Signal transduction and transcriptional activation protein inhibitor compound and application thereof

Abstract

The invention relates to an STAT inhibitor compound shown in a formula (I) or pharmaceutically acceptable salt thereof, a pharmaceutical composition containing the STAT inhibitor compound or the pharmaceutically acceptable salt, and application of the STAT inhibitor compound or the pharmaceutically acceptable salt in preparation of drugs for preventing or treating STAT-mediated diseases. # imgabs0 #

Description

[0001] Cross - reference to related applications

[0002] This application claims the rights and priorities of the following Chinese patent applications, the entire contents of which are hereby incorporated herein by reference in their entirety:

[0003] Patent Application No. 202311856157.X filed with the National Intellectual Property Administration on December 28, 2023. Technical field

[0004] The present disclosure belongs to the field of medicine and relates to a signal transducer and activator of transcription (STAT) inhibitor compound or a pharmaceutically acceptable salt thereof, a pharmaceutical composition containing them, and their use as a STAT inhibitor in the prevention or treatment of related diseases. Background art

[0005] Diseases such as atopic dermatitis, asthma, and chronic obstructive pulmonary disease are usually driven by type 2 inflammation. IL - 4 and IL - 13 are key cytokines that induce and maintain type 2 inflammatory responses. When IL - 4 / IL - 13 binds to the receptor IL - 4Rα, tyrosine residues on the receptor are phosphorylated by JAK1, JAK3, or Tyk2. STAT6 is recruited to the phosphorylated tyrosine residue of the IL - 4Rα receptor through its SH2 domain and phosphorylated at the Tyr641 site. Subsequently, STAT6 dimerizes through SH2 domain - pTyr641 interaction, translocates to the nucleus, and activates the expression of downstream related genes. The expression of these genes is crucial for the balance between host immune defense and allergic inflammatory responses.

[0006] STAT6 is a key factor in the IL - 4 / IL - 13 pathway. STAT6 plays a crucial role in the pathogenesis of allergic asthma. Studies have found that the level of STAT6 is elevated in the bronchial epithelium of asthma patients. Another study has shown that gain - of - function mutations in STAT6 lead to severe allergic disorders, manifested as atopic dermatitis, eosinophilia, and elevated IgE. Pre - clinical data indicate that STAT6 - knockout mice do not develop asthma - related airway hyperresponsiveness (AHR) or pulmonary pathological manifestations, including Th2 cell accumulation, chemokine production, airway eosinophilia, peribronchial inflammation, and epithelial mucous metaplasia. STAT6 signal transduction is essential for IL - 4 - and IL - 13 - induced diseases. Therefore, inhibiting the activity of STAT6 is expected to become a new therapy for the treatment of type 2 inflammatory diseases such as asthma.

[0007] Currently, there are multiple strategies targeting the IL-4 / IL-13 / STAT6 pathway, including IL-4 / IL-13 specific neutralizing antibodies, IL-4R / IL-13R antibodies, small molecule compounds targeting STAT6 and other signaling molecules (such as JAK) in the IL-4 / IL-13 pathway. Dupixent is a monoclonal antibody drug targeting IL-4Rα and has been approved by the FDA for the treatment of type 2 inflammatory diseases including atopic dermatitis, asthma, chronic rhinosinusitis with nasal polyps, prurigo nodularis, and eosinophilic esophagitis. Lebrikizumab is a monoclonal antibody against IL-13 that can bind soluble IL-13 with high affinity and block IL-13 signal transduction. Lebrikizumab has been approved for marketing in the European Union for the treatment of moderate to severe atopic dermatitis, but it performed poorly in the phase III clinical study of asthma. Reversible oral JAK inhibitors have been approved for the treatment of Th2-mediated atopic dermatitis. However, the currently marketed drugs all have certain limitations: macromolecular antibodies usually require regular injections, are only applicable to specific patient populations, and may trigger immunogenicity; JAK inhibition can have negative effects on antiviral immunity and hematopoiesis, leading to safety issues. Finding a treatment strategy with good patient compliance and few side effects has better efficacy and a broader market. STAT6 is essential for the signal transduction of IL-4 and IL-13 and is specifically located downstream of the IL4 and IL13 pathways and is not utilized by other cytokines and growth factors. Therefore, highly selective oral STAT6 inhibitors are considered to have stronger targeting and fewer side effects. Summary of the Invention

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

[0009]

[0010] wherein:

[0011] q is 0 or 1;

[0012] t is 0, 1 or 2;

[0013] p is 1 or 2;

[0014] X is selected from O, S(O), -C(=O)-NR 10 -, and NR 8 ;

[0015] R 1 is selected from -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 Ty [NH(AA)C(O)OR T or -P(O)[OR 1b [NH(AA)C(O)OR T substituted 8 - 10 - membered heteroaryl, the 8 - 10 - membered heteroaryl is additionally optionally substituted by amino, halogen, cyano, C1 - C4 alkyl or C1 - C4 alkoxy; -CR 1a R 2a P(O)OR 1b OR 2b 、 -CR 1a R 2a P(O)[OR 1b [NH(AA)C(O)OR T 、 -P(O)OR 1b OR 2b 、 -P(O)[NHR Ty [NH(AA)C(O)OR T or -P(O)[OR 1b [NH(AA)C(O)OR T substituted 8 - 10 - membered heterocyclic group, the 8 - 10 - membered heterocyclic group is additionally optionally substituted by amino, halogen, cyano, C1 - C4 alkyl or C1 - C4 alkoxy; -CR 1a R 2a P(O)OR 1b OR 2b 、 -CR 1a R 2a P(O)[OR 1b [NH(AA)C(O)OR T 、 -P(O)OR 1b OR 2b 、 -P(O)[NHR Ty [NH(AA)C(O)OR T or -P(O)[OR 1b [NH(AA)C(O)OR T substituted C6 - C 10 aryl, the C6 - C 10 aryl is additionally optionally substituted by cyano, C1 - C4 alkoxy or halogen; -C1 - C4 alkylene aryl, the aryl of the -C1 - C4 alkylene aryl is -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 Ty [NH(AA)C(O)OR T or -P(O)[OR 1b [NH(AA)C(O)OR T substituted; -C2-C4 alkenylaryl, wherein the aryl of the -C2-C4 alkenylaryl is substituted by -CR 1a R 2a P(O)OR 1b OR 2b 、 -CR 1a R 2a P(O)[OR 1b [NH(AA)C(O)OR T 、 -P(O)OR 1b OR 2b 、 -P(O)[NHR Ty [NH(AA)C(O)OR T or -P(O)[OR 1b [NH(AA)C(O)OR T substituted;

[0016] R 1a and R 2a are independently selected from hydrogen, halogen, cyano, C1-C4 alkyl, C1-C4 haloalkyl and C1-C4 hydroxyalkyl, or R 1a and R 2a together form =O;

[0017] R 1b and R 2b are independently selected from hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, -(C1-C4 alkylene)-OC(O)-(C1-C4 alkyl), -(C1-C4 alkylene)-C(O)O-(C1-C4 alkyl), -(C1-C4 alkylene)-O-(C1-C 20-(C1-C4 alkyl), -(C1-C4 alkylene)-OC(O)-[(C1-C4) haloalkyl], (C1-C4 alkylene)-OC(O)O-[5-7 membered heterocyclic group], (C1-C4 alkylene)-OC(O)-[5-7 membered heterocyclic group], -(C1-C4 alkylene)-OC(O)-(C1-C4 alkylene)-OH, -(C1-C4 alkylene)-OC(O)-(C1-C4 alkylene)-O-(C1-C4 alkyl), -(C1-C4 alkylene)-OC(O)O-(C1-C4 alkyl), -(C1-C4 alkylene)-OC(O)O-[(C1-C4) haloalkyl], -(C1-C4 alkylene)-OC(O)O-(C1-C4 alkylene)-OH, -(C1-C4 alkylene)-OC(O)O-(C1-C4 alkylene)-O-(C1-C4 alkyl), -(C1-C4 alkylene)-SC(O)-(C1-C6 alkyl), -(C1-C4 alkylene)-SC(O)-[(C1-C4) haloalkyl], -(C1-C4 alkylene)-SC(O)-(C1-C4 alkyl)-OH, -(C1-C4 alkylene)-SC(O)-(C1-C4 alkylene)-O-(C1-C4 alkyl), -(C1-C4 alkylene)-OC(O)NH(C1-C4 alkyl)], -(C1-C4 alkylene)-OC(O)N(C1-C4 alkyl)2, C6-C 10 aryl and 5-6 membered heteroaryl, the C6-C 10 aryl and 5-6 membered heteroaryl are optionally substituted by halogen, cyano or C1-C4 alkyl, and the 5-7 membered heterocyclic group in (C1-C4 alkylene)-OC(O)O-[5-7 membered heterocyclic group] and (C1-C4 alkyl)-OC(O)-[5-7 membered heterocyclic group] is optionally substituted by C(O)OR h substituted;

[0018] R 2 is selected from hydrogen, halogen, COOH, hydroxy, cyano, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 haloalkyl, C1-C4 hydroxy-substituted alkyl;

[0019] R 3 and R 4 are independently selected from hydrogen, halogen, hydroxy, cyano, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxy-substituted alkyl, -C1-C4 alkylphenyl, C1-C4 alkoxy, C1-C4 haloalkoxy, -C1-C4 alkyl C1-C4 alkoxy, NR a R b 、C3-C6 cycloalkyl, C6-C 10An aryl group, a 5- to 10-membered heteroaryl group, and a 4- to 10-membered heterocyclic group, wherein the C3-C6 cycloalkyl group, C6-C 10 The aryl group, 5- to 10-membered heteroaryl group, and 4- to 10-membered heterocyclic group are optionally substituted by R S ;

[0020] R 5 and R 6 are independently selected from hydrogen, phenyl, and C1-C4 alkyl;

[0021] R 7 is selected from C1-C4 alkyl, phenyl, 4- to 9-membered heterocyclic group, and 5- to 10-membered heteroaryl group, and the C1-C4 alkyl is optionally substituted by R Y ; the phenyl, 4- to 9-membered heterocyclic group, and 5- to 10-membered heteroaryl group are optionally substituted by R Z ;

[0022] Alternatively, R 6 and R 7 together with the N atom to which they are attached form a 4- to 14-membered heterocyclic group or a 5- to 12-membered heteroaryl group, and the 4- to 14-membered heterocyclic group or 5- to 12-membered heteroaryl group is optionally substituted by R Q ;

[0023] R 8 is selected from 4- to 10-membered heterocyclic groups, and the 4- to 10-membered heterocyclic group is optionally substituted by R 8a ;

[0024] Alternatively, when X is NR 8 , R 3 and the C atom to which it is attached together with R 8 and the N atom to which it is attached form a 4- to 8-membered heterocyclic ring or a 5- to 6-membered heteroaromatic ring, and the 4- to 8-membered heterocyclic ring and 5- to 6-membered heteroaromatic ring are optionally substituted by halogen, cyano, amino, or C1-C4 alkyl;

[0025] R 8a is selected from halogen, cyano, amino, C1-C4 alkyl, -C(O)C1-C4 alkyl, and =O;

[0026] R 9 is selected from -C(O)C1-C4 alkyl, C1-C4 alkyl, C1-C4 cyano-substituted alkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl, 4- to 9-membered heterocyclic group, C6-C 10 aryl, and 5- to 10-membered heteroaryl;

[0027] R 10 is selected from hydrogen, C1-C4 alkyl, C1-C4 cyano-substituted alkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl, 4- to 9-membered heterocyclic group, C6-C 10 aryl, and 5- to 10-membered heteroaryl;

[0028] AA is a residue of an α- or β-natural or non-natural amino acid;

[0029] R T and R Ty are independently selected from C1-C4 alkyl, benzyl and phenyl, and the phenyl is optionally substituted by halogen, C1-C4 alkyl or C1-C4 haloalkyl;

[0030] R Q is independently selected from halogen, cyano, hydroxy, phenyl, C2-C4 alkenyl, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, 4-9 membered heterocyclic group, 5-10 membered heteroaryl, C3-C6 cycloalkyl, =O, imine, -OR e , -C(O)R g , -C(O)OR e , -NR c C(O)R e , -C(O)NR c R d , -NR a R b , -S(O)R e R f , -S(O)2R f , -S(O)=NH(C1-C4) alkyl, -S(O)NR e R f and -S(O)2NR e R f , and the C2-C4 alkenyl and C1-C4 alkyl are optionally substituted by R M , and the phenyl, 5-10 membered heteroaryl, C3-C6 cycloalkyl and 4-9 membered heterocyclic group are optionally substituted by R F ;

[0031] R Y is independently selected from halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, cyano, -C(O)R g , -C(O)OR e , NHC(O)R e , -NR a R b , S-S(O)R e R f , -S(O)2R f , -S(O)=NH(C1-C4) alkyl, -S(O)NR e R f , -S(O)2NR e R f, hydroxyl, phenyl, 4- to 6-membered heterocyclic group, and 5- to 10-membered heteroaryl, wherein the phenyl, 4- to 6-membered heterocyclic group, and 5- to 10-membered heteroaryl are optionally substituted by R X substituted;

[0032] R F R S R X R Z are independently selected from halogen, cyano, C1-C4 alkyl, C1-C4 cyano-substituted alkyl, C3-C6 cycloalkyl, C1-C4 haloalkyl, -C1-C4 alkyl C(O)NR e R f , -(C1-C4)alkyl-(C1-C4)alkoxy, C1-C4 hydroxyalkyl, -(C1-C4)alkylphenyl, -(C1-C4)alkylheteroaryl, C2-C4 alkenyl, C2-C4 haloalkenyl, C2-C4 alkynyl, C2-C4 haloalkynyl, C1-C4 alkoxy, C1-C4 haloalkoxy, -OR e R f , =O, imine, phenyl, 4- to 6-membered heterocyclic group, 5- to 6-membered heteroaryl, -S(O)R f R e R f , -S(O)2NR e R f , -C(O)OR e , -NR c C(O)R e , -(C1-C4 alkyl)C(O)R g , -C(O)R g , -(C1-C4 alkyl)C(O)NR c R d , -C(O)NR c R d , -NO2 and -NR a R b , wherein the C1-C4 alkyl is optionally substituted by cyano, and the phenyl of the phenyl, 4- to 6-membered heterocyclic group, 5- to 6-membered heteroaryl, -(C1-C4)alkylphenyl is optionally substituted by halogen, cyano, =O, (C1-C 10 )alkyl, (C2-C 10 )alkenyl, (C2-C 10 )alkynyl, (C1-C 10 )haloalkyl, (C1-C 10 )alkoxy or (C1-C 10 )haloalkoxy, and the (C1-C 10 )alkyl, (C2-C 10) The alkenyl or (C2-C 10 ) alkynyl is optionally substituted by a 5- to 10-membered heteroaryl or a 4- to 10-membered heterocyclic group, and the 4- to 10-membered heterocyclic group is optionally substituted by oxo;

[0033] R M is independently selected from halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, cyano, -C(O)R g , -C(O)OR e , -NHC(O)R e , -C(O)NR c R d , -NR a R b , -S(O)R f , -S(O)2R f , -S(O)NR e R f , -S(O)═NH(C1-C4) alkyl, -S(O)2NR e R f , hydroxy, phenyl, 4- to 6-membered heterocyclic group, and 5- to 10-membered heteroaryl, and the phenyl, 4- to 6-membered heterocyclic group, and 5- to 10-membered heteroaryl are optionally substituted by R X ;

[0034] R a , R b , R c , R d , R e , R f , R g and R h are independently selected from hydrogen, C1-C4 alkyl, C2-C4 alkynyl, -C1-C4 alkylphenyl, phenyl, C3-C6 cycloalkyl, 4- to 6-membered heterocyclic group, and 5- to 6-membered heteroaryl, and the C1-C4 alkyl is optionally substituted by halogen, cyano, hydroxy, or amino, and the phenyl, C3-C6 cycloalkyl, 4- to 6-membered heterocyclic group, and 5- to 6-membered heteroaryl are optionally substituted by halogen, cyano, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, hydroxy, phenyl, or benzyl;

[0035] One or more hydrogen atoms of the compound are optionally deuterium atoms.

[0036] In some embodiments, p is 1.

[0037] In some embodiments, t is 1 or 2.

[0038] In some embodiments, t is 1.

[0039] In some embodiments, t is 2.

[0040] In some embodiments, q is 0.

[0041] In some embodiments, q is 1.

[0042] In some embodiments, X is selected from O, -C(=O)-NH-, S(O), and NR 8 .

[0043] In some embodiments, X is selected from NR 8 .

[0044] In some embodiments, R 8 is selected from 4- to 6-membered heterocyclic groups, and the 4- to 6-membered heterocyclic groups are optionally substituted with R 8a .

[0045] In some embodiments, R 8 is selected from 4-membered heterocyclic groups, and the 4-membered heterocyclic groups are optionally substituted with R 8a .

[0046] In some embodiments, R 8 is selected from oxetanyl, azetidinyl, thietanyl, and thietan-1,1-dioxide, and the oxetanyl, azetidinyl, thietanyl, and thietan-1,1-dioxide are optionally substituted with R 8a .

[0047] In some embodiments, R 8 is selected from oxetanyl, azetidinyl, and thietan-1,1-dioxide, and the oxetanyl, azetidinyl, and thietan-1,1-dioxide are optionally substituted with R 8a .

[0048] In some embodiments, R 8a is selected from C1-C4 alkyl, =O, and -C(O)C1-C4 alkyl.

[0049] In some embodiments, R 8a is selected from C1-C4 alkyl and -C(O)C1-C4 alkyl.

[0050] In some embodiments, R 8a is selected from methyl, =O, and -C(O)CH2CH3.

[0051] In some embodiments, R 8a is selected from methyl and -C(O)CH2CH3.

[0052] In some embodiments, when X is NR 8 , R 3 and the C to which it is attached and R8 Together with the connected N, they jointly form a 5-membered heterocycle or 5-membered heteroaryl.

[0053] In some embodiments, when X is NR 8 , R 3 Together with the connected C and R 8 Together with the connected N, they jointly form an imidazole ring or a pyrrolidine ring.

[0054] In some embodiments, R 1 is selected from an 8- to 10-membered heteroaryl substituted by -CR 1a R 2a P(O)OR 1b OR 2b , -CR 1a R 2a P(O)[OR 1b [NH(AA)C(O)OR T , -P(O)OR 1b OR 2b , -[P(O)[NHR Ty [NH(AA)C(O)OR T or -P(O)[OR 1b [NH(AA)C(O)OR T , and the 8- to 10-membered heteroaryl is additionally optionally substituted by amino, halogen, cyano, C1-C4 alkyl or C1-C4 alkoxy; an 8- to 10-membered heterocyclic group substituted by -CR 1a R 2a P(O)OR 1b OR 2b , -CR 1a R 2a P(O)[OR 1b [NH(AA)C(O)OR T , -P(O)OR 1b OR 2b , -[P(O)[NHR Ty [NH(AA)C(O)OR T or -P(O)[OR 1b [NH(AA)C(O)OR T , and the 8- to 10-membered heterocyclic group is additionally optionally substituted by amino, halogen, cyano, C1-C4 alkyl or C1-C4 alkoxy; or an 8- to 10-membered heterocyclic group substituted by -CR 1a R 2a P(O)OR 1b OR 2b , -CR 1a R 2a P(O)[OR 1b [NH(AA)C(O)ORT , -P(O)OR 1b OR 2b , -[P(O)[NHR Ty [NH(AA)C(O)OR T or -P(O)[OR 1b [NH(AA)C(O)OR T substituted C6-C 10 aryl, wherein the C6-C 10 aryl is further optionally substituted with cyano, C1-C4 alkoxy or halogen.

[0055] In some embodiments, R 1 is selected from -CR 1a R 2a P(O)OR 1b OR 2b , -CR 1a R 2a P(O)[OR 1b [NH(AA)C(O)OR T , -P(O)OR 1b OR 2b , -[P(O)[NHR Ty [NH(AA)C(O)OR T or -P(O)[OR 1b [NH(AA)C(O)OR T substituted 8-10-membered heteroaryl; -CR 1a R 2a P(O)OR 1b OR 2b , -CR 1a R 2a P(O)[OR 1b [NH(AA)C(O)OR T , -P(O)OR 1b OR 2b , -[P(O)[NHR Ty [NH(AA)C(O)OR T or -P(O)[OR 1b [NH(AA)C(O)OR T substituted C6-C 10 aryl or -CR 1a R 2a P(O)OR 1b OR 2b , -CR 1a R 2a P(O)[OR 1b [NH(AA)C(O)ORT , -P(O)OR 1b OR 2b , -[P(O)[NHR Ty [NH(AA)C(O)OR T or -P(O)[OR 1b [NH(AA)C(O)OR T substituted 8 - 10 membered heterocyclic group.

[0056] In some embodiments, R 1 is selected from

[0057] In some embodiments, R 1 is selected from

[0058] In some embodiments, R 1 is selected from

[0059] In some embodiments, R 2b and R 3b are independently selected from hydrogen, C1 - C4 alkyl, -(C1 - C4 alkylene)-OC(O)-(C1 - C4 alkyl), -(C1 - C4 alkylene)-OC(O)-[5 - 7 membered heterocyclic group], -(C1 - C4 alkylene)-SC(O)-(C1 - C6 alkyl), -(C1 - C4 alkylene)-OC(O)O-(C1 - C4 alkyl), -(C1 - C4 alkylene)-OC(O)N(C1 - C4 alkyl)2, -(C1 - C4 alkylene)-OC(O)O-(C1 - C4 alkylene)-O-(C1 - C4 alkyl) and C6 - C 10 aryl, the C6 - C 10 aryl is optionally substituted by halogen, cyano or C1 - C4 alkyl, the 5 - 7 membered heterocyclic group is optionally substituted by C(O)OR h .

[0060] In some embodiments, R h is selected from C1 - C4 alkyl, preferably methyl.

[0061] In some embodiments, R 2b and R 3b are independently selected from hydrogen, phenyl, -(C1 - C4 alkylene)-OC(O)O-(C1 - C4 alkyl) and -(C1 - C4 alkylene)-SC(O)-(C1 - C5 alkyl).

[0062] In some embodiments, -CR 1a R 2a P(O)OR 1bOR 2b selected from

[0063]

[0064] In some embodiments, -CR 1a R 2a P(O)OR 1b OR 2b selected from

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

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

[0067] In some embodiments, AA is a residue of alanine.

[0068] In some embodiments, R T is selected from C1-C4 alkyl.

[0069] In some embodiments, -CR 1a R 2a P(O)[OR 1b [NH(AA)C(O)OR T is

[0070] In some embodiments, R 2 is hydrogen.

[0071] In some embodiments, R 3 is hydrogen.

[0072] In some embodiments, R 4 is hydrogen.

[0073] In some embodiments, R 5 is hydrogen.

[0074] In some embodiments, R 6 and R 7Together with the N atom to which they are attached, form a 4- to 14-membered heterocyclic group, and the 4- to 14-membered heterocyclic group is optionally substituted by R Q Substituted.

[0075] In some embodiments, R 6 and R 7 Together with the N atom to which they are attached, form a 4- to 7-membered heterocyclic group, and the 4- to 7-membered heterocyclic group is optionally substituted by R Q Substituted.

[0076] In some embodiments, R 6 and R 7 The heterocyclic group formed together with the N atom to which they are attached is selected from Said Optionally substituted by R Q Substituted.

[0077] In some embodiments, R Q Is selected from cyano, phenyl, 4- to 9-membered heterocyclic group and =O, and the 4- to 9-membered heterocyclic group is optionally substituted by =O.

[0078] In some embodiments, R Q Is selected from cyano, phenyl, 6- to 7-membered heterocyclic group and =O, and the 6- to 7-membered heterocyclic group is optionally substituted by =O.

[0079] In some embodiments, R Q Is selected from cyano, phenyl, And =O.

[0080] In some embodiments, R 6 and R 7 The heterocyclic group formed together with the N atom to which they are attached is selected from

[0081] In some embodiments, the compound of formula (I) or its stereoisomer or its pharmaceutically acceptable salt is selected from the compound of formula (II) or its stereoisomer or its pharmaceutically acceptable salt,

[0082]

[0083] Wherein, q, t, p, X, R 1 、R 2 、R 3 、R 4 、R 5 、R 6 and R 7 Are as defined for the compound of formula (I).

[0084] In some embodiments, the compound of formula (I) 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,

[0085]

[0086]

[0087] On the other hand, the present disclosure provides a pharmaceutical composition comprising the compound of formula (I) of the present disclosure, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0088] On the other hand, the present disclosure provides a method for treating a STAT6-mediated disease in an individual (such as a mammal), comprising administering to an individual (such as a mammal, preferably a human) in need of such treatment a therapeutically effective amount of the compound of formula (I), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0089] On the other hand, the present disclosure provides the use of the compound of formula (I), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the preparation of a drug for preventing or treating a STAT6-mediated disease.

[0090] On the other hand, the present disclosure provides the use of the compound of formula (I), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in preventing or treating a STAT6-mediated disease.

[0091] On the other hand, 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 preventing or treating a STAT6-mediated disease.

[0092] In some embodiments, the STAT6-mediated disease is asthma, atopic dermatitis or chronic obstructive pulmonary disease.

[0093] Term Definitions and Explanations

[0094] Unless otherwise specified, the terms used in the present disclosure have the following meanings. The definitions of the groups and terms described in the present disclosure, including their definitions as examples, exemplary definitions, preferred definitions, definitions recorded in tables, definitions of specific compounds in examples, etc., can be combined and combined with each other arbitrarily. A particular term should not be considered indeterminate or unclear without a special definition, but should be understood according to its ordinary meaning in the art. When a trade name appears in this document, it is intended to refer to the corresponding product or its active ingredient.

[0095] As used herein represents a connecting site.

[0096] The graphical representation of racemates or enantiomerically pure compounds in this article is from Maehr, J. Chem. Ed. 1985, 62: 114 - 120. Unless otherwise specified, solid wedges and dashed wedges are used to represent the absolute configuration of a stereocenter, and solid lines and dashed lines are used to represent the relative configuration of a stereocenter (such as the cis - trans configuration of alicyclic compounds).

[0097] The term “[NH(AA)C(O)OR T ”, where both NH and C(O)O are part of an amino acid residue, NH represents the amino - terminus, and C(O)O represents the carboxyl - terminus.

[0098] The compounds of the present disclosure may have asymmetric atoms such as carbon, sulfur, nitrogen, phosphorus atoms or asymmetric double bonds, and thus the compounds of the present disclosure may exist in specific geometric or stereoisomeric forms. Specific geometric or stereoisomeric forms may be cis - and trans - isomers, E - and Z - geometric isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereoisomers, (D)-isomers, (L)-isomers, and their racemic mixtures or other mixtures, such as enantiomer - or diastereomer - enriched mixtures. All of the above - mentioned isomers and their mixtures are within the scope of the definition of the compounds of the present disclosure. Additional asymmetric carbon, sulfur, nitrogen or phosphorus atoms may be present in substituents such as alkyl groups, and these isomers and their mixtures involved in all substituents are also included within the scope of the definition of the compounds of the present disclosure. The compounds of the present disclosure containing asymmetric atoms may be isolated in optically active pure form or in racemic form. The optically active pure form can be resolved from the racemic mixture or synthesized by using chiral starting materials or chiral reagents.

[0099] The term “substituted” means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, provided that the valence of the particular atom is normal and the resulting compound is stable. When the substituent is oxo (i.e., =O), it means that two hydrogen atoms are replaced, and oxo does not occur on an aromatic group.

[0100] The term "optionally" or "optionally" means that the subsequently described event or situation may or may not occur, and this description includes the occurrence and non-occurrence of the described event or situation. For example, when ethyl is "optionally" substituted by one or more halogens, it means that ethyl can be unsubstituted (CH2CH3), monosubstituted (CH2CH2F, CH2CH2Cl, etc.), polysubstituted (CHFCH2F, CH2CHF2, CHFCH2Cl, CH2CHCl2, etc.) or fully substituted (CF2CF3, CF2CCl3, CCl2CCl3, etc.). Those skilled in the art will understand that for any group containing one or more substituents, no substitution or substitution pattern that is spatially impossible and / or cannot be synthesized will be introduced.

[0101] When any variable (such as R a , R b ) appears more than once in the composition or structure of a compound, its definition in each case is independent. For example, if a group is substituted by two R b , then each R b has an independent option.

[0102] When the number of a linking group is 0, such as -(CH2)0-, it means that the linking group is a bond.

[0103] C m -C n in this article means having an integer number of carbon atoms in the range of m - n. For example, "C1 - C 10 " means that the group can have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, 6 carbon atoms, 7 carbon atoms, 8 carbon atoms, 9 carbon atoms or 10 carbon atoms.

[0104] When the linking group involved in this article does not specify its linking direction, its linking direction is arbitrary. For example, when L in the structural unit 1 is selected from "C1 - C3 alkylene - O", at this time L 1 can either connect the ring Q and R 1 in the left - to - right direction to form "ring Q - C1 - C3 alkylene - O - R 1 ", or connect the ring Q and R 1 in the right - to - left direction to form "ring Q - O - C1 - C3 alkylene - R 1 ".

[0105] When a substituent's bond cross - connects to two atoms on a ring, this substituent can bond to any atom on this ring. For example, the structural unit represents R5 Substitution can occur at any position on the benzene ring.

[0106] C in this article m -C n refers to having an integer number of carbon atoms in the range of m - n. For example, "C1 - C 10 " means that the group can have 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms.

[0107] The term "alkyl" refers to a hydrocarbon group with the general formula C n H 2n+1 and this alkyl can be straight-chain or branched. The term "C1 - C 20 alkyl" can be understood to represent a straight-chain or branched saturated hydrocarbon group having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 carbon atoms. The term "C1 - C 10 alkyl" can be understood to represent a straight-chain or branched saturated hydrocarbon group having 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms. Specific examples of said alkyl 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, etc.; The term "C1 - C6 alkyl" can be understood to represent an alkyl having 1 to 6 carbon atoms, and specific examples include, but are 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, etc. The term "C1 - C4 alkyl" can be understood to represent a straight-chain or branched saturated alkyl having 1 to 4 carbon atoms. The term "C1 - C3 alkyl" can be understood to represent a straight-chain or branched saturated alkyl having 1 to 3 carbon atoms. The said "C1 - C 10"Alkyl" may include ranges such as "C1-C6 alkyl", "C1-C4 alkyl", or "C1-C3 alkyl", and the "C1-C6 alkyl" may further include "C1-C4 alkyl" or "C1-C3 alkyl". The term "alkylene" refers to a straight-chain or branched-chain divalent hydrocarbon chain that connects the rest of the molecule to a group, which consists only of carbon and hydrogen and is saturated. The term "haloalkyl" is intended to include monohaloalkyl and polyhaloalkyl. For example, the term "C1-C 10 haloalkyl" means a C1-C as defined above that is substituted by one or more halogens 10 alkyl, including but not limited to trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, trichloromethyl, pentafluoroethyl, pentachloroethyl, and the like.

[0108] The term "alkoxy" refers to a group formed by removing the hydrogen atom on the hydroxyl group of a straight-chain or branched-chain alcohol, and can be understood as "alkyloxy" or "alkyl-O-". The term "C1-C 10 alkoxy" can be understood as "C1-C 10 alkyloxy" or "C1-C 10 alkyl-O-"; the term "C1-C6 alkoxy" can be understood as "C1-C6 alkyloxy" or "C1-C6 alkyl-O-". The "C1-C 10 alkoxy" may include ranges such as "C1-C6 alkoxy" and "C1-C3 alkoxy", and the "C1-C6 alkoxy" may further include "C1-C3 alkoxy". The term "haloalkoxy" is intended to include monohaloalkoxy and polyhaloalkoxy.

[0109] The term "alkenyl" refers to a straight-chain or branched-chain unsaturated aliphatic hydrocarbon group composed of carbon atoms and hydrogen atoms and having at least one double bond. The term "C2-C 10 alkenyl" can be understood to represent a straight-chain or branched-chain unsaturated hydrocarbon group that contains one or more double bonds and has 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms. The "C2-C 10 alkenyl" may include "C2-C6 alkenyl", "C2-C4 alkenyl", C2 or C3 alkenyl. It is understood that in the case where the alkenyl contains more than one double bond, the double bonds may be separated or conjugated to each other. Specific examples of the alkenyl include but are not limited to vinyl, allyl, (E)-2-methylvinyl, (Z)-2-methylvinyl, (E)-but-2-enyl, (Z)-but-2-enyl, (E)-but-1-enyl, (Z)-but-1-enyl, isopropenyl, 2-methylprop-2-enyl, 1-methylprop-2-enyl, 2-methylprop-1-enyl, (E)-1-methylprop-1-enyl, or (Z)-1-methylprop-1-enyl, etc. The term "haloalkenyl" is intended to include monohaloalkenyl and polyhaloalkenyl.

[0110] The term "alkynyl" refers to a straight-chain or branched-chain unsaturated aliphatic hydrocarbon group composed of carbon atoms and hydrogen atoms and having at least one triple bond. The term "C2-C 10 alkynyl" can be understood to mean a straight-chain or branched-chain unsaturated hydrocarbon group that contains one or more triple bonds and has 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms. Examples of "C2-C 10 alkynyl" include, but are not limited to, ethynyl (-C≡CH), propynyl (-C≡CCH 3、 -CH2C≡CH), but-1-ynyl, but-2-ynyl, or but-3-ynyl. "C2-C 10 alkynyl" may include "C2-C3 alkynyl", and examples of "C2-C3 alkynyl" include ethynyl (-C≡CH), prop-1-ynyl (-C≡CCH3), prop-2-ynyl (-CH2C≡CH). The term "haloalkynyl" is intended to include monohaloalkynyl and polyhaloalkynyl.

[0111] The term "cycloalkyl" refers to a carbocyclic group that is completely saturated and exists in the form of a monocyclic, fused-ring, bridged-ring, or spiro-ring, etc. Unless otherwise indicated, the carbocyclic ring is usually a 3- to 20-membered ring. The term "C3-C 10 cycloalkyl" refers to a cycloalkyl having 3, 4, 5, 6, 7, 8, 9, or 10 ring carbon atoms. The term "C3-C6 cycloalkyl" refers to a cycloalkyl having 3, 4, 5, or 6 ring carbon atoms.

