Naphthalene ring derivative as Kappa receptor antagonist and composition and application thereof

Abstract

The present invention relates to a pyridino aryl or heteroaryl derivative having a Kappa receptor antagonistic activity. In particular, the present invention relates to a compound represented by general formula (I), a stereoisomer thereof, a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable salt of the stereoisomer. The invention also relates to a pharmaceutical composition containing the compound, a preparation method of the pharmaceutical composition, and a treatment method and application of diseases related to the antagonistic activity of the Kappa receptor, such as depression, depression with pleasant sensation deficiency, bipolar affective disorder, anxiety and other mental diseases. Wherein each substituent group in the general formula (I) is as defined in the specification.

Description

Technical Field

[0001] This invention relates to a bicyclic aryl or heteroaryl derivative with Kappa receptor antagonistic activity. The invention also relates to methods for preparing said bicyclic aryl or heteroaryl derivatives, pharmaceutical compositions, and treatment methods and uses for diseases related to Kappa receptor antagonistic activity, such as depression, depression with anhedonia, bipolar disorder, anxiety, and other mental illnesses. Background Technology

[0002] Opioid ligands act on four known opioid receptors: μ (MOR), δ (DOR), κ (KOR), and opioid-like peptide receptors (ORLs). These receptors all belong to the G protein-coupled receptor (GPCR) family and share a common seven-transmembrane helix structure. Among them, the κ receptor (KOR) primarily binds to its endogenous ligand—dynorphin. KOR is widely distributed in the brain, spinal cord, and peripheral tissues, particularly concentrated in brain regions associated with reward, cognitive function, and stress response. KOR plays a crucial role in regulating antisensory and various behavioral states, such as anxiety, depression, and substance abuse. Studies have shown that dynorphin levels increase under pain and stress conditions, and that disrupting KOR can produce anti-stress effects. Therefore, medicinal chemists have shown great interest in developing KOR antagonists, hoping to use them to treat depression, anxiety, addictive disorders, and other stress-related mental illnesses.

[0003] Extensive research has shown that KOR antagonists can effectively block stress-induced psychological adaptation. Stress leads to increased dynorphin expression in the nucleus accumbens (NAc), a key part of the mesolimbic system involved in the stimulation and pathological processes of psychosis. According to the literature (Depression and Anxiety, 33: 895-906, 2016), CREB-mediated increased dynorphin expression leads to depressive-like signs, which KOR antagonists can alleviate. Stress activates CREB in the NAc, thereby increasing dynorphin expression and enhancing KOR activation. KORs are expressed in the cell bodies and at the terminals of mesocorticolimbic dopamine (DA) neurons, and their activation inhibits DA release.

[0004] Treatment with KOR antagonists can block the action of dynorphin and restore dopamine (DA) function, thus demonstrating antidepressant and anxiolytic-like effects in various animal models. Therefore, KOR antagonists may offer more advantages than traditional antidepressants in treating major depressive disorder and disorders related to substance abuse or addiction, particularly major depressive disorder and its associated anhedonia. This presents significant prospects for the development of KOR antagonists and new treatment methods, potentially improving the treatment outcomes of related diseases. Summary of the Invention

[0005] This invention relates to a novel class of compounds that, as Kappa receptor antagonists, possess anti-neuropsychiatric activity, i.e., therapeutic or preventative effects against neuropsychiatric disorders. In some embodiments, the compounds of this invention exhibit good antagonistic activity against Kappa receptors. In some embodiments, the compounds of this invention possess favorable pharmacokinetic properties (e.g., suitable half-life, good plasma concentration, Kpuu, area under the curve, and / or bioavailability). In some embodiments, the compounds of this invention possess improved in vivo efficacy, and / or improved safety (lower toxicity and / or fewer side effects), and / or good patient compliance, and / or superior drug-like properties such as less susceptibility to tolerance.

[0006] Specifically, the antagonistic activity results of the Kappa receptor (KOR) of this disclosure indicate that the compound of the present invention is an effective Kappa receptor (KOR) antagonist with good antagonistic effect on the Kappa receptor (KOR). Mouse pharmacokinetic experiments showed that the compound of the present invention exhibits good drug metabolism properties, with an excellent half-life t1 / 2 and a rapid time to peak concentration Tmax. Furthermore, metabolic parameters such as maximum plasma concentration Cmax, area under the curve (AUC(0-t)), and oral bioavailability F all showed good performance. Compounds with good oral bioavailability are of great significance in reducing drug dosage, alleviating side effects, and improving drug efficacy.

[0007] On one hand, the present invention relates to a compound represented by formula (I),

[0008]

[0009] Or its stereoisomers, tautomers, pharmaceutically acceptable salts thereof, pharmaceutically acceptable salts of its stereoisomers, pharmaceutically acceptable salts of its tautomers, solvates thereof, prodrugs thereof, or deuterated derivatives thereof, wherein:

[0010] Each (R1, R2, R3, R4, R5, or R6) is independently selected from hydrogen, halogen, and -C each time it appears. 1-6 Alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl group, -C 1-6 Halogenated alkyl, -C 1-6 Halogenated alkoxy groups, -CN, -NO2, -NH2, -NH(C) 1-6 alkyl), -N(C) 1-6 alkyl)2、-NH(C 3-7 cycloalkyl), -OH, -O(C1-6 Alkyl), -O(C) 3-7 cycloalkyl), -SH, -S(C 1-6 alkyl), -S(C 3-7 cycloalkyl), -C(=O)(C 1-6 Alkyl), -S(=O)(C 1-6 Alkyl), -S(=O)2(C 1-6 Alkyl), -S(=O)(=NH)(C 1-6 Alkyl), -C(=O)OH, -C(=O)(OC 1-6 Alkyl), -OC (=O)(C 1-6 Alkyl groups), -C(=O)NH2, -C(=O)NH(C 1-6 Alkyl), -C(=O)N(C 1-6 Alkyl)2、-NHC(=O)(C 1-6 alkyl), -N(C) 1-6 Alkyl)C(=O)(C 1-6 Alkyl groups), -S(=O)NH2, -S(=O)NH(C 1-6 Alkyl), -S(=O)N(C 1-6 Alkyl)2、-NHS(=O)(C 1-6 alkyl), -N(C) 1-6 Alkyl)S(=O)(C 1-6 Alkyl groups), -S(=O)2NH2, -S(=O)2NH(C 1-6 Alkyl), -S(=O)2N(C 1-6 alkyl)2、-NHS(=O)2(C 1-6 alkyl), -N(C) 1-6 Alkyl)S(=O)2(C 1-6 Alkyl), 3-14 membered carbocyclic, 3-14 membered heterocyclic, 6-14 membered aryl, and 5-14 membered heteroaryl; wherein each (R1, R2, R3, R4, R5, or R6) is optionally surrounded by one or more elements selected from halogens, -C 1-6 Alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl group, -C 1-6 Alkoxy, -C 1-6 Halogenated alkyl, -C 1-6 Halogenated alkoxy groups, -CN, -NO2, oxo, -NH2, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl group 2, -OH, -O(C) 1-6 Alkyl), -SH, -S(C 1-6 Alkyl), -C(=O)(C 1-6 Alkyl), -S(=O)(C1-6 Alkyl), -S(=O)2(C 1-6 Alkyl), -S(=O)(=NH)(C 1-6 Alkyl), -C(=O)OH, -C(=O)(OC 1-6 Alkyl), -OC (=O)(C 1-6 Alkyl groups), -C(=O)NH2, -C(=O)NH(C 1-6 Alkyl), -C(=O)N(C 1-6 Alkyl)2、-NHC(=O)(C 1-6 alkyl), -N(C) 1-6 Alkyl)C(=O)(C 1-6 Alkyl groups), -S(=O)NH2, -S(=O)NH(C 1-6 Alkyl), -S(=O)N(C 1-6 Alkyl)2、-NHS(=O)(C 1-6 alkyl), -N(C) 1-6 Alkyl)S(=O)(C 1-6 Alkyl groups), -S(=O)2NH2, -S(=O)2NH(C 1-6 Alkyl), -S(=O)2N(C 1-6 alkyl)2、-NHS(=O)2(C 1-6 alkyl), -N(C) 1-6 Alkyl)S(=O)2(C 1-6 Substituents of alkyl, 3-14 membered carbocyclic, 3-14 membered heterocyclic, 6-14 membered aryl and 5-14 membered heteroaryl groups;

[0011] The ring G is a five-membered diene heterocycle or a five-membered diene carbon ring;

[0012] Each (R) 10A 、or R 10B Each time it appears, it is independently selected from hydrogen, halogen, -C 1-6 Alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl group, -C 1-6 Halogenated alkyl, -C 1-6 Halogenated alkoxy groups, -CN, -NO2, -NH2, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl group 2, -OH, -O(C) 1-6 Alkyl), -SH, -S(C 1-6 Alkyl), -C(=O)(C 1-6 Alkyl), -S(=O)(C 1-6 Alkyl), -S(=O)2(C 1-6 Alkyl), -S(=O)(=NH)(C1-6 Alkyl), -C(=O)OH, -C(=O)(OC 1-6 Alkyl), -OC (=O)(C 1-6 Alkyl groups), -C(=O)NH2, -C(=O)NH(C 1-6 Alkyl), -C(=O)N(C 1-6 Alkyl)2、-NHC(=O)(C 1-6 alkyl), -N(C) 1-6 Alkyl)C(=O)(C 1-6 Alkyl groups), -S(=O)NH2, -S(=O)NH(C 1-6 Alkyl), -S(=O)N(C 1-6 Alkyl)2、-NHS(=O)(C 1-6 alkyl), -N(C) 1-6 Alkyl)S(=O)(C 1-6 Alkyl groups), -S(=O)2NH2, -S(=O)2NH(C 1-6 Alkyl), -S(=O)2N(C 1-6 alkyl)2、-NHS(=O)2(C 1-6 alkyl), -N(C) 1-6 Alkyl)S(=O)2(C 1-6 Alkyl), 3-14 membered carbocyclic, 3-14 membered heterocyclic, 6-14 membered aryl, and 5-14 membered heteroaryl; wherein each (R) 10A 、or R 10B )Optionally selected by one or more halogens, -C 1-6 Alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl group, -C 1-6 Alkoxy, -C 1-6 Halogenated alkyl, -C 1-6 Halogenated alkoxy groups, -CN, -NO2, oxo, -NH2, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl group 2, -OH, -O(C) 1-6 Alkyl), -SH, -S(C 1-6 Alkyl), -C(=O)(C 1-6 Alkyl), -S(=O)(C 1-6 Alkyl), -S(=O)2(C 1-6 Alkyl), -S(=O)(=NH)(C 1-6 Alkyl), -C(=O)OH, -C(=O)(OC 1-6 Alkyl), -OC (=O)(C 1-6 Alkyl groups), -C(=O)NH2, -C(=O)NH(C 1-6Alkyl), -C(=O)N(C 1-6 Alkyl)2、-NHC(=O)(C 1-6 alkyl), -N(C) 1-6 Alkyl)C(=O)(C 1-6 Alkyl groups), -S(=O)NH2, -S(=O)NH(C 1-6 Alkyl), -S(=O)N(C 1-6 Alkyl)2、-NHS(=O)(C 1-6 alkyl), -N(C) 1-6 Alkyl)S(=O)(C 1-6 Alkyl groups), -S(=O)2NH2, -S(=O)2NH(C 1-6 Alkyl), -S(=O)2N(C 1-6 alkyl)2、-NHS(=O)2(C 1-6 alkyl), -N(C) 1-6 Alkyl)S(=O)2(C 1-6 Substituents of alkyl, 3-14 membered carbocyclic, 3-14 membered heterocyclic, 6-14 membered aryl and 5-14 membered heteroaryl groups;

[0013] R 12 Each time it appears, it is independently selected from hydrogen, -C 1-3 Alkyl, or -C 1-3 Halogenated alkyl groups;

[0014] Ring B can be a 3-14 membered carbocyclic group, a 3-14 membered heterocyclic group, a 6-14 membered aryl group, or a 5-14 membered heteroaryl group;

[0015] Each (R) S1 、or R S2 Each time it appears, it is independently selected from halogens, -C 1-6 Alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl group, -C 1-6 Halogenated alkyl, -C 1-6 Halogenated alkoxy groups, -CN, oxo, -NH2, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl group 2, -OH, -O(C) 1-6 Alkyl), -SH, -S(C 1-6 Alkyl), -S (halogenated C) 1-6 Alkyl), -C(=O)(C 1-6 Alkyl), -S(=O)(C 1-6 Alkyl), -S(=O)2(C 1-6 Alkyl), -S(=O)(=NH)(C 1-6 Alkyl), -C(=O)OH, -C(=O)(OC1-6 Alkyl), -OC (=O)(C 1-6 Alkyl groups), -C(=O)NH2, -C(=O)NH(C 1-6 Alkyl), -C(=O)N(C 1-6 Alkyl)2、-NHC(=O)(C 1-6 alkyl), -N(C) 1-6 Alkyl)C(=O)(C 1-6 Alkyl), -S(=O)(OC 1-6 Alkyl), -OS (=O) (C 1-6 Alkyl groups), -S(=O)NH2, -S(=O)NH(C 1-6 Alkyl), -S(=O)N(C 1-6 Alkyl)2、-NHS(=O)(C 1-6 alkyl), -N(C) 1-6 Alkyl)S(=O)(C 1-6 Alkyl), -S(=O)2(OC 1-6 Alkyl), -OS(=O)2(C 1-6 Alkyl groups), -S(=O)2NH2, -S(=O)2NH(C 1-6 Alkyl), -S(=O)2N(C 1-6 alkyl)2、-NHS(=O)2(C 1-6 alkyl), -N(C) 1-6 Alkyl)S(=O)2(C 1-6 alkyl), -PH(C) 1-6 alkyl), -P(C 1-6 Alkyl)2、-P(=O)H(C 1-6 Alkyl), -P(=O)(C 1-6 Alkyl) 2, 3-14 membered cycloalkyl, 3-14 membered heterocyclic, 6-14 membered aryl or 5-14 membered heteroaryl, wherein each (R S1 、or R S2 Independently and optionally by one or more elements selected from halogens, -C 1-6 Alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl group, -C 1-6 Halogenated alkyl, -C 1-6 Halogenated alkoxy groups, -CN, oxo, -NH2, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl group 2, -OH, -O(C) 1-6 Alkyl), -SH, -S(C 1-6 Alkyl), -S (halogenated C) 1-6 Alkyl), -C(=O)(C 1-6 Alkyl), -S(=O)(C1-6 Alkyl), -S(=O)2(C 1-6 Alkyl), -S(=O)(=NH)(C 1-6 Alkyl), -C(=O)OH, -C(=O)(OC 1-6 Alkyl), -OC (=O)(C 1-6 Alkyl groups), -C(=O)NH2, -C(=O)NH(C 1-6 Alkyl), -C(=O)N(C 1-6 Alkyl)2、-NHC(=O)(C 1-6 alkyl), -N(C) 1-6 Alkyl)C(=O)(C 1-6 Alkyl), -S(=O)(OC 1-6 Alkyl), -OS (=O) (C 1-6 Alkyl groups), -S(=O)NH2, -S(=O)NH(C 1-6 Alkyl), -S(=O)N(C 1-6 Alkyl)2、-NHS(=O)(C 1-6 alkyl), -N(C) 1-6 Alkyl)S(=O)(C 1-6 Alkyl), -S(=O)2(OC 1-6 Alkyl), -OS(=O)2(C 1-6 Alkyl groups), -S(=O)2NH2, -S(=O)2NH(C 1-6 Alkyl), -S(=O)2N(C 1-6 alkyl)2、-NHS(=O)2(C 1-6 alkyl), -N(C) 1-6 Alkyl)S(=O)2(C 1-6 alkyl), -PH(C) 1-6 alkyl), -P(C 1-6 Alkyl)2、-P(=O)H(C 1-6 Alkyl), -P(=O)(C 1-6 Substituents of alkyl groups (2-, 3-, 14-membered cycloalkyl groups, 3-, 14-membered heterocyclic groups, 6-, 14-membered aryl groups, or 5-, 14-membered heteroaryl groups);

[0016] Each (n) S1 、 or n S2 () is independently selected from 0, 1, 2, 3, 4, 5, and 6;

[0017] Each heterocyclic group independently contains 1, 2, 3, 4 or 5 heteroatoms selected from N, O or S each time it appears;

[0018] Each heteroaryl group independently contains 1, 2, 3, 4 or 5 heteroatoms selected from N, O or S each time it appears.

[0019] In some embodiments, the compound represented by formula (I) is a compound represented by any one of formulas (I-1) to (I-12):

[0020]

[0021]

[0022] Among them, R2, R3, R4, R5, ring G, R 10A R 10B R 12 Ring B, R S1 R S2 n S1 and n s2 The definition is the same as that of formula (I).

[0023] In some implementations, fragments Selected from

[0024] exist In the above, A1 is selected from N and CR. A1 A2 is selected from N and CR. A2 A3 is selected from N and CR. A3 A4 is selected from C(R) A41 2. NR A42 O and S;

[0025] exist In this context, W1 is selected from N and CR. W1 W2 is selected from C(R) W21 2. NR W22 O, and S; W3 is selected from N, and CR W3 W4 is selected from N and CR W4 ;

[0026] exist In this context, Z1 is selected from N and CR. Z1 Z2 is selected from N and CR. Z2 Z3 is selected from N and CR. Z3 Z4 is selected from N and CR. Z4 Z5 is selected from N and CR. Z5 ;

[0027] (in CR) Al R in A1 ), (in CR A2 R in A2 ), (in CR A3 R in A3 ), or (in CRA41 R in A41 ), (in CR W1 R in W1 ), (in CR W21 R in W21 ), (in CR W3 R in W3 ), (in CR W4 R in W4 ), (in CR Z1 R in Z1 ), (in CR Z2 R in Z2 ), (in CR Z3 R in Z3 ), (in CR Z4 R in z4 ), or (in CR z5 R in z5 Each time it appears, it is independently selected from hydrogen, halogen, -C 1-6 Alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl group, -C 1-6 Halogenated alkyl groups, -OC 1-6 Halogenated alkyl groups, -CN, -NO2, -NH2, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl group 2, -OH, -O(C) 1-6 Alkyl), -SH, -S(C 1-6 Alkyl), -C(=O)(C 1-6 Alkyl), -S(=O)(C 1-6 Alkyl), -S(=O)2(C 1-6 Alkyl), -S(=O)(=NH)(C 1-6 Alkyl), -C(=O)OH, -C(=O)(OC 1-6 Alkyl), -OC (=O)(C 1-6 Alkyl groups), -C(=O)NH2, -C(=O)NH(C 1-6 Alkyl), -C(=O)N(C 1-6 Alkyl)2、-NHC(=O)(C 1-6 alkyl), -N(C) 1-6 Alkyl)C(=O)(C 1-6 Alkyl groups), -S(=O)NH2, -S(=O)NH(C 1-6 Alkyl), -S(=O)N(C 1-6 Alkyl)2、-NHS(=O)(C 1-6 alkyl), -N(C) 1-6 Alkyl)S(=O)(C 1-6Alkyl groups), -S(=O)2NH2, -S(=O)2NH(C 1-6 Alkyl), -S(=O)2N(C 1-6 alkyl)2、-NHS(=O)2(C 1-6 alkyl), -N(C) 1-6 Alkyl)S(=O)2(C 1-6 Alkyl), 3-14 membered carbocyclic, 3-14 membered heterocyclic, 6-14 membered aryl and 5-14 membered heteroaryl; wherein, each of the above (in CR) A1 R in A1 ), (in CR A2 R in A2 ), (in CR A3 R in A3 ), or (in CR A41 R in A41 ), (in CR W1 R in W1 ), (in CR W21 R in W21 ), (in CR W3 R in W3 ), (in CR W4 R in W4 ), (in CR Z1 R in Z1 ), (in CR Z2 R in Z2 ), (in CR Z3 R in Z3 ), (in CR Z4 R in Z4 ), or (in CR Z5 R in Z5 )Optionally selected by one or more halogens, -C 1-6 Alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl group, -C 1-6 Halogenated alkyl groups, -OC 1-6 Halogenated alkyl groups, -CN, -NO2, oxo, -NH2, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl group 2, -OH, -O(C) 1-6 Alkyl), -SH, -S(C 1-6 Alkyl), -S(=O)(C 1-6 Alkyl), -S(=O)2(C 1-6 Alkyl), -S(=O)(=NH)(C 1-6 Alkyl), -C(=O)(C 1-6 Alkyl), -C(=O)OH, -C(=O)(OC 1-6Alkyl), -OC (=O)(C 1-6 Alkyl groups), -C(=O)NH2, -C(=O)NH(C 1-6 Alkyl), -C(=O)N(C 1-6 Alkyl)2、-NHC(=O)(C 1-6 alkyl), -N(C) 1-6 Alkyl)C(=O)(C 1-6 Alkyl groups), -S(=O)NH2, -S(=O)NH(C 1-6 Alkyl), -S(=O)N(C 1-6 Alkyl)2、-NHS(=O)(C 1-6 alkyl), -N(C) 1-6 Alkyl)S(=O)(C 1-6 Alkyl groups), -S(=O)2NH2, -S(=O)2NH(C 1-6 Alkyl), -S(=O)2N(C 1-6 alkyl)2、-NHS(=O)2(C 1-6 alkyl), -N(C) 1-6 Alkyl)S(=O)2(C 1-6 Substituents of alkyl, 3-14 membered carbocyclic, 3-14 membered heterocyclic, 6-14 membered aryl and 5-14 membered heteroaryl groups;

[0028] (in NR) A42 R in A42 ), or (in NR W22 R in W22 Each time it appears, it is independently selected from hydrogen, -C 1-6 Alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl group, -C 1-6 Haloalkyl, -CHO, -C(=O)(C 1-6 Alkyl), -S(=O)(C 1-6 Alkyl), -S(=O)2(C 1-6 Alkyl), -S(=O)(=NH)(C 1-6 Alkyl groups), -C(=O)NH2, -C(=O)NH(C 1-6 Alkyl), -C(=O)N(C 1-6 Alkyl) 2, 3-14 membered carbocyclic, 3-14 membered heterocyclic, 6-14 membered aryl or 5-14 membered heteroaryl; wherein, the (in NR) A42 R in A42 ), or (in NR W22 R in W22 )Optionally selected by one or more halogens, -C 1-6 Alkyl, -C 2-6 alkenyl, -C2-6 alkynyl group, -C 1-6 Halogenated alkyl groups, -OC 1-6 Halogenated alkyl groups, -CN, -NO2, -N3, oxo, -NH2, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl group 2, -OH, -O(C) 1-6 Alkyl), -SH, -S(C 1-6 Alkyl), -C(=O)(C 1-6 Alkyl), -S(=O)(C 1-6 Alkyl), -S(=O)2(C 1-6 Alkyl), -S(=O)(=NH)(C 1-6 Alkyl), -C(=O)OH, -C(=O)(OC 1-6 Alkyl), -OC (=O)(C 1-6 Alkyl groups), -C(=O)NH2, -C(=O)NH(C 1-6 Alkyl), -C(=O)N(C 1-6 Alkyl)2、-NHC(=O)(C 1-6 alkyl), -N(C) 1-6 Alkyl)C(=O)(C 1-6 Alkyl groups), -S(=O)NH2, -S(=O)NH(C 1-6 Alkyl), -S(=O)N(C 1-6 Alkyl)2、-NHS(=O)(C 1-6 alkyl), -N(C) 1-6 Alkyl)S(=O)(C 1-6 Alkyl groups), -S(=O)2NH2, -S(=O)2NH(C 1-6 Alkyl), -S(=O)2N(C 1-6 alkyl)2、-NHS(=O)2(C 1-6 alkyl), -N(C) 1-6 Alkyl)S(=O)2(C 1-6 Substituents of alkyl, 3-14 membered carbon cycloyl, 3-14 membered heterocyclic, 6-14 membered aryl, and 5-14 membered heteroaryl.

[0029] In some embodiments, the compound represented by formula (I) is a compound represented by any one of formulas (I-3) to (I-4):

[0030]

[0031]

[0032] In some implementations, fragments for

[0033] A1 is selected from N and CR. A1 ;

[0034] A2 is selected from N and CR. A2 ;

[0035] A3 is selected from N and CR. A3 ;

[0036] A4 is selected from C(R) A41 2. NR A42 O and S;

[0037] Each (in CR) A1 R in A1 ), (in CR A2 R in A2 ), (in CR A3 R in A3 ), or (in CR A41 R in A41 Each time it appears, it is independently selected from hydrogen, halogen, -C 1-3 Alkyl, -C 2-3 alkenyl, -C 2-3 alkynyl group, -C 1-3 Halogenated alkyl groups, -OC 1-3 Halogenated alkyl groups, -CN, -NH2, -NH(C) 1-3 alkyl), -N(C) 1-3 Alkyl group 2, -OH, -O(C) 1-3 Alkyl), -SH, -S(C 1-3 Alkyl), -C(=O)(C 1-3 Alkyl), -S(=O)(C 1-3 Alkyl), -S(=O)2(C 1-3 Alkyl), -S(=O)(=NH)(C 1-3 Alkyl), -C(=O)OH, -C(=O)(OC 1-3 Alkyl), -OC (=O)(C 1-3 Alkyl groups), -C(=O)NH2, -C(=O)NH(C 1-3 Alkyl), -C(=O)N(C 1-3 Alkyl)2、-NHC(=O)(C 1-3 Alkyl groups), -S(=O)NH2, -S(=O)NH(C 1-3 Alkyl), -S(=O)N(C 1-3 Alkyl)2、-NHS(=O)(C 1-3 Alkyl groups), -S(=O)2NH2, -S(=O)2NH(C 1-3Alkyl), -S(=O)2N(C 1-3 alkyl)2、-NHS(=O)2(C 1-3 Alkyl groups), -S(=O)(=NH)NH2, -S(=O)(=NH)NH(C 1-3 Alkyl), -S(=O)(=NH)N(C 1-3 Alkyl)2、-NHS(=O)(=NH)(C 1-3 Alkyl groups, 3-7 membered carbocyclic groups, 3-7 membered heterocyclic groups, phenyl groups, and 5-10 membered heteroaryl groups; preferably, each (in CR) A1 R in A1 ), (in CR A2 R in A2 ), (in CR A3 R in A3 ), or (in CR A41 R in A41 Each time it appears, it is independently selected from hydrogen, halogen, -C 1-3 Alkyl and -C 1-3 Halogenated alkyl groups; more preferably, each (in CR) A1 R in A1 ), (in CR A2 R in A2 ), (in CR A3 R in A3 ), or (in CR A41 R in A41 Each time it appears, it is independently selected from hydrogen and -C. 1-3 alkyl.

