Cycloalkene derivative acting as orexin receptor agonist, and composition and use thereof

Abstract

The present invention relates to a cycloalkene derivative having an orexin 2 receptor (OX2R) agonistic activity. Specifically, the present invention relates to a compound as represented by general formula (I), a stereoisomer thereof, a tautomer thereof, a pharmaceutically acceptable salt thereof, and pharmaceutically acceptable salts of said stereoisomer and tautomer. The present invention further relates to a pharmaceutical composition containing the compound, a preparation method therefor, and the use thereof as an orexin 2 receptor (OX2R) agonist in the prevention or treatment of diseases associated with the orexin 2 receptor (OX2R) agonistic effect, such as narcolepsy, hypersomnia, sleep apnea, post-anesthesia recovery or respiratory inhibition amelioration, wherein each substituent in the general formula (I) is the same as that defined in the description.

Description

Cycloolefin derivatives as orexin receptor agonists, their compositions and uses

[0001] This application claims priority to Chinese Patent Application No. 202410956321.2, filed on July 17, 2024; Chinese Patent Application No. 202411920329.X, filed on December 25, 2024; and Chinese Patent Application No. 202510528880.8, filed on April 25, 2025, the entire contents of which are incorporated herein by reference. Technical Field

[0002] This invention relates to a cyclic olefin derivative having orexin receptor 2 (OX2R) agonist activity. The invention also relates to methods for preparing said cyclic olefin derivative, pharmaceutical compositions, and treatment methods and uses for diseases related to orexin receptor 2 (OX2R) agonist activity, such as narcolepsy, recovery from anesthesia, and improvement of respiratory depression. Background Technology

[0003] Orexin is an excitatory neuropeptide secreted by the hypothalamus, first discovered in 1998 by Sakurai et al. using chromatography. Orexin is divided into orexin-A (OXA) and orexin-B (OXB), which share certain sequence homology. Currently, two orexin receptors are known: the orexin 1 receptor (OX1R) and the orexin 2 receptor (OX2R). OXA has roughly equal affinity for both receptors, while OXB tends to bind more strongly to OX2R. Orexin and its receptors are widely distributed in the central nervous system, participating in the regulation of various physiological functions, including the sleep-wake cycle, energy balance, and stress response. For example, dysregulation of the orexin system is closely related to various disease states, such as narcolepsy, recovery from anesthesia, improvement of respiratory depression, obesity, and anxiety disorders. In-depth research on the orexin system not only helps to understand the fundamental mechanisms of these physiological processes but also provides new drug targets for the treatment of related diseases.

[0004] In recent years, with a deeper understanding of the function of the orexin system, the development of drugs targeting orexin receptors has become an important research direction. Orexin receptor agonists have shown great potential, particularly in the treatment of narcolepsy, recovery from anesthesia, and improvement of respiratory depression. OX1R or OX2R receptor agonists can effectively improve patients' sleep quality, while selective OX2R agonists have shown significant efficacy in the treatment of narcolepsy, recovery from anesthesia, and improvement of respiratory depression. International patent document WO2017135306A1 discloses a class of substituted piperidine compounds with OX2R agonist activity, which can be used as a preventive or therapeutic agent for narcolepsy. Further research into the function and mechanism of action of orexin receptor 2 (OX2R) and the development of new drugs and treatment methods are of great significance for improving the treatment efficacy of related diseases. Summary of the Invention

[0005] This invention relates to a novel class of compounds that, as orexin receptor agonists, stimulate sleep disturbances, thereby promoting anesthesia recovery, respiratory function, and regulating anxiety and depression. In some embodiments, the compounds of this invention exhibit good agonistic activity against orexin receptor 2 (OX2R). In some embodiments, the compounds of this invention possess favorable pharmacokinetic properties (e.g., suitable half-life and duration of action, good plasma concentrations, 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 better drug-like properties such as better patient compliance.

[0006] The results of the orexin receptor agonistic activity disclosed in this invention demonstrate that the compounds of this invention are effective orexin receptor 2 (OX2R) agonists, exhibiting good agonistic effects on the orexin receptor 2 (OX2R). In some embodiments, the compounds of this invention exhibit favorable drug metabolism properties, with excellent half-life t1 / 2 and rapid time to peak concentration Tmax, and also show good performance in metabolic parameters such as maximum plasma concentration Cmax and area under the curve AUC(0-t).

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

[0008] 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:

[0009] Y 1 Selected from non-existent, -C(R) Y1A )2-、-O-、-NRY1B -、-S-、-C(=O)-、-S(=O)-、or-S(=O)2-;

[0010] R Y1A 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 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), -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 Alkyl), 3-10 membered carbocyclic, 3-10 membered heterocyclic, 6-10 membered aryl, or 5-10 membered heteroaryl; wherein, the R Y1A Optionally, it is selected from one or more halogens, -C 1-6 Alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl group, -C 1-6 Alkoxy, -C1-6 Halogenated alkyl groups, -CN, -NO2, oxo, -NH2, -NH(C) 1-6 alkyl), -N(C) 1- 6-alkyl)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), -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, 3-10 membered carbocyclic groups, 3-10 membered heterocyclic groups, 6-10 membered aryl groups or 5-10 membered heteroaryl groups;

[0011] Optionally, two R atoms attached to the same C atom Y1A Together with the C atoms they are connected to, they form an optional n S1 R S1 Substituted 3-14 membered carbocyclic rings, 3-14 membered heterocyclic rings, 6-10 membered aryl rings or 5-10 membered heteroaryl rings;

[0012] n S1 Choose from 0, 1, 2, 3, 4, 5, or 6;

[0013] R Y1B Each time it appears, it is independently selected from hydrogen, -C 1-6 Alkyl, -C2-6 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 groups), -C(=O)NH2, -C(=O)NH(C 1-6 Alkyl), -C(=O)N(C 1-6 Alkyl) 2, 3-10 membered carbocyclic, 3-10 membered heterocyclic, 6-10 membered aryl or 5-10 membered heteroaryl; wherein, the R Y1B Optionally, it is selected from 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), -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(C1-6 Substitution with alkyl groups, 3-10 membered carbocyclic groups, 3-10 membered heterocyclic groups, 6-10 membered aryl groups or 5-10 membered heteroaryl groups;

[0014] n1 is selected from 0, 1, 2, 3, or 4;

[0015] n2 is selected from 0, 1, 2, 3, or 4;

[0016] And n1 + n2 ≤ 4;

[0017] R 3 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 Halogenated alkyl groups, -OC 1-6 Haloalkyl, -(C=O)R 3A -S(=O)R 3B -S(=O)2R 3C -(C=S)R 3D -(C=Se)R 3E -(C=NR) 3T )R 3F -(C=O)OR 3H -(C=S)SR 3I -P(=O)R 3G (OR 3J -(C=O)NR 3K R 3L -(C=S)NR 3M R 3N -S(=O)NR 3P R 3Q -S(=O)2NR 3R R 3S , 3-10 membered carbocyclic group, 3-10 membered heterocyclic group, 6-10 membered aryl or 5-10 membered heteroaryl;

[0018] Each R 3A R 3B R 3C R 3D R 3E R 3F or R 3G Independently selected from hydrogen, -C 1-6 Alkyl, -C 1-6 Halogenated alkyl groups, -OC 1-6 Halogenated alkyl groups, -NH2, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl group 2, -OH, -O(C) 1-6Alkyl), 3-14 membered carbocyclic, 3-14 membered heterocyclic, 6-10 membered aryl, or 5-10 membered heteroaryl; wherein, the (R) 3A R 3B R 3C R 3D R 3E R 3F or R 3G )Optionally selected by one or more halogens, -C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OC 1-6 Halogenated alkyl, -C 2-6 alkenyl, -C 2-6 Alkyne, -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), -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, 3-10 membered carbocyclic groups, 3-10 membered heterocyclic groups, 6-10 membered aryl groups or 5-10 membered heteroaryl groups;

[0019] Each R3H R 3I 、or R 3J Independently selected from hydrogen, -C 1-6 Alkyl, -C 1-6 Halogenated alkyl, 3-14 membered carbocyclic, 3-14 membered heterocyclic, 6-10 membered aryl, or 5-10 membered heteroaryl; wherein, the (R) 3H R 3I 、or R 3J )Optionally selected by one or more halogens, -C 1-6 Alkyl, -C 1-6 Halogenated alkyl groups, -OC 1-6 Halogenated alkyl, -C 2-6 alkenyl, -C 2-6 Alkyne, -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), -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, 3-10 membered carbocyclic groups, 3-10 membered heterocyclic groups, 6-10 membered aryl groups or 5-10 membered heteroaryl groups;

[0020] Each R 3K R 3L R 3M R 3N R 3P R 3Q R 3R R 3S or R 3T Independently selected from hydrogen, -C 1-6 Alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl group, -C 1-6 Halogenated alkyl groups, -NH2, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl) 2, 3-14 membered carbocyclic, 3-14 membered heterocyclic, 6-10 membered aryl or 5-10 membered heteroaryl; wherein, the (R) 3K R 3L R 3M R 3N R 3P R 3Q R 3R R 3S or R 3T )Optionally selected by one or more halogens, -C 1-6 Alkyl, -C 1-6 Halogenated alkyl groups, -OC 1-6 Halogenated alkyl, -C 2-6 alkenyl, -C 2-6 Alkyne, -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), -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(C1-6 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, 3-10 membered carbocyclic groups, 3-10 membered heterocyclic groups, 6-10 membered aryl groups or 5-10 membered heteroaryl groups;

[0021] R 4 Each time it appears, it is independently selected from hydrogen, -C 1-3 Alkyl, or -C 1-3 Halogenated alkyl groups;

[0022] R 5 Each occurrence is independently selected from -C(=O)-R 51 -S(=O)R 52 -S(=O)2R 53 、or -P(=O)R 54 (OR 55 );

[0023] Each (R) 51 R 52 R 53 、or R 54 Each time it appears, it is independently selected from hydrogen, -C 1-6 Alkyl, -C 1-6 Halogenated alkyl groups, -OC 1-6 Halogenated alkyl groups, -NH2, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl)2, =NH, -OH, -O(C 1-6 Alkyl groups), -C(=O)NH2, -C(=O)NH(C 1-6 Alkyl), -C(=O)N(C 1-6 Alkyl) 2, 3-10 membered carbocyclic, 3-10 membered heterocyclic, 6-10 membered aryl or 5-10 membered heteroaryl; wherein, the (R) 51 R 52 R 53 、or R 54 )Optionally selected by one or more halogens, -C 1-6 Alkyl, -C 1-6 Halogenated alkyl groups, -OC 1-6 Halogenated alkyl, -C2-6 alkenyl, -C 2-6 Alkyne, -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), -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)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)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- Substituents of 6-alkyl, 3-10-membered carbocyclic, 3-10-membered heterocyclic, 6-10-membered aryl or 5-10-membered heteroaryl groups;

[0024] Each R 55 Independently selected from hydrogen, -C 1-6 Alkyl, -C 1-6 Haloalkyl, 3-10 membered carbocyclic, 3-10 membered heterocyclic, 6-10 membered aryl, or 5-10 membered heteroaryl; wherein, the R 55 Optionally, it is selected from one or more halogens, -C 1-6 Alkyl, -C 1-6 Halogenated alkyl groups, -OC 1-6 Halogenated alkyl, -C 2- 6-alkenyl, -C 2-6Alkyne, -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), -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- 6alkyl)S(=O)2(C 1-6 Substitution with alkyl groups, 3-10 membered carbocyclic groups, 3-10 membered heterocyclic groups, 6-10 membered aryl groups or 5-10 membered heteroaryl groups;

[0025] (R 4A R 4B 、or R 4C 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 Alkoxy, -CN, -NH2, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl group 2, -OH, -O(C) 1-6 Alkyl), -SH, -S(C 1-6Alkyl), -C(=O)(C 1-6 Alkyl), -S(=O)(C 1-6 Alkyl), -S(=O)2(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), 3-10 membered carbocyclic, 3-10 membered heterocyclic, 6-10 membered aryl, or 5-10 membered heteroaryl; wherein each of the (R) 4A R 4B 、or R 4C 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 Alkoxy, -CN, -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), -C(=O)OH, -C(=O)(OC 1-6 Alkyl), -OC (=O)(C 1-6Alkyl 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, 3-10 membered carbocyclic groups, 3-10 membered heterocyclic groups, 6-10 membered aryl groups or 5-10 membered heteroaryl groups;

[0026] Ring A is selected from 3-14 membered carbocyclic rings, 3-14 membered heterocyclic rings, 6-14 membered aromatic rings, or 5-14 membered heteroaryl rings;

[0027] R S2 Each time it appears, it is independently selected from halogens and -C. 1-6 Alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl group, -C 1-6 Halogenated alkyl groups, -OC 1-6 Halogenated alkyl, -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(=O)(C 1-6 Alkyl), -S(=O)2(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)(C1-6 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), 3-7 membered carbocyclic, 3-7 membered heterocyclic, 6-10 membered aryl or 5-10 membered heteroaryl; wherein, the 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, -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(=O)(C 1-6 Alkyl), -S(=O)2(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), -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 Substituents of alkyl, 3-7 membered carbocyclic, 3-7 membered heterocyclic, 6-10 membered aryl or 5-10 membered heteroaryl;

[0028] n S2 Choose from 0, 1, 2, 3, 4, 5, or 6;

[0029] X is selected from N or CR 6 ;

[0030] R 6 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 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), -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) 1-6Alkyl)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), 3-10 membered carbocyclic, 3-10 membered heterocyclic, 6-10 membered aryl, or 5-10 membered heteroaryl; wherein, the R 6 Optionally, it is selected from 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)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), -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 1-6Alkyl 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 Substitution with alkyl groups, 3-10 membered carbocyclic groups, 3-10 membered heterocyclic groups, 6-10 membered aryl groups or 5-10 membered heteroaryl groups;

[0031] Y 3 Selected from non-existent, -C(R) Y3A )2-、-O-、-NR Y3B -、-S-、-C(=O)-、-S(=O)-、or-S(=O)2-;

[0032] R Y3A 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 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), -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(C1-6 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), 3-10 membered carbocyclic, 3-10 membered heterocyclic, 6-10 membered aryl, or 5-10 membered heteroaryl; wherein, the R Y3A Optionally, it is selected from 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)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), -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, 3-10 membered carbocyclic groups, 3-10 membered heterocyclic groups, 6-10 membered aryl groups or 5-10 membered heteroaryl groups;

[0033] 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 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;

[0034] n S4 Choose from 0, 1, 2, 3, 4, 5, or 6;

[0035] R Y3B 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 groups), -C(=O)NH2, -C(=O)NH(C 1-6 Alkyl), -C(=O)N(C 1-6 Alkyl) 2, 3-10 membered carbocyclic, 3-10 membered heterocyclic, 6-10 membered aryl or 5-10 membered heteroaryl; wherein, the R Y3B Optionally, it is selected from 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)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), -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 1-6Alkyl 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, 3-10 membered carbocyclic groups, 3-10 membered heterocyclic groups, 6-10 membered aryl groups or 5-10 membered heteroaryl groups;

[0036] n3 is selected from 0, 1, 2, 3, or 4;

[0037] n4 is selected from 0, 1, 2, 3, or 4;

[0038] n5 is selected from 0, 1, 2, 3, or 4;

[0039] And n3 + n4 + n5 ≤ 5;

[0040] Y 2 Selected from -O-, -NR Y2B -、or -S-;

[0041] R Y2B 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 groups), -C(=O)NH2, -C(=O)NH(C 1-6 Alkyl), -C(=O)N(C 1-6 Alkyl) 2, 3-10 membered carbocyclic, 3-10 membered heterocyclic, 6-10 membered aryl or 5-10 membered heteroaryl; wherein, the R Y2B Optionally, it is selected from one or more halogens, -C 1-6 Alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl group, -C 1-6 Halogenated alkyl groups, -OC 1-6Halogenated alkyl groups, -CN, -NO2, oxo, -NH2, -NH(C) 1-6 alkyl), -N(C) 1- 6-alkyl)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), -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, 3-10 membered carbocyclic groups, 3-10 membered heterocyclic groups, 6-10 membered aryl groups or 5-10 membered heteroaryl groups;

[0042] R 2 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, 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 1-6Alkyl), -S(=O)2(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 Alkyl), 3-10 membered carbocyclic, 3-10 membered heterocyclic, 6-10 membered aryl, or 5-10 membered heteroaryl; wherein, the R 2 Optionally, it is selected from 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), -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, 3-10 membered carbocyclic groups, 3-10 membered heterocyclic groups, 6-10 membered aryl groups or 5-10 membered heteroaryl groups;

[0043] Optionally, two R atoms attached to the same C atom 2 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;

[0044] n S5 Choose from 0, 1, 2, 3, 4, 5, or 6;

[0045] Each (R) S1 R S2 R S3 R S4 、or R S5 Independently selected from halogens, -C 1-6 Alkyl, -C 1-6 Halogenated alkyl, -C 2-6 alkenyl, -C 2-6 Alkyne, -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), -S(=O)(C 1-6 Alkyl), -S(=O)2(C 1-6 Alkyl), -C(=O)(C 1-6Alkyl), -C(=O)OH, -C(=O)(OC 1-6 Alkyl), -OC (=O)(C 1- 6-alkyl), -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, 3-6 membered cycloalkyl, 3-6 membered heterocyclic, 6-10 membered aryl or 5-10 membered heteroaryl, wherein each (R S1 R S2 R S3 R S4 、or R S5 ) independently and optionally selected by 1, 2, 3, 4, 5 or 6 elements selected from halogen, -C 1-6 Alkyl, -C 1-6 Halogenated alkyl, -C 2-6 alkenyl, -C 2-6 Alkyne, -CN, oxo, -NH2, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl group 2, -OH, -O(C) 1-6 Alkyl), -SH, -S(C 1-6Alkyl), -S (halogenated C) 1-6 Alkyl), -S(=O)(C 1-6 Alkyl), -S(=O)2(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), -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 Substitution of alkyl groups (2-, 3-, 6-membered cycloalkyl groups, 3-, 6-membered heterocyclic groups, 6-, 10-membered aryl groups, or 5-, 10-membered heteroaryl groups);

[0046] Each heterocyclic group independently contains 1, 2, 3, 4 or 5 heteroatoms selected from N, O or S each time it appears;

[0047] Each heteroaryl group independently contains 1, 2, 3, 4 or 5 heteroatoms selected from N, O or S each time it appears.

[0048] In some implementation schemes, R Y1AEach time it appears, it is independently selected from hydrogen, halogen, -C. 1-3 Alkyl, or -C 1-3 Halogenated alkyl groups.

[0049] In some specific implementation schemes, R Y1A Each time it appears, it is independently selected from -H, -Cl, -F, -CH3, -CH2CH3, -CH2CH2CH3, or -CH(CH3)2; more preferably, R Y1A Each time it appears, it is independently selected from -H, -CH3, -Cl, or -F.

[0050] In some implementations, two R atoms attached to the same C atom Y1A Together with the C atoms they are connected to, they form a group optionally bounded by 1, 2, or 3 R atoms. S1 Substituted 3-7 membered cycloalkyl rings (cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl); each of the R... S1 Independently selected from halogens, -C 1-3 Alkyl, -C 1-3 alkoxy or -C 1-3 Haloalkyl. In some specific embodiments, two R atoms attached to the same C atom... Y1A Together with the C atoms they are attached to, they form a cyclopropyl ring.

[0051] In some implementation schemes, R Y1B Each time it appears, it is independently selected from hydrogen, -C 1-3 Alkyl, or -C 1-3 Halogenated alkyl groups. In some specific embodiments, R Y1B 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, R Y1B It is -H.

[0052] In some implementations, the fragment for

[0053] In some implementations, the fragment for

[0054] In some specific implementations, n1 is 0. In some specific implementations, n1 is 1.

[0055] In some specific implementations, n2 is 0. In some specific implementations, n2 is 1.

[0056] In some specific implementations, n1 is 0 and n2 is 0.

[0057] In some specific implementations, n1 is 1 and n2 is 0.

[0058] In some specific implementations, n1 is 0 and n2 is 1.

[0059] In some specific implementations, n1 is 1 and n2 is 1.

[0060] In some implementations, the fragment Selected from

[0061] In some implementations, the fragment Selected from

[0062] In some implementations, fragments Selected from or Preferably, fragments Selected from Preferably, fragments for

[0063] In some specific implementation schemes, fragments for

[0064] In some specific implementation schemes, fragments for

[0065] In some specific implementation schemes, fragments for

[0066] In some specific implementation schemes, fragments for

[0067] In some implementation schemes, R 3 -(C=O)R 3A 、or -(C=O)OR 3H ;

[0068] in,

[0069] Each R 3AIndependently selected from -C 1-3 Alkyl, 3-7 membered cycloalkyl, 3-7 membered heterocyclic, phenyl, or 5-6 membered heteroaryl; wherein, the R 3A Optionally, it is selected from 1, 2, or 3 halogens, -OH, or -O(C) 1-3 Alkyl groups are substituted; preferably, each R 3A Independently selected from -C 1-3 Alkyl, 3-7 membered monocyclic cycloalkyl, 3-7 membered spirocyclic cycloalkyl, 3-7 membered bridged cycloalkyl, 3-7 membered heterocyclic, phenyl or 5-6 membered heteroaryl, wherein R 3A Optionally, it is selected from 1, 2, or 3 halogens, -OH, -O(C 1-3 Substitution of alkyl groups;

[0070] Each R 3H Independently selected from -C 1-3 Alkyl, -C 1-3 Halogenated alkyl, 3-7 membered cycloalkyl, 3-7 membered heterocyclic, phenyl, or 5-6 membered heteroaryl; preferably, each R 3H Independently selected from -C 1-3 alkyl.

[0071] In some specific implementation schemes, R 3 Each time it appears, it is selected independently. Preferably, R 3 Each time it appears, it is selected independently.

[0072] In some implementation schemes, R 3 -(C=O)OR 3H , where each R 3H Independently selected from -C 1-3 Alkyl, -C 1-3 Halogenated alkyl, 3-7 membered cycloalkyl, 3-7 membered heterocyclic, phenyl or 5-6 membered heteroaryl; preferably, R3 为 -(C=O)OR 3H , where R 3H Selected independently from -C each time it appears. 1-3 alkyl.

[0073] In some specific implementation schemes, R 3 Each time it appears, it is selected independently. In some specific implementations, R3 is selected independently each time it occurs.

[0074] In some implementation schemes, R 3-(C=O)NR 3K R 3L -(C=S)NR 3M R 3N -S(=O)NR 3P R 3Q 、or -S(=O)2NR 3R R 3S , where each (R 3K R 3L R 3M R 3N R 3P R 3Q R 3R 、or R 3S Independently selected from hydrogen, -C 1-3 Alkyl, -C 1-3 Halogenated alkyl groups, -NH2, -NH(C) 1- 3-alkyl), -N(C) 1-3 Alkyl) 2, 3-7 membered cycloalkyl, 3-7 membered heterocyclic, phenyl or 5-6 membered heteroaryl;

[0075] In some specific implementation schemes, R 3 -(C=O)NR 3K R 3L -(C=S)NR 3M R 3N -S(=O)NR 3P R 3Q 、or -S(=O)2NR 3R R 3S ; where each (R) 3K R 3L R 3M R 3N R 3P R 3Q R 3R 、or R 3S The radical is independently selected from -H, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CHFCH3, -CF2CH3, -NH2, -NH(CH3), -N(CH3)2, -N(CH3)(CH2CH3), -NH(CH2CH3), -NH(CH(CH3)2), cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxacyclobutyl, aziridine, piperidinyl, tetrahydrothiophene, tetrahydropyranyl, pyrrolidinyl, or tetrahydrofuranyl;

[0076] In some specific implementation schemes, R 3Each time it appears, it is selected independently. Preferably, R 3 Each time it appears, it is selected independently.

[0077] In some specific implementation schemes, R 3 Each time it appears, it is selected independently.

[0078] In some implementation schemes, R 4 Each time it appears, it is independently selected from hydrogen or -C. 1-3 alkyl.

[0079] In some specific implementation schemes, R 4 Each occurrence is independently selected from -H, -CH3, -CH2CH3, -CH2CH2CH3, or -CH(CH3)2; preferably, R 4 It is selected independently from -H or -CH3 each time it appears.

[0080] In some implementation schemes, R 5 Selected from -S(=O)2R 53 , where R 53 Selected independently from -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) 2, 3-7 membered cycloalkyl, or 3-7 membered heterocyclic group. In some specific embodiments, R 53 Each occurrence is independently selected from -H, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CHFCH3, -CF2CH3, -NH2, -NH(CH3), -N(CH3)2, -NH(CH2CH3), -NH(CH2CH2CH3), -NH(CH( CH3)2), -OH, -O-CH3, -O-CH2CH3, -O-CH2CH2CH3, -O-CH(CH3)2, -C(=O)NH2, -C(=O)NH(CH3), -C(=O )NH(CH2CH3), -C(=O)NH(CH2CH2CH3), -C(=O)NH(CH(CH3)2), -C(=O)N(CH3)2, -C(=O)N(CH2CH3)2, Pyrrole, furanyl, thiophene, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, indoleyl. In some specific embodiments, R 53 Each time it appears, it is independently selected from -CH3, -CH2CH3, -CH2CH2CH3, or -CH(CH3)2. In some specific embodiments, R 53 Each occurrence is independently selected from -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CHFCH3, or -CF2CH3. In some specific implementations, R 53 Each time it appears, it is independently selected from -NH2, -NH(CH3), -N(CH3)2, -NH(CH2CH3), -NH(CH2CH2CH3), or -NH(CH(CH3)2).

[0081] In some specific implementations, -S(=O)2R 53 Each time it appears, it is independently selected from -S(=O)2-CH3, -S(=O)2-CH2CH3, -S(=O)2-CH2CH2CH3, -S(=O)2-CH(CH3)2, -S(=O)2-CH2F, -S(=O)2-CHF2, -S(=O)2-CF3, -S(=O)2-CH2CH2F, -S(=O)2-CH2CHF2, -S(= O)2-CH2CF3, -S(=O)2-CHFCH3, -S(=O)2-CF2CH3, -S(=O)2-NH2, -S(=O)2-NH(CH3), -S(= O)2-N(CH3)2, -S(=O)2-NH(CH2CH3), -S(=O)2-NH(CH2CH2CH3), -S(=O)2-NH(CH(CH3)2), In some specific implementations, S(=O)2R 53 Each time it appears, it is independently selected from -S(=O)2-CH3, -S(=O)2-CH2CH3, -S(=O)2-CH2CH2CH3, or -S(=O)2-CH(CH3)2.

[0082] In some specific implementations, the fragment-NR in equation (I) 4 R 5Selected from -NH-S(=O)2-CH3, -NH-S(=O)2-CH2CH3, -NH-S(=O)2-CH2CH2CH3, -NH-S(=O)2-CH(CH3)2, -NH-S(=O )2-CH2F, -NH-S(=O)2-CHF2, -NH-S(=O)2-CF3, -NH-S(=O)2-CH2CH2F, -NH-S(=O)2-CH2CHF2, -NH-S(=O )2-CH2CF3, -NH-S(=O)2-CHFCH3, -NH-S(=O)2-CF2CH3, -NH-S(=O)2-NH2, -NH-S(=O)2-NH(CH3), -NH-S (=O)2-N(CH3)2, -NH-S(=O)2-NH(CH2CH3), -NH-S(=O)2-NH(CH2CH2CH3), -NH-S(=O)2-NH(CH(CH3)2),

[0083] Preferably, the fragment-NR in formula (I) 4 R 5 Selected from -NH-S(=O)2-CH3, -NH-S(=O)2-CH2CH3, -NH-S(=O)2-CH(CH3)2, -HS(=O)2-CH2F, -NH-S(=O)2 -CHF2, -NH-S(=O)2-CF3, -NH-S(=O)2-NH(CH3), -NH-S(=O)2-N(CH3)2, -NH-(=O)2-NH(CH2CH3),

[0084] More preferably, the fragment -NR in formula (I) 4 R 5 Selected from

[0085] In some specific implementations, fragments Selected from

[0086] Preferably, fragments Selected from More preferably, fragments Selected from

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

[0088] *Representation and fragment The connection point.

[0089] In some implementations, -Y 2 Selected from -O-, -NH-, -N(CH3)-, -N(CH2CH3)-, -N(CH(CH3)2)-, or -S-. In some specific embodiments, Y 2 For -O-. In some specific implementations, Y 2 For -S-. In some specific implementations, Y 2 It is -NH- or -N(CH3)-.

[0090] In some implementation schemes, R 2 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, -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 1-3 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, R2 Each time it appears, it is independently selected from hydrogen, halogen, -C. 1-3 Alkyl, or -C 1-3 Halogenated alkyl groups. More preferably, R 2 Each time it appears, it is independently selected from hydrogen or -C. 1-3 Alkyl group. In some embodiments, R 2 It is hydrogen. In some embodiments, R 2 -C 1-3 alkyl.

[0091] In some implementation schemes, W is

[0092] in,

[0093] Ring A is selected from 3-10 membered carbocyclic rings, 3-10 membered heterocyclic rings, 6-10 membered aromatic rings, or 5-10 membered heteroaryl rings;

[0094] 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- 3alkyl)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(C1-6 Alkyl), 3-7 membered carbon cycloyl, 3-7 membered heterocyclic, phenyl or 5-10 membered heteroaryl.

[0095] In some embodiments, ring A is selected from 3-10 member monocyclic-cycloalkyl rings, 5-10 member bridged-cycloalkyl rings, 5-10 member spirocyclic-cycloalkyl rings, 4-10 member fused-ring-cycloalkyl rings, 3-10 member monocyclic-heterocyclic alkyl rings, 5-10 member bridged-heterocyclic alkyl rings, 5-10 member spirocyclic-heterocyclic alkyl rings, 4-10 member fused-ring-heterocyclic alkyl rings, 3-10 member monocyclic-cycloalkenyl rings (containing at least one double bond), and 5-10 member bridged-cycloalkenyl rings (containing at least one double bond). ), 5-10 membered spirocyclic-cycloalkenyl ring (containing at least one double bond), 5-10 membered fused-ring-cycloalkenyl ring (containing at least one double bond), 3-10 membered monocyclic-heterocyclic-alkenyl ring (containing at least one double bond), 5-10 membered bridged-ring-heterocyclic-alkenyl ring (containing at least one double bond), 5-10 membered spirocyclic-heterocyclic-alkenyl ring (containing at least one double bond), 5-10 membered fused-ring-heterocyclic-alkenyl ring (containing at least one double bond), benzene ring, naphthyl ring, 5-10 membered heteroaryl ring; wherein ring A is optionally divided by n S2 R S2 Substitution; preferably, ring A is a benzene ring; said ring A is optionally replaced by n S2 R S2 replace.

[0096] In some embodiments, ring A is a 3-7 membered monocyclic-cycloalkyl ring, optionally surrounded by 1, 2, 3, 4, 5, or 6 R groups. S2 Replacement. In some embodiments, ring A is selected from 5-6 membered monocyclic-cycloalkyl rings, optionally replaced by 1, 2, 3, 4, 5 or 6 Rs. S2 Replacement. In some specific embodiments, ring A is selected from cyclopropyl rings optionally surrounded by 1, 2, 3, 4, 5 or 6 Rs. S2 Replacement. In some specific embodiments, ring A is selected from cyclobutyl rings optionally replaced by 1, 2, 3, 4, 5 or 6 R. S2 Replacement. In some specific embodiments, ring A is selected from cyclopentyl rings optionally replaced by 1, 2, 3, 4, 5 or 6 R... S2 Replacement. In some specific embodiments, ring A is selected from cyclohexyl rings optionally replaced by 1, 2, 3, 4, 5 or 6 Rs. S2 Replacement. In some specific embodiments, ring A is selected from the heptyl ring, optionally replaced by 1, 2, 3, 4, 5 or 6 R... S2 replace.

[0097] In other embodiments, ring A is selected from 3-7 membered monocyclic-cycloalkenyl rings (containing one double bond), optionally surrounded by 1, 2, 3, 4, 5 or 6 R groups. S2Replacement. In other embodiments, ring A is selected from a 5-6 membered monocyclic-cycloalkenyl ring (containing one double bond), optionally replaced by 1, 2, 3, 4, 5 or 6 R groups. S2 Replacement. In some specific embodiments, ring A is selected from cyclopropene rings optionally surrounded by 1, 2, 3, 4, 5 or 6 Rs. S2 Replacement. In some specific embodiments, ring A is selected from cyclobutenyl rings optionally surrounded by 1, 2, 3, 4, 5 or 6 R groups. S2 Replacement. In some specific embodiments, ring A is selected from cyclopentenyl rings optionally surrounded by 1, 2, 3, 4, 5 or 6 Rs. S2 Replacement. In some specific embodiments, ring A is selected from the cyclohexenyl ring, optionally surrounded by 1, 2, 3, 4, 5, or 6 R groups. S2 Replacement. In some specific embodiments, ring A is selected from the cycloheptenyl ring, optionally surrounded by 1, 2, 3, 4, 5, or 6 R groups. S2 replace.

[0098] In other embodiments, ring A is selected from 5-10 membered spirocyclic-cycloalkenyl rings (containing one double bond), optionally surrounded by 1, 2, 3, 4, 5, or 6 R groups. S2 Replacement. In other embodiments, ring A is selected from 7-10 membered spirocyclic-cycloalkenyl rings (containing one double bond), optionally replaced by 1, 2, 3, 4, 5 or 6 R groups. S2 Replacement. In some specific embodiments, ring A is selected from a 5-membered spirocyclic-cycloalkenyl ring optionally replaced by 1, 2, 3, 4, 5 or 6 Rs. S2 Replacement. In some specific embodiments, ring A is selected from a 6-membered spirocyclic-cycloalkenyl ring optionally replaced by 1, 2, 3, 4, 5 or 6 Rs. S2 Replacement. In some specific embodiments, ring A is selected from a 7-membered spirocyclic-cycloalkenyl ring optionally replaced by 1, 2, 3, 4, 5 or 6 R... S2 Replacement. In some specific embodiments, ring A is selected from an 8-membered spirocyclic-cycloalkenyl ring optionally replaced by 1, 2, 3, 4, 5 or 6 R... S2 Replacement. In some specific embodiments, ring A is selected from an 8-membered spirocyclic-cycloalkenyl ring optionally replaced by 1, 2, 3, 4, 5 or 6 R... S2 Replacement. In some specific embodiments, ring A is selected from a 9-membered spirocyclic-cycloalkenyl ring optionally replaced by 1, 2, 3, 4, 5, or 6 Rs. S2 Replacement. In some specific embodiments, ring A is selected from a 10-membered spirocyclic-cycloalkenyl ring optionally replaced by 1, 2, 3, 4, 5 or 6 R... S2 replace.

[0099] In some specific embodiments, ring A selected from 5-10 membered spirocyclic-cycloalkenyl rings includes, but is not limited to, those with other characteristics. In some specific embodiments, ring A of the 5-10 membered spirocyclic-cycloalkenyl ring is selected from... In some specific embodiments, ring A of the 5-10 membered spirocyclic-cycloalkenyl ring is selected from... In some specific embodiments, ring A of the 5-10 membered spirocyclic-cycloalkenyl ring is selected from...

[0100] In other embodiments, ring A is a 3-7 membered monocyclic-heterocyclic alkenyl ring (containing one double bond), optionally surrounded by 1, 2, 3, 4, 5, or 6 R groups. S2 Substitution; the 3-7 membered monocyclic-heterocyclic alkenyl ring contains at least one heteroatom selected from N, O, or S. In some specific embodiments, ring A is a 3-membered monocyclic-heterocyclic alkenyl ring (containing one double bond), optionally replaced by 1, 2, 3, 4, 5, or 6 R atoms. S2 Substitution; ring A is a 4-membered monocyclic-heterocyclic alkenyl ring (containing one double bond), optionally replaced by 1, 2, 3, 4, 5 or 6 R groups. S2 Substitution; ring A is a 5-membered monocyclic-heterocyclic alkenyl ring (containing one double bond), optionally replaced by 1, 2, 3, 4, 5 or 6 R groups. S2 Substitution; ring A is a 6-membered monocyclic-heterocyclic alkenyl ring (containing one double bond), optionally replaced by 1, 2, 3, 4, 5 or 6 R groups. S2 Substitution; ring A is a 7-membered monocyclic-heterocyclic alkenyl ring (containing one double bond), optionally replaced by 1, 2, 3, 4, 5 or 6 R groups. S2 replace.

[0101] In some specific embodiments, ring A, selected from 3-7 membered monocyclic-heterocyclic alkenyl rings (containing one double bond), is selected from...

