C4 alkyl, C2-C4 alkynyl, -C1-C4 alkylphenyl, phenyl, C3-C6 cycloalkyl, 4-6 heterocyclic alkyl-membered heterocyclic and 5-6 heteroaryl, wherein the C1-C4 alkyl is optionally substituted with halogen, cyano, hydroxy or amino, and the phenyl, C3-C6 cycloalkyl, 4-6 heterocyclic and 5-6 heteroaryl are optionally substituted with halogen, cyano, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, hydroxy, phenyl or benzyl; 8. The compound of Formula (I) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof of any one of claims 1-7, wherein, 2. The compound of claim 1 of formula (I) or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, -Q- is selected from -NH-C(O)-; or -Q- is selected from -NH-C(O)-*, wherein * indicates the attachment to R 1 ; or -Q- is selected from 5-10 membered heteroarylene optionally substituted with 1 or more R q ; or -Q- is selected from 5-7 membered heteroarylene optionally substituted with 1 or more R q ; or -Q- is selected from 5 membered heteroarylene optionally substituted with 1 or more R q ; or -Q- is selected from isoxazolene optionally substituted with 1 or more R q ; or -Q- is selected from -NH-C(O)- and 3. The compound of formula (I) as claimed in any one of claims 1-2, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, R q selected from halogen and C1-C4alkyl.

4. The compound of any one of claims 1-3 of formula (I) or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, Ring A is selected from a 3-7 membered heterocyclyl, optionally substituted with 1 or more R Aa substituents; or ring A is selected from a pyrrolidinyl optionally substituted with 1 or more R Aa substituents; or ring A is selected from a pyrrolidinyl optionally substituted with 1 or more R and / or each R Aa is independently selected from halogen, =0 and methyl, halogen preferably being F.

5. The compound of any one of claims 1-4 of formula (I) or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, Ring D is selected from a 4-5 membered heterocyclyl and a 7-12 membered heterocyclyl, optionally substituted with 1 or more R Dd substituents; or ring D is selected from a 4-5 membered heterocyclyl, optionally substituted with 1 or more R Dd substituents; or ring D is selected from a 4-5 membered heterocyclyl, optionally substituted with 1 or more R Dd substituents; or ring D is selected from a 4-5 membered heterocyclyl, optionally substituted with 1 or more R substituents; or ring D is selected from a 4-5 membered heterocyclyl, optionally substituted with 1 or more R Dd substituents; or ring D is selected from a 4-5 membered heterocyclyl, optionally substituted with 1 or more R Dd substituents; or ring D is selected from a 4-5 membered heterocyclyl, optionally substituted with 1 or more R 6. The compound of any one of claims 1-5 of formula (I) or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, Ring C is selected from C6-C 10 Aryl and 5-10 heteroaryl, the C6-C 10 Aryl and 5-10 heteroaryl groups are optionally coated with one or more R groups. Cc Substitution; or the ring C is selected from phenyl and 5-7 heteroaryl groups, wherein the phenyl and 5-7 heteroaryl groups are optionally converted by one or more R groups. Cc Substitution; or the ring C is selected from phenyl, pyridyl, isothiazolyl, and thiophene, wherein the phenyl, pyridyl, isothiazolyl, and thiophene are optionally replaced by one or more R... Cc Substitution; or the ring C is selected from phenyl, pyridyl, isothiazolyl, and thiophenyl; or the ring C is phenyl; and / or R Cc It is independently selected from hydroxyl and amino groups.

7. The compound of any one of claims 1-6 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 T y)[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 T y)[NH(AA)C(O)OR T ], or -P(O)(OR 1b )[NH(AA)C(O)OR T ]; or C6-Ci2aryl 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 T y)[NH(AA)C(O)OR T ], or -P(O)(OR 1b )[NH(AA)C(O)OR T ]; 10 aryl, which C6-Ci0aryl is optionally substituted with one or more substituents selected from the group consisting of cyano, halogen, C1-C4alkyl, C1-C4haloalkyl, C1-C4alkoxy and halogen-C1-C4alkoxy; or R 10 aryl is additionally optionally substituted with cyano, C1-C4alkoxy or halogen; or R 1 selected from the group consisting of 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 STAT is a group as shown below: -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 selected from 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 2 and R 3 are independently selected from hydrogen, halogen, hydroxyl, cyano, amino, Ci-C6alkyl, C3-C6cycloalkyl, and 3-10 membered heterocyclyl, said hydroxyl, amino, Ci-C6alkyl, C3-C6cycloalkyl, and 3-10 membered heterocyclyl optionally substituted with 1 or more R S ; or R 2 is H, R 3 is selected from Ci-C4alkyl, C3-C6cycloalkyl, and 3-6 membered heterocyclyl, said Ci-C4alkyl, C3-C6cycloalkyl, and 3-6 membered heterocyclyl optionally substituted with 1 or more R S ; or R 2 is H, R 3 is selected from Ci-C4alkyl; or R 2 and R 3 are independently selected from hydrogen, methyl, isopropyl, t-butyl, cyclopropyl, and epoxyethyl, said methyl, t-butyl, cyclopropyl, and epoxyethyl optionally substituted with 1 or more R S ; or R 2 is hydrogen, R 3 is selected from t-butyl, isopropyl, cyanomethyl, cyclopropyl, and epoxyethyl; or R 2 is hydrogen, R 3 is t-butyl; or R 2 and R 3 , and the atoms to which they are attached, together form a C3-C 10 saturated carbocyclic ring and 4-8 membered heterocyclic ring, said C3-C 10 saturated carbocyclic ring and 4-8 membered heterocyclic ring optionally substituted with halogen, cyano, amino, or Ci-C4alkyl; or R 2 and R 3 , and the atoms to which they are attached, together form an oxetane, cyclobutane, cyclopentane, and cyclohexane; and / or each R S is independently selected from halogen, cyano, hydroxyl, amino, thiol, and Ci-C4alkyl; or R S is cyano.

10. The compound of any one of claims 1-9 of Formula (I): or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, The STAT is or the STAT is linked to L via ring C, i.e. the STAT is or the STAT is linked to L via ring A, i.e. the STAT is 11. The compound of claim 1 of formula (I) or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, STAT is a group as shown below: wherein Q, R 1 , R 2 , R 3 , R Dd , ring A and ring C are as defined in any one of claims 1-10.

12. The compound of claim 1 of formula (I) or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, LBM is selected from a structure as shown in Formula (LBM-1) or (LBM-2): wherein R 1 , R 2 , R 3 , R 4 , ring A and ring C are as defined in claims 1-10.

13. The compound of any one of claims 1-12 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 - and -, 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 each independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl, heteroaryl or cycloalkenyl, wherein each of said cycloalkyl, heterocyclyl, aryl, heteroaryl and cycloalkenyl is independently optionally substituted with a group selected from halogen, alkyl, alkoxy, haloalkyl, 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.

14. The compound of any one of claims 1-13 of Formula (I): or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, wherein: r is selected from 0 or 1; selected from 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; Each R A Independently selected from H or C1-C3 alkyl groups, wherein the C1-C3 alkyl groups are optionally divided by C6-C 10 Aryl or 5-10 heteroaryl substitutions; Each R A 'Independently selected from C1-C3 alkyl groups;' each R is independently selected from H, 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; Each R D It is independently selected from halogens, NO2, NH2, OH, COOH, C1-C6 alkyl or C1-C6 alkoxy groups; Each R E Independently selected from C1-C6 alkyl, C2-C6 alkenyl, C3-C8 cycloalkyl, 3-8 membered heterocyclic alkyl, C(O)-C1-C6 alkyl, C(O)-C2-C6 alkenyl, C(O)-C3-C8 cycloalkyl or C(O)-3-8 membered heterocyclic alkyl, wherein R E Optional substitution with groups 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 heteroaryl group may be further substituted with a group selected from the following: halogen, NH2, CN, NO2, OH, COOH, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy or C1-C6 haloalkoxy. R E is selected from 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; m is selected from 0, 1, 2, or 3; o is selected from 0, 1, or 2; or, LBM is selected from a structure as shown in Formula (LBM-5): wherein: ring E, ring F, ring G are each independently selected from phenyl, 6-membered heteroaryl, 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 with =0; 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 halo, 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', -NP(O)R'2, -N(R')P(O)(OR')2, -N(R')P(O)(OR')NR'2, or -N(R')P(O)(NR'2)2; H each R' is independently selected from H, deuterium, R Each R H Independently selected from C1-C6 alkyl, phenyl, 4-7 membered heterocyclic or 5-6 membered heteroaryl; 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; 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-; g is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16; or, LBM is selected from a structure as shown in Formula (LBM-6): or, 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 above; LBM is selected from a structure as shown in Formula (LBM-7): LBM is selected from a structure as shown below: wherein X C , X D , X E , R F , R G , L 1 , ring E and k are as defined above.

15. The compound of claim 1 of formula (I) or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, the compound is selected from the following compounds or a stereoisomer thereof or a pharmaceutically acceptable salt thereof: or said LBM is selected from the group consisting of the following structures:

16. The compound of claim 1 of formula (I) or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, 17. A pharmaceutical composition comprising a compound of Formula (I) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof of any one of claims 1-16 and a pharmaceutically acceptable excipient.

18. Use of a compound of Formula (I) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof of any one of claims 1-16, or a pharmaceutical composition of claim 17, for the manufacture of a medicament for the prevention or treatment of a STAT6-mediated disease. ​

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