[0038] (in NR) A42 R in A42 Each time it appears, it is independently selected from hydrogen, -C 1-3 Alkyl, -C 2-3 alkenyl, -C 2-3 alkynyl group, -C 1-3 Haloalkyl, -C(=O)(C 1-3 Alkyl), -S(=O)(C 1-3 Alkyl), -S(=O)2(C 1-3 Alkyl), -S(=O)(=NH)(C 1-3 Alkyl groups), -C(=O)NH2, -C(=O)NH(C 1-3 Alkyl), -C(=O)N(C 1-3 Alkyl) 2, 3-7 membered carbocyclic, 3-7 membered heterocyclic, 6-10 membered aryl or 5-10 membered heteroaryl; wherein, the R A42 Optionally, it is selected from one or more halogens, -C 1-3 Alkyl, CN, oxo, -NH2, -NH(C)1-3 alkyl), -N(C) 1-3 Alkyl group 2, -OH, -O(C) 1-3 Alkyl), -SH, -S(C 1-3 Alkyl), -S(=O)(C 1-3 Alkyl), -S(=O)2(C 1-3 Alkyl), -C(=O)(C 1-3 Alkyl), -C(=O)OH, -C(=O)(OC 1-3 Alkyl), -OC (=O)(C 1-3 Alkyl groups), -C(=O)NH2, -C(=O)NH(C 1-3 Alkyl), -C(=O)N(C 1-3 Alkyl)2, -S(=O)NH2, -S(=O)NH(C 1-3 Alkyl), -S(=O)N(C 1-3 Alkyl)2, -S(=O)2NH2, -S(=O)2NH(C 1-3 Alkyl), -S(=O)2N(C 1-3 Substituents of alkyl groups (2, 3-7 membered carbocyclic groups, 3-7 membered heterocyclic groups, phenyl groups, or 5-10 membered heteroaryl groups); preferably, (in NR) A42 R in A42 Each time it appears, it is independently selected from hydrogen, -C 1-3 Alkyl, -C 2-3 alkenyl, -C 2-3 alkynyl group, -C 1-3 Haloalkyl, -C(=O)(C 1-3 Alkyl), -S(=O)(C 1-3 Alkyl), -S(=O)2(C 1-3 Alkyl), -S(=O)(=NH)(C 1-3 Alkyl), -C(=O)NH2, -C(=O)NH(C 1-3 Alkyl), -C(=O)N(C 1-3 Alkyl) 2, 3-7 membered carbocyclic, 3-7 membered heterocyclic, 6-10 membered aryl or 5-10 membered heteroaryl; more preferably, (in NR) A42 R in A42 Each time it appears, it is independently selected from hydrogen, -C 1-3 Alkyl, or -C 1-3 Halogenated alkyl groups.

[0039] In some specific implementation schemes, each (in CR) A1 R in A1 ), (in CR A2 R in A2 ), (in CR A3 R inA3 ), or (in CR A41 R in A41 Each occurrence is independently selected from -H, -Cl, -F, -Br, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CHFCH3, and -CF2CH3; preferably, each (in CR A1 R in A1 ), (in CR A2 R in A2 ), (in CR A3 R in A3 ), or (in CR A41 R in A41 Each time it appears, it is independently selected from -H, -CH3, -CH2CH3, -CH2CH2CH3, and -CH(CH3)2; more preferably, (in CR A1 R in A1 ), (in CR A2 R in A2 ), (in CR A3 R in A3 ), or (in CR A41 R in A41 Each time it appears, it is independently selected from -H and -CH3.

[0040] In some specific implementation schemes, (in NR) A42 R in A42 Each occurrence is independently selected from -H, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CHFCH3, or -CF2CH3. In some specific implementations, (in NR...) A42 R in A42 Each time it appears, it is independently selected from -H, -CH3, -CH2CH3, -CH2CH2CH3, or -CH(CH3)2.

[0041] In some implementations, fragments Selected from

[0042]

[0043] Preferably, fragments for

[0044] In some specific implementation schemes, fragments Selected from

[0045] Preferably, fragments

[0046] Selected from

[0047] More preferably, fragments Selected from More preferably, R9 is

[0048] In some embodiments, the compound represented by formula (I) is a compound represented by any one of formulas (II-1) to (II-4):

[0049]

[0050] Among them, R 10A R 10B R 12 R A1 R A2 R A42 Ring B, R S2 and n S2 The definition is the same as that of formula (I).

[0051] In some implementation schemes, R 10A Or R 10B Each time it appears, it is independently selected from hydrogen, halogen, -C. 1-3 Alkyl, -C 2-3 alkenyl, -C 2-3 alkynyl group, -C 1-3 Halogenated alkyl groups, -OC 1-3 Haloalkyl, -(C 1-3 (alkylene)-OC 1-3 Alkyl, -CN, -NO2, oxo, -NH2, -NH(C) 1-3 alkyl), -N(C) 1-3 Alkyl group 2, -OH, -O(C) 1-3 Alkyl), -SH, -S(C 1-3 Alkyl), -C(=O)OH, -C(=O)(OC1-3 Alkyl), -OC (=O)(C 1-3 Alkyl), -C(=O)(C 1-3 Alkyl), -S(=O)(C 1-3 Alkyl), -S(=O)2(C 1-3 Alkyl groups), -C(=O)NH2, -C(=O)NH(C 1-3 Alkyl), -C(=O)N(C 1-3 Alkyl)2、-NHC(=O)(C 1-3 Alkyl groups), -S(=O)NH2, -S(=O)NH(C 1-3 Alkyl), -S(=O)N(C 1-3 Alkyl)2、-NHS(=O)(C 1-3 Alkyl groups), -S(=O)2NH2, -S(=O)2NH(C 1-3 Alkyl), -S(=O)2N(C 1-3 alkyl)2、-NHS(=O)2(C 1-3 Alkyl group, or 3-7 membered carbocyclic group, 3-7 membered heterocyclic group, phenyl group, or 5-10 membered heteroaryl group; preferably, R 10A Or R 10B Each time it appears, it is independently selected from hydrogen, halogen, -C. 1-3 Alkyl, -C 1-3 Halogenated alkyl groups, -OC 1-3 Halogenated alkyl, -CN, oxo, -NH2, -NH(C) 1-3 alkyl), -N(C) 1-3 Alkyl group 2, -OH, -O(C) 1-3 Alkyl), -SH, -S(C 1-3 Alkyl), -C(=O)(C 1-3 Alkyl), -S(=O)(C 1-3 Alkyl), -S(=O)2(C 1-3 Alkyl groups), -C(=O)NH2, -C(=O)NH(C 1-3 Alkyl), -C(=O)N(C 1-3 Alkyl)2, -S(=O)NH2, -S(=O)NH(C 1-3 Alkyl), -S(=O)N(C 1-3 Alkyl)2, -S(=O)2NH2, -S(=O)2NH(C 1-3 Alkyl), -S(=O)2N(C 1-3 Alkyl) 2 or 3-7 membered cycloalkyl; more preferably, R 10A Or R 10B Each time it appears, it is independently selected from hydrogen, halogen, -C. 1-3 Alkyl, -C 1-3Halogenated alkyl groups, -CN, -NH2, -NH(C) 1-3 alkyl), -N(C) 1-3 Alkyl group 2, -OH, -O(C) 1-3 Alkyl), -SH, and -S(C 1-3 Alkyl); more preferably, R 10A Or R 10B Each time it appears, it is independently selected from -H or -C. 1-3 Alkyl, -NH(C) 1-3 alkyl), -N(C) 1-3 Alkyl)2、-O(C 1-3 alkyl), and -S(C 1-3 Alkyl); more preferably, R 10A Or R 10B Each time it appears, it is independently selected from -H or -C. 1-3 Alkyl groups and -O(C) 1-3 alkyl).

[0052] In some specific implementation schemes, R 10A Or R 10B Each occurrence is independently selected from -H, -Cl, -F, -Br, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CHFCH3, -CF2CH3, -CN, -NH2, -NH-(CH3), -NH-(CH2CH3), -NH-(CH2CH2CH3), -NH-(CH(CH3)2), -N(CH3)2, -OH, -O-(CH3), -O-(CH2CH3), -O-(CH2CH2CH3), -O-(CH(CH3)2), -SH, -S-(CH3), -S-(CH2CH3), -S-(CH2CH2CH3), and -S-(CH(CH3)2); preferably, R 10A Or R 10B Each occurrence is independently selected from -H, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -OH, -O-(CH3), -O-(CH2CH3), -O-(CH2CH2CH3), and -O-(CH(CH3)2). In some embodiments, R 10A Or R 10B Each occurrence is independently selected from -OH, -O-(CH3), -O-(CH2CH3), -O-(CH2CH2CH3), and -O-(CH(CH3)2); preferably, R 10A Or R 10BIt is independently selected from -O-(CH3) each time it appears. In some implementations, R 10A Or R 10B All are -H. In some implementations, R 10A Or R 10B Each time it appears, it is independently selected from -H, -CH3, -CH2CH3, -CH2CH2CH3, and -CH(CH3)2.

[0053] In some specific implementation plans,

[0054] R 10A It is -H, and R 10B -H;

[0055] R 10A -C 1-3 Alkyl, and R 10B -H; or

[0056] R 10A It is -H, and R 10B -O(C) 1-3 alkyl).

[0057] In some specific implementation schemes, R 10A It is -H, and R 10B It is -H.

[0058] In some implementation schemes, R 12 Each time it appears, it is independently selected from hydrogen, -C 1-3 Alkyl, or -C 1-3 Halogenated alkyl; preferably, R 12 Each time it appears, it is independently selected from hydrogen or -C. 1-3 Alkyl group. In some embodiments, R 12 It is hydrogen. In some specific implementations, R 12 Each occurrence is independently selected from -H, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CHFCH3, or -CF2CH3; preferably, R 12 Each occurrence is independently selected from -H, -CH3, -CH2CH3, -CH2CH2CH3, or -CH(CH3)2. In some specific implementations, R 2 It is -H.

[0059] In some implementation schemes, Selected from

[0060] Y3 is selected from non-existent, -C(R) Y3A )2-、-O-、-NR Y3B -、-S-、-C(=O)-、-S(=O)-、or-S(=O)2-;

[0061] Y4 is selected from non-existent, -C(R) Y4A )2-、-O-、-NR Y4B -、-S-、-C(=O)-、-S(=O)-、or-S(=O)2-;

[0062] Y5 is selected from non-existent, -C(R) Y5A )2-、-O-、-NR Y5B -、-S-、-C(=O)-、-S(=O)-、or-S(=O)2-;

[0063] Each R 13 (R in Y3) Y3A (R in Y4) Y4A ), or (R in Y5) Y5A Each time it appears, it is independently selected from hydrogen, halogen, -C 1-6 Alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl group, -C 1-6 Halogenated alkyl groups, -CN, -NO2, -NH2, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl group 2, -OH, -O(C) 1-6 Alkyl), -SH, -S(C 1-6 Alkyl), -S(=O)(C 1-6 Alkyl), -C(=O)(C 1-6 Alkyl), -S(=O)2(C 1-6 Alkyl), -S(=O)(=NH)(C 1-6 Alkyl), -C(=O)OH, -C(=O)(OC 1-6 Alkyl), -OC (=O)(C 1-6 Alkyl groups), -C(=O)NH2, -C(=O)NH(C 1-6 Alkyl), -C(=O)N(C 1-6 Alkyl)2、-NHC(=O)(C 1-6 alkyl), -N(C) 1-6 Alkyl)C(=O)(C 1-6 Alkyl groups), -S(=O)NH2, -S(=O)NH(C 1-6 Alkyl), -S(=O)N(C 1-6 Alkyl)2、-NHS(=O)(C 1-6 alkyl), -N(C)1-6 Alkyl)S(=O)(C 1-6 Alkyl groups), -S(=O)2NH2, -S(=O)2NH(C 1-6 Alkyl), -S(=O)2N(C 1-6 alkyl)2、-NHS(=O)2(C 1-6 alkyl), -N(C) 1-6 Alkyl)S(=O)2(C 1-6 Alkyl), 3-14 membered carbocyclic, 3-14 membered heterocyclic, 6-14 membered aryl or 5-14 membered heteroaryl; wherein, each of the (R in Y3) Y3A (R in Y4) Y4A ), or (R in Y5) Y5A )Optionally selected by one or more halogens, -C 1-6 Alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl group, -C 1-6 Halogenated alkyl groups, -CN, -NO2, oxo, -NH2, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl group 2, -OH, -O(C) 1-6 Alkyl), -O(C) 1-6 Halogenated alkyl groups), -SH, -S(C 1-6 Alkyl), -C(=O)(C 1-6 Alkyl), -S(=O)(C 1-6 Alkyl), -S(=O)2(C 1-6 Alkyl), -S(=O)(=NH)(C 1-6 Alkyl), -C(=O)OH, -C(=O)(OC 1-6 Alkyl), -OC (=O)(C 1-6 Alkyl groups), -C(=O)NH2, -C(=O)NH(C 1-6 Alkyl), -C(=O)N(C 1-6 Alkyl)2、-NHC(=O)(C 1-6 alkyl), -N(C) 1-6 Alkyl)C(=O)(C 1-6 Alkyl groups), -S(=O)NH2, -S(=O)NH(C 1-6 Alkyl), -S(=O)N(C 1-6 Alkyl)2、-NHS(=O)(C 1-6 alkyl), -N(C) 1-6 Alkyl)S(=O)(C 1-6 Alkyl groups), -S(=O)2NH2, -S(=O)2NH(C 1-6 Alkyl), -S(=O)2N(C1-6 alkyl)2、-NHS(=O)2(C 1-6 alkyl), -N(C) 1-6 Alkyl)S(=O)2(C 1-6 Substitution with alkyl groups, 3-14 membered carbocyclic groups, 3-14 membered heterocyclic groups, 6-14 membered aryl groups or 5-14 membered heteroaryl groups;

[0064] Optionally, two R atoms attached to the same C atom Y3A Together with the C atoms they are connected to, they form an optional n s3 R s3 Substituted 3-14 membered carbocyclic rings, 3-14 membered heterocyclic rings, 6-10 membered aryl rings or 5-10 membered heteroaryl rings;

[0065] Optionally, two R atoms attached to the same C atom Y4A Together with the C atoms they are connected to, they form an optional n S4 R S4 Substituted 3-14 membered carbocyclic rings, 3-14 membered heterocyclic rings, 6-10 membered aryl rings or 5-10 membered heteroaryl rings;

[0066] Optionally, two R atoms attached to the same C atom Y5A Together with the C atoms they are connected to, they form an optional n S5 R S5 Substituted 3-14 membered carbocyclic rings, 3-14 membered heterocyclic rings, 6-10 membered aryl rings or 5-10 membered heteroaryl rings;

[0067] Each (R in Y3) Y3B (R in Y4) Y4B ), or (R in Y5) Y5B Each time it appears, it is independently selected from hydrogen, -C 1-6 Alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl group, -C 1-6 Haloalkyl, -C(=O)(C 1-6 Alkyl), -S(=O)(C 1-6 Alkyl), -S(=O)2(C 1-6 Alkyl), -S(=O)(=NH)(C 1-6 Alkyl groups), -C(=O)NH2, -C(=O)NH(C 1-6 Alkyl), -C(=O)N(C 1-6 Alkyl) 2, 3-14 membered carbocyclic, 3-14 membered heterocyclic, 6-14 membered aryl or 5-14 membered heteroaryl; wherein, each of the (R in Y3) Y3B (R in Y4) Y4B), or (R in Y5) Y5B )Optionally selected by one or more halogens, -C 1-6 Alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl group, -C 1-6 Alkoxy, -C 1-6 Halogenated alkyl groups, -CN, -NO2, oxo, -NH2, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl group 2, -OH, -O(C) 1-6 Alkyl), -SH, -S(C 1-6 Alkyl), -S(=O)(C 1-6 Alkyl), -S(=O)2(C 1-6 Alkyl), -S(=O)(=NH)(C 1-6 Alkyl), -C(=O)(C 1-6 Alkyl), -C(=O)OH, -C(=O)(OC 1-6 Alkyl), -OC (=O)(C 1-6 Alkyl groups), -C(=O)NH2, -C(=O)NH(C 1-6 Alkyl), -C(=O)N(C 1-6 Alkyl)2、-NHC(=O)(C 1-6 alkyl), -N(C) 1-6 Alkyl)C(=O)(C 1-6 Alkyl groups), -S(=O)NH2, -S(=O)NH(C 1-6 Alkyl), -S(=O)N(C 1-6 Alkyl)2、-NHS(=O)(C 1-6 alkyl), -N(C) 1-6 Alkyl)S(=O)(C 1-6 Alkyl groups), -S(=O)2NH2, -S(=O)2NH(C 1-6 Alkyl), -S(=O)2N(C 1-6 alkyl)2、-NHS(=O)2(C 1-6 alkyl), -N(C) 1-6 Alkyl)S(=O)2(C 1-6 Substitution with alkyl groups, 3-14 membered carbocyclic groups, 3-14 membered heterocyclic groups, 6-14 membered aryl groups or 5-14 membered heteroaryl groups;

[0068] Each n6, n7, n8, n9, n 10 n 11 n 12 n 13 n 14 n 15 n 16、 or n 17 Independently selected from 0, 1, 2, 3, 4, 5, and 6;

[0069] And n6+n7+n8+n9≤6;

[0070] And n 10 +n 11 +n 12 +n 13 ≤6;

[0071] And n 14 +n 15 +n 16 +n 17 ≤6;

[0072] Each (R) S3 R S4 、or R S5 Each time it appears, it is independently selected from halogens, -C 1-6 Alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl group, -C 1-6 Halogenated alkyl, -C 1-6 Halogenated alkoxy groups, -CN, oxo, -NH2, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl group 2, -OH, -O(C) 1-6 Alkyl), -SH, -S(C 1-6 Alkyl), -S (halogenated C) 1-6 Alkyl), -C(=O)(C 1-6 Alkyl), -S(=O)(C 1-6 Alkyl), -S(=O)2(C 1-6 Alkyl), -S(=O)(=NH)(C 1-6 Alkyl), -C(=O)OH, -C(=O)(OC 1-6 Alkyl), -OC (=O)(C 1-6 Alkyl groups), -C(=O)NH2, -C(=O)NH(C 1-6 Alkyl), -C(=O)N(C 1-6 Alkyl)2、-NHC(=O)(C 1-6 alkyl), -N(C) 1-6 Alkyl)C(=O)(C 1-6 Alkyl), -S(=O)(OC 1-6 Alkyl), -OS (=O) (C 1-6 Alkyl groups), -S(=O)NH2, -S(=O)NH(C 1-6 Alkyl), -S(=O)N(C 1-6 Alkyl)2、-NHS(=O)(C1-6 alkyl), -N(C) 1-6 Alkyl)S(=O)(C 1-6 Alkyl), -S(=O)2(OC 1-6 Alkyl), -OS(=O)2(C 1-6 Alkyl groups), -S(=O)2NH2, -S(=O)2NH(C 1-6 Alkyl), -S(=O)2N(C 1-6 alkyl)2、-NHS(=O)2(C 1-6 alkyl), -N(C) 1-6 Alkyl)S(=O)2(C 1-6 alkyl), -PH(C) 1-6 alkyl), -P(C 1-6 Alkyl)2、-P(=O)H(C 1-6 Alkyl), -P(=O)(C 1-6 Alkyl) 2, 3-14 membered cycloalkyl, 3-14 membered heterocyclic, 6-14 membered aryl or 5-14 membered heteroaryl, wherein each (R S1 、or R S2 Independently and optionally by one or more elements selected from halogens, -C 1-6 Alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl group, -C 1-6 Halogenated alkyl, -C 1-6 Halogenated alkoxy groups, -CN, oxo, -NH2, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl group 2, -OH, -O(C) 1-6 Alkyl), -SH, -S(C 1-6 Alkyl), -S (halogenated C) 1-6 Alkyl), -C(=O)(C 1-6 Alkyl), -S(=O)(C 1-6 Alkyl), -S(=O)2(C 1-6 Alkyl), -S(=O)(=NH)(C 1-6 Alkyl), -C(=O)OH, -C(=O)(OC 1-6 Alkyl), -OC (=O)(C 1-6 Alkyl groups), -C(=O)NH2, -C(=O)NH(C 1-6 Alkyl), -C(=O)N(C 1-6 Alkyl)2、-NHC(=O)(C 1-6 alkyl), -N(C) 1-6 Alkyl)C(=O)(C 1-6 Alkyl), -S(=O)(OC 1-6 Alkyl), -OS (=O) (C1-6 Alkyl groups), -S(=O)NH2, -S(=O)NH(C 1-6 Alkyl), -S(=O)N(C 1-6 Alkyl)2、-NHS(=O)(C 1-6 alkyl), -N(C) 1-6 Alkyl)S(=O)(C 1-6 Alkyl), -S(=O)2(OC 1-6 Alkyl), -OS(=O)2(C 1-6 Alkyl groups), -S(=O)2NH2, -S(=O)2NH(C 1-6 Alkyl), -S(=O)2N(C 1-6 alkyl)2、-NHS(=O)2(C 1-6 alkyl), -N(C) 1-6 Alkyl)S(=O)2(C 1-6 alkyl), -PH(C) 1-6 alkyl), -P(C 1-6 Alkyl)2、-P(=O)H(C 1-6 Alkyl), -P(=O)(C 1-6 Alkyl) 2, 3-14 membered cycloalkyl, 3-14 membered heterocyclic, 6-14 membered aryl or 5-14 membered heteroaryl substituents;

[0073] Each (n) s3 n S4 、 or n S5 ) is independently selected from 0, 1, 2, 3, 4, 5, and 6.

[0074] In some implementations, fragments for In some specific implementations, Y4 is selected from non-existent or -O-.

[0075] In some specific implementations, Y4 is not present.

[0076] In some specific implementations, Y4 is -O-.

[0077] In some implementations, Y3 is selected from -C(R) Y3A -2, -O, and -NR Y3B - Preferably, Y3 is selected from -O- and -NR. Y3B -; More preferably, Y3 is -O-.

[0078] In some specific implementations, Y3 is -C(R) Y3A )2-.

[0079] In some specific implementations, Y3 is -O-.

[0080] In some implementations, fragments Selected from Preferably, fragments Selected from More preferably, fragments Selected from

[0081] In some implementation schemes,

[0082] n6 is selected from 0, 1, 2, and 3; preferably, n6 is selected from 0, 1, and 2; more preferably, n6 is selected from 0 and 1;

[0083] n7 is selected from 0, 1, 2, and 3; preferably, n7 is selected from 0, 1, and 2; more preferably, n7 is selected from 0 and 1;

[0084] n8 is selected from 0, 1, 2, and 3; preferably, n8 is selected from 0, 1, and 2; more preferably, n8 is selected from 0 and 1;

[0085] n9 is selected from 0, 1, 2, and 3; preferably, n9 is selected from 0, 1, and 2; more preferably, n9 is selected from 0 and 1;

[0086] And n6+n7+n8+n9≤5.

[0087] In some implementations, fragments Selected from Preferably, fragments Selected from

[0088] In some implementation schemes, R 13 Each time it appears, it is independently selected from hydrogen, halogen, -C. 1-3 Alkyl, -C 2-3 alkenyl, -C 2-3 alkynyl group, -C 1-3 Halogenated alkyl groups, -CN, -NO2, -NH2, -NH(C) 1-3 alkyl), -N(C) 1-3 Alkyl group 2, -OH, -O(C) 1-3 Alkyl), -SH, -S(C 1-3 Alkyl), -C(=O)(C 1-3 Alkyl), -S(=O)(C 1-3 Alkyl), -S(=O)2(C 1-3 Alkyl), -S(=O)(=NH)(C1-3 Alkyl), -C(=O)OH, -C(=O)(OC 1-3 Alkyl), -OC (=O)(C 1-3 Alkyl groups), -C(=O)NH2, -C(=O)NH(C 1-3 Alkyl), -C(=O)N(C 1-3 Alkyl)2、-NHC(=O)(C 1-3 Alkyl), S(=O)NH2, -S(=O)NH(C 1-3 Alkyl), -S(=O)N(C 1-3 Alkyl)2、-NHS(=O)(C 1-3 Alkyl groups), -S(=O)2NH2, -S(=O)2NH(C 1-6 Alkyl), -S(=O)2N(C 1-3 alkyl)2、-NHS(=O)2(C 1-3 Alkyl group, 3-7 membered carbocyclic group, 3-7 membered heterocyclic group, phenyl group or 5-10 membered heteroaryl group; preferably, R 13 Each time it appears, it is independently selected from hydrogen, halogen, -C. 1-3 Alkyl, -C 1-3 Halogenated alkyl groups, -CN, -NH2, -NH(C) 1-3 alkyl), -N(C) 1-3 Alkyl group 2, -OH, -O(C) 1-3 Alkyl), -SH, and -S(C 1-3 Alkyl); more preferably, R 13 Each occurrence is independently selected from -H, -NH2, -NH(C) 1-3 alkyl), -N(C) 1-3 Alkyl group 2, -OH, -O(C) 1-3 Alkyl), -SH, and -S(C 1-3 Alkyl group). In some embodiments, R 13 Each time it appears, it is independently selected from -NH2, -NH(C) 1-3 alkyl), -N(C) 1-3 Alkyl groups, -OH groups, and -O(C) groups 1-3 Alkyl group). In some embodiments, R 13 It is independently selected from -H each time it appears. In some implementations, R 13 Each time it appears, it is independently selected from hydrogen, halogen, -C. 1-3 Alkyl and -C 1-3 Halogenated alkyl groups.

[0089] In some specific implementation schemes, R 13Each occurrence is independently selected from -H, -Cl, -F, -Br, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CHFCH3, -CF2CH3, -CN, -NH2, -NH-(CH3), -NH-(CH2CH3), -NH-(CH2CH2CH3), -NH-(CH(CH3)2), -N(CH3)2, -OH, -O-(CH3), -O-(CH2CH3), -O-(CH2CH2CH3), -O-(CH(CH3)2), -SH, -S-(CH3), -S-(CH2CH3), -S-(CH2CH2CH3), and -S-(CH(CH3)2); preferably, R 13 Each occurrence is independently selected from -H, -Cl, -F, -CH3, -CH2CH3, -NH2, -NH-(CH3), -NH-(CH2CH3), -N(CH3)2, -OH, -O-(CH3), and -O-(CH2CH3). In some embodiments, R 13 Each occurrence is independently selected from -H, -NH2, -NH-(CH3), -NH-(CH2CH3), -NH-(CH2CH2CH3), -NH-(CH(CH3)2), and -N(CH3)2; preferably, R 13 It is -N(CH3)2. In some implementations, R 13 Each occurrence is independently selected from -OH, -O-(CH3), -O-(CH2CH3), -O-(CH2CH2CH3), and -O-(CH(CH3)2); preferably, R 13 It is independently selected from -OH each time it appears. In some embodiments, R 13 For -H. In some implementations, R 13 Each time it appears, it is independently selected from -H, -Cl, -F, -Br, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CHFCH3, and -CF2CH3.

[0090] In some implementations, fragments Selected from Preferably, fragments Selected from

[0091] In some implementation schemes, R Y3A Each time it appears, it is independently selected from hydrogen, halogen, -C. 1-3 Alkyl, -C 2-3 alkenyl, -C 2-3 alkynyl group, -C 1-3 Halogenated alkyl groups, -OC 1-3 Haloalkyl, -(C 1-3 (alkylene)-OC 1-3 Alkyl, -(C 1-3 alkylene)-O-(C 1-3 Halogenated alkyl groups, -CN, -NO2, oxo, -NH2, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl group 2, -OH, -O(C) 1-6 Alkyl), -SH, -S(C 1-3 Alkyl), -C(=O)(C 1-3 Alkyl), -S(=O)(C 1-3 Alkyl), -S(=O)2(C 1-3 Alkyl), -C(=O)OH, -C(=O)(OC 1-3 Alkyl), -OC (=O)(C 1-3 Alkyl groups), -C(=O)NH2, -C(=O)NH(C 1-3 Alkyl), -C(=O)N(C 1-3 Alkyl)2、-NHC(=O)(C 1-3 Alkyl), S(=O)NH2, -S(=O)NH(C 1-3 Alkyl), -S(=O)N(C 1-3 Alkyl)2、-NHS(=O)(C 1-3 Alkyl groups), -S(=O)2NH2, -S(=O)2NH(C 1-3 Alkyl), -S(=O)2N(C 1-3 alkyl)2、-NHS(=O)2(C 1-3 Alkyl group, 3-7 membered carbocyclic group, 3-7 membered heterocyclic group, phenyl group or 5-10 membered heteroaryl group; preferably, R Y3A Each time it appears, it is independently selected from hydrogen, halogen, -C. 1-3 Alkyl, -C 1-3 Haloalkyl, -(C 1-3 alkylene)-O-(C 1-3 alkyl), -(C 1-3 alkylene)-O-(C 1-3 Halogenated alkyl groups, -OH groups, or -O(C) groups 1-3 Alkyl group). In some embodiments, RY3A It is independently selected from hydrogen each time it appears. In some implementations, R Y3A Each time it appears, it is independently selected from -(C 1-3 alkylene)-O-(C 1-3 (Haloalkyl). In some embodiments, R Y3A Each time it appears, it is independently selected from -OH or -O(C). 1-3 Alkyl group). In some embodiments, R Y3A Each time it appears, it is independently selected from hydrogen, halogen, -C. 1-3 Alkyl and -C 1-3 Halogenated alkyl groups.

[0092] In some specific implementation schemes, R Y3A Each occurrence is independently selected from -H, -Cl, -F, -Br, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CHFCH3, -CF2CH3, -(CH2)-O-CH3, -(CH2)-O-(CH2CH3), -(CH2)-O-(CH2CH2CH3), -(CH2)-O-(CH(CH3)2), -(CH2)-O-(CH2F), -(CH2)-O-(CHF2) , -(CH2)-O-CF3, -(CH2)-O-(CH2CH2F), -(CH2)-O-(CH2CHF2), -(CH2)-O-(CH2CF3), -(CH2)-O-(CHFCH3), -(CH2)-O-(CF2CH3), -(CH 2) -O-(CH2Cl), -(CH2)-O-(CH2CH2Cl), -(CH2)-O-(CHClCH3), -OH, -O(CH3), -O-(CH2CH3), -O-(CH2CH2CH3), or -O-(CH(CH3)2); preferably, R Y3A Each time it appears, it is independently selected from -H, -(CH2)-O-(CH2Cl), -(CH2)-O-(CH2CH2Cl), -(CH2)-O-(CHClCH3), -OH, -O(CH3), -O-(CH2CH3), -O-(CH2CH2CH3), or -O-(CH(CH3)2); more preferably, R Y3A Each time it appears, it is independently selected from -H, -(CH2)-O-(CH2Cl), and -OH. In some specific embodiments, R Y3AEach occurrence is independently selected from -(CH2)-O-(CH2F), -(CH2)-O-(CHF2), -(CH2)-O-CF3, -(CH2)-O-(CH2CH2F), -(CH2)-O-(CH2CHF2), -(CH2)-O-(CH2CF3), -(CH2)-O-(CHFCH3), -(CH2)-O-(CF2CH3), -(CH2)-O-(CH2Cl), -(CH2)-O-(CH2CH2Cl), and -(CH2)-O-(CHClCH3); preferably, R Y3A Each time it appears, it is independently selected from -(CH2)-O-(CH2Cl), -(CH2)-O-(CH2CH2Cl), and -(CH2)-O-(CHClCH3); more preferably, R Y3A It is independently selected from -(CH2)-O-(CH2Cl) each time it appears. In some specific embodiments, R Y3A It is independently selected from -OH each time it appears. In some specific embodiments, R Y3A It is independently selected from -H each time it appears. In some specific implementations, R Y3A Each time it appears, it is independently selected from -OH, -O(CH3), -O-(CH2CH3), -O-(CH2CH2CH3), and -O-(CH(CH3)2).

[0093] In some implementation schemes, R Y3B Each time it appears, it is independently selected from 3-7 membered carbocyclic groups, 3-7 membered heterocyclic groups, phenyl groups, or 5-10 membered heteroaryl groups; preferably, R Y3B Each time it appears, it is independently a 3-7 membered heterocyclic group; more preferably, R Y3B Each time it appears, it is independently a 3-7 membered oxo-heterocyclic group. In some specific embodiments, R Y3B Selected independently each time it appears. Preferably, R Y3B for

[0094] More preferably, R Y3B for In some specific implementation schemes, R Y3B for

[0095] In some implementations, fragments Selected from Preferably, fragments Selected from

[0096] In some implementations, fragments for

[0097] In some specific implementations, Y5 is selected from -C(R) Y5A -2, -O, and -NR Y5B -; Preferably, Y5 is selected from -O- and -C(R) Y5A )2-; more preferably, Y5 is -O-. In some specific embodiments, Y5 is -NR. Y5B - In some specific implementations, Y5 is -C(R Y5A )2-. In some specific implementations, Y5 is -O-.

[0098] In some implementations, fragments Selected from Preferably, fragments Selected from

[0099] More preferably, fragments

[0100] In some implementations, each n 10 n 11 n 12 n 13 n 14 n 15 n 16 、 or n 17 Independently selected from 0, 1, 2, 3, and 4; preferably, each n 10 n 11 n 12 n 13 n 14 n 15 n 16 、 or n 17 Independently selected from 0, 1, and 2; preferably, each n 10 n 11 n 12 n 13 n 14 n 15 n 16 、 or n 17 It is independently selected from 0 and 1.

[0101] In some implementation schemes,

[0102] n 10 Selected from 0, 1, and 2; preferably, n 10 Selected from 0 and 1;

[0103] n 11 Selected from 0, 1, and 2; preferably, n 11 Selected from 0 and 1;

[0104] n 12 Selected from 0, 1, and 2; preferably, n 12 Selected from 0 and 1;

[0105] n 13 Selected from 0, 1, and 2; preferably, n 13 Selected from 0 and 1;

[0106] n 14 Selected from 0, 1, and 2; preferably, n 14 Selected from 0 and 1;

[0107] n 15 Selected from 0, 1, and 2; preferably, n 15 Selected from 0 and 1;

[0108] n 16 Selected from 0, 1, and 2; preferably, n 16 Selected from 0 and 1;

[0109] n 17 Selected from 0, 1, and 2; preferably, n 17 Selected from 0 and 1;

[0110] And n 10 +n 11 +n 12 +n 13 ≤6;

[0111] And n 14 +n 15 +n 16 +n 17 ≤6.

[0112] In some implementations, fragments Selected from Preferably, fragments Selected from More preferably, fragments Selected from

[0113] In some implementation schemes, R Y5A Each time it appears, it is independently selected from hydrogen, halogen, -C. 1-3 Alkyl, -C 2-3 alkenyl, -C 2-3alkynyl group, -C 1-3 Halogenated alkyl groups, -OC 1-3 Haloalkyl, -(C 1-3 (alkylene)-OC 1-3 Alkyl, -CN, -NO2, oxo, -NH2, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl group 2, -OH, -O(C) 1-6 Alkyl), -SH, -S(C 1-6 Alkyl), -C(=O)(C 1-3 Alkyl), -S(=O)(C 1-3 Alkyl), -S(=O)2(C 1-3 Alkyl), -S(=O)(=NH)(C 1-3 Alkyl), -C(=O)OH, -C(=O)(OC 1-3 Alkyl), -OC (=O)(C 1-3 Alkyl groups), -C(=O)NH2, -C(=O)NH(C 1-3 Alkyl), -C(=O)N(C 1-3 Alkyl)2、-NHC(=O)(C 1-3 Alkyl), S(=O)NH2, -S(=O)NH(C 1-3 Alkyl), -S(=O)N(C 1-3 Alkyl)2、-NHS(=O)(C 1-3 Alkyl groups), -S(=O)2NH2, -S(=O)2NH(C 1-6 Alkyl), -S(=O)2N(C 1-6 alkyl)2、-NHS(=O)2(C 1-6 Alkyl group, 3-7 membered carbocyclic group, 3-7 membered heterocyclic group, phenyl group or 5-10 membered heteroaryl group; preferably, R Y5A Each time it appears, it is independently selected from hydrogen, halogen, -C. 1-3 Alkyl, -C 1-3 Halogenated alkyl groups, -OC 1-3 Halogenated alkyl, -CN, oxo, -NH2, -NH(C) 1-3 alkyl), -N(C) 1-3 Alkyl group 2, -OH, -O(C) 1-3 Alkyl), -SH, -S(C 1-3 Alkyl), -C(=O)(C 1-3 Alkyl), -S(=O)(C 1-3 Alkyl), -S(=O)2(C 1-3 Alkyl groups), -C(=O)NH2, -C(=O)NH(C 1-3 Alkyl), -C(=O)N(C 1-3Alkyl)2, -S(=O)NH2, -S(=O)NH(C 1-3 Alkyl), -S(=O)N(C 1-3 Alkyl)2, -S(=O)2NH2, -S(=O)2NH(C 1-3 Alkyl), -S(=O)2N(C 1-3 Alkyl) 2 or 3-7 membered cycloalkyl; more preferably, R Y5A Each time it appears, it is independently selected from hydrogen, halogen, -C. 1-3 Alkyl, or -C 1-3 Halogenated alkyl; more preferably, R Y5A Each time it appears, it is independently selected from hydrogen and -C. 1-3 alkyl;

[0114] In some specific implementation schemes, R Y5A Each occurrence is independently selected from -H, -Cl, -F, -Br, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CHFCH3, or -CF2CH3; preferably, R Y5A Each time it appears, it is independently selected from -H, -CH3, -CH2CH3, -CH2CH2CH3, or -CH(CH3)2; more preferably, R Y5A It is independently selected from -H and -CH3 each time it appears. In some specific implementations, R Y5A It is -H.

[0115] In some implementations, fragments Selected from

[0116] In some implementations, fragments for

[0117] Preferably, fragments Selected from

[0118] In some implementations, fragments for Preferably, fragments for More preferably, preferably, fragments for

[0119] In some implementation schemes, Selected from

[0120] Among them, R 10A R 10B R 12 R 13 ,n6,n7,n8,n9,Y3,Y4,R S2 n S2 n 10 n 11 n 12 n 13 n 14 n 15 n 16 n 17 The definitions of Y and Y5 are the same as in equation (I).

[0121] In some implementation schemes, Selected from Preferably Selected from

[0122] Among them, R 10A R 10B R 12 R 13 ,n6,n7,n8,n9,Y3,Y4,R S2 n S2 n 10 n 11 n 12 n 13 n 14 n 15 n 16 n 17 The definitions of Y and Y5 are the same as in equation (I).

[0123] In some implementation schemes, middle,

[0124] R 10A -H or -C 1-3 alkyl;

[0125] R 10B -H or -C 1-3 alkyl;

[0126] R12 Each time it appears, it is independently selected from hydrogen, -C 1-3 Alkyl, or -C 1-3 Halogenated alkyl groups;

[0127] n6 is selected from 0, 1, and 2;

[0128] n7 is selected from 0, 1, and 2;

[0129] n8 is selected from 0, 1, and 2;

[0130] n9 is selected from 0, 1, and 2;

[0131] And n6+n7+n8+n9≤5;

[0132] Y4 does not exist;

[0133] Y3 is selected from -C(R) Y3A )2- and -O-;

[0134] R Y3A Each time it appears, it is independently selected from hydrogen, halogen, -C. 1-3 Alkyl, -C 1-3 Haloalkyl, -(C 1-3 alkylene)-O-(C 1-3 alkyl), -(C 1-3 alkylene)-O-(C 1-3 Halogenated alkyl groups, -OH groups, or -O(C) groups 1-3 alkyl).

[0135] In some implementation schemes, for Preferably, for

[0136] In some implementation schemes, middle;

[0137] R 10A -H or -C 1-3 alkyl;

[0138] R 10B -H or -C 1-3 alkyl;

[0139] R 12 Each time it appears, it is independently selected from hydrogen, -C 1-3 Alkyl, or -C 1-3 Halogenated alkyl groups;

[0140] n6 is selected from 0, 1, and 2;

[0141] n7 is selected from 0, 1, and 2;

[0142] n8 is selected from 0, 1, and 2;

[0143] n9 is selected from 0, 1, and 2;

[0144] And n6+n7+n8+n9≤5;

[0145] Y4 does not exist;

[0146] Y3 is selected from -C(R) Y3A Y2- and -O-; preferably, Y3 is -O-;

[0147] R Y3A Each time it appears, it is independently selected from hydrogen, halogen, -C. 1-3 Alkyl, -C 1-3 Haloalkyl, -(C 1-3 alkylene)-O-(C 1-3 alkyl), -(C 1-3 alkylene)-O-(C 1-3 Halogenated alkyl groups, -OH groups, or -O(C) groups 1-3 alkyl).

[0148] In some implementation schemes, for

[0149]

[0150]

[0151] In some implementation schemes, R 10 Selected from Among them, R 10A Or R 10B Each time it appears, it is independently selected from hydrogen, halogen, -C. 1-3 Alkyl, -C 1-3 Halogenated alkyl groups, -OC 1-3 Halogenated alkyl, -CN, oxo, -NH2, -NH(C) 1-3 alkyl), -N(C) 1-3 Alkyl group 2, -OH, -O(C) 1-3 Alkyl), -SH, -S(C 1-3 Alkyl), -C(=O)(C 1-3 Alkyl), -S(=O)(C 1-3 Alkyl), -S(=O)2(C 1-3 Alkyl groups), -C(=O)NH2, -C(=O)NH(C 1-3 Alkyl), -C(=O)N(C1-3 Alkyl)2, -S(=O)NH2, -S(=O)NH(C 1-3 Alkyl), -S(=O)N(C 1-3 Alkyl)2, -S(=O)2NH2, -S(=O)2NH(C 1-3 Alkyl), -S(=O)2N(C 1-3 Alkyl)2 or 3-7 membered cycloalkyl; preferably, R 10A Or R 10B Each time it appears, it is independently selected from -H or -C. 1-3 Alkyl, -NH(C) 1-3 alkyl), -N(C) 1-3 Alkyl)2、-O(C 1-3 alkyl), and -S(C 1-3 alkyl);

[0152] R 12 Each time it appears, it is independently selected from hydrogen, -C 1-3 Alkyl, or -C 1-3 Halogenated alkyl groups;

[0153] n 10 Selected from 0, 1, and 2; preferably, n 10 Selected from 0 and 1;

[0154] n 11 Selected from 0, 1, and 2; preferably, n 11 Selected from 0 and 1;

[0155] n 12 Selected from 0, 1, and 2; preferably, n 12 Selected from 0 and 1;

[0156] n 13 Selected from 0, 1, and 2; preferably, n 13 Selected from 0 and 1;

[0157] n 14 Selected from 0, 1, and 2; preferably, n 14 Selected from 0 and 1;

[0158] n 15 Selected from 0, 1, and 2; preferably, n 15 Selected from 0 and 1;

[0159] n 16 Selected from 0, 1, and 2; preferably, n 16 Selected from 0 and 1;

[0160] n 17 Selected from 0, 1, and 2; preferably, n 17 Selected from 0 and 1;

[0161] And n 10 +n 11 +n 12 +n 13 ≤6;

[0162] And n 14 +n 15 +n 16 +n 17 ≤6;

[0163] Y5 is selected from -O- and -C(R) Y5A )2-; More preferably, Y5 is -O-;

[0164] R Y5A Each time it appears, it is independently selected from hydrogen, halogen, -C. 1-3 Alkyl, -C 1-3 Halogenated alkyl groups, -OC 1-3 Halogenated alkyl, -CN, oxo, -NH2, -NH(C) 1-3 alkyl), -N(C) 1-3 Alkyl group 2, -OH, -O(C) 1-3 Alkyl), -SH, -S(C 1-3 Alkyl), -C(=O)(C 1-3 Alkyl), -S(=O)(C 1-3 Alkyl), -S(=O)2(C 1-3 Alkyl groups), -C(=O)NH2, -C(=O)NH(C 1-3 Alkyl), -C(=O)N(C 1-3 Alkyl)2, -S(=O)NH2, -S(=O)NH(C 1-3 Alkyl), -S(=O)N(C 1-3 Alkyl)2, -S(=O)2NH2, -S(=O)2NH(C 1-3 Alkyl), -S(=O)2N(C 1-3 Alkyl) 2 or 3-7 membered cycloalkyl; more preferably, R Y5A Each time it appears, it is independently selected from hydrogen, halogen, -C. 1-3 Alkyl, or -C 1-3 Halogenated alkyl groups;

[0165] R S2 and n S2 The definition is the same as that of formula (I).

[0166] In some implementation schemes, R 10 for

[0167] Among them, R 10A R10B R 12 n 10 n 11 n 12 n 13 n 14 n 15 n 16 n 17 The definition of Y5 is the same as that of Y5.

[0168] In some implementation schemes, for

[0169] Preferably, for

[0170] In some specific implementation plans, for

[0171] In some implementations, fragments Selected from

[0172] In some implementation schemes, R 10 for

[0173] In some embodiments, the compound represented by formula (I) is a compound represented by any of the following formulas: In some embodiments, the compound represented by formula (I) is a compound represented by any of formulas (III-1) to (III-4):

[0174]

[0175]

[0176]

[0177]

[0178]

[0179]

[0180] Among them, R2, R3, R4, R5, A1, A2, A3, A4, RA1 R A2 R A42 R 10A R 10B R 12 R 13 , Y3, Y4, Y5, n6, n7, n8, n9, n 10 n 11 n 12 n 13 n 14 n 15 n 16 n 17 R S2 and n s2 The definition is the same as that of formula (I).

[0181] This invention relates to a compound of formula (III-1), or its stereoisomers, tautomers, pharmaceutically acceptable salts thereof, pharmaceutically acceptable salts of its stereoisomers, pharmaceutically acceptable salts of its tautomers, its solvates, its prodrugs, or its deuterated derivatives thereof, wherein,

[0182]

[0183] R2 is independently selected from hydrogen, halogen, and -C each time it appears. 1-3 Alkyl and -C 1-3 Haloalkyl; preferably, R2 is independently selected from hydrogen and -C each time it appears. 1-3 alkyl;

[0184] R3 is independently selected from hydrogen, halogen, and -C each time it appears. 1-3 Alkyl, -C 1-3 Halogenated alkyl groups, -CN, -NH2, -NH(C) 1-3 alkyl), -N(C) 1-3 alkyl)2、-NH(C 3-7 cycloalkyl), -OH, -O(C 1-3 Alkyl), -O(C) 3-7 cycloalkyl), -SH, -S(C 1-3 alkyl), and -S(C 3-7 (cycloalkyl); preferably, R3 is independently selected from hydrogen, -C, and -C each time it appears. 1-3 Alkyl, -OH, -O(C) 1-3 alkyl), and -O(C 3-7 cycloalkyl);

[0185] R4 is independently selected from hydrogen, halogen, and -C each time it appears. 1-3 Alkyl and -C 1-3Haloalkyl; preferably, R4 is independently selected from hydrogen and -C each time it appears. 1-3 alkyl;

[0186] R5 is independently selected from hydrogen, halogen, and -C each time it appears. 1-3 Alkyl, -C 1-3 Halogenated alkyl groups, -NH2, -NH(C) 1-3 alkyl), -N(C) 1-3 Alkyl group 2, -OH, -O(C) 1-3 Alkyl), -SH, -S(C 1-3 Alkyl groups), -C(=O)NH2, -C(=O)NH(C 1-3 Alkyl), -C(=O)N(C 1-3 Alkyl)2, -S(=O)NH2, -S(=O)NH(C 1-3 Alkyl), -S(=O)N(C 1-3 Alkyl)2, -S(=O)2NH2, -S(=O)2NH(C 1-3 Alkyl groups), and -S(=O)2N(C 1-3 Alkyl group 2; preferably, R5 is independently selected from hydrogen, halogen, -C each time it appears. 1-3 Alkyl, -C 1-3 Halogenated alkyl groups, -OH, -O(C) 1-3 Alkyl groups), -C(=O)NH2, -C(=O)NH(C 1-3 Alkyl groups), and -C(=O)N(C 1-3 Alkyl)2;

[0187] A1 is selected from N and CR. A1 ;

[0188] A2 is selected from N and CR. A2 ;

[0189] A3 is selected from N and CR. A3 ;

[0190] A4 is selected from C(R) A41 2. NR A42 O and S;

[0191] Each (in CR) A1 R in A1 ), (in CR A2 R in A2 ), (in CR A3 R in A3 ), or (in CR A41 R in A41 Each time it appears, it is independently selected from hydrogen, halogen, -C 1-3 Alkyl and -C1-3 Halogenated alkyl groups; preferably, each (in CR) A1 R in A1 ), (in CR A2 R in A2 ), (in CR A3 R in A3 ), or (in CR A41 R in A41 Each time it appears, it is independently selected from hydrogen and -C. 1-3 alkyl;

[0192] (in NR) A42 R in A42 Each time it appears, it is independently selected from hydrogen, -C 1-3 Alkyl, or -C 1-3 Halogenated alkyl groups;

[0193] R 10A Or R 10B Each time it appears, it is independently selected from hydrogen, halogen, -C. 1-3 Alkyl, -C 1-3 Halogenated alkyl groups, -CN, -NH2, -NH(C) 1-3 alkyl), -N(C) 1-3 Alkyl group 2, -OH, -O(C) 1-3 Alkyl), -SH, and -S(C 1-3 Alkyl); preferably, R 10A Or R 10B Each time it appears, it is independently selected from -H or -C. 1-3 Alkyl, -NH(C) 1-3 alkyl), -N(C) 1-3 Alkyl)2、-O(C 1-3 alkyl), and -S(C 1-3 Alkyl); more preferably, R 10A Or R 10B Each time it appears, it is independently selected from -H or -C. 1-3 Alkyl groups and -O(C) 1-3 alkyl);

[0194] R 12 Each time it appears, it is independently selected from hydrogen, -C 1-3 Alkyl, or -C 1-3 Halogenated alkyl; preferably, R 12 Each time it appears, it is independently selected from hydrogen or -C. 1-3 alkyl;

[0195] R 13 Each time it appears, it is independently selected from hydrogen, halogen, -C. 1-3 Alkyl and -C 1-3 Halogenated alkyl groups;

[0196] Y4 is selected from non-existent and -O-;

[0197] Y3 is selected from -O- and -C(R) Y3A )2-;

[0198] R Y3A Each time it appears, it is independently selected from hydrogen, halogen, -C. 1-3 Alkyl, -C 1-3 Haloalkyl, -(C 1-3 alkylene)-O-(C 1-3 alkyl), -(C 1-3 alkylene)-O-(C 1-3 Halogenated alkyl groups, -OH groups, or -O(C) groups 1-3 Alkyl); preferably, R Y3A Each time it appears, it is independently selected from hydrogen, halogen, -C. 1-3 Alkyl and -C 1-3 Halogenated alkyl groups;

[0199] n6 is selected from 0, 1, 2, and 3; preferably, n6 is selected from 0, 1, and 2; more preferably, n6 is selected from 0 and 1;

[0200] n7 is selected from 0, 1, 2, and 3; preferably, n7 is selected from 0, 1, and 2; more preferably, n7 is selected from 0 and 1;

[0201] n8 is selected from 0, 1, 2, and 3; preferably, n8 is selected from 0, 1, and 2; more preferably, n8 is selected from 0 and 1;

[0202] n9 is selected from 0, 1, 2, and 3; preferably, n9 is selected from 0, 1, and 2; more preferably, n9 is selected from 0 and 1;

[0203] And n6+n7+n8+n9≤5;

[0204] R S2 Each time it appears, it is independently selected from halogens and -C. 1-3 Alkyl, -C 2-3 alkenyl, -C 2-3 alkynyl group, -C 1-3 Halogenated alkyl groups, -OC 1-3 Halogenated alkyl groups, -CN, -NO2, oxo, -NH2, -NH(C) 1-3 alkyl), -N(C) 1-3 Alkyl group 2, -OH, -O(C) 1-3 Alkyl), -SH, -S(C 1-3 Alkyl), -C(=O)(C 1-3 Alkyl), -S(=O)(C 1-3Alkyl), -S(=O)2(C 1-3 Alkyl), -C(=O)OH, -C(=O)(OC 1-3 Alkyl), -OC (=O)(C 1-3 Alkyl groups), -C(=O)NH2, -C(=O)NH(C 1-3 Alkyl), -C(=O)N(C 1-3 Alkyl)2、-NHC(=O)(C 1-3 Alkyl), S(=O)NH2, -S(=O)NH(C 1-3 Alkyl), -S(=O)N(C 1-3 Alkyl)2、-NHS(=O)(C 1-3 Alkyl groups), -S(=O)2NH2, -S(=O)2NH(C 1-6 Alkyl), -S(=O)2N(C 1-6 alkyl)2、-NHS(=O)2(C 1-6 Alkyl group, 3-7 membered carbon cyclo group, 3-7 membered heterocyclic group, phenyl group or 5-10 membered heteroaryl group;

[0205] n S2 Choose from 0, 1, 2, or 3.

[0206] This invention relates to a compound of formula (III-3), or its stereoisomers, tautomers, pharmaceutically acceptable salts thereof, pharmaceutically acceptable salts of its stereoisomers, pharmaceutically acceptable salts of its tautomers, its solvates, its prodrugs, or its deuterated derivatives thereof, wherein,

[0207]

[0208] R2 is independently selected from hydrogen, halogen, and -C each time it appears. 1-3 Alkyl and -C 1-3 Haloalkyl; preferably, R2 is independently selected from hydrogen and -C each time it appears. 1-3 alkyl;

[0209] R3 is independently selected from hydrogen, halogen, and -C each time it appears. 1-3 Alkyl, -C 1-3 Halogenated alkyl groups, -CN, -NH2, -NH(C) 1-3 alkyl), -N(C) 1-3 alkyl)2、-NH(C 3-7 cycloalkyl), -OH, -O(C 1-3 Alkyl), -O(C) 3-7 cycloalkyl), -SH, -S(C 1-3 alkyl), and -S(C 3-7(cycloalkyl); preferably, R3 is independently selected from hydrogen, -C, and -C each time it appears. 1-3 Alkyl, -OH, -O(C) 1-3 alkyl), and -O(C 3-7 cycloalkyl);

[0210] R4 is independently selected from hydrogen, halogen, and -C each time it appears. 1-3 Alkyl and -C 1-3 Haloalkyl; preferably, R4 is independently selected from hydrogen and -C each time it appears. 1-3 alkyl;

[0211] R5 is independently selected from hydrogen, halogen, and -C each time it appears. 1-3 Alkyl, -C 1-3 Halogenated alkyl groups, -NH2, -NH(C) 1-3 alkyl), -N(C) 1-3 Alkyl group 2, -OH, -O(C) 1-3 Alkyl), -SH, -S(C 1-3 Alkyl groups), -C(=O)NH2, -C(=O)NH(C 1-3 Alkyl), -C(=O)N(C 1-3 Alkyl)2, -S(=O)NH2, -S(=O)NH(C 1-3 Alkyl), -S(=O)N(C 1-3 Alkyl)2, -S(=O)2NH2, -S(=O)2NH(C 1-3 Alkyl groups), and -S(=O)2N(C 1-3 Alkyl group 2; preferably, R5 is independently selected from hydrogen, halogen, -C each time it appears. 1-3 Alkyl, -C 1-3 Halogenated alkyl groups, -OH, -O(C) 1-3 Alkyl groups), -C(=O)NH2, -C(=O)NH(C 1-3 Alkyl groups), and -C(=O)N(C 1-3 Alkyl)2;

[0212] A1 is selected from N and CR. A1 ;

[0213] A2 is selected from N and CR. A2 ;

[0214] A3 is selected from N and CR. A3 ;

[0215] A4 is selected from C(R) A41 2. NR A42 O and S;

[0216] Each (in CR) A1R in A1 ), (in CR A2 R in A2 ), (in CR A3 R in A3 ), or (in CR A41 R in A41 Each time it appears, it is independently selected from hydrogen, halogen, -C 1-3 Alkyl and -C 1-3 Halogenated alkyl groups; preferably, each (in CR) A1 R in A1 ), (in CR A2 R in A2 ), (in CR A3 R in A3 ), or (in CR A41 R in A41 Each time it appears, it is independently selected from hydrogen and -C. 1-3 alkyl;

[0217] (in NR) A42 R in A42 Each time it appears, it is independently selected from hydrogen, -C 1-3 Alkyl, or -C 1-3 Halogenated alkyl groups;

[0218] R 10A Or R 10B Each time it appears, it is independently selected from hydrogen, halogen, -C. 1-3 Alkyl, -C 1-3 Halogenated alkyl groups, -CN, -NH2, -NH(C) 1-3 alkyl), -N(C) 1-3 Alkyl group 2, -OH, -O(C) 1-3 Alkyl), -SH, and -S(C 1-3 Alkyl); preferably, R 10A Or R 10B Each time it appears, it is independently selected from -H or -C. 1-3 Alkyl, -NH(C) 1-3 alkyl), -N(C) 1-3 Alkyl)2、-O(C 1-3 alkyl), and -S(C 1-3 Alkyl); more preferably, R 10A Or R 10B Each time it appears, it is independently selected from -H or -C. 1-3 Alkyl groups and -O(C) 1-3 alkyl);

[0219] R 12 Each time it appears, it is independently selected from hydrogen, -C 1-3 Alkyl, or -C1-3 Halogenated alkyl; preferably, R 12 Each time it appears, it is independently selected from hydrogen or -C. 1-3 alkyl;

[0220] Y5 is selected from -O- and -C(R) Y5A )2-; Preferably, Y5 is -O-;

[0221] R Y5A Each time it appears, it is independently selected from hydrogen, halogen, -C. 1-3 Alkyl, or -C 1-3 Halogenated alkyl; preferably, R Y5A Each time it appears, it is independently selected from hydrogen and -C. 1-3 alkyl;

[0222] n 10 Selected from 0, 1, and 2; preferably, n 10 Selected from 0 and 1;

[0223] n 11 Selected from 0, 1, and 2; preferably, n 11 Selected from 0 and 1;

[0224] n 12 Selected from 0, 1, and 2; preferably, n 12 Selected from 0 and 1;

[0225] n 13 Selected from 0, 1, and 2; preferably, n 13 Selected from 0 and 1;

[0226] n 14 Selected from 0, 1, and 2; preferably, n 14 Selected from 0 and 1;

[0227] n 15 Selected from 0, 1, and 2; preferably, n 15 Selected from 0 and 1;

[0228] n 16 Selected from 0, 1, and 2; preferably, n 16 Selected from 0 and 1;

[0229] n 17 Selected from 0, 1, and 2; preferably, n 17 Selected from 0 and 1;

[0230] And n 10 +n 11 +n 12 +n 13 ≤6;

[0231] And n 14+n 15 +n 16 +n 17 ≤6;

[0232] R S2 Each time it appears, it is independently selected from halogens and -C. 1-3 Alkyl, -C 2-3 alkenyl, -C 2-3 alkynyl group, -C 1-3 Halogenated alkyl groups, -OC 1-3 Halogenated alkyl groups, -CN, -NO2, oxo, -NH2, -NH(C) 1-3 alkyl), -N(C) 1-3 Alkyl group 2, -OH, -O(C) 1-3 Alkyl), -SH, -S(C 1-3 Alkyl), -C(=O)(C 1-3 Alkyl), -S(=O)(C 1-3 Alkyl), -S(=O)2(C 1-3 Alkyl), -C(=O)OH, -C(=O)(OC 1-3 Alkyl), -OC (=O)(C 1-3 Alkyl groups), -C(=O)NH2, -C(=O)NH(C 1-3 Alkyl), -C(=O)N(C 1-3 Alkyl)2、-NHC(=O)(C 1-3 Alkyl), S(=O)NH2, -S(=O)NH(C 1-3 Alkyl), -S(=O)N(C 1-3 Alkyl)2、-NHS(=O)(C 1-3 Alkyl groups), -S(=O)2NH2, -S(=O)2NH(C 1-6 Alkyl), -S(=O)2N(C 1-6 alkyl)2、-NHS(=O)2(C 1-6 Alkyl group, 3-7 membered carbon cyclo group, 3-7 membered heterocyclic group, phenyl group or 5-10 membered heteroaryl group;

[0233] n S2 Choose from 0, 1, 2, or 3.

[0234] This invention relates to a compound of formula (III-53), or its stereoisomers, tautomers, pharmaceutically acceptable salts thereof, pharmaceutically acceptable salts of its stereoisomers, pharmaceutically acceptable salts of its tautomers, solvates thereof, prodrugs thereof, or deuterated derivatives thereof, wherein,

[0235]

[0236] R2 is independently selected from hydrogen, halogen, and -C each time it appears. 1-3 Alkyl and -C 1-3 Haloalkyl; preferably, R2 is independently selected from hydrogen and -C each time it appears. 1-3 alkyl;

[0237] R3 is independently selected from hydrogen, halogen, and -C each time it appears. 1-3 Alkyl, -C 1-3 Halogenated alkyl groups, -CN, -NH2, -NH(C) 1-3 alkyl), -N(C) 1-3 alkyl)2、-NH(C 3-7 cycloalkyl), -OH, -O(C 1-3 Alkyl), -O(C) 3-7 cycloalkyl), -SH, -S(C 1-3 alkyl), and -S(C 3-7 (cycloalkyl); preferably, R3 is independently selected from hydrogen, -C, and -C each time it appears. 1-3 Alkyl, -OH, -O(C) 1-3 alkyl), and -O(C 3-7 cycloalkyl);

[0238] R4 is independently selected from hydrogen, halogen, and -C each time it appears. 1-3 Alkyl and -C 1-3 Haloalkyl; preferably, R4 is independently selected from hydrogen and -C each time it appears. 1-3 alkyl;

[0239] R5 is independently selected from hydrogen, halogen, and -C each time it appears. 1-3 Alkyl, -C 1-3 Halogenated alkyl groups, -NH2, -NH(C) 1-3 alkyl), -N(C) 1-3 Alkyl group 2, -OH, -O(C) 1-3 Alkyl), -SH, -S(C 1-3 Alkyl groups), -C(=O)NH2, -C(=O)NH(C 1-3 Alkyl), -C(=O)N(C 1-3 Alkyl)2, -S(=O)NH2, -S(=O)NH(C 1-3 Alkyl), -S(=O)N(C 1-3 Alkyl)2, -S(=O)2NH2, -S(=O)2NH(C 1-3 Alkyl groups), and -S(=O)2N(C 1-3 Alkyl group 2; preferably, R5 is independently selected from hydrogen, halogen, -C each time it appears. 1-3 Alkyl, -C 1-3 Halogenated alkyl groups, -OH, -O(C)1-3 Alkyl groups), -C(=O)NH2, -C(=O)NH(C 1-3 Alkyl groups), and -C(=O)N(C 1-3 Alkyl)2;

[0240] A1 is selected from N and CR. A1 ;

[0241] A2 is selected from N and CR. A2 ;

[0242] A3 is selected from N and CR. A3 ;

[0243] A4 is selected from C(R) A41 2. NR A42 O and S;

[0244] Each (in CR) A1 R in A1 ), (in CR A2 R in A2 ), (in CR A3 R in A3 ), or (in CR A41 R in A41 Each time it appears, it is independently selected from hydrogen, halogen, -C 1-3 Alkyl and -C 1-3 Halogenated alkyl groups; preferably, each (in CR) A1 R in A1 ), (in CR A2 R in A2 ), (in CR A3 R in A3 ), or (in CR A41 R in A41 Each time it appears, it is independently selected from hydrogen and -C. 1-3 alkyl;

[0245] (in NR) A42 R in A42 Each time it appears, it is independently selected from hydrogen, -C 1-3 Alkyl, or -C 1-3 Halogenated alkyl groups;

[0246] R 10A Or R 10B Each time it appears, it is independently selected from hydrogen, halogen, -C. 1-3 Alkyl, -C 1-3 Halogenated alkyl groups, -CN, -NH2, -NH(C) 1-3 alkyl), -N(C) 1-3 Alkyl group 2, -OH, -O(C) 1-3Alkyl), -SH, and -S(C 1-3 Alkyl); preferably, R 10A Or R 10B Each time it appears, it is independently selected from -H or -C. 1-3 Alkyl, -NH(C) 1-3 alkyl), -N(C) 1-3 Alkyl)2、-O(C 1-3 alkyl), and -S(C 1-3 Alkyl); more preferably, R 10A Or R 10B Each time it appears, it is independently selected from -H or -C. 1-3 Alkyl groups and -O(C) 1-3 alkyl);

[0247] Y3 is selected from -C(R) Y3A )2-, or -O-;

[0248] R Y3A Each time it appears, it is independently selected from hydrogen, halogen, -C. 1-3 Alkyl, -C 1-3 Haloalkyl, -(C 1-3 alkylene)-O-(C 1-3 alkyl), -(C 1-3 alkylene)-O-(C 1-3 Halogenated alkyl groups, -OH groups, or -O(C) groups 1-3 alkyl);

[0249] R 12 Each time it appears, it is independently selected from hydrogen, -C 1-3 Alkyl, or -C 1-3 Halogenated alkyl; preferably, R 12 Each time it appears, it is independently selected from hydrogen or -C. 1-3 alkyl;

[0250] n6 is selected from 0, 1, 2, and 3; preferably, n6 is selected from 0, 1, and 2; more preferably, n6 is selected from 0 and 1;

[0251] n7 is selected from 0, 1, 2, and 3; preferably, n7 is selected from 0, 1, and 2; more preferably, n7 is selected from 0 and 1;

[0252] n8 is selected from 0, 1, 2, and 3; preferably, n8 is selected from 0, 1, and 2; more preferably, n8 is selected from 0 and 1;

[0253] n9 is selected from 0, 1, 2, and 3; preferably, n9 is selected from 0, 1, and 2; more preferably, n9 is selected from 0 and 1;

[0254] And n6+n7+n8+n9≤5.

[0255] This invention relates to a compound of formula (III-54), or its stereoisomers, tautomers, pharmaceutically acceptable salts thereof, pharmaceutically acceptable salts of its stereoisomers, pharmaceutically acceptable salts of its tautomers, its solvates, its prodrugs, or its deuterated derivatives thereof, wherein,

[0256]

[0257] R2 is independently selected from hydrogen, halogen, and -C each time it appears. 1-3 Alkyl and -C 1-3 Haloalkyl; preferably, R2 is independently selected from hydrogen and -C each time it appears. 1-3 alkyl;

[0258] R3 is independently selected from hydrogen, halogen, and -C each time it appears. 1-3 Alkyl, -C 1-3 Halogenated alkyl groups, -CN, -NH2, -NH(C) 1-3 alkyl), -N(C) 1-3 alkyl)2、-NH(C 3-7 cycloalkyl), -OH, -O(C 1-3 Alkyl), -O(C) 3-7 cycloalkyl), -SH, -S(C 1-3 alkyl), and -S(C 3-7 (cycloalkyl); preferably, R3 is independently selected from hydrogen, -C, and -C each time it appears. 1-3 Alkyl, -OH, -O(C) 1-3 alkyl), and -O(C 3-7 cycloalkyl);

[0259] R4 is independently selected from hydrogen, halogen, and -C each time it appears. 1-3 Alkyl and -C 1-3 Haloalkyl; preferably, R4 is independently selected from hydrogen and -C each time it appears. 1-3 alkyl;

[0260] R5 is independently selected from hydrogen, halogen, and -C each time it appears. 1-3 Alkyl, -C 1-3 Halogenated alkyl groups, -NH2, -NH(C) 1-3 alkyl), -N(C) 1-3 Alkyl group 2, -OH, -O(C) 1-3 Alkyl), -SH, -S(C 1-3 Alkyl groups), -C(=O)NH2, -C(=O)NH(C 1-3 Alkyl), -C(=O)N(C 1-3 Alkyl)2, -S(=O)NH2, -S(=O)NH(C1-3 Alkyl), -S(=O)N(C 1-3 Alkyl)2, -S(=O)2NH2, -S(=O)2NH(C 1-3 Alkyl groups), and -S(=O)2N(C 1-3 Alkyl group 2; preferably, R5 is independently selected from hydrogen, halogen, -C each time it appears. 1-3 Alkyl, -C 1-3 Halogenated alkyl groups, -OH, -O(C) 1-3 Alkyl groups), -C(=O)NH2, -C(=O)NH(C 1-3 Alkyl groups), and -C(=O)N(C 1-3 Alkyl)2;

[0261] A1 is selected from N and CR. A1 ;

[0262] A2 is selected from N and CR. A2 ;

[0263] A3 is selected from N and CR. A3 ;

[0264] A4 is selected from C(R) A41 2. NR A42 O and S;

[0265] Each (in CR) A1 R in A1 ), (in CR A2 R in A2 ), (in CR A3 R in A3 ), or (in CR A41 R in A41 Each time it appears, it is independently selected from hydrogen, halogen, -C 1-3 Alkyl and -C 1-3 Halogenated alkyl groups; preferably, each (in CR) A1 R in A1 ), (in CR A2 R in A2 ), (in CR A3 R in A3 ), or (in CR A41 R in A41 Each time it appears, it is independently selected from hydrogen and -C. 1-3 alkyl;

[0266] (in NR) A42 R in A42 Each time it appears, it is independently selected from hydrogen, -C 1-3 Alkyl, or -C 1-3 Halogenated alkyl groups;

[0267] Y3 is selected from -C(R) Y3A )2-, or -O-;

[0268] R Y3A Each time it appears, it is independently selected from hydrogen, halogen, -C. 1-3 Alkyl, -C 1-3 Haloalkyl, -(C 1-3 alkylene)-O-(C 1-3 alkyl), -(C 1-3 alkylene)-O-(C 1-3 Halogenated alkyl groups, -OH groups, or -O(C) groups 1-3 alkyl);

[0269] R 10A Or R 10B Each time it appears, it is independently selected from hydrogen, halogen, -C. 1-3 Alkyl, -C 1-3 Halogenated alkyl groups, -CN, -NH2, -NH(C) 1-3 alkyl), -N(C) 1-3 Alkyl group 2, -OH, -O(C) 1-3 Alkyl), -SH, and -S(C 1-3 Alkyl); preferably, R 10A Or R 10B Each time it appears, it is independently selected from -H or -C. 1-3 Alkyl, -NH(C) 1-3 alkyl), -N(C) 1-3 Alkyl)2、-O(C 1-3 alkyl), and -S(C 1-3 Alkyl); more preferably, R 10A Or R 10B Each time it appears, it is independently selected from -H or -C. 1-3 Alkyl groups and -O(C) 1-3 alkyl);

[0270] R 12 Each time it appears, it is independently selected from hydrogen, -C 1-3 Alkyl, or -C 1-3 Halogenated alkyl; preferably, R 12 Each time it appears, it is independently selected from hydrogen or -C. 1-3 alkyl;

[0271] n6 is selected from 0, 1, 2, and 3; preferably, n6 is selected from 0, 1, and 2; more preferably, n6 is selected from 0 and 1;

[0272] n7 is selected from 0, 1, 2, and 3; preferably, n7 is selected from 0, 1, and 2; more preferably, n7 is selected from 0 and 1;

[0273] n8 is selected from 0, 1, 2, and 3; preferably, n8 is selected from 0, 1, and 2; more preferably, n8 is selected from 0 and 1;

[0274] n9 is selected from 0, 1, 2, and 3; preferably, n9 is selected from 0, 1, and 2; more preferably, n9 is selected from 0 and 1;

[0275] And n6+n7+n8+n9≤5.

[0276] This invention relates to a compound of formula (III-55), or its stereoisomers, tautomers, pharmaceutically acceptable salts thereof, pharmaceutically acceptable salts of its stereoisomers, pharmaceutically acceptable salts of its tautomers, solvates thereof, prodrugs thereof, or deuterated derivatives thereof, wherein,

[0277]

[0278] R2 is independently selected from hydrogen, halogen, and -C each time it appears. 1-3 Alkyl and -C 1-3 Haloalkyl; preferably, R2 is independently selected from hydrogen and -C each time it appears. 1-3 alkyl;

[0279] R3 is independently selected from hydrogen, halogen, and -C each time it appears. 1-3 Alkyl, -C 1-3 Halogenated alkyl groups, -CN, -NH2, -NH(C) 1-3 alkyl), -N(C) 1-3 alkyl)2、-NH(C 3-7 cycloalkyl), -OH, -O(C 1-3 Alkyl), -O(C) 3-7 cycloalkyl), -SH, -S(C 1-3 alkyl), and -S(C 3-7 (cycloalkyl); preferably, R3 is independently selected from hydrogen, -C, and -C each time it appears. 1-3 Alkyl, -OH, -O(C) 1-3 alkyl), and -O(C 3-7 cycloalkyl);

[0280] R4 is independently selected from hydrogen, halogen, and -C each time it appears. 1-3 Alkyl and -C 1-3 Haloalkyl; preferably, R4 is independently selected from hydrogen and -C each time it appears. 1-3 alkyl;

[0281] R5 is independently selected from hydrogen, halogen, and -C each time it appears. 1-3 Alkyl, -C 1-3 Halogenated alkyl groups, -NH2, -NH(C)1-3 alkyl), -N(C) 1-3 Alkyl group 2, -OH, -O(C) 1-3 Alkyl), -SH, -S(C 1-3 Alkyl groups), -C(=O)NH2, -C(=O)NH(C 1-3 Alkyl), -C(=O)N(C 1-3 Alkyl)2, -S(=O)NH2, -S(=O)NH(C 1-3 Alkyl), -S(=O)N(C 1-3 Alkyl)2, -S(=O)2NH2, -S(=O)2NH(C 1-3 Alkyl groups), and -S(=O)2N(C 1-3 Alkyl group 2; preferably, R5 is independently selected from hydrogen, halogen, -C each time it appears. 1-3 Alkyl, -C 1-3 Halogenated alkyl groups, -OH, -O(C) 1-3 Alkyl groups), -C(=O)NH2, -C(=O)NH(C 1-3 Alkyl groups), and -C(=O)N(C 1-3 Alkyl)2;

[0282] A1 is selected from N and CR. A1 ;

[0283] A2 is selected from N and CR. A2 ;

[0284] A3 is selected from N and CR. A3 ;

[0285] A4 is selected from C(R) A41 2. NR A42 O and S;

[0286] Each (in CR) A1 R in A1 ), (in CR A2 R in A2 ), (in CR A3 R in A3 ), or (in CR A41 R in A41 Each time it appears, it is independently selected from hydrogen, halogen, -C 1-3 Alkyl and -C 1-3 Halogenated alkyl groups; preferably, each (in CR) A1 R in A1 ), (in CR A2 R in A2 ), (in CR A3 R in A3 ), or (in CR A41R in A41 Each time it appears, it is independently selected from hydrogen and -C. 1-3 alkyl;

[0287] (in NR) A42 R in A42 Each time it appears, it is independently selected from hydrogen, -C 1-3 Alkyl, or -C 1-3 Halogenated alkyl groups;

[0288] R 10A Or R 10B Each time it appears, it is independently selected from hydrogen, halogen, -C. 1-3 Alkyl, -C 1-3 Halogenated alkyl groups, -CN, -NH2, -NH(C) 1-3 alkyl), -N(C) 1-3 Alkyl group 2, -OH, -O(C) 1-3 Alkyl), -SH, and -S(C 1-3 Alkyl); preferably, R 10A Or R 10B Each time it appears, it is independently selected from -H or -C. 1-3 Alkyl, -NH(C) 1-3 alkyl), -N(C) 1-3 Alkyl)2、-O(C 1-3 alkyl), and -S(C 1-3 Alkyl); more preferably, R 10A Or R 10B Each time it appears, it is independently selected from -H or -C. 1-3 Alkyl groups and -O(C) 1-3 alkyl);

[0289] R 12 Each time it appears, it is independently selected from hydrogen, -C 1-3 Alkyl, or -C 1-3 Halogenated alkyl; preferably, R 12 Each time it appears, it is independently selected from hydrogen or -C. 1-3 alkyl;

[0290] Y5 is selected from -O- and -C(R) Y5A )2-; Preferably, Y5 is -O-;

[0291] R Y5A Each time it appears, it is independently selected from hydrogen, halogen, -C. 1-3 Alkyl, or -C 1-3 Halogenated alkyl; preferably, R Y5A Each time it appears, it is independently selected from hydrogen and -C. 1-3 alkyl;

[0292] n10 Selected from 0, 1, and 2; preferably, n 10 Selected from 0 and 1;

[0293] n 11 Selected from 0, 1, and 2; preferably, n 11 Selected from 0 and 1;

[0294] n 12 Selected from 0, 1, and 2; preferably, n 12 Selected from 0 and 1;

[0295] n 13 Selected from 0, 1, and 2; preferably, n 13 Selected from 0 and 1;

[0296] n 14 Selected from 0, 1, and 2; preferably, n 14 Selected from 0 and 1;

[0297] n 15 Selected from 0, 1, and 2; preferably, n 15 Selected from 0 and 1;

[0298] n 16 Selected from 0, 1, and 2; preferably, n 16 Selected from 0 and 1;

[0299] n 17 Selected from 0, 1, and 2; preferably, n 17 Selected from 0 and 1;

[0300] And n 10 +n 11 +n 12 +n 13 ≤6;

[0301] And n 14 +n 15 +n 16 +n 17 ≤6.

[0302] This invention relates to a compound of formula (III-33) or formula (III-35), or its stereoisomers, tautomers, pharmaceutically acceptable salts thereof, pharmaceutically acceptable salts of its stereoisomers, pharmaceutically acceptable salts of its tautomers, solvates thereof, prodrugs thereof, or deuterated derivatives thereof, wherein,

[0303]

[0304]

[0305] R2 is independently selected from hydrogen, halogen, and -C each time it appears. 1-3 Alkyl and -C 1-3 Haloalkyl; preferably, R2 is independently selected from hydrogen and -C each time it appears. 1-3 alkyl;

[0306] R3 is independently selected from hydrogen, halogen, and -C each time it appears. 1-3 Alkyl, -C 1-3 Halogenated alkyl groups, -CN, -NH2, -NH(C) 1-3 alkyl), -N(C) 1-3 alkyl)2、-NH(C 3-7 cycloalkyl), -OH, -O(C 1-3 Alkyl), -O(C) 3-7 cycloalkyl), -SH, -S(C 1-3 alkyl), and -S(C 3-7 (cycloalkyl); preferably, R3 is independently selected from hydrogen, -C, and -C each time it appears. 1-3 Alkyl, -OH, -O(C) 1-3 alkyl), and -O(C 3-7 cycloalkyl);

[0307] R4 is independently selected from hydrogen, halogen, and -C each time it appears. 1-3 Alkyl and -C 1-3 Haloalkyl; preferably, R4 is independently selected from hydrogen and -C each time it appears. 1-3 alkyl;

[0308] R5 is independently selected from hydrogen, halogen, and -C each time it appears. 1-3 Alkyl, -C 1-3 Halogenated alkyl groups, -NH2, -NH(C) 1-3 alkyl), -N(C) 1-3 Alkyl group 2, -OH, -O(C) 1-3 Alkyl), -SH, -S(C 1-3 Alkyl groups), -C(=O)NH2, -C(=O)NH(C 1-3 Alkyl), -C(=O)N(C 1-3 Alkyl)2, -S(=O)NH2, -S(=O)NH(C 1-3 Alkyl), -S(=O)N(C 1-3 Alkyl)2, -S(=O)2NH2, -S(=O)2NH(C 1-3 Alkyl groups), and -S(=O)2N(C 1-3 Alkyl group 2; preferably, R5 is independently selected from hydrogen, halogen, -C each time it appears. 1-3 Alkyl, -C 1-3 Halogenated alkyl groups, -OH, -O(C)1-3 Alkyl groups), -C(=O)NH2, -C(=O)NH(C 1-3 Alkyl groups), and -C(=O)N(C 1-3 Alkyl)2;

[0309] Each R A1 R A2 、or R A42 Each time it appears, it is independently selected from hydrogen, halogen, -C. 1-3 Alkyl and -C 1-3 Halogenated alkyl; more preferably, each R A1 R A2 、or R A42 Each time it appears, it is independently selected from hydrogen and -C. 1-3 alkyl;

[0310] R 10A Or R 10B Each time it appears, it is independently selected from hydrogen, halogen, -C. 1-3 Alkyl, -C 1-3 Halogenated alkyl groups, -CN, -NH2, -NH(C) 1-3 alkyl), -N(C) 1-3 Alkyl group 2, -OH, -O(C) 1-3 Alkyl), -SH, and -S(C 1-3 Alkyl); preferably, R 10A Or R 10B Each time it appears, it is independently selected from -H or -C. 1-3 Alkyl, -NH(C) 1-3 alkyl), -N(C) 1-3 Alkyl)2、-O(C 1-3 alkyl), and -S(C 1-3 Alkyl); more preferably, R 10A Or R 10B Each time it appears, it is independently selected from -H or -C. 1-3 Alkyl groups and -O(C) 1-3 alkyl);

[0311] R 12 Each time it appears, it is independently selected from hydrogen, -C 1-3 Alkyl, or -C 1-3 Halogenated alkyl; preferably, R 12 Each time it appears, it is independently selected from hydrogen or -C. 1-3 alkyl;

[0312] n6 is selected from 0, 1, and 2; preferably, n6 is selected from 0 and 1;

[0313] n7 is selected from 0, 1, and 2; preferably, n7 is selected from 0 and 1;

[0314] n8 is selected from 0, 1, and 2; preferably, n8 is selected from 0 and 1;

[0315] n9 is selected from 0, 1, and 2; preferably, n9 is selected from 0 and 1;

[0316] And n6+n7+n8+n9≤5.

[0317] This invention relates to a compound of formula (III-34) or formula (III-36), or its stereoisomers, tautomers, pharmaceutically acceptable salts thereof, pharmaceutically acceptable salts of its stereoisomers, pharmaceutically acceptable salts of its tautomers, solvates thereof, prodrugs thereof, or deuterated derivatives thereof, wherein,

[0318]

[0319] Each R A1 R A2 、or R A42 Each time it appears, it is independently selected from hydrogen, halogen, -C. 1-3 Alkyl and -C 1-3 Halogenated alkyl; more preferably, each R A1 R A2 、or R A42 Each time it appears, it is independently selected from hydrogen and -C. 1-3 alkyl;

[0320] R 10A Or R 10B Each time it appears, it is independently selected from hydrogen, halogen, -C. 1-3 Alkyl, -C 1-3 Halogenated alkyl groups, -CN, -NH2, -NH(C) 1-3 alkyl), -N(C) 1-3 Alkyl group 2, -OH, -O(C) 1-3 Alkyl), -SH, and -S(C 1-3 Alkyl); preferably, R 10A Or R 10B Each time it appears, it is independently selected from -H or -C. 1-3 Alkyl, -NH(C) 1-3 alkyl), -N(C) 1-3 Alkyl)2、-O(C 1-3 alkyl), and -S(C 1-3 Alkyl); more preferably, R 10A Or R 10B Each time it appears, it is independently selected from -H or -C. 1-3 Alkyl groups and -O(C) 1-3 alkyl);

[0321] R12 Each time it appears, it is independently selected from hydrogen, -C 1-3 Alkyl, or -C 1-3 Halogenated alkyl; preferably, R 12 Each time it appears, it is independently selected from hydrogen or -C. 1-3 alkyl;

[0322] n6 is selected from 0, 1, and 2; preferably, n6 is selected from 0 and 1;

[0323] n7 is selected from 0, 1, and 2; preferably, n7 is selected from 0 and 1;

[0324] n8 is selected from 0, 1, and 2; preferably, n8 is selected from 0 and 1;

[0325] n9 is selected from 0, 1, and 2; preferably, n9 is selected from 0 and 1;

[0326] And n6+n7+n8+n9≤5.