[0102] Preferably, ring A, selected from 3-7 membered monocyclic-heterocyclic alkenyl rings (containing one double bond), is selected from...

[0103] In other embodiments, ring A is selected from 6-10 membered aryl rings, optionally surrounded by 1, 2, 3, 4, 5 or 6 R groups. S2 Replacement. In some specific embodiments, ring A is selected from benzene ring or naphthalene ring; each ring is optionally replaced by 1, 2, 3, 4, 5 or 6 R... S2 Replacement. In some specific embodiments, ring A is selected from benzene rings; each ring is optionally replaced by 1, 2, 3, 4, 5 or 6 R... S2 replace.

[0104] In other embodiments, ring A is selected from 5-10 membered heteroaryl rings, optionally surrounded by 1, 2, 3, 4, 5 or 6 R groups. S2 Substitution. In some specific embodiments, ring A, selected from 5-10 membered heteroaryl rings, is selected from pyrrole rings, furan rings, thiophene rings, imidazole rings, oxazole rings, isoxazole rings, thiazole rings, isothiazole rings, tetrazolium rings, pyrazole rings, triazole rings, thiadiazole rings, oxadiazole rings, pyridine rings, pyrimidine rings, pyrazine rings, pyridazine rings, indole rings, isoindole rings, indazine rings, benzofuran rings, isobenzofuran rings, benzo[b]thiophene rings, benzo[c]thiophene rings, indazole rings, benzo[d]imidazolium rings, pyrrolo[3,2-b]pyridine rings, and pyrrolo[3,2-c]pyridine rings. 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]isothiazole ring Benz[d]thiazole 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-c]pyridazine ring, pyrrolo[3,2-c]pyridazine ring, pyrrolo[3,2-c]pyridazine ring, pyrrolo[4,5-b]pyridine ... 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; each ring is optionally composed of 1, 2, 3, 4, 5 or 6 independently selected from R S2The substituents are substituted. In some specific embodiments, ring A is selected from pyrrole rings, furan rings, thiophene rings, imidazole rings, oxazole rings, isoxazole rings, thiazole rings, isothiazole rings, tetrazolium rings, pyrazole rings, triazole rings, thiadiazole rings, oxadiazole rings, pyridine rings, pyrimidine rings, pyrazine rings, pyridazine rings, indole rings, or isoindole rings. In some specific embodiments, ring A is selected from pyrrole rings or indole rings. In some specific embodiments, ring A is selected from pyrrole rings, furan rings, thiophene rings, imidazole rings, oxazole rings, isoxazole rings, thiazole rings, isothiazole rings, pyrazole rings, pyrimidine rings, pyrazine rings, pyridazine rings, indole rings, or isoindole rings. In some specific embodiments, ring A is selected from pyrimidine rings or indole rings.

[0105] In some implementation schemes, R S2 Each occurrence is independently selected from halogen, -CN, -C. 1-3 Alkyl, -OC 1-3 Alkyl, -C 1-3 Halogenated alkyl, or -OC 1-3 Halogenated alkyl groups. In some embodiments, R S2 Each time it appears, it is independently selected from halogens and -C. 1-3 Alkyl, or -C 1-3 Halogenated alkyl groups. In some embodiments, R S2 Halogen, or -C 1-3 Halogenated alkyl groups. In some embodiments, R S2 -C 1-3 Alkyl group. In some embodiments, R S2 -C 1-3 Halogenated alkyl groups.

[0106] In some specific implementation schemes, R S2 Each occurrence is independently selected from -Cl, -F, -Br, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CHFCH3, -CF2CH3, -O-CH2F, -O-CHF2, -O-CF3, -O-CH2CH2F, -O-CH2CHF2, -O-CH2CF3, -O-CHFCH3, -O-CF2CH3, -CN, Preferably, R S2 Each time it appears, it is independently selected from -CH3, -F, -CF3, -O-CF3, or -CN.

[0107] In some specific implementation schemes, R S2Each occurrence is independently selected from -Cl, -F, -Br, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CHFCH3, -CF2CH3, -O-CH2F, -O-CHF2, -O-CF3, -O-CH2CH2F, -O-CH2CHF2, -O-CH2CF3, -O-CHFCH3, -O-CF2CH3, or -CN; preferably, R S2 Each time it appears, it can be independently selected from -F, -CF3, -O-CF3, or -CN.

[0108] In some specific implementation schemes, R S2 Each occurrence is independently selected from -CH3, -CH2CH3, -CH2CH2CH3, or -CH(CH3)2; preferably, R S2 It is -CH3 independently each time it appears.

[0109] In some specific implementation schemes, R S2 Each occurrence is independently selected from -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CHFCH3, or -CF2CH3; preferably, R S2 It is -CF3 independently each time it appears.

[0110] In some implementation schemes, W is Wherein, ring A is a benzene ring, and R S2 Selected from halogens, -CN, -C 1-3 Halogenated alkyl, or -OC 1- 3-Hydroalkyl, n S2 It can be 0, 1, 2, or 3.

[0111] In some implementation schemes, W is Among them, ring A is a 5-10 membered heteroaryl ring, R S2 Selected from halogens, -C 1-3 Alkyl, or -C 1- 3-Haloalkyl, n S2 It can be 0, 1, 2, or 3.

[0112] In some specific implementation schemes, W is selected from

[0113] In some implementation schemes, W is selected from

[0114] In some implementations, in fragments middle,

[0115] X is selected from N or CR 6 ;

[0116] R 6 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, 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- 3alkyl)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 carbon cyclo group, 3-7 membered heterocyclic group, phenyl group or 5-10 membered heteroaryl group;

[0117] n3 is selected from 0, 1, 2, or 3;

[0118] n4 is selected from 0, 1, 2, or 3;

[0119] n5 is selected from 0, 1, 2, or 3;

[0120] And n3 + n4 + n5 ≤ 5;

[0121] Y 3 Selected from non-existent, -C(R) Y3A )2-, or -O-;

[0122] R Y3A Each time it appears, it is independently selected from hydrogen, halogen, -C.1-3 Alkyl, -C 1-3 Halogenated alkyl groups;

[0123] In some implementation schemes, R 6 Each time it appears, it is independently selected from hydrogen, halogen, -C. 1-3 Alkyl, or -C 1-3 Halogenated alkyl groups. In some embodiments, R 6 Each time it appears, it is independently selected from hydrogen, halogen, or -C. 1-3 Alkyl group. In some specific embodiments, R 6 It is hydrogen. In some specific implementations, R 6 It is a halogen. In some specific implementations, R 6 -C 1-3 Alkyl group. In some specific embodiments, R 6 -C 1-3 Halogenated alkyl groups.

[0124] In some specific implementation schemes, R 6 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. In some specific embodiments, R 6 Each time it appears, it is independently selected from -H, -Cl, -F, -Br, -CH3, -CH2CH3, -CH2CH2CH3, or -CH(CH3)2. In some specific embodiments, R 6 It is independently selected from -H, -F, or -CH3 each time it appears. In some specific implementations, R 6 It is independently selected from -H each time it appears. In some specific implementations, R 6 Each occurrence is independently selected from -Cl, -F, or -Br. In some specific implementations, R 6 Each time it appears, it is independently selected from -CH3, -CH2CH3, -CH2CH2CH3, or -CH(CH3)2.

[0125] In some implementations, X is selected from N or CH, C-(halogen), C-(-C) 1-3 Alkyl), or C-(C 1-3 (Haloalkyl). In some embodiments, X is N. In some embodiments, X is CH. In some embodiments, X is C-(halogen). In some embodiments, X is C-(-C) 1-3 alkyl).

[0126] In some specific implementations, X is independently selected from N, C-(H), C-(Cl), C(-F), C-(Br), C-(CH3), C-(CH2CH3), C-(CH2CH2CH3), C-(CH(CH3)2), C-(CH2F), C-(CHF2), C-(CF3), C-(CH2CH2F), C-(CH2CHF2), C-(CH2CF3), C-(CHFCH3), or C-(CF2CH3) each time it appears.

[0127] In some embodiments, n3 is selected from 0, 1, or 2; preferably, n3 is selected from 0 or 1. In some specific embodiments, n3 is 0. In some specific embodiments, n3 is 1.

[0128] In some embodiments, n4 is selected from 0, 1, or 2; preferably, n4 is selected from 0 or 1. In some specific embodiments, n4 is 0. In some specific embodiments, n4 is 1.

[0129] In some embodiments, n5 is selected from 0, 1, or 2; preferably, n5 is selected from 0 or 1. In some specific embodiments, n5 is 0. In some specific embodiments, n5 is 1.

[0130] In some specific implementation schemes, n3 is 1, n4 is 1, and n5 is 1.

[0131] In some specific implementation schemes, n3 is 0, n4 is 1, and n5 is 1.

[0132] In some specific implementation schemes, n3 is 1, n4 is 0, and n5 is 1.

[0133] In some specific implementation schemes, n3 is 0, n4 is 0, and n5 is 1.

[0134] In some implementation schemes, R Y3A Each time it appears, it is independently selected from hydrogen, halogen, -C. 1-3 Alkyl, or -C 1-3 Halogenated alkyl groups. In some embodiments, R Y3A Each time it appears, it is independently selected from hydrogen, halogen, or -C. 1-3 Alkyl group. In some embodiments, R Y3A It is independently selected from hydrogen each time it appears. In some implementations, R Y3A It is independently selected from halogens each time it appears. In some implementations, R Y3A Selected independently from -C each time it appears. 1-3 alkyl.

[0135] In some specific implementation schemes, RY3A 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. In some specific embodiments, R Y3A Each occurrence is independently selected from -H, -Cl, -F, -CH3, -CH2CH3, -CH2CH2CH3, or -CH(CH3)2. In some specific implementations, R Y1A For -H. In some specific implementations, R Y1A For Cl, or -F. In some specific implementations, R Y1A Each time it appears, it is independently selected from -CH3, -CH2CH3, -CH2CH2CH3, or -CH(CH3)2.

[0136] In some implementation schemes, Y 3 Selected from non-existent, or -O-.

[0137] In some implementation schemes, Y 3 Selected from non-existent.

[0138] In some implementation schemes, Y 3 Selected from -O-.

[0139] In some implementations, in fragments middle,

[0140] x is selected from N or CR 6 R 6 Each time it appears, it is independently selected from hydrogen, halogen, -C. 1-3 Alkyl, or -C 1-3 Halogenated alkyl groups;

[0141] n3 is selected from 0, 1, or 2;

[0142] n4 is selected from 0, 1, or 2;

[0143] n5 is selected from 0, 1, or 2;

[0144] And n3 + n4 + n5 ≤ 5;

[0145] Y 3 Selected from non-existent, -C(R) Y3A )2-, or -O-;

[0146] R Y3A Each time it appears, it is independently selected from hydrogen, halogen, -C. 1-3 Alkyl, or -C 1-3 Halogenated alkyl groups.

[0147] In some implementations, fragments Selected from Preferably, fragments Selected from

[0148] In some implementations, fragments Selected from

[0149] X is selected from N or CR 6 R 6 Each time it appears, it is independently selected from hydrogen, halogen, -C. 1-3 Alkyl, or -C 1-3 Halogenated alkyl groups;

[0150] n3 is selected from 0, 1, or 2;

[0151] n4 is selected from 0, 1, or 2;

[0152] n5 is selected from 0, 1, or 2;

[0153] And n3+n4+n5≤5.

[0154] In some implementations, fragments Selected from

[0155] R 6 Each time it appears, it is independently selected from hydrogen, halogen, -C. 1-3 Alkyl, or -C 1-3 Halogenated alkyl; preferably, R 6 It is hydrogen;

[0156] n3 is selected from 0, 1, or 2;

[0157] n4 is selected from 0, 1, or 2;

[0158] n5 is selected from 0, 1, or 2;

[0159] And n3+n4+n5≤5.

[0160] In some implementations, fragments Selected from

[0161] R 6 Each time it appears, it is independently selected from hydrogen, halogen, -C. 1-3 Alkyl, or -C 1-3 Halogenated alkyl; preferably, R 6 It is hydrogen; preferably, R 6 It is a halogen.

[0162] In some implementations, in fragments middle,

[0163] W is

[0164] Ring A is selected from 3-7 membered monocyclic-cycloalkyl rings, 5-10 membered bridged-cycloalkyl rings, 3-7 membered monocyclic-cycloalkenyl rings (containing one double bond), 5-10 membered spirocyclic-cycloalkenyl rings (containing one double bond), 3-7 membered monocyclic-heterocyclic alkenyl rings (containing one double bond), phenyl, and 5-10 membered heteroaryl; preferably, ring A is a benzene ring;

[0165] Preferably, R S2 Each occurrence is independently selected from halogen, -CN, -C. 1-3 Alkyl, -C 1-3 Halogenated alkyl groups, -OC 1-3 Halogenated alkyl, -C 2-3 alkenyl, or -C 2-3 alkynyl group;

[0166] n S2 It can be 0, 1, 2, or 3;

[0167] X is selected from N or CR 6 ;

[0168] R 6 Each time it appears, it is independently selected from hydrogen, halogen, -C. 1-3 Alkyl, -C 1-3 Halogenated alkyl; preferably, R 6 It is hydrogen or halogen;

[0169] n3 is selected from 0, 1, or 2; preferably, n3 is selected from 0 or 1;

[0170] n4 is selected from 0, 1, or 2; preferably, n4 is selected from 0 or 1;

[0171] n5 is selected from 0, 1, or 2; preferably, n5 is selected from 0 or 1;

[0172] And n3 + n4 + n5 ≤ 5;

[0173] Y 3 Selected from non-existent, -C(R) Y3A )2-, or -O-;

[0174] 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 Alkoxy, -C 1-3Halogenated 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), -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- 3alkyl)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 Y3A Each time it appears, it is independently selected from hydrogen, halogen, -C. 1-3 Alkyl, or -C 1-3 Halogenated alkyl groups.

[0175] In some implementations, in fragments middle,

[0176] W is Wherein, ring A is a benzene ring; R S2 Each occurrence is independently selected from halogen, -CN, -C. 1-3 Alkyl, -OC 1-3 Alkyl, -C 1-3 Halogenated alkyl, or -OC 1-3 Halogenated alkyl; preferably, R S2 Each time it appears, it is independently selected from halogens and -C. 1-3 Alkyl, -C 1-3 Halogenated alkyl; n S2 It can be 0, 1, 2, or 3;

[0177] X is selected from N or CR 6 CR is preferred6 Among them, R 6 Each time it appears, it is independently selected from hydrogen, halogen, -C. 1-3 Alkyl, or -C 1-3 Halogenated alkyl; preferably, R 6 It is hydrogen or halogen;

[0178] n3 is selected from 0, 1, or 2; preferably, n3 is selected from 0 or 1;

[0179] n4 is selected from 0, 1, or 2; preferably, n4 is selected from 0 or 1;

[0180] n5 is selected from 0, 1, or 2; preferably, n5 is selected from 0 or 1;

[0181] And n3 + n4 + n5 ≤ 5;

[0182] Y 3 Selected from non-existent.

[0183] In some specific implementation schemes, fragments Selected from Preferably, fragments Selected from

[0184] In some embodiments, the compound represented by formula (I) is a compound represented by any one of formulas (I-1) to (I-12):

[0185] Or its stereoisomers, its tautomers, its pharmaceutically acceptable salts, its pharmaceutically acceptable salts, its pharmaceutically acceptable salts, its solvates, its prodrugs, or its deuterated derivatives;

[0186] Among them, W, X, Y 3 n3, n4, n5, Y 2 R S2 n S2 R 2 R 3 R 6 R 3A R 3H n1, n2, R 4 R 51 R 53 and R Y1A The definition is the same as that of formula (I).

[0187] In some embodiments, the compound represented by formula (I) is a compound represented by any one of formulas (II-1) to (II-5):

[0188] Or its stereoisomers, its tautomers, its pharmaceutically acceptable salts, its pharmaceutically acceptable salts, its pharmaceutically acceptable salts, its solvates, its prodrugs, or its deuterated derivatives;

[0189] Among them, R 4A R 4B R 4C Ring A, R 6 R S2 n S2 n3, n4, n5, R 2 R 4 R 53 R 3A R 3H n1, n2, and R Y1A The definition is the same as that of formula (I).

[0190] In some embodiments, the compound represented by formula (I) is a compound represented by any one of formulas (III-1) to (III-6):

[0191] Or its stereoisomers, its tautomers, its pharmaceutically acceptable salts, its pharmaceutically acceptable salts, its pharmaceutically acceptable salts, its solvates, its prodrugs, or its deuterated derivatives;

[0192] Among them, R S2 n S2 R 6 n3, n4, n5, R 2 R 3 R 3A R 3H R 4 R 53 n1, n2, and R Y1A The definition is the same as that of formula (I).

[0193] In some embodiments, the compound represented by formula (I) is a compound represented by any one of formulas (III-1A) to (III-3H):

[0194] Or its stereoisomers, its tautomers, its pharmaceutically acceptable salts, its pharmaceutically acceptable salts, its pharmaceutically acceptable salts, its solvates, its prodrugs, or its deuterated derivatives;

[0195] Among them, R S2 n S2 R 6 n3, n4, n5, R 2 R 3 R 3A R 3H R 4 R 53 n1, n2, and R Y1A The definition is the same as that of formula (I).

[0196] This invention relates to a compound represented by formula (IV),

[0197] Or its stereoisomers, tautomers, pharmaceutically acceptable salts, pharmaceutically acceptable salts of its stereoisomers, pharmaceutically acceptable salts of its tautomers, its solvates, its prodrugs, or its deuterated derivatives.

[0198] in,

[0199] R Y1A 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) 1-6 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), -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 1-3Alkyl), 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 Y1A Each time it appears, it is independently selected from hydrogen, halogen, -C. 1-3 Alkyl, or -C 1-3 Halogenated alkyl groups;

[0200] Optionally, two R atoms attached to the same C atom Y1A Together with the C atoms they are connected to, they form a group optionally bounded by 1, 2, or 3 R atoms. S1 Substituted 3-7 membered cycloalkyl rings (cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl); each of the R... S1 Independently selected from halogens, -C 1-3 Alkyl, -C 1-3 alkoxy or -C 1-3 Haloalkyl; preferably, two R atoms attached to the same C atom Y1A Together with the C atoms they are connected to, they form a group optionally bounded by 1, 2, or 3 R atoms. S1 Substituted cyclopropyl ring; each of the R S1 Independently selected from halogens, -C 1-3 Alkyl, -C 1-3 alkoxy or -C 1-3 Halogenated alkyl groups;

[0201] n1 is selected from 0, 1, 2, or 3;

[0202] n2 is selected from 0, 1, 2, or 3;

[0203] And n1 + n2 ≤ 4;

[0204] R 3 -(C=O)R 3A 、or -(C=O)OR 3H ;

[0205] Each R 3A Independently selected from -C 1-3 Alkyl, 3-7 membered cycloalkyl, 3-7 membered heterocyclic, phenyl, or 5-6 membered heteroaryl; wherein, the R 3AOptionally, 1, 2, 3, 4, 5, or 6 elements selected from halogens and -C 1-3 Alkyl, -C 2-3 alkenyl, -C 2-3 Alkyne, -CN, oxo, -NH2, -NH(C) 1-3 alkyl), -N(C) 1-3 Alkyl group 2, -OH, -O(C) 1-3 Alkyl), -SH or -S(C 1-3 Alkyl groups are substituted; preferably, each R 3A Independently selected from -C 1-3 Alkyl, 3-7 membered monocyclic cycloalkyl, 3-7 membered spirocyclic cycloalkyl, 3-7 membered bridged cycloalkyl, 3-7 membered heterocyclic, phenyl or 5-6 membered heteroaryl, wherein R 3A Optionally, it is selected from 1, 2, or 3 halogens, -OH, -O(C 1-3 Substitution of alkyl groups;

[0206] Each R 3H Independently selected from -C 1-3 Alkyl, -C 1-3 Halogenated alkyl, 3-7 membered cycloalkyl, 3-7 membered heterocyclic, phenyl, or 5-6 membered heteroaryl; preferably, R 3H Selected independently from -C each time it appears. 1-3 alkyl;

[0207] R 4 Each time it appears, it is independently selected from hydrogen or -C. 1-3 alkyl;

[0208] R 53 Each time it appears, it is independently selected from hydrogen, -C 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 groups), -C(=O)NH2, -C(=O)NH(C 1-3 Alkyl), -C(=O)N(C 1-3 Alkyl) 2, 3-7 membered cycloalkyl, 3-7 membered heterocyclic, phenyl, or 5-10 membered heteroaryl; preferably, R 53 Selected independently from -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) 2 or 3-7 membered cycloalkyl;

[0209] R 2Each time it appears, it is independently selected from hydrogen, halogen, -C. 1-3 Alkyl, or -C 1-3 Halogenated alkyl groups;

[0210] X is selected from N or CR 6 ;

[0211] R 6 Each time it appears, it is independently selected from hydrogen, halogen, -C. 1-3 Alkyl, or -C 1-3 Halogenated alkyl groups;

[0212] Y 3 Selected from non-existent, -NR Y3B -O- or -S-;

[0213] R Y3B Each time it appears, it is independently selected from hydrogen, -C 1-3 Alkyl, or -C 1-3 Halogenated alkyl groups;

[0214] n3 is selected from 0, 1, or 2;

[0215] n4 is selected from 0, 1, or 2;

[0216] n5 is selected from 0, 1, or 2;

[0217] And n3 + n4 + n5 ≤ 5;

[0218] 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 1-3Alkyl), S(=O)NH2, -S(=O)NH(C 1-3 Alkyl), -S(=O)N(C 1- 3alkyl)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;

[0219] n S2 Choose from 0, 1, 2, 3, 4, 5, or 6;

[0220] Each heterocyclic group independently contains 1, 2, or 3 heteroatoms selected from N, O, or S each time it appears;

[0221] Each heteroaryl group independently contains 1, 2, or 3 heteroatoms selected from N, O, or S each time it appears.

[0222] This invention relates to a compound represented by formula (VI),

[0223] Or its stereoisomers, tautomers, pharmaceutically acceptable salts, pharmaceutically acceptable salts of its stereoisomers, pharmaceutically acceptable salts of its tautomers, its solvates, its prodrugs, or its deuterated derivatives.

[0224] in,

[0225] R Y1A Each time it appears, it is independently selected from hydrogen, halogen, -C. 1-3 Alkyl, or -C 1-3 Halogenated alkyl groups;

[0226] Optionally, two R atoms attached to the same C atom Y1A Together with the C atoms they are connected to, they form a group optionally bounded by 1, 2, or 3 R atoms. S1 Substituted 3-7 membered cycloalkyl groups (cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl); each of the R groups S1 Independently selected from halogens, -C 1-3 Alkyl, -C 1-3 alkoxy or -C 1-3 Halogenated alkyl groups;

[0227] n1 is selected from 0, 1, or 2;

[0228] n2 is selected from 0, 1, or 2;

[0229] And n1 + n2 ≤ 4;

[0230] R 3 -(C=O)R 3A -(C=O)OR 3H , or -(C=O)NR 3K R 3L ;

[0231] Each R 3A Independently selected from -C 1-3 Alkyl, 3-7 membered cycloalkyl, 3-7 membered heterocyclic, phenyl, or 5-6 membered heteroaryl; wherein, the R 3A Optionally, it is selected from 1, 2, or 3 ions chosen from halogens, -C 1-3 Alkyl, -CN, -NH2, -NH(C) 1-3 alkyl), -N(C) 1-3 Alkyl group 2, -OH, -O(C) 1-3 Alkyl), -SH or -S(C 1-3 Substitution of alkyl groups;

[0232] R 3H Selected independently from -C each time it appears. 1-3 alkyl;

[0233] R 3K 、or R 3L Independently selected from hydrogen, -C 1-3 Alkyl, -C 1-3 Halogenated alkyl groups, -NH2, -NH(C) 1-3 alkyl), -N(C) 1-3 Alkyl) 2, 3-7 membered cycloalkyl, 3-7 membered heterocyclic, phenyl or 5-6 membered heteroaryl;

[0234] R 4 Each time it appears, it is independently selected from hydrogen or -C. 1-3 alkyl;

[0235] R 53 Each time it appears, it is independently selected from hydrogen, -C 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 groups), -C(=O)NH2, -C(=O)NH(C 1-3 Alkyl), -C(=O)N(C 1-3 Alkyl) 2, 3-7 membered cycloalkyl, 3-7 membered heterocyclic, phenyl, or 5-10 membered heteroaryl;

[0236] R 2Each time it appears, it is independently selected from hydrogen, halogen, -C. 1-3 Alkyl, or -C 1-3 Halogenated alkyl groups;

[0237] Y 2 -O-, -S-, or -NR Y2B -;

[0238] R Y2B Each time it appears, it is independently selected from hydrogen, -C 1-3 Alkyl, or -C 1-3 Halogenated alkyl groups;

[0239] R 6 Each time it appears, it is independently selected from hydrogen, halogen, -C. 1-3 Alkyl, or -C 1-3 Halogenated alkyl groups;

[0240] n3 is selected from 0, 1, or 2;

[0241] n4 is selected from 0, 1, or 2;

[0242] n5 is selected from 0, 1, or 2;

[0243] And n3 + n4 + n5 ≤ 5;

[0244] R S2 Each occurrence is independently selected from halogen, -CN, -C. 1-3 Alkyl, -OC 1-3 Alkyl, -C 1-3 Halogenated alkyl, or -OC 1-3 Halogenated alkyl groups;

[0245] n S2 Selected from 0, 1, 2, or 3;

[0246] Each heterocyclic group independently contains 1, 2, or 3 heteroatoms selected from N, O, or S each time it appears;

[0247] Each heteroaryl group independently contains 1, 2, or 3 heteroatoms selected from N, O, or S each time it appears.

[0248] This invention relates to formulas (III-1), (III-1A), (III-1B), (III-1C), (III-1D), (III-1E), (III-1F), (III-1G), (III-1H), (III-2), (III-2A), (III-2B), (III-2C), (III-2D), (III-2E), (III-2F), and (III-2G) as described above. Compounds of formula (III-2H), formula (III-3), formula (III-3A), formula (III-3B), formula (III-3C), formula (III-3D), formula (III-3E), formula (III-3F), formula (III-3G), or formula (III-3H), or their stereoisomers, tautomers, pharmaceutically acceptable salts, pharmaceutically acceptable salts of their stereoisomers, pharmaceutically acceptable salts of their tautomers, solvates, prodrugs, or deuterated derivatives thereof.

[0249] in,

[0250] R Y1A Each time it appears, it is independently selected from hydrogen, halogen, -C. 1-3 Alkyl, or -C 1-3 Halogenated alkyl groups;

[0251] Optionally, two R atoms attached to the same C atom Y1A Together with the C atoms they are connected to, they form a group optionally bounded by 1, 2, or 3 R atoms. S1 Substituted 3-7 membered cycloalkyl groups (cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl); each of the R groups S1 Independently selected from halogens, -C 1-3 Alkyl, -C 1-3 alkoxy or -C 1-3 Halogenated alkyl groups;

[0252] n1 is selected from 0, 1, or 2;

[0253] n2 is selected from 0, 1, or 2;

[0254] And n1 + n2 ≤ 4;

[0255] R 3 -(C=O)R 3A -(C=O)OR 3H , or -(C=O)NR 3K R 3L ;

[0256] Each R 3A Independently selected from -C 1-3Alkyl, 3-7 membered cycloalkyl, 3-7 membered heterocyclic, phenyl, or 5-6 membered heteroaryl; wherein, the R 3A Optionally, it is selected from 1, 2, or 3 ions chosen from halogens, -C 1-3 Alkyl, -CN, -NH2, -NH(C) 1-3 alkyl), -N(C) 1-3 Alkyl group 2, -OH, -O(C) 1-3 Alkyl), -SH or -S(C 1-3 Substitution of alkyl groups;

[0257] R 3H Selected independently from -C each time it appears. 1-3 alkyl;

[0258] R 3K 、or R 3L Independently selected from hydrogen, -C 1-3 Alkyl, -C 1-3 Halogenated alkyl groups, -NH2, -NH(C) 1-3 alkyl), -N(C) 1-3 Alkyl) 2, 3-7 membered cycloalkyl, 3-7 membered heterocyclic, phenyl or 5-6 membered heteroaryl;

[0259] R 4 Each time it appears, it is independently selected from hydrogen or -C. 1-3 alkyl;

[0260] R 53 Each time it appears, it is independently selected from hydrogen, -C 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 groups), -C(=O)NH2, -C(=O)NH(C 1-3 Alkyl), -C(=O)N(C 1-3 Alkyl) 2, 3-7 membered cycloalkyl, 3-7 membered heterocyclic, phenyl, or 5-10 membered heteroaryl;

[0261] R 2 Each time it appears, it is independently selected from hydrogen, halogen, -C. 1-3 Alkyl, or -C 1-3 Halogenated alkyl groups;

[0262] R 6 Each time it appears, it is independently selected from hydrogen, halogen, -C. 1-3 Alkyl, or -C 1-3 Halogenated alkyl groups;

[0263] n3 is selected from 0, 1, or 2;

[0264] n4 is selected from 0, 1, or 2;

[0265] n5 is selected from 0, 1, or 2;

[0266] And n3 + n4 + n5 ≤ 5;

[0267] R S2 Each occurrence is independently selected from halogen, -CN, -C. 1-3 Alkyl, -OC 1-3 Alkyl, -C 1-3 Halogenated alkyl, or -OC 1-3 Halogenated alkyl groups;

[0268] n S2 Selected from 0, 1, 2, or 3;

[0269] Each heterocyclic group independently contains 1, 2, or 3 heteroatoms selected from N, O, or S each time it appears;

[0270] Each heteroaryl group independently contains 1, 2, or 3 heteroatoms selected from N, O, or S each time it appears.

[0271] This invention relates to a compound represented by formula (VII),

[0272] 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:

[0273] R 3 -(C=O)R 3A -(C=O)OR 3H , or -(C=O)NR 3K R 3L ;

[0274] Each R 3A Independently selected from -C 1-3 Alkyl, 3-7 membered cycloalkyl, 3-7 membered heterocyclic, phenyl, or 5-6 membered heteroaryl; wherein, the R 3A Optionally, it is selected from 1, 2, or 3 ions chosen from halogens, -C 1-3 Alkyl, -CN, -NH2, -NH(C) 1-3 alkyl), -N(C) 1-3 Alkyl group 2, -OH, -O(C) 1-3 Alkyl), -SH or -S(C 1-3 Substitution of alkyl groups;

[0275] R 3HSelected independently from -C each time it appears. 1-3 alkyl;

[0276] R 3K 、or R 3L Independently selected from hydrogen, -C 1-3 Alkyl, -C 1-3 Halogenated alkyl groups, -NH2, -NH(C) 1-3 alkyl), -N(C) 1-3 Alkyl) 2, 3-7 membered cycloalkyl, 3-7 membered heterocyclic, phenyl or 5-6 membered heteroaryl;

[0277] R 53 Each time it appears, it is independently selected from hydrogen, -C 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 groups), -C(=O)NH2, -C(=O)NH(C 1-3 Alkyl), -C(=O)N(C 1-3 Alkyl) 2, 3-7 membered cycloalkyl, 3-7 membered heterocyclic, phenyl, or 5-10 membered heteroaryl;

[0278] R 6 Each time it appears, it is independently selected from hydrogen, halogen, -C. 1-3 Alkyl, or -C 1-3 Halogenated alkyl groups;

[0279] R S2 Each occurrence is independently selected from halogen, -CN, -C. 1-3 Alkyl, -OC 1-3 Alkyl, -C 1-3 Halogenated alkyl, or -OC 1-3 Halogenated alkyl groups;

[0280] n S2 Selected from 0, 1, 2, or 3;

[0281] The compound represented by formula (VII) is any compound represented by formula (VII-1) to (VII-8):

[0282] In some embodiments, the compound represented by formula (I) is selected from the compounds represented by any of the formulas in Table 1 below:

[0283] On the other hand, the present invention provides a method for preparing the compound of formula (I), its stereoisomers, its tautomers, its pharmaceutically acceptable salts, pharmaceutically acceptable salts of its stereoisomers, pharmaceutically acceptable salts of its tautomers, its solvates, its prodrugs, or its deuterated derivatives, comprising the following steps:

[0284] Step A: Compound (V-1) reacts with R3-LG1 via a condensation reaction to yield compound (V-2), wherein,

[0285] In R3-LG1, LG1 is a leaving group or -OH. Preferably, the leaving group is selected from -OC(=O)-X1, halogens (e.g., -Cl, -Br or -I), or -OS(=O)2-X2, wherein X1 is selected from -C 1-3 Alkyl, or -OC 1-3 Alkyl; the X2 is selected from -C 1-3 alkyl, More preferably, the leaving group LG1 is selected from -OH, -OC(=O)-CH3, -OC(=O)-(OCH3), -Cl, -Br, -I, -OS(=O)2-CH3,

[0286] Step B: Compound (V-2) undergoes a series of enol tautomerization and esterification reactions to yield compound (V-3), wherein,

[0287] In the compound of formula (V-3), X3 together with the O atom it is attached to forms a leaving group LG2, wherein LG2 includes, but is not limited to, -OTf(CF3SO3-) and -OTs. -OMs (CH3SO3-) or -ONs

[0288] Step C: Compound (V-3) is coupled to give compound (I), wherein,

[0289] In W-LG3, LG3 is a borate group or a borate ester group; preferably, LG3 includes, but is not limited to, [other than].

[0290] Among them, W, X, Y 3 n3, n4, n5, Y 2 R 2 R 3 n1, n2, R 4 R 5 and Y 1 The definition is the same as that of formula (I).

[0291] On the other hand, the present invention provides a method for preparing the compound of formula (VII), its stereoisomers, its tautomers, its pharmaceutically acceptable salts, pharmaceutically acceptable salts of its stereoisomers, pharmaceutically acceptable salts of its tautomers, its solvates, its prodrugs, or its deuterated derivatives, comprising the following steps:

[0292] Each step is the same as steps A, B, and C in equation (I); where R 3 R 6 R 53 R S2 and n S2 The definition is the same as in equation (VII).

[0293] On the other hand, the present invention provides a pharmaceutical composition comprising a compound of formula (I) as described in the present invention, its stereoisomer, its tautomer, its pharmaceutically acceptable salt, a pharmaceutically acceptable salt of its stereoisomer, a pharmaceutically acceptable salt of its tautomer, its solvate, its prodrug, or a deuterated derivative thereof, and one or more pharmaceutically acceptable carriers or excipients.

[0294] On the other hand, the present invention provides the use of the compound of formula (I) described herein, its stereoisomer, its tautomer, its pharmaceutically acceptable salt, the pharmaceutically acceptable salt of its stereoisomer, the pharmaceutically acceptable salt of its tautomer, its solvate, its prodrug, or its deuterated derivative in the preparation of a medicament for the prevention / treatment of diseases related to orexin receptor 2 (OX2R) activation; preferably, the diseases related to orexin receptor 2 (OX2R) activation are sleep disorders and postoperative recovery-related diseases; more preferably, the sleep disorders and postoperative recovery-related diseases are selected from diseases such as narcolepsy, hypersomnia, sleep apnea, recovery from anesthesia, or improvement of respiratory depression.

[0295] On the other hand, the present invention provides a method for treating a subject suffering from a disease related to orexin receptor 2 (OX2R) activation, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (I), its stereoisomer, its tautomer, its pharmaceutically acceptable salt, a pharmaceutically acceptable salt of its stereoisomer, a pharmaceutically acceptable salt of its tautomer, its solvate, its prodrug, or a deuterated derivative thereof; or a pharmaceutical composition comprising thereof; preferably, the disease related to orexin receptor 2 (OX2R) activation is a sleep disorder or a postoperative recovery-related disease; more preferably, the sleep disorder or postoperative recovery-related disease is selected from diseases such as narcolepsy, hypersomnia, sleep apnea, recovery from anesthesia, or improvement of respiratory depression.

[0296] On the other hand, the present invention provides the use of a compound of formula (I) of the present invention, its stereoisomer, its tautomer, its pharmaceutically acceptable salt, its pharmaceutically acceptable salt of the stereoisomer, its pharmaceutically acceptable salt of the tautomer, its solvate, its prodrug, or its deuterated derivative; or a pharmaceutical composition comprising thereof, in the treatment of diseases related to orexin receptor 2 (OX2R) activation; preferably, the diseases related to orexin receptor 2 (OX2R) activation are sleep disorders and postoperative recovery-related diseases; more preferably, the sleep disorders and postoperative recovery-related diseases are selected from diseases such as narcolepsy, hypersomnia, sleep apnea, anesthesia recovery, and improvement of respiratory depression.

[0297] Terminology Definition

[0298] Unless otherwise stated, the following terms have the meanings described below. Other terms are defined elsewhere throughout this specification.

[0299] 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.

[0300] 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.

[0301] 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.

[0302] 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.

[0303] 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 1-8 An 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.

[0304] 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 1-10This 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.

[0305] 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)-).

[0306] 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. Non-limiting alkenyl groups include vinyl, propenyl, butenyl, 2-methyl-2-buten-1-yl, heptenyl, octenyl, etc.

[0307] 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 ranging from 2 to 20 carbon atoms in length. In some embodiments, the alkynyl group is -C 2-10 Alkyne group. In some embodiments, -C 2-10 The alkynyl group is a -C group containing 2-6 carbon atoms. 2- 6. Alynyl. Non-restrictive alkynyl groups include ethynyl, 1-propynyl, 1-butynyl, heptyynyl, octyynyl, etc.

[0308] 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.

[0309] 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.

[0310] 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.

[0311] Unless otherwise stated, the term "heterocyclic" as used herein refers to a fully or partially saturated monocyclic, bicyclic, bridged, fused, or spirocyclic non-aromatic ring that contains 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). In some embodiments, the heterocyclic 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 rings), having 1 to 3 heteroatoms when the heterocyclic is monocyclic (e.g., 3- to 8-membered monocyclic), and 1 to 6 heteroatoms when the heterocyclic is bicyclic (e.g., 8- to 12-membered bicyclic). When the heterocycle is a tricyclic or polycyclic system, it has 1-9 heteroatoms. The heterocycle includes a saturated heterocyclic alkyl ring, a heterocyclic alkenyl ring containing at least one double bond (preferably), and a heterocyclic alkynyl ring containing at least one triple bond (preferably). 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. Examples of exemplary monocyclic-heterocyclic alkyl rings include piperazine, piperidine, tetrahydrothiophene, tetrahydropyran, dioxane, morpholine, tetrahydrofuran, aziridine butane, aziridine propane, aziridine heptane, pyrrolidine, oxacyclobutane, oxacyclopropane, tetrahydrofuran, tetrahydroimidazolium, tetrahydrothiazole, tetrahydropyran, thiomorpholine, etc. Examples of exemplary 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.

[0312] 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.

[0313] 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.

[0314] "Heteroaryl" refers to an aromatic group having a fully conjugated π-electron system of 6-20 carbon atoms having at least one ring containing an O, N, and / or S heteroatom, or a heteroaryl refers to an aromatic ring containing at least one O, N, and / or S heteroatom and 1-6 carbon atoms. Preferably, a heteroaryl 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.

[0315] Unless otherwise stated, the term "oxo" refers to an oxygen substituent (i.e., =O) linked by a double bond.

[0316] 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.

[0317] 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.

[0318] 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.

[0319] 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.

[0320] 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.

[0321] 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.

[0322] 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.

[0323] "Pharmaceutical-acceptable excipients" refer to substances that are non-toxic, biologically tolerable, and otherwise biologically suitable for administration to a subject, such as inert substances, and that are added to or otherwise used as a medium, 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.

[0324] "Solvate" refers to a compound represented by Formula I that has one or more solvent molecules.

[0325] A "leaving group" refers to an atom or a group of atoms that are replaced in a chemical reaction. These are stable substances with bond electrons, and for example, they usually form anions. Preferably, the leaving group is selected from the following groups, including: halogen, 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.

[0326] 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.

[0327] 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).

[0328] 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.

[0329] 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.

[0330] 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.

[0331] 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.

[0332] 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.

[0333] 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.

[0334] 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%.

[0335] 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.

[0336] These and other aspects will become apparent from the following written description of the invention. Detailed Implementation

[0337] 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.

[0338] 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.

[0339] Example

[0340] 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:

[0341] Preparation of intermediate A1(INT 1)

[0342] Under ice-water bath conditions, INT 1-1 (3.78 g, 23.91 mmol, 1.0 eq.) was added to a THF (100 mL) dispersion of NaH (0.96 g, 23.91 mmol, 1.0 eq., dispersed in mineral oil at 60% by mass). After stirring for 30 minutes, 3-bromo-2-(bromomethyl)pyridine (5.0 g, 19.93 mmol, 0.8 eq.) was added. The reaction mixture was stirred at room temperature for 16 hours, cooled to 0 °C, quenched with water (100 mL), and extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (using V... PE :V EA(Eluted at a ratio of 3:1) to obtain INT 1-2 (6.7 g, 72% yield). LCMS: m / z = 328, 330 [M+H] + .

[0343] INT 1-2 (5.0 g, 15.3 mmol, 1.0 eq.), methanesulfonamide (1.74 g, 18.3 mmol, 1.2 eq.), methanesulfonic acid (2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (1.21 g, 1.5 mmol, 0.1 eq.), and cesium carbonate (14.9 g, 45.8 mmol, 3.0 eq.) were added to 1,4-dioxane (100 ml). The reaction mixture was stirred for 16 hours under a nitrogen atmosphere and at 100 °C. After cooling to room temperature, the mixture was filtered through diatomaceous earth. The resulting filtrate was concentrated, dissolved in ethyl acetate, washed with water, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (eluent gradient V). PE :V EA =2:1 to V EA The yield was INT 1-3 (4.56 g, 87% yield). LCMS: m / z = 343 [M+H] + .

[0344] INT 1-3 (4.56 g, 13.3 mmol, 1.0 eq) and platinum dioxide (0.3 g, 1.33 mmol, 0.1 eq.) were added to a mixed solution of acetic acid (20 mL) and methanol (60 mL). The reaction mixture was stirred for 12 hours under a hydrogen atmosphere at 50 °C. After filtration through diatomaceous earth, the mixture was concentrated to obtain the crude product INT 1-4, which required no further purification and was used directly in the next reaction. LCMS: m / z = 349 [M+H] + .

[0345] An aqueous HCl solution (6N) was added to a THF dispersion (40 ml) of the crude products of INT 1-4. After stirring at room temperature for 9 hours, the pH was adjusted to neutral by adding an aqueous sodium bicarbonate solution. The resulting mixture was concentrated under reduced pressure, extracted with ethyl acetate, and concentrated to give INT 1 (2.39 g, yield 59%). LCMS: m / z = 305 [M+H] + .

[0346] Preparation of intermediate A2(INT 2)

[0347] Diisopropylethylamine (37.48 g, 0.290 mol, 2.0 eq.) was added to a DCM solution of INT 2-1 (29.62 g, 0.145 mol, 1.0 eq.) in 150 mL. Meanwhile, a DCM solution of tert-butyldimethoxytrifluoromethanesulfonate (40.18 g, 0.152 mol, 1.05 eq.) in 150 mL was slowly added dropwise at 0 °C. The reaction mixture was stirred at 0 °C for 5 hours, then poured into water and extracted with DCM. The organic phase was washed with water, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (eluent gradient V). PE :V EA =50:1 to 20:1), yielding INT 2-2 (45.30g, yield 98%).

[0348] At 0 °C, 1-chloromethyl-4-fluoro-1,4-diazidobicyclo[2.2.2]octane bis(tetrafluoroborate) (100.66 g, 0.284 mol, 2.0 eq.) was added in portions over 1 hour to a DMF (300 mL) solution of INT 2-2 (45.30 g, 0.142 mol, 1.0 eq.). The reaction mixture was slowly heated to room temperature and stirred for 17 hours, then poured into a 5% sodium bicarbonate aqueous solution (2.0 L) and extracted with EA. The organic phase was washed with water, dried over anhydrous sodium sulfate, and concentrated. The resulting residue was purified by silica gel column chromatography (eluent gradient V). PE :V EA =10:1 to 5:1), yielding INT 2-3 (25.6g, yield 81%).

[0349] Triethyl orthoformate (34.04 g, 0.230 mol, 2.0 eq.) and p-toluenesulfonic acid monohydrate (2.19 g, 0.0115 mol, 0.1 eq.) were added to an INT 2-3 solution (25.6 g, 0.115 mol, 1.0 eq.) in 150 mL of anhydrous ethanol. After stirring at room temperature for 12 hours, 7.8 mL of 20% w / w sodium ethoxide in ethanol was added, and stirring continued for 10 minutes. Water (800 mL) was then added, and the mixture was extracted with methyl tert-butyl ether. The organic phase was washed with water, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (eluent gradient V). PE :V EA =8:1), yielding INT 2-4 (33.5g, yield 98.1%).

[0350] Under a hydrogen atmosphere, palladium on carbon (3.35 g, 0.1 w / w) was added to a methanol solution of INT 2-4 (33.5 g, 0.113 mol, 1.0 eq.). After reacting at room temperature for 12 hours, the mixture was filtered under reduced pressure and washed with methanol. The resulting filtrate was concentrated to obtain crude INT 2-5 (22.6 g), which did not require further purification and was used directly in the next reaction.

[0351] At 0 °C, INT 2-5 (22.6 g, 0.11 mol, 1.0 eq.) was added to a THF (275 mL) dispersion of NaH (8.8 g, 0.22 mol, 2.0 eq., dispersed in mineral oil at 60% by mass). After stirring for 30 minutes, 3-bromo-2-(bromomethyl)pyridine (32.62 g, 0.13 mol, 1.2 eq.) was added. The reaction mixture was stirred at room temperature for 16 hours, cooled to 0 °C, quenched with water (800 mL), and extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (using V... PE :V EA (Eluted at a ratio of 3:1) to obtain INT 2-6 (33.3 g, yield 80.4%). LCMS: m / z = 376, 378 [M+H] + .

[0352] INT 2-6 (33.3 g, 88.5 mmol, 1.0 eq.), methanesulfonamide (10.09 g, 106.2 mmol, 1.2 eq.), methanesulfonic acid (2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (7.03 g, 8.85 mmol, 0.1 eq.), and cesium carbonate (71.9 g, 221.25 mmol, 2.5 eq.) were added to 1,4-dioxane (500 ml). The reaction mixture was stirred for 16 hours under a nitrogen atmosphere at 100 °C, cooled to room temperature, and filtered. The resulting filtrate was concentrated, diluted with water, and the pH was adjusted to 7 with hydrochloric acid (0.5 mol / L). Extraction was performed using EA, followed by washing with water, drying over anhydrous sodium sulfate, and purification by silica gel column chromatography (eluent gradient V). PE :V EA =2:1 to V EA The yield was INT 2-7 (29.0 g, yield 83.8%). LCMS: m / z = 391 [M+H] + .

[0353] INT 2-7 (29.0 g, 74.1 mmol, 1.0 eq) and platinum dioxide (1.68 g, 7.41 mmol, 0.1 eq.) were added to a mixed solution of acetic acid (58 mL) and methanol (290 mL). The mixture was stirred for 12 hours under a hydrogen atmosphere at 50 °C and then filtered. The resulting filtrate was concentrated under reduced pressure to obtain crude INT 2-8, which required no further purification and was used directly in the next reaction. LCMS: m / z = 397 [M+H] + .

[0354] An aqueous HCl solution (6N) (150 ml) was added to the THF dispersion (150 ml) of the crude INT 2-8 product. After stirring at room temperature for 9 hours, the pH was adjusted to neutral with an aqueous sodium bicarbonate solution, concentrated under reduced pressure, and extracted with ethyl acetate. The organic phase was concentrated to give INT 2 (12.92 g, yield 54%). LCMS: m / z = 323 [M+H] + .

[0355] Example 1: Preparation of N-(1-acetyl-2-(((2,3,4,5-tetrahydro-[1,1'-biphenyl]-4-yl)oxy)methyl)piperidin-3-yl)methanesulfonamide (compound 1)

[0356] Under ice-water bath conditions, acetic anhydride (0.21 g, 2.06 mmol, 1.2 eq.) was slowly added dropwise to a DCM solution of INT 1 (0.5 g, 1.7 mmol, 1.0 eq.) and TEA (0.26 g, 2.6 mmol, 1.5 eq.). After stirring for 12 hours, the solution was extracted with DCM. The organic phase was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent gradient V). PE :V EA =3:1 to V EA Compound 1-1 was obtained (0.39 g, yield 66%), LCMS: m / z = 347 [M+H]. + .

[0357] Under a nitrogen atmosphere and at -70°C, lithium bis(trimethylsilyl)amino / THF (1.0 M, 3 mL, 3.3 mmol, 3.0 eq.) was added dropwise to a solution of compound 1-1 (0.39 g, 1.1 mmol, 1.0 eq.) and N-phenylbis(trifluoromethanesulfonyl)imide (0.79 g, 2.2 mmol, 2.0 eq.) in 10 mL of THF. After stirring for 30 minutes, the mixture was heated to room temperature and stirred for another 3 hours. The resulting reaction solution was then slowly quenched in water and extracted with EA. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution gradient V). PE :V EA =3:1 to V EA Compounds 1-2 were obtained (0.24 g, yield 45%), LCMS: m / z = 479 [M+H]. + .

[0358] Compounds 1-2 (0.2 g, 0.4 mmol, 1.0 eq.), phenylboronic acid (0.06 g, 0.48 mmol, 1.2 eq.), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (0.015 g, 0.02 mmol, 0.05 eq.), and potassium carbonate (0.17 g, 1.2 mmol, 3.0 eq.) were added to a mixed solvent of 1,4-dioxane (4 mL) and water (0.4 mL). Under a nitrogen atmosphere, the reaction mixture was heated at 80 °C for 16 hours, filtered, and the resulting filtrate was concentrated under reduced pressure and extracted with EA. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by high-performance liquid chromatography (C18 column, eluent gradient V). H2O(0.1％二乙胺) / V 乙腈 =50:50-0:100-50:50), yielding compound 1 (0.046 g, yield 23%), LCMS: m / z = 407 [M+H) + .

[0359] Example 2: Preparation of methyl 3-(methanesulfonamide)-2-(((2,3,4,5-tetrahydro-[1,1'-biphenyl]-4-yl)oxy)methyl)piperidine-1-carboxylate (compound 2)

[0360] Under ice-water bath conditions, dimethyl pyrocarbonate (0.53 g, 3.96 mmol, 1.2 eq.) was slowly added dropwise to a DCM solution of INT 1 (1.0 g, 3.3 mmol, 1.0 eq.) and TEA (0.66 g, 6.6 mmol, 2.0 eq.). After stirring for 12 hours, the resulting reaction solution was extracted with DCM. The organic phase was washed with water, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent gradient V). PE :V EA =3:1 to V EA Compound 2-1 was obtained (0.85 g, yield 72%), LCMS: m / z = 363 [M+H]. + .

[0361] Under a nitrogen atmosphere and at -70°C, lithium bis(trimethylsilyl)amino / THF (5 mL, 5.04 mmol, 3.0 eq.) was added dropwise to a THF solution of compound 2-1 (0.61 g, 1.68 mmol, 1.0 eq.) and N-phenylbis(trifluoromethanesulfonyl)imide (1.2 g, 3.67 mmol, 2.0 eq.) (20 mL). After stirring for 30 minutes, the mixture was heated to room temperature and stirred for another 3 hours. The resulting reaction solution was then slowly quenched in water and extracted with EA. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent gradient V). PE :V EA =3:1 to V EA Compound 2-2 (0.4 g, yield 48%) was obtained, LCMS: m / z = 495 [M+H]. + .

[0362] Compound 2-2 (0.15 g, 0.3 mmol, 1.0 eq.), phenylboronic acid (0.04 g, 0.36 mmol, 1.2 eq.), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (0.011 g, 0.015 mmol, 0.05 eq.), and potassium carbonate (0.13 g, 0.91 mmol, 3.0 eq.) were added to a mixed solvent of 1,4-dioxane (6 mL) and water (0.6 mL). The reaction mixture was heated at 80 °C for 16 hours under a nitrogen atmosphere, filtered, and the filtrate was concentrated under reduced pressure and extracted with EA. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography (C18 column, eluent gradient V). H2O(0.1％二乙胺) / V 乙腈 =50:50), yielding compound 2 (0.04 g, yield 31%), LCMS: m / z = 423 [M+H) + .

[0363] Example 3: Preparation of methyl 2-(((3',5'-difluoro-2,3,4,5-tetrahydro-[1,1'-biphenyl]-4-yl)oxy)methyl)-3-(methanesulfonamide)piperidine-1-carboxylate (compound 3)

[0364] Compound 2-2 (0.15 g, 0.3 mmol, 1.0 eq.), 3,5-difluorophenylboronic acid (0.057 g, 0.36 mmol, 1.2 eq.), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (0.011 g, 0.015 mmol, 0.05 eq.), and potassium carbonate (0.13 g, 0.91 mmol, 3.0 eq.) were added to a mixed solvent of 1,4-dioxane (6 mL) and water (0.6 mL). The reaction mixture was heated at 80 °C for 16 hours under a nitrogen atmosphere, filtered, and the filtrate was concentrated under reduced pressure and extracted with EA. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography (C18 column, eluent gradient V). H2O(0.1％二乙胺) / V 乙腈 =50:50-0:100-50:50), yielding compound 3 (0.041 g, yield 29%), LCMS: m / z = 459 [M+H) + .

[0365] Example 4: Preparation of methyl 3-(methanesulfonamide)-2-(((2'-(trifluoromethyl)-2,3,4,5-tetrahydro-[1,1'-biphenyl]-4-yl)oxy)methyl)piperidine-1-carboxylate (compound 4) and its enantiomers

[0366] Compound 2-2 (0.15 g, 0.3 mmol, 1.0 eq.), 2-(trifluoromethyl)phenylboronic acid (0.099 g, 0.36 mmol, 1.2 eq.), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (0.011 g, 0.015 mmol, 0.05 eq.), and potassium carbonate (0.13 g, 0.91 mmol, 3.0 eq.) were added to a mixed solvent of 1,4-dioxane (6 mL) and water (0.6 mL). Under a nitrogen atmosphere, the reaction mixture was heated at 80 °C for 16 hours, filtered, and the resulting filtrate was concentrated under reduced pressure and extracted with EA. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product of compound 4 (0.11 g), LCMS: m / z = 491 [M+H]. + .

[0367] The crude product of compound 4 was subjected to the following three separations to obtain compound 4A with a retention time of 12.72 min. Compound 4A is one of compound 4-1, compound 4-2, compound 4-3, compound 4-4, compound 4-5, compound 4-6, compound 4-7, and compound 4-8.

[0368] First separation: The crude product of compound 4 was purified by high performance liquid chromatography (C18 column, eluent gradient V). H2O(0.1％二乙胺) / V 乙腈 =50:50-0:100-50:50), yielding compound 4A-1 (0.049 g, yield 33%).

[0369] Second separation: Compound 4A-1 was initially separated by supercritical fluid chromatography (SFC) to obtain compound 4A-2 with a retention time of 6.24 min. Specific preparation parameters were as follows: SFC chiral column: Chiralpak IC, 250 × 30 mm ID, 10 μm; eluent: V 二氧化碳 / V 异 Propanol (0.1% ammonia) = 60:40; back pressure: 100 bar; column temperature: 40℃; flow rate: 80 ml / min; circulation time: 4.5 min.

[0370] Third separation: Compound 4A-2, with a retention time of 6.24 min, was initially separated by supercritical fluid chromatography (SFC) to obtain compound 4A with a retention time of 12.72 min. Specific preparation parameters were as follows: SFC chiral column: Chiralcel OJ, 250 × 30 mm ID, 10 μm; eluent: gradient V. 二氧化碳 / V 异丙醇(0.1％氨水) =85:15; Back pressure: 100 bar; Column temperature: 40℃; Flow rate: 60 ml / min; Circulation time: 4.0 min.

[0371] Example 5: Preparation of methyl 2-(((2',6'-difluoro-2,3,4,5-tetrahydro-[1,1'-biphenyl]-4-yl)oxy)methyl)-3-(methanesulfonamide)piperidine-1-carboxylate (compound 5)

[0372] Compound 2-2 (0.15 g, 0.3 mmol, 1.0 eq.), 2,6-difluorophenylboronic acid (0.057 g, 0.36 mmol, 1.2 eq.), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (0.011 g, 0.015 mmol, 0.05 eq.), and potassium carbonate (0.13 g, 0.91 mmol, 3.0 eq.) were added to a mixed solvent of 1,4-dioxane (6 mL) and water (0.6 mL). Under a nitrogen atmosphere, the reaction mixture was heated at 80 °C for 16 hours, filtered, and the resulting filtrate was concentrated under reduced pressure and extracted with EA. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by high-performance liquid chromatography (C18 column, eluent gradient V). H2O(0.1％二乙胺) / V 乙腈 =50:50), yielding compound 5 (0.036 g, yield 26%), LCMS: m / z = 459 [M+H) + .

[0373] Example 6: Preparation of N-[1-(cyclopropaneformyl)-2-(((2,3,4,5-tetrahydro-[1,1'-biphenyl]-4-yl)oxy)methyl)piperidin-3-yl]methanesulfonamide (compound 6)

[0374] At 0 °C, cyclopropylformyl chloride (0.21 g, 20.6 mmol, 1.2 eq.) was slowly added dropwise to a DCM solution of INT 1 (0.5 g, 1.7 mmol, 1.0 eq.) and TEA (0.26 g, 2.6 mmol, 1.5 eq.). After stirring for 12 hours, the resulting mixture was extracted with DCM. The organic phase was washed with water, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent gradient V). PE :V EA =3:1 to V EA Compound 6-1 was obtained (0.41 g, yield 66%), LCMS: m / z = 373 [M+H]. + .

[0375] Under a nitrogen atmosphere and at -70°C, lithium bis(trimethylsilyl)amino / THF (1.0 M, 3 mL, 3.3 mmol, 3.0 eq.) was added dropwise to a solution of compound 6-1 (0.4 g, 1.1 mmol, 1.0 eq.) and N-phenylbis(trifluoromethanesulfonyl)imide (0.79 g, 2.2 mmol, 2.0 eq.) in 10 mL of THF. After stirring for 30 minutes, the mixture was heated to room temperature and stirred for another 3 hours. The resulting reaction solution was then slowly quenched in water and extracted with EA. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent gradient V). PE :V EA =3:1 to V EA Compound 6-2 was obtained (0.31 g, yield 57%), LCMS: m / z = 505 [M+H]. + .

[0376] Compound 6-2 (0.2 g, 0.4 mmol, 1.0 eq.), phenylboronic acid (0.06 g, 0.48 mmol, 1.2 eq.), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (0.015 g, 0.02 mmol, 0.05 eq.), and potassium carbonate (0.17 g, 1.2 mmol, 3.0 eq.) were added to a mixed solvent of 1,4-dioxane (4 mL) and water (0.4 mL). The reaction mixture was heated at 80 °C for 16 hours under a nitrogen atmosphere, filtered, and the filtrate was concentrated under reduced pressure and extracted with EA. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography (C18 column, eluent gradient V). H2O(0.1％二乙胺) / V 乙腈 =50:50), yielding compound 6 (0.041 g, yield 24%), LCMS: m / z = 433 [M+H) + .

[0377] Example 7: Preparation of N-ethyl-2-(((2'-fluoro-2,3,4,5-tetrahydro-[1,1'-biphenyl]-4-yl)oxy)methyl)-3-(methanesulfonamide)piperidine-1-carboxamide (compound 7)

[0378] At 0 °C, ethyl isocyanate (0.15 g, 2.06 mmol, 1.2 eq.) was slowly added dropwise to a DCM solution of INT 1 (0.5 g, 1.7 mmol, 1.0 eq.) and TEA (0.26 g, 2.6 mmol, 1.5 eq.). After stirring for 12 hours, the resulting mixture was extracted with DCM. The organic phase was washed with water, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent gradient V).PE :V EA =3:1 to V EA Compound 7-1 was obtained (0.39 g, yield 66%), LCMS: m / z = 376 [M+H]. + .

[0379] Under a nitrogen atmosphere and at -70°C, lithium bis(trimethylsilyl)amino / THF (1.0 M, 3 mL, 3.3 mmol, 3.0 eq.) was added dropwise to a THF (10 mL) solution of compound 7-1 (0.4 g, 1.1 mmol, 1.0 eq.) and N-phenylbis(trifluoromethanesulfonyl)imide (0.79 g, 2.2 mmol, 2.0 eq.). After stirring for 30 minutes, the mixture was heated to room temperature and stirred for another 3 hours. The resulting reaction solution was then slowly quenched in water and extracted with EA. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent gradient V). PE :V EA =3:1 to V EA Compound 7-2 (0.25 g, yield 46%) was obtained, LCMS: m / z = 508 [M+H] + .

[0380] Compound 7-2 (0.2 g, 0.4 mmol, 1.0 eq.), 2-fluorophenylboronic acid (0.07 g, 0.47 mmol, 1.2 eq.), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (0.015 g, 0.02 mmol, 0.05 eq.), and potassium carbonate (0.17 g, 1.2 mmol, 3.0 eq.) were added to a mixed solvent of 1,4-dioxane (4 mL) and water (0.4 mL). The reaction mixture was heated at 80 °C for 16 hours under a nitrogen atmosphere, filtered, and the filtrate was concentrated under reduced pressure and extracted with EA. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by high-performance liquid chromatography (C18 column, eluent gradient V). H2O(0.1％二乙胺) / V 乙腈 =50:50), yielding compound 7 (0.063 g, yield 35%), LCMS: m / z = 454 [M+H) + .

[0381] Example 8: Preparation of methyl 2-(((2'-fluoro-6'-(trifluoromethyl)-2,3,4,5-tetrahydro-[1,1'-biphenyl]-4-yl)oxy)methyl)-3-(methanesulfonamide)piperidine-1-carboxylate (compound 8)

[0382] Compound 2-2 (1.5 g, 3.03 mmol, 1.0 eq.), 2-fluoro-6-trifluoromethylphenylboronic acid (0.76 g, 3.63 mmol, 1.2 eq.), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (0.11 g, 0.15 mmol, 0.05 eq.), and potassium carbonate (1.26 g, 9.1 mmol, 3.0 eq.) were added to a mixed solvent of 1,4-dioxane (60 mL) and water (6 mL). Under a nitrogen atmosphere, the reaction mixture was heated at 80 °C for 16 hours, concentrated under reduced pressure, and extracted with EA. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting residue was purified by high-performance liquid chromatography (C18 column, eluent gradient V). H2O(0.1％二乙胺) / 乙腈 =50:50-0:100-50:50), yielding compound 8 (0.59 g, yield 33%), LCMS: m / z = 509 [M+H) + .

[0383] Example 9: Preparation of methyl 2-(((6-fluoro-2'-(trifluoromethyl)-2,3,4,5-tetrahydro-[1,1'-biphenyl]-4-yl)oxy)methyl)-3-(methanesulfonamide)piperidine-1-carboxylate (compound 9) and its enantiomers

[0384] At 0 °C, dimethyl pyrocarbonate (7.48 g, 55.8 mmol, 1.5 eq.) was slowly added dropwise to a DCM solution of INT 2 (12.0 g, 37.2 mmol, 1.0 eq.) and TEA (7.51 g, 74.4 mmol, 2.0 eq.). After stirring for 12 hours, the resulting reaction solution was extracted with DCM. The organic phase was washed with water, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent gradient V). PE :V EA =3:1 to V EA Compound 9-1 (9.8 g, yield 69.1%) was obtained, LCMS: m / z = 381 [M+H]. + .

[0385] Under a nitrogen atmosphere and at -70°C, lithium bis(trimethylsilyl)amino / THF (33 mL, 33.0 mmol, 3.0 eq.) was added dropwise to a THF solution of compound 9-1 (4.2 g, 11.0 mmol, 1.0 eq.) and N-phenylbis(trifluoromethanesulfonyl)imide (7.85 g, 22.0 mmol, 2.0 eq.) (150 mL). After stirring for 30 minutes, the mixture was heated to room temperature and stirred for another 3 hours. The resulting reaction solution was then slowly quenched in water and extracted with EA. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent gradient V). PE :V EA =3:1 to V EA Compound 9-2 (3.5 g, yield 62.1%) was obtained, LCMS: m / z = 513 [M+H]. + .

[0386] Compound 9-2 (3.5 g, 6.8 mmol, 1.0 eq.), 2-(trifluoromethyl)phenylboronic acid (1.54 g, 8.16 mmol, 1.2 eq.), methanesulfonic acid (2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (0.27 g, 0.34 mmol, 0.05 eq.), and cesium carbonate (6.63 g, 20.4 mmol, 3.0 eq.) were added to a mixed solvent of 1,4-dioxane (60 mL) and water (6 mL). Under a nitrogen atmosphere, the reaction mixture was heated at 100 °C for 16 hours, filtered, and the resulting filtrate was concentrated under reduced pressure and extracted with EA. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product of compound 9, LCMS: m / z = 509 [M+H]. + .

[0387] The crude product of compound 9 was subjected to the following three separations:

[0388] First separation: The crude product of compound 9 was purified by high performance liquid chromatography (C18 column, eluent gradient V). H2O(0.1％二乙胺) / V 乙腈 =50:50-0:100-50:50), to obtain compound 9A-1.

[0389] Second separation: Compound 9A-1 was initially separated by supercritical fluid chromatography (SFC) to obtain compound 9A-2 with a retention time of 7.75 min; the specific preparation and detection parameters are as follows:

[0390] Preparation parameters and conditions: SFC chiral column: Chiralpak IG, 250×30mm ID, 10μm; eluent: V 二氧化碳 / V 乙醇(0.1％氨水) =75:25; Back pressure: 100 bar; Column temperature: 40℃; Flow rate: 140 ml / min; Circulation time: 4.2 min.

[0391] Third separation: Compound 9A-2 with a retention time of 7.75 min was initially separated by supercritical fluid chromatography (SFC) to obtain compound 9A with a retention time of 5.66 min and compound 9B with a retention time of 6.16 min; the specific preparation and detection parameters are as follows:

[0392] Preparation parameters and conditions: SFC chiral column: Chiralpak IC, 250×30mm ID, 10μm; eluent: gradient of V 二氧化碳 / V 异丙醇(0.1％氨 水) =65:35; Back pressure: 100 bar; Column temperature: 40℃; Flow rate: 80 ml / min; Circulation time: 5.0 min.

[0393] Compounds 9A and 9B are two different isomers of compounds 9-1', 9-2', 9-3', 9-4', 9-5', 9-6', 9-7', and 9-8'.

[0394] Example 10: Preparation of methyl 2-(((2',6-difluoro-2,3,4,5-tetrahydro-[1,1'-biphenyl]-4-yl)oxy)methyl)-3-(methanesulfonamide)piperidine-1-carboxylate (compound 32)

[0395] Compound 9-2 (1.0 g, 1.95 mmol, 1.0 eq.), 2-fluorophenylboronic acid (0.33 g, 2.34 mmol, 1.2 eq.), methanesulfonic acid (2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (0.77 g, 0.098 mmol, 0.05 eq.), and cesium carbonate (1.90 g, 5.85 mmol, 3.0 eq.) were added to a mixed solvent of 1,4-dioxane (10 ml) and water (1 ml). The reaction mixture was heated at 100 °C for 16 hours under a nitrogen atmosphere, filtered, and the filtrate was concentrated under reduced pressure and extracted with EA. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by high-performance liquid chromatography (C18 column, eluent gradient V). H2O(0.1％二乙胺) / 乙腈 =45:55-0:100-45:55), yielding compound 32 (0.098 g, yield 11%), LCMS: m / z = 459 [M+H) + .

[0396] Example 11: Preparation of N-[1-isobutyryl-2-(((2'-(trifluoromethyl)-2,3,4,5-tetrahydro-[1,1'-biphenyl]-4-yl)oxy)methyl)piperidin-3-yl]methanesulfonamide (compound 117)

[0397] At room temperature, INT 1 (10.0 g, 32.9 mmol, 1.0 eq.) was added to 100 mL of DCM, followed by di-tert-butyl dicarbonate (8.6 g, 39.5 mmol, 1.2 eq.) and TEA (9.97 g, 98.7 mmol, 3.0 eq.). After stirring at room temperature for 16 hours, the resulting mixture was extracted with DCM. The organic phase was washed with water, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent gradient V). PE :V EA =3:1 to V EA Compound 117-1 was obtained (8.1 g, yield 61%), LCMS: m / z = 405 [M+H]. + .

[0398] Under a nitrogen atmosphere and at -70°C, lithium bis(trimethylsilyl)amino / THF (1.0 M, 14.9 mL, 14.85 mmol, 3.0 eq.) was added dropwise to a THF solution of compound 117-1 (2.0 g, 4.95 mmol, 1.0 eq.) and N-phenylbis(trifluoromethanesulfonyl)imide (3.53 g, 9.9 mmol, 2.0 eq.) (20 mL). After stirring for 30 minutes, the mixture was heated to room temperature and stirred for another 3 hours. The resulting reaction solution was then slowly quenched in water and extracted with EA. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent gradient V). PE :V EA =3:1 to V EA Compound 117-2 (1.45 g, 55% yield) was obtained, LCMS: m / z = 537 [M+H] + .

[0399] Compound 117-2 (1.45 g, 2.7 mmol, 1.0 eq.), 2-(trifluoromethyl)phenylboronic acid (0.61 g, 3.24 mmol, 1.2 eq.), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (0.10 g, 0.14 mmol, 0.05 eq.), and potassium carbonate (1.12 g, 8.1 mmol, 3.0 eq.) were added to a mixed solvent of 1,4-dioxane (14 mL) and water (1.4 mL). The reaction mixture was heated at 80 °C for 16 hours under a nitrogen atmosphere, filtered, and the resulting filtrate was concentrated under reduced pressure and extracted with EA. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent gradient V). PE :V EA =3:1 to V EA Compound 117-3 (0.58 g, yield 40%) was obtained, LCMS: m / z = 533 [M+H] + .

[0400] Compound 117-3 (0.58 g, 1.1 mmol, 1.0 eq.) was added to a 1,4-dioxane solution (5 mL) in hydrochloric acid. After reacting at room temperature for 4 hours, the solution was evaporated to dryness to give compound 117-4. LCMS: m / z = 433 [M+H] + .

[0401] Compound 117-4 (0.2 g, 0.46 mmol, 1.0 eq.) was added to 2 mL of DCM, along with isobutyric acid (0.05 g, 0.55 mmol, 1.2 eq.), TEA (0.18 g, 1.84 mmol, 4 eq.), and Carter's condensing agent (0.3 g, 0.69 mmol, 1.5 eq.). The reaction was carried out at room temperature for 16 hours. The mixture was extracted with DCM, and the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution gradient V). PE :V EA =5:1 to V EA The crude product was further purified by high performance liquid chromatography (C18 column, eluent gradient V). H2O(0.1％二乙胺) / 乙腈 =40:60-0:100-40:60), yielding compound 117 (0.081 g, yield 35%), LCMS: m / z = 503 [M+H] + .

[0402] Example 12: Preparation of 3-(methanesulfonamide)-2-(((2'-(trifluoromethyl)-2,3,4,5-tetrahydro-[1,1'-biphenyl]-4-yl)oxy)methyl)piperidine-1-carboxylic acid isopropyl ester (compound 118)

[0403] At 0 °C, isopropyl chloroformate (0.07 g, 0.55 mmol, 1.2 eq.) was slowly added dropwise to 2 mL of DCM solution containing compound 117-4 (0.2 g, 0.46 mmol, 1.0 eq.) and TEA (0.18 g, 1.84 mmol, 4 eq.). The reaction was carried out for 16 hours, followed by DCM extraction. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (elution gradient V). PE :V EA =5:1 to V EA The crude product was further purified by high performance liquid chromatography (C18 column, eluent gradient V). H2O(0.1％二乙胺) / 乙腈 =25:75-0:100-25:75), yielding compound 118 (0.093 g, yield 39%), LCMS: m / z = 519 [M+H] + .

[0404] Example 13: Preparation of methyl 2-(((5',6-difluoro-2'-(trifluoromethyl)-2,3,4,5-tetrahydro-[1,1'-biphenyl]-4-yl)oxy)methyl)-3-(methanesulfonamide)piperidine-1-carboxylate (compound 119)

[0405] Compound 9-2 (1.0 g, 1.95 mmol, 1.0 eq.), 5-fluoro-2-trifluoromethylphenylboronic acid (0.48 g, 2.34 mmol, 1.2 eq.), methanesulfonic acid (2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (0.77 g, 0.098 mmol, 0.05 eq.), and cesium carbonate (1.90 g, 5.85 mmol, 3.0 eq.) were added to a mixed solvent of 1,4-dioxane (10 ml) and water (1 ml). The reaction mixture was heated at 100 °C for 16 hours under a nitrogen atmosphere, filtered, and the resulting filtrate was concentrated under reduced pressure and extracted with EA. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting residue was purified by high performance liquid chromatography (C18 column, eluent gradient V). H2O(0.1％二乙胺) / 乙腈 =40:60-0:100-40:60), yielding compound 119 (0.061 g, yield 6%), LCMS: m / z = 527 [M+H] + .

[0406] Example 14: Preparation of methyl 2-(((4',6-difluoro-2'-(trifluoromethyl)-2,3,4,5-tetrahydro-[1,1'-biphenyl]-4-yl)oxy)methyl)-3-(methanesulfonamide)piperidine-1-carboxylate (compound 120)

[0407] Compound 9-2 (1.0 g, 1.95 mmol, 1.0 eq.), 4-fluoro-2-trifluoromethylphenylboronic acid (0.48 g, 2.34 mmol, 1.2 eq.), methanesulfonic acid (2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (0.77 g, 0.098 mmol, 0.05 eq.), and cesium carbonate (1.90 g, 5.85 mmol, 3.0 eq.) were added to a mixed solvent of 1,4-dioxane (10 ml) and water (1 ml). The reaction mixture was heated at 100 °C for 16 hours under a nitrogen atmosphere, filtered, and the resulting filtrate was concentrated under reduced pressure and extracted with EA. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting residue was purified by high performance liquid chromatography (C18 column, eluent gradient V). H2O(0.1％二乙胺) / 乙腈 =40:60-0:100-40:60), yielding compound 120 (0.072 g, yield 7%), LCMS: m / z = 527 [M+H] + .

[0408] Example 15: Preparation of N-[2-(((2'-(trifluoromethyl)-2,3,4,5-tetrahydro-[1,1'-biphenyl]-4-yl)oxy)methyl)-1-(3,3,3-trifluoropropionyl)piperidin-3-yl]methanesulfonamide (compound 121)

[0409] Compound 117-4 (0.2 g, 0.46 mmol, 1.0 eq.) was added to 2 mL of DCM, along with 3,3,3-trifluoropropionic acid (0.07 g, 0.55 mmol, 1.2 eq.), TEA (0.18 g, 1.84 mmol, 4 eq.), and Carter's condensing agent (0.3 g, 0.69 mmol, 1.5 eq.). The reaction was carried out at room temperature for 16 hours. The mixture was extracted with DCM, and the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography (C18 column, eluent gradient V). H2O(0.1％二乙胺) / 乙腈 =50:50-0:100-50:50), yielding compound 121 (0.065 g, yield 26%), LCMS: m / z = 543 [M+H) + .

[0410] Example 16: Preparation of N-[1-(2-hydroxyacetyl)-2-(((2'-(trifluoromethyl)-2,3,4,5-tetrahydro-[1,1'-biphenyl]-4-yl)oxy)methyl)piperidin-3-yl]methanesulfonamide (compound 122)

[0411] Compound 117-4 (0.2 g, 0.46 mmol, 1.0 eq.) was added to 2 ml of DCM, along with 2-acetoxyacetic acid (0.06 g, 0.55 mmol, 1.2 eq.), TEA (0.18 g, 1.84 mmol, 4 eq.), and Carter's condensing agent (0.3 g, 0.69 mmol, 1.5 eq.). The mixture was reacted at room temperature for 16 hours, extracted with DCM, and concentrated under reduced pressure to obtain crude compound 122-1.

[0412] The crude compound 122-1 was added to 2 ml of methanol, and the pH was adjusted to 11-12 with 10% sodium hydroxide aqueous solution. The reaction was carried out at room temperature for 4 hours, followed by EA extraction. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluting gradient V). PE :V EA =5:1 to V EA The crude product was further purified by high performance liquid chromatography (C18 column, eluent gradient V). H2O(0.1％二乙胺) / 乙腈 =45:55-0:100-45:55), yielding compound 122 (0.041 g, yield 18%), LCMS: m / z = 491 [M+H] + .

[0413] Example 17: Preparation of N-[1-(bicyclo[1.1.1]pentane-1-formyl)-2-(((2'-(trifluoromethyl)-2,3,4,5-tetrahydro-[1,1'-biphenyl]-4-yl)oxy)methyl)piperidin-3-yl]methanesulfonamide (compound 123)

[0414] Compound 117-4 (0.2 g, 0.46 mmol, 1.0 eq.) was added to 2 mL of DCM, along with 3-fluorobicyclo[1.1.1]pentane-1-carboxylic acid (0.07 g, 0.55 mmol, 1.2 eq.), TEA (0.18 g, 1.84 mmol, 4 eq.), and Carter's condensing agent (0.3 g, 0.69 mmol, 1.5 eq.). The reaction was carried out at room temperature for 16 hours. The mixture was extracted with DCM, and the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution gradient V). PE:V EA =5:1 to V EA The crude product was further purified by high performance liquid chromatography (C18 column, eluent gradient V). H2O(0.1％ 二乙胺) / 乙腈 =30:70-0:100-30:70), yielding compound 123 (0.085 g, yield 34%), LCMS: m / z = 545 [M+H] + .

[0415] Using the above method or a modified method, the following compounds and their single enantiomers were synthesized from the corresponding starting materials:

[0416] Pharmacological test examples

[0417] Test Example 1: Assay of the agonistic activity of orexin receptor 2 (OX2R)

[0418] Preparation of (1 x Stimulation) buffer: Dilute the 5 x Stimulation buffer from the Cisbio IP-one kit with ddH2O at a ratio of 1:4 to obtain (1 x Stimulation) buffer.

[0419] Preparation of test solutions: Each test compound was diluted to a 5 mM stock solution with DMSO, and then serially diluted to 10 gradients at a factor of 3.16. The solutions were then diluted with (1 x Stimulation) buffer to obtain test 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).

[0420] Preparation of cell suspension: CHO-K1-OX1 / CHO-K1-OX2 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 1.71 x 10⁻⁶ cells / mL. 6Cells / mL (using a Countstar cell counter) were used to obtain a cell suspension.

[0421] Preparation of detection reagent IP1-d2: Dilute IP1-d2 with Lysis & detection buffer from the Cisbio IP-one detection kit (d2 to buffer volume ratio is 1:20) to obtain detection reagent IP1-d2.

[0422] Preparation of Anti-IP1 cryptate: Dilute Anti-IP1 cryptate with Lysis & detection buffer from the Cisbio IP-one detection kit (cryptate to buffer volume ratio of 1:20) to obtain Anti-IP1 cryptate.

[0423] Specific experimental steps and testing methods:

[0424] Cell suspension (7 μL / well, approximately 12,000 cells / well) and various concentrations of test solution (7 μL / well) were sequentially added to 96-well plates. After incubating the 96-well plates at 37°C for 60 minutes, IP1-d (3 μL / well) and Anti-IP1 cryptate (3 μL / well) were added to each well, and the 96-well plates were incubated at room temperature for 60 minutes. Wells containing the same percentage of DMSO served as a blank control group.

[0425] 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 agonistic effect values ​​at different concentrations of the compound sample, the agonistic effect curve of the test compound on the orexin receptor was fitted using GraphPad Prism software, and the EC50 was calculated. 50 The results of the orexin receptor agonist assay are shown in Table 2 below:

[0426] Table 1-1 Results of orexin receptor agonist assay

[0427] Table 1-2 Results of orexin receptor agonist assay

[0428] The enantiomers of compounds TAK-925 and TAK-32, as well as TAK-32, are described in Examples 5 and 32 of International Patent Document WO2017135306A1, respectively, and their structural formulas are shown below:

[0429] TAK-925 is:

[0430] The enantiomers of TAK-925 are: as well as

[0431] The TAK-32 is:

[0432] As can be seen from Tables 1-1 and 1-2, the compounds in the embodiments of the present invention have good agonistic activity against orexin receptor 2 (OX2R).

[0433] Test Example 2: Pharmacokinetic Test of Orexin Receptor 2 (OX2R)

[0434] Healthy SD rats were administered the test compound at a dose of 1.0 mg / kg (based on free bases) via tail vein injection. Whole blood samples (0.3 mL) were collected via the jugular vein before administration and at 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 7 h, and 10 h after administration. The whole blood samples were then centrifuged at 4000 rpm for 10 min to obtain plasma. The plasma concentrations of the target compound at different time points were detected using liquid chromatography-mass spectrometry (LC-MS / MS). The data were analyzed using WinNonlin 8.0 software, and pharmacokinetic parameters were calculated.

[0435] Table 2-1 Results of orexin receptor pharmacokinetic assay

[0436] As shown in Table 2-1, the compounds in the embodiments of the present invention exhibit a longer half-life. This characteristic enables them to better maintain effective blood drug concentrations during drug application, optimize the dosing regimen, and improve the overall therapeutic effect.

[0437] Test Example 3: Brain Transdermal Experiment of Orexin Receptor 2 (OX2R)

[0438] Healthy SD rats were administered the test compound at a dose of 1.0 mg / kg (based on free bases) via tail vein injection. Fifteen minutes after administration, a whole blood sample (0.3 mL) was collected via the rat's jugular vein. The whole blood sample was then centrifuged at 4000 rpm for 10 minutes to separate plasma. After anesthetizing the rats with isoflurane, the heart was exposed via thoracotomy. A perfusion needle was inserted into the apex of the heart, the right atrial appendage was cut open, and a sufficient volume of physiological saline was infused. The brain tissue was then dissected, blotted dry with filter paper, weighed, and homogenized with an appropriate amount of physiological saline (1:4, w:v) to prepare a brain tissue homogenate. The drug concentrations in plasma and brain tissue at different time points were measured using LC-MS / MS to determine the brain-blood ratio.

[0439] The compounds in the embodiments of the present invention exhibit considerable blood-brain barrier permeability. In animal experiments, they were able to cross the blood-brain barrier, enter brain tissue, and exert their effects, providing strong support for the treatment of central nervous system-related diseases.

[0440] Test Example 4: Evaluation of the effect of compounds on recovery time during isoflurane-induced anesthesia in rats by righting reflex.

[0441] Male Sprague-Dawley rats, 8 weeks old, were purchased from Sprague (Beijing). To induce and maintain isoflurane anesthesia, rats were placed in a pre-filled anesthesia induction chamber (4% isoflurane). Induction of anesthesia was defined as the rat's inability to right itself to a prone position after being placed in a supine position (loss of righting reflex: LORR). After confirming LORR, rats were exposed to 3% isoflurane inhalation using a face mask for 45 minutes. Isoflurane inhalation was terminated, and the compound was administered intravenously (IV) to the rats at a volume of 10 mL / kg body weight (BW). As a control, a 20% (w / v) distilled aqueous solution of hydroxypropyl betacyclodextrin (Xideli) was administered to the rats. The time from LORR recovery was recorded as the duration of anesthesia. Body temperature was maintained at 37.0–37.5°C using a heating pad during and after anesthesia.

[0442] Table 4-1 Experimental results of orexin receptor response to isoflurane-induced anesthesia recovery time

[0443] As shown in Table 4-1, the compounds in the embodiments of the present invention reduced the recovery time of isoflurane-induced anesthesia.

[0444] All publicly available texts, patents, patent applications, and published patent applications used in this document are incorporated herein by reference in their entirety. Although the invention has been described in detail by way of example for clarity of understanding, it will be apparent to those skilled in the art that certain changes and modifications can be made. Therefore, the descriptions and embodiments in this specification should not be construed as limiting the scope of protection of this invention.

Claims

1. A compound represented by Formula (I), or a stereoisomer thereof, a tautomer thereof, a pharmaceutically acceptable salt of the stereoisomer thereof, a pharmaceutically acceptable salt of the tautomer thereof, a solvate thereof, a prodrug thereof, or a deuterated derivative thereof, Formula (I) ​ wherein, Y 1 selected from the group consisting of absent, -C(R Y1A )2- -O-, -NR Y1B -, or -S-; R Y1A is independently selected at each occurrence from hydrogen, halogen, -C 1-3 alkyl, -C 2-3 alkenyl, -C 2-3 alkynyl, -C 1-3 haloalkyl, -O-C 1-3 haloalkyl, -(C 1-3 alkylene)-O-C 1-3 alkyl, -CN, -NO2, oxo, -NH2, -NH(C 1-6 alkyl), -N(C 1-6 alkyl)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), -C(=O)OH, -C(=O)(OC 1- 3alkyl), -OC(=O)(C 1-3 alkyl), -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), -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), 3-7 membered carbocyclyl, 3-7 membered heterocyclyl, phenyl, or 5-10 membered heteroaryl; optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, C1-6alkyl, C1-6alkoxy, and hydroxy; or two R Y1A together with the C atom to which they are both attached form an optionally substituted 3-7 membered cycloalkyl ring; n S1 S1 substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, C1-6alkyl, C1-6alkoxy, and hydroxy; or two R S1 is selected from 0, 1, 2, or 3;​ R Y1B is independently selected at each occurrence from hydrogen, -C 1-3 alkyl, -C(=O)(C 1-3 alkyl), -S(=O)(C 1-3 alkyl), -S(=O)2(C 1-3 alkyl), 3-7 membered carbocyclyl, 3-7 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl; wherein said R Y1B is optionally substituted with one or more substituents selected from halogen, -C 1-3 alkyl, CN, oxo, -NH2, -NH(C 1-3 alkyl), -N(C 1-3 alkyl)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), -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, 3-7 membered carbocyclyl, 3-7 membered heterocyclyl, phenyl, or 5-10 membered heteroaryl; n1 is selected from 0, 1, 2, or 3; n2 is selected from 0, 1, 2, or 3; and n1 + n2 < 4; R 3 -(C=O)R 3A , -(C=O)O-R 3H , or -(C=O)NR 3K R 3L ; Each R 3A Independently selected from -C 1-3 Alkyl, 3-10-membered carbocyclic, 3-10-membered heterocyclic, 6-10-membered aryl, or 5-10-membered heteroaryl; wherein R 3A Optionally, it is selected from one or more halogens, -C 1-3 Alkyl, -C 2-3 alkenyl, -C 2-3 Alkyne, -CN, oxo, -NH2, -NH(C) 1-3 alkyl), -N(C) 1- 3alkyl)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、-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 Substituents of alkyl, 3-7 membered carbon cyclo group, 3-7 membered heterocyclic group, phenyl or 5-10 membered heteroaryl group; Each R 3H Independently selected from hydrogen, -C 1-3 Alkyl, -C 1-3 Halogenated alkyl, 3-7 membered carbocyclic, 3-7 membered heterocyclic, phenyl, or 5-10 membered heteroaryl; wherein, the R 3H Optionally, it is selected from one or more halogens, -C 1-3 Alkyl, -C 2-6 alkenyl, -C 2-6 Alkyne, -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、-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 Substituents of alkyl, 3-7 membered carbon cyclo group, 3-7 membered heterocyclic group, phenyl or 5-10 membered heteroaryl group; Each (R) 3K Or R 3L Independently selected from hydrogen, -C 1-3 Alkyl, -C 2-3 alkenyl, -C 2-3 alkynyl group, -C 1-3 Halogenated alkyl groups, -NH2, -NH(C) 1-3 alkyl), -N(C) 1-3 Alkyl) 2, 3-10 membered carbocyclic, 3-10 membered heterocyclic, 6-10 membered aryl or 5-10 membered heteroaryl; the (R) 3K 、or R 3L )Optionally selected by one or more halogens, -C 1-3 Alkyl, -C 2-3 alkenyl, -C 2-3 Alkyne, -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、-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 Substituents of alkyl, 3-7 membered carbon cyclo group, 3-7 membered heterocyclic group, phenyl or 5-10 membered heteroaryl group; R 4 is independently at each occurrence selected from hydrogen, -C 1-3 alkyl, or -C 1-3 haloalkyl; R 5 selected from -C(=O)-R 51 , -S(=O)2R 53 , or -P(=O)R 54 (OR 55 ); R 51 independently at each occurrence selected from hydrogen, -C 1-3 alkyl, -C 1-3 haloalkyl, -NH2, -NH(C 1-3 alkyl), -N(C 1-3 alkyl)2, -OH, -O(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 cycloalkyl, 3-7 membered heterocyclyl, phenyl, or 5-10 membered heteroaryl; R 53 is independently at each occurrence selected from hydrogen, -C 1-3 alkyl, -C 1-3 haloalkyl, -NH2, -NH(C 1-3 alkyl), -N(C 1-3 alkyl)2, -OH, -O(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 cycloalkyl, 3-7 membered heterocyclyl, phenyl, or 5-10 membered heteroaryl; R 54 is independently at each occurrence selected from hydrogen, -C 1-3 alkyl, -C 1-3 haloalkyl, -OH, -O(C 1-3 alkyl), or 3-7 membered cycloalkyl; R 55 is independently at each occurrence selected from hydrogen, -C 1-3 alkyl, -C 1-3 haloalkyl, 3-7 membered cycloalkyl, 3-7 membered heterocyclyl, phenyl, or 5-10 membered heteroaryl; Y 2 is -0-, -S-, or -NR Y2B -; R Y2B is independently selected at each occurrence from hydrogen, -C 1-3 alkyl, -C(=O)(C 1-3 alkyl), -S(=O)(C 1-3 alkyl), -S(=O)2(C 1-3 alkyl), 3-7 membered carbocyclyl, 3-7 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl; wherein said R Y2B is optionally substituted with one or more substituents selected from halogen, -C 1-3 alkyl, CN, oxo, -NH2, -NH(C 1-3 alkyl), -N(C 1-3 alkyl)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), -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, 3-7 membered carbocyclyl, 3-7 membered heterocyclyl, phenyl, or 5-10 membered heteroaryl; R 2 is independently at each occurrence selected from hydrogen, halogen, -C 1-3 alkyl, or -C 1-3 haloalkyl; W is (R 4A , R 4B , or R 4C ) is independently selected at each occurrence from hydrogen, halogen, -C 1-4 alkyl, -C 1-3 haloalkyl, or phenyl; wherein each (R 4A , R 4B , or R 4C ) is independently optionally substituted by one or more substituents selected from halogen, -C 1-3 alkyl, -C 1-3 haloalkyl, -CN, oxo, -NH2, -NH(C 1-3 alkyl), -N(C 1-3 alkyl)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)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; Ring A is selected from a 3-10 membered carbocyclyl ring, a 3-10 membered heterocyclyl ring, a 6-10 membered aryl ring, or a 5-10 membered heteroaryl ring; X is selected from N or C-R 6 ; R 6 is independently selected at each occurrence from hydrogen, halogen, -C 1-3 alkyl, -C 2-3 alkenyl, -C 2-3 alkynyl, -C 1-3 haloalkyl, -CN, -NO2, oxo, -NH2, -NH(C 1-3 alkyl), -N(C 1-3 alkyl)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), -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- 3alkyl)2, -NHS(=O)(C 1-3 alkyl), -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), 3-7 membered carbocyclyl, 3-7 membered heterocyclyl, phenyl, or 5-10 membered heteroaryl; Y 3 selected from the group consisting of absent, -C(R Y3A )2- -O-, -NR Y3B -, or -S-; R Y3A independently at each occurrence selected from hydrogen, halogen, -C 1-3 alkyl, -C 2-3 alkenyl, -C 2-3 alkynyl, -C 1-3 alkoxy, -C 1-3 haloalkyl, -CN, -NO2, oxo, -NH2, -NH(C 1-3 alkyl), -N(C 1-3 alkyl)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), -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), -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), 3-7 membered carbocyclyl, 3-7 membered heterocyclyl, phenyl, or 5-10 membered heteroaryl; R Y3B is independently at each occurrence selected from hydrogen, -C 1-3 alkyl, -C(=O)(C 1-3 alkyl), -S(=O)(C 1-3 alkyl), -S(=O)2(C 1-3 alkyl), 3-7 membered carbocyclyl, 3-7 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl; wherein said R Y3B is optionally substituted with one or more substituents selected from halogen, -C 1-3 alkyl, CN, oxo, -NH2, -NH(C 1-3 alkyl), -N(C 1-3 alkyl)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), -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, 3-7 membered carbocyclyl, 3-7 membered heterocyclyl, phenyl, or 5-10 membered heteroaryl; n3 is selected from 0, 1, 2, 3, or 4; n4 is selected from 0, 1, 2, 3, or 4; n5 is selected from 0, 1, 2, 3, or 4; and n3 + n4 + n5 < 5; Each (R) S1 、or R S2 Independently selected from halogens, -C 1-6 Alkyl, -C 1-6 Haloalkyl, -C 2-6 alkenyl, -C 2-6 Alkyne, -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), -S(=O)(C 1- 6-alkyl), -S(=O)2(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), -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, 3-6 membered cycloalkyl, 3-6 membered heterocyclic, 6-10 membered aryl or 5-10 membered heteroaryl, wherein each (R S1 、or R S2 ) independently and optionally selected by 1, 2, 3, 4, 5 or 6 elements selected from halogen, -C 1-6 Alkyl, -C 1-6 Haloalkyl, -C 2-6 alkenyl, -C 2-6 Alkyne, -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), -S(=O)(C 1-6 Alkyl), -S(=O)2(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), -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(=0)H(C 1-6 alkyl), -P(=0)(C 1-6 alkyl)2, 3-6 membered cycloalkyl, 3-6 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl; n S2 is selected from 0, 1, 2, 3, 4, 5, or 6; each heterocyclyl independently at each occurrence contains 1, 2, 3, 4, or 5 heteroatoms selected from N, O, or S; each heteroaryl independently at each occurrence contains 1, 2, 3, 4, or 5 heteroatoms selected from N, O, or S.

