STAT 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. 202311846594.3, 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 is 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 available marketed drugs all have certain limitations: large molecule antibodies usually require regular injections, are only suitable for 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] is a double bond or a single bond;

[0012] t and q are independently selected from 0, 1, and 2;

[0013] p is 1 or 2;

[0014] X 1 is selected from CH2, O, S, S(O), SO2, and NR 7 ;

[0015] X 2 is selected from N, C, or CH;

[0016] Ring A is selected from C3-C 12Saturated carbocyclic rings, 4- to 10-membered heterocyclic rings, C6-C 10 Aromatic rings and 5- to 12-membered heteroaromatic rings, where the C3-C 12 Saturated carbocyclic rings, 4- to 10-membered heterocyclic rings, C6-C 10 Aromatic rings and 5- to 12-membered heteroaromatic rings are optionally substituted by R a ;

[0017] R a Is independently selected from halogen, COOH, hydroxyl, cyano, =O, C1-C4 alkyl, C1-C4 alkoxy, and C1-C4 haloalkyl;

[0018] R 1 And R 2 Are independently selected from hydrogen, halogen, hydroxyl, cyano, =O, 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 1a R 1b 、C3-C6 cycloalkyl, C6-C 10 Aryl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocyclic groups, where the C3-C6 cycloalkyl, C6-C 10 Aryl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocyclic groups are optionally substituted by R S ;

[0019] R 3 Is selected from hydrogen, halogen, COOH, hydroxyl, cyano, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 haloalkyl, and C1-C4 hydroxy-substituted alkyl;

[0020] R 4 Is selected from hydrogen, phenyl, and C1-C4 alkyl;

[0021] R 7 Is selected from hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, and 4- to 10-membered heterocyclic groups;

[0022] R 5 And R 6 Together with the N atom to which they are attached form a 4- to 14-membered heterocyclic group or a 5- to 12-membered heteroaromatic group, where the 4- to 14-membered heterocyclic group or 5- to 12-membered heteroaromatic group is optionally substituted by R Q ;

[0023] R Q Is independently selected from halogen, cyano, hydroxyl, C2-C4 alkenyl, C1-C4 alkyl, C1-C4 alkoxy, C6-C 10Aryl, 4- to 9-membered heterocyclic group, 5- to 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 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, C1-C4 alkyl, C1-C4 alkoxy are optionally substituted by R M , the C6-C 10 aryl, 5- to 10-membered heteroaryl, C3-C6 cycloalkyl and 4- to 9-membered heterocyclic group are optionally substituted by R F ;

[0024] Ring B is selected from C6-C 10 aryl, 8- to 10-membered heterocyclic group and 8- to 10-membered heteroaryl, the C6-C 10 aryl, 8- to 10-membered heterocyclic group and 8- to 10-membered heteroaryl are optionally substituted by amino, halogen, cyano, C1-C4 alkyl or C1-C4 alkoxy;

[0025] W is selected from -CR 2a R 3a P(O)OR 2b OR 3b , -CR 2a R 3a P(O)[OR 2b [NH(AA)C(O)OR T , -P(O)OR 2b OR 3b , -[P(O)[NHR Ty [NH(AA)C(O)OR T and -P(O)[OR 2b [NH(AA)C(O)OR T ;

[0026] R 2a and R 3a are independently selected from hydrogen, halogen, cyano, C1-C4 alkyl, C1-C4 haloalkyl and C1-C4 hydroxyalkyl, or R 2a and R3a Together form =O;

[0027] R 2b and R 3b 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 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 alkyl)-OH, -(C1-C4 alkylene)-OC(O)O-(C1-C4 alkylene)-O-(C1-C4 alkyl), -(C1-C4 alkylene)-SC(O)-(C1-C4 alkyl), -(C1-C4 alkylene)-SC(O)-[(C1-C4) haloalkyl], -(C1-C4 alkylene)-SC(O)-(C1-C4 alkylene)-OH, -(C1-C4 alkylene)-SC(O)-(C1-C4 alkylene)-O-(C1-C4 alkyl), -(C1-C4 alkylene)-OC(O)NH(C1-C4 alkyl), -(C1-C4 alkylene)-OC(O)N(C1-C4 alkyl)2, C6-C 10 aryl and 5-6 membered heteroaryl, the C6-C 10 aryl and 5-6 membered heteroaryl are optionally substituted by halogen, cyano or C1-C4 alkyl, and the 5-7 membered heterocyclic group in the -(C1-C4 alkylene)-OC(O)O-[5-7 membered heterocyclic group] and -(C1-C4 alkylene)-OC(O)-[5-7 membered heterocyclic group] is optionally substituted by C(O)OR h ;

[0028] AA is a residue of an α or β natural or unnatural 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 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 、hydroxy, phenyl, 4-6-membered heterocyclic group and 5-10-membered heteroaryl, said phenyl, 4-6-membered heterocyclic group, 5-10-membered heteroaryl optionally substituted by R X ;

[0031] R F 、R S and R X 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 、=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 , wherein the C1-C4 alkyl is optionally substituted with a cyano group, and the phenyl, 4-6 membered heterocyclic group, 5-6 membered heteroaryl, phenyl of -(C1-C4)alkylphenyl is optionally substituted with a 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 )alkenyl, (C2-C 10 )alkynyl is optionally substituted with a 5-10 membered heteroaryl or 4-10 membered heterocyclic group, and the 4-10 membered heterocyclic group is optionally substituted with oxo;

[0032] R 1a 、R 1b 、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, 4-6 membered heterocyclic group and 5-6 membered heteroaryl, wherein the C1-C4 alkyl is optionally substituted with a halogen, cyano, hydroxyl or phenyl, and the phenyl, C3-C6 cycloalkyl, 4-6 membered heterocyclic group and 5-6 membered heteroaryl are optionally substituted with a halogen, cyano, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, hydroxyl, phenyl or benzyl;

[0033] One or more hydrogen atoms of the compound are optionally deuterium atoms.

[0034] In some embodiments, is a single bond.

[0035] In some embodiments, p is 1.

[0036] In some embodiments, t is 0 or 1.

[0037] In some embodiments, t is 0.

[0038] In some embodiments, q is 1 or 2.

[0039] In some embodiments, q is 1.

[0040] In some embodiments, q is 2.

[0041] In some embodiments, X 1 is selected from CH2, O, and NR 7 .

[0042] In some embodiments, R 7 is selected from hydrogen, C1-C4 alkyl, and C1-C4 haloalkyl.

[0043] In some embodiments, R 7 is hydrogen.

[0044] In some embodiments, X 1 is CH2.

[0045] In some embodiments, X 2 is selected from N and C.

[0046] In some embodiments, X 2 is C.

[0047] In some embodiments, ring A is selected from 4- to 10-membered heterocycles, C6-C 10 aryl rings, and 5- to 12-membered heteroaryl rings, and the 4- to 10-membered heterocycles, C6-C 10 aryl rings, and 5- to 12-membered heteroaryl rings are optionally substituted with R a .

[0048] In some embodiments, ring A is selected from 5- to 6-membered heterocycles, C6-C 10 aryl rings, and 5- to 6-membered heteroaryl rings, and the 5- to 6-membered heterocycles, C6-C 10 aryl rings, and 5- to 6-membered heteroaryl rings are optionally substituted with R a .

[0049] In some embodiments, ring A is selected from benzene rings, pyridine rings, dihydropyridine rings, and imidazole rings, and the benzene rings, pyridine rings, dihydropyridine rings, and imidazole rings are optionally substituted with R a .

[0050] In some embodiments, R a is independently selected from halogen, COOH, hydroxy, cyano, ═O, and C1-C4 alkyl.

[0051] In some embodiments, R a is ═O.

[0052] In some embodiments, ring A is selected from benzene rings, pyridine rings, pyridin-2(1H)-one, and imidazole rings.

[0053] In some embodiments, ring A is selected from a benzene ring or a pyridine ring.

[0054] In some embodiments, R 1 and R 2 are hydrogen or ═O.

[0055] In some embodiments, R 3 is hydrogen.

[0056] In some embodiments, R 4 is selected from hydrogen and C1-C4 alkyl.

[0057] In some embodiments, R 4 is hydrogen.

[0058] In some embodiments, R 5 and R 6 together with the N atom to which they are attached form a 4- to 14-membered heterocyclic group, which 4- to 14-membered heterocyclic group is optionally substituted with R Q substituent.

[0059] In some embodiments, R 5 and R 6 together with the N atom to which they are attached form a 4- to 10-membered heterocyclic group, which 4- to 10-membered heterocyclic group is optionally substituted with R Q substituent.

[0060] In some embodiments, R 5 and R 6 together with the N atom to which they are attached form a 5- to 7-membered heterocyclic group, which 5- to 7-membered heterocyclic group is optionally substituted with R Q substituent.

[0061] In some embodiments, R 5 and R 6 together with the N atom to which they are attached form a 5- to 6-membered heterocyclic group, which 5- to 6-membered heterocyclic group is optionally substituted with R Q substituent.

[0062] In some embodiments, R 5 and R 6 together with the N atom to which they are attached form the which is optionally substituted with R Q substituent.

[0063] In some embodiments, R 5 and R 6 together with the N atom to which they are attached form the which is optionally substituted with R Q substituent.

[0064] In some embodiments, R Q is independently selected from halogen, cyano, hydroxy, C2-C4 alkenyl, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, and C6-C 10 aryl.

[0065] In some embodiments, R Q is independently selected from cyano and phenyl.

[0066] In some embodiments, ring B is selected from the optionally substituted with amino, halogen, cyano, C1-C4 alkyl, or C1-C4 alkoxy.

[0067] In some embodiments, ring B is selected from

[0068] In some embodiments, ring B is

[0069] In some embodiments, W is selected from -CR 2a R 3a P(O)OR 2b OR 3b and -CR 2a R 3a P(O)[OR 2b [NH(AA)C(O)OR T .

[0070] In some embodiments, W is selected from -CR 2a R 3a P(O)OR 2b OR 3b .

[0071] 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-C4 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 10The aryl 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 substituted.

[0072] In some embodiments, R h is selected from C1-C4 alkyl, preferably methyl.

[0073] In some embodiments, R 2b and R 3b are independently selected from hydrogen, phenyl and -(C1-C4 alkylene)-SC(O)-(C1-C4 alkyl).

[0074] In some embodiments, -CR 2a R 3a P(O)OR 2b OR 3b is selected from

[0075] In some embodiments, AA is selected from alanine residues.

[0076] In some embodiments, -CR 2a R 3a P(O)[OR 2b [NH(AA)C(O)OR T is

[0077] In some embodiments, -CR 2a R 3a P(O)OR 2b OR 3b is

[0078] In some embodiments, -CR 2a R 3a P(O)OR 2b OR 3b is

[0079] In some embodiments, W is selected from

[0080] 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,

[0081]

[0082] wherein q, X 1 、X 2 、R 1 、R3 , R 4 , R 5 , R 6 , ring A, ring B and W are as defined in the compound of formula (I).

[0083] In some embodiments, the compound of formula (I) or its stereoisomer or its pharmaceutically acceptable salt is selected from the compound of formula (III) or its stereoisomer or its pharmaceutically acceptable salt,

[0084]

[0085] wherein q, X 1 , R 4 , R 5 , R 6 , ring B and W are as defined in the compound of formula (I), and X is independently selected from N or CH.

[0086] In some embodiments, the compound of formula (I) of the present disclosure or its stereoisomer or its pharmaceutically acceptable salt is selected from the following compounds or their pharmaceutically acceptable salts,

[0087]

[0088]

[0089] On the other hand, the present disclosure provides a pharmaceutical composition comprising the compound of formula (I) of the present disclosure or its stereoisomer or its pharmaceutically acceptable salt and a pharmaceutically acceptable excipient.

[0090] 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 its stereoisomer or its pharmaceutically acceptable salt, or a pharmaceutical composition thereof.

[0091] On the other hand, the present disclosure provides the use of the compound of formula (I) or its stereoisomer or its pharmaceutically acceptable salt, or a pharmaceutical composition thereof, in the preparation of a drug for preventing or treating a STAT6-mediated disease.

[0092] On the other hand, the present disclosure provides the use of the compound of formula (I) or its stereoisomer or its pharmaceutically acceptable salt, or a pharmaceutical composition thereof, in preventing or treating a STAT6-mediated disease.

[0093] On the other hand, the present disclosure provides the compound of formula (I) or its stereoisomer or its pharmaceutically acceptable salt, or a pharmaceutical composition thereof, for preventing or treating a STAT6-mediated disease.

[0094] In some embodiments, the STAT6-mediated disease is asthma, atopic dermatitis, or chronic obstructive pulmonary disease.

[0095] Term Definitions and Explanations

[0096] Unless otherwise specified, the terms used in this disclosure have the following meanings. The definitions of the groups and terms recited in this disclosure, including their definitions by way of example, exemplary definitions, preferred definitions, definitions recited in tables, definitions of specific compounds in the examples, etc., may 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 in accordance with the ordinary meaning in the art. When a trade name appears herein, it is intended to refer to the corresponding commodity or its active ingredient.

[0097] As used herein represents a double bond or a single bond.

[0098] As used herein represents a point of attachment.

[0099] The graphical representation of a racemic or enantiomerically pure compound herein is from Maehr, J. Chem. Ed. 1985, 62: 114-120. Unless otherwise specified, a solid wedge and a dashed wedge are used to represent the absolute configuration of a stereocenter, and a straight solid bond and a straight dashed bond are used to represent the relative configuration of a stereocenter (such as the cis-trans configuration of an alicyclic compound).

[0100] 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.

[0101] The compounds of the present disclosure may have asymmetric atoms such as carbon atoms, sulfur atoms, nitrogen atoms, phosphorus atoms, or asymmetric double bonds, and thus the compounds of the present disclosure 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 isomers and their mixtures are within the scope of the definition of the compounds of the present disclosure. Additional asymmetric carbon atoms, asymmetric sulfur atoms, asymmetric nitrogen atoms, or asymmetric 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 pure form or in racemic form. The optically pure form may be resolved from a racemic mixture or synthesized by using chiral starting materials or chiral reagents.

[0102] The term "substituted" means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, provided that the valence state 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.

[0103] The term "optionally" or "optionally" means that the subsequent described event or situation may or may not occur, and the description includes the occurrence and non-occurrence of the described event or situation. For example, ethyl "optionally" being substituted by one or more halogens 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 substitutions or substitution patterns that are spatially impossible to exist and / or cannot be synthesized will be introduced.

[0104] When any variable (e.g., 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 independent options.

[0105] When the linking groups involved in this text do not specify their linking directions, the linking directions are arbitrary. For example, when the structural unit contains L 1 selected from "C1-C3 alkylene-O", at this time L 1 can be linked to ring Q and R in the direction from left to right 1 to form "ring Q-C1-C3 alkylene-O-R 1 ", or can be linked to ring Q and R in the direction from right to left 1 to form "ring Q-O-C1-C3 alkylene-R 1 ".

[0106] When a substituent's bond cross-links to two atoms on a ring, this substituent can bond to any atom on this ring. For example, the structural unit represents that R 5 can be substituted at any position on the benzene ring.

[0107] C m -C n in this text means having an integer number of carbon atoms in the range of m-n. For example, "C1-C 10 " means that this group can have 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms.

[0108] 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-chain 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-chain saturated alkyl having 1 to 4 carbon atoms. The term "C1-C3 alkyl" can be understood to represent a straight-chain or branched-chain saturated alkyl having 1 to 3 carbon atoms. The "C1-C 10 alkyl" can include ranges such as "C1-C6 alkyl", "C1-C4 alkyl" or "C1-C3 alkyl", and the "C1-C6 alkyl" can 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 10 alkyl as defined above that is substituted by one or more halogens, including but not limited to trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, trichloromethyl, pentafluoroethyl and pentachloroethyl, etc.