[0327] This invention relates to a compound of formula (III-41) or formula (III-42), or its stereoisomers, tautomers, pharmaceutically acceptable salts thereof, pharmaceutically acceptable salts of its stereoisomers, pharmaceutically acceptable salts of its tautomers, solvates thereof, prodrugs thereof, or deuterated derivatives thereof, wherein,

[0328]

[0329] R2 is independently selected from hydrogen, halogen, and -C each time it appears. 1-3 Alkyl and -C 1-3 Haloalkyl; preferably, R2 is independently selected from hydrogen and -C each time it appears. 1-3 alkyl;

[0330] R3 is independently selected from hydrogen, halogen, and -C each time it appears. 1-3 Alkyl, -C 1-3 Halogenated alkyl groups, -CN, -NH2, -NH(C) 1-3 alkyl), -N(C) 1-3 alkyl)2、-NH(C 3-7 cycloalkyl), -OH, -O(C 1-3 Alkyl), -O(C) 3-7 cycloalkyl), -SH, -S(C 1-3 alkyl), and -S(C 3-7 (cycloalkyl); preferably, R3 is independently selected from hydrogen, -C, and -C each time it appears. 1-3 Alkyl, -OH, -O(C) 1-3 alkyl), and -O(C 3-7 cycloalkyl);

[0331] R4 is independently selected from hydrogen, halogen, and -C each time it appears. 1-3 Alkyl and -C 1-3 Haloalkyl; preferably, R4 is independently selected from hydrogen and -C each time it appears. 1-3 alkyl;

[0332] R5 is independently selected from hydrogen, halogen, and -C each time it appears. 1-3 Alkyl, -C 1-3 Halogenated alkyl groups, -NH2, -NH(C) 1-3 alkyl), -N(C) 1-3 Alkyl group 2, -OH, -O(C) 1-3 Alkyl), -SH, -S(C 1-3 Alkyl groups), -C(=O)NH2, -C(=O)NH(C 1-3 Alkyl), -C(=O)N(C 1-3 Alkyl)2, -S(=O)NH2, -S(=O)NH(C 1-3 Alkyl), -S(=O)N(C 1-3 Alkyl)2, -S(=O)2NH2, -S(=O)2NH(C 1-3 Alkyl groups), and -S(=O)2N(C 1-3 Alkyl group 2; preferably, R5 is independently selected from hydrogen, halogen, -C each time it appears. 1-3 Alkyl, -C 1-3 Halogenated alkyl groups, -OH, -O(C) 1-3 Alkyl groups), -C(=O)NH2, -C(=O)NH(C 1-3 Alkyl groups), and -C(=O)N(C 1-3 Alkyl)2;

[0333] Each R A2 Each time it appears, it is independently selected from hydrogen, halogen, -C. 1-3 Alkyl and -C 1-3 Halogenated alkyl; preferably, each R A2 Each time it appears, it is independently selected from hydrogen and -C. 1-3 alkyl;

[0334] R 10A Or R 10B Each time it appears, it is independently selected from hydrogen, halogen, -C. 1-3 Alkyl, -C 1-3 Halogenated alkyl groups, -CN, -NH2, -NH(C) 1-3 alkyl), -N(C) 1-3 Alkyl group 2, -OH, -O(C) 1-3 Alkyl), -SH, and -S(C 1-3Alkyl); preferably, R 10A Or R 10B Each time it appears, it is independently selected from -H or -C. 1-3 Alkyl, -NH(C) 1-3 alkyl), -N(C) 1-3 Alkyl)2、-O(C 1-3 alkyl), and -S(C 1-3 Alkyl); more preferably, R 10A Or R 10B Each time it appears, it is independently selected from -H or -C. 1-3 Alkyl groups and -O(C) 1-3 alkyl);

[0335] R 12 Each time it appears, it is independently selected from hydrogen, -C 1-3 Alkyl, or -C 1-3 Halogenated alkyl; preferably, R 12 Each time it appears, it is independently selected from hydrogen or -C. 1-3 alkyl;

[0336] n6 is selected from 0, 1, and 2; preferably, n6 is selected from 0 and 1;

[0337] n7 is selected from 0, 1, and 2; preferably, n7 is selected from 0 and 1;

[0338] n8 is selected from 0, 1, and 2; preferably, n8 is selected from 0 and 1;

[0339] n9 is selected from 0, 1, and 2; preferably, n9 is selected from 0 and 1;

[0340] And n6+n7+n8+n9≤5.

[0341] This invention relates to a compound of formula (III-49) or formula (III-50), or its stereoisomers, tautomers, pharmaceutically acceptable salts thereof, pharmaceutically acceptable salts of its stereoisomers, pharmaceutically acceptable salts of its tautomers, solvates thereof, prodrugs thereof, or deuterated derivatives thereof, wherein,

[0342]

[0343] R2 is independently selected from hydrogen, halogen, and -C each time it appears. 1-3 Alkyl and -C 1-3 Haloalkyl; preferably, R2 is independently selected from hydrogen and -C each time it appears. 1-3 alkyl;

[0344] R3 is independently selected from hydrogen, halogen, and -C each time it appears. 1-3 Alkyl, -C 1-3Halogenated alkyl groups, -CN, -NH2, -NH(C) 1-3 alkyl), -N(C) 1-3 alkyl)2、-NH(C 3-7 cycloalkyl), -OH, -O(C 1-3 Alkyl), -O(C) 3-7 cycloalkyl), -SH, -S(C 1-3 alkyl), and -S(C 3-7 (cycloalkyl); preferably, R3 is independently selected from hydrogen, -C, and -C each time it appears. 1-3 Alkyl, -OH, -O(C) 1-3 alkyl), and -O(C 3-7 cycloalkyl);

[0345] R4 is independently selected from hydrogen, halogen, and -C each time it appears. 1-3 Alkyl and -C 1-3 Haloalkyl; preferably, R4 is independently selected from hydrogen and -C each time it appears. 1-3 alkyl;

[0346] R5 is independently selected from hydrogen, halogen, and -C each time it appears. 1-3 Alkyl, -C 1-3 Halogenated alkyl groups, -NH2, -NH(C) 1-3 alkyl), -N(C) 1-3 Alkyl group 2, -OH, -O(C) 1-3 Alkyl), -SH, -S(C 1-3 Alkyl groups), -C(=O)NH2, -C(=O)NH(C 1-3 Alkyl), -C(=O)N(C 1-3 Alkyl)2, -S(=O)NH2, -S(=O)NH(C 1-3 Alkyl), -S(=O)N(C 1-3 Alkyl)2, -S(=O)2NH2, -S(=O)2NH(C 1-3 Alkyl groups), and -S(=O)2N(C 1-3 Alkyl group 2; preferably, R5 is independently selected from hydrogen, halogen, -C each time it appears. 1-3 Alkyl, -C 1-3 Halogenated alkyl groups, -OH, -O(C) 1-3 Alkyl groups), -C(=O)NH2, -C(=O)NH(C 1-3 Alkyl groups), and -C(=O)N(C 1-3 Alkyl)2;

[0347] Each R A2 Each time it appears, it is independently selected from hydrogen, halogen, -C. 1-3 Alkyl and -C 1-3Halogenated alkyl; preferably, each R A2 Each time it appears, it is independently selected from hydrogen and -C. 1-3 alkyl;

[0348] R 10A Or R 10B Each time it appears, it is independently selected from hydrogen, halogen, -C. 1-3 Alkyl, -C 1-3 Halogenated alkyl groups, -CN, -NH2, -NH(C) 1-3 alkyl), -N(C) 1-3 Alkyl group 2, -OH, -O(C) 1-3 Alkyl), -SH, and -S(C 1-3 Alkyl); preferably, R 10A Or R 10B Each time it appears, it is independently selected from -H or -C. 1-3 Alkyl, -NH(C) 1-3 alkyl), -N(C) 1-3 Alkyl)2、-O(C 1-3 alkyl), and -S(C 1-3 Alkyl); more preferably, R 10A Or R 10B Each time it appears, it is independently selected from -H or -C. 1-3 Alkyl groups and -O(C) 1-3 alkyl);

[0349] R 12 Each time it appears, it is independently selected from hydrogen, -C 1-3 Alkyl, or -C 1-3 Halogenated alkyl; preferably, R 12 Each time it appears, it is independently selected from hydrogen or -C. 1-3 alkyl;

[0350] n 10 Selected from 0, 1, and 2; preferably, n 10 Selected from 0 and 1;

[0351] n 11 Selected from 0, 1, and 2; preferably, n 11 Selected from 0 and 1;

[0352] n 12 Selected from 0, 1, and 2; preferably, n 12 Selected from 0 and 1;

[0353] n 13 Selected from 0, 1, and 2; preferably, n 13 Selected from 0 and 1;

[0354] n 14Selected from 0, 1, and 2; preferably, n 14 Selected from 0 and 1;

[0355] n 15 Selected from 0, 1, and 2; preferably, n 15 Selected from 0 and 1;

[0356] n 16 Selected from 0, 1, and 2; preferably, n 16 Selected from 0 and 1;

[0357] n 17 Selected from 0, 1, and 2; preferably, n 17 Selected from 0 and 1;

[0358] And n 10 +n 11 +n 12 +n 13 ≤6;

[0359] And n 14 +n 15 +n 16 +n 17 ≤6.

[0360] In some embodiments, the compound represented by formula (I) is selected from:

[0361]

[0362] On the other hand, the present invention provides a pharmaceutical composition comprising a compound of formula (I) of the present invention, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt thereof, a solvate thereof, a prodrug thereof, or a deuterated derivative thereof, and one or more pharmaceutically acceptable carriers or excipients.

[0363] On the other hand, the present invention provides a method for preparing the compound of formula (I), its stereoisomers, its pharmaceutically acceptable salts, pharmaceutically acceptable salts of its stereoisomers, its solvates, its prodrugs, or its deuterated derivatives, comprising the following steps:

[0364]

[0365] Compound (I-1) and compound (I-2) are reacted via a reductive amination reaction to yield compound (I);

[0366] Among them, R1, R2, R3, R4, R5, R6, fragments and its (rings G, R) S2 and n S2 ), R 10A R 10BR 12 fragments and its (rings B, R) S2 and n S2 The definition of ) is the same as that of formula (I).

[0367] On the other hand, the present invention provides the use of a compound of formula (I) of the present invention, its stereoisomer, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt thereof, a solvate thereof, a prodrug thereof, or a deuterated derivative thereof; or a pharmaceutical composition containing the above compound in the preparation of a medicament for treating central nervous system diseases related to Kappa receptor antagonism; preferably, the central nervous system diseases related to Kappa receptor antagonism include, but are not limited to, central nervous system diseases related to anxiety, central nervous system diseases related to depression, central nervous system diseases related to mood disorders, central nervous system diseases related to substance dependence and abuse, and others such as psychosis. Central nervous system disorders related to mental illnesses such as schizophrenia or Parkinson's disease; among them, central nervous system disorders related to anxiety include, but are not limited to, anxiety disorders, phobias, stress-related anxiety disorders, post-traumatic stress disorder (PTSD), and generalized anxiety disorder (GAD); central nervous system disorders related to depression include, but are not limited to, depression, major depressive disorder (MDD), major depressive disorder, treatment-resistant depression, and major depressive disorder with moderate to severe anhedonia; central nervous system disorders related to mood disorders include, but are not limited to, mood disorders, anhedonia, and bipolar disorder; central nervous system disorders related to substance dependence and abuse include, but are not limited to, smoking cessation and opioid withdrawal.

[0368] On the other hand, the present invention provides a method for treating a subject suffering from a central nervous system disorder related to Kappa receptor antagonism, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (I), its stereoisomer, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt thereof, a solvate thereof, its prodrug, or a deuterated derivative thereof; or a pharmaceutical composition containing the above compound; the central nervous system disorder related to Kappa receptor antagonism includes, but is not limited to, central nervous system disorders related to anxiety, central nervous system disorders related to depression, central nervous system disorders related to mood disorders, central nervous system disorders related to substance dependence and abuse, and others. Central nervous system disorders (CNS) related to mental illnesses such as schizophrenia or Parkinson's disease; among them, CNS disorders related to anxiety include, but are not limited to, anxiety disorders, phobias, stress-related anxiety disorders, post-traumatic stress disorder (PTSD), and generalized anxiety disorder (GAD); CNS disorders related to depression include, but are not limited to, depression, major depressive disorder (MDD), major depressive disorder, treatment-resistant depression, and major depressive disorder with moderate to severe anhedonia; CNS disorders related to mood disorders include, but are not limited to, mood disorders, anhedonia, and bipolar disorder; and CNS disorders related to substance dependence and abuse include, but are not limited to, smoking cessation and opioid withdrawal.

[0369] This invention provides the use of a compound of formula (I) as described in this invention, its stereoisomer, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of its stereoisomer, its solvate, its prodrug, or a deuterated derivative thereof; or a pharmaceutical composition containing the above compound in the context of central nervous system diseases associated with Kappa receptor antagonism; preferably, the central nervous system diseases associated with Kappa receptor antagonism include, but are not limited to, central nervous system diseases associated with anxiety, central nervous system diseases associated with depression, central nervous system diseases associated with mood disorders, central nervous system diseases associated with substance dependence and abuse, and others such as schizophrenia or Parkinson's disease. Central nervous system disorders related to mental illnesses, including anxiety disorders, phobias, stress-related anxiety disorders, post-traumatic stress disorder (PTSD), and generalized anxiety disorder (GAD); central nervous system disorders related to depression, including but not limited to depression, major depressive disorder (MDD), major depressive disorder, treatment-resistant depressive disorder, and major depressive disorder with moderate to severe anhedonia; central nervous system disorders related to mood disorders, including but not limited to mood disorders, anhedonia, and bipolar disorder; and central nervous system disorders related to substance dependence and abuse, including but not limited to smoking cessation and opioid withdrawal.

[0370] definition

[0371] Unless otherwise stated, the following terms have the meanings described below. Other terms are defined elsewhere throughout this specification.

[0372] As used herein, the singular forms "a," "an," and "the" include the plural forms unless the context clearly indicates otherwise. It should also be noted that claims may be drafted to exclude any optional elements. Therefore, this statement is intended as a priori basis for the use of such proprietary terms as "unique," "only," etc., in connection with reference to or use of negative limitations of claim elements.

[0373] The term "substituted" means that an atom or group of atoms formally replaces hydrogen as a "substituent" attached to another group. The term "substitution," unless otherwise stated, refers to any number of substitutions, such as mono-, di-, tri-, tetra-, or penta-substitution, if such substitution is permitted. Substituents are chosen independently, and substitution can occur at any chemically accessible position. It should be understood that substitution at a particular atom is limited by valence. The term "optionally substituted" means either unsubstituted or substituted. The term "substituted" means that a hydrogen atom is removed and replaced by a substituent. A single divalent substituent, such as oxo, can replace two hydrogen atoms.

[0374] The term "Cn-m" represents a range, including the endpoints, where n and m are integers representing the number of carbon atoms. For example, the term "C 1-6 "Alkyl" specifically refers to methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl. "C0 alkyl" refers to a covalent bond.

[0375] It should also be understood that, for clarity, certain features of the invention described in the context of individual embodiments may also be provided in combination with individual embodiments. Conversely, for the sake of brevity, various features of the invention described in the context of individual embodiments may also be provided individually or in any suitable sub-combination.

[0376] Unless otherwise stated, the term "alkyl" as used herein, either alone or as part of another substituent, refers to a straight-chain or branched saturated hydrocarbon group. Alkyl groups may contain from 1 to about 20, from 2 to about 20, from 1 to about 10, from 1 to about 8, from 1 to about 6, from 1 to about 4, or from 1 to about 3 carbon atoms. Similarly, C 1-6 C 1-8An alkyl group is defined as having 1, 2, 3, 4, 5, or 6 carbon atoms arranged in a straight or branched chain. Exemplary alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, tert-butyl), pentyl (e.g., n-pentyl, isopentyl, neopentyl), etc.

[0377] Unless otherwise stated, the term "haloalkyl" as used herein refers to the aforementioned alkyl group substituted with one or more (e.g., 1, 2, 3, 4, 5, or 6) halogens (such as -F, -Cl, or -Br). In some embodiments, the haloalkyl group is interchangeably -C 1-10 Halogenated alkyl or halogenated C 1-10 Alkyl, wherein -C 1-10 Halogenated alkyl or halogenated C 1-10 C in alkyl 1-10 This indicates that the total number of carbon atoms in an alkyl group is 1 to 10. In some embodiments, -C 1-10 Haloalkyl is -C 1-6 Haloalkyl. In some embodiments, -C 1-6 Haloalkyl is -C 1-3 Haloalkyl. In some embodiments, -C 1-3 The haloalkyl group is a methyl, ethyl, propyl, or isopropyl group substituted with 1, 2, 3, 4, 5, or 6 -F groups; preferably, -C 1-3 The alkyl halotype is -CF3.

[0378] Unless otherwise stated, the term "alkylene" as used herein refers to a bifunctional group obtained by removing an additional hydrogen atom from an alkyl group as defined above. In some embodiments, the alkylene group is C10. 0-6 Alkylene. In some embodiments, the C 0-6 Alkylene is C 1-3 Alkylene. The C preceding the alkylene group... 0-6 The total number of carbon atoms in the alkylene group is 0 to 6, and 0 indicates that the two ends of the alkylene group are directly connected. Non-limiting alkylene groups include methylene (i.e., -CH2-), ethylene (i.e., -CH2-CH2- or -CH(CH3)-), and propylene (i.e., -CH2-CH2-CH2-, -CH(-CH2-CH3)- or -CH2-CH(CH3)-).

[0379] Unless otherwise stated, the term "alkenyl" as used herein refers to a straight-chain or branched hydrocarbon group containing one or more double bonds, typically with a length of 2 to 20 carbon atoms. In some embodiments, the alkenyl group is -C 2-10 Alkenyl. In some embodiments, -C 2-10 Alkenyl groups are -C groups containing 2-6 carbon atoms.2-6 Alkenyl groups. Non-limiting alkenyl groups include vinyl, propenyl, butenyl, 2-methyl-2-buten-1-yl, heptenyl, octenyl, etc.

[0380] Unless otherwise stated, the term "alkynyl" as used herein refers to a straight-chain or branched hydrocarbon group containing one or more triple bonds, typically with a length of 2 to 20 carbon atoms. In some embodiments, the alkynyl group is -C 2-10 Alkynyl group. In some embodiments, -C 2-10 The alkynyl group is a -C group containing 2-6 carbon atoms. 2-6 Alkyne group. Non-restrictive alkyne groups include ethynyl, 1-propynyl, 1-butynyl, heptynyl, octyynyl, etc.

[0381] The term "alkoxy group" refers to an alkyl group attached to the remainder of a molecule via an oxygen atom, wherein the alkyl group has the meaning as described in this invention. In one embodiment, the alkoxy group contains 1-6 carbon atoms. In another embodiment, the alkoxy group contains 1-5 carbon atoms; in yet another embodiment, the alkoxy group contains 1-3 carbon atoms. The alkoxy group may optionally be substituted by one or more substituents described in this invention. Examples of alkoxy groups include, but are not limited to, methoxy (MeO, -OCH3), ethoxy (EtO, -OCH2CH3), 1-propoxy (n-PrO, n-propoxy, -OCH2CH2CH3), 2-propoxy (i-PrO, i-propoxy, -OCH(CH3)2), 1-butoxy (n-BuO, n-butoxy, -OCH2CH2CH2CH3), 2-methyl-l-propoxy (i-BuO, i-butoxy, -OCH2CH(CH3)2), 2-butoxy (s-BuO, s-butoxy, -OCH(CH3)CH2CH3), 2-methyl-2-propoxy (t-BuO, t-butoxy, -OC(CH3)3), etc.

[0382] Unless otherwise stated, the term "carbocyclic ring" as used herein refers to a fully saturated or partially saturated non-aromatic ring, including monocyclic, bicyclic, bridged, fused, or spirocyclic rings, containing only carbon atoms as ring members. In some embodiments, the carbocyclic ring is a ternary to 20-membered (e.g., 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, 12-, 13-, 14-, 15-, 16-, 17-, 18-, 19-, or 20-membered) carbocyclic ring and is fully saturated or has one or more degrees of unsaturation. The carbocyclic ring includes cycloalkyl rings where all ring carbon atoms are saturated, cycloalkenyl rings containing at least one double bond (preferably), and cycloalkynyl rings containing at least one triple bond (preferably). The carbocyclic base ring includes monocyclic-carbocyclic base rings with only one ring, and bicyclic or polycyclic carbocyclic base rings shared between rings by one, two, three, or more atoms. Monocyclic-carbocyclic rings with only one ring include saturated monocyclic-cycloalkyl rings, monocyclic-cycloalkenyl rings containing at least one double bond, and monocyclic-cycloynyl rings. Exemplary monocyclic-cycloalkyl rings include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, and cyclodecyl rings. Exemplary monocyclic-cycloalkenyl rings include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclononenyl, and cyclodecenyl rings. A carbon ring in which each ring shares only one ring atom with another ring is called a "spirocyclic-carbocyclic ring". In some embodiments, the spirocyclic-carbocyclic ring is a bicyclic spirocycle. The "spirocyclic-carbocyclic ring" includes saturated "spirocyclic-cycloalkyl rings", "spirocyclic-cycloalkenyl rings" containing at least one double bond, and "spirocyclic-cycloynyl rings" containing at least one triple bond. Non-limiting examples of “spirocyclic-cycloalkyl rings” include spiro[2.2]pentane, spiro[3.3]heptane, spiro[2.4]heptane, spiro[3.4]octane, spiro[2.5]octane, spiro[3.5]nonane, spiro[4.4]nonane, spiro[2.6]nonane, spiro[4.5]decane, spiro[3.6]decane, spiro[5.5]undecane, etc. A carbon ring in which each ring shares two adjacent ring atoms with another ring is called a “fused-ring-carbocyclic ring”. In some embodiments, the “fused-ring-carbocyclic ring” is a bicyclic fused ring. A “fused-ring-carbocyclic ring” includes a saturated “fused-ring-cycloalkyl ring”, a “fused-ring-cycloalkenyl ring” containing at least one double bond, and a “fused-ring-cycloalkynyl ring” containing at least one triple bond. A monocyclic carbon ring fused with an aromatic ring (e.g., phenyl) is included in the definition of a fused carbon ring. The term "bridged ring-carbocyclic ring" refers to a carbon ring containing at least two bridgehead carbon atoms and at least one bridging carbon atom. The bridged carbon ring includes bicyclic bridged carbon rings containing two bridgehead carbon atoms and polycyclic bridged carbon rings containing more than two bridgehead carbon atoms.The term "bridged ring-carbocyclic ring" includes a saturated "bridged ring-cycloalkyl ring", a "bridged ring-cycloalkenyl ring" containing at least one double bond, and a "bridged ring-cycloalkynyl ring" containing at least one triple bond. In some embodiments, the "bridged ring-carbocyclic ring" is a bicyclic bridged carbocyclic ring. Non-limiting examples of bicyclic "fused ring-cycloalkyl ring" / bicyclic "bridged ring-cycloalkyl ring" include: bicyclo[1.1.0]butane, bicyclo[2.1.0]pentane, bicyclo[1.1.1]pentane, bicyclo[3.1.0]hexane, bicyclo[2.1.1]hexane, bicyclo[3.2.0]heptane, bicyclo[4.1.0]heptane, bicyclo[2.2.1]heptane, bicyclo[3.1.1]heptane, bicyclo[4.2.0]octane, bicyclo[3.2.1]octane. Alkane, bicyclo[2.2.2]octane, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, bicyclo[4.4.0]decane, bicyclo[4.1.1]octane, bicyclo[3.3.1]nonane, bicyclo[4.2.1]nonane, bicyclo[3.3.2]decane, bicyclo[4.2.2]decane, bicyclo[4.3.1]decane, bicyclo[3.3.3]undecane, bicyclo[4.3.2]undecane, or bicyclo[4.3.3]dodecane, etc. In this invention, "carbocyclic ring" and "carbocyclic base ring" are interchangeable.

[0383] Unless otherwise stated, the term "carbocyclic group" as used herein refers to a monovalent group obtained by removing a hydrogen atom from a carbon atom of a carbocyclic ring as defined above.

[0384] Unless otherwise stated, the term "heterocycle" as used herein refers to a non-aromatic ring that is fully or partially saturated and consists of a monocyclic, bicyclic, bridged, fused, or spirocyclic ring containing not only carbon atoms as ring members but also one or more (e.g., 1, 2, 3, 4, 5, or 6) heteroatoms. Preferred heteroatoms include N, O, S, N oxides (NO), sulfur oxides (SO), and sulfur dioxide (SO2). Heterocycles containing only N atoms are called nitrogen heterocycles, heterocycles containing only O atoms are called oxygen heterocycles, and heterocycles containing only S atoms are called sulfur heterocycles. In some embodiments, the heterocycle is a monocyclic, bicyclic, tricyclic, or polycyclic system having 3 to 20 ring atoms (e.g., 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, 12-, 13-, 14-, 15-, 16-, 17-, 18-, 19-, or 20-membered). When the heterocycle is monocyclic (e.g., a 3- to 8-membered monocycle), it has 1 to 3 heteroatoms. When the heterocycle is bicyclic (e.g., an 8- to 12-membered bicycle), it has 1 to 6 heteroatoms. When the heterocycle is tricyclic or polycyclic, it has 1 to 9 heteroatoms. The heterocycle includes a saturated heterocyclic alkyl ring, a heterocyclic alkenyl ring containing at least one double bond (preferably containing one double bond), and a heterocyclic alkynyl ring containing at least one triple bond (preferably containing one triple bond). The heterocyclic base ring includes monocyclic-heterocyclic base rings with only one ring, and bicyclic or polycyclic heterocyclic base rings shared between rings by one, two, three, or more atoms. Monocyclic-heterocyclic base rings with only one ring include saturated monocyclic-heterocyclic alkyl rings, monocyclic-heterocyclic alkenyl rings containing at least one double bond, and monocyclic-heterocyclic alkynyl rings containing at least one triple bond. Exemplary examples of monocyclic-heterocyclic alkyl rings include piperazine, piperidine, tetrahydrothiophene, tetrahydropyran, dioxane, morpholine, tetrahydrofuran, aziridine, aziridine propane, aziridine heptane, pyrrolidine, oxacyclobutane, oxacyclopropane, tetrahydrofuran, tetrahydroimidazolium, tetrahydrothiazole, tetrahydropyran, thiomorpholine, etc. Exemplary examples of monocyclic-heterocyclic alkenyl rings include... A heterocycle in which each ring shares only one ring atom with another ring is called a "spirocyclic-heterocyclic base ring". In some embodiments, the spirocycle is a bicyclic spirocycle. The "spirocyclic-heterocyclic base ring" includes a saturated "spirocyclic-heterocyclic alkyl ring", a "spirocyclic-heterocyclic alkenyl ring" containing at least one double bond, and a "spirocyclic-heterocyclic alkynyl ring" containing at least one triple bond. Non-limiting examples of “spirocyclic-heterocyclic alkyl rings” include: 2-azaspiro[2.2]pentyl ring, 4-azaspiro[2.5]octyl ring, 1-azaspiro[3.5]nonyl ring, 2-azaspiro[3.5]nonyl ring, 7-azaspiro[3.5]nonyl ring, 2-azaspiro[4.4]nonyl ring, 6-azaspiro[2.6]nonyl ring, 1,7-diazaspiro[4.5]decyl ring, 7-azaspiro[4.5]decyl ring, 2,5-diazaspiro[3.6]decyl ring, 3-azaspiro[5.5]undecyl ring, 2- Oxaspiro[2.2]pentyl ring, 4-oxaspiro[2.5]octyl ring, 1-oxaspiro[3.5]nonyl ring, 2-oxaspiro[3.5]nonyl ring, 7-oxaspiro[3.5]nonyl ring, 2-oxaspiro[4.4]nonyl ring, 6-oxaspiro[2.6]nonyl ring, 1,7-dioxaspiro[4.5]decyl ring, 2,5-dioxaspiro[3.6]decyl ring, 1-oxaspiro[5.5]undecyl ring, 3-oxaspiro[5.5]undecyl ring, 3-oxa-9-azaspiro[5.5]undecyl ring, etc. A heterocyclic ring in which each ring shares two adjacent ring atoms with another ring is called a "fused ring-heterocyclic ring". In some embodiments, the fused ring is a bicyclic fused ring. The term "fused-ring-heterocyclic base ring" includes a saturated "fused-ring-heterocyclic alkyl ring," a "fused-ring-heterocyclic alkenyl ring" containing at least one double bond, and a "fused-ring-heterocyclic alkynyl ring" containing at least one triple bond. Monocyclic heterocycles fused to an aromatic ring (e.g., phenyl) are included in the definition of fused heterocycles. The term "bridged-ring-heterocyclic base ring" refers to a heterocycle containing at least two bridgehead carbon atoms and at least one bridging carbon atom. The bridged heterocycle includes bicyclic bridged heterocycles containing two bridgehead carbon atoms and polycyclic bridged heterocycles containing more than two bridgehead carbon atoms. The term "bridged-ring-heterocyclic base ring" includes a saturated "bridged-ring-heterocyclic alkyl ring," a "bridged-ring-heterocyclic alkenyl ring" containing at least one double bond, and a "bridged-ring-heterocyclic alkynyl ring" containing at least one triple bond. In some embodiments, the "bridged-ring-heterocyclic base ring" is a bicyclic bridged heterocycle.Non-limiting examples of “fused-ring-heterocyclic alkyl ring” / “bridged-ring-heterocyclic alkyl ring” include: 2-azabicyclo[1.1.0]butyl ring, 2-azabicyclo[2.1.0]pentyl ring, 2-azabicyclo[1.1.1]pentyl ring, 3-azabicyclo[3.1.0]hexyl ring, 5-azabicyclo[2.1.1]hexyl ring, 3-azabicyclo[3.2.0]heptyl ring, octahydrocyclopent[c]pyrrole ring, 3-azabicyclo[4.1.0]heptyl ring, 7-azabicyclo[2.2.1]heptyl ring, 6-azabicyclo[3.1.1]heptyl ring, 7-azabicyclo[4.2.0]octyl ring, 2-azabicyclo[2.2.2] Octyl ring, 3-azabicyclo[3.2.1]octyl ring, 2-oxabicyclo[1.1.0]butyl ring, 2-oxabicyclo[2.1.0]pentyl ring, 2-oxabicyclo[1.1.1]pentyl ring, 3-oxabicyclo[3.1.0]hexyl ring, 5-oxabicyclo[2.1.1]hexyl ring, 3-oxabicyclo[3.2.0]heptyl ring, 3-oxabicyclo[4.1.0]heptyl ring, 7-oxabicyclo[2.2.1]heptyl ring, 6-oxabicyclo[3.1.1]heptyl ring, 7-oxabicyclo[4.2.0]octyl ring, 2-oxabicyclo[2.2.2]octyl ring, 3-oxabicyclo[3.2.1]octyl ring, etc. In this invention, "heterocyclic ring" and "heterocyclic base ring" are interchangeable.

[0385] Unless otherwise stated, the term "heterocyclic group" as used herein refers to a monovalent group obtained by removing a hydrogen atom from a ring carbon atom of a heterocycle as defined above.

[0386] Unless otherwise stated, the terms "aryl" or "aromatic ring" as used herein refer to a monocyclic or polycyclic aromatic ring system containing only a carbon ring atom. Preferred aryl groups are 6-10 membered aromatic rings, either monocyclic or bicyclic. Phenyl and naphthyl are preferred aryl groups.

[0387] A heteroaryl group refers to an aromatic group having a fully conjugated π-electron system with 6-20 carbon atoms and at least one ring containing an O, N, and / or S heteroatom, or a heteroaryl group refers to an aromatic ring containing at least one O, N, and / or S heteroatom and 1-6 carbon atoms. Preferably, a heteroaryl group contains 1-4, more preferably 1, 2, or 3 O and / or N heteroatoms. Non-limiting examples of heteroaryl groups include: pyrrole ring, furan ring, thiophene ring, imidazole ring, oxazole ring, isoxazole ring, thiazole ring, isothiazole ring, tetrazolium ring, pyrazole ring, triazole ring, thiadiazole ring, oxadiazole ring, pyridine ring, pyrimidine ring, pyrazine ring, pyridazine ring, indole ring, isoindole ring, indazine ring, benzofuran ring, isobenzofuran ring, benzo[b]thiophene ring, benzo[c]thiophene ring, indazole ring, benzo[d]imidazolium ring, pyrrolo[3,2-b]pyridine ring, pyrrolo[3,2-c]pyridine ring, Pyrrolo[2,3-c]pyridine ring, pyrrolo[2,3-b]pyridine ring, pyrrolo[3,4-b]pyridine ring, pyrrolo[3,4-c]pyridine ring, benzo[d]isoxazole ring, benzo[d]oxazole ring, furano[3,2-b]pyridine ring, furano[3,2-c]pyridine ring, furano[2,3-c]pyridine ring, furano[2,3-b]pyridine ring, benzo[c]isoxazole ring, furano[3,4-b]pyridine ring, furano[3,4-c]pyridine ring, benzo[ [d]isothiazolium ring, benzo[d]thiazolium ring, thieno[3,2-b]pyridine ring, thieno[3,4-c]pyridine ring, benzo[d][1,2,3]triazole ring, pyrazolo[4,3-b]pyridine ring, pyrazolo[4,3-c]pyridine ring, pyrazolo[3,4-c]pyridine ring, pyrazolo[3,4-b]pyridine ring, imidazo[4,5-b]pyridine ring, imidazo[4,5-c]pyridine ring, imidazo[4,5-c]pyridine ring, imidazo[4,5-b]pyridine ring Pyrrolo[3,2-c]pyridazine ring, pyrrolo[3,2-d]pyrimidine ring, pyrrolo[2,3-b]pyrazine ring, pyrrolo[2,3-d]pyridazine ring, pyrrolo[2,3-d]pyrimidine ring, pyrrolo[2,3-c]pyridazine ring, pyrrolo[3,4-c]pyridazine ring, pyrrolo[3,4-d]pyrimidine ring, pyrrolo[3,4-b]pyrazine ring, pyrrolo[3,4-d]pyridazine ring, pyrrolo[3,4-d]pyrimidine ring, 6H-pyrrolo[3,4-c]pyridazine ring, etc.

[0388] Unless otherwise stated, the term “five-membered diene cycloyl” as used herein includes “five-membered diene heterocycloyl” and “five-membered diene carbocycloyl”. “Five-membered diene heterocycloyl” refers to a five-membered heterocycloyl group among the aforementioned heterocycloyl groups containing two double bonds or a five-membered heteroaryl group among the aforementioned heteroaryl groups. “Five-membered diene carbocycloyl” refers to a “five-membered diene cycloalkenyl” group among the aforementioned heterocycloyl groups containing two double bonds.

[0389] Unless otherwise stated, the term "oxo" refers to an oxygen substituent (i.e., =O) linked by a double bond.

[0390] The compounds described in this invention may be asymmetric (e.g., having one or more stereocenters). Unless otherwise stated, all stereoisomers, such as enantiomers and diastereomers, are included within the scope of this invention. Compounds containing asymmetrically substituted carbon atoms described in this invention may be optically active or racemic. Methods for preparing the optically active form from optically active starting materials are known in the art, for example, by resolution of racemic mixtures or by stereoselective synthesis. Many geometrical isomers of alkenes, C=N double bonds, etc., may also be present in the compounds described in this invention, and all stable isomers are also within the scope of this invention. Cis and trans geometrical isomers of the compounds described in this invention are also within the scope of this invention and may be isolated as mixtures of isomers or as isolated isomeric forms.

[0391] The compounds of this invention also include tautomers. Tautomers arise from the exchange of single bonds with adjacent double bonds and the accompanying proton migration. Tautomers include proton-transfer tautomers having the same chemical formula and total charge. Exemplary proton-transfer tautomers include keto-enol tautomers, amide-imino tautomers, lactam-lactide tautomers, amide-imino tautomers, and enamine-imino tautomers, in which protons in the cyclic structure can interleave at two or more positions in the heterocyclic system, for example, 1H- and 3H-imidazolium, 1H-, 2H- and 4H-1,2,4-triazole, 1H- and 2H-isoindole, and 1H- and 2H-pyrazole; certain hydroxyl-substituted compounds can exist as tautomers, as shown below: Tautomers can be in equilibrium, or their space can be fixed by suitable substitution to form a single form. When tautomers are present in the compounds of this invention, this invention includes any possible tautomers and their pharmaceutically acceptable salts and mixtures thereof, unless otherwise specifically stated.

[0392] In some cases, the compounds described in this invention may exist in the form of rotational isomers. The description of the compounds of this invention is intended to cover any single rotational isomer, and any mixture of rotational isomers in any proportion, and does not represent any particular rotational isomer. The description of a particular rotational isomer means that the described rotational isomer substantially free of other rotational isomers.

[0393] It should also be understood that compounds having the same molecular formula but different atomic bonding properties or sequences or spatial arrangements are called "isomers". Isomers with different spatial arrangements of atoms are called "stereoisomers", such as diastereomers, enantiomers, and rotational isomers. The compounds of the present invention may have one or more asymmetric centers; therefore, such compounds may be produced as separate (R)- or (S)-stereoisomers at each asymmetric center or as mixtures thereof. Unless otherwise specified, the description or naming of a particular compound in the specification and claims is intended to include all its racemic or other stereoisomers and mixtures thereof. When a structure contains one chiral center but does not show the specific stereochemistry of that center, the structure comprises two enantiomers, individually or as a mixture of enantiomers. When a structure contains more than one chiral center but does not show the specific stereochemistry of that center, the structure comprises all enantiomers and diastereomers, individually or as a mixture thereof. Methods for determining stereochemistry and separating stereoisomers are well known in the art.

[0394] This invention further includes isotopic labels of the compounds or intermediates described herein. "Isotope" refers to atoms having the same number of atoms but different molecular weights. For example, isotopes of hydrogen include protium and deuterium. In some embodiments, the compounds described herein or their salts are substantially isolated. "Substantially isolated" means that the compound is at least partially or substantially isolated from the environment in which it was formed or detected. Partial isolation may include, for example, compositions rich in the compounds of this invention. Substantially isolated may include compositions containing at least about 50 wt%, at least about 60 wt%, at least about 70 wt%, at least about 80 wt%, at least about 90 wt%, at least about 95 wt%, at least about 97 wt%, or at least about 99 wt% of the compounds of this invention or their salts. Methods for separating compounds and their salts are conventional in the art.

[0395] This invention also includes pharmaceutically acceptable salts of the compounds described herein. As used herein, "pharmaceutically acceptable salt" refers to a derivative of the compounds described herein, wherein the parent compound is modified by converting an existing acid or base moiety into its salt form. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral acid or organic acid salts of basic residues (such as amines); basic or organic salts of acidic residues (such as carboxylic acids); etc. Pharmaceutically acceptable salts of this invention include, for example, non-toxic salts of parent compounds formed from non-toxic inorganic or organic acids. Pharmaceutically acceptable salts of this invention can be synthesized from parent compounds containing basic or acidic moieties using conventional chemical methods. Typically, the salts are prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of a suitable base or acid in water or an organic solvent or a mixture thereof; typically, a non-aqueous medium such as ether, ethyl acetate, alcohol (e.g., methanol, ethanol, isopropanol, or butanol), or acetonitrile (ACN) is preferred. The list of suitable salts can be found in Remington's Pharmaceutical Sciences, 17th edition, Mack Publishing Company, Easton, Pa., 1985, p. 1418 and Journal of Pharmaceutical Science, 66, 2 (1977), which are incorporated herein by reference in their entirety.

[0396] The term “pharmaceutically acceptable” is used herein to refer to compounds, substances, compositions, and / or dosage forms that, to the extent of reasonable medical judgment, are suitable for contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, in proportion to a reasonable benefit / risk ratio.

[0397] "Pharmaceutically acceptable excipients" refers to those added to or otherwise used as a medium in a pharmacological composition.

[0398] Excipients are substances that are non-toxic, biologically tolerable, and otherwise biologically suitable for administration to a subject, such as inert substances, that act as a carrier or diluent to facilitate the administration of a pharmaceutical agent. Examples of excipients include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycol.

[0399] "Solvate" refers to a compound represented by Formula I that has one or more solvent molecules.

[0400] A "leaving group" refers to a single atom or a group of atoms that are substituted in a chemical reaction; these atoms are electrically charged.

[0401] Stable substances, for example, typically form anions. Preferably, the leaving group is selected from the following groups, including: halogens, especially chlorine, bromine or iodine, (methylsulfonyl)oxy-, [(4-methylphenyl)sulfonyl]oxy-, [(trifluoromethyl)sulfonyl]oxy-, [(nonofluorobutyl)sulfonyl]oxy-, [(4-bromophenyl)sulfonyl]oxy-, [(4-nitrophenyl)sulfonyl]oxy-, [(2-nitrophenyl)sulfonyl]oxy-, [(4-isopropylphenyl)sulfonyl]oxy-, [(2,4,6-triisopropylphenyl)sulfonyl]oxy-, [(2,4,6-trimethylphenyl)sulfonyl]oxy-, [(4-tert-butyltert-butylphenyl)sulfonyl]oxy-, (phenylsulfonyl)oxy-, and [(4-ethoxymethoxyphenyl)sulfonyl]oxy.

[0402] Unless otherwise stated, the term "one or more" as used herein means one or more. In some embodiments, "one or more" means 1, 2, 3, 4, 5, or 6. In some embodiments, "one or more" means 1, 2, 3, or 4. In some embodiments, "one or more" means 1, 2, or 3. In some embodiments, "one or more" means 1 or 2. In some embodiments, "one or more" means 1. In some embodiments, "one or more" means 2. In some embodiments, "one or more" means 3. In some embodiments, "one or more" means 4. In some embodiments, "one or more" means 5. In some embodiments, "one or more" means up to 6.

[0403] The pharmaceutical composition may be in a form suitable for oral administration (e.g., tablets, lozenges, hard capsules or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), may be for injection (e.g., aqueous or oily suspensions, or emulsions containing sesame oil, corn oil, cottonseed oil or peanut oil, as well as elixirs, mannitol, glucose or sterile aqueous solutions, and similar drug carriers), may be for topical use (e.g., creams, ointments, gels, or aqueous or oily solutions or suspensions), may be for inhalation (e.g., fine powders or liquid aerosols), may be for inhalation (e.g., fine powders), or may be for parenteral administration (e.g., sterile aqueous or oily solutions for intravenous, subcutaneous, intramuscular, intraperitoneal or intramuscular administration, or as suppositories for rectal administration).

[0404] The composition can be obtained using conventional pharmaceutical excipients well known in the art through routine procedures. Therefore, compositions intended for oral use may contain, for example, one or more colorants, sweeteners, flavorings, and / or preservatives.

[0405] The compound shown in formula (I) or its pharmaceutical salt, in a medically effective amount, can effectively treat or prevent the proliferative disease mentioned herein, slow its progression and / or alleviate the symptoms associated with the disease.

[0406] The amount of active ingredient required to produce a single dosage form in combination with one or more excipients varies depending on the individual being treated and the specific route of administration. For example, formulations for oral administration to humans typically contain, for example, 0.1 mg to 1000 mg of a compound of formula (I) or a pharmaceutical salt thereof, and a suitable and appropriate amount of excipients, the amount of which may vary from about 5% to about 98% of the total weight of the composition.

[0407] The dosage of the compound of formula (I) used for therapeutic or preventative purposes varies, according to well-known medical principles, depending on the nature and severity of the condition, the age and sex of the animal or patient, and the route of administration.

[0408] The compound represented by formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising such compound may be administered to a subject by any convenient method of administration, whether systemic / peripheral or local (i.e., at the site of desired action). Methods of administration include, but are not limited to: oral (e.g., by ingestion); sublingual; sublingual; transdermal (including, for example, by patches, plasters, etc.); transmucosal (including, for example, by patches, plasters, etc.); intranasal (e.g., by nasal spray); ocular (e.g., by eye drops); pulmonary (e.g., by inhalation or blowing therapy, for example, by aerosols, for example, by mouth or nose); rectal (e.g., by suppositories or enemas); vaginal (e.g., by pessaries); parenteral, for example, by injection, including subcutaneous, intradermal, intramuscular, intravenous, intraarticular, intracardiac, intrasheath, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subepidermal, intra-articular, subarachnoid, and intrathoracic; and by implantation into a reservoir or pouch, for example, subcutaneous or intramuscular.

[0409] The method typically involves administering a therapeutically effective amount of the compound of the invention to a subject. The therapeutically effective amount of the combination of target compounds may vary depending on the intended application (in vitro or in vivo) or the subject being treated and the nature of the disease, such as the subject's weight and age, the severity of the disease, the route of administration, etc., which can be readily determined by those skilled in the art. The term also applies to doses that will induce a specific response in target cells, such as reduced proliferation or downregulation of target proteins. The specific dose will vary depending on the specific compound selected, the administration regimen followed, whether it is administered in combination with other compounds, the time of administration, the tissue to which it is administered, and the physical delivery system on which it is carried.

[0410] Unless the context otherwise indicates, when a value is expressed as “about” X or “approximately” X, the specified value of X shall be understood to be accurate to ±10%, preferably ±5%, ±2%.

[0411] Unless otherwise stated herein or clearly contradicted by the context, all methods described herein may be performed in any suitable order. The use of any and all examples or exemplary language (such as “such as”) provided herein is intended only to better illustrate the invention and does not constitute a limitation on the scope of the otherwise claimed invention.

[0412] These and other aspects will become apparent from the following written description of the invention. Detailed Implementation

[0413] The compounds of this invention can be synthesized from commercially available reagents using the synthetic methods and reaction schemes described herein. Examples outlining specific synthetic routes and the following general schemes are intended to provide guidance to ordinary synthetic chemists, who will easily understand that solvents, concentrations, reagents, protecting groups, the order of synthetic steps, time, temperature, etc., can be modified as needed within the skill and judgment of a person of ordinary skill.

[0414] In this invention, "room temperature" and "rt" generally refer to temperature in the art, such as reaction temperature, which refers to the temperature of the surrounding environment during the reaction operation, for example, about 20°C to about 30°C.

[0415] Example

[0416] The following examples will better illustrate the invention. Unless otherwise expressly stated, all parts and percentages are by weight and all temperatures are in degrees Celsius. The abbreviations in the following table are used in the examples:

[0417] DMF dimethylformamide EA Ethyl acetate PE petroleum ether <![CDATA[CH3CN]]> Acetonitrile MeOH methanol DCM dichloromethane NaH Sodium hydride THF Tetrahydrofuran TEA Triethylamine <![CDATA[H2O]]> water <![CDATA[K2CO3]]> Potassium carbonate HCl hydrochloric acid sat. saturated h / hrs Hour

[0418] Intermediate 1 (INT 1)

[0419]

[0420] 7-Ethyl-5-fluoro-4-hydroxy-1-methyl-2-naphthamide (1.56 g, 6.3 mmol) was added to N,N-dimethylformamide (30 ml), followed by tert-butyldimethylchlorosilane (1.42 g, 9.4 mmol) and imidazole (1.29 g, 18.9 mmol). The mixture was stirred at 25 °C for 12 h. The solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (using V...). PE :V EA (Eluting ratio 100:0 to 50:50) yielded INT 1-1 (1.8 g, 79% yield). LCMS: m / z = 362.1 [M+H] + .

[0421] Add INT 1-1 (1.8 g, 5.0 mmol) to 1,1-dimethoxy-N,N-dimethylethylamine (10 ml), and heat to 100 °C for 10 min. Concentrate under reduced pressure, and purify the residue by silica gel column chromatography (using V... DCM :V MeOH (Eluting ratio 100:0 to 90:10) yielded INT 1-2 (2.0 g, 87% yield). LCMS: m / z = 432.1 [M+H] + .

[0422] Add INT 1-2 (2.0 g, 4.6 mmol) to a mixture of 1,4-dioxane (30 ml) and glacial acetic acid (30 ml), then add hydroxylamine hydrochloride (0.91 g, 13.8 mmol), and stir at 90 °C for 1 h. Concentrate under reduced pressure, and purify the residue by silica gel column chromatography (using V... DCM :V MeOH =100:0~97:3 elution) to obtain INT 1-3 (1.6g, yield 87%). LCMS: m / z = 401.1 [M+H] + .

[0423] Add INT 1-3 (1.6 g, 4.0 mmol) to tetrahydrofuran (30 ml), then add tetrabutylammonium fluoride (8.0 ml, 8.0 mmol), and stir at 25 °C for 1 h. Concentrate under pressure, and purify the residue by silica gel column chromatography (using V... DCM :V MeOH (Eluting ratio 100:0 to 97:3) yielded INT 1-4 (1.0 g, 87% yield). LCMS: m / z = 286.1 [M+H] + .

[0424] Add INT 1-4 (1.0 g, 3.5 mmol, 1.0 eq.) to glacial acetic acid (30 ml), then add N-bromosuccinimide (0.75 g, 4.2 mmol), and react at 55 °C for 3 h. Concentrate under reduced pressure, and purify the residue by silica gel column chromatography (using V... DCM :V MeOH (Eluting ratio 100:0 to 97:3) yielded INT 1-5 (0.7 g, 63% yield). LCMS: m / z = 321.1 [M+H] + .

[0425] Add INT 1-5 (0.72 g, 2.24 mmol) to dichloromethane (20 mL), add trifluoromethanesulfonic anhydride (0.82 g, 2.92 mmol), and add pyridine (0.53 g, 6.73 mmol) dropwise under ice bath conditions. Incubate the reaction for 1 h. Concentrate under reduced pressure, and purify the residue by silica gel column chromatography (using V...PE :V EA (Eluting ratio 100:0 to 80:20) yielded INT 1-6 (0.93 g, 91% yield). LCMS: m / z = 453.1 [M+H] + .

[0426] Add INT 1-6 (1.4 g, 3.09 mmol) to DMF (50 ml), then add zinc cyanide (0.36 g, 3.09 mmol), tris(dibenzylacetone)palladium (0.43 g, 0.46 mmol), and 1,1'-bis(diphenylphosphine)ferrocene (0.51 g, 0.93 mmol). React at 120 °C for 3 h. Cool to room temperature, concentrate under reduced pressure, and purify the residue by silica gel column chromatography (using V... PE :V EA =100:0~75:25 elution) to obtain INT 1-7 (0.43g, yield 39%). LCMS: m / z = 330.1 [M+H] + .

[0427] Add INT 1-7 (0.43 g, 1.3 mmol) to 4-piperidinone ethylene glycol (4 ml), seal, react at 150 °C for 1.5 h, cool to room temperature, concentrate under reduced pressure, and purify the residue by silica gel column chromatography (using V... PE :V EA (Eluting ratio 100:0 to 75:25) yielded INT 1-8 (0.52 g, 91% yield). LCMS: m / z = 437.2 [M+H] + .

[0428] INT 1-8 (0.52 g, 1.2 mmol) was added to tetrahydrofuran (5 mL), followed by 10% sulfuric acid aqueous solution (5 mL). The reaction mixture was reacted at 45 °C for 16 h. The reaction solution was then added to an aqueous sodium bicarbonate solution, extracted twice with ethyl acetate, and the extracts were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to give INT 1 (0.42 g, 90% yield). LCMS: m / z = 393.1 [M+H] + .

[0429] Example 1

[0430] 6-Ethyl-8-fluoro-4-methyl-3-(3-methyl-1,2,4-oxadiazacyclopentanyl-5-yl)-2-[4-(3,4,5,6-tetrahydro-2H-pyr-4-ylamino)hexahydropyridin-1-yl]naphthalene-1-carboxylonitrile (Compound 1)

[0431]

[0432] Add INT 1 (0.1 g, 0.25 mmol) to 1,2-dichloroethane (5 ml), add 4-aminotetrahydropyran (0.05 g, 0.5 mmol), and stir at 25 °C for 2 h under nitrogen protection. Then add glacial acetic acid (0.03 g, 0.5 mmol) and sodium triacetoxyborohydride (0.11 g, 0.5 mmol), and react at 25 °C for 16 h. Add sodium bicarbonate aqueous solution, extract twice with ethyl acetate, combine the extracts, wash with water, dry to anhydrous sodium sulfate, filter, concentrate to dryness, and purify the residue by silica gel column chromatography (using V... DCM :V MeOH = 100:0 to 95:5 elution) to give compound 1 (0.07 g, yield 58%).

[0433] 1 H NMR(400MHz, DMSO-d6)δ7.88(s,1H),7.61(d,J=13.3Hz,1H),3.85–3.76(m,2H),3.33–3.16(m,5H),2.87–2.78(m,2H),2 .51–2.46(m,3H),1.72(d,J=12.4Hz,4H),1.33–1.21(m,3H),1.19(d,J=12.3Hz,2H),1.08(s,3H).LCMS:m / z=478.2[M+H] + .

[0434] Example 2

[0435] 6-Ethyl-8-fluoro-2-[4-({[(2S)-oxacyclobut-2-yl]methyl}amino)hexahydropyridin-1-yl]-4-methyl-3-(3-methyl-1,2,4-oxadiazacyclopentan-5-yl)naphthalene-1-carboxylonitrile (Compound 2)

[0436]

[0437] Add INT 1 (0.1 g, 0.25 mmol) to 1,2-dichloroethane (5 ml), then add (S)-oxetane-2-methylamine (0.044 g, 0.5 mmol), and stir at 25 °C for 2 h under nitrogen protection. Next, add glacial acetic acid (0.03 g, 0.5 mmol) and sodium triacetoxyborohydride (0.11 g, 0.5 mmol), and react at 25 °C for 16 h. Add sodium bicarbonate aqueous solution, extract twice with ethyl acetate, combine the extracts, wash with water, dry to anhydrous sodium sulfate, filter, and concentrate to dryness. Purify the residue by silica gel column chromatography (using V... DCM :V MeOH (Eluting at a ratio of 100:0 to 95:5) yielded compound 2 (0.05 g, 42% yield).

[0438] 1 H NMR (400MHz, DMSO-d6) δ7.18(d,J=1.5Hz,1H),7.11(dd,J=8.0,1.5Hz,1H),4.27(p,J=7.0H z,1H),3.88–3.76(m,2H),3.54(t,J=7.1Hz,4H),3.08–2.95(m,2H),2.94–2.84(m,2H),2.8 1–2.73(m,4H),2.42(s,3H),2.40–2.32(m,1H),2.20(dq,J=12.5,7.1Hz,1H),1.80(dq,J=1 2.3,7.1Hz,2H),1.61(dq,J=12.4,7.1Hz,2H),1.25(t,J=8.0Hz,3H).LCMS:m / z=464.2[M+H] + .

[0439] Example 3

[0440] 6-Ethyl-8-fluoro-2-(4-{[(1S,3R)-3-hydroxycyclopentyl]amino}hexahydropyridin-1-yl)-4-methyl-3-(3-methyl-1,2,4-oxadiazacyclopentan-5-yl)naphthalene-1-carboxylonitrile (Compound 3)

[0441]

[0442] Add INT 1 (0.1 g, 0.25 mmol) to 1,2-dichloroethane (5 ml), then add (1R,3S)-3-aminocyclopentanol (0.05 g, 0.5 mmol), and stir at 25°C for 2 h under nitrogen protection. Next, add glacial acetic acid (0.03 g, 0.5 mmol) and sodium triacetoxyborohydride (0.11 g, 0.5 mmol), and react at 25°C for 16 h. Add sodium bicarbonate aqueous solution, extract twice with ethyl acetate, combine the extracts, wash with water, dry to anhydrous sodium sulfate, filter, and concentrate to dryness. Purify the residue by silica gel column chromatography (using V... DCM :V MeOH (Eluting at a ratio of 100:0 to 95:5) yielded compound 3 (0.05 g, 41% yield).

[0443] 1H NMR(400MHz, DMSO-d6)δ7.19(d,J=1.5Hz,1H),7.11(dd,J=8.0,1.5Hz,1H),4.14–4.04(m,1H),3.59–3.45(m,4H),2.96(dp,J=9.5,7.0Hz, 1H),2.86(dpd,J=8.6,7.0,0.7Hz,1H),2.80–2.73(m,5H),2.41(s,3H),1.87–1.48(m,10H),1.25(t,J=8.0Hz,3H).LCMS:m / z=478.2[M+H] + .

[0444] Example 4

[0445] 6-Ethyl-8-fluoro-4-methyl-3-(3-methyl-1,2,4-oxadiazacyclopentanyl-5-yl)-2-[4-(2-oxaspiro[3.3]hept-6-ylamino)hexahydropyridin-1-yl]naphthalene-1-carboxylonitrile (Compound 4)

[0446]

[0447] Add INT 1 (0.1 g, 0.25 mmol) to 1,2-dichloroethane (5 ml), then add 2-oxaspiro[3.3]hept-6-amine hydrochloride (0.057 g, 0.5 mmol) and N,N-diisopropylethylamine (0.065 g, 0.5 mmol), and stir at 25 °C for 2 h under nitrogen protection. Then add glacial acetic acid (0.03 g, 0.5 mmol) and sodium triacetoxyborohydride (0.11 g, 0.5 mmol), and react at 25 °C for 16 h. Add sodium bicarbonate aqueous solution, extract twice with ethyl acetate, combine the extracts, wash with water, dry to dryness with anhydrous sodium sulfate, filter, and concentrate to dryness. Purify the residue by silica gel column chromatography (using V... DCM :V MeOH (Eluting at a ratio of 100:0 to 95:5) yielded compound 4 (0.06 g, 48% yield).

[0448] 1H NMR (400MHz, DMSO-d6) δ7.19(d,J=1.5Hz,1H),7.13(dd,J=7.9,1.5Hz,1H),3.76(s,4H),3.59–3.46(m,4H),2.97(ddp,J=10.8,8.1,6 .9Hz,2H),2.81–2.73(m,5H),2.41(s,3H),1.93–1.81(m,6H),1.59(dq,J=12.5,7.1Hz,2H),1.28–1.21(m,3H).LCMS:m / z=490.2[M+H] + .

[0449] Using the above method or a modified method, the following compounds were synthesized from the corresponding starting materials:

[0450]

[0451]

[0452] Pharmacological test examples

[0453] Pharmacological Testing Example 1: In Vitro Binding Test of Kappa Receptor Antagonists

[0454] 1. Preparation of Buffer and Compound

[0455] 1.1 Buffer Preparation:

[0456] Weigh 11.7 mg EDTA and 380.84 mg MgCl2, add them to a 50 mM Tris-HCl buffer solution to a total volume of 400 mL, and adjust the pH to 7.4. This will result in final concentrations of 0.1 mM EDTA and 10 mM MgCl2.

[0457] 1.2 Compound preparation:

[0458] Calculate the theoretical sample weight based on the designed concentration and required volume. Generally, 5.0 × 10⁻³ M is used as the initial preparation dose, dissolved in DMSO. Then, sequentially dilute with DMSO to 5.0 × 10⁻⁴ M to 5.0 × 10⁻⁹ M. Dilute the diluted DMSO solution with buffer to the working concentration, 5.0 × 10⁻⁵ M to 5.0 × 10⁻¹¹ M. The final DMSO concentration in the working solution is 1% (the final DMSO concentration in the reaction system is 0.2%). Store the prepared sample at 4℃ and discard after the test.

[0459] 2. Preparation of receptor membrane

[0460] CHO-μ, Kappa, and delta cells were removed from the -80℃ freezer and thawed naturally. They were then centrifuged at 1000g at 4℃ for 10 minutes. The pellet was collected, and the supernatant was discarded. Buffer was added to the pellet, and the mixture was homogenized for 20-30 seconds, then centrifuged at 50000g at 4℃ for 15 minutes. The supernatant was carefully discarded, and buffer was added again, mixed, and centrifuged at 50000g at 4℃ for 15 minutes. This process was repeated three times. The cells were stored at -80℃.

[0461] 3. Receptor competition binding assay

[0462] 3.1 μ receptor affinity assay

[0463] Step 1: Add 50 μL of solvent (1% DMSO) to the total binding tube (TB), add 50 μL of LAMGO (final concentration 1.0 × 10⁻⁵ M) to the nonspecific binding tube (NB), and add 50 μL of the test compound to each test compound tube (CB).

[0464] Step 2: Add 100 μL of buffer solution (homogeneous solution A) to each reaction tube.

[0465] Step 3: First, prepare a 10 mg / mL membrane suspension using homogenizing solution A for later use.

[0466] Step 4: Add 50 μL of radioactive ligand [3H]DAMGO to each reaction tube to a final concentration of 2 nM.

[0467] Step 5: Add 50 μL of membrane solution to each reaction tube.

[0468] Step 6: Incubate each reaction tube at 25°C for 90 min. After the reaction is complete, the bound ligands are rapidly filtered under reduced pressure. The UniFilter GF / C plate is saturated with 0.5% PEI solution 1 h in advance, thoroughly washed with ice-cold Tris buffer, filtered, and then dried in a constant temperature drying oven for 30 min. Remove the filter plate and add MICROM-ICROSCINT PS scintillation buffer, 40 μL / well.

[0469] Step 7: Place the scintillation cup into the liquid scintillation counter for counting.

[0470] 3.2 Kappa receptor competitive binding assay

[0471] Step 1: Add 50 μL of solvent (1% DMSO) to the total binding tube (TB), add 350 μL of U69593 (final concentration 1.0 × 10⁻⁵ M) to the nonspecific binding tube (NB), and add 50 μL of the test compound to each test compound tube (CB).

[0472] Step 2: Add 100 μL of buffer solution (homogeneous solution A) to each reaction tube.

[0473] Step 3: First, prepare a 15 mg / mL membrane suspension using homogenizing solution A for later use.

[0474] Step 4: Add 50 μL of radioactive ligand 3H-U69593 to each reaction tube, with a final concentration of 2 nM.

[0475] Step 5: Add 50 μL of membrane solution to each reaction tube.

[0476] Step 6: Incubate each reaction tube at 25°C for 90 min. After the reaction is complete, the bound ligands are rapidly filtered under reduced pressure. The UniFilter GF / C plate is saturated with 0.5% PEI solution 1 h in advance, thoroughly washed with ice-cold Tris buffer, filtered, and then dried in a constant temperature drying oven for 30 min. Remove the filter plate and add MICROSCINT PS scintillation buffer, 40 μL / well.

[0477] Step 7: Place the filter plate into the liquid scintillation counter for counting.

[0478] 3.3 Delta receptor competitive binding assay

[0479] Step 1: Add 50 μL of solvent (1% DMSO) to the total binding tube (TB), add 50 μL of DADLE (final concentration 1.0 × 10⁻⁵ M) to the nonspecific binding tube (NB), and add 50 μL of the test compound to each test compound tube (CB).

[0480] Step 2: Add 100 μL of buffer solution (homogeneous solution A) to each reaction tube.

[0481] Step 3: First, prepare a 10 mg / mL membrane suspension using homogenizing solution A for later use.

[0482] Step 4: Add 50 μL of radioactive ligand 3H-DADLE to each reaction tube, to a final concentration of 4 nM.

[0483] Step 5: Add 50 μL of membrane solution to each reaction tube.

[0484] Step 6: Incubate each reaction tube at 25°C for 90 min. After the reaction is complete, the bound ligands are rapidly filtered under reduced pressure. The UniFilter GF / C plate is saturated with 0.5% PEI solution 1 h in advance, thoroughly washed with ice-cold Tris buffer, filtered, and then dried in a constant temperature drying oven for 30 min. Remove the filter plate and add MICROSCINT PS scintillation buffer, 40 μL / well.

[0485] Step 7: Place the filter plate into the liquid scintillation counter for counting.

[0486] 4. Data Analysis

[0487] Based on the effect values ​​at different concentration test points of the compound sample, the GraphPad Prism software was used to fit the curve of the compound sample's interaction with the receptor, and the Ki value was calculated.

[0488] Table 1-1 Results of in vitro opioid affinity tests for the target compounds

[0489]

[0490] As shown in Table 1-1, the compounds in the embodiments of the present invention have good affinity for the Kappa receptor and good selectivity for KOR.

[0491] Pharmacological Test Example 2: Assay of Agonistaltic and Antagonistic Activity of Opioid Receptors (OPRK1 / Mu)

[0492] 1. Preparation of buffer solution (1x Stimulation):

[0493] Dilute the 5x Stimulation buffer from the Cisbio cAMP-Gi kit with ddH2O at a ratio of 1:4 to obtain the (1x Stimulation) buffer.

[0494] 2. Preparation of the test solution:

[0495] Each analyte was diluted to a 5 mM stock solution using DMSO. The solution was then serially diluted 3.16 times to create 10 different concentrations, and finally diluted with 1x Stimulation buffer to obtain analyte solutions with concentrations of (20 μM, 6.32 μM, 2 μM, 632 nM, 200 nM, 63.2 nM, 20 nM, 6.32 nM, 2 nM, and 0.63 nM).

[0496] 3. Preparation of cell suspension:

[0497] CHO-OPRK1 / CHO-Mu cells on trypsin digestion culture dishes were washed with culture medium (F12 + 10% FBS + 400 μg / ml G418), centrifuged (1000 rpm) for 5 minutes, the supernatant was removed, PBS (3 mL) was added and mixed, centrifuged again (1000 rpm) for 5 minutes, the supernatant was removed, and the cells were resuspended in 1x Stimulation buffer until the cell density was 6 x 10⁵ cells / mL (counted using a Countstar cell counter) to obtain a cell suspension.

[0498] 4. Preparation of the detection reagent cAMP-d2:

[0499] cAMP-d2 was diluted with Lysis & detection buffer from the Cisbio cAMP-Gi assay kit (d2 to buffer volume ratio of 1:20) to obtain the assay reagent cAMP-d2.

[0500] 5. Preparation of the detection reagent Anti-cAMP cryptate:

[0501] Dilute Anti-cAMP cryptate with the Lysis & detection buffer from the Cisbio cAMP-Gi detection kit (cryptate to buffer volume ratio of 1:20) to obtain the detection reagent Anti-cAMP cryptate.

[0502] 6. Specific experimental steps and testing methods:

[0503] 6.1 Excitement Mode:

[0504] Cell suspension (5 μL / well, approximately 3000 cells / well) and various concentrations of test solution (4 μL / well) were sequentially added to 96-well plates. The plates were incubated at 37°C for 20 minutes. Then, 10x adenylate cyclase agonist (final concentration 1 μM Forskolin) solution was added at 1 μL / well. After gentle shaking, the plates were incubated at 37°C for 45 minutes. 6.2 Antagonistic Mode:

[0505] Cell suspension (5 μL / well, approximately 3000 cells / well) and various concentrations of test solution (2 μL / well) were sequentially added to 96-well plates. The 96-well plates were incubated at 37°C for 20 minutes. EC90 agonist (OPRK1 / U-50488, Mu / DAMGO) diluted with Stimulation buffer was added to the experimental plate at 2 μL / well. After gentle shaking, the experimental plate was incubated at 37°C for 20 minutes. 10x adenylate cyclase agonist (final concentration 1 μM Forskolin) solution was added at 1 μL / well. After gentle shaking, the experimental plate was incubated at 37°C for 45 minutes.

[0506] Add 5 μL of cAMP-d2 and 5 μL of Anti-cAMP cryptate to each well, respectively, and incubate the 96-well plate at room temperature for 60 minutes. Wells containing the same percentage of DMSO serve as a blank control group.

[0507] HTRF signals were measured using a PE Envision multi-mode microplate reader. The detection parameters were: F665: excitation wavelength 320 nm, emission wavelength 665 nm, delay time 90 μs, integration time 300 μs; F615: excitation wavelength 320 nm, emission wavelength 615 nm, delay time 90 μs, integration time 300 μs. The HTRF ratio for each well was calculated as: HTRF ratio = (F665 / F615) * 10000. Compound activity % = (HTRF ratio compound - HTRF ratio blank) / (HTRF ratio positive - HTRF ratio blank) * 100. Experimental readings: The plate was read on the Envision in top-read mode, detecting the readings of the 665 nm and 615 nm channels, and the ratio of the 665 nm / 615 nm readings was calculated. Based on the agonist effect values ​​at different concentrations of the compound sample, the GraphPad Prism software was used to fit the agonist-antagonist curves of the test compound on the opioid receptor, and the EC50 was calculated. 50 IC 50 .

[0508] Table 2-1 Results of in vitro functional tests of the target compound

[0509]

[0510] As shown in Table 2-1, the compounds in the embodiments of the present invention have good antagonistic activity against Kappa receptors and good selectivity for KOR.

[0511] If this invention references any prior art publications, it should be understood that such reference does not imply that such publication is recognized as part of the common knowledge in the field in any country. All published texts, patents, patent applications, and published patent applications used in this document by reference are incorporated herein by reference in their entirety. Although the invention has been described in detail by way of example for clarity, it will be apparent to those skilled in the art that certain changes and modifications can be made. Therefore, the descriptions and embodiments should not be construed as limiting the scope of the invention.

Claims

1. A compound of formula (III-1), or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt thereof, a solvate thereof, a prodrug thereof, or a deuterated derivative thereof, in: R2 is independently selected from hydrogen, halogen, and -C each time it appears. 1-3 Alkyl and -C 1-3 Haloalkyl; preferably, R2 is independently selected from hydrogen and -C each time it appears. 1-3 alkyl; R3 is independently selected from hydrogen, halogen, and -C each time it appears. 1-3 Alkyl, -C 1-3 Halogenated alkyl groups, -CN, -NH2, -NH(C) 1-3 alkyl), -N(C) 1-3 alkyl)2、-NH(C 3-7 cycloalkyl), -OH, -O(C 1-3 Alkyl), -O(C) 3-7 cycloalkyl), -SH, -S(C 1-3 alkyl), and -S(C 3-7 (cycloalkyl); preferably, R3 is independently selected from hydrogen, -C, and -C each time it appears. 1-3 Alkyl, -OH, -O(C) 1-3 alkyl), and -O(C 3-7 cycloalkyl); R4 is independently selected from hydrogen, halogen, and -C each time it appears. 1-3 Alkyl and -C 1-3 Haloalkyl; preferably, R4 is independently selected from hydrogen and -C each time it appears. 1-3 alkyl; R5 is independently selected from hydrogen, halogen, and -C each time it appears. 1-3 Alkyl, -C 1-3 Halogenated alkyl groups, -NH2, -NH(C) 1-3 alkyl), -N(C) 1-3 Alkyl group 2, -OH, -O(C) 1-3 Alkyl), -SH, -S(C 1-3 Alkyl groups), -C(=O)NH2, -C(=O)NH(C 1-3 Alkyl), -C(=O)N(C 1-3 Alkyl)2, -S(=O)NH2, -S(=O)NH(C 1-3 Alkyl), -S(=O)N(C 1-3 Alkyl)2, -S(=O)2NH2, -S(=O)2NH(C 1-3 Alkyl groups), and -S(=O)2N(C 1-3 Alkyl group 2; preferably, R5 is independently selected from hydrogen, halogen, -C each time it appears. 1-3 Alkyl, -C 1-3 Halogenated alkyl groups, -OH, -O(C) 1-3 Alkyl groups), -C(=O)NH2, -C(=O)NH(C 1-3 Alkyl groups), and -C(=O)N(C 1-3 Alkyl)2; A1 is selected from N and CR. A1 ; A2 is selected from N and CR. A2 ; A3 is selected from N and CR. A3 ; A4 is selected from C(R) A41 2. NR A42 O and S; Each (in CR) A1 R in A1 ), (in CR A2 R in A2 ), (in CR A3 R in A3 ), or (in CR A41 R in A41 Each time it appears, it is independently selected from hydrogen, halogen, -C. 1-3 Alkyl and -C 1-3 Halogenated alkyl groups; preferably, each (in CR) A1 R in A1 ), (in CR A2 R in A2 ), (in CR A3 R in A3 ), or (in CR A41 R in A41 Each time it appears, it is independently selected from hydrogen and -C. 1-3 alkyl; (in NR) A42 R in A42 Each time it appears, it is independently selected from hydrogen, -C 1-3 Alkyl and -C 1-3 Halogenated alkyl groups; R 10A Or R 10B Each time it appears, it is independently selected from hydrogen, halogen, -C. 1-3 Alkyl, -C 1-3 Halogenated alkyl groups, -CN, -NH2, -NH(C) 1-3 alkyl), -N(C) 1-3 Alkyl group 2, -OH, -O(C) 1-3 Alkyl), -SH, and -S(C 1-3 Alkyl); preferably, R 10A Or R 10B Each time it appears, it is independently selected from -H or -C. 1-3 Alkyl, -NH(C) 1-3 alkyl), -N(C) 1-3 Alkyl)2、-O(C 1-3 alkyl), and -S(C 1-3 Alkyl); more preferably, R 10A Or R 10B Each time it appears, it is independently selected from -H or -C. 1-3 Alkyl groups and -O(C) 1-3 alkyl); R 12 Each time it appears, it is independently selected from hydrogen, -C 1-3 Alkyl and -C 1-3 Halogenated alkyl; preferably, R 12 Each time it appears, it is independently selected from hydrogen and -C. 1-3 alkyl; R 13 Each time it appears, it is independently selected from hydrogen, halogen, -C. 1-3 Alkyl and -C 1-3 Halogenated alkyl groups; Y4 is selected from non-existent and -O-; Y3 is selected from -O- and -C(R) Y3A )2-; R Y3A Each time it appears, it is independently selected from hydrogen, halogen, -C. 1-3 Alkyl, -C 1-3 Haloalkyl, -(C 1-3 alkylene)-O-(C 1-3 alkyl), -(C 1-3 alkylene)-O-(C 1-3 Halogenated alkyl groups, -OH groups, or -O(C) groups 1-3 Alkyl); preferably, R Y3A Each time it appears, it is independently selected from hydrogen, halogen, -C. 1-3 Alkyl and -C 1-3 Halogenated alkyl groups; n6 is selected from 0, 1, 2, and 3; preferably, n6 is selected from 0, 1, and 2; more preferably, n6 is selected from 0 and 1; n7 is selected from 0, 1, 2, and 3; preferably, n7 is selected from 0, 1, and 2; more preferably, n7 is selected from 0 and 1; n8 is selected from 0, 1, 2, and 3; preferably, n8 is selected from 0, 1, and 2; more preferably, n8 is selected from 0 and 1; n9 is selected from 0, 1, 2, and 3; preferably, n9 is selected from 0, 1, and 2; more preferably, n9 is selected from 0 and 1; And n6+n7+n8+n9≤5; R S2 Each time it appears, it is independently selected from halogens and -C. 1-3 Alkyl, -C 2-3 alkenyl, -C 2-3 alkynyl group, -C 1-3 Halogenated alkyl groups, -OC 1-3 Halogenated alkyl groups, -CN, -NO2, oxo, -NH2, -NH(C) 1-3 alkyl), -N(C) 1-3 Alkyl group 2, -OH, -O(C) 1-3 Alkyl), -SH, -S(C 1-3 Alkyl), -C(=O)(C 1-3 Alkyl), -S(=O)(C 1-3 Alkyl), -S(=O)2(C 1-3 Alkyl), -C(=O)OH, -C(=O)(OC 1-3 Alkyl), -OC (=O)(C 1-3 Alkyl groups), -C(=O)NH2, -C(=O)NH(C 1-3 Alkyl), -C(=O)N(C 1-3 Alkyl)2、-NHC(=O)(C 1-3 Alkyl), S(=O)NH2, -S(=O)NH(C 1-3 Alkyl), -S(=O)N(C 1-3 Alkyl)2、-NHS(=O)(C 1-3 Alkyl groups), -S(=O)2NH2, -S(=O)2NH(C 1-6 Alkyl), -S(=O)2N(C 1-6 alkyl)2、-NHS(=O)2(C 1-6 Alkyl groups, 3-7 membered carbon cycloyl groups, 3-7 membered heterocyclic groups, phenyl groups, and 5-10 membered heteroaryl groups; n S2 Selected from 0, 1, 2, and 3.

2. A compound of formula (III-3), or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt thereof, a solvate thereof, a prodrug thereof, or a deuterated derivative thereof. in: R2 is independently selected from hydrogen, halogen, and -C each time it appears. 1-3 Alkyl and -C 1-3 Haloalkyl; preferably, R2 is independently selected from hydrogen and -C each time it appears. 1-3 alkyl; R3 is independently selected from hydrogen, halogen, and -C each time it appears. 1-3 Alkyl, -C 1-3 Halogenated alkyl groups, -CN, -NH2, -NH(C) 1-3 alkyl), -N(C) 1-3 alkyl)2、-NH(C 3-7 cycloalkyl), -OH, -O(C 1-3 Alkyl), -O(C) 3-7 cycloalkyl), -SH, -S(C 1-3 alkyl), and -S(C 3-7 (cycloalkyl); preferably, R3 is independently selected from hydrogen, -C, and -C each time it appears. 1-3 Alkyl, -OH, -O(C) 1-3 alkyl), and -O(C 3-7 cycloalkyl); R4 is independently selected from hydrogen, halogen, and -C each time it appears. 1-3 Alkyl and -C 1-3 Haloalkyl; preferably, R4 is independently selected from hydrogen and -C each time it appears. 1-3 alkyl; R5 is independently selected from hydrogen, halogen, and -C each time it appears. 1-3 Alkyl, -C 1-3 Halogenated alkyl groups, -NH2, -NH(C) 1-3 alkyl), -N(C) 1-3 Alkyl group 2, -OH, -O(C) 1-3 Alkyl), -SH, -S(C 1-3 Alkyl groups), -C(=O)NH2, -C(=O)NH(C 1-3 Alkyl), -C(=O)N(C 1-3 Alkyl)2, -S(=O)NH2, -S(=O)NH(C 1-3 Alkyl), -S(=O)N(C 1-3 Alkyl)2, -S(=O)2NH2, -S(=O)2NH(C 1-3 Alkyl groups), and -S(=O)2N(C 1-3 Alkyl group 2; preferably, R5 is independently selected from hydrogen, halogen, -C each time it appears. 1-3 Alkyl, -C 1-3 Halogenated alkyl groups, -OH, -O(C) 1-3 Alkyl groups), -C(=O)NH2, -C(=O)NH(C 1-3 Alkyl groups), and -C(=O)N(C 1-3 Alkyl)2; A1 is selected from N and CR. A1 ; A2 is selected from N and CR. A2 ; A3 is selected from N and CR. A3 ; A4 is selected from C(R) A41 2. NR A42 O and S; Each (in CR) A1 R in A1 ), (in CR A2 R in A2 ), (in CR A3 R in A3 ), or (in CR A41 R in A41 Each time it appears, it is independently selected from hydrogen, halogen, -C. 1-3 Alkyl and -C 1-3 Halogenated alkyl groups; preferably, each (in CR) A1 R in A1 ), (in CR A2 R in A2 ), (in CR A3 R in A3 ), or (in CR A41 R in A41 Each time it appears, it is independently selected from hydrogen and -C. 1-3 alkyl; (in NR) A42 R in A42 Each time it appears, it is independently selected from hydrogen, -C 1-3 Alkyl and -C 1-3 Halogenated alkyl groups; R 10A Or R 10B Each time it appears, it is independently selected from hydrogen, halogen, -C. 1-3 Alkyl, -C 1-3 Halogenated alkyl groups, -CN, -NH2, -NH(C) 1-3 alkyl), -N(C) 1-3 Alkyl group 2, -OH, -O(C) 1-3 Alkyl), -SH, and -S(C 1-3 Alkyl); preferably, R 10A Or R 10B Each time it appears, it is independently selected from -H or -C. 1-3 Alkyl, -NH(C) 1-3 alkyl), -N(C) 1-3 Alkyl)2、-O(C 1-3 alkyl), and -S(C 1-3 Alkyl); more preferably, R 10A Or R 10B Each time it appears, it is independently selected from -H or -C. 1-3 Alkyl groups and -O(C) 1-3 alkyl); R 12 Each time it appears, it is independently selected from hydrogen, -C 1-3 Alkyl and -C 1-3 Halogenated alkyl; preferably, R 12 Each time it appears, it is independently selected from hydrogen and -C. 1-3 alkyl; Y5 is selected from -O- and -C(R) Y5A )2-; Preferably, Y5 is -O-; R Y5A Each time it appears, it is independently selected from hydrogen, halogen, -C. 1-3 Alkyl and -C 1-3 Halogenated alkyl; preferably, R Y5A Each time it appears, it is independently selected from hydrogen and -C. 1-3 alkyl; n 10 Selected from 0, 1, and 2; preferably, n 10 Selected from 0 and 1; n 11 Selected from 0, 1, and 2; preferably, n 11 Selected from 0 and 1; n 12 Selected from 0, 1, and 2; preferably, n 12 Selected from 0 and 1; n 13 Selected from 0, 1, and 2; preferably, n 13 Selected from 0 and 1; n 14 Selected from 0, 1, and 2; preferably, n 14 Selected from 0 and 1; n 15 Selected from 0, 1, and 2; preferably, n 15 Selected from 0 and 1; n 16 Selected from 0, 1, and 2; preferably, n 16 Selected from 0 and 1; n 17 Selected from 0, 1, and 2; preferably, n 17 Selected from 0 and 1; And n 10 +n 11 +n 12 +n 13 ≤6; And n 14 +n 15 +n 16 +n 17 ≤6; R S2 Each time it appears, it is independently selected from halogens and -C. 1-3 Alkyl, -C 2-3 alkenyl, -C 2-3 alkynyl group, -C 1-3 Halogenated alkyl groups, -OC 1-3 Halogenated alkyl groups, -CN, -NO2, oxo, -NH2, -NH(C) 1-3 alkyl), -N(C) 1-3 Alkyl group 2, -OH, -O(C) 1-3 Alkyl), -SH, -S(C 1-3 Alkyl), -C(=O)(C 1-3 Alkyl), -S(=O)(C 1-3 Alkyl), -S(=O)2(C 1-3 Alkyl), -C(=O)OH, -C(=O)(OC 1-3 Alkyl), -OC (=O)(C 1-3 Alkyl groups), -C(=O)NH2, -C(=O)NH(C 1-3 Alkyl), -C(=O)N(C 1-3 Alkyl)2、-NHC(=O)(C 1-3 Alkyl), S(=O)NH2, -S(=O)NH(C 1-3 Alkyl), -S(=O)N(C 1-3 Alkyl)2、-NHS(=O)(C 1-3 Alkyl groups), -S(=O)2NH2, -S(=O)2NH(C 1-6 Alkyl), -S(=O)2N(C 1-6 alkyl)2、-NHS(=O)2(C 1-6 Alkyl groups, 3-7 membered carbon cycloyl groups, 3-7 membered heterocyclic groups, phenyl groups, and 5-10 membered heteroaryl groups; n S2 Selected from 0, 1, 2, and 3.

3. A compound of formula (III-53), or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt thereof, a solvate thereof, a prodrug thereof, or a deuterated derivative thereof. in: R2 is independently selected from hydrogen, halogen, and -C each time it appears. 1-3 Alkyl and -C 1-3 Haloalkyl; preferably, R2 is independently selected from hydrogen and -C each time it appears. 1-3 alkyl; R3 is independently selected from hydrogen, halogen, and -C each time it appears. 1-3 Alkyl, -C 1-3 Halogenated alkyl groups, -CN, -NH2, -NH(C) 1-3 alkyl), -N(C) 1-3 alkyl)2、-NH(C 3-7 cycloalkyl), -OH, -O(C 1-3 Alkyl), -O(C) 3-7 cycloalkyl), -SH, -S(C 1-3 alkyl), and -S(C 3-7 (cycloalkyl); preferably, R3 is independently selected from hydrogen, -C, and -C each time it appears. 1-3 Alkyl, -OH, -O(C) 1-3 alkyl), and -O(C 3-7 cycloalkyl); R4 is independently selected from hydrogen, halogen, and -C each time it appears. 1-3 Alkyl and -C 1-3 Haloalkyl; preferably, R4 is independently selected from hydrogen and -C each time it appears. 1-3 alkyl; R5 is independently selected from hydrogen, halogen, and -C each time it appears. 1-3 Alkyl, -C 1-3 Halogenated alkyl groups, -NH2, -NH(C) 1-3 alkyl), -N(C) 1-3 Alkyl group 2, -OH, -O(C) 1-3 Alkyl), -SH, -S(C 1-3 Alkyl groups), -C(=O)NH2, -C(=O)NH(C 1-3 Alkyl), -C(=O)N(C 1-3 Alkyl)2, -S(=O)NH2, -S(=O)NH(C 1-3 Alkyl), -S(=O)N(C 1-3 Alkyl)2, -S(=O)2NH2, -S(=O)2NH(C 1-3 Alkyl groups), and -S(=O)2N(C 1-3 Alkyl group 2; preferably, R5 is independently selected from hydrogen, halogen, -C each time it appears. 1-3 Alkyl, -C 1-3 Halogenated alkyl groups, -OH, -O(C) 1-3 Alkyl groups), -C(=O)NH2, -C(=O)NH(C 1-3 Alkyl groups), and -C(=O)N(C 1-3 Alkyl)2; A1 is selected from N and CR. A1 ; A2 is selected from N and CR. A2 ; A3 is selected from N and CR. A3 ; A4 is selected from C(R) A41 2. NR A42 O and S; Each (in CR) A1 R in A1 ), (in CR A2 R in A2 ), (in CR A3 R in A3 ), or (in CR A41 R in A41 Each time it appears, it is independently selected from hydrogen, halogen, -C. 1-3 Alkyl and -C 1-3 Halogenated alkyl groups; preferably, each (in CR) A1 R in A1 ), (in CR A2 R in A2 ), (in CR A3 R in A3 ), or (in CR A41 R in A41 Each time it appears, it is independently selected from hydrogen and -C. 1-3 alkyl; (in NR) A42 R in A42 Each time it appears, it is independently selected from hydrogen, -C 1-3 Alkyl and -C 1-3 Halogenated alkyl groups; R 10A Or R 10B Each time it appears, it is independently selected from hydrogen, halogen, -C. 1-3 Alkyl, -C 1-3 Halogenated alkyl groups, -CN, -NH2, -NH(C) 1-3 alkyl), -N(C) 1-3 Alkyl group 2, -OH, -O(C) 1-3 Alkyl), -SH, and -S(C 1-3 Alkyl); preferably, R 10A Or R 10B Each time it appears, it is independently selected from -H or -C. 1-3 Alkyl, -NH(C) 1-3 alkyl), -N(C) 1-3 Alkyl)2、-O(C 1-3 alkyl), and -S(C 1-3 Alkyl); more preferably, R 10A Or R 10B Each time it appears, it is independently selected from -H or -C. 1-3 Alkyl groups and -O(C) 1-3 alkyl); Y3 is selected from -C(R) Y3A )2- and -O-; R Y3A Each time it appears, it is independently selected from hydrogen, halogen, -C. 1-3 Alkyl, -C 1-3 Haloalkyl, -(C 1-3 alkylene)-O-(C 1-3 alkyl), -(C 1-3 alkylene)-O-(C 1-3 Halogenated alkyl groups), -OH, and -O(C) 1-3 alkyl); R 12 Each time it appears, it is independently selected from hydrogen, -C 1-3 Alkyl and -C 1-3 Halogenated alkyl; preferably, R 12 Each time it appears, it is independently selected from hydrogen and -C. 1-3 alkyl; n6 is selected from 0, 1, 2, and 3; preferably, n6 is selected from 0, 1, and 2; more preferably, n6 is selected from 0 and 1; n7 is selected from 0, 1, 2, and 3; preferably, n7 is selected from 0, 1, and 2; more preferably, n7 is selected from 0 and 1; n8 is selected from 0, 1, 2, and 3; preferably, n8 is selected from 0, 1, and 2; more preferably, n8 is selected from 0 and 1; n9 is selected from 0, 1, 2, and 3; preferably, n9 is selected from 0, 1, and 2; more preferably, n9 is selected from 0 and 1; And n6+n7+n8+n9≤5.

4. A compound of formula (III-34), or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt thereof, a solvate thereof, a prodrug thereof, or a deuterated derivative thereof. in: R A2 Each time it appears, it is independently selected from hydrogen, halogen, -C. 1-3 Alkyl and -C 1-3 Halogenated alkyl; more preferably, R A2 Each time it appears, it is independently selected from hydrogen and -C. 1-3 alkyl; R 10A Or R 10B Each time it appears, it is independently selected from hydrogen, halogen, -C. 1-3 Alkyl, -C 1-3 Halogenated alkyl groups, -CN, -NH2, -NH(C) 1-3 alkyl), -N(C) 1-3 Alkyl group 2, -OH, -O(C) 1-3 Alkyl), -SH, and -S(C 1-3 Alkyl); preferably, R 10A Or R 10B Each time it appears, it is independently selected from -H or -C. 1-3 Alkyl, -NH(C) 1-3 alkyl), -N(C) 1-3 Alkyl)2、-O(C 1-3 alkyl), and -S(C 1-3 Alkyl); more preferably, R 10A Or R 10B Each time it appears, it is independently selected from -H or -C. 1-3 Alkyl groups and -O(C) 1-3 alkyl); R 12 Each time it appears, it is independently selected from hydrogen, -C 1-3 Alkyl, or -C 1-3 Halogenated alkyl; preferably, R 12 Each time it appears, it is independently selected from hydrogen or -C. 1-3 alkyl; n6 is selected from 0, 1, and 2; preferably, n6 is selected from 0 and 1; n7 is selected from 0, 1, and 2; preferably, n7 is selected from 0 and 1; n8 is selected from 0, 1, and 2; preferably, n8 is selected from 0 and 1; n9 is selected from 0, 1, and 2; preferably, n9 is selected from 0 and 1; And n6+n7+n8+n9≤5.

5. The compound according to any one of claims 1-4, or its stereoisomer, pharmaceutically acceptable salt thereof, pharmaceutically acceptable salt of its stereoisomer, its solvate, its prodrug, or its deuterated derivative, characterized in that, R A2 Each time it appears, it is independently selected from hydrogen and -C. 1-3 Alkyl; preferably, R A2 It is -CH3; R 10A Or R 10B Each time it appears, it is independently selected from -H or -C. 1-3 Alkyl groups and -O(C) 1-3 Alkyl); preferably, R 10A Or R 10B -H; R 12 Each time it appears, it is independently selected from hydrogen or -C. 1-3 Alkyl; preferably, R 12 -H; n6 is selected from 0 and 1; n7 is selected from 0 and 1; n8 is selected from 0 and 1; n9 is selected from 0 and 1; And n6+n7+n8+n9≤5.

6. A compound of formula (III-54), or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt thereof, a solvate thereof, a prodrug thereof, or a deuterated derivative thereof. in: R2 is independently selected from hydrogen, halogen, and -C each time it appears. 1-3 Alkyl and -C 1-3 Haloalkyl; preferably, R2 is independently selected from hydrogen and -C each time it appears. 1-3 alkyl; R3 is independently selected from hydrogen, halogen, and -C each time it appears. 1-3 Alkyl, -C 1-3 Halogenated alkyl groups, -CN, -NH2, -NH(C) 1-3 alkyl), -N(C) 1-3 alkyl)2、-NH(C 3-7 cycloalkyl), -OH, -O(C 1-3 Alkyl), -O(C) 3-7 cycloalkyl), -SH, -S(C 1-3 alkyl), and -S(C 3-7 (cycloalkyl); preferably, R3 is independently selected from hydrogen, -C, and -C each time it appears. 1-3 Alkyl, -OH, -O(C) 1-3 alkyl), and -O(C 3-7 cycloalkyl); R4 is independently selected from hydrogen, halogen, and -C each time it appears. 1-3 Alkyl and -C 1-3 Haloalkyl; preferably, R4 is independently selected from hydrogen and -C each time it appears. 1-3 alkyl; R5 is independently selected from hydrogen, halogen, and -C each time it appears. 1-3 Alkyl, -C 1-3 Halogenated alkyl groups, -NH2, -NH(C) 1-3 alkyl), -N(C) 1-3 Alkyl group 2, -OH, -O(C) 1-3 Alkyl), -SH, -S(C 1-3 Alkyl groups), -C(=O)NH2, -C(=O)NH(C 1-3 Alkyl), -C(=O)N(C 1-3 Alkyl)2, -S(=O)NH2, -S(=O)NH(C 1-3 Alkyl), -S(=O)N(C 1-3 Alkyl)2, -S(=O)2NH2, -S(=O)2NH(C 1-3 Alkyl groups), and -S(=O)2N(C 1-3 Alkyl group 2; preferably, R5 is independently selected from hydrogen, halogen, -C each time it appears. 1-3 Alkyl, -C 1-3 Halogenated alkyl groups, -OH, -O(C) 1-3 Alkyl groups), -C(=O)NH2, -C(=O)NH(C 1-3 Alkyl groups), and -C(=O)N(C 1-3 Alkyl)2; A1 is selected from N and CR. A1 ; A2 is selected from N and CR. A2 ; A3 is selected from N and CR. A3 ; A4 is selected from C(R) A41 2. NR A42 O and S; Each (in CR) A1 R in A1 ), (in CR A2 R in A2 ), (in CR A3 R in A3 ), or (in CR A41 R in A41 Each time it appears, it is independently selected from hydrogen, halogen, -C. 1-3 Alkyl and -C 1-3 Halogenated alkyl groups; preferably, each (in CR) A1 R in A1 ), (in CR A2 R in A2 ), (in CR A3 R in A3 ), or (in CR A41 R in A41 Each time it appears, it is independently selected from hydrogen and -C. 1-3 alkyl; (in NR) A42 R in A42 Each time it appears, it is independently selected from hydrogen, -C 1-3 Alkyl and -C 1-3 Halogenated alkyl groups; Y3 is selected from -C(R) Y3A )2- and -O-; R Y3A Each time it appears, it is independently selected from hydrogen, halogen, -C. 1-3 Alkyl, -C 1-3 Haloalkyl, -(C 1-3 alkylene)-O-(C 1-3 alkyl), -(C 1-3 alkylene)-O-(C 1-3 Halogenated alkyl groups), -OH, and -O(C) 1-3 alkyl); R 10A Or R 10B Each time it appears, it is independently selected from hydrogen, halogen, -C. 1-3 Alkyl, -C 1-3 Halogenated alkyl groups, -CN, -NH2, -NH(C) 1-3 alkyl), -N(C) 1-3 Alkyl group 2, -OH, -O(C) 1-3 Alkyl), -SH, and -S(C 1-3 Alkyl); preferably, R 10A Or R 10B Each time it appears, it is independently selected from -H or -C. 1-3 Alkyl, -NH(C) 1-3 alkyl), -N(C) 1-3 Alkyl)2、-O(C 1-3 alkyl), and -S(C 1-3 Alkyl); more preferably, R 10A Or R 10B Each time it appears, it is independently selected from -H or -C. 1-3 Alkyl groups and -O(C) 1-3 alkyl); R 12 Each time it appears, it is independently selected from hydrogen, -C 1-3 Alkyl and -C 1-3 Halogenated alkyl; preferably, R 12 Each time it appears, it is independently selected from hydrogen and -C. 1-3 alkyl; n6 is selected from 0, 1, 2, and 3; preferably, n6 is selected from 0, 1, and 2; more preferably, n6 is selected from 0 and 1; n7 is selected from 0, 1, 2, and 3; preferably, n7 is selected from 0, 1, and 2; more preferably, n7 is selected from 0 and 1; n8 is selected from 0, 1, 2, and 3; preferably, n8 is selected from 0, 1, and 2; more preferably, n8 is selected from 0 and 1; n9 is selected from 0, 1, 2, and 3; preferably, n9 is selected from 0, 1, and 2; more preferably, n9 is selected from 0 and 1; And n6+n7+n8+n9≤5.

7. A compound of formula (III-42), or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt thereof, a solvate thereof, a prodrug thereof, or a deuterated derivative thereof. in: R A2 Each time it appears, it is independently selected from hydrogen, halogen, -C. 1-3 Alkyl and -C 1-3 Halogenated alkyl; preferably, each R A2 Each time it appears, it is independently selected from hydrogen and -C. 1-3 alkyl; R 10A Or R 10B Each time it appears, it is independently selected from hydrogen, halogen, -C. 1-3 Alkyl, -C 1-3 Halogenated alkyl groups, -CN, -NH2, -NH(C) 1-3 alkyl), -N(C) 1-3 Alkyl group 2, -OH, -O(C) 1-3 Alkyl), -SH, and -S(C 1-3 Alkyl); preferably, R 10A Or R 10B Each time it appears, it is independently selected from -H or -C. 1-3 Alkyl, -NH(C) 1-3 alkyl), -N(C) 1-3 Alkyl)2、-O(C 1-3 alkyl), and -S(C 1-3 Alkyl); more preferably, R 10A Or R 10B Each time it appears, it is independently selected from -H or -C. 1-3 Alkyl groups and -O(C) 1-3 alkyl); R 12 Each time it appears, it is independently selected from hydrogen, -C 1-3 Alkyl, or -C 1-3 Halogenated alkyl; preferably, R 12 Each time it appears, it is independently selected from hydrogen or -C. 1-3 alkyl; n6 is selected from 0, 1, and 2; preferably, n6 is selected from 0 and 1; n7 is selected from 0, 1, and 2; preferably, n7 is selected from 0 and 1; n8 is selected from 0, 1, and 2; preferably, n8 is selected from 0 and 1; n9 is selected from 0, 1, and 2; preferably, n9 is selected from 0 and 1; And n6+n7+n8+n9≤5.

8. The compound according to claim 7, or its stereoisomer, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of its stereoisomer, its solvate, its prodrug, or its deuterated derivative, characterized in that, R A2 Selected independently from -C each time it appears. 1-3 Alkyl; preferably, R A2 -CH3; R 10A Or R 10B Each time it appears, it is independently selected from -H or -C. 1-3 Alkyl groups and -O(C) 1-3 Alkyl); preferably, R 10A Or R 10B For H. R 12 Each time it appears, it is independently selected from hydrogen or -C. 1-3 alkyl; n6 is selected from 0 and 1; n7 is selected from 0 and 1; n8 is selected from 0 and 1; n9 is selected from 0 and 1; And n6+n7+n8+n9≤5.

9. A compound of formula (III-55), or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt thereof, a solvate thereof, a prodrug thereof, or a deuterated derivative thereof. in: R2 is independently selected from hydrogen, halogen, and -C each time it appears. 1-3 Alkyl and -C 1-3 Haloalkyl; preferably, R2 is independently selected from hydrogen and -C each time it appears. 1-3 alkyl; R3 is independently selected from hydrogen, halogen, and -C each time it appears. 1-3 Alkyl, -C 1-3 Halogenated alkyl groups, -CN, -NH2, -NH(C) 1-3 alkyl), -N(C) 1-3 alkyl)2、-NH(C 3-7 cycloalkyl), -OH, -O(C 1-3 Alkyl), -O(C) 3-7 cycloalkyl), -SH, -S(C 1-3 alkyl), and -S(C 3-7 (cycloalkyl); preferably, R3 is independently selected from hydrogen, -C, and -C each time it appears. 1-3 Alkyl, -OH, -O(C) 1-3 alkyl), and -O(C 3-7 cycloalkyl); R4 is independently selected from hydrogen, halogen, and -C each time it appears. 1-3 Alkyl and -C 1-3 Haloalkyl; preferably, R4 is independently selected from hydrogen and -C each time it appears. 1-3 alkyl; R5 is independently selected from hydrogen, halogen, and -C each time it appears. 1-3 Alkyl, -C 1-3 Halogenated alkyl groups, -NH2, -NH(C) 1-3 alkyl), -N(C) 1-3 Alkyl group 2, -OH, -O(C) 1-3 Alkyl), -SH, -S(C 1-3 Alkyl groups), -C(=O)NH2, -C(=O)NH(C 1-3 Alkyl), -C(=O)N(C 1-3 Alkyl)2, -S(=O)NH2, -S(=O)NH(C 1-3 Alkyl), -S(=O)N(C 1-3 Alkyl)2, -S(=O)2NH2, -S(=O)2NH(C 1-3 Alkyl groups), and -S(=O)2N(C 1-3 Alkyl group 2; preferably, R5 is independently selected from hydrogen, halogen, -C each time it appears. 1-3 Alkyl, -C 1-3 Halogenated alkyl groups, -OH, -O(C) 1-3 Alkyl groups), -C(=O)NH2, -C(=O)NH(C 1-3 Alkyl groups), and -C(=O)N(C 1-3 Alkyl)2; A1 is selected from N and CR. A1 ; A2 is selected from N and CR. A2 ; A3 is selected from N and CR. A3 ; A4 is selected from C(R) A41 2. NR A42 O and S; Each (in CR) A1 R in A1 ), (in CR A2 R in A2 ), (in CR A3 R in A3 ), or (in CR A41 R in A41 Each time it appears, it is independently selected from hydrogen, halogen, -C. 1-3 Alkyl and -C 1-3 Halogenated alkyl groups; preferably, each (in CR) A1 R in A1 ), (in CR A2 R in A2 ), (in CR A3 R in A3 ), or (in CR A41 R in A41 Each time it appears, it is independently selected from hydrogen and -C. 1-3 alkyl; (in NR) A42 R in A42 Each time it appears, it is independently selected from hydrogen, -C 1-3 Alkyl and -C 1-3 Halogenated alkyl groups; R 10A Or R 10B Each time it appears, it is independently selected from hydrogen, halogen, -C. 1-3 Alkyl, -C 1-3 Halogenated alkyl groups, -CN, -NH2, -NH(C) 1-3 alkyl), -N(C) 1-3 Alkyl group 2, -OH, -O(C) 1-3 Alkyl), -SH, and -S(C 1-3 Alkyl); preferably, R 10A Or R 10B Each time it appears, it is independently selected from -H or -C. 1-3 Alkyl, -NH(C) 1-3 alkyl), -N(C) 1-3 Alkyl)2、-O(C 1-3 alkyl), and -S(C 1-3 Alkyl); more preferably, R 10A Or R 10B Each time it appears, it is independently selected from -H or -C. 1-3 Alkyl groups and -O(C) 1-3 alkyl); R 12 Each time it appears, it is independently selected from hydrogen, -C 1-3 Alkyl and -C 1-3 Halogenated alkyl; preferably, R 12 Each time it appears, it is independently selected from hydrogen and -C. 1-3 alkyl; Y5 is selected from -O- and -C(R) Y5A )2-; Preferably, Y5 is -O-; R Y5A Each time it appears, it is independently selected from hydrogen, halogen, -C. 1-3 Alkyl and -C 1-3 Halogenated alkyl; preferably, R Y5A Each time it appears, it is independently selected from hydrogen and -C. 1-3 alkyl; n 10 Selected from 0, 1, and 2; preferably, n 10 Selected from 0 and 1; n 11 Selected from 0, 1, and 2; preferably, n 11 Selected from 0 and 1; n 12 Selected from 0, 1, and 2; preferably, n 12 Selected from 0 and 1; n 13 Selected from 0, 1, and 2; preferably, n 13 Selected from 0 and 1; n 14 Selected from 0, 1, and 2; preferably, n 14 Selected from 0 and 1; n 15 Selected from 0, 1, and 2; preferably, n 15 Selected from 0 and 1; n 16 Selected from 0, 1, and 2; preferably, n 16 Selected from 0 and 1; n 17 Selected from 0, 1, and 2; preferably, n 17 Selected from 0 and 1; And n 10 +n 11 +n 12 +n 13 ≤6; And n 14 +n 15 +n 16 +n 17 ≤6.

10. A compound of formula (III-50), or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt thereof, a solvate thereof, a prodrug thereof, or a deuterated derivative thereof. in: R A2 Each time it appears, it is independently selected from hydrogen, halogen, -C. 1-3 Alkyl and -C 1-3 Halogenated alkyl; preferably, R A2 Each time it appears, it is independently selected from hydrogen and -C. 1-3 alkyl; R 10A Or R 10B Each time it appears, it is independently selected from hydrogen, halogen, -C. 1-3 Alkyl, -C 1-3 Halogenated alkyl groups, -CN, -NH2, -NH(C) 1-3 alkyl), -N(C) 1-3 Alkyl group 2, -OH, -O(C) 1-3 Alkyl), -SH, and -S(C 1-3 Alkyl); preferably, R 10A Or R 10B Each time it appears, it is independently selected from -H or -C. 1-3 Alkyl, -NH(C) 1-3 alkyl), -N(C) 1-3 Alkyl)2、-O(C 1-3 alkyl), and -S(C 1-3 Alkyl); more preferably, R 10A Or R 10B Each time it appears, it is independently selected from -H or -C. 1-3 Alkyl groups and -O(C) 1-3 alkyl); R 12 Each time it appears, it is independently selected from hydrogen, -C 1-3 Alkyl, or -C 1-3 Halogenated alkyl; preferably, R 12 Each time it appears, it is independently selected from hydrogen or -C. 1-3 alkyl; n 10 Selected from 0, 1, and 2; preferably, n 10 Selected from 0 and 1; n 11 Selected from 0, 1, and 2; preferably, n 11 Selected from 0 and 1; n 12 Selected from 0, 1, and 2; preferably, n 12 Selected from 0 and 1; n 13 Selected from 0, 1, and 2; preferably, n 13 Selected from 0 and 1; n 14 Selected from 0, 1, and 2; preferably, n 14 Selected from 0 and 1; n 15 Selected from 0, 1, and 2; preferably, n 15 Selected from 0 and 1; n 16 Selected from 0, 1, and 2; preferably, n 16 Selected from 0 and 1; n 17 Selected from 0, 1, and 2; preferably, n 17 Selected from 0 and 1; And n 10 +n 11 +n 12 +n 13 ≤6; And n 14 +n 15 +n 16 +n 17 ≤6.

11. The compound according to any one of claims 6-10, or its stereoisomer, pharmaceutically acceptable salt thereof, pharmaceutically acceptable salt of its stereoisomer, its solvate, its prodrug, or its deuterated derivative, characterized in that, R A2 Each time it appears, it is independently selected from hydrogen and -C. 1-3 Alkyl; preferably, R A2 -CH3; R 10A Or R 10B Each time it appears, it is independently selected from -H or -C. 1-3 Alkyl groups and -O(C) 1-3 Alkyl); preferably, R 10A Or R 10B -H; R 12 Each time it appears, it is independently selected from hydrogen or -C. 1-3 Alkyl; preferably, R 12 -H; n 10 Selected from 0 and 1; n 11 Selected from 0 and 1; n 12 Selected from 0 and 1; n 13 Selected from 0 and 1; n 14 Selected from 0 and 1; n 15 Selected from 0 and 1; n 16 Selected from 0 and 1; n 17 Selected from 0 and 1; And n 10 +n 11 +n 12 +n 13 ≤6; And n 14 +n 15 +n 16 +n 17 ≤6.

12. The compound according to any one of claims 1-11, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt thereof, a solvate thereof, a prodrug thereof, or a deuterated derivative thereof, wherein the compound is selected from:

13. A pharmaceutical composition comprising a therapeutically effective dose of any one of claims 1 to 12, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt thereof, a solvate thereof, a prodrug thereof, or a deuterated derivative thereof, and one or more pharmaceutically acceptable carriers or excipients.

14. A compound of formula (III-1), (III-3), (III-34), (III-42), (III-50), (III-53), (III-54), or (III-55) according to any one of claims 1 to 12, its stereoisomer, its pharmaceutically acceptable salt, a pharmaceutically acceptable salt of its stereoisomer, its solvate, its prodrug, or its deuterated derivative; or use of the pharmaceutical composition according to claim 13 in the preparation of a medicament for treating central nervous system disorders associated with Kappa receptor antagonism; preferably, the central nervous system disorders associated with Kappa receptor antagonism include, but are not limited to, central nervous system disorders associated with anxiety, central nervous system disorders associated with depression, central nervous system disorders associated with mood disorders, central nervous system disorders associated with substance dependence and abuse, and other central nervous system disorders associated with mental illnesses such as schizophrenia or Parkinson's disease.

15. The use according to claim 14, wherein, Central nervous system disorders related to anxiety include, but are not limited to, anxiety disorders, phobias, stress-related anxiety disorders, post-traumatic stress disorder (PTSD), and generalized anxiety disorder (GAD); central nervous system disorders related to depression include, but are not limited to, depression, major depressive disorder (MDD), major depressive disorder, treatment-resistant depression, and major depressive disorder with moderate to severe anhedonia; central nervous system disorders related to mood disorders include, but are not limited to, mood disorders, anhedonia, and bipolar disorder; central nervous system disorders related to substance dependence and abuse include, but are not limited to, smoking cessation and opioid withdrawal.

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