2. The compound of formula (I) according to claim 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 formula (I) further has the structure shown in formula (VI): or a stereoisomer thereof, a tautomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of a stereoisomer thereof, a pharmaceutically acceptable salt of a tautomer thereof, a solvate thereof, a prodrug thereof, or a deuterated derivative thereof, wherein, R Y1A is independently at each occurrence selected from hydrogen, halogen, -C 1-3 alkyl, or -C 1-3 haloalkyl; optionally substituted with 1, 2, or 3 R Y1A with the C atom to which they are both attached to form a 3-7 membered cycloalkyl ring (cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl ring); each said R S1 is independently selected from the group consisting of halogen, -C S1 alkyl, -C 1-3 alkyl, -C 1-3 alkoxy, or -C 1-3 haloalkyl; n1 is selected from 0, 1, or 2; n2 is selected from 0, 1, or 2; and n1 + n2 < 4; R 3 -(C=O)R 3A , -(C=O)O-R 3H , or -(C=O)NR 3K R 3L ; Each R 3A Independently selected from -C 1-3 Alkyl, 3-7 membered cycloalkyl, 3-7 membered heterocyclic, phenyl, or 5-6 membered heteroaryl; wherein, the R 3A Optionally, it is selected from 1, 2, or 3 ions chosen from halogens, -C 1-3 Alkyl, -CN, -NH2, -NH(C) 1-3 alkyl), -N(C) 1-3 Alkyl group 2, -OH, -O(C) 1-3 Alkyl), -SH or -S(C 1-3 Substitution of alkyl groups; R 3H independently at each occurrence selected from -C 1-3 alkyl; R 3K , or R 3L is independently selected from hydrogen, -C 1-3 alkyl, -C 1-3 haloalkyl, -NH2, -NH(C 1-3 alkyl), -N(C 1-3 alkyl)2, 3-7 membered cycloalkyl, 3-7 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl; R 4 is independently at each occurrence selected from hydrogen, or -C 1-3 alkyl; R 53 is independently at each occurrence selected from hydrogen, -C 1-3 alkyl, -C 1-3 haloalkyl, -NH2, -NH(C 1-3 alkyl), -N(C 1-3 alkyl)2, -OH, -O(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 cycloalkyl, 3-7 membered heterocyclyl, phenyl, or 5-10 membered heteroaryl; R 2 is independently at each occurrence selected from hydrogen, halogen, -C 1-3 alkyl, or -C 1-3 haloalkyl; Y 2 is -0-, -S-, or -NR Y2B -; R Y2B independently at each occurrence selected from hydrogen, -C 1-3 alkyl, or -C 1-3 haloalkyl; R 6 is independently at each occurrence selected from hydrogen, halogen, -C 1-3 alkyl, or -C 1-3 haloalkyl; n3 is selected from 0, 1, or 2; n4 is selected from 0, 1, or 2; n5 is selected from 0, 1, or 2; and n3 + n4 + n5 < 5; R S2 independently at each occurrence selected from halogen, -CN, -C 1-3 alkyl, -O-C 1-3 alkyl, -C 1-3 haloalkyl, or -O-C 1-3 haloalkyl; n S2 is selected from 0, 1, 2, or 3; each heterocyclyl independently at each occurrence contains 1, 2, or 3 heteroatoms selected from N, O, or S; each heteroaryl independently at each occurrence contains 1, 2, or 3 heteroatoms selected from N, O, or S.

3. The compound of claim 1 or 2, or a stereoisomer thereof, a tautomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of a stereoisomer thereof, a pharmaceutically acceptable salt of a tautomer thereof, a solvate thereof, a prodrug thereof, or a deuterated derivative thereof, wherein: R 6 independently at each occurrence selected from hydrogen, halogen, -C 1-3 alkyl, or -C 1-3 haloalkyl; n3 is 1, n4 is 1, and n5 is 1; or n3 is 0, n4 is 1, and n5 is 1; or n3 is 1, n4 is 0, and n5 is 1.

4. The compound of any one of claims 1-3, or a stereoisomer thereof, a tautomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of a stereoisomer thereof, a pharmaceutically acceptable salt of a tautomer thereof, a solvate thereof, a prodrug thereof, or a deuterated derivative thereof, wherein: fragment selected from the group consisting of Preferably, the fragment selected from the group consisting of More preferably, the fragment selected from the group consisting of 5. The compound of any one of claims 1-4, or a stereoisomer thereof, a tautomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of a stereoisomer thereof, a pharmaceutically acceptable salt of a tautomer thereof, a solvate thereof, a prodrug thereof, or a deuterated derivative thereof, wherein: R S2 independently at each occurrence selected from halogen, -CN, -C 1-3 alkyl, -O-C 1-3 alkyl, -C 1-3 haloalkyl, or -O-C 1-3 haloalkyl; preferably, R S2 independently at each occurrence selected from halogen, -C 1-3 alkyl, -C 1-3 haloalkyl; n S2 is 0, 1, 2, or 3; R 6 is independently at each occurrence selected from hydrogen, halogen, -C 1-3 alkyl, or -C 1-3 haloalkyl; more preferably, R 6 is hydrogen; n3 is 1, n4 is 1, and n5 is 1; or n3 is 0, n4 is 1, and n5 is 1; or n3 is 1, n4 is 0, and n5 is 1.

6. The compound of any one of claims 1-5, or a stereoisomer thereof, a tautomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of a stereoisomer thereof, a pharmaceutically acceptable salt of a tautomer thereof, a solvate thereof, a prodrug thereof, or a deuterated derivative thereof, wherein: Preferably, the fragment selected from the group consisting of More preferably, the fragment selected from the group consisting of 7. The compound of any one of claims 1-6, or a stereoisomer thereof, a tautomer thereof, a pharmaceutically acceptable salt of a stereoisomer thereof, a pharmaceutically acceptable salt of a tautomer thereof, a solvate of any thereof, a prodrug of any thereof, or a deuterated derivative thereof, characterized in that, In the segment , n1 is selected from 0, 1, 2, or 3; n2 is selected from 0, 1, 2, or 3; and n1 + n2 < 4; R 3 -(C=O)R 3A , or -(C=O)O-R 3H ; Among them, each R 3A Independently selected from -C 1-3 Alkyl, 3-7 membered cycloalkyl, 3-7 membered heterocyclic; wherein, the R 3A Optionally, it is selected from 1, 2, or 3 ions chosen from halogens, -C 1-3 Alkyl, -CN, -NH2, -NH(C) 1-3 alkyl), -N(C) 1-3 Alkyl group 2, -OH, -O(C) 1-3 Alkyl), -SH or -S(C 1-3 Substitution of alkyl groups; R 3H independently at each occurrence selected from -C 1-3 alkyl; R 4 is independently at each occurrence selected from hydrogen, -C 1-3 alkyl, or -C 1-3 haloalkyl; preferably, R 4 is independently at each occurrence selected from hydrogen, or -C 1-3 alkyl; more preferably, R 4 is hydrogen; R 53 is independently at each occurrence selected from hydrogen, -C 1-3 alkyl, -C 1-3 haloalkyl, -NH2, -NH(C 1-3 alkyl), -N(C 1-3 alkyl)2, 3-7 membered cycloalkyl, or 3-7 membered heterocyclyl.

8. The compound of any one of claims 1-7, or a stereoisomer thereof, a tautomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of a stereoisomer thereof, a pharmaceutically acceptable salt of a tautomer thereof, a solvate thereof, a prodrug thereof, or a deuterated derivative thereof, characterized in that, R 3 each occurrence is selected from Preferably, R is independently at each occurrence selected from R 3 each occurrence is selected from R is preferably selected from the group consisting of 3 each occurrence is independently selected from the group consisting of 9. The compound of any one of claims 1-8, or a stereoisomer thereof, a tautomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of a stereoisomer thereof, a pharmaceutically acceptable salt of a tautomer thereof, a solvate thereof, a prodrug thereof, or a deuterated derivative thereof, characterized in that, n1 is 0, and n2 is 0; n1 is 1, and n2 is 0; n1 is 0, and n2 is 1; or n1 is 1, and n2 is 1.

10. The compound of any one of claims 1-9, or a stereoisomer thereof, a tautomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of a stereoisomer thereof, a pharmaceutically acceptable salt of a tautomer thereof, a solvate thereof, a prodrug thereof, or a deuterated derivative thereof, characterized in that, R 53 is independently selected from hydrogen, -C 1-3 alkyl, -C 1-3 haloalkyl, -NH2, -NH(C 1-3 alkyl), -N(C 1-3 alkyl)2, 3-7 membered cycloalkyl, 3-7 membered heterocyclyl, phenyl, or 5-10 membered heteroaryl; preferably, R 53 is independently selected from -C 1-3 alkyl, -C 1-3 haloalkyl, -NH2, -NH(C 1-3 alkyl), -N(C 1-3 alkyl)2, 3-7 membered cycloalkyl, or 3-7 membered heterocyclyl; more preferably, R 53 is independently selected from -C 1-3 alkyl, -C 1-3 haloalkyl, -NH2, -NH(C 1-3 alkyl), -N(C 1-3 alkyl)2, or 3-7 membered cycloalkyl.

11. The compound of any one of claims 1-10, or a stereoisomer thereof, a tautomer thereof, a pharmaceutically acceptable salt of a stereoisomer thereof, a pharmaceutically acceptable salt of a tautomer thereof, a solvate of any thereof, a prodrug of any thereof, or a deuterated derivative thereof, characterized in that, fragment selected from Preferably, the fragment selected from the group consisting of **Representative and Fragments the point of attachment of 12. The compound of any one of claims 1-11, or a stereoisomer thereof, a tautomer thereof, a pharmaceutically acceptable salt of a stereoisomer thereof, a pharmaceutically acceptable salt of a tautomer thereof, a solvate of any thereof, a prodrug of any thereof, or a deuterated derivative thereof, characterized in that, fragment selected from **Representative and Fragments the point of attachment of 13. The compound of formula (I) according to claim 1, its stereoisomers, its tautomers, its pharmaceutically acceptable salts, pharmaceutically acceptable salts of its stereoisomers, pharmaceutically acceptable salts of its tautomers, its solvates, its prodrugs, or its deuterated derivatives, wherein formula (I) further has the structure shown in formula (VII): or a stereoisomer thereof, a tautomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of a stereoisomer thereof, a pharmaceutically acceptable salt of a tautomer thereof, a solvate thereof, a prodrug thereof, or a deuterated derivative thereof, wherein: R 3 -(C=O)R 3A , -(C=O)O-R 3H , or -(C=O)NR 3K R 3L ; each R is independently selected from -C 3A alkyl, 3-7 membered cycloalkyl, 3-7 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl; wherein said R 1-3 is optionally substituted with 1, 2, or 3 substituents selected from halogen, -C 3A alkyl, -CN, -NH2, -NH(C 1-3 alkyl), -N(C 1-3 alkyl)2, -OH, -O(C 1-3 alkyl), -SH, or -S(C 1-3 alkyl); and 1-3 each R is independently selected from -C R 3H independently at each occurrence selected from -C 1-3 alkyl; R 3K , or R 3L is independently selected from hydrogen, -C 1-3 alkyl, -C 1-3 haloalkyl, -NH2, -NH(C 1-3 alkyl), -N(C 1-3 alkyl)2, 3-7 membered cycloalkyl, 3-7 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl; R 53 independently at each occurrence selected from hydrogen, -C 1-3 alkyl, -C 1-3 haloalkyl, -NH2, -NH(C 1-3 alkyl), -N(C 1-3 alkyl)2, -OH, -O(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 cycloalkyl, 3-7 membered heterocyclyl, phenyl, or 5-10 membered heteroaryl; R 6 independently at each occurrence selected from hydrogen, halogen, -C 1-3 alkyl, or -C 1-3 haloalkyl; R S2 independently at each occurrence selected from halogen, -CN, -C 1-3 alkyl, -O-C 1-3 alkyl, -C 1-3 haloalkyl, or -O-C 1-3 haloalkyl; n S2 is selected from 0, 1, 2, or 3.

14. The compound of any one of claim 13, or a stereoisomer thereof, a tautomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of a stereoisomer thereof, a pharmaceutically acceptable salt of a tautomer thereof, a solvate thereof, a prodrug thereof, or a deuterated derivative thereof, characterized in that, R 3 -(C=O)R 3A , or -(C=O)O-R 3H ; Each R 3A Independently selected from -C 1-3 Alkyl, 3-7 membered cycloalkyl, 3-7 membered heterocyclic, phenyl, or 5-6 membered heteroaryl; wherein, the R 3A Optionally, it is selected from 1, 2, or 3 ions chosen from halogens, -C 1-3 Alkyl, -CN, -NH2, -NH(C) 1-3 alkyl), -N(C) 1-3 Alkyl group 2, -OH, -O(C) 1-3 Alkyl), -SH or -S(C 1-3 Substitution of alkyl groups; R 3H independently at each occurrence selected from -C 1-3 alkyl.

15. The compound according to any one of claims 13 and 14, wherein the compound represented by formula (VII) is a compound represented by any one of formulas (VII-1) to (VII-8):

16. The compound of claim 1, or a stereoisomer thereof, a tautomer thereof, a pharmaceutically acceptable salt of a stereoisomer thereof, a pharmaceutically acceptable salt of a tautomer thereof, a solvate of any thereof, a prodrug of any thereof, or a deuterated derivative thereof, characterized in that, The compound of Formula (I) is a compound of any one of Formula (III-1) to Formula (III-3): wherein R S2 , n S2 , R 6 , n3, n4, n5, R 2 , R 3 , R 3A , R 3H , R 4 , R 53 , n1, n2, and R Y1A are as defined in formula (I).

17. The compound of claim 16, or a stereoisomer thereof, a tautomer thereof, a pharmaceutically acceptable salt of a stereoisomer thereof, a pharmaceutically acceptable salt of a tautomer thereof, a solvate thereof, a prodrug thereof, or a deuterated derivative thereof, characterized in that, The compound of Formula (I) is a compound of any one of Formula (III-1A) to Formula (III-3H): wherein R S2 , n S2 , R 6 , n3, n4, n5, R 2 , R 3 , R 3A , R 3H , R 4 , R 53 , n1, n2, and R Y1A are as defined in any one of claims 1-20.

18. A compound of Formula (I), or a stereoisomer thereof, a tautomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of a stereoisomer thereof, a pharmaceutically acceptable salt of a tautomer thereof, a solvate thereof, a prodrug thereof, or a deuterated derivative thereof, selected from any one of the compounds of Formulae shown in Table 1 of the specification.

19. A pharmaceutical composition comprising a therapeutically effective amount of a compound of any one of claims 1-18, or a stereoisomer thereof, a tautomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of a stereoisomer thereof, a pharmaceutically acceptable salt of a tautomer thereof, a solvate thereof, a prodrug thereof, or a deuterated derivative thereof, and one or more pharmaceutically acceptable carriers or excipients.

20. Use of a compound of formula (I), stereoisomers thereof, tautomers thereof, pharmaceutically acceptable salts of the compound of formula (I), stereoisomers thereof, pharmaceutically acceptable salts of the stereoisomers thereof, tautomers thereof, pharmaceutically acceptable salts of the tautomers thereof, solvates thereof, prodrugs thereof, or deuterated derivatives thereof according to any one of claims 1-18; or a pharmaceutical composition according to claim 19 in the manufacture of a medicament for the prevention / treatment of a disease associated with the agonism of orexin receptor 2 (OX2R); preferably, the disease associated with the agonism of orexin receptor 2 (OX2R) is a sleep disorder, a postoperative recovery related disease; more preferably, the sleep disorder, the postoperative recovery related disease is selected from the group consisting of narcolepsy, hypersomnia, sleep apnea, improvement of anesthesia recovery or respiratory depression.

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