[0109] The term "alkoxy" refers to a group produced 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.

[0110] 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. "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.

[0111] 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 represent 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. "C2-C 10 alkynyl" examples 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.

[0112] The term "heterocyclic" or "heterocyclic group" refers to a monocyclic, fused-ring, spiro-ring or bridged-ring group that is fully saturated or partially saturated (not heteroaromatic with aromaticity as a whole), and contains 1 to 5 (e.g., 1 to 3 or 1 to 2) heteroatoms or heteroatomic groups (i.e., atomic groups containing heteroatoms) among its ring atoms. The "heteroatoms or heteroatomic groups" include, but are 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- to 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 to 5 heteroatoms or heteroatomic groups independently selected from the above-mentioned ones among its ring atoms. The term "4- to 10-membered heterocyclic group" refers to a heterocyclic group 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 among its ring atoms. The "4- to 10-membered heterocyclic group" may include the "4- to 7-membered heterocyclic group". The term "8- to 10-membered heterocyclic group" refers to a heterocyclic group having 8, 9 or 10 ring atoms, and containing 1 to 5 heteroatoms or heteroatomic groups independently selected from the above-mentioned ones among its ring atoms. The term "4- to 9-membered heterocyclic group" refers to a heterocyclic group having 4, 5, 6, 7, 8 or 9 ring atoms, and containing 1 to 5 heteroatoms or heteroatomic groups independently selected from the above-mentioned ones among its ring atoms. The term "4- to 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 heteroatomic groups independently selected from the above-mentioned ones among its ring atoms. The term "4- to 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 heteroatomic groups independently selected from the above-mentioned ones among its ring atoms. The term "5- to 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 heteroatomic groups independently selected from the above-mentioned ones 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, tetrahydrofuryl, 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-bicyclic group include, but are not limited to, hexahydrocyclopenta[c]pyrrol-2(1H)-yl; specific examples of the 5,6-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 and the like. 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 heteroaryl 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 heteroatom groups (i.e., atomic groups containing heteroatoms) among the ring atoms of the ring. 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)-, -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 contains 1 to 5 heteroatoms or heteroatom groups independently selected from the above-mentioned ones among its ring atoms. The term "5- to 10-membered heterocycloalkyl" refers to a heterocycloalkyl having 5, 6, 7, 8, 9 or 10 ring atoms, and contains 1 to 5 heteroatoms or heteroatom groups independently selected from the above-mentioned ones among its ring atoms. "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 "cycloalkyl" refers to a carbocyclic group that is fully saturated and exists in the form of a monocyclic, fused-ring, bridged-ring or spiro-ring, etc. Unless otherwise indicated, this 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.

[0115] The term "aryl" refers to an aromatic ring group of a fully carbon monocyclic or fused polycyclic 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.

[0116] 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 "5-14 membered heteroaryl" can be understood to include such monocyclic or polycyclic aromatic ring systems: having 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 ring atoms, such as 5 or 6 or 9 or 10 or 11 or 12 or 13 or 4 ring atoms, and containing 1-5, such as 1-3 heteroatoms independently selected from N, O, and S. 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. 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, such as 8 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, benzisoxazolyl, 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 "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.

[0117] The term "halo" or "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0118] The term "hydroxy" refers to the -OH group.

[0119] The term "cyano" refers to the -CN group.

[0120] The term "amino" refers to the -NH2 group.

[0121] The term "nitro" refers to the -NO2 group.

[0122] The term "treatment" means administering a compound or preparation described in the present application to ameliorate or eliminate a disease or one or more symptoms associated with the disease, and includes:

[0123] (i) inhibiting a disease or disease state, i.e., curbing its development;

[0124] (ii) alleviating a disease or disease state, i.e., causing the disease or disease state to regress.

[0125] The term "therapeutically effective amount" means the amount of a compound of the present disclosure that (i) treats a particular disease, condition, or disorder, and (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 a person skilled in the art based on their own knowledge and the present disclosure.

[0126] The term "prevention" means administering a compound or preparation 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.

[0127] 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 animals, 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" may be used interchangeably.

[0128] 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.

[0129] 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.

[0130] The term "pharmaceutical composition" refers to a mixture comprising 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.

[0131] The term "pharmaceutically acceptable excipients" refers to those excipients that do not cause significant irritation to the 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.

[0132] The words "comprise" or "comprising" and their English variants such as "comprises" or "comprising" can be understood in an open, non-exclusive sense, i.e., "including but not limited to".

[0133] 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 that 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.

[0134] 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. Tritium labeling (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 18F 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 unlabeled reagents with isotopically labeled reagents by procedures similar to those in the protocols and / or examples disclosed below.

[0135] 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.

[0136] 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.

[0137] The pharmaceutical compositions of the present disclosure can be manufactured by methods well known in the art, such as conventional mixing, dissolving, granulating, emulsifying, lyophilizing methods, etc.

[0138] 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.

[0139] 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.

[0140] The pharmaceutical composition is also suitable for parenteral administration, such as sterile solutions, suspensions or lyophilized products in suitable unit dosage forms.

[0141] 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.

[0142] In all methods of administration of the compounds of general formula (I) described herein, in the case of oral administration, the daily dose is from 0.001 mg / kg to 5000 mg / kg body weight, preferably from 0.01 mg / kg to 100 mg / kg body weight, in the form of a single or divided dose. The daily dose and the unit dose are varied according to a number of 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.

[0143] 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 substitution methods well known to those skilled in the art. Preferred embodiments include but are not limited to the examples of the present disclosure.

[0144] The chemical reactions of the specific embodiments of the present disclosure are carried out in a suitable solvent, which 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, it is sometimes necessary for those skilled in the art to modify or select the synthesis steps or reaction processes on the basis of the existing embodiments.

[0145] The following abbreviations are used in the present disclosure:

[0146] BnBr represents benzyl bromide; Bn represents benzyl; DMAP represents 4-dimethylaminopyridine; DMF represents N,N-dimethylformamide; DCM represents dichloromethane; TFA represents trifluoroacetic acid; TFAA represents trifluoroacetic anhydride; 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; EA represents ethyl acetate; HATU represents O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea); BOC represents tert-butylcarbonyl; IC 50 represents the half 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. Specific Embodiments

[0147] The compounds of the present disclosure can be prepared by a variety of synthetic methods well-known to those skilled in the art, including the specific embodiments listed herein, the embodiments formed by their combination with other chemical synthesis methods, and the equivalent substitution methods well-known to those skilled in the art. Preferred embodiments include, but are not limited to, the examples of the present disclosure.

[0148] 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 specific embodiments thereof 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 embodiments 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.

[0149] Unless otherwise stated, the ratio represented by the mixed solvent is the volume mixing ratio.

[0150] Unless otherwise stated, % refers to weight percentage wt%.

[0151] The compounds were named manually or by software, and commercially available compounds were named using the supplier's catalog name.

[0152] The structures of the compounds were 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 measurement are deuterated dimethyl sulfoxide, deuterated chloroform, deuterated methanol, etc., and the internal standard is tetramethylsilane (TMS);

[0153] 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.

[0154] Preparation Example 1 Synthesis of Intermediate (Difluoro(2-((4-nitrophenoxy)carbonyl)benzo[b]thiophen-5-yl)methyl)phosphonic Acid (Compound I)

[0155]

[0156] Step 1: Synthesis of Benzyl 5-bromobenzo[b]thiophene-2-carboxylate (Compound I-2)

[0157] 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 completed. 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).

[0158] 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).

[0159] Step 2: Synthesis of benzyl 5-iodobenzo[b]thiophene-2-carboxylate (Compound I-3)

[0160] 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).

[0161] Step 3: Synthesis of benzyl 5-(diethoxyphosphoryl)difluoromethyl)benzo[b]thiophene-2-carboxylate (Compound I-4)

[0162] Cadmium powder (2.49 g, 22.20 mmol) was added to a three-necked flask, an argon balloon was installed, and the gas was displaced 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 displaced three times. Under argon protection, the above newly prepared organocadmium reagent solution was added, and the resulting reaction solution was placed in an oil bath at 30 °C for reaction 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 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, petroleum ether / ethyl acetate = 3 / 1) to obtain compound I-4 (1.82 g).

[0163] MS m / z(ESI):=455.0[M+H] + 。

[0164] 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).

[0165] Step 4: Synthesis of 5-((diethoxyphosphoryl)difluoromethyl)benzo[b]thiophene-2-carboxylic acid (Compound I-5)

[0166] 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 displace 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).

[0167] MS m / z(ESI):=363.0[M-H] - 。

[0168] Step 5: Synthesis of 5-((diethoxyphosphoryl)difluoromethyl)benzo[b]thiophene-2-carboxylic acid (4-nitrophenyl) ester (Compound I-6)

[0169] 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 with dichloromethane three times (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).

[0170] 1 H 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).

[0171] Step 6: Synthesis of (difluoro(2-((4-nitrophenoxy)carbonyl)benzothiophen-5-yl)methyl)phosphonic acid (Compound I)

[0172] 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 a 1 mL mixture 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).

[0173] MS m / z (ESI): = 427.9 [M-H] - 。

[0174] 1 H 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).

[0175] Synthesis of the intermediate of Preparation Example 2, trans-4-phenylpyrrolidine-3-carbonitrile (Compound II)

[0176]

[0177] Step 1: Synthesis of trans-1-benzyl-4-phenylpyrrolidine-3-carbonitrile (Compound II-2)

[0178] 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. The reaction mixture was stirred at room temperature for 12 hours. LC-MS indicated the completion of the reaction. The reaction was quenched by adding saturated aqueous sodium bicarbonate solution, and then extracted with dichloromethane 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 / ethyl acetate = 19 / 1) to obtain Compound II-2 (1.01 g).

[0179] MS m / z (ESI): = 263.1 [M+H] + 。

[0180] 1 H 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).

[0181] Step 2: Synthesis of trans-4-phenylpyrrolidine-3-carbonitrile (Compound II)

[0182] 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. Then, an argon balloon was installed and the gas was replaced three times. The reaction mixture was reacted at 70 °C for 12 hours under argon protection. After completion, the reaction mixture was concentrated under reduced pressure. Then, the reaction mixture was slowly added dropwise to methanol (25 mL) at room temperature, and stirred at room temperature for 10 minutes and then transferred to 70 °C for 1 hour. LC-MS indicated the completion of the reaction. The reaction was quenched by adding saturated aqueous sodium bicarbonate solution, and then 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, dichloromethane / methanol = 19 / 1) to obtain Compound II (1.67 g).

[0183] MS m / z (ESI): = 173.1 [M+H] + 。

[0184] 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).

[0185] Synthesis of Intermediate (S)-N-(2,5-dioxotetrahydrofuran-3-yl)-2,2,2-trifluoroacetamide (Compound III) in Preparation Example 3

[0186]

[0187] Compound III-1 (5 g, 37.57 mmol) was added to a reaction flask, dissolved in trifluoroacetic acid (15 mL), then cooled in a -10 °C cold trap. Trifluoroacetic anhydride (22.09 g, 105.18 mmol) was added with stirring. The reaction was maintained at this temperature for 1.5 hours, then heated to 45 °C for 2 hours, and then transferred to room temperature for 16 hours. The resulting reaction solution was concentrated under reduced pressure to obtain Compound III (7.79 g), which was used directly in the next step without purification.

[0188] 1 1H NMR (400 MHz, DMSO-d6) δ 10.26 (d, J = 7.8 Hz, 1H), 5.06–4.94 (m, 1H), 3.41–3.28 (m, 1H), 3.17–3.06 (m, 1H).

[0189] Synthesis of Compound IV in Preparation Example 4

[0190]

[0191] Step 1: Synthesis of Compound IV-2

[0192] Butyryl chloride (13.29 ml, 127.99 mmol), triethylamine (17.86 ml, 127.99 mmol), and dichloromethane (100 ml) were added to a reaction flask, and then the gas was replaced with an argon balloon three times. Starting material IV-1 (10 g, 127.99 mmol) was slowly added at -78 °C. 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 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 IV-2 (7.56 g).

[0193] 11H 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).

[0194] Step 2: Synthesis of Compound IV

[0195] The starting material IV-2 (1 g, 6.75 mmol), triphenylphosphine (1.77 g, 6.75 mmol), and dichloromethane (20 ml) were added to a reaction flask, and then N-iodosuccinimide (1.52 g, 6.75 mmol) was added at 0 °C. The reaction mixture was stirred at room temperature for 1 hour. Then it was quenched with saturated aqueous 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 Intermediate IV (1.37 g).

[0196] 1 1H 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).

[0197] Synthesis of Compound V in Preparation Example 5

[0198]

[0199] Step 1: Synthesis of Compound V-2

[0200] Compound V-1 (240 mg, 0.66 mmol) and perfluorophenol (145.5 mg, 0.79 mmol) were added to a reaction flask, dissolved in anhydrous dichloromethane (3 mL), and 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 mixture was reacted overnight at room temperature. The reaction was monitored by LC-MS until completion. The reaction mixture was concentrated under reduced pressure and purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 4 / 1) to obtain Compound V-2 (220 mg).

[0201] MS m / z (ESI): = 531.0 [M + H] + 。

[0202] 1H NMR (400MHz, CDCl3) δ8.44–8.35(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=7.1Hz,6H).

[0203] Step 2: Synthesis of Compound V-3

[0204] Compound V-2 (220 mg, 0.41 mmol) was added to the reaction bottle, N, O-bis (trimethylsilyl) trifluoroacetamide (534 mg, 2.07 mmol) and anhydrous dichloromethane (2.5 mL) were added, and then an argon balloon was installed, the gas was replaced three times, and the gas was protected, and then it was placed in an ice bath to cool, and trimethylsilyl iodide (332 mg, 1.66 mmol) was added, and the ice bath was kept for 15 minutes, and then moved to room temperature for 15 minutes. LC-MS monitored the reaction to be complete. 3 mL of a mixed solution of water and acetonitrile (water: acetonitrile = 2: 1, containing 0.1% trifluoroacetic acid) was added to quench, and stirred at room temperature for 15 minutes. The mixture was transferred to a round-bottom flask, concentrated under reduced pressure to remove dichloromethane in the system, and then an appropriate amount of water and acetonitrile were added for freeze-drying to obtain compound V-3 (178 mg).

[0205] MS m / z(ESI):=472.9[MH] - .

[0206] 1 H NMR (400MHz, DMSO-d6) δ8.80(s,1H),8.35–8.27(m,2H),7.78–7.71(m,1H).

[0207] Step 3: Synthesis of Compound V-4

[0208] Compound V-3 (700 mg, 1.48 mmol) was added to a reaction flask, and tetrahydrofuran (4.5 mL) and water (9 mL) were added, and then Amberlite IR 120, Na resin cation exchange resin (4.60 g) was added. The resulting reaction solution was stirred at room temperature overnight, 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 was precipitated. The reaction was filtered, and the filter cake was collected and freeze-dried to obtain compound V-4 (940 mg).

[0209] Step 4: Preparation of Compound V

[0210] Compound V-4 (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 (Compound IV, 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 V (237 mg).

[0211] 1 H 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).

[0212] Example 1: Synthesis of ((2-(((3S,6S)-6-((trans)-3-cyano-4-phenylpyrrolidin-1-carbonyl)-4-oxo-1,2,3,4,6,7-hexahydroazepino[3,2,1-hi]indol-3-yl)carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphonic acid (Compound 1)

[0213]

[0214] Step 1: Synthesis of (S)-4-((S)-2-(methoxycarbonyl)indolin-1-yl)-4-oxo-3-(2,2,2-trifluoroacetamido)butanoic acid (Compound 1-2)

[0215] (S)-Methyl indoline-2-carboxylate (Compound 1-1, 2 g, 11.29 mmol) was dissolved in anhydrous ethyl acetate (100 mL), cooled in an ice bath, and then (S)-N-(2,5-dioxotetrahydrofuran-3-yl)-2,2,2-trifluoroacetamide (Compound III, 2.62 g, 12.42 mmol) was added. The resulting reaction solution was stirred at room temperature for 16 hours. LC-MS showed that the reaction was complete. The reaction solution was concentrated under reduced pressure and purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 1 / 1) to obtain Compound 1-2 (3.56 g).

[0216] MS m / z (ESI): = 389.0 [M+H] + 。

[0217] 11H NMR (400 MHz, CDCl3) δ 8.19 (d, J = 8.2 Hz, 1H), 7.45 (d, J = 8.8 Hz, 1H), 7.25–7.18 (m, 2H), 7.14–7.07 (m, 1H), 5.50–5.40 (m, 1H), 5.19–5.09 (m, 1H), 3.72 (s, 3H), 3.66–3.58 (m, 1H), 3.37 (d, J = 16.4 Hz, 1H), 3.14–3.06 (m, 1H), 2.88–2.81 (m, 1H).

[0218] Step 2: Synthesis of methyl (3S,6S)-1,4-dioxo-3-(2,2,2-trifluoroacetamido)-1,2,3,4,6,7-hexahydroazepino[3,2,1-hi]indole-6-carboxylate (Compound 1-3)

[0219] Compound 1-2 (2.2 g, 5.67 mmol) was added to a single-necked flask, dissolved in anhydrous 1,2-dichloroethane (25 mL), and oxalyl chloride (2.88 g, 22.66 mmol) and N,N-dimethylformamide (41.41 mg, 0.567 mmol) were added under stirring at room temperature. Then, an argon balloon was installed to displace the gas three times, and the mixture was stirred at room temperature for 2 hours under argon protection. A sample was taken and methanol was added, and the reaction was monitored by LC-MS to be complete. The reaction solution was concentrated under reduced pressure to remove the excess oxalyl chloride, and then dissolved in anhydrous 1,2-dichloroethane (50 mL), cooled in an ice bath, and anhydrous aluminum trichloride (3.40 g, 25.50 mmol) was added. The resulting reaction solution was reacted in an oil bath at 50 °C for 12 hours. The reaction solution was cooled, poured into ice water, and then extracted three times with ethyl acetate. The combined organic phases were 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 = 7 / 3 to 1 / 1) to obtain Compound 1-3 (525 mg).

[0220] MS m / z (ESI): = 371.0 [M + H] + 。

[0221] Compound 3: 1 1H NMR (400 MHz, CDCl3) δ 8.02 (d, J = 8.0 Hz, 1H), 7.74–7.64 (m, 1H), 7.51–7.46 (m, 1H), 7.26–7.22 (m, 1H), 5.48–5.38 (m, 1H), 4.94–4.86 (m, 1H), 3.78 (s, 3H), 3.68–3.57 (m, 1H), 3.35–3.16 (m, 3H).

[0222] Step 3: Synthesis of Methyl (3S,6S)-4-oxo-3-(2,2,2-trifluoroacetamido)-1,2,3,4,6,7-hexahydroazepino[3,2,1-hi]indole-6-carboxylate (Compound 1-4)

[0223] Dissolve Compound 1-3 (525 mg, 1.42 mmol) in trifluoroacetic acid (9 mL), add 10% Pd / C (106 mg), then install a hydrogen balloon, displace the gas three times, and stir at room temperature under a hydrogen atmosphere for 24 hours. Filter the reaction solution, concentrate the filtrate under reduced pressure, then dissolve it in ethyl acetate, pour it into water, separate the layers, extract the aqueous phase with ethyl acetate three times, combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify by column chromatography (silica gel, petroleum ether / ethyl acetate = 83 / 17) to obtain Compound 1-4 (200 mg).

[0224] MS m / z (ESI): = 357.1 [M+H] + 。

[0225] 1 H NMR (400 MHz, CDCl3) δ 7.98–7.81 (m, 1H), 7.15–7.00 (m, 3H), 5.34–5.25 (m, 1H), 4.49–4.39 (m, 1H), 3.76 (s, 3H), 3.58–3.46 (m, 1H), 3.47–3.33 (m, 1H), 3.25–3.11 (m, 2H), 2.50–2.37 (m, 1H), 2.28–2.12 (m, 1H).

[0226] Steps 4 and 5: Synthesis of (3S,6S)-3-((tert-Butoxycarbonyl)amino)-4-oxo-1,2,3,4,6,7-hexahydroazepino[3,2,1-hi]indole-6-carboxylic Acid (Compound 1-6)

[0227] Compound 1-4 (200 mg, 0.561 mmol) was dissolved in a mixed solvent of tetrahydrofuran (3.6 mL) and water (1.8 mL). Lithium hydroxide monohydrate (141.32 mg, 3.37 mmol) was added, and the resulting reaction mixture was stirred at room temperature for 2 hours. The reaction was monitored by LC-MS and was found to be complete. The pH of the system was adjusted to 3 with 1 M dilute hydrochloric acid, and then sodium carbonate (178.48 mg, 1.68 mmol) and di-tert-butyl dicarbonate (367.53 mg, 1.68 mmol) were added. The resulting reaction mixture was stirred overnight at room temperature, and the reaction was monitored by LC-MS and was found to be complete. The reaction mixture was poured into ice water, the pH of the system was adjusted to 3 with 1 M dilute hydrochloric acid, and then it was extracted with ethyl acetate multiple times. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a colorless oil. The oil was triturated with petroleum ether, filtered, the filter cake was collected, and dried to obtain compound 1-6 (180 mg).

[0228] MS m / z (ESI): = 291.1 [M+H-56] + 。

[0229] 1 H NMR (400 MHz, CDCl3) δ 7.12–6.98 (m, 3H), 5.92–5.77 (m, 1H), 5.34–5.24 (m, 1H), 4.35–4.23 (m, 1H), 3.50–3.41 (m, 1H), 3.40–3.20 (m, 2H), 3.16–3.03 (m, 1H), 2.42–2.30 (m, 1H), 2.18–2.03 (m, 1H), 1.45 (s, 9H).

[0230] Step 6: Synthesis of tert-butyl ((3S,6S)-6-((trans)-3-cyano-4-phenylpyrrolidine-1-carbonyl)-4-oxo-1,2,3,4,6,7-hexahydroazepino[3,2,1-hi]indol-3-yl)carbamate (Compound 1-7)

[0231] Compound 1-6 (100 mg, 0.289 mmol) and trans-4-phenylpyrrolidine-3-carbonitrile (Compound II, 59.67 mg, 0.346 mmol) were added to a reaction flask, dissolved in anhydrous N,N-dimethylformamide (2.5 mL), and N,N-diisopropylethylamine (111.94 mg, 0.866 mmol) and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (141.59 mg, 0.375 mmol) were added under stirring at room temperature. The resulting reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into water, extracted three times 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 gel, petroleum ether / ethyl acetate = 1 / 1) to obtain Compound 1-7 (140 mg).

[0232] MS m / z (ESI): = 401.1 [M+H-100] + 。

[0233] 1 1H NMR (400 MHz, CDCl3) δ 7.47–7.30 (m, 5H), 7.09–6.93 (m, 3H), 5.89–5.74 (m, 1H), 5.35–5.21 (m, 1H), 4.61–4.18 (m, 2H), 4.13–3.59 (m, 4H), 3.55–3.43 (m, 1H), 3.37–2.95 (m, 4H), 2.41–2.28 (m, 1H), 2.25–2.10 (m, 1H), 1.46 (s, 9H).

[0234] Step 7: Synthesis of 1-((3S,6S)-3-amino-4-oxo-1,2,3,4,6,7-hexahydroazepino[3,2,1-hi]indole-6-carbonyl)-(trans)-4-phenylpyrrolidine-3-carbonitrile (Compound 1-8)

[0235] Compound 1-7 (140 mg, 0.280 mmol) was dissolved in dichloromethane (1 mL), and trifluoroacetic acid (0.2 mL) was added under stirring at room temperature. The resulting reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure to obtain crude Compound 1-8 (200 mg), which was used directly in the next step without purification.

[0236] MS m / z (ESI): = 401.1 [M+H] + 。

[0237] Step 8: Synthesis of ((2-(((3S,6S)-6-((trans)-3-cyano-4-phenylpyrrolidin-1-carbonyl)-4-oxo-1,2,3,4,6,7-hexahydroazepino[3,2,1-hi]indol-3-yl)carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphonic acid (Compound 1)

[0238] Add compound 1-8 (12 mg, 0.03 mmol) into a reaction flask, dissolve it with N,N-dimethylformamide (0.2 mL), add N,N-diisopropylethylamine (24.11 mg, 0.187 mmol) and (difluoro(2-((4-nitrophenoxy)carbonyl)benzo[b]thiophen-5-yl)methyl)phosphonic acid (Compound I, 10 mg, 0.023 mmol) under stirring at room temperature. Stir the resulting reaction solution at room temperature for 2 hours. Monitor the completion of the reaction by LC-MS. Filter the reaction solution and purify it by preparative HPLC [YMC TAR-C18 column, 30 mm in diameter, 150 mm in length, using a mixed solution of water (containing 7 mmol / L NH4HCO3) and acetonitrile (acetonitrile content: 30%-60%) as the eluent], and lyophilize to obtain the target compound 1 (6 mg).

[0239] MS m / z (ESI): = 691.1 [M+H] + 。

[0240] 1 1H NMR (400 MHz, DMSO-d6) δ 9.21–9.09 (m, 1H), 8.32–8.23 (m, 1H), 8.11–8.04 (m, 1H), 8.03–7.96 (m, 1H), 7.70–7.61 (m, 1H), 7.55–7.29 (m, 5H), 7.16–7.06 (m, 2H), 7.04–6.95 (m, 1H), 5.42–5.21 (m, 1H), 4.71–4.56 (m, 1H), 4.39–4.08 (m, 1H), 4.03–3.77 (m, 3H), 3.75–3.54 (m, 4H), 3.09–2.91 (m, 2H), 2.29–2.16 (m, 2H).

[0241] Example 2: Synthesis of Compound 2

[0242]

[0243] Step 1: Synthesis of Compound 2-2

[0244] Compound 2-1 (66 mg, 0.33 mmol), compound 1-6 (115 mg, 0.33 mmol), N,N-diisopropylethylamine (232 μL, 1.33 mmol), and N,N-dimethylformamide (1 mL) were added to a reaction flask. Then, O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (118 mg, 0.31 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 = 3 / 1) to obtain compound 2-2 (110 mg).

[0245] MS m / z (ESI): = 549.2 [M+Na] + 。

[0246] 1 1H NMR (400 MHz, CDCl3) δ 7.51–7.34 (m, 5H), 7.08–6.90 (m, 3H), 5.90–5.70 (m, 1H), 5.27–5.17 (m, 1H), 4.30–4.20 (m, 1H), 3.90–3.65 (m, 1H), 3.57–3.36 (m, 2H), 3.36–3.22 (m, 1H), 3.19–3.06 (m, 1H), 3.03–2.92 (m, 1H), 2.46–2.28 (m, 2H), 2.25–2.10 (m, 1H), 1.96–1.56 (m, 2H), 1.46 (s, 9H), 1.12–0.96 (m, 1H), 0.74–0.63 (m, 1H).

[0247] Step 2: Synthesis of compound 2-3

[0248] Compound 2-2 (30 mg, 56.97 μmol) and dichloromethane (1 mL) were added to a reaction flask. Then, trifluoroacetic acid (0.5 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 2-3 (40 mg), which was used directly in the next step without further purification.

[0249] MS m / z (ESI): = 427.2 [M+H] + 。

[0250] Step 3: Synthesis of compound 2

[0251] Compound 2-3 (25 mg, 58.62 μmol), compound V (44.7 mg, 58.62 μmol), N,N-diisopropylethylamine (20.4 μL, 117.23 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 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, petroleum ether / ethyl acetate = 50 / 50) to obtain compound 2 (28 mg).

[0252] 1 H NMR (400 MHz, Chloroform-d) δ 8.12 (s, 1H), 7.97 (d, J = 8.6 Hz, 1H), 7.91 (d, J = 1.9 Hz, 1H), 7.71–7.63 (m, 2H), 7.53–7.34 (m, 5H), 7.14–6.98 (m, 3H), 5.26 (s, 1H), 4.67–4.52 (m, 2H), 4.29–4.12 (m, 5H), 3.93–3.70 (m, 2H), 3.49 (dd, J = 42.5, 10.1 Hz, 3H), 3.23–3.11 (m, 4H), 3.02 (t, J = 14.2 Hz, 1H), 2.49 (s, 1H), 2.43 (d, J = 7.1 Hz, 4H), 2.26 (d, J = 12.9 Hz, 1H), 2.19–2.09 (m, 2H), 1.98 (s, 1H), 1.19–0.99 (m, 2H), 0.94 (d, J = 6.7 Hz, 12H), 0.75 (d, J = 20.4 Hz, 1H).

[0253] Example 3: Synthesis of Compound 3

[0254]

[0255] Compound 2-3 (39 mg, 91.44 μmol), compound V-3 (26.69 mg, 56.27 μmol), N,N-diisopropylethylamine (39.2 μL, 225.08 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 Prep-HPLC [YMC TAR-C18 column, 30 mm diameter, 150 mm length, using a mixture of water (containing 7 mmol / L NH4HCO3) and acetonitrile (acetonitrile content: 30%-60%) as the eluent] to obtain the target compound 3 (21 mg).

[0256] MS m / z (ESI): = 715.1 [M-H] - 。

[0257] 1 H NMR (400 MHz, DMSO-d6) δ 9.21 (t, J = 6.8 Hz, 1H), 8.27 (s, 1H), 8.06 (s, 1H), 7.98 (d, J = 8.5 Hz, 1H), 7.64 (d, J = 8.7 Hz, 1H), 7.60–7.50 (m, 2H), 7.49–7.28 (m, 3H), 7.10 (t, J = 7.9 Hz, 2H), 6.98 (t, J = 7.5 Hz, 1H), 5.36–5.17 (m, 1H), 4.67–4.55 (m, 1H), 4.42–4.17 (m, 1H), 4.13–4.00 (m, 1H), 3.94–3.76 (m, 2H), 3.76–3.66 (m, 1H), 3.18–3.05 (m, 2H), 3.03–2.88 (m, 1H), 2.28–1.99 (m, 3H), 1.73–1.55 (m, 1H), 0.92–0.74 (m, 1H), 0.74–0.56 (m, 1H).

[0258] Example 4: Synthesis of Compound 4

[0259]

[0260] The starting materials, compound 2-3 (20 mg, 46.89 μmol), compound 4-1 (21.4 mg, 46.89 μmol), N,N-diisopropylethylamine (32.7 μL, 187.57 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 filtered, and the filtrate was concentrated under reduced pressure and purified by Prep-HPLC [YMC TAR-C18 column, 30 mm diameter, 150 mm length, using a mixture of water (containing 7 mmol / L NH4HCO3) and acetonitrile (acetonitrile content: 30%-60%) as the eluent] to obtain the target compound 4 (8 mg).

[0261] MS m / z (ESI): = 699.2 [M+H] + 。

[0262] 1 H NMR (400 MHz, DMSO-d6) δ 9.25–9.10 (m, 1H), 8.22 (s, 1H), 7.97–7.84 (m, 2H), 7.60–7.49 (m, 3H), 7.44–7.31 (m, 3H), 7.09 (t, J = 8.2 Hz, 2H), 6.98 (t, J = 7.5 Hz, 1H), 5.57–5.39 (m, 1H), 5.34–5.19 (m, 1H), 4.64–4.54 (m, 1H), 4.41–4.27 (m, 1H), 4.12–4.03 (m, 1H), 3.90–3.80 (m, 2H), 3.76–3.70 (m, 1H), 3.23–3.16 (m, 1H), 3.15–3.07 (m, 1H), 3.00–2.90 (m, 1H), 2.25–2.15 (m, 2H), 2.15–2.04 (m, 1H), 1.74–1.57 (m, 1H), 0.86–0.73 (m, 1H), 0.72–0.61 (m, 1H).

[0263] Example 5: Synthesis of Compound 5

[0264]

[0265] Compound 1-7 (35 mg, 69.92 μmol), compound 5-2 (23.9 mg, 49.94 μmol), N,N-diisopropylethylamine (34.8 μL, 199.76 μmol), and N,N-dimethylformamide (0.5 mL) were added to a reaction flask. Then, O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (28.3 mg, 74.91 μmol) was added, and the reaction mixture was stirred at room temperature for 1 h. After completion of the reaction as monitored by LC-MS, the reaction mixture was quenched with saturated aqueous ammonium chloride solution and extracted three times with ethyl acetate (10 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 1 / 3) to give product 5 (15 mg).

[0266] MS m / z (ESI): = 862.2 [M+H] + 。

[0267] 1 H NMR (400 MHz, DMSO-d6) δ 9.25–9.12 (d, J = 9.3 Hz, 1H), 8.36–8.27 (m, 1H), 8.18–8.05 (m, 2H), 7.63 (d, J = 8.3 Hz, 1H), 7.55–7.27 (m, 7H), 7.26–7.07 (m, 5H), 7.04–6.96 (m, 1H), 6.34–6.08 (m, 2H), 5.41–5.21 (m, 1H), 4.72–4.59 (m, 1H), 4.31–4.08 (m, 1H), 3.94–3.82 (m, 3H), 3.77–3.62 (m, 2H), 3.61–3.43 (m, 2H), 3.29–3.10 (m, 2H), 2.28–2.14 (m, 2H), 1.56–1.39 (m, 2H), 1.35–1.21 (m, 2H), 1.21–1.10 (m, 2H), 1.00–0.92 (m, 1H), 0.88–0.75 (m, 3H).

[0268] Example 6: Synthesis of Compound 6

[0269]

[0270] Compound 2-3 (42 mg, 98.5 μmol), compound 5-2 (28.10 mg, 58.62 μmol), N,N-diisopropylethylamine (40.8 μL, 234.46 μmol), and N,N-dimethylformamide (0.5 mL) were added to a reaction flask, and then O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (33.17 mg, 87.92 μmol) was added. The reaction mixture was stirred at room temperature for 1 h. 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, petroleum ether / ethyl acetate = 3 / 7) to give the product compound 6 (14 mg).

[0271] MS m / z (ESI): = 888.3 [M+H] + 。

[0272] 1 H NMR (400 MHz, DMSO-d6) δ 9.22 (s, 1H), 8.30 (s, 1H), 8.19–8.03 (m, 2H), 7.63 (d, J = 8.6 Hz, 1H), 7.59–7.48 (m, 2H), 7.48–7.27 (m, 5H), 7.26–7.05 (m, 5H), 6.99 (t, J = 7.5 Hz, 1H), 6.31–6.08 (m, 2H), 5.37–5.16 (m, 1H), 4.69–4.56 (m, 1H), 4.24–3.94 (m, 2H), 3.91–3.65 (m, 4H), 3.19–3.06 (m, 1H), 3.03–2.87 (m, 1H), 2.29–2.14 (m, 2H), 2.10–2.03 (m, 1H), 1.74–1.57 (m, 1H), 1.56–1.38 (m, 2H), 1.31–1.08 (m, 4H), 0.95 (d, J = 7.2 Hz, 1H), 0.89–0.73 (m, 4H), 0.72–0.60 (m, 1H).

[0273] Biological Test Experiment

[0274] Test Example 1 Detection of the inhibitory effect of the compound on the binding of STAT6 to the peptide by the HTRF method

[0275] 1. Experimental Materials

[0276] Dilution buffer: 50 mM HEPES, 150 mM NaCl, 0.03% Tween-20, 1 mM DTT, 0.1% BSA.

[0277] 2. Experimental Procedures

[0278] Preparation of compound working solution: The initial concentration of the compound was 100 μM (solvent: DMSO), and it was serially diluted with DMSO at a 3-fold dilution factor for a total of 7 points. Then, each concentration of the compound was further diluted 25-fold with dilution buffer to form the compound working solution (containing 4% DMSO). In a 384-well white flat-bottom plate (Perkinelmer, part number: 6007290), 5 μL / well of the compound working solution with a concentration gradient, 5 μL / well of the protein his-TEV-STAT6 (STAT6 (W123-T658)) (in-house, batch number: 20231117703) (working concentration prepared with dilution buffer: 600 nM), and 5 μL / well of the peptide 5-FAM-ApYKPFQDLI (Gill, part number: 1122994) (working concentration prepared with dilution buffer: 600 nM) were added successively. After mixing, it was centrifuged at 1000 rpm for 2 minutes at room temperature. After sealing the plate, the reaction mixture was placed on a shaker and incubated with shaking at 300 rpm for 30 minutes at room temperature. Then, 5 μL of MAb Anti-6HIS-Tb cryptate Gold (CisBio, part number: 61HI2TLF) (working concentration prepared with dilution buffer: 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 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 control group was replaced with dilution buffer containing 4% DMSO instead of the compound working solution, and the other reagents remained unchanged. The fluorescence intensities at an excitation wavelength of 340 nm, emission wavelengths of 495 nm and 520 nm were detected in HTRF mode using a microplate reader (Perkinelmer, model Envision). The HTRF ratio 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% to calculate the inhibition percentage of the compound at each concentration and the maximum inhibition rate E 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 prepared in Example 1 has good inhibitory ability on the function of STAT6 protein.

[0279] Table 1. IC of compound inhibiting the binding of STAT6 to peptide 50

[0280] Test Compound <![CDATA[IC 50 (μM)]]> Compound 1 0.166 Compound 3 0.057

[0281] Test Example 2 Detection of the inhibitory effect of compounds on the binding of STAT3 to peptide by HTRF method

[0282] 1. Experimental materials

[0283] Dilution buffer: 50 mM HEPES, 150 mM NaCl, 0.03% Tween-20, 1 mM DTT, 0.1% BSA.

[0284] 2. Experimental procedures

[0285] Preparation of compound working solution: The initial concentration of the compound is 5 mM (the solvent is DMSO), and it is diluted 3-fold with DMSO, with a total of 8 points. Then, the compounds at each concentration are 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, product number: ST3-H5149) (the working concentration prepared with the dilution buffer is 100 nM), and 5 μL / well of the peptide 5-FAM-GpYLPQTV (Gill, product number: 1120697) (the working concentration prepared with the dilution buffer is 200 nM) are added successively to a 384-well white flat-bottom plate (Perkinelmer, product number: 6007290). After mixing, centrifuge at 1000 rpm for 2 minutes at room temperature. Place the reactants on a shaker and incubate at 300 rpm with shaking at room temperature for 30 minutes. Add 5 μL of MAb Anti-6HIS-Tb cryptate Gold (CisBio, product number: 61HI2TLF) (the working concentration prepared with the dilution buffer is 1.32 nM) to each well. After mixing, centrifuge at 1000 rpm for 2 minutes at room temperature and continue to incubate at 300 rpm with shaking at room temperature for 1 hour. The final volume of the experimental system is 20 μL, the initial and final concentrations of the compound are 50 μM, with a 3-fold gradient, and the final concentration of DMSO is 1%. The solvent group uses the dilution buffer containing 4% DMSO to replace the compound working solution, and the other reagents remain unchanged. Use a microplate reader (Perkinelmer, model Envision) to detect the fluorescence intensities at the excitation wavelength of 340 nm, emission wavelengths of 495 nm and 520 nm in the 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% 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.

[0286] Table 2. IC 50

[0287] Test Compound <![CDATA[IC 50 (μM)]]> Compound 1 2.390 Compound 3 >30

Claims

1. A compound of formula (I) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, in: is a double bond or a single bond; t, q are independently selected from 0, 1 and 2; p is 1 or 2; X 1 Selected from CH2, O, S, S(O), SO2, and NR 7 ; X 2 is selected from N, C or CH; Ring A is selected from C3-C 12 Saturated carbocyclic ring, 4-10 membered heterocyclic ring, C6-C 10 Aromatic ring and 5-12 membered heteroaromatic ring, the C3-C 12 Saturated carbocyclic ring, 4-10 membered heterocyclic ring, C6-C 10 The aromatic ring and the 5-12 membered heteroaromatic ring are optionally replaced by R a replace; R a independently selected from halogen, COOH, hydroxy, cyano, =O, C1-C4 alkyl, C1-C4 alkoxy and C1-C4 haloalkyl; R 1 and R 2 independently selected from hydrogen, halogen, hydroxy, cyano, =O, 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 1a R 1b , 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 heterocyclic group are optionally replaced by R S replace; R 3 is selected from the group consisting of hydrogen, halogen, COOH, hydroxy, cyano, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 haloalkyl and C1-C4 hydroxy-substituted alkyl; R 4 is selected from hydrogen, phenyl and C1-C4 alkyl; R 7 is selected from hydrogen, C1-C4 alkyl, C1-C4 haloalkyl and 4-10 membered heterocyclyl; R 5 and R 6 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 Q independently selected from halogen, cyano, hydroxyl, C2-C4 alkenyl, C1-C4 alkyl, C1-C4 alkoxy, C6-C 10 Aryl, 4-9 membered heterocyclic and 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 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, C1-C4 alkyl, C1-C4 alkoxy group is optionally replaced by R M Substitution, the C6-C 10 Aryl, 5-10 membered heteroaryl, C3-C6 cycloalkyl and 4-9 membered heterocyclic groups are optionally replaced by R F replace; Ring B is selected from C6-C 10 Aryl, 8-10 membered heterocyclic group and 8-10 membered heteroaryl, the C6-C 10 Aryl, 8-10 membered heterocyclyl and 8-10 membered heteroaryl are optionally substituted with amino, halogen, cyano, C1-C4 alkyl or C1-C4 alkoxy; W is selected from -CR 2a R 3a P(O)OR 2b OR 3b 、-CR 2a R 3a P(O)[OR 2b [NH(AA)C(O)OR T 、-P(O)OR 2b OR 3b 、-[P(O)[NHR Ty [NH(AA)C(O)OR T 和-P(O)[OR 2b [NH(AA)C(O)OR T ; R 2a and R 3a is independently selected from hydrogen, halogen, cyano, C1-C4 alkyl, C1-C4 haloalkyl and C1-C4 hydroxyalkyl, or R 2a and R 3a co-form = O; R 2b and R 3b 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)-OH, -(C1-C4 alkylene)-OC(O)O-(C1-C4 alkylene)-O-(C1-C4 alkyl), -(C1-C4 alkylene)-SC(O)-(C1-C4 alkyl), -(C1-C4 alkylene)-SC(O)-[(C1-C4)haloalkyl], -(C1-C4 alkylene)-SC(O)-(C1-C4 alkylene)-OH, -(C1-C4 alkylene)-SC(O)-(C1-C4 alkylene)-O-(C1-C4 alkyl), -(C1-C4 alkylene)-OC(O)NH(C1-C4 alkyl), -(C1-C4 alkylene)-OC(O)N(C1-C4 alkyl)2, C6-C 10 Aryl and 5-6 membered heteroaryl, the C6-C 10 The aryl and 5-6 membered heteroaryl groups are optionally substituted with halogen, cyano or C1-C4 alkyl groups, and the 5-7 membered heterocyclyl in the (C1-C4 alkylene)-OC(O)O-[5-7 membered heterocyclyl] and (C1-C4 alkylene)-OC(O)-[5-7 membered heterocyclyl] is optionally substituted with C(O)OR h replace; 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 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, 5-10 membered heteroaryl are optionally replaced by R X replace; R F , R S and R X 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 1a , R 1b , 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, wherein the C1-C4 alkyl is optionally substituted with halogen, cyano, hydroxyl or phenyl, and 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: It is a single bond.

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: p is 1.

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: t is either 0 or 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: q is 1 or 2.

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: X 1 Selected from CH2, O and NR 7 .

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 7 is selected from hydrogen, C1-C4 alkyl and C1-C4 haloalkyl; or R 7 It's hydrogen.

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: X 1 It is CH2.

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: X 2 Selected from N and C; or X 2 It is C.

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: Ring A is selected from 4-10 membered heterocyclic ring, C6-C 10 Aromatic ring and 5-12 membered heteroaromatic ring, the 4-10 membered heterocyclic ring, C6-C 10 The aromatic ring and the 5-12 membered heteroaromatic ring are optionally replaced by R a or ring A is selected from 5-6 membered heterocyclic ring, C6-C 10 Aromatic ring and 5-6 membered heteroaromatic ring, the 5-6 membered heterocyclic ring, C6-C 10 The aromatic ring and the 5-6 membered heteroaromatic ring are optionally replaced by R a or ring A is selected from a benzene ring, a pyridine ring, a dihydropyridine ring and an imidazole ring, wherein the benzene ring, the pyridine ring, the dihydropyridine ring and the imidazole ring are optionally replaced by R a substituted; or ring A is selected from a benzene ring, a pyridine ring, pyridin-2(1H)-one and an imidazole ring; or ring A is selected from a benzene ring or a pyridine ring.

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: R a is independently selected from halogen, COOH, hydroxy, cyano, =O and C1-C4 alkyl; or R a is =O.

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: R 1 and R 2 It is hydrogen or =O.

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 4 is selected from hydrogen and C1-C4 alkyl; or R 4 It's 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 5 and R 6 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 5 and R 6 Together with the nitrogen atom to which they are attached, they form a 4-10 membered heterocyclic group, wherein the 4-10 membered heterocyclic group is optionally substituted by R Q Replace; or R 5 and R 6 Together with the nitrogen atom to which they are attached, they form a 5-7 membered heterocyclic group, wherein the 5-7 membered heterocyclic group is optionally substituted by R Q Replace; or R 5 and R 6 Together with the nitrogen atom to which they are attached, they form a 5-6 membered heterocyclic group, wherein the 5-6 membered heterocyclic group is optionally substituted by R Q Replace; or R 5 and R 6 Together with the N atoms to which they are attached, they form Said Optional R Q Replace; or R 5 and R 6 Together with the N atoms to which they are attached, they form Said Optional R Q replace.

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 independently selected from halogen, cyano, hydroxyl, C2-C4 alkenyl, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy and C6-C 10 or R Q are independently selected from cyano and phenyl.

16. The compound of formula (I) according to any one of claims 1 to 15, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: Ring B is selected from Said Optionally substituted with amino, halogen, cyano, C1-C4 alkyl or C1-C4 alkoxy; or Ring B is selected from Or ring B is 17. The compound of formula (I) according to any one of claims 1 to 16, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: W is selected from -CR 2a R 3a P(O)OR 2b OR 3b and-CR 2a R 3a P(O)[OR 2b ][NH(AA)C(O)OR T ]; or W is selected from -CR 2a R 3a P(O)OR 2b OR 3b ; or W is selected from Or W is selected from 18. The compound of formula (I) according to any one of claims 1 to 17, 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-C4 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 and -(C1-C4 alkylene)-SC(O)-(C1-C4 alkyl).

19. 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, X 1 , X 2 , R 1 , R 3 , R 4 , R 5 , R 6 , Ring A, Ring B and W are as defined in claims 1-18.

20. 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 (III) or its stereoisomer or its pharmaceutically acceptable salt: Among them, q, X 1 , R 4 , R 5 , R 6 , Ring B and W are as defined in claims 1-18, and X is independently selected from N or CH.

21. The compound of formula (I) according to claim 1 or its stereoisomer or a pharmaceutically acceptable salt thereof is selected from the following compounds or pharmaceutically acceptable salts thereof, 22. 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 21 and a pharmaceutically acceptable excipient.

23. Use of the compound of formula (I) according to any one of claims 1 to 21 or its stereoisomer or pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 22 in the preparation of a medicament for preventing or treating a STAT6-mediated disease.

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