[0112] The term "heterocyclic" or "heterocyclic group" refers to a monocyclic, fused-ring, spiro or bridged-ring group that is fully saturated or partially saturated (not heteroaromatic with aromaticity as a whole), and contains 1-5 (e.g., 1-3 or 1-2) heteroatoms or heteroatom groups (i.e., atomic groups containing heteroatoms) among its ring atoms. The "heteroatom or heteroatom group" includes, but is not limited to, nitrogen atom (N), oxygen atom (O), sulfur atom (S), phosphorus atom (P), boron atom (B), -S(=O)2-, -S(=O)-, -P(=O)2-, -P(=O)-, -NH-, -S(=O)(=NH)-, -C(=O)NH- or -NHC(=O)NH-, etc. The term "4-14 membered heterocyclic group" refers to a heterocyclic group having 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms, and containing 1-5 heteroatoms or heteroatom groups independently selected from the above-mentioned heteroatoms or heteroatom groups among its ring atoms. The term "4-10 membered heterocyclic group" refers to a heterocyclic group having 4, 5, 6, 7, 8, 9 or 10 ring atoms, and containing 1-5 heteroatoms or heteroatom groups independently selected from the above-mentioned heteroatoms or heteroatom groups among its ring atoms. The term "4-9 membered heterocyclic group" refers to a heterocyclic group having 4, 5, 6, 7, 8 or 9 ring atoms, and containing 1-5 heteroatoms or heteroatom groups independently selected from the above-mentioned heteroatoms or heteroatom groups among its ring atoms. The term "8-10 membered heterocyclic group" refers to a heterocyclic group having 8, 9 or 10 ring atoms, and containing 1-5 heteroatoms or heteroatom groups independently selected from the above-mentioned heteroatoms or heteroatom groups among its ring atoms. The "4-10 membered heterocyclic group" may include the "4-7 membered heterocyclic group". The term "4-7 membered heterocyclic group" refers to a heterocyclic group having 4, 5, 6 or 7 ring atoms, and containing 1, 2, 3, 4 or 5 heteroatoms or heteroatom groups independently selected from the above-mentioned heteroatoms or heteroatom groups among its ring atoms. The term "4-6 membered heterocyclic group" refers to a heterocyclic group having 4, 5 or 6 ring atoms, and containing 1, 2, 3, 4 or 5 heteroatoms or heteroatom groups independently selected from the above-mentioned heteroatoms or heteroatom groups among its ring atoms. The term "5-7 membered heterocyclic group" refers to a heterocyclic group having 5, 6 or 7 ring atoms, and containing 1, 2, 3, 4 or 5 heteroatoms or heteroatom groups independently selected from the above-mentioned heteroatoms or heteroatom groups among its ring atoms. Among them, specific examples of the 4-membered heterocyclic group include, but are not limited to, azetidinyl or oxetanyl; specific examples of the 5-membered heterocyclic group include, but are not limited to, tetrahydrofuranyl, dioxolanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl, 4,5-dihydrooxazolyl or 2,5-dihydro-1H-pyrrolyl; specific examples of the 6-membered heterocyclic group include, but are not limited to, tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, trithianyl, tetrahydropyridyl or 4H-[1,3,4]thiadiazinyl; specific examples of the 7-membered heterocyclic group include, but are not limited to, diazepanyl.The heterocyclic group may also be a bicyclic group. Specific examples of the 5,5-membered bicyclic group include, but are not limited to, hexahydrocyclopenta[c]pyrrol-2(1H)-yl; specific examples of the 5,6-membered bicyclic group include, but are not limited to, hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl, 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazinyl, or 5,6,7,8-tetrahydroimidazo[1,5-a]pyrazinyl. Optionally, the heterocyclic group may be a benzo-fused ring group of the above 4- to 7-membered heterocyclic group, and specific examples include, but are not limited to, dihydroisoquinolinyl, etc. The "4- to 10-membered heterocyclic group" may include ranges such as "5- to 10-membered heterocyclic group", "4- to 7-membered heterocyclic group", "5- to 6-membered heterocyclic group", "6- to 8-membered heterocyclic group", "4- to 10-membered heterocycloalkyl group", "5- to 10-membered heterocycloalkyl group", "4- to 7-membered heterocycloalkyl group", "5- to 6-membered heterocycloalkyl group", "6- to 8-membered heterocycloalkyl group", etc. The "4- to 7-membered heterocyclic group" may further include ranges such as "4- to 6-membered heterocyclic group", "5- to 6-membered heterocyclic group", "4- to 7-membered heterocycloalkyl group", "4- to 6-membered heterocycloalkyl group", "5- to 6-membered heterocycloalkyl group", etc. Although some bicyclic heterocyclic groups in the present disclosure partially contain a benzene ring or a heteroaromatic ring, the heterocyclic group as a whole is still non-aromatic.

[0113] The term "heterocycloalkyl" refers to a fully saturated cyclic group that exists in the form of a monocyclic, fused-ring, bridged-ring, or spiro-ring, etc., and contains 1 to 5 heteroatoms or heteroatomic groups (i.e., atomic groups containing heteroatoms) among the ring atoms of the ring. The "heteroatom or heteroatomic group" includes, but is not limited to, nitrogen atom (N), oxygen atom (O), sulfur atom (S), phosphorus atom (P), boron atom (B), -S(=O)2-, -S(=O)-, -NH-, -S(=O)(=NH)-, -C(=O)NH- or -NHC(=O)NH-, etc. The term "4- to 10-membered heterocycloalkyl" refers to a heterocycloalkyl having 4, 5, 6, 7, 8, 9, or 10 ring atoms, and containing 1 to 5 heteroatoms or heteroatomic groups independently selected from the above-mentioned ones. The term "4- to 6-membered heterocycloalkyl" refers to a heterocycloalkyl having 4, 5, or 6 ring atoms, and containing 1 to 5 heteroatoms or heteroatomic groups independently selected from the above-mentioned ones. The term "5- to 10-membered heterocycloalkyl" refers to a heterocycloalkyl having 5, 6, 7, 8, 9, or 10 ring atoms, and containing 1 to 5 heteroatoms or heteroatomic groups independently selected from the above-mentioned ones. "4- to 10-membered heterocycloalkyl" and "5- to 10-membered heterocycloalkyl" include "4- to 7-membered heterocycloalkyl". Among them, specific examples of 4-membered heterocycloalkyl include, but are not limited to, azetidinyl, oxetanyl, or thietanyl; specific examples of 5-membered heterocycloalkyl include, but are not limited to, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, isoxazolidinyl, oxazolidinyl, isothiazolidinyl, thiazolidinyl, imidazolidinyl, or tetrahydropyrazolyl; specific examples of 6-membered heterocycloalkyl include, but are not limited to, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, piperazinyl, 1,4-thioxanyl, 1,4-dioxanyl, thiomorpholinyl, 1,3-dithianyl, or 1,4-dithianyl; specific examples of 7-membered heterocycloalkyl include, but are not limited to, azepanyl, oxepanyl, or thiepanyl.

[0114] The term "aryl" refers to an all-carbon monocyclic or fused polycyclic aromatic ring group having a conjugated π-electron system. An aryl can have 6 to 20 carbon atoms, 6 to 14 carbon atoms, or 6 to 12 carbon atoms. The term "C6-C 10 aryl" can be understood as an aryl having 6 to 10 carbon atoms. For example, a ring having 6 carbon atoms ("C6 aryl"), such as phenyl; or a ring having 9 carbon atoms ("C9 aryl"), such as indanyl or indenyl; or a ring having 10 carbon atoms ("C 10 aryl"), such as tetrahydronaphthyl, dihydronaphthyl, or naphthyl.

[0115] The term "heteroaryl" refers to a monocyclic or fused polycyclic system having aromaticity, wherein the ring atoms include at least one ring atom selected from N, O, and S, and the remaining ring atoms are C aromatic ring groups. The term "5-10 membered heteroaryl" can be understood to include such monocyclic or bicyclic aromatic ring systems: having 5, 6, 7, 8, 9, or 10 ring atoms, such as 5 or 6 or 9 or 10 ring atoms, and containing 1-5, such as 1-3 heteroatoms independently selected from N, O, and S. In particular, heteroaryl is selected from thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, or thiadiazolyl, etc. and their benzo derivatives, such as benzofuryl, benzothienyl, benzothiazolyl, benzoxazolyl, benzoisoxazolyl, benzimidazolyl, benzotriazolyl, indazolyl, indolyl, or isoindolyl, etc.; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, or triazinyl, etc. and their benzo derivatives, such as quinolinyl, quinazolinyl, or isoquinolinyl, etc.; or azocinyl, indolizinyl, purinyl, etc. and their benzo derivatives; or cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, or phenoxazinyl, etc. The term "6-10 membered heteroaryl" can be understood to include such monocyclic or bicyclic aromatic ring systems: having 6, 7, 8, 9, or 10 ring atoms, such as 6 or 9 or 10 ring atoms, and containing 1-5, such as 1-3 heteroatoms independently selected from N, O, and S. The term "8-10 membered heteroaryl" can be understood to include such monocyclic or bicyclic aromatic ring systems: having 8, 9, or 10 ring atoms, and containing 1-5, such as 1-3 heteroatoms independently selected from N, O, and S. The term "5-6 membered heteroaryl" refers to an aromatic ring system having 5 or 6 ring atoms, and containing 1-3, such as 1-2 heteroatoms independently selected from N, O, and S.

[0116] The term "halo" or "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0117] The term "hydroxy" refers to the -OH group.

[0118] The term "cyano" refers to the -CN group.

[0119] The term "amino" refers to the -NH2 group.

[0120] The term "nitro" refers to the -NO2 group.

[0121] The term "treat" means administering the compounds or formulations described in this application to improve or eliminate a disease or one or more symptoms associated with the disease, and includes:

[0122] (i) inhibiting the disease or disease state, i.e., curbing its development;

[0123] (ii) alleviating a disease or disease state, even if the disease or disease state regresses.

[0124] The term "therapeutically effective amount" means an amount of a compound of the present disclosure that (i) treats a particular disease, condition, or disorder, or (ii) alleviates, ameliorates, or eliminates one or more symptoms of a particular disease, condition, or disorder. The amount of the compound of the present disclosure that constitutes a "therapeutically effective amount" varies depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by those skilled in the art based on their own knowledge and the present disclosure.

[0125] The term "prevent" means administering a compound or formulation described in the present application to prevent a disease or one or more symptoms associated with the disease, and includes preventing the occurrence of a disease or disease state in an individual (e.g., a mammal), particularly when such an individual (e.g., a mammal) is susceptible to the disease state but has not been diagnosed as having the disease state.

[0126] The term "individual" includes mammals and non-mammals. Examples of mammals include, but are not limited to, any member of the class Mammalia: humans, non-human primates (e.g., chimpanzees and other apes and monkeys); domestic animals, such as cows, horses, sheep, goats, pigs; household pets, such as rabbits, dogs, and cats; laboratory animals, including rodents, such as rats, mice, and guinea pigs, etc. Examples of non-human mammals include, but are not limited to, birds and fish, etc. In one embodiment of the methods and compositions provided herein, the mammal is a human. The terms "patient" and "individual" are used interchangeably.

[0127] The term "pharmaceutically acceptable" pertains to those compounds, materials, compositions, and / or dosage forms that, within the scope of sound medical judgment, are suitable for use in contact with the tissues of humans and animals without excessive toxicity, irritation, allergic response, or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0128] The term "pharmaceutically acceptable salt" refers to salts of pharmaceutically acceptable acids or bases, including salts formed by the compound with inorganic acids or organic acids, and salts formed by the compound with inorganic bases or organic bases.

[0129] The term "pharmaceutical composition" refers to a mixture of one or more compounds of the present disclosure or salts thereof and pharmaceutically acceptable excipients. The purpose of the pharmaceutical composition is to facilitate the administration of the compounds of the present disclosure to an organism.

[0130] The term "pharmaceutically acceptable excipient" refers to those excipients that do not cause significant irritation to an organism and do not impair the biological activity and properties of the active compound. Suitable excipients are well known to those skilled in the art, such as carbohydrates, waxes, water-soluble and / or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, etc.

[0131] The term "comprise" or "comprising" and its English variants such as "comprises" or "comprising" can be understood in an open, non-exclusive sense, i.e., "including but not limited to".

[0132] The present disclosure also includes isotopically labeled compounds of the present disclosure that are the same as those described herein, but in which one or more atoms are replaced by atoms having an atomic weight or mass number different from the atomic weight or mass number normally found in nature. Examples of isotopes that can be incorporated into the compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, 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, etc.

[0133] Certain isotopically labeled compounds of the present disclosure (e.g., labeled with 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 because of their ease of preparation and detectability. Positron-emitting isotopes, such as 15 O, 13 N, 11 C, and 18 F can be used in positron emission tomography (PET) studies to determine substrate occupancy. Isotopically labeled compounds of the present disclosure can generally be prepared by substituting an isotopically labeled reagent for an unlabeled reagent by procedures similar to those described in the protocols and / or examples disclosed below.

[0134] The pharmaceutical compositions of the present disclosure can be prepared by combining the compounds of the present disclosure with suitable pharmaceutically acceptable excipients, and can be formulated into solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres and aerosols, etc.

[0135] Typical routes of administration of the compounds of the present disclosure, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, include but are not limited to oral, rectal, topical, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, intravenous administration.

[0136] The pharmaceutical compositions of the present disclosure can be manufactured by methods well known in the art, such as conventional mixing methods, dissolution methods, granulation methods, emulsification methods, lyophilization methods, etc.

[0137] In some embodiments, the pharmaceutical composition is in oral form. For oral administration, the pharmaceutical composition can be formulated by mixing the active compound with pharmaceutically acceptable excipients well known in the art. These excipients enable the compounds of the present disclosure to be formulated into tablets, pills, lozenges, dragees, capsules, liquids, gels, syrups, suspensions, etc. for oral administration to a patient.

[0138] Solid oral compositions can be prepared by conventional mixing, filling or tableting methods. For example, it can be obtained by the following method: mixing the active compound with solid excipients, optionally milling the resulting mixture, adding other suitable excipients if necessary, and then processing the mixture into granules to obtain the core of a tablet or dragee. Suitable excipients include but are not limited to: binders, diluents, disintegrants, lubricants, glidants or flavoring agents, etc.

[0139] The pharmaceutical composition is also suitable for parenteral administration, such as sterile solutions, suspensions or lyophilized products in suitable unit dosage forms.

[0140] The dosage administered depends on factors such as the specific compound, the disease condition and its severity, the identity of the subject or host to be treated (e.g., weight, gender), and is determined by the specific circumstances of the case, including, for example, the specific formulation administered, the route of administration, the disorder being treated, and the subject or host being treated.

[0141] In all methods of administration of the compounds of general formula (I) described herein, in the case of oral administration, the daily dosage is from 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 being treated, and the judgment of the practitioner.

[0142] The compounds of the present disclosure can be prepared by a variety of synthetic methods well-known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by their combination with other chemical synthesis methods, and equivalent replacement methods well-known to those skilled in the art. Preferred embodiments include, but are not limited to, the examples of the present disclosure.

[0143] The chemical reactions of the specific embodiments of the present disclosure are carried out in a suitable solvent, and the solvent must be suitable for the chemical changes of the present disclosure and the reagents and materials required therefor. In order to obtain the compounds of the present disclosure, sometimes those skilled in the art need to modify or select the synthesis steps or reaction processes on the basis of the existing embodiments.

[0144] The following abbreviations are used in the present disclosure:

[0145] BnBr represents benzyl bromide; Bn represents benzyl; DMAP represents 4-dimethylaminopyridine; DMF represents N,N-dimethylformamide; DCM represents dichloromethane; TFA represents trifluoroacetic acid; DIEA represents N,N-diisopropylethylamine; MeOH represents methanol; TMS represents trimethylsilyl; DCE represents 1,2-dichloroethane; LC-MS represents liquid chromatography-mass spectrometry; MS represents mass spectrometry; 1 1H NMR represents nuclear magnetic resonance hydrogen spectrum; ESI represents electrospray ionization; HPLC represents high performance liquid chromatography; DMSO represents dimethyl sulfoxide; EDCI represents 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride; ISiMe3 represents iodotrimethylsilane; HATU represents 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; DIPEA represents N,N-diisopropylethylamine; BOC represents tert-butylcarbonyl; STAB represents sodium triacetoxyborohydride; AcOH represents acetic acid; DMP represents Dess-Martin periodinane; TLC represents thin layer chromatography; tBuOK represents potassium tert-butoxide; Boc2O represents di-tert-butyl dicarbonate; (MeO)2POCl represents dimethyl chlorophosphate; LiHMDS represents lithium bis(trimethylsilyl)amide; THF represents tetrahydrofuran; NEt3 represents triethylamine; PPh3 represents triphenylphosphine; NIS represents N-iodosuccinimide; LDA represents lithium diisopropylamide; Ti(OiPr)4 represents titanium(IV) isopropoxide; Amberlite IR 120,Na resin represents Amberlite ion exchange resin IR120; DMF represents N,N-dimethylformamide; IC 50 represents the half maximal inhibitory concentration, which refers to the concentration at which half of the maximum inhibitory effect is achieved; Emax represents the maximum inhibition rate; HEPES represents 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid; DTT represents dithiothreitol; BSA represents bovine serum albumin. Detailed implementation manners

[0146] 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 implementation manners listed herein, the implementation manners formed by their combination with other chemical synthesis methods, and the equivalent replacement manners well-known to those skilled in the art. Preferred implementation manners include, but are not limited to, the examples of the present disclosure.

[0147] The present disclosure will be described in detail below by way of examples, but this does not mean any adverse limitation to the present disclosure. The present disclosure has been described in detail herein, and its specific implementation manners have also been disclosed. It will be obvious to those skilled in the art that various changes and improvements can be made to the specific implementation manners of the present disclosure without departing from the spirit and scope of the present disclosure. All reagents used in the present disclosure are commercially available and can be used without further purification.

[0148] Unless otherwise stated, the ratio represented by the mixed solvent is the volume mixing ratio.

[0149] Unless otherwise stated, % refers to weight percentage wt%.

[0150] The compounds are named manually or by software, and commercially available compounds use the supplier catalog names.

[0151] The structures of the compounds are determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). The unit of the NMR shift is 10 -6 (ppm). The solvents for NMR determination are deuterated dimethyl sulfoxide, deuterated chloroform, deuterated methanol, etc., and the internal standard is tetramethylsilane (TMS);

[0152] The eluent or mobile phase can be a mixed eluent or mobile phase composed of two or more solvents, and the ratio thereof is the volume ratio of each solvent.

[0153] Preparation Example 1 Synthesis of Intermediate (Difluoro(2-((4-nitrophenoxy)carbonyl)benzo[b]thiophen-5-yl)methyl)phosphonic Acid (Compound I)

[0154]

[0155] Step 1: Synthesis of Benzyl 5-bromobenzo[b]thiophene-2-carboxylate (Compound I-2)

[0156] The starting material compound I-1 (200 mg, 0.78 mmol), benzyl bromide (126 mg, 1.17 mmol), potassium carbonate (165 mg, 1.56 mmol), and dimethyl sulfoxide (2 mL) were added to a reaction flask, and the reaction solution was stirred at 50 °C for 14 hours. LC-MS showed that the reaction was complete. The reaction solution was cooled, quenched with water, and extracted three times with ethyl acetate (20 mL). The combined organic phases were washed three times with water (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 19 / 1) to obtain compound I-2 (231 mg).

[0157] 1 H NMR (400 MHz, CDCl3) δ 8.00 (m, 2H), 7.71 (d, J = 8.7 Hz, 1H), 7.54 (m, 1H), 7.46 (m, 2H), 7.43–7.35 (m, 3H), 5.39 (s, 2H).

[0158] Step 2: Synthesis of benzyl 5-iodobenzo[b]thiophene-2-carboxylate (Compound I-3)

[0159] Compound I-2 (4.5 g, 12.96 mmol), potassium iodide (10.76 mg, 64.80 mmol), copper(I) iodide (494 mg, 2.59 mmol), N 1 , N 2 -dimethylethane-1,2-diamine (0.31 ml, 2.59 mmol), and 1,4-dioxane (50 mL) were added to a reaction flask, and then an argon balloon was installed to displace the gas three times. The reaction solution was refluxed at 110 °C for 24 hours under argon protection. The reaction solution was cooled, quenched with water, and extracted three times with ethyl acetate (200 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 19 / 1) to obtain compound I-3 (3.37 g).

[0160] Step 3: Synthesis of benzyl 5-(diethoxyphosphoryl)difluoromethyl)benzo[b]thiophene-2-carboxylate (Compound I-4)

[0161] Cadmium powder (2.49 g, 22.20 mmol) was added to a three-necked flask, an argon balloon was installed, and the gas was replaced three times. Under argon protection, anhydrous N,N-dimethylformamide (25 mL) was added, and the mixture was stirred at room temperature for 20 minutes. Subsequently, diethyl bromodifluoromethylphosphonate (3.39 g, 12.68 mmol) was gradually added. After the reaction was initiated, the system exothermed significantly. The reaction was maintained at room temperature for 3 hours, then allowed to stand for precipitation, and the supernatant was the newly prepared organocadmium reagent. In another three-necked flask, compound I-3 (2.5 g, 6.34 mmol) and cuprous bromide (1.82 g, 12.68 mmol) were added. An argon balloon was installed, and the gas was replaced three times. Under argon protection, the above newly prepared organocadmium reagent solution was added. The resulting reaction solution was placed in an oil bath at 30 °C and reacted for 24 hours. LC-MS showed that the reaction was complete. The reaction solution was poured into water, 150 mL of ethyl acetate was added, and a large amount of solid was precipitated. It was filtered through diatomaceous earth, the filtrate was separated, the aqueous phase was extracted twice with ethyl acetate, the organic phases were combined, washed with water, saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (silica, petroleum ether / ethyl acetate = 3 / 1) to obtain compound I-4 (1.82 g).

[0162] MS m / z(ESI):=455.0[M+H] + 。

[0163] 1 H NMR(400MHz,CDCl3)δ8.17–8.10(m,2H),7.99–7.89(m,1H),7.75–7.65(m,1H),7.51–7.31(m,5H),5.40(s,2H),4.28–4.12(m,4H),1.36–1.30(m,6H).

[0164] Step 4: Synthesis of 5-(diethoxyphosphoryl)difluoromethyl)benzo[b]thiophene-2-carboxylic acid (Compound I-5)

[0165] Compound I-4 (3.62 g, 7.97 mmol), palladium / carbon (0.72 g, w / w = 20%), and methanol (50 mL) were added to a reaction flask, and then a hydrogen balloon was installed to replace the gas three times. The reaction solution was reacted at room temperature for 20 hours. LC-MS showed that the reaction was complete. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain compound I-5 (2.21 g).

[0166] MS m / z(ESI):=363.0[M-H] - 。

[0167] Step 5: Synthesis of 5-((diethoxyphosphoryl)difluoromethyl)benzo[b]thiophene-2-carboxylic acid (4-nitrophenyl) ester (Compound I-6)

[0168] Compound I-5 (2.21 g, 6.07 mmol), 4-dimethylaminopyridine (185 mg, 1.52 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.74 g, 9.10 mmol), and dichloromethane (40 mL) were added to a reaction flask and stirred at room temperature for 15 minutes. Then, p-nitrophenol (1.05 g, 7.58 mmol) was added, and the reaction mixture was stirred at room temperature for 18 hours. LC-MS showed that the reaction was complete. The reaction was quenched by adding water, and the mixture was extracted three times with dichloromethane (100 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 4 / 1) to obtain compound I-6 (2.12 g).

[0169] 1 1H NMR (400 MHz, CDCl3) δ 8.43–8.18 (m, 4H), 8.02 (d, J = 8.9 Hz, 1H), 7.77 (d, J = 8.6 Hz, 1H), 7.48 (d, J = 8.6 Hz, 2H), 4.24 (m, 4H), 1.35 (m, 6H).

[0170] Step 6: Synthesis of (difluoro(2-((4-nitrophenoxy)carbonyl)benzothiophen-5-yl)methyl)phosphonic acid (Compound I)

[0171] Compound I-6 (0.5 g, 1.37 mmol), N,O-bis(trimethylsilyl)trifluoroacetamide (1.77 g, 6.86 mmol), and dichloromethane (4 mL) were added to a reaction flask and stirred at 0 °C for 15 minutes. Then, iodotrimethylsilane (1.10 g, 5.49 mmol) was added, and the reaction mixture was stirred at room temperature for 15 minutes. LC-MS showed that the reaction was complete. The reaction was quenched by adding 1 mL of a mixed solution of water and acetonitrile (water:acetonitrile = 2:1, containing 0.1% trifluoroacetic acid), filtered, and the solid was washed twice with a small amount of water and dried to obtain compound I (0.3 g).

[0172] MS m / z (ESI): = 427.9 [M-H] - 。

[0173] 1 1H NMR (400 MHz, DMSO-d6) δ 8.65 (s, 1H), 8.41–8.35 (m, 2H), 8.31–8.23 (m, 2H), 7.71 (m, 3H).

[0174] Synthesis of Intermediate trans-4-phenylpyrrolidine-3-carbonitrile (Compound II) in Preparation Example 2

[0175]

[0176] Step 1: Synthesis of trans-1-benzyl-4-phenylpyrrolidine-3-carbonitrile (Compound II-2)

[0177] The starting material II-1 (500 mg, 3.87 mmol), N-benzyl-1-methoxy-N-((trimethylsilyl)methyl)methanamine (919 mg, 3.87 mmol), trifluoroacetic acid (28.8 μL, 0.39 mmol), and dichloromethane (10 mL) were added to a reaction flask, and the reaction solution was stirred at room temperature for 12 hours. LC-MS showed that the reaction was complete. The reaction was quenched by adding saturated aqueous sodium bicarbonate solution, and the mixture was extracted three times with dichloromethane (50 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 19 / 1) to obtain Compound II-2 (1.01 g).

[0178] MS m / z (ESI): = 263.1 [M+H] + 。

[0179] 1 1H NMR (400 MHz, CDCl3) δ 7.29–7.15 (m, 10H), 3.67–3.56 (m, 2H), 3.56–3.48 (m, 1H), 3.06–2.88 (m, 3H), 2.83 (m, 1H), 2.70 (m, 1H).

[0180] Step 2: Synthesis of trans-4-phenylpyrrolidine-3-carbonitrile (Compound II)

[0181] The starting material Compound II-2 (4.0 g, 15.25 mmol), 1-chloroethyl chloroformate (16.45 ml, 152.47 mmol), and 1,2-dichloroethane (50 mL) were added to a reaction flask, and then an argon balloon was installed to displace the gas three times. The reaction solution was reacted at 70 °C for 12 hours under argon protection. After completion, the reaction solution was concentrated under reduced pressure. Then, the reaction solution was slowly added dropwise to methanol (25 mL) at room temperature, and the mixture was stirred at room temperature for 10 minutes and then transferred to 70 °C for reaction for 1 hour. LC-MS showed that the reaction was complete. The reaction was quenched by adding saturated aqueous sodium bicarbonate solution, and the mixture was extracted three times with dichloromethane (200 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (silica gel, dichloromethane / methanol = 19 / 1) to obtain Compound II (1.67 g).

[0182] MS m / z (ESI): = 173.1 [M+H] + 。

[0183] 1 1H NMR (400 MHz, CDCl3) δ 7.43–7.33 (m, 2H), 7.33–7.23 (m, 3H), 3.60–3.44 (m, 3H), 3.42–3.34 (m, 1H), 2.98 (m, 2H), 2.11 (s, 1H).

[0184] Preparation Example 3: Preparation of Compound A

[0185]

[0186] Step 1: Synthesis of Compound A-2

[0187] The starting material A-1 (12 g, 64.09 mmol) and dichloromethane (200 mL) were added to a reaction flask, and Dess-Martin periodinane (35.34 g, 83.32 mmol) was slowly added at 0 °C. The reaction mixture was stirred at room temperature for 12 hours. TLC showed the reaction was complete, and the reaction was quenched by adding saturated aqueous sodium bicarbonate solution. The mixture was extracted with dichloromethane three times (200 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 4 / 1) to obtain Compound A-2 (10.4 g).

[0188] 1 1H NMR (400 MHz, CDCl3) δ 9.14 (s, 1H), 5.21 (s, 1H), 1.52–1.46 (m, 2H), 1.44 (s, 9H), 1.36–1.23 (m, 2H).

[0189] Step 2: Synthesis of Compound A-3

[0190] p-Toluenesulfonylmethyl isocyanide (421.64 mg, 2.16 mmol), potassium tert-butoxide (484.66 mg, 4.32 mmol), and tetrahydrofuran (5 mL) were added to a reaction flask, and then an argon balloon was installed to displace the gas three times. A solution of the starting material A-2 (200 mg, 1.08 mmol) in tetrahydrofuran was slowly added at -60 °C. The reaction mixture was reacted at -60 °C for 30 minutes under gas protection. Then the reaction mixture was transferred to room temperature and stirred for 1 hour. After that, methanol (5 mL) was slowly added to the reaction system, and the reaction was carried out at 60 °C for 15 minutes. TLC showed the reaction was complete, and the reaction was quenched by adding saturated aqueous ammonium chloride solution. The mixture was extracted with ethyl acetate three times (20 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 4 / 1) to obtain Compound A-3 (168 mg).

[0191] 11H NMR (400 MHz, CDCl3) δ 5.16 (s, 1H), 2.73 (s, 2H), 1.45 (s, 9H), 0.97–0.90 (m, 2H), 0.90–0.84 (m, 2H).

[0192] Step 3: Synthesis of Compound A-4

[0193] The starting material A-3 (1 g, 5.10 mmol) and dichloromethane (10 mL) were added to a reaction flask, and then dioxane hydrochloride solution (5 mL, 4.0 mol / L, with 1,4-dioxane as the solvent) was added. The reaction mixture was stirred at room temperature for 2 hours. TLC showed the reaction was complete. A small amount of dichloromethane was added, and the mixture was filtered. The solid was dried to obtain Compound A-4 (480 mg).

[0194] 1 1H NMR (400 MHz, DMSO-d6) δ 8.94 (s, 3H), 3.12 (s, 2H), 1.16–1.01 (m, 2H), 0.93–0.77 (m, 2H).

[0195] Step 4: Synthesis of Compound A-5

[0196] The starting material A-4 (3.2 g, 24.13 mmol), bromoacetophenone (4.8 g, 24.13 mmol), potassium phosphate (12.81 g, 60.34 mmol), and N,N-dimethylformamide (50 mL) were added to a reaction flask. The reaction mixture was stirred at room temperature for 4 hours. TLC showed the reaction was complete. 1 M hydrochloric acid was added to adjust the pH to 1, and the mixture was washed three times with ethyl acetate (100 mL). Then, the aqueous phase was adjusted to pH 9 with 1 M sodium hydroxide, and extracted three times with ethyl acetate (100 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain Compound A-5 (4.84 g).

[0197] MS m / z (ESI): = 215.1 [M+H] + 。

[0198] 1 1H NMR (400 MHz, CDCl3) δ 7.99–7.92 (m, 2H), 7.60 (d, J = 7.4 Hz, 1H), 7.53–7.44 (m, 2H), 4.29 (s, 2H), 2.61 (s, 2H), 0.91–0.84 (m, 2H), 0.77–0.71 (m, 2H).

[0199] Step 5: Synthesis of Compound A-6

[0200] The starting material A-5 (1.0 g, 4.67 mmol), di-tert-butyl dicarbonate (3.06 g, 14.00 mmol), sodium bicarbonate (392 mg, 4.67 mmol), tetrahydrofuran (5 ml), and water (5 ml) were added to a reaction flask, and the reaction mixture was stirred at room temperature for 24 hours. TLC showed the completion of the reaction. The mixture was extracted three times with ethyl acetate (50 ml). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 9:1) to obtain compound A-6 (1.4 g).

[0201] 1 H NMR (400 MHz, CDCl3) δ 7.91–7.82 (m, 2H), 7.57–7.47 (m, 1H), 7.46–7.36 (m, 2H), 4.66 (d, J = 9.7 Hz, 2H), 2.86–2.56 (m, 2H), 1.48–1.22 (m, 9H), 0.99–0.76 (m, 4H).

[0202] Step 6: Synthesis of compound A-7

[0203] The starting material A-6 (171 mg, 0.54 mmol) and methanol (2 ml) were added to a reaction flask. Sodium borohydride (20.6 mg, 0.54 mmol) was slowly added at 0 °C. The reaction mixture was stirred at 0 °C for 10 minutes and then at room temperature for 30 minutes. TLC showed the completion of the reaction. The reaction was quenched with saturated ammonium chloride, and the mixture was extracted three times with ethyl acetate (20 ml). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound A-7 (165 mg).

[0204] MS m / z (ESI): = 261.1 [M-tBu + 2H] + 。

[0205] 1 H NMR (400 MHz, CDCl3) δ 7.40–7.27 (m, 5H), 4.94 (s, 1H), 3.64–3.36 (m, 2H), 2.84–2.41 (m, 2H), 1.54 (s, 9H), 1.02–0.78 (m, 4H).

[0206] Step 7: Synthesis of compound A-8

[0207] Add the starting material A-7 (2.85 g, 9.01 mmol) and tetrahydrofuran (30 mL) to a reaction flask, then install an argon balloon and displace the gas three times. Slowly add dimethyl chlorophosphate (1.37 g, 9.46 mmol) at -15 °C, and then slowly add lithium bis(trimethylsilyl)amide (22.5 mL, 1.0 M, solvent is THF) at -15 °C. The addition is completed dropwise within 30 minutes, and the reaction solution is stirred at -15 °C for 30 minutes. Then quench with 1 M hydrochloric acid and extract three times with ethyl acetate (20 mL). Combine the organic phases, dry over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify by column chromatography (silica gel, petroleum ether / ethyl acetate = 9:1) to obtain compound A-8 (0.9 g).

[0208] MS m / z(ESI):=243.1[M-tBu+2H] + 。

[0209] 1 1H NMR(400MHz,DMSO-d6)δ7.51–7.29(m,5H),4.03(d,J=10.5Hz,1H),3.94–3.84(m,1H),3.73–3.63(m,1H),3.49–3.41(m,1H),2.01–1.78(m,1H),1.43–1.40(m,1H),1.38(s,9H),0.89–0.80(m,1H),0.73–0.66(m,1H).

[0210] Step 8: Synthesis of compound A

[0211] Add the starting material A-8 (210 mg, 0.70 mmol) and dichloromethane (1 mL) to a reaction flask, then add trifluoroacetic acid (1 mL). Stir the reaction solution at room temperature for 2 hours. Then quench with saturated sodium bicarbonate and extract three times with ethyl acetate (20 mL). Combine the organic phases, dry over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify by column chromatography (silica gel, dichloromethane / methanol = 30:1) to obtain compound A (100 mg).

[0212] MS m / z(ESI):=199.1[M+H] + 。

[0213] 11H NMR (400 MHz, CDCl3) δ 7.41–7.33 (m, 2H), 7.33–7.27 (m, 3H), 3.77–3.65 (m, 1H), 3.59–3.50 (m, 1H), 3.14–3.04 (m, 1H), 2.93 (d, J = 7.6 Hz, 1H), 2.48 (s, 1H), 1.12–0.96 (m, 3H), 0.84–0.73 (m, 1H).

[0214] Preparation Example 4: Synthesis of Compound B

[0215]

[0216] Step 1: Synthesis of Compound B-2

[0217] Add butyryl chloride (13.29 ml, 127.99 mmol), triethylamine (17.86 ml, 127.99 mmol), and dichloromethane (100 ml) to the reaction flask, then install an argon balloon and displace the gas three times. Slowly add the starting material B-1 (10 g, 127.99 mmol) at -78 °C, and react the reaction solution at -78 °C for 1 hour under gas protection. Then transfer the reaction solution to room temperature and continue stirring for 1 hour. Then quench with saturated ammonium chloride aqueous solution, extract three times with dichloromethane (200 mL), combine the organic phases, dry over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify by column chromatography (silica gel, petroleum ether / ethyl acetate = 10 / 1) to obtain Compound B-2 (7.56 g).

[0218] 1 1H NMR (400 MHz, CDCl3) δ 3.71 (t, J = 6.2 Hz, 2H), 3.05 (t, J = 6.2 Hz, 2H), 2.53 (t, J = 7.4 Hz, 3H), 1.74–1.60 (m, 2H), 0.92 (t, J = 7.4 Hz, 3H).

[0219] Step 2: Synthesis of Compound B

[0220] Add the starting material B-2 (1 g, 6.75 mmol), triphenylphosphine (1.77 g, 6.75 mmol), and dichloromethane (20 ml) to the reaction flask, then add N-iodosuccinimide (1.52 g, 6.75 mmol) at 0 °C, and stir the reaction solution at room temperature for 1 hour. Then quench with saturated sodium bicarbonate, extract three times with ethyl acetate (50 ml), combine the organic phases, dry over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify by column chromatography (silica gel, petroleum ether) to obtain the intermediate B (1.37 g).

[0221] 11H NMR (400 MHz, CDCl3) δ 3.36–3.28 (m, 2H), 3.28–3.20 (m, 2H), 2.53 (t, J = 7.4 Hz, 2H), 1.75–1.63 (m, 2H), 0.95 (t, J = 7.4 Hz, 3H).

[0222] Preparation Example 5: Synthesis of Compound C

[0223]

[0224] Step 1: Synthesis of Compound C-2

[0225] 3-Methylbutanoyl chloride (6.24 mL, 51.19 mmol), triethylamine (7.15 mL, 51.19 mmol), and dichloromethane (50 mL) were added to a reaction flask, and then an argon balloon was installed to displace the gas three times. Starting material C-1 (4 g, 51.19 mmol) was slowly added at -78 °C, and the reaction solution was reacted at -78 °C for 1 hour under gas protection. Then the reaction solution was transferred to room temperature and stirred for another 1 hour. Then it was quenched with saturated ammonium chloride aqueous solution and extracted with dichloromethane three times (200 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 10 / 1) to obtain intermediate C-2 (4.81 g).

[0226] 1 1H NMR (400 MHz, CDCl3) δ 3.67 (t, J = 6.2 Hz, 2H), 3.01 (t, J = 6.2 Hz, 2H), 2.65 (s, 1H), 2.39 (d, J = 7.1 Hz, 2H), 2.17–2.02 (m, 1H), 0.89 (d, J = 6.7 Hz, 6H).

[0227] Step 2: Synthesis of Compound C

[0228] Starting material C-2 (1 g, 6.16 mmol), triphenylphosphine (1.62 g, 6.16 mmol), and dichloromethane (20 ml) were added to a reaction flask, and 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 it was quenched with saturated sodium bicarbonate and extracted with ethyl acetate three times (50 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (silica gel, petroleum ether) to obtain Compound C (1.41 g).

[0229] 11H NMR (400 MHz, CDCl3) 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).

[0230] Preparation Example 6: Synthesis of Compound D

[0231]

[0232] Step 1: Synthesis of S-(2-hydroxyethyl)-3,3-dimethylbutanethioate

[0233] 3,3-Dimethylbutanoyl chloride (7.11 ml, 51.19 mmol), triethylamine (7.15 ml, 51.19 mmol), and dichloromethane (50 mL) were added to a reaction flask, and then an argon balloon was installed to displace the gas three times. Starting material D-1 (4 g, 51.19 mmol) was slowly added at -78 °C, and the reaction solution was stirred at -78 °C under gas protection for 1 hour. Then the reaction solution was transferred to room temperature and stirred for another 1 hour. Then it was quenched with saturated ammonium chloride aqueous solution and extracted three times with dichloromethane (200 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 10 / 1) to obtain compound D-2 (5.3 g).

[0234] 1 1H NMR (400 MHz, CDCl3) δ 3.66 (t, J = 6.3 Hz, 2H), 2.99 (t, J = 6.3 Hz, 2H), 2.91 (s, 1H), 2.40 (s, 2H), 0.96 (s, 9H).

[0235] Step 2: Synthesis of Compound D

[0236] Starting material D-2 (1 g, 5.67 mmol), triphenylphosphine (1.49 g, 5.67 mmol), and dichloromethane (20 mL) were added to a reaction flask, and then N-iodosuccinimide (1.28 g, 5.67 mmol) was added at 0 °C. The reaction solution was stirred at room temperature for 1 hour. Then it was quenched with saturated sodium bicarbonate and extracted three times with ethyl acetate (50 ml). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (silica gel, petroleum ether) to obtain compound D (1.15 g).

[0237] 11H NMR (400 MHz, CDCl3) δ 3.32–3.22 (m, 2H), 3.22–3.14 (m, 2H), 2.38 (s, 2H), 0.97 (s, 9H).

[0238] Preparation Example 7: Synthesis of Compound E

[0239]

[0240] Step 1: Synthesis of Compound E-2

[0241] Add 2,2-dimethylpropanoyl chloride (7.87 mL, 63.99 mmol), triethylamine (8.93 ml, 63.99 mmol), and dichloromethane (50 mL) to the reaction flask. Then, install an argon balloon and displace the gas three times. Slowly add the starting material E-1 (5 g, 63.99 mmol) at -78 °C. The reaction solution is reacted at -78 °C for 1 hour under gas protection. Then, transfer the reaction solution to room temperature and continue stirring for 1 hour. Then, quench with saturated ammonium chloride aqueous solution and extract three times with dichloromethane (200 mL). The combined organic phases are dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure and purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 10 / 1) to obtain Compound E-2 (8.2 g).

[0242] 1 1H NMR (400 MHz, CDCl3) δ 3.75–3.62 (m, 2H), 3.05–2.97 (m, 2H), 2.70–2.51 (m, 1H), 1.20 (s, 9H).

[0243] Step 2: Synthesis of Compound E

[0244] Add the starting material E-2 (1 g, 6.16 mmol), triphenylphosphine (1.62 g, 6.16 mmol), and dichloromethane (20 mL) to the reaction flask. Then, add N-iodosuccinimide (1.39 g, 6.16 mmol) at 0 °C. The reaction solution is stirred at room temperature for 1 hour. Then, quench with saturated sodium bicarbonate and extract three times with ethyl acetate (50 mL). The combined organic phases are dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure and purified by column chromatography (silica gel, petroleum ether) to obtain Compound E (1.02 g).

[0245] 1 1H NMR (400 MHz, CDCl3) δ 3.34–3.26 (m, 2H), 3.26–3.17 (m, 2H), 1.24 (s, 9H).

[0246] Preparation Example 8: Synthesis of Compound F

[0247]

[0248] Step 1: Synthesis of Compound F-2

[0249] Methyl phenylacetate (5.0 g, 33.29 mmol) and tetrahydrofuran (50 mL) were added to a reaction flask, and then an argon balloon was installed to displace the gas three times. Lithium diisopropylamide (20 mL, 40.0 mmol, 2 M in THF) was slowly added at -78 °C. The reaction solution was reacted at -78 °C for 0.5 h under gas protection, and then bromoacetonitrile (2.55 mL, 36.62 mmol) was slowly added. The reaction solution was continued to react at -78 °C for 0.5 h. Then, saturated ammonium chloride aqueous solution was added to quench the reaction, and the mixture was extracted with ethyl acetate three times (200 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 90 / 10) to obtain Compound F-2 (5.28 g).

[0250] 1 H NMR (400 MHz, Chloroform-d) δ 7.42–7.31 (m, 3H), 7.31–7.24 (m, 2H), 3.94 (t, J = 7.6 Hz, 1H), 3.73 (s, 3H), 3.04 (dd, J = 16.8, 7.5 Hz, 1H), 2.81 (dd, J = 16.8, 7.6 Hz, 1H).

[0251] Step 2: Synthesis of Compound F-3

[0252] Compound F-2 (0.5 g, 2.64 mmol) and tetrahydrofuran (5 mL) were added to a reaction flask, and then an argon balloon was installed to displace the gas three times. Tetraisopropyl titanate (805.7 mg, 2.83 mmol) was slowly added at -78 °C. The reaction solution was reacted at -78 °C for 10 min under gas protection, and then ethylmagnesium bromide (5.8 mL, 5.8 mmol, 1 M in THF) was slowly added. After the reaction solution was reacted at -78 °C for 10 min, it was transferred to room temperature and stirred for an additional 30 min. After the reaction was completed, water was added to quench the reaction, and the mixture was extracted with 3 M hydrochloric acid (30 mL), and washed with ethyl acetate three times (30 mL). Then, it was neutralized with 10% sodium hydroxide to adjust the pH to 8 - 9, and then extracted with ethyl acetate three times (30 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain Compound F-3 (0.31 g).

[0253] MS m / z (ESI): = 188.1 [M+H] + .

[0254] Step 3: Synthesis of Compound F

[0255] Compound F-3 (1.5 g, 8.01 mmol), sodium borohydride (1.52 g, 40.06 mmol), and tetrahydrofuran (20 mL) were added to a reaction flask. Then, an argon balloon was installed and the gas was replaced three times. Boron trifluoride etherate (10.9 mL, 40.06 mmol, 47%) was slowly added at room temperature. The reaction solution was reacted at room temperature for 10 minutes under gas protection and then transferred to room temperature and stirred for an additional 30 minutes. Then, water was added to quench the reaction, and the mixture was extracted three times with ethyl acetate (200 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (silica gel, dichloromethane / methanol = 90 / 10) to obtain Compound F (0.83 g).

[0256] MS m / z (ESI): = 174.1 [M+H] + 。

[0257] Preparation Example 9: Synthesis of Compound G

[0258]

[0259] Step 1: Synthesis of Compound G-2

[0260] Compound G-1 (240 mg, 0.66 mmol) and perfluorophenol (145.5 mg, 0.79 mmol) were added to a reaction flask, and anhydrous dichloromethane (3 mL) was added to dissolve them. 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (189.4 mg, 0.99 mmol) and 4-dimethylaminopyridine (20.1 mg, 0.17 mmol) were added under stirring at room temperature. The resulting reaction solution was reacted overnight at room temperature. The reaction was monitored by LC-MS until completion. The reaction solution was concentrated under reduced pressure and purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 4 / 1) to obtain Compound G-2 (220 mg).

[0261] MS m / z (ESI): = 531.0 [M+H] + 。

[0262] 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).

[0263] Step 2: Synthesis of Compound G

[0264] Compound G-2 (220 mg, 0.41 mmol) was added to a reaction flask, followed by N,O-bis(trimethylsilyl)trifluoroacetamide (534 mg, 2.07 mmol) and anhydrous dichloromethane (2.5 mL). Then an argon balloon was attached, and the gas was displaced three times under gas protection. The mixture was then cooled in an ice bath, and trimethylsilyl iodide (332 mg, 1.66 mmol) was added. The reaction was maintained in the ice bath for 15 minutes and then allowed to react at room temperature for 15 minutes. The reaction was monitored by LC-MS until completion. The reaction was quenched by adding 3 mL of a mixed solution of water and acetonitrile (water:acetonitrile = 2:1, containing 0.1% trifluoroacetic acid), and the mixture was stirred at room temperature for 15 minutes. The mixture was transferred to a round-bottom flask, and dichloromethane in the system was removed by concentration under reduced pressure. Then an appropriate amount of water and acetonitrile were added, and the mixture was freeze-dried to obtain compound G (178 mg).

[0265] MS m / z (ESI): = 472.9 [M-H] - 。

[0266] 1 H NMR (400 MHz, DMSO-d6) δ 8.80 (s, 1H), 8.35–8.27 (m, 2H), 7.78–7.71 (m, 1H). Preparation Example 10: Synthesis of Compound H

[0267]

[0268] Step 1: Synthesis of Compound H-2

[0269] Compound G (700 mg, 1.48 mmol) was added to a reaction flask, followed by tetrahydrofuran (4.5 mL) and water (9 mL). Then Amberlite IR 120, Na resin cation exchange resin (4.60 g) was added. The resulting reaction solution was stirred overnight at room temperature, filtered, and the filter cake was washed with a small amount of deionized water. The mother liquor was collected, and then an aqueous solution (1 mL) of silver nitrate (551.62 mg, 3.25 mmol) was added. The resulting reaction solution was stirred at room temperature for 3 hours, and a large amount of white solid precipitated. The solid was filtered, and the filter cake was collected and freeze-dried to obtain compound H-2 (940 mg).

[0270] Step 2: Synthesis of Compound H

[0271] Compound H-2 (210 mg, 305.25 μmol) was added to a reaction flask, followed by anhydrous toluene (2 mL) and S-(2-iodoethyl) butyl sulfate (236.37 mg, 915.75 μmol). The resulting reaction solution was reacted at room temperature in the dark for 14 hours. The reaction solution was concentrated under reduced pressure and purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 4 / 1) to obtain compound H (71 mg).

[0272] 1 1H NMR (400 MHz, CDCl3) δ 8.41 (s, 1H), 8.24 (s, 1H), 8.08–8.00 (m, 1H), 7.81–7.75 (m, 1H), 4.32–4.18 (m, 4H), 3.25–3.07 (m, 4H), 2.54 (t, J = 7.4 Hz, 4H), 1.73–1.65 (m, 4H), 0.95 (t, J = 7.4 Hz, 6H).

[0273] Preparation Example 11: Synthesis of Compound J

[0274]

[0275] Compound H-2 (600 mg, 872.14 μmol) was added to a reaction flask, and ultradry toluene (6 mL) was added. Then, S-(2-iodoethyl)-3-methylbutyl sulfate (712.05 mg, 2.62 mmol) was added. An argon balloon was installed, and the gas was displaced three times. The reaction was carried out overnight at room temperature under gas protection. The reaction solution was concentrated under reduced pressure and purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 4 / 1) to obtain Compound J (237 mg).

[0276] 1 1H NMR (400 MHz, CDCl3) δ 8.41 (s, 1H), 8.24 (s, 1H), 8.08–7.99 (m, 1H), 7.82–7.75 (m, 1H), 4.33–4.15 (m, 4H), 3.24–3.08 (m, 4H), 2.43 (d, J = 7.2 Hz, 4H), 2.19–2.08 (m, 2H), 0.94 (d, J = 6.7 Hz, 12H).

[0277] Preparation Example 12: Synthesis of Compound K

[0278]

[0279] Compound H-2 (250 mg, 363.39 μmol) was added to a reaction flask, and ultradry toluene (2.5 mL) was added. Then, S-(2-iodoethyl)-3,3-dimethylbutyl sulfate (311.98 mg, 1.09 mmol) was added. An argon balloon was installed, and the gas was displaced three times. The reaction was carried out overnight at room temperature under gas protection. The reaction solution was concentrated under reduced pressure and purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 4 / 1) to obtain Compound K (131 mg).

[0280] 11H NMR (400 MHz, CDCl3) δ 8.41 (s, 1H), 8.25 (s, 1H), 8.07–8.00 (m, 1H), 7.82–7.75 (m, 1H), 4.32–4.15 (m, 4H), 3.21–3.07 (m, 4H), 2.43 (s, 4H), 1.02 (s, 18H).

[0281] Synthesis of Example 1 2-(((5S,8S,10aR)-8-((trans)-3-cyano-4-phenylpyrrolidine-1-carbonyl)-3-(oxetan-3-yl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)carbamoyl)benzothiophen-5-yl)difluoromethyl)phosphonic acid (Compound 1)

[0282]

[0283] Step 1: Synthesis of (5S,8S,10aR)-5-((tert-butoxycarbonyl)amino)-3-(oxetan-3-yl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocin-8-carboxylic acid methyl ester (Compound 1-2)

[0284] (5S,8S,10aR)-5-((tert-Butoxycarbonyl)amino)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocin-8-carboxylic acid methyl ester Compound 1-1 (2 g, 5.86 mmol) and 3-oxetanone (844.31 mg, 11.72 mmol) were added to a reaction flask, dissolved in anhydrous dichloromethane (29 mL), sodium triacetoxyborohydride (2.48 g, 11.72 mmol) and acetic acid (527.68 mg, 8.79 mmol) were added, and the resulting reaction solution was stirred at room temperature overnight. LC-MS showed that the reaction was complete. The reaction solution was poured into water, extracted three times with dichloromethane, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 2 / 3) to obtain Compound 1-2 (2.29 g).

[0285] MS m / z (ESI): = 398.2 [M+H] + 。

[0286] 11H NMR (400 MHz, CDCl3) δ 5.67 (d, J = 7.1 Hz, 1H), 4.71–4.39 (m, 7H), 4.03–3.95 (m, 1H), 3.76 (s, 3H), 2.95–2.73 (m, 3H), 2.53–2.44 (m, 1H), 2.39–2.29 (m, 1H), 2.21–2.08 (m, 1H), 2.04–1.95 (m, 1H), 1.85–1.77 (m, 1H), 1.76–1.63 (m, 2H), 1.42 (s, 9H).

[0287] Step 2: Synthesis of (5S,8S,10aR)-5-((tert-butoxycarbonyl)amino)-3-(oxetan-3-yl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocin-8-carboxylic acid (Compound 1-3)

[0288] Compound 1-2 (100 mg, 0.252 mmol) was added to a reaction flask, dissolved in methanol (1.2 mL), and then water (0.3 mL) and lithium hydroxide monohydrate (31.67 mg, 0.755 mmol) were added. The resulting reaction solution was stirred at room temperature overnight. LC-MS showed that the reaction was complete. The reaction solution was concentrated under reduced pressure to obtain crude Compound 1-3 (132 mg), which was used directly in the next step without purification.

[0289] MS m / z (ESI): = 384.2 [M+H] + 。

[0290] Step 3: Synthesis of tert-butyl ((5S,8S,10aR)-8-((trans)-3-cyano-4-phenylpyrrolidine-1-carbonyl)-3-(oxetan-3-yl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)carbamate (Compound 1-4)

[0291] The crude compound 1-3 (132 mg, 0.256 mmol) was dissolved in anhydrous N,N-dimethylformamide (2 mL), and (trans)-4-phenylpyrrolidine-3-carbonitrile (Compound II, 52.82 mg, 0.307 mmol), N,N-diisopropylethylamine (99.09 mg, 0.767 mmol) and 2-(7-azabenzotriazol)-N,N,N',N'-tetramethyluronium hexafluorophosphate (125.35 mg, 0.332 mmol) were added. The resulting reaction mixture was reacted at room temperature for 2 hours, and LC-MS showed that the reaction was complete. The reaction mixture was poured into water and extracted three times with ethyl acetate. The combined organic phases were washed with water, saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (silica gel, ethyl acetate = 100%) to obtain compound 1-4 (115 mg).

[0292] MS m / z(ESI):=538.2[M+H] + 。

[0293] Step 4: Synthesis of 1-((5S,8S,10aR)-5-amino-3-(oxetan-3-yl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocin-8-carbonyl)-(trans)-4-phenylpyrrolidine-3-carbonitrile (Compound 1-5)

[0294] Compound 1-4 (220 mg, 0.409 mmol) was added to a reaction flask, dissolved in dichloromethane (2 mL), and trifluoroacetic acid (0.5 mL) was added under stirring at room temperature. The resulting reaction mixture was reacted at room temperature for 2 hours. LC-MS showed that the reaction was complete. The reaction mixture was concentrated under reduced pressure to obtain crude compound 1-5 (300 mg), which was used directly in the next step without purification

[0295] MS m / z(ESI):=438.2[M+H] + 。

[0296] Step 5: Synthesis of (2-(((5S,8S,10aR)-8-((trans)-3-cyano-4-phenylpyrrolidine-1-carbonyl)-3-(oxetan-3-yl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)carbamoyl)benzothiophen-5-yl)difluoromethyl)phosphonic acid (Compound 1-6)

[0297] The crude compound 1-5 (50 mg, 0.075 mmol) was added to a reaction flask, anhydrous N,N-dimethylformamide (0.6 mL) and N,N-diisopropylethylamine (77.67 mg, 0.602 mmol) were added, and then (difluoro(2-((4-nitrophenoxy)carbonyl)benzo[b]thiophen-5-yl)methyl)phosphonic acid (Compound I, 35.47 mg, 0.083 mmol) was added. The resulting reaction solution was stirred at room temperature for 2 hours, and LC-MS showed that the reaction was complete. The reaction solution was filtered and purified by preparative HPLC [YMC TAR-C18 column, 30 mm in diameter, 150 mm in length, using a mixture of water (containing 7 mmol / L NH4HCO3) and acetonitrile (acetonitrile content: 20%-50%) as the eluent], and freeze-dried to obtain the target compound 1 (22 mg).

[0298] MS m / z(ESI):=728.2[M+H] + 。

[0299] 1 1H NMR(400MHz,DMSO-d6)δ8.65–8.52(m,1H),8.30–8.21(m,1H),8.09–7.97(m,

[0300] 2H),7.67–7.55(m,1H),7.49–7.33(m,5H),7.32–6.99(m,2H),5.00–4.85(m,1H),4.68–

[0301] 4.53(m,3H),4.51–4.44(m,2H),4.44–4.10(m,2H),4.07–3.93(m,2H),3.86–3.59(m,3H),

[0302] 3.31–3.26(m,1H),2.91–2.74(m,3H),2.73–2.64(m,1H),2.36–2.21(m,1H),2.17–2.02

[0303] (m,1H),1.93–1.56(m,4H).

[0304] Example 2: Synthesis of Compound 2

[0305]

[0306] Step 1: Synthesis of Compound 2-3

[0307] Compound 1-2 (220 mg, 0.57 mmol), compound 2-2 (99.8 mg, 0.50 mmol), diisopropylethylamine (350.7 μL, 2.01 mmol), and N,N-dimethylformamide (1 mL) were added to a reaction flask. Then, 2-(7-azabenzotriazol)-N,N,N',N'-tetramethyluronium hexafluorophosphate (284.8 mg, 0.76 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour. After completion of the reaction as indicated by LC-MS, the reaction mixture was quenched with saturated aqueous ammonium chloride solution and extracted three times with ethyl acetate (20 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 1 / 1) to obtain product 2-3 (260 mg).

[0308] MS m / z (ESI): = 564.3 [M+H] + 。

[0309] 1 1H NMR (400 MHz, CDCl3) δ 7.45–7.30 (m, 5H), 5.77–5.62 (m, 1H), 4.75–4.57 (m, 5H), 4.55–4.35 (m, 3H), 4.30–4.14 (m, 0.5H), 4.09–3.91 (m, 1.5H), 3.87–3.57 (m, 2H), 3.57–3.37 (m, 1H), 2.87–2.79 (m, 2H), 2.56–2.34 (m, 2H), 2.26–2.12 (m, 1H), 1.91–1.75 (m, 4H), 1.63–1.53 (m, 1H), 1.51–1.34 (m, 9H), 1.12–0.99 (m, 1H), 0.90–0.80 (m, 1H), 0.76–0.64 (m, 1H).

[0310] Step 2: Synthesis of compound 2-4

[0311] Starting material 2-3 (100 mg, 0.18 mmol) and dichloromethane (1 mL) were added to a reaction flask. Then, trifluoroacetic acid (1 mL) was added. The reaction mixture was stirred at room temperature for 2 hours. Then, the reaction mixture was concentrated under reduced pressure to obtain compound 2-4 (120 mg), which was used directly in the next step without further purification.

[0312] MS m / z (ESI): = 464.2 [M+H] + 。

[0313] Step 3: Synthesis of compound 2

[0314] Compound 2-4 (40 mg, 86.4 μmol), compound G (30.69 mg, 64.72 μmol), N,N-diisopropylethylamine (45.1 μL, 258.86 μmol), and N,N-dimethylformamide (0.5 mL) were added to a reaction flask, and the reaction mixture was reacted at room temperature for 1 hour. After completion of the reaction as shown by LC-MS, the reaction mixture was quenched by adding saturated ammonium chloride aqueous solution, extracted three times with ethyl acetate (10 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by Prep-HPLC [YMC TAR-C18 column, 30 mm in diameter, 150 mm in length, using a mixture of water (containing 0.5% HCOOH) and acetonitrile (acetonitrile content: 30%-60%) as the eluent] to obtain the target compound 2 (20 mg).

[0315] MS m / z (ESI): = 754.2 [M+H] + 。

[0316] 1 H NMR (400 MHz, DMSO-d6) δ 8.83–8.61 (m, 1H), 8.30 (d, J = 6.5 Hz, 1H), 8.14–8.00 (m, 2H), 7.59 (d, J = 8.6 Hz, 1H), 7.55–7.46 (m, 2H), 7.44–7.36 (m, 2H), 7.36–7.26 (m, 1H), 5.02–8.84 (m, 1H), 4.64–4.43 (m, 5H), 4.42–4.32 (m, 1H), 4.21 (t, J = 8.5 Hz, 1H), 4.08–3.97 (m, 1H), 3.95–3.88 (m, 1H), 3.85–3.78 (m, 1H), 3.76–3.70 (m, 1H), 2.92–2.62 (m, 4H), 2.38–2.10 (m, 2H), 2.10–1.95 (m, 1H), 1.91–1.45 (m, 5H), 0.91–0.75 (m, 1H), 0.75–0.59 (m, 1H).

[0317] Example 3: Synthesis of Compound 3

[0318]

[0319] Step 1: Synthesis of Compound 3-1

[0320] Compound 1-3 (91 mg, 237.33 μmol) and 6-phenyl-4-azaspiro[2.4]heptane (Compound F, 49.34 mg, 284.79 μmol) were added to a reaction flask, dissolved in anhydrous N,N-dimethylformamide (2 mL), and N,N-diisopropylethylamine (92.02 mg, 711.98 μmol) and 2-(7-azabenzotriazol)-N,N,N',N'-tetramethyluronium hexafluorophosphate (116.40 mg, 308.52 μmol) were added under stirring at room temperature. The resulting reaction mixture was reacted at room temperature for 2 hours. The reaction mixture was poured into water and extracted three times with ethyl acetate. The combined organic phases were washed with water, saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 3 / 7) to obtain Compound 3-1 (109 mg).

[0321] MS m / z (ESI): = 539.3 [M+H] + 。

[0322] Step 2: Synthesis of Compound 3-2

[0323] Compound 3-1 (109 mg, 202.35 μmol) was added to a reaction flask, and dichloromethane (1.6 mL) and trifluoroacetic acid (0.4 mL) were added. The resulting reaction mixture was reacted at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure to obtain crude Compound 3-2, which was used directly in the next step without purification.

[0324] MS m / z (ESI): = 439.2 [M+H] + 。

[0325] Step 3: Synthesis of Compound 3

[0326] Crude Compound 3-2 (30 mg) and Compound G (21.34 mg, 45.00 μmol) were added to a reaction vial, and N,N-dimethylformamide (0.3 mL) and N,N-diisopropylethylamine (46.53 mg, 360.03 μmol) were added. The resulting reaction mixture was reacted at room temperature for 1 hour. The reaction mixture was filtered and purified by preparative HPLC (column: YMC TA-C18, 30×150 mm, 5 μm; mobile phase A: water (0.05% FA), mobile phase B: acetonitrile; flow rate: 30 mL / min; gradient: 35% B - 65% B), and lyophilized to obtain the target compound 3 (12 mg).

[0327] MS m / z (ESI): = 729.2 [M+H] + 。

[0328] 11H NMR (400 MHz, DMSO-d6) δ 8.71–8.56 (m, 1H), 8.34–8.24 (m, 1H), 8.11–7.99 (m, 2H), 7.65–7.54 (m, 1H), 7.39–7.21 (m, 5H), 5.02–4.79 (m, 1H), 4.65–4.45 (m, 5H), 4.42–4.28 (m, 1H), 4.18–3.95 (m, 1.5H), 3.80–3.72 (m, 0.5H), 3.63–3.51 (m, 2H), 2.92–2.70 (m, 3H), 2.36–2.19 (m, 2H), 2.14–1.47 (m, 9H), 0.60–0.40 (m, 2H).

[0329] Example 4: Synthesis of Compound 4

[0330]

[0331] Step 1: Synthesis of Compound 4-2

[0332] Compound 1-3 (96 mg, 250.37 μmol) and 3-phenylpyrrolidine (44.23 mg, 300.44 μmol) were added to a reaction flask, dissolved in anhydrous N,N-dimethylformamide (2 mL), and N,N-diisopropylethylamine (97.07 mg, 751.10 μmol) and 2-(7-azabenzotriazol)-N,N,N',N'-tetramethyluronium hexafluorophosphate (122.79 mg, 325.48 μmol) were added under stirring at room temperature. The resulting reaction solution was reacted at room temperature for 2 hours. The reaction solution was poured into water and extracted three times with ethyl acetate. The combined organic phases were washed with water, saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (silica gel, dichloromethane / methanol = 96 / 4) to obtain Compound 4-2 (128 mg).

[0333] MS m / z (ESI): = 513.3 [M+H] + 。

[0334] Step 2: Synthesis of Compound 4-3

[0335] Compound 4-2 (128 mg, 249.69 μmol) was added to a reaction flask, and dichloromethane (1.2 mL) and trifluoroacetic acid (0.3 mL) were added. The resulting reaction solution was reacted at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure to obtain crude Compound 4-3, which was used directly in the next step without purification.

[0336] MS m / z (ESI): = 413.2 [M+H] + 。

[0337] Step 3: Synthesis of Compound 4

[0338] The crude compound 4-3 (30 mg) and compound G (22.21 mg, 46.83 μmol) were added to a reaction flask, followed by the addition of N,N-dimethylformamide (0.3 mL) and N,N-diisopropylethylamine (48.42 mg, 374.67 μmol). The resulting reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was filtered and purified by preparative HPLC (column: YMC TA-C18, 30×150 mm, 5 μm; mobile phase A: water (0.05% FA), mobile phase B: acetonitrile; flow rate: 30 mL / min; gradient: 25% B - 55% B), and then lyophilized to obtain the target compound 4 (19 mg).

[0339] MS m / z (ESI): = 703.2 [M+H] + 。

[0340] 1 1H NMR (400 MHz, DMSO-d6) δ 8.66–8.45 (m, 1H), 8.31–8.15 (m, 1H), 8.14–7.94 (m,

[0341] 2H), 7.79–7.59 (m, 1H), 7.40–7.17 (m, 5H), 4.98–4.82 (m, 1H), 4.67–4.37 (m, 6H), 4.08–

[0342] 3.65 (m, 4H), 3.22–3.13 (m, 1H), 2.95–2.82 (m, 2H), 2.82–2.72 (m, 1H), 2.72–2.63 (m, 1H),

[0343] 2.37–2.20 (m, 2H), 2.19–1.44 (m, 7H).

[0344] Example 5: Synthesis of Compound 5

[0345]

[0346] Compound 2-4 (27 mg, 58.24 μmol), compound J (30 mg, 39.33 μmol), diisopropylethylamine (27.4 μL, 157.33 μmol), and N,N-dimethylformamide (0.5 mL) were added to a reaction flask, and the reaction mixture was stirred at room temperature for 1 hour. After completion of the reaction as indicated by LC-MS, the reaction mixture was quenched with saturated aqueous ammonium chloride and extracted three times with ethyl acetate (10 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (silica gel, dichloromethane / methanol = 30 / 1) to give the product compound 5 (19 mg).

[0347] MS m / z (ESI): = 1042.2 [M+H] + 。

[0348] 1 H NMR (400 MHz, CDCl3) δ 8.09 (s, 1H), 7.94 (d, J = 8.5 Hz, 1H), 7.84 (d, J = 3.5 Hz, 1H), 7.65 (d, J = 8.7 Hz, 1H), 7.59–7.50 (m, 1H), 7.45–7.33 (m, 5H), 4.98–4.88 (m, 1H), 4.77–4.62 (m, 4H), 4.60–4.44 (m, 2H), 4.32–4.00 (m, 7H), 3.90–3.63 (m, 2H), 3.56–3.41 (m, 1H), 3.18–3.11 (m, 4H), 2.97–2.81 (m, 2H), 2.70–2.46 (m, 2H), 2.43 (d, J = 7.1 Hz, 4H), 2.34–2.20 (m, 1H), 2.20–2.10 (m, 2H), 2.10–1.96 (m, 2H), 1.94–1.75 (m, 3H), 1.74–1.64 (m, 1H), 1.17–1.04 (m, 1H), 0.94 (d, J = 6.6 Hz, 12H), 0.80–0.69 (m, 1H).

[0349] Example 6: Synthesis of Compound 6

[0350]

[0351] The starting material compound 2-4 (30 mg, 64.71 μmol), compound H (31.7 mg, 43.14 μmol), diisopropylethylamine (30.1 μL, 172.57 μmol), and N,N-dimethylformamide (0.5 mL) were added to a reaction flask, and the reaction solution was reacted at room temperature for 1 hour. After completion of the reaction as indicated by LC-MS, the reaction solution was quenched by adding saturated aqueous ammonium chloride solution, extracted three times with ethyl acetate (10 ml), the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (silica gel, ethyl acetate) to obtain compound 6 (18 mg).

[0352] MS m / z (ESI): = 1014.2 [M+H] + 。

[0353] 1 H NMR (400 MHz, CDCl3) δ 8.09 (s, 1H), 7.95 (d, J = 8.5 Hz, 1H), 7.85 (d, J = 3.3 Hz, 1H), 7.65 (d, J = 8.4, 1H), 7.58–7.51 (m, 1H), 7.47–7.30 (m, 5H), 5.00–4.86 (m, 1H), 4.77–4.62 (m, 4H), 4.61–4.46 (m, 2H), 4.28–4.15 (m, 4H), 4.11–4.01 (m, 1H), 3.90–3.61 (m, 2H), 3.55–3.41 (m, 1H), 3.24–3.06 (m, 5H), 2.97–2.80 (m, 2H), 2.70–2.58 (m, 1H), 2.54 (t, J = 7.4 Hz, 4H), 2.44–2.19 (m, 2H), 2.14–2.00 (m, 2H), 2.00–1.76 (m, 3H), 1.74–1.63 (m, 4H), 1.58–1.53 (m, 2H), 1.19–1.01 (m, 1H), 0.95 (t, J = 7.4 Hz, 6H), 0.80–0.68 (m, 1H).

[0354] Example 7: Synthesis of Compound 7

[0355]

[0356] Compound 1-5 (25 mg) was added to a reaction flask, followed by the addition of N,N-dimethylformamide (0.3 mL), perfluorophenyl 5-((bis(2-((3-methylbutanoyl)thio)ethoxy)phosphoryl)difluoromethyl)benzo[b]thiophene-2-carboxylate (Compound J, 28.60 mg, 37.50 μmol), and N,N-diisopropylethylamine (24.23 mg, 187.52 μmol). The resulting reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water and extracted with ethyl acetate three times. The combined organic phases were washed with water, saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (silica gel, dichloromethane / methanol = 96 / 4). Then, water and acetonitrile were added and the mixture was freeze-dried to obtain the target compound 7 (13 mg).

[0357] MS m / z(ESI):=1016.3[M+H] + 。

[0358] 1 H NMR(400MHz,DMSO-d6)δ8.76–8.63(m,1H),8.39–8.30(m,1H),8.27–8.19(m,

[0359] 1H),8.19–8.12(m,1H),7.63–7.54(m,1H),7.50–7.31(m,5H),5.00–4.85(m,1H),4.65–

[0360] 4.54(m,3H),4.50–4.10(m,8H),4.08–3.43(m,6H),3.21–3.06(m,4H),2.94–2.62(m,4H),

[0361] 2.46–2.40(m,4H),2.32–2.20(m,1H),2.14–1.94(m,3H),1.93–1.58(m,4H),0.90–0.83

[0362] (m,12H).

[0363] Example 8: Synthesis of Compound 8

[0364]

[0365] Compound 1-5 (25 mg) was added to a reaction flask, followed by the addition of N,N-dimethylformamide (0.3 mL), perfluorophenyl 5-((bis(2-((3,3-dimethylbutanoyl)thio)ethoxy)phosphoryl)difluoromethyl)benzo[b]thiophene-2-carboxylate (Compound K, 29.70 mg, 37.56 μmol) and N,N-diisopropylethylamine (24.27 mg, 187.81 μmol). The resulting reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water and extracted three times with ethyl acetate. The combined organic phases were washed with water, saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 1 / 4). Then, water and acetonitrile were added and the mixture was freeze-dried to obtain the target compound 8 (31 mg).

[0366] MS m / z (ESI): = 1044.3 [M+H] + 。

[0367] 1 1H NMR (400 MHz, CDCl3) δ 8.17–8.06 (m, 1H), 8.01–7.91 (m, 1H), 7.89–7.80 (m, 1H), 7.71–7.62 (m, 1H), 7.61–7.50 (m, 1H), 7.47–7.32 (m, 5H), 4.99–4.88 (m, 1H), 4.78–4.51 (m, 6H), 4.40–3.97 (m, 8H), 3.93–3.47 (m, 3H), 3.40–3.05 (m, 6H), 2.98–2.82 (m, 2H), 2.71–2.55 (m, 1H), 2.44 (s, 4H), 2.39–2.25 (m, 1H), 2.20–2.13 (m, 1H), 1.99–1.67 (m, 3H), 1.02 (s, 18H).

[0368] Example 9: Synthesis of Compound 9

[0369]

[0370] Compound 3-2 (25 mg) was added to a reaction flask, followed by the addition of N,N-dimethylformamide (0.3 mL), perfluorophenyl 5-((bis(2-((3-methylbutanoyl)thio)ethoxy)phosphoryl)difluoromethyl)benzo[b]thiophene-2-carboxylate (Compound J, 28.60 mg, 37.50 μmol) and N,N-diisopropylethylamine (24.23 mg, 187.52 μmol). The resulting reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water and extracted three times with ethyl acetate. The combined organic phases were washed with water, saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 4 / 6). Then, water and acetonitrile were added and the mixture was freeze-dried to obtain the target compound 9 (24 mg).

[0371] MS m / z (ESI): = 1017.3 [M+H] + 。

[0372] 1 H NMR (400 MHz, CDCl3) δ 8.12–8.05 (m, 1H), 7.98–7.92 (m, 1H), 7.87–7.81 (m, 1H),

[0373] 7.68–7.59 (m, 2H), 7.40–7.27 (m, 5H), 4.96–4.86 (m, 1H), 4.77–4.64 (m, 4H), 4.63–4.48

[0374] (m, 2.5H), 4.31–4.12 (m, 4H), 4.11–3.89 (m, 2H), 3.75–3.52 (m, 1.5H), 3.22–3.06 (m, 5H),

[0375] 3.02–2.82 (m, 2H), 2.70–2.59 (m, 1H), 2.55–2.47 (m, 0.5H), 2.46–2.37 (m, 5H), 2.36–1.96

[0376] (m, 6.5H), 1.95–1.74 (m, 3H), 1.72–1.65 (m, 1H), 0.94 (d, J = 6.7 Hz, 12H), 0.64–0.47 (m,

[0377] 2H).

[0378] Example 10: Synthesis of Compound 10

[0379]

[0380] Compound 4-3 (25 mg) was added to a reaction flask, followed by the addition of N,N-dimethylformamide (0.3 mL), perfluorophenyl 5-((bis(2-((3-methylbutanoyl)thio)ethoxy)phosphoryl)difluoromethyl)benzo[b]thiophene-2-carboxylate (Compound J, 29.77 mg, 39.03 μmol), and N,N-diisopropylethylamine (25.22 mg, 195.14 μmol). The resulting reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water and extracted three times with ethyl acetate. The combined organic phases were washed with water, saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 1 / 9). Then, water and acetonitrile were added and the mixture was freeze-dried to obtain the target compound 10 (24 mg).

[0381] MS m / z (ESI): = 991.3 [M+H] + 。

[0382] 1 H NMR (400 MHz, CDCl3) δ 8.10–8.05 (m, 1H), 7.98–7.91 (m, 1H), 7.86–7.81 (m, 1H), 7.69–7.58 (m, 2H), 7.41–7.27 (m, 4H), 7.26–7.22 (m, 1H), 5.01–4.87 (m, 1H), 4.78–4.55 (m, 6H), 4.36–4.12 (m, 5H), 4.11–3.84 (m, 2H), 3.84–3.64 (m, 1H), 3.62–3.37 (m, 2H), 3.22–3.09 (m, 5H), 3.08–2.97 (m, 1H), 2.95–2.84 (m, 1H), 2.74–2.62 (m, 1H), 2.52–2.28 (m, 6H), 2.22–2.01 (m, 5H), 1.98–1.79 (m, 2H), 1.81–1.68 (m, 1H), 0.97–0.90 (m, 12H).

[0383] Example 11: Synthesis of Compound 11

[0384]

[0385] Compound 1-5 (30 mg, 68.56 μmol), compound 11-1 (21.9 mg, 45.71 μmol), diisopropylethylamine (31.9 μL, 182.84 μmol), and N,N-dimethylformamide (0.5 mL) were added to a reaction flask. Then, 2-(7-azabenzotriazol)-N,N,N',N'-tetramethyluronium hexafluorophosphate (25.9 mg, 68.57 μmol) was added. The reaction mixture was stirred at room temperature for 1 hour. After completion of the reaction as indicated by LC-MS, the reaction mixture was quenched with saturated aqueous ammonium chloride and extracted three times with ethyl acetate (10 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (silica gel, ethyl acetate) to give the product compound 11 (10 mg).

[0386] MS m / z (ESI): = 899.2 [M+H] + 。

[0387] 1 H NMR (400 MHz, DMSO-d6) δ 8.75–8.58 (m, 1H), 8.35–8.25 (m, 1H), 8.15–8.00 (m, 2H), 7.62 (d, J = 8.4 Hz, 1H), 7.52–7.30 (m, 7H), 7.25–7.08 (m, 3H), 6.32–6.05 (m, 2H), 4.99–4.86 (m, 1H), 4.65–4.52 (m, 3H), 4.51–4.36 (m, 3H), 4.26–4.07 (m, 1H), 4.04–3.67 (m, 7H), 3.58–3.48 (m, 1H), 2.88–2.77 (m, 3H), 2.74–2.67 (m, 1H), 2.31–2.20 (m, 1H), 2.14–2.01 (m, 1H), 1.83–1.61 (m, 3H), 1.54–1.42 (m, 2H), 1.30–1.21 (m, 2H), 1.18–1.09 (m, 2H), 0.94 (d, J = 7.1 Hz, 1H), 0.85–0.76 (m, 3H).

[0388] Biological test experiment

[0389] Test Example 1 Detection of the inhibitory effect of compounds on the binding of STAT6 to peptides by HTRF method

[0390] 1. Experimental materials

[0391] Dilution buffer: 50 mM HEPES, 150 mM NaCl, 0.03% Tween-20, 1 mM DTT, 0.1% BSA.

[0392] 2. Experimental Procedures

[0393] Preparation of compound working solutions: The initial concentration of the compound was 100 μM (solvent: DMSO), and it was serially diluted 3-fold with DMSO, with a total of 7 points. Subsequently, each concentration of the compound was further diluted 25-fold with dilution buffer to form compound working solutions (containing 4% DMSO). 5 μL / well of the compound working solutions with concentration gradients were sequentially added to a 384-well white flat-bottom plate (Perkinelmer, catalog number: 6007290), 5 μL / well of the protein his-TEV-STAT6 (STAT6 (W123 - T658)) (in-house, batch number: 20231117703) (working concentration prepared with dilution buffer was 600 nM), and 5 μL / well of the peptide 5-FAM-ApYKPFQDLI (Gill, catalog number: 1122994) (working concentration prepared with dilution buffer was 600 nM). After mixing, centrifuge at 1000 rpm for 2 minutes at room temperature. After sealing the plate, place the reactants on a shaker and incubate with shaking at 300 rpm for 30 minutes at room temperature. Then, 5 μL of MAb Anti-6HIS-Tb cryptate Gold (CisBio, catalog number: 61HI2TLF) (working concentration prepared with dilution buffer: 1.32 nM) was added to each well. After mixing, centrifuge at 1000 rpm for 2 minutes at room temperature, and continue to incubate with shaking at 300 rpm for 1 hour at room temperature. The final volume of the experimental system was 20 μL, the initial and final concentrations of the compound were 1 μM with a 3-fold gradient, and the final concentration of DMSO was 1%. The solvent group was replaced with dilution buffer containing 4% DMSO instead of the compound working solution, and the other reagents remained unchanged. Use a microplate reader (Perkinelmer, model Envision) to detect the fluorescence intensities at an excitation wavelength of 340 nm and emission wavelengths of 495 nm and 520 nm in HTRF mode. Calculate the ratio value using the formula HTRF ratio = (520 nm / 495 nm) × 10 4 Calculate the ratio value, and then use the formula Inhibition% = ((Ratio 溶媒组 - Ratio 给药组 ) / (Ratio 溶媒组 - Ratio 肽段组 )) × 100% to calculate the inhibition percentage and the maximum inhibition rate E of the compound at each concentration max . Use Graphpad Prism 10 software to perform three-parameter fitting with compound concentration - inhibition percentage to obtain the inhibition activity curve of the compound, and calculate the IC 50 value of the compound according to the software. The IC 50 values of the test compounds are shown in Table 1. The experimental results show that Compound 1 obtained in Example 1 of the preparation has good inhibitory ability on the function of STAT6 protein.

[0394] Table 1. IC of the compound inhibiting the binding of STAT6 to the peptide 50

[0395] Test Compound <![CDATA[IC 50 (μM)]]> Compound 1 0.096 Compound 2 0.014 Compound 3 0.041 Compound 4 0.31

[0396] Test Example 2 Detection of the inhibitory effect of the compound on the binding of STAT3 to the peptide by HTRF method

[0397] 1. Experimental materials

[0398] Dilution buffer: 50 mM HEPES, 150 mM NaCl, 0.03% Tween-20, 1 mM DTT, 0.1% BSA.

[0399] 2. Experimental procedures

[0400] Preparation of the compound working solution: The initial concentration of the compound was 5 mM (the solvent was DMSO), and it was diluted 3-fold with DMSO, with a total of 8 points. Then, each concentration of the compound was diluted 25-fold with the dilution buffer to form the compound working solution (containing 4% DMSO). 5 μL / well of the concentration-gradient compound, 5 μL / well of the protein STAT3-his (ACROBiosystems, catalog number: ST3-H5149) (the working concentration prepared with the dilution buffer was 100 nM), and 5 μL / well of the peptide 5-FAM-GpYLPQTV (Gill, catalog number: 1120697) (the working concentration prepared with the dilution buffer was 200 nM) were added successively to a 384-well white flat-bottom plate (Perkinelmer, catalog number: 6007290). After mixing, it was centrifuged at 1000 rpm for 2 minutes at room temperature. The reactants were placed on a shaker and incubated with shaking at 300 rpm at room temperature for 30 minutes. 5 μL of MAb Anti-6HIS-Tb cryptate Gold (CisBio, catalog number: 61HI2TLF) (the working concentration prepared with the dilution buffer was 1.32 nM) was added to each well. After mixing, it was centrifuged at 1000 rpm for 2 minutes at room temperature and continued to be incubated at 300 rpm on the shaker at room temperature for 1 hour. The final volume of the experimental system was 20 μL, the initial and final concentrations of the compound were 50 μM, with a 3-fold gradient, and the final concentration of DMSO was 1%. The solvent group was replaced with the dilution buffer containing 4% DMSO instead of the compound working solution, and the other reagents remained unchanged. The fluorescence intensities at the excitation wavelength of 340 nm, the emission wavelengths of 495 nm and 520 nm were detected in the HTRF mode using a microplate reader (Perkinelmer, model Envision). The ratio value was calculated using the formula HTRF ratio = (520 nm / 495 nm) × 10 4 Calculate the ratio value, and then use the formula Inhibition% = ((Ratio溶媒组 -Ratio 给药组 ) / (Ratio 溶媒组 -Ratio 肽段组 )) × 100% was used to calculate the inhibition percentage and the maximum inhibition rate E of the compound at each concentration. max . The three-parameter fitting of the compound concentration-inhibition percentage was performed using Graphpad Prism 10 software to obtain the inhibition activity curve of the compound, and the IC 50 value of the compound was calculated according to the software. The IC 50 values of the test compounds are shown in Table 2. The experimental results prove that the compound 1 prepared in Example 1 has an inhibitory effect on the function of STAT3 protein, but the inhibitory effect is weaker than that on the function of STAT6 protein.

[0401] Table 2. IC of the compound inhibiting the binding of STAT3 to the peptide 50

[0402] Test Compound <![CDATA[IC 50 (μM)]]> Compound 1 1.290 Compound 2 3.32 Compound 3 2.39 Compound 4 0.48

Claims

1. A compound of formula (I) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, in: q is 0 or 1; t is 0, 1, or 2; p is 1 or 2; X is selected from O, S(O), -C(=O)-NR 10 - and NR 8 ; R 1 Selected from -CR 1a R 2a P(O)OR 1b OR 2b , -CR 1a R 2a P(O)[OR 1b ][NH(AA)C(O)OR T ]、-P(O)OR 1b OR 2b 、-P(O)[NHR Ty ][NH(AA)C(O)OR T ] or -P(O)[OR 1b ][NH(AA)C(O)OR T ] substituted 8-10 membered heteroaryl, the 8-10 membered heteroaryl is further optionally substituted by amino, halogen, cyano, C1-C4 alkyl or C1-C4 alkoxy; by -CR 1a R 2a P(O)OR 1b OR 2b , -CR 1a R 2a P(O)[OR 1b ][NH(AA)C(O)OR T ]、-P(O)OR 1b OR 2b 、-P(O)[NHR Ty ][NH(AA)C(O)OR T ] or -P(O)[OR 1b ][NH(AA)C(O)OR T ] substituted 8-10 membered heterocyclic group, the 8-10 membered heterocyclic group is optionally substituted by amino, halogen, cyano, C1-C4 alkyl or C1-C4 alkoxy; by -CR 1a R 2a P(O)OR 1b OR 2b , -CR 1a R 2a P(O)[OR 1b ][NH(AA)C(O)OR T ]、-P(O)OR 1b OR 2b 、-P(O)[NHR Ty ][NH(AA)C(O)OR T ] or -P(O)[OR 1b ][NH(AA)C(O)OR T ] substituted C6-C 10 Aryl, the C6-C 10 Aryl is optionally substituted by cyano, C1-C4 alkoxy or halogen; -C1-C4 alkylene aryl, the aryl group of which is replaced by -CR 1a R 2a P(O)OR 1b OR 2b , -CR 1a R 2a P(O)[OR 1b ][NH(AA)C(O)OR T ]、-P(O)OR 1b OR 2b 、-P(O)[NHR Ty ][NH(AA)C(O)OR T ] or -P(O)[OR 1b ][NH(AA)C(O)OR T ] substituted; -C2-C4 alkenyl aryl, the aryl group of the -C2-C4 alkenyl aryl is replaced by -CR 1a R 2a P(O)OR 1b OR 2b , -CR 1a R 2a P(O)[OR 1b ][NH(AA)C(O)OR T ]、-P(O)OR 1b OR 2b 、-P(O)[NHR Ty ][NH(AA)C(O)OR T ] or -P(O)[OR 1b ][NH(AA)C(O)OR T ]replace; R 1a and R 2a is independently selected from hydrogen, halogen, cyano, C1-C4 alkyl, C1-C4 haloalkyl and C1-C4 hydroxyalkyl, or R 1a and R 2a co-form = O; R 1b and R 2b independently selected from hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, -(C1-C4 alkylene)-OC(O)-(C1-C4 alkyl), -(C1-C4 alkylene)-C(O)O-(C1-C4 alkyl), -(C1-C4 alkylene)-O-(C1-C 20 -(C1-C4 alkylene)-OC(O)-[(C1-C4)haloalkyl], (C1-C4 alkylene)-OC(O)O-[5-7 membered heterocyclyl], (C1-C4 alkylene)-OC(O)-[5-7 membered heterocyclyl], -(C1-C4 alkylene)-OC(O)-(C1-C4 alkylene)-OH, -(C1-C4 alkylene)-OC(O)-(C1-C4 alkylene)-O-(C1-C4 alkyl), -(C1-C4 alkylene)-OC(O)O-[(C1-C4)haloalkyl], -(C1-C4 alkylene)-OC(O)O-(C1-C4 alkyl), -(C1-C4 alkylene)-OH, -(C1-C4 alkylene)-OC(O)O-(C1-C4 alkylene)-O-(C1-C4 alkyl), -(C1-C4 alkylene)-SC(O)-(C1-C6 alkyl), -(C1-C4 alkylene)-SC(O)-[(C1-C4)haloalkyl], -(C1-C4 alkylene)-SC(O)-(C1-C4 alkyl)-OH, -(C1-C4 alkylene)-SC(O)-(C1-C4 alkylene)-O-(C1-C4 alkyl), -(C1-C4 alkylene)-OC(O)NH(C1-C4 alkyl)], -(C1-C4 alkylene)-OC(O)N(C1-C4 alkyl)2, C6-C 10 Aryl and 5-6 membered heteroaryl, the C6-C 10 The aryl and 5-6 membered heteroaryl groups are optionally substituted with halogen, cyano or C1-C4 alkyl groups, and the 5-7 membered heterocyclyl in the (C1-C4 alkylene)-OC(O)O-[5-7 membered heterocyclyl] and (C1-C4 alkyl)-OC(O)-[5-7 membered heterocyclyl] is optionally substituted with C(O)OR h replace; R 2 Selected from hydrogen, halogen, COOH, hydroxy, cyano, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 haloalkyl, C1-C4 hydroxy-substituted alkyl; R 3 and R 4 independently selected from hydrogen, halogen, hydroxy, cyano, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxy substituted alkyl, -C1-C4 alkylphenyl, C1-C4 alkoxy, C1-C4 haloalkoxy, -C1-C4 alkyl C1-C4 alkoxy, NR a R b , C3-C6 cycloalkyl, C6-C 10 aryl, 5-10 membered heteroaryl and 4-10 membered heterocyclic group, the C3-C6 cycloalkyl, C6-C 10 Aryl, 5-10 membered heteroaryl and 4-10 membered heterocyclyl are optionally replaced by R S replace; R 5 and R 6 independently selected from hydrogen, phenyl and C1-C4 alkyl; R 7 is selected from C1-C4 alkyl, phenyl, 4-9 membered heterocyclic group and 5-10 membered heteroaryl, wherein the C1-C4 alkyl is optionally replaced by R Y The phenyl, 4-9 membered heterocyclic and 5-10 membered heteroaryl groups are optionally substituted by R Z replace; Or, R 6 and R 7 Together with the N atom to which they are attached, they form a 4-14-membered heterocyclic group or a 5-12-membered heteroaryl group, wherein the 4-14-membered heterocyclic group or the 5-12-membered heteroaryl group is optionally substituted by R Q replace; R 8 is selected from 4-10 membered heterocyclic groups, wherein the 4-10 membered heterocyclic groups are optionally substituted by R 8a replace; Or, when X is NR 8 When R 3 And the connected C and R 8 and the N to which it is connected together form a 4-8 membered heterocyclic ring or a 5-6 membered heteroaromatic ring, wherein the 4-8 membered heterocyclic ring and the 5-6 membered heteroaromatic ring are optionally substituted by halogen, cyano, amino or C1-C4 alkyl; R 8a is selected from halogen, cyano, amino, C1-C4 alkyl, -C(O)C1-C4 alkyl and =O; R 9 Selected from -C(O)C1-C4 alkyl, C1-C4 alkyl, C1-C4 cyano substituted alkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl, 4-9 membered heterocyclic group, C6-C 10 Aryl and 5-10 membered heteroaryl; R 10 is selected from hydrogen, C1-C4 alkyl, C1-C4 cyano substituted alkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl, 4-9 membered heterocyclic group, C6-C 10 Aryl and 5-10 membered heteroaryl; AA is the residue of an α or β natural or unnatural amino acid; R T and R Ty independently selected from C1-C4 alkyl, benzyl and phenyl, wherein the phenyl is optionally substituted with halogen, C1-C4 alkyl or C1-C4 haloalkyl; R Q independently selected from halogen, cyano, hydroxyl, phenyl, C2-C4 alkenyl, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, 4-9 membered heterocyclyl, 5-10 membered heteroaryl, C3-C6 cycloalkyl, =O, imine, -OR e ,-C(O)R g 、-C(O)OR e 、-NR c C(O)R e 、-C(O)NR c R d 、-NR a R b 、-S(O)R e R f 、-S(O)2R f 、-S(O)=NH(C1-C4)alkyl、-S(O)NR e R f and -S(O)2NR e R f The C2-C4 alkenyl group, C1-C4 alkyl group is optionally replaced by R M The phenyl, 5-10 membered heteroaryl, C3-C6 cycloalkyl and 4-9 membered heterocyclic group are optionally substituted by R F replace; R Y independently selected from halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, cyano, -C(O)R g 、-C(O)OR e 、NHC(O)R e 、-NR a R b SS(O)R e R f ,-S(O)2R f 、-S(O)=NH(C1-C4)alkyl、-S(O)NR e R f 、-S(O)2NR e R f , hydroxyl, phenyl, 4-6 membered heterocyclic group and 5-10 membered heteroaryl, wherein the phenyl, 4-6 membered heterocyclic group and 5-10 membered heteroaryl are optionally replaced by R X replace; R F , R S , R X , R Z independently selected from halogen, cyano, C1-C4 alkyl, C1-C4 cyano substituted alkyl, C3-C6 cycloalkyl, C1-C4 haloalkyl, -C1-C4 alkyl C(O)NR e R f , -(C1-C4)alkyl-(C1-C4)alkoxy, C1-C4hydroxyalkyl, -(C1-C4)alkylphenyl, -(C1-C4)alkylheteroaryl, C2-C4alkenyl, C2-C4haloalkenyl, C2-C4alkynyl, C2-C4haloalkynyl, C1-C4alkoxy, C1-C4haloalkoxy, -OR e , =O, imine, phenyl, 4-6 membered heterocyclic group, 5-6 membered heteroaryl, -S(O)R f 、-S(O)2R f 、-S(O)=NH(C1-C4)alkyl、-S(O)NR e R f 、-S(O)2NR e R f 、-C(O)OR e 、-NR c C(O)R e 、-(C1-C4 alkyl)C(O)R g 、-C(O)R g 、-(C1-C4 alkyl)C(O)NR c R d 、-C(O)NR c R d , -NO2 and -NR a R b The C1-C4 alkyl group is optionally substituted with a cyano group, and the phenyl group, the 4-6 membered heterocyclic group, the 5-6 membered heteroaryl group, and the phenyl group of the -(C1-C4)alkylphenyl group are optionally substituted with a halogen group, a cyano group, a =O group, a (C1-C 10 )alkyl, (C2-C 10 )alkenyl, (C2-C 10 ) alkynyl, (C1-C 10 ) haloalkyl, (C1-C 10 ) alkoxy or (C1-C 10 ) is substituted with a haloalkoxy group, wherein (C1-C 10 )alkyl, (C2-C 10 )alkenyl, (C2-C 10 ) alkynyl is optionally substituted by a 5-10 membered heteroaryl or a 4-10 membered heterocyclic group, and the 4-10 membered heterocyclic group is optionally substituted by oxo; R M independently selected from halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, cyano, -C(O)R g 、-C(O)OR e 、-NHC(O)R e 、-C(O)NR c R d 、-NR a R b 、-S(O)R f 、-S(O)2R f 、-S(O)NR e R f 、-S(O)=NH(C1-C4)alkyl、-S(O)2NR e R f , hydroxyl, phenyl, 4-6 membered heterocyclic group and 5-10 membered heteroaryl, wherein the phenyl, 4-6 membered heterocyclic group and 5-10 membered heteroaryl are optionally replaced by R X replace; R a , R b , R c , R d , R e , R f , R g and R h independently selected from hydrogen, C1-C4 alkyl, C2-C4 alkynyl, -C1-C4 alkylphenyl, phenyl, C3-C6 cycloalkyl, 4-6 membered heterocyclyl and 5-6 membered heteroaryl, the C1-C4 alkyl is optionally substituted with halogen, cyano, hydroxyl or amino, the phenyl, C3-C6 cycloalkyl, 4-6 membered heterocyclyl and 5-6 membered heteroaryl are optionally substituted with halogen, cyano, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, hydroxyl, phenyl or benzyl; One or more hydrogen atoms of the compound are optionally deuterium atoms.

2. The compound of formula (I) according to claim 1, or its stereoisomer or a pharmaceutically acceptable salt thereof, wherein: p is 1.

3. The compound of formula (I) according to any one of claims 1 to 2, or its stereoisomer or a pharmaceutically acceptable salt thereof, wherein: t is 1 or 2.

4. The compound of formula (I) according to any one of claims 1 to 3, or its stereoisomer or a pharmaceutically acceptable salt thereof, wherein: q is 0; or q is 1.

5. The compound of formula (I) according to any one of claims 1 to 4, or its stereoisomer or a pharmaceutically acceptable salt thereof, wherein: X is selected from O, -C(=O)-NH-, S(O) and NR 8 ; or X is selected from NR 8 .

6. The compound of formula (I) according to any one of claims 1 to 5, or its stereoisomer or a pharmaceutically acceptable salt thereof, wherein: R 8 is selected from 4-6 membered heterocyclic groups, wherein the 4-6 membered heterocyclic groups are optionally substituted by R 8a Replace; or R 8 is selected from a 4-membered heterocyclic group, wherein the 4-membered heterocyclic group is optionally substituted by R 8a Replace; or R 8 is selected from oxetanyl, azetidinyl, thietanyl and thietanyl-1,1-dioxide, wherein the oxetanyl, azetidinyl, thietanyl and thietanyl-1,1-dioxide are optionally replaced by R 8a Replace; or R 8 is selected from oxetanyl, azetidinyl and thietanyl-1,1-dioxide, wherein the oxetanyl, azetidinyl and thietanyl-1,1-dioxide are optionally replaced by R 8a replace.

7. The compound of formula (I) according to any one of claims 1 to 6, or its stereoisomer or a pharmaceutically acceptable salt thereof, wherein: R 8a is selected from C1-C4 alkyl, =O and -C(O)C1-C4 alkyl; or R 8a Selected from C1-C4 alkyl and -C(O)C1-C4 alkyl; or R 8a is selected from methyl, =O and -C(O)CH2CH3; or R 8a Selected from methyl and -C(O)CH2CH3.

8. The compound of formula (I) according to any one of claims 1 to 7, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: When X is NR 8 When R 3 And the connected C and R 8 and the N to which it is connected together form a 5-membered heterocyclic ring or a 5-membered heteroaryl; or when X is NR 8 When R 3 And the connected C and R 8 and the N to which it is connected together form an imidazole ring or a tetrahydropyrrole ring.

9. The compound of formula (I) according to any one of claims 1 to 8, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: R 1 Selected from -CR 1a R 2a P(O)OR 1b OR 2b , -CR 1a R 2a P(O)[OR 1b ][NH(AA)C(O)OR T ]、-P(O)OR 1b OR 2b 、-[P(O)[NHR Ty ][NH(AA)C(O)OR T ] or -P(O)[OR 1b ][NH(AA)C(O)OR T ] substituted 8-10 membered heteroaryl, the 8-10 membered heteroaryl is further optionally substituted by amino, halogen, cyano, C1-C4 alkyl or C1-C4 alkoxy; by -CR 1a R 2a P(O)OR 1b OR 2b , -CR 1a R 2a P(O)[OR 1b ][NH(AA)C(O)OR T ]、-P(O)OR 1b OR 2b 、-[P(O)[NHR Ty ][NH(AA)C(O)OR T ] or -P(O)[OR 1b ][NH(AA)C(O)OR T ] substituted 8-10 membered heterocyclic group, the 8-10 membered heterocyclic group is optionally substituted by amino, halogen, cyano, C1-C4 alkyl or C1-C4 alkoxy; or by -CR 1a R 2a P(O)OR 1b OR 2b , -CR 1a R 2a P(O)[OR 1b ][NH(AA)C(O)OR T ]、-P(O)OR 1b OR 2b 、-[P(O)[NHR Ty ][NH(AA)C(O)OR T ] or -P(O)[OR 1b ][NH(AA)C(O)OR T ] substituted C6-C 10 Aryl, the C6-C 10 Aryl is optionally further substituted by cyano, C1-C4alkoxy or halogen; or R 1 Selected from -CR 1a R 2a P(O)OR 1b OR 2b , -CR 1a R 2a P(O)[OR 1b ][NH(AA)C(O)OR T ]、-P(O)OR 1b OR 2b 、-[P(O)[NHR Ty ][NH(AA)C(O)OR T ] or -P(O)[OR 1b ][NH(AA)C(O)OR T ] substituted 8-10 membered heteroaryl; 1a R 2a P(O)OR 1b OR 2b , -CR 1a R 2a P(O)[OR 1b ][NH(AA)C(O)OR T ]、-P(O)OR 1b OR 2b 、-[P(O)[NHR Ty ][NH(AA)C(O)OR T ] or -P(O)[OR 1b ][NH(AA)C(O)OR T ] substituted C6-C 10 Aryl or -CR 1a R 2a P(O)OR 1b OR 2b , -CR 1a R 2a P(O)[OR 1b ][NH(AA)C(O)OR T ]、-P(O)OR 1b OR 2b 、-[P(O)[NHR Ty ][NH(AA)C(O)OR T ] or -P(O)[OR 1b ][NH(AA)C(O)OR T ] substituted 8-10 membered heterocyclic group; or R 1 Selected from or R 1 Selected from or R 1 Selected from or R 1 Selected from 10. The compound of formula (I) according to any one of claims 1 to 9, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: R 2b and R 3b independently selected from hydrogen, C1-C4 alkyl, -(C1-C4 alkylene)-OC(O)-(C1-C4 alkyl), -(C1-C4 alkylene)-OC(O)-[5-7 membered heterocyclyl], -(C1-C4 alkylene)-SC(O)-(C1-C6 alkyl), -(C1-C4 alkylene)-OC(O)O-(C1-C4 alkyl), -(C1-C4 alkylene)-OC(O)N(C1-C4 alkyl)2, -(C1-C4 alkylene)-OC(O)O-(C1-C4 alkylene)-O-(C1-C4 alkyl) and C6-C 10 Aryl, the C6-C 10 The aryl group is optionally substituted by halogen, cyano or C1-C4 alkyl, and the 5-7 membered heterocyclic group is optionally substituted by C(O)OR h Replace; or R 2b and R 3b Independently selected from hydrogen, phenyl, -(C1-C4 alkylene)-OC(O)O-(C1-C4 alkyl) and -(C1-C4 alkylene)-SC(O)-(C1-C5 alkyl).

11. The compound of formula (I) according to any one of claims 1 to 10, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: -CR 1a R 2a P(O)OR 1b OR 2b selected from or -CR 1a R 2a P(O)OR 1b OR 2b Selected from or -CR 1a R 2a P(O)OR 1b OR 2b Selected from or -CR 1a R 2a P(O)OR 1b OR 2b for 12. The compound of formula (I) according to any one of claims 1 to 11, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: -CR 1a R 2a P(O)[OR 1b [NH(AA)C(O)OR T is 13. The compound of formula (I) according to any one of claims 1 to 12, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: R 2 , R 3 , R 4 and R 5 All are hydrogen.

14. The compound of formula (I) according to any one of claims 1 to 13, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: R 6 and R 7 Together with the nitrogen atom to which they are attached, they form a 4-14-membered heterocyclic group, wherein the 4-14-membered heterocyclic group is optionally substituted by R Q Replace; or R 6 and R 7 Together with the nitrogen atom to which they are attached, they form a 4-7 membered heterocyclic group, wherein the 4-7 membered heterocyclic group is optionally substituted by R Q Replace; or R 6 and R 7 The heterocyclic group formed together with the N atom to which they are attached is selected from Said Optional R Q Replace; or R 6 and R 7 The heterocyclic group formed together with the N atom to which they are attached is selected from 15. The compound of formula (I) according to any one of claims 1 to 14, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: R Q is selected from cyano, phenyl, 4-9 membered heterocyclyl and =O, wherein the 4-9 membered heterocyclyl is optionally substituted by =O; or R Q is selected from cyano, phenyl, 6-7 membered heterocyclyl and =O, wherein the 6-7 membered heterocyclyl is optionally substituted by =O; or R Q Selected from cyano, phenyl, And = O.

16. The compound of formula (I) according to claim 1, or its stereoisomer, or a pharmaceutically acceptable salt thereof, wherein: The compound of formula (I) or its stereoisomer or its pharmaceutically acceptable salt is selected from the compound of formula (II) or its stereoisomer or its pharmaceutically acceptable salt: Among them, q, t, p, X, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 As defined in claims 1-15.

17. The compound of formula (I) according to claim 1, or its stereoisomer, or its pharmaceutically acceptable salt, is selected from the following compounds, or their stereoisomers, or their pharmaceutically acceptable salts, 18. A pharmaceutical composition comprising a compound of formula (I) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 17 and a pharmaceutically acceptable excipient.

19. Use of the compound of formula (I) according to any one of claims 1 to 17 or its stereoisomer or pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 18 in the preparation of a medicament for preventing or treating a STAT6-mediated disease.

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