Orexin receptor modulator, and preparation method therefor and use thereof

Abstract

Disclosed in the present invention are an orexin receptor modulator, and a preparation method therefor and the use thereof, and specifically disclosed is an orexin receptor antagonist as shown in the following formula. The orexin receptor antagonist provided by the present invention can be used for treating diseases related to the nervous system.

Description

Orexin receptor modulator and its preparation method and use

[0001] This application claims the benefit of Chinese patent application No. 2024101188562, filed on January 29, 2024. This application incorporates the entirety of the aforementioned Chinese patent application. Technical Field

[0002] This patent application relates to the field of medicine, and relates to orexin receptor modulators, their preparation methods and their applications in medicine. Background Art

[0003] Orexin, also known as hypocretin or appetite peptide, includes orexin A and orexin B (or hypocretin-1 and hypocretin-2). It is a neuropeptide secreted by the hypothalamus. Its main physiological effects are: 1. Regulating food intake. Orexin can activate neurons that regulate food intake, significantly promoting food intake, and has a dose-dependent response; 2. Participating in the regulation of energy metabolism. Orexin can significantly increase the metabolic rate; 3. Participating in the regulation of sleep-wakefulness. Orexin can inhibit rapid eye movement sleep and prolong wakefulness. Blocking the effect of orexin can promote sleep; 4. Participating in endocrine regulation. Orexin has a significant effect on pituitary hormone endocrine secretion; 5. Related to the sense of reward, learning and memory; 6. Promoting gastric acid secretion; 7. Promoting increased water intake; 8. Raising blood pressure; 9. Playing an important role in the reward system and drug addiction mechanism, etc.

[0004] Orexins produce their physiological effects by acting on orexin receptors (OXRs). Orexin receptors are G-protein-coupled receptors of two types, OX1 and OX2. OX1 receptors selectively bind orexin A, while OX2 receptors can bind both orexin A and orexin B. OX1 and OX2 receptors are found almost exclusively in brain tissue and are selectively expressed. OX1 receptors are expressed at high densities in the locus coeruleus (locus coeruleus), the originating nucleus of noradrenergic neurons, while OX2 receptors are expressed at high densities in the tuberomammillary nucleus, the originating nucleus of histaminergic neurons. Both OX1 and OX2 receptors are expressed in the raphe nucleus, the originating nucleus of serotonergic neurons, and in the ventral tegmental area, the originating nucleus of dopaminergic neurons.

[0005] It can be seen that orexin receptors are of great significance in pathology and are involved in a variety of diseases, such as sleep disorders, depression, anxiety disorders, panic disorders, obsessive-compulsive disorders, affective neurosis, depressive neurosis, anxiety neurosis, mood disorders, panic attack disorders, behavioral disorders, mood disorders, post-traumatic stress disorder, sexual dysfunction, psychosis, schizophrenia, manic depression, mental disorders, dementia, drug dependence, addiction, cognitive impairment, Alzheimer's disease, Parkinson's disease, movement disorders, eating disorders, headaches, migraines, pain, digestive system diseases, epilepsy, inflammation, cardiovascular disease, diabetes, metabolic diseases, immune-related diseases, endocrine-related diseases and hypertension.

[0006] Currently, there are many drugs in the clinical stage or on the market, such as Merck's Suvoraxant, Eisai's Lemborexant, etc. Seltorexant developed by Johnson & Johnson is in the clinical stage. Summary of the Invention

[0007] The present invention provides a class of orexin receptor antagonists, and it is found that compounds with this type of structure exhibit good activity, selectivity, brain exposure, brain-blood ratio (the ratio of drug concentration in the brain to drug concentration in plasma, abbreviated as B / P), few toxic and side effects, and long half-life.

[0008] The present invention relates to a compound of the following formula, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein the compound structure is as follows:

[0009] Ra, Rb, and Rc are each independently selected from H, deuterium, halogen, amino, nitro, mercapto, cyano, carboxyl, C1-6 alkyl, C1-6 haloalkyl, C1-6 deuterated alkyl, C1-6 hydroxyalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkoxy, C3-8 cycloalkyl, C3-8 heterocyclyl, C5-10 aryl, C5-10 heteroaryl, and the C3-8 cycloalkyl, C3-8 heterocyclyl, C5-10 aryl, and C5-10 heteroaryl are optionally substituted with deuterium, halogen, amino, nitro, mercapto, cyano, carboxyl, C1-6 alkyl, C1-6 haloalkyl, C1-6 deuterated alkyl, C1-6 hydroxyalkyl, C1-6 alkoxy, C1-6 haloalkoxy, and C1-6 hydroxyalkoxy;

[0010] R4 is selected from H, deuterium, halogen, hydroxyl, amino, nitro, sulfhydryl, cyano, carboxyl, C1-6 alkyl, C1-6 haloalkyl, C1-6 deuterated alkyl, C1-6 hydroxyalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkoxy, C3-8 cycloalkyl, C3-8 heterocyclyl, C6-10 aryl and C5-10 heteroaryl, wherein the C3-8 cycloalkyl, C3-8 heterocyclyl, C6-10 aryl and C5-10 heteroaryl are optionally substituted with deuterium, halogen, amino, nitro, sulfhydryl, cyano, carboxyl, C1-6 alkyl, C1-6 haloalkyl, C1-6 deuterated alkyl, C1-6 hydroxyalkyl, C1-6 alkoxy, C1-6 haloalkoxy and C1-6 hydroxyalkoxy;

[0011] R5-R 12 、R e 、R d Each is independently selected from hydrogen, deuterium, halogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 deuterated alkyl;

[0012] X1 and X2 are independently selected from CH or N;

[0013] The heteroatoms in the C3-8 heterocyclic group and the C5-10 heteroaryl group are one, two or three of N, O and S, and the number of heteroatoms is 1, 2 or 3.

[0014] In some embodiments, the compound has the following structure:

[0015] Ra, Rb, and Rc are each independently selected from H, deuterium, halogen, amino, nitro, mercapto, cyano, carboxyl, C1-6 alkyl, C1-6 haloalkyl, C1-6 deuterated alkyl, C1-6 hydroxyalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkoxy, C3-8 cycloalkyl, C3-8 heterocyclyl, C5-10 aryl, C5-10 heteroaryl, and the C3-8 cycloalkyl, C3-8 heterocyclyl, C5-10 aryl, and C5-10 heteroaryl are optionally substituted with deuterium, halogen, amino, nitro, mercapto, cyano, carboxyl, C1-6 alkyl, C1-6 haloalkyl, C1-6 deuterated alkyl, C1-6 hydroxyalkyl, C1-6 alkoxy, C1-6 haloalkoxy, and C1-6 hydroxyalkoxy;

[0016] R4 is selected from H, deuterium, halogen, hydroxyl, amino, nitro, sulfhydryl, cyano, carboxyl, C1-6 alkyl, C1-6 haloalkyl, C1-6 deuterated alkyl, C1-6 hydroxyalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkoxy, C3-8 cycloalkyl, C3-8 heterocyclyl, wherein the C3-8 cycloalkyl and C3-8 heterocyclyl are optionally substituted with deuterium, halogen, amino, nitro, sulfhydryl, cyano, carboxyl, C1-6 alkyl, C1-6 haloalkyl, C1-6 deuterated alkyl, C1-6 hydroxyalkyl, C1-6 alkoxy, C1-6 haloalkoxy and C1-6 hydroxyalkoxy;

[0017] R5-R 12 、R e 、R d Each is independently selected from hydrogen, deuterium, halogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 deuterated alkyl;

[0018] X1 and X2 are selected from C or N.

[0019] In some embodiments, the compounds of the present invention have a structure as shown in Formula Ia or Ib:

[0020] R1, R2 and R3 are each independently selected from H, deuterium, halogen, amino, nitro, sulfhydryl, cyano, carboxyl, C1-6 alkyl, C1-6 haloalkyl, C1-6 deuterated alkyl, C1-6 hydroxyalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkoxy, C3-8 cycloalkyl, C3-8 heterocyclyl, C5-10 aryl, C5-10 heteroaryl, said C3-8 cycloalkyl, C3-8 heterocyclyl, C5-10 aryl, C5-10 heteroaryl optionally substituted with deuterium, halogen, amino, nitro, sulfhydryl, cyano, carboxyl, C1-6 alkyl, C1-6 haloalkyl, C1-6 deuterated alkyl, C1-6 hydroxyalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkoxy;

[0021] The other substituents are as defined above.

[0022] In some embodiments, the compounds of the present invention have a structure as shown in Formula IIIa or IIIb:

[0023] R1, R2 and R3 are each independently selected from H, deuterium, halogen, amino, nitro, sulfhydryl, cyano, carboxyl, C1-6 alkyl, C1-6 haloalkyl, C1-6 deuterated alkyl, C1-6 hydroxyalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkoxy, C3-8 cycloalkyl, C3-8 heterocyclyl, C5-10 aryl, C5-10 heteroaryl, said C3-8 cycloalkyl, C3-8 heterocyclyl, C5-10 aryl, C5-10 heteroaryl optionally substituted with deuterium, halogen, amino, nitro, sulfhydryl, cyano, carboxyl, C1-6 alkyl, C1-6 haloalkyl, C1-6 deuterated alkyl, C1-6 hydroxyalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkoxy;

[0024] The other substituents are as defined above.

[0025] In other embodiments, the compounds of the present invention have a structure as shown in Formula IIa or IIb:

[0026] Here, the substituents are as defined above.

[0027] In some embodiments, in the compounds described herein, their stereoisomers, or pharmaceutically acceptable salts thereof, R1, R2, and R3 are each independently selected from H, deuterium, halogen, amino, nitro, thiol, cyano, carboxyl, C1-6 alkyl, C1-6 haloalkyl, C1-6 deuterated alkyl, C1-6 hydroxyalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkoxy, and C3-8 cycloalkyl.

[0028] In some embodiments, in the compounds of the present invention, their stereoisomers or pharmaceutically acceptable salts thereof, R1, R2, and R3 are independently selected from C1-3 alkyl, C1-3 haloalkyl, C1-3 deuterated alkyl, C1-3 hydroxyalkyl, C1-3 alkoxy, C1-3 haloalkoxy, C1-3 hydroxyalkoxy, and C3-8 cycloalkyl.

[0029] In some embodiments, in the compounds described herein, their stereoisomers, or pharmaceutically acceptable salts thereof, R1 and R3 are independently selected from C1-3 alkyl, C1-3 deuterated alkyl, C1-3 haloalkyl, C1-3 hydroxyalkyl, C1-3 alkoxy, C1-3 haloalkoxy, and R2 is hydrogen.

[0030] In some embodiments, in the compounds of the present invention, their stereoisomers, or pharmaceutically acceptable salts thereof, R1 and R3 are independently selected from methyl, deuterated methyl, and hydroxymethyl, and R2 is hydrogen.

[0031] In some embodiments, in the compounds described herein, their stereoisomers, or pharmaceutically acceptable salts thereof, R1, R2, and R3 are each independently selected from H, deuterium, halogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 deuterated alkyl, C1-6 hydroxyalkyl, C1-6 alkoxy, C1-6 haloalkoxy, and C1-6 hydroxyalkoxy.

[0032] In some embodiments, in the compounds of the present invention, their stereoisomers or pharmaceutically acceptable salts thereof, R4 is selected from halogen, hydroxy, C1-3 alkyl, C1-3 haloalkyl, C1-3 deuterated alkyl, C1-3 hydroxyalkyl, C1-3 alkoxy, C1-3 haloalkoxy, C1-3 hydroxyalkoxy, C3-8 cycloalkyl, and the C3-8 cycloalkyl is optionally substituted with deuterium, halogen, or C1-3 alkyl.

[0033] In some embodiments, in the compound of the present invention, its stereoisomer or pharmaceutically acceptable salt thereof, R4 is selected from fluorine, trifluoromethyl, cyclopropyl, and the cyclopropyl is optionally substituted with halogen or methyl.

[0034] In some embodiments, in the compounds described herein, their stereoisomers, or pharmaceutically acceptable salts thereof, R5-R 12 are each independently selected from hydrogen, deuterium or methyl.

[0035] In some embodiments, in the compounds described herein, their stereoisomers, or pharmaceutically acceptable salts thereof, R4 is hydrogen.

[0036] In some embodiments, in the compounds described herein, stereoisomers thereof, or pharmaceutically acceptable salts thereof, R1 and R3 are each independently selected from hydrogen, C1-6 alkyl, C1-6 deuterated alkyl, and C1-6 hydroxyalkyl.

[0037] In some embodiments, in the compound described herein, its stereoisomers, or pharmaceutically acceptable salts thereof, R4 is H, C1-6 haloalkyl, or C3-8 cycloalkyl.

[0038] In some embodiments, in the compounds described herein, their stereoisomers, or pharmaceutically acceptable salts thereof, R4 is H, trifluoromethyl, or cyclopropyl.

[0039] In some embodiments, in the compounds described herein, stereoisomers thereof, or pharmaceutically acceptable salts thereof, R1 and R3 are each independently selected from hydrogen, C1-3 alkyl, and C1-3 deuterated alkyl.

[0040] In some embodiments, in the compounds described herein, their stereoisomers, or pharmaceutically acceptable salts thereof, R2 is hydrogen or halogen.

[0041] In some embodiments, in the compounds described herein, their stereoisomers, or pharmaceutically acceptable salts thereof, R4 is hydrogen, C1-3 alkyl, or C1-3 haloalkyl.

[0042] In some embodiments, in the compounds described herein, their stereoisomers, or pharmaceutically acceptable salts thereof, R5-R 12 are each independently hydrogen.

[0043] In some embodiments, in the compounds described herein, stereoisomers thereof, or pharmaceutically acceptable salts thereof, R1 and R3 are each independently selected from C1-3 alkyl and C1-3 deuterated alkyl.

[0044] In some embodiments, in the compounds described herein, stereoisomers thereof, or pharmaceutically acceptable salts thereof, R1 and R3 are independently C1-3 deuterated alkyl.

[0045] In some embodiments, in the compounds described herein, their stereoisomers, or pharmaceutically acceptable salts thereof, R4 is hydrogen or C1-3 haloalkyl.

[0046] In some embodiments, in the compounds described herein, stereoisomers thereof, or pharmaceutically acceptable salts thereof, R1 and R3 are each independently selected from hydrogen, methyl, and deuterated methyl.

[0047] In some embodiments, in the compounds described herein, their stereoisomers, or pharmaceutically acceptable salts thereof, R1 and R3 are independently methyl or deuterated methyl.

[0048] In some embodiments, in the compounds described herein, their stereoisomers, or pharmaceutically acceptable salts thereof, R1 and R3 are deuterated methyl.

[0049] In some embodiments, in the compounds described herein, their stereoisomers, or pharmaceutically acceptable salts thereof, R1 and R3 are independently H, -CH3, -CHD2, -CH2D, or -CD3.

[0050] In some embodiments, in the compounds described herein, their stereoisomers, or pharmaceutically acceptable salts thereof, R1 and R3 are independently H, -CH3, or -CD3.

[0051] In some embodiments, in the compounds described herein, stereoisomers thereof, or pharmaceutically acceptable salts thereof, R1 and R3 are -CD3.

[0052] In some embodiments, in the compounds described herein, their stereoisomers, or pharmaceutically acceptable salts thereof, R1 and R3 are independently -CH3 or -CD3.

[0053] In some embodiments, in the compounds described herein, their stereoisomers, or pharmaceutically acceptable salts thereof, R4 is hydrogen or trifluoromethyl.

[0054] In some embodiments, in the compounds described herein, their stereoisomers, or pharmaceutically acceptable salts thereof, R2 is hydrogen or fluoro.

[0055] In some embodiments, in the compounds described herein, their stereoisomers, or pharmaceutically acceptable salts thereof, R2 is hydrogen.

[0056] In some embodiments, in the compounds described herein, stereoisomers thereof, or pharmaceutically acceptable salts thereof, R1 and R3 are independently C1-3 alkyl, R2 is halogen, and R4 is hydrogen.

[0057] In some embodiments, in the compounds described herein, their stereoisomers, or pharmaceutically acceptable salts thereof, R1 and R3 are methyl.

[0058] In some embodiments, in the compounds described herein, their stereoisomers, or pharmaceutically acceptable salts thereof, R2 is fluoro.

[0059] In some embodiments, in the compounds of the present invention, their stereoisomers, or pharmaceutically acceptable salts thereof, R4 is H, -F, -CF3,

[0060] In some embodiments, in the compounds described herein, their stereoisomers, or pharmaceutically acceptable salts thereof, R c For H, -F, -Cl, -CH3, -CH2CH3, -CD3, -CF3, Or -OCH3.

[0061] In some embodiments, in the compounds of the present invention, their stereoisomers, or pharmaceutically acceptable salts thereof, R1 is H, -CH3, -CH2CH3, -CD3, -CF3,

[0062] In some embodiments, in the compounds described herein, their stereoisomers, or pharmaceutically acceptable salts thereof, R2 is H, -Cl, -F, -CF3, or -OCH3.

[0063] In some embodiments, in the compounds of the present invention, their stereoisomers, or pharmaceutically acceptable salts thereof, R3 is H, -CH3, -CD3, or

[0064] In another aspect, the present invention provides a compound having the structure described below, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0065] In another aspect, the present invention provides a pharmaceutical composition comprising the above-mentioned compound, its stereoisomers or pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable carriers or excipients.

[0066] In another aspect, the present invention provides use of the above-mentioned compound, its stereoisomer or pharmaceutically acceptable salt, or the above-mentioned pharmaceutical composition in the preparation of an orexin receptor antagonist; preferably, use in the preparation of an OX2 receptor antagonist.

[0067] On the other hand, the present invention provides the use of the above-mentioned compound, its stereoisomer or pharmaceutically acceptable salt, or the above-mentioned pharmaceutical composition in the preparation of a drug for treating nervous system diseases; the nervous system diseases are preferably insomnia, depression or anxiety, drug addiction, and more preferably major depressive disorder, primary and secondary insomnia, or depression accompanied by insomnia.

[0068] In another aspect, the present invention provides use of the above-mentioned compound, its stereoisomer or pharmaceutically acceptable salt, or the above-mentioned pharmaceutical composition in the preparation of a drug for treating orexin receptor-related diseases; the disease is preferably a nervous system disease.

[0069] In some embodiments, the neurological disease is insomnia, depression or anxiety, drug addiction, preferably major depressive disorder, primary and secondary insomnia, or depression associated with insomnia.

[0070] In another aspect, the present invention provides a method for preparing a compound of formula I, comprising the following steps:

[0071] It further comprises the steps of:

[0072] It further comprises the steps of:

[0073] Alternatively, the present invention provides an intermediate of the following structure:

[0074] Wherein, each substituent is as defined above.

[0075] In another aspect, the present invention provides a method for preparing a compound of formula II, comprising the following steps:

[0076] It further comprises the steps of:

[0077] It further comprises the steps of:

[0078] Alternatively, the present invention provides the following intermediate:

[0079] Wherein, each substituent is as defined above.

[0080] Terminology

[0081] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0082] In the present invention, an alkyl group refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 8 carbon atoms, more preferably an alkyl group containing 1 to 6 carbon atoms, and most preferably an alkyl group containing 1 to 3 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2, 3-Dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched-chain isomers thereof.

[0083] More preferred are lower alkyl groups containing 1 to 6 carbon atoms, non-limiting examples of which include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, and the like.

[0084] The alkyl group may be substituted or unsubstituted. When substituted, the substituent may be substituted at any available point of attachment. The substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate groups. Methyl, ethyl, isopropyl, tert-butyl, haloalkyl, deuterated alkyl, alkoxy-substituted alkyl and hydroxy-substituted alkyl are preferred in the present invention; the hydroxy-substituted alkyl may be 2-hydroxyisopropyl or 1-hydroxyethyl.

[0085] In the present invention, the cycloalkyl group refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent, and the cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, more preferably 3 to 8 carbon atoms, and further preferably 3 to 6 carbon atoms.

[0086] Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like; and polycyclic cycloalkyls include spirocycloalkyls, fused cycloalkyls, and bridged cycloalkyls.

[0087] In the present invention, spiroalkyl refers to a polycyclic group that shares a carbon atom (called spiro atom) between 5 to 20 monocycles, which may contain one or more double bonds, but no ring has a completely conjugated π electron system. Preferably, it is 6 to 14 members, more preferably 7 to 10 members. According to the number of shared spiro atoms between rings, spiroalkyl is divided into single spiroalkyl, double spiroalkyl or multiple spiroalkyl, preferably single spiroalkyl and double spiroalkyl. More preferably, it is 4 / 4 members, 4 / 5 members, 4 / 6 members, 5 / 5 members or 5 / 6 members of single spiroalkyl. Non-limiting examples of spiroalkyl include:

[0088] It also includes spirocycloalkyl groups that share a spiro atom with a heterocycloalkyl group. Non-limiting examples include:

[0089] In the present invention, fused cycloalkyl refers to a 5 to 20-membered, all-carbon polycyclic group in which each ring in the system shares a pair of adjacent carbon atoms with other rings in the system, wherein one or more rings may contain one or more double bonds, but no ring has a completely conjugated π electron system. Preferably, it is 6 to 14 members, more preferably 7 to 10 members. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl, preferably bicyclic or tricyclic, more preferably 5-membered / 5-membered or 5-membered / 6-membered bicyclic alkyl. Non-limiting examples of fused cycloalkyl include:

[0090] In the present invention, a bridged cycloalkyl group refers to a 5-20 membered, all-carbon polycyclic group in which any two rings share two carbon atoms that are not directly connected, which may contain one or more double bonds, but no ring has a completely conjugated π electron system. Preferably, it is 6-14 members, more preferably 7-10 members. Depending on the number of constituent rings, it can be classified as a bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl group, preferably a bicyclic, tricyclic or tetracyclic group, more preferably a bicyclic or tricyclic group. Non-limiting examples of bridged cycloalkyl groups include:

[0091] The cycloalkyl ring may be fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring attached to the parent structure is a cycloalkyl, non-limiting examples of which include indanyl, tetrahydronaphthyl, benzocycloheptanyl, etc. The cycloalkyl group may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate.

[0092] In the present invention, heterocyclic group refers to a saturated or partially unsaturated monocyclic or polycyclic heterocyclic group containing 3 to 20 ring atoms, wherein one or more ring atoms are selected from nitrogen, oxygen or S(O) m(wherein m is an integer from 0 to 2) heteroatoms, but excluding the ring portion of -OO-, -OS- or -SS-, the remaining ring atoms are carbon. Preferably, it contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably, it contains 3 to 10 ring atoms; and further preferably, it contains 3 to 8 ring atoms. Non-limiting examples of monocyclic heterocyclic groups include pyrrolidinyl, pyrrolidonyl, piperidin-2-onyl, 3,4-dihydropyridin-2(1H)-onyl, 4,5-dihydropyridazin-3(2H)-onyl, azetidinyl, oxetanyl, oxanyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, etc.; preferably pyrrolidyl, pyrrolidonyl, piperidin-2-one, 3,4-dihydropyridin-2 (1H) -one, 4,5-dihydropyridazine-3 (2H) -one, azetidinyl, oxetanyl, dihydropyrrolyl, tetrahydrofuranyl, pyrazolidinyl, morpholinyl, Piperazinyl and pyranyl; more preferably dihydropyrrolyl, pyrrolidinyl, pyrrolidonyl, piperidin-2-onyl, 3,4-dihydropyridin-2 (1H) -onyl, 4,5-dihydropyridazin-3 (2H) -onyl, azetidinyl, oxetanyl, oxanyl, morpholinyl, piperidinyl, piperazinyl,

[0093] Pyranyl. Polycyclic heterocyclic groups include spirocyclic, fused-ring, and bridged heterocyclic groups; wherein the spirocyclic, fused-ring, and bridged heterocyclic groups are optionally connected to other groups through single bonds, or further connected to other cycloalkyl, heterocyclic, aryl, and heteroaryl groups through any two or more atoms on the ring.

[0094] In the present invention, spiro heterocyclic group refers to a polycyclic heterocyclic group in which 5 to 20-membered monocyclic rings share one atom (called spiro atom), wherein one or more ring atoms are selected from nitrogen, oxygen or S(O) m (wherein m is an integer 0 to 2) heteroatom, and the remaining ring atoms are carbon. It may contain one or more double bonds, but no ring has a completely conjugated π electron system. It is preferably 6 to 14 members, more preferably 7 to 10 members. According to the number of shared spiral atoms between the rings, the spiro heterocyclic group is divided into a monospiro heterocyclic group, a dispiro heterocyclic group or a polyspiro heterocyclic group, preferably a monospiro heterocyclic group and a dispiro heterocyclic group. It is more preferably 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan or 5 yuan / 6 yuan monospiro heterocyclic group. Non-limiting examples of spiro heterocyclic groups include:

[0095] In the present invention, a fused heterocyclic group refers to a polycyclic heterocyclic group of 5 to 20 members, wherein each ring in the system shares a pair of adjacent atoms with other rings in the system, one or more rings may contain one or more double bonds, but no ring has a completely conjugated π electron system, wherein one or more ring atoms are selected from nitrogen, oxygen or S(O) m (wherein m is an integer from 0 to 2) heteroatoms, the remaining ring atoms being carbon. Preferably, it is 6 to 14 members, more preferably 7 to 10 members. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups, preferably bicyclic or tricyclic, more preferably 5-membered / 5-membered or 5-membered / 6-membered bicyclic fused heterocyclic groups. Non-limiting examples of fused heterocyclic groups include:

[0096] In the present invention, a bridged heterocyclic group refers to a polycyclic heterocyclic group of 5 to 14 members, wherein any two rings share two atoms that are not directly connected, which may contain one or more double bonds, but no ring has a completely conjugated π electron system, wherein one or more ring atoms are selected from nitrogen, oxygen or S(O) m (wherein m is an integer from 0 to 2) heteroatoms, the remaining ring atoms being carbon. Preferably, it is 6 to 14 members, more preferably 7 to 10 members. Depending on the number of constituent rings, it can be classified as a bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic group, preferably a bicyclic, tricyclic or tetracyclic group, more preferably a bicyclic or tricyclic group. Non-limiting examples of bridged heterocyclic groups include:

[0097] The heterocyclyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring attached to the parent structure is a heterocyclyl, non-limiting examples of which include:

[0098] The heterocyclyl group may be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate.

[0099] In the present invention, aryl refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (i.e., rings sharing adjacent pairs of carbon atoms) group having a conjugated π electron system, preferably 6- to 10-membered, more preferably 6- to 8-membered, such as phenyl and naphthyl, preferably phenyl. The aryl ring may be fused to a heteroaryl, heterocyclyl, or cycloalkyl ring, wherein the ring connected to the parent structure is the aryl ring, non-limiting examples of which include:

[0100] The aryl group may be substituted or unsubstituted. When substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

[0101] In the present invention, heteroaryl refers to a heteroaromatic system comprising 1 to 4 heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. Heteroaryl is preferably 5 to 10 yuan, more preferably 5 to 8 yuan, most preferably 5 yuan or 6 yuan, such as pyrazinyl, pyridazinyl, imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, isoxazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, oxadiazole, pyrazinyl etc., preferably pyrimidinyl, pyrazolyl, oxazolyl, isoxazolyl, oxadiazole, pyridine. The heteroaryl ring can be fused on an aryl, heterocyclic or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring, and its non-limiting examples include:

[0102] The heteroaryl group may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

[0103] In the present invention, alkoxy refers to -O-(alkyl) and -O-(unsubstituted cycloalkyl), wherein the definition of alkyl is as described above, preferably an alkyl group containing 1 to 8 carbon atoms, more preferably an alkyl group containing 1 to 6 carbon atoms, and most preferably an alkyl group containing 1 to 3 carbon atoms. Non-limiting examples of alkoxy include: methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy. Alkoxy may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate;

[0104] Non-limiting examples of alkoxy also include propan-2-oxy and the like.

[0105] In the present invention, haloalkyl refers to an alkyl group substituted by one or more halogens, wherein alkyl is as defined above. Non-limiting examples of haloalkyl include: trifluoromethyl, trifluoroethyl;

[0106] Non-limiting examples of haloalkyl also include difluoromethyl, 1,1,2,2-tetrafluoroethyl, perfluoroethyl, and the like.

[0107] In the present invention, haloalkoxy refers to an alkoxy group substituted by one or more halogens, wherein alkoxy is as defined above;

[0108] The halogenated alkoxy group may be fully halogenated or partially halogenated, and the number of halogenations may be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, etc.; the halogen is preferably F, Cl, Br, I; for example, it may be trifluoromethoxy, difluoromethoxy, 1,1,2,2-tetrafluoroethoxy, perfluoroethoxy, etc.

[0109] In the present invention, hydroxyalkyl refers to an alkyl group substituted by a hydroxy group, wherein the alkyl group is as defined above.

[0110] In the present invention, alkenyl refers to a chain alkenyl group, also known as an alkene group, preferably an alkenyl group containing 2 to 8 carbon atoms, more preferably an alkenyl group containing 2 to 6 carbon atoms, further preferably an alkenyl group containing 2 to 4 carbon atoms, and most preferably an alkenyl group containing 2 to 3 carbon atoms. Non-limiting examples of alkenyl groups include: ethenyl and propenyl. The alkenyl group may be further substituted with other related groups, for example: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, sulfhydryl, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate groups.

[0111] In the present invention, alkynyl refers to a chain alkynyl, also known as an alkyne group, which refers to an unsaturated hydrocarbon group containing -C≡C-; preferably, an alkynyl group containing 2 to 8 carbon atoms, more preferably an alkynyl group containing 2 to 6 carbon atoms, further preferably an alkynyl group containing 2 to 4 carbon atoms, and most preferably an alkynyl group containing 2 to 3 carbon atoms. The alkynyl group may be further substituted with other related groups, such as alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, carboxyl, or carboxylate.

[0112] In the present invention, a hydroxyl group refers to an -OH group.

[0113] In the present invention, halogen refers to fluorine, chlorine, bromine or iodine.

[0114] In the present invention, amino group refers to -NH2.

[0115] In the present invention, cyano refers to -CN.

[0116] In the present invention, nitro refers to -NO2.

[0117] In the present invention, the carboxyl group refers to -C(O)OH.

[0118] The hydrogen atoms described in the present invention can all be replaced by their isotope deuterium, and any hydrogen atom in the example compounds of the present invention can also be replaced by a deuterium atom.

[0119] In the present invention, unless otherwise specified, according to the technology described in the present invention or the technology known in the art disclosed immediately, the substituents on the cyclic group (for example, aryl, heteroaryl, fused ring, saturated or unsaturated cycloalkyl or heterocycloalkyl) are intended to represent that any ring position of the cyclic group or any ring of the fused ring group is substituted by one or more substituents. When there are multiple substituents, each substituent may be the same or different. For example, the cyclic group Indicates that any substitutable position of ring A is substituted by one or more Rc. For example, the cyclic group The following non-limiting examples are included: When there is more than one Rc substituted on the benzene ring, each Rc may be the same or different. The following non-limiting examples are included: And when there is more than one Rc substituted on a ring, each Rc may be the same or different.

[0120] In the present invention, "optional" or "optionally" means that the event or circumstances described subsequently may but need not occur. For example, "a heterocyclic group optionally substituted with an alkyl group" means that an alkyl group may but need not be present, and this description includes both situations in which the heterocyclic group is substituted with an alkyl group and situations in which the heterocyclic group is not substituted with an alkyl group.

[0121] In the present invention, "substituted" means that one or more hydrogen atoms, preferably up to 5, more preferably 1 to 3 hydrogen atoms, in a group are independently replaced by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art can determine (by experiment or theory) whether substitution is possible or not without undue effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom with an unsaturated (e.g., olefinic) bond.

[0122] The compounds of this patent application include isotopic derivatives thereof. The term "isotopic derivative" refers to a compound whose structure differs only in the presence of one or more isotopically enriched atoms. For example, compounds having the structure of this patent application, with "deuterium" or "tritium" replacing hydrogen, or with 18F-fluorine labeling (18F isotope) replacing fluorine, or with 11C-, 13C-, or 14C-enriched carbon (11C-, 13C-, or 14C-carbon labeling; 11C-, 13C-, or 14C-isotope) replacing carbon atoms are within the scope of this patent application. Such compounds can be used as analytical tools or probes in, for example, biological assays, or can be used as in vivo diagnostic imaging tracers for diseases, or as tracers for pharmacodynamics, pharmacokinetics, or receptor studies. The various deuterated forms of the compounds of this patent application refer to compounds in which each available hydrogen atom connected to a carbon atom can be independently replaced by a deuterium atom. Those skilled in the art can synthesize deuterated forms of compounds with reference to relevant literature. Deuterated forms of the compounds can be prepared using commercially available deuterated starting materials, or they can be synthesized using conventional techniques using deuterated reagents, including but not limited to deuterated borane, trideuterated borane in tetrahydrofuran, deuterated lithium aluminum hydride, deuterated iodoethane, and deuterated iodomethane. Deuterated compounds generally retain comparable activity to the undeuterated compounds, and when deuterated at certain sites, they can achieve improved metabolic stability, thereby conferring certain therapeutic advantages.

[0123] The compounds of this patent application may exist in specific stereoisomeric forms. The term "stereoisomer" refers to isomers with the same structure but different arrangements of atoms in space. It includes cis and trans (or Z and E) isomers, (-)- and (+)-isomers, (R)- and (S)-enantiomers, diastereomers, (D)- and (L)-isomers, tautomers, atropisomers, conformers and mixtures thereof (such as racemates, mixtures of diastereomers). The substituents in the compounds of this patent application may have additional asymmetric atoms. All of these stereoisomers and their mixtures are included within the scope of this patent application. Optically active (-)- and (+)-isomers, (R)- and (S)-enantiomers and (D)- and (L)-isomers can be prepared by chiral synthesis, chiral reagents or other conventional techniques. An isomer of a compound of the present patent application can be prepared by asymmetric synthesis or the use of a chiral auxiliary, or, when the molecule contains a basic functional group (e.g., an amino group) or an acidic functional group (e.g., a carboxyl group), by forming a diastereomeric salt with an appropriate optically active acid or base, followed by diastereomeric resolution by conventional methods known in the art to obtain the pure isomer. Furthermore, separation of enantiomers and diastereoisomers is typically accomplished by chromatography.

[0124] The structures of the compounds of the present application can be confirmed by conventional methods well known to those skilled in the art. For example, when the present application involves the absolute configuration of the compound, the absolute configuration can be confirmed by conventional techniques in the art. For example, single crystal X-ray diffraction (SXRD) is used to collect diffraction intensity data on the cultured single crystal using a Bruker D8 venture diffractometer, using CuKα radiation as the light source and scanning mode: After scanning and collecting relevant data, the crystal structure is further analyzed using the direct method (Shelxs97) to confirm the absolute configuration.

[0125] In the chemical structure of the compound described in this patent application, the bond " / " indicates an unspecified configuration, that is, if there are chiral isomers in the chemical structure, the bond " / " can be or contain both configurations. Unless otherwise specified, the wedge-shaped solid bond in this invention is and dotted wedge key Indicates cis-trans isomerism of a stereocenter, e.g. Wedge-shaped dashed key It means that the two substituents Rd and Re are cis, that is, Rd and Re are located on the same side of the plane.

[0126] The compound of this patent application can exist in different tautomeric forms, and all such forms are included in the scope of this patent application.Term " tautomer " or " tautomeric form " refer to the structural isomer that exists in equilibrium and is easily converted into another isomeric form from one isomeric form.It includes all possible tautomers, i.e. exists in the form of a single isomer or in the form of a mixture of any proportions of the tautomer.Non-limiting examples include: keto-enol, imine-enamine, lactam-lactim etc.All tautomeric forms are within the scope of this patent application, and the naming of compound does not exclude any tautomer.

[0127] In the present invention, a pharmaceutical composition refers to a mixture containing one or more compounds described herein, or their physiologically / pharmaceutically acceptable salts or prodrugs, and other chemical components, as well as other components such as physiologically / pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitating absorption of the active ingredient and thereby exerting its biological activity.

[0128] In the present invention, pharmaceutically acceptable salts refer to salts of the compounds of the present invention, which are safe and effective when used in mammals and have the desired biological activity.

[0129] With respect to a drug or pharmacologically active agent, the term "therapeutically effective amount" refers to an amount of the drug or agent sufficient to achieve, or at least partially achieve, the desired effect. The determination of a therapeutically effective amount varies from person to person, depending on the age and general condition of the recipient, as well as the specific active substance. The appropriate therapeutically effective amount in each individual case can be determined by those skilled in the art through routine experimentation.

[0130] The term "pharmaceutically acceptable" as used herein refers to compounds, materials, compositions and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with patient tissues without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit / risk ratio, and effective for the intended use.

[0131] As used herein, the singular form "a," "an," and "the" include plural references and vice versa unless the context clearly dictates otherwise.

[0132] In the present invention, "plurality" refers to 2 or more, for example, it can be an integer such as 2, 3, 4, 5, 6, 7, 8, etc.

[0133] When the term "about" is applied to a parameter such as pH, concentration, temperature, etc., it indicates that the parameter can vary by ±10%, and sometimes more preferably within ±5%. As will be understood by those skilled in the art, when a parameter is not critical, numbers are generally given for illustration purposes only and are not limiting. BRIEF DESCRIPTION OF THE DRAWINGS

[0134] FIG1 shows the change rate of NREM sleep latency in SD male rats in Example 30. FIG1 shows the change rate of NREM sleep latency in SD male rats in Example 30.

[0135] FIG2 shows the change rate of REM sleep latency in SD male rats in Example 30.

[0136] FIG3 shows the change rate of wake duration in SD rats 2 hours after drug administration in Example 30.

[0137] FIG4 shows the change rate of wake duration in SD rats 6 hours after drug administration in Example 30.

[0138] FIG5 shows the change rate of NREM duration (non-rapid eye movement sleep duration) in SD rats 2 hours after drug administration in Example 30.

[0139] FIG6 shows the change rate of NREM duration (non-rapid eye movement sleep duration) in SD rats 6 hours after drug administration in Example 30.

[0140] FIG7 shows the change rate of REM duration (rapid eye movement sleep duration) in SD rats 2 hours after drug administration in Example 30.

[0141] FIG8 shows the change rate of REM duration (rapid eye movement sleep duration) in SD rats 6 hours after drug administration in Example 30.

[0142] Figure 9 shows the change rate of NREM sleep latency in SD male rats in Example 31.

[0143] Figure 10 shows the change rate of REM sleep latency in SD male rats in Example 31.

[0144] FIG11 shows the change rate of wake duration in SD rats 2 hours after drug administration in Example 31.

[0145] FIG12 shows the change rate of wake duration in SD rats 6 hours after drug administration in Example 31.

[0146] FIG13 shows the change rate of NREM duration (non-rapid eye movement sleep duration) in SD rats 2 hours after drug administration in Example 31.

[0147] FIG14 shows the change rate of NREM duration (non-rapid eye movement sleep duration) in SD rats 6 hours after drug administration in Example 31.

[0148] Figure 15 shows the change rate of REM duration (rapid eye movement sleep duration) in SD rats 2 hours after drug administration in Example 31.

[0149] Figure 16 shows the change rate of REM duration (rapid eye movement sleep duration) in SD rats 6 hours after drug administration in Example 31.

[0150] Figure 17 shows the change rate of NREM sleep latency in SD rats in Example 35.

[0151] Figure 18 shows the change rate of wake duration in SD rats 6 hours after drug administration in Example 35.

[0152] FIG19 shows the change rate of NREM duration (non-rapid eye movement sleep duration) in SD rats 6 hours after drug administration in Example 35. DETAILED DESCRIPTION

[0153] The abbreviations used in this document have the following meanings:

[0154] Unless otherwise specified, the reaction temperature is room temperature (20°C to 30°C).

[0155] The structures of the compounds described in the following examples were confirmed by H NMR spectroscopy ( 1 H-NMR) or mass spectrometry (MS).

[0156] Example 1 Synthesis of Compound KH01

[0157] Compound KH01-1: To a solution of compound 1 (1.5 g, 5.99 mmol) in toluene (15 mL) were added cyclopropylboronic acid (927 mg, 10.78 mmol), palladium acetate (68 mg, 0.30 mmol), potassium phosphate (3.805 g, 17.97 mmol), tricyclohexylphosphine (Cy3P, 168 mg, 0.599 mmol), and water (1.5 mL). The mixture was reacted at 100°C for 2 h. After the reaction was complete, the reaction solution was allowed to return to room temperature and water was added. The organic phase was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was then purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain compound KH01-1. LCMS (ESI, m / z): 212.0 [M+1]. + . 1 H NMR (400MHz, DMSO) δ8.40 (d, J = 2.5 Hz, 1H), 7.85 (d, J = 2.5 Hz, 1H), 3.87 (s, 3H), 2.04–1.96 (m, 1H), 1.05–1.02 (m, 2H), 0.82–0.80 (m, 2H).

[0158] Compound KH01-2: To a solution of compound KH01-1 (450 mg, 2.13 mmol) in 1,4-dioxane (10 mL) were added compound 2 (900 mg, 2.34 mmol) and bistriphenylphosphine palladium dichloride (155 mg, 0.213 mmol). The reaction was incubated at 100°C for 12 h. After completion of the reaction, the mixture was concentrated under reduced pressure to obtain a crude product, which was then purified by silica gel column chromatography (petroleum ether:ethyl acetate = 3:1) to obtain compound KH01-2. LCMS (ESI, m / z): 261.1 [M+1]. + . 1 H NMR (400MHz, DMSO) δ8.56(d,J=2.1Hz,1H),7.94(d,J=3.0Hz,1H),7.86(d,J=3.1Hz,1H),7. 65(d,J=2.1Hz,1H),3.79(s,3H),2.12–2.05(m,1H),1.10–1.07(m,2H),0.89–0.87(m,2H).

[0159] Compound KH01-3: Compound KH01-2 (500 mg, 1.92 mmol) and LiOH (138 mg, 5.76 mmol) were dissolved in methanol (5 mL) and water (5 mL) and reacted at 60°C for 1 h. After the reaction was complete, 1M hydrochloric acid (6 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (30 mL x 2). The organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered, and dried to give compound KH01-3. LCMS (ESI, m / z): 247.0 [M+1] + .

[0160] Compound KH01-5: Compound 3 (500 mg, 2.36 mmol, CAS: 250275-15-1), KH01-4 (430 mg, 2.36 mmol), and Cs2CO3 (844 mg, 2.59 mmol) were dissolved in DMF (5 mL) and reacted at 100°C for 16 h. After completion of the reaction, water (50 mL) was added to quench the reaction and the mixture was extracted with ethyl acetate (20 mL x 2). The organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5 / 1 to 2 / 1) to obtain KH01-5. 1 H NMR (400MHz, CDCl3) δ8.50(s,2H),3.91–3.81(m,2H),3.66–3.54(m,4H),3.36–3.26(m,2H),3.06–2.96(m,2H),1.45(s,9H).

[0161] Compound KH01-6: To a solution of compound KH01-5 (630 mg, 1.76 mmol) in ethyl acetate (5 mL) was added a 1 M hydrochloric acid / ethyl acetate solution (17.6 mL, 17.6 mmol) and allowed to react at room temperature for 12 h. After the reaction was complete, the mixture was concentrated under reduced pressure to yield KH01-6. LCMS (ESI, m / z): 259.0 [M+1] + .

[0162] Compound KH01: To a solution of compound KH01-6 (450 mg, 1.53 mmol), KH01-3 (376 mg, 1.53 mmol), and HATU (700 mg, 1.84 mmol) in DMF (10 mL) was added DIEA (790 mg, 6.11 mmol) and allowed to react at room temperature overnight. After the reaction was complete, the mixture was purified by reverse preparative chromatography to yield compound KH01. LCMS (ESI, m / z): 487.0 [M+1]. + . 1H NMR (400MHz, DMSO-d6) δ8.74–8.64(m,2H),8.48(d,J=1.9Hz,1H),7.88–7.78(m,2H),7.47(d,J=2.1Hz,1H),3.9 3–3.51(m,5H),3.50–3.38(m,2H),3.14–2.81(m,3H),2.11–2.01(m,1H),1.13–1.03(m,2H),0.93–0.83(m,2H).

[0163] Example 2 Synthesis of Compound KH02

[0164] Compound KH02-2: Compound 1 (416 mg, 2.29 mmol) and cesium carbonate (680 mg, 2.09 mmol) were added to a solution of compound KH02-1 (400 mg, 1.89 mmol) in DMF (8 mL). The mixture was reacted at 100°C for 12 h. After the reaction was complete, the reaction solution was cooled to room temperature and water was added. The organic phase was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was then purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain compound KH02-2. LCMS (ESI, m / z): 302.9 [M+1]. + .

[0165] Compound KH02-3: To a solution of compound KH02-2 (700 mg, 1.96 mmol) in EA (35 mL) was added a solution of hydrogen chloride in ethyl acetate (17.5 mL) and the mixture was allowed to react at room temperature for 12 h. After the reaction was complete, the mixture was concentrated under vacuum to afford compound KH02-3. LCMS (ESI, m / z): 259.1 [M+1] + .

[0166] Compound KH02: To a solution of compound KH02-3 (218 mg, 0.74 mmol) in DMF (4 mL) were added KH01-3 (190 mg, 0.88 mmol), HATU (422 mg, 1.11 mmol), and DIEA (0.5 mL, 2.96 mmol), and the mixture was stirred at room temperature for 12 h. After the reaction was complete, compound KH02 was purified by reverse-phase preparative chromatography. LCMS (ESI, m / z): 487.1 [M+1] + . 1H NMR(400MHz,DMSO-d6)δ8.66(d,J=24.8Hz,1H),8.48(d,J=2.0Hz,1H),7.78-7.66 (m,2H),7.47(d,J=1.9Hz,1H),7.01(d,J=4.7Hz,1H),3.88–3.51(m,5H),3.42(br s,2H),3.11–2.82(m,3H),2.06(br s,1H),1.07(d,J=7.1Hz,2H),0.88(s,2H).

[0167] Example 3 Synthesis of Compound KH03

[0168] Compound KH03-2: Compound 1 (500 mg, 2.36 mmol), KH03-1 (440 mg, 2.36 mmol), and Cs2CO3 (844 mg, 2.59 mmol) were added to DMF (5 mL) and reacted at 100°C for 16 h. After the reaction was complete, water (50 mL) was added to quench the reaction and the mixture was extracted with ethyl acetate (50 mL x 2). The organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5 / 1 to 1 / 1) to obtain KH03-2. 1 H NMR(400MHz, CDCl3)δ7.03(s,1H),3.93(s,3H),3.90–3.80(m,2H),3.66–3. 54(m,4H),3.36–3.24(m,2H),3.00–2.90(m,2H),2.41(s,3H),1.44(s,9H).

[0169] Compound KH03-3: Dissolve compound KH03-2 (400 mg, 1.1 mmol) in tetrahydrofuran (5 mL), cool to 0°C, add LiAlH4 (83 mg, 2.2 mmol), and react at 0°C for 1 h. After the reaction is complete, quench the reaction with water (0.4 mL), add anhydrous sodium sulfate, stir for 10 min, filter, and dry to obtain compound KH03-3. LCMS (ESI, m / z): 335.2 [M+1] + .

[0170] Compound KH03-4: To a solution of compound KH03-3 (250 mg, 0.747 mmol) in ethyl acetate (3 mL) was added 1 M hydrochloric acid in ethyl acetate (7.48 mL, 7.48 mmol) and allowed to react at room temperature for 12 h. After the reaction was complete, the mixture was filtered to obtain compound KH03-4. LCMS (ESI, m / z): 235.1 [M+1] + .

[0171] Compound KH03: To a solution of compound KH03-4 (150 mg, 0.554 mmol), KH01-3 (137 mg, 0.554 mmol), and HATU (253 mg, 0.665 mmol) in DMF (5 mL) was added DIEA (215 mg, 1.66 mmol) and allowed to react at room temperature overnight. After the reaction was complete, the mixture was purified by reverse preparative chromatography to afford compound KH03. LCMS (ESI, m / z): 463.3 [M+1]. + . 1 H NMR(400MHz,DMSO-d6)δ8.47(d,J=1.5Hz,1H),7.95–7.65(m,2H),7.46(s,1H),6.62(s,1H),4.33(s,2H),3 .85–3.50(m,7H),3.05–2.85(m,3H),2.29(s,3H),2.10–2.00(m,1H),1.12–1.02(m,2H),0.93–0.83(m,2H).

[0172] Example 4 Synthesis of Compound KH04

[0173] The synthesis method of compound KH04-1 is shown in compound KH03-2.

[0174] Compound KH04-2: Methylmagnesium bromide (2 mL, 5.74 mmol) was added to a solution of compound KH04-1 (500 mg, 1.44 mmol) in THF (10 mL) at -30°C and stirred at room temperature overnight. After the reaction was complete, saturated aqueous ammonium chloride was added to the reaction mixture to quench the reaction system. The mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was then purified by silica gel column chromatography (petroleum ether:ethyl acetate = 3:1) to obtain compound KH04-2. LCMS (ESI, m / z): 349.1 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ8.29(d,J=5.1Hz,1H),6.83(d,J=5.1Hz,1H),5.14(s,1H),3.69(br s,2H),3.52(br s, 2H), 3.33 (s, 2H), 3.16 (d, J = 9.6Hz, 2H), 2.94 (s, 2H), 1.38 (d, J = 5.9Hz, 15H).

[0175] Compound KH04-3: To a solution of compound KH04-2 (480 mg, 1.38 mmol) in ethyl acetate (24 mL) was added hydrogen chloride in ethyl acetate (12 mL), and the mixture was allowed to react at 60°C for 1 h. After the reaction was complete, the mixture was concentrated under vacuum to obtain compound KH04-3. LCMS (ESI, m / z): 249.1 [M+1] + .

[0176] Compound KH04: To a solution of compound KH04-3 (209 mg, 0.73 mmol) in DMF (3 mL) were added KH01-3 (150 mg, 0.61 mmol), HATU (348 mg, 0.91 mmol), and DIEA (0.5 mL, 2.44 mmol), and the mixture was stirred at room temperature for 12 h. After the reaction was complete, compound KH04 was purified by reverse-phase preparative chromatography. LCMS (ESI, m / z): 477.0 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ8.47(d,J=2.0Hz,1H),8.30(s,1H),7.89(m,J=57.8,54.4Hz,2H),7.47(d,J=2.1H z,1H),6.86(d,J=5.2Hz,1H),3.887-3.58(m,4H),3.34(m,J=11.6,4.0Hz,3H),3.10–2.85(m,3H),2.06(br s, 1H), 1.38 (s, 6H), 1.07 (d, J = 7.5Hz, 2H), 0.89 (br s, 2H).

[0177] Example 5 Synthesis of Compound KH05

[0178] Compound KH05-2: To a solution of compound KH05-1 (1 g, 4.02 mmol) in toluene (10 mL) were added compound KH05-1a (622 mg, 4.02 mmol), palladium acetate (46 mg, 0.2 mmol), potassium phosphate (2.56 g, 12 mmol), tricyclohexylphosphine (112 mg, 0.4 mmol), and water (1 mL). The mixture was reacted at 100°C for 2 h. After the reaction was complete, the reaction solution was cooled to room temperature and diluted with water. Extraction was performed with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was then purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain compound KH05-2. LCMS (ESI, m / z): 198.1 [M+1] + . 1H NMR (400MHz, CDCl3) δ8.48 (d, J=2.4Hz, 1H), 8.18 (d, J=2.4Hz, 1H), 6.69 (m, J=1 7.6, 11.0Hz, 1H), 5.89 (d, J=17.6Hz, 1H), 5.49 (d, J=11.0Hz, 1H), 3.97 (s, 3H).

[0179] Compound KH05-3: To a solution of compound KH05-2 (550 mg, 2.78 mmol) in THF (5 mL) were added CF3-TMS (1.7 mL, 11.1 mmol) and sodium iodide (84 mg, 0.556 mmol), and the mixture was allowed to react at 70°C for 4 h. After completion of the reaction, the mixture was concentrated under vacuum to obtain a crude product, which was then purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain compound KH05-3. LCMS (ESI, m / z): 248.0 [M+1] + . 1 H NMR (400MHz, CDCl3) δ8.40 (d, J=2.3Hz, 1H), 7.98 (d, J=2.3Hz, 1H), 3.96 (s, 3H), 2.79-2.73 (m, 1H), 2.04-1.92 (m, 1H), 1.77-1.65 (m, 1H).

[0180] Compound KH05-4: To a solution of compound KH05-3 (360 mg, 1.45 mmol) in 1,4-dioxane (8 mL) were added compound KH05-3a (600 mg, 1.60 mmol) and bistriphenylphosphine palladium dichloride (102 mg, 0.145 mmol). The mixture was reacted at 100°C for 12 h. After completion of the reaction, the mixture was concentrated under reduced pressure to obtain a crude product, which was then purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain compound KH05-4. LCMS (ESI, m / z): 297.0 [M+1]. + . 1 H NMR (400MHz, DMSO) δ8.72(d,J=2.1Hz,1H),7.98(d,J=3.2Hz,1H),7.94(d,J=2.0Hz,1H),7. 92(d,J=3.2Hz,1H),3.81(s,3H),3.26-3.19(m,1H),2.36-2.28(m,1H),2.19-2.08(m,1H).

[0181] Compound KH05-5: To a solution of compound KH05-4 (336 mg, 1.14 mmol) in methanol (10 mL) were added lithium hydroxide monohydrate (143 mg, 3.4 mmol) and water (5 mL), and the mixture was stirred at 60°C for 1 h. After the reaction was complete, the pH was adjusted to 5 with dilute hydrochloric acid, and the mixture was extracted with ethyl acetate. The mixture was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound KH05-5. LCMS (ESI, m / z): 282.9 [M+1] + . 1 H NMR (400MHz, DMSO) δ13.46(s,1H),8.67(d,J=2.0Hz,1H),7.97(d,J=3.2Hz,1H),7.91(d,J= 3.2Hz,1H),7.90(d,J=2.0Hz,1H),3.24-3.17(m,1H),2.34-2.28(m,1H),2.17–2.07(m,1H).

[0182] Compound KH05-6: To a solution of compound KH05-5a (500 mg, 3.53 mmol) in 1,4-dioxane (17 mL) were added compound KH05-5b (1.125 g, 5.30 mmol), Pd2(dba)3 (324 mg, 10.6 mmol), Xantphos (205 mg, 0.353 mmol), and cesium carbonate (3.737 g, 0.353 mmol). The mixture was reacted at 90°C overnight. After completion of the reaction, the reaction solution was poured into water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was then purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain compound KH05-6. LCMS (ESI, m / z): 318.1 [M+1] + . 1 H NMR(400MHz,DMSO)δ6.27(s,1H),6.05(s,1H),3.52(br s,4H),3.24(br s,2H),3.13(d,J=9.9Hz,2H),2.93(s,2H),2.23(s,3H),2.15(s,3H),1.38(s,9H).

[0183] Compound KH05-7: To a solution of compound KH05-6 (643 mg, 2.03 mmol) in ethyl acetate (32 mL) was added hydrogen chloride in ethyl acetate (16 mL), and the mixture was allowed to react at 60°C for 1 h. After the reaction was complete, the mixture was concentrated under vacuum to obtain compound KH05-7. LCMS (ESI, m / z): 218.2 [M+1] + .

[0184] Compound KH05: To a solution of compound KH05-5 (138 mg, 0.5 mmol) in DMF (3 mL) were added KH05-7 (153 mg, 0.6 mmol), HATU (285 mg, 0.75 mmol), and DIEA (0.34 mL, 2.0 mmol), and the mixture was stirred at room temperature for 1 h. After the reaction was complete, compound KH05 was purified by reverse-phase preparative chromatography. LCMS (ESI, m / z): 482.0 [M+1] + . 1 H NMR(400MHz,DMSO)δ8.62(s,1H),7.79-7.65(m,3H),6.27(s,1H),6.04(s,1H),3.75 -3.58(m,5H),3.25–3.11(m,3H),3.07-2.89(m,3H),2.23(s,4H),2.21-2.07(m,4H).

[0185] Example 6 Synthesis of Compound KH06

[0186] Compound KH06-2: To a solution of compound KH06-1 (300 mg, 2.10 mmol) in DMF (6 mL) were added compound KH06-1a (494 mg, 2.32 mmol) and cesium carbonate (826 mg, 2.53 mmol), and the mixture was reacted at 100°C for 2 h. After completion of the reaction, the reaction system was diluted with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was then purified by silica gel column chromatography (petroleum ether:ethyl acetate = 3:1) to obtain compound KH06-2. LCMS (ESI, m / z): 319.1 [M+1] + . 1 H NMR(400MHz,DMSO)δ6.38(s,1H),3.67(br s,2H),3.50(br s,2H),3.35(d,J=12.5Hz,2H),3.17-3.12(m,2H),2.91(s,2H),2.21(s,6H),1.38(s,9H).

[0187] Compound KH06-3: To a solution of compound KH06-2 (320 mg, 1.01 mmol) in ethyl acetate (16 mL) was added ethyl acetate (8 mL) and the mixture was allowed to react at 60°C for 1 h. After the reaction was complete, the mixture was concentrated under vacuum to obtain compound KH06-3. LCMS (ESI, m / z): 219.2 [M+1] + . 1H NMR (400MHz, DMSO) δ9.65 (d, J = 50.5Hz, 2H), 6.69 (s, 1H), 3.86-3.79 (m, 4H), 3.47-3.42 (m, 2H), 3.16–3.06 (m, 4H), 2.39 (s, 6H).

[0188] Compound KH06: To a solution of compound KH06-3 (174 mg, 0.68 mmol) in DMF (3 mL) were added KH05-5 (160 mg, 0.57 mmol), HATU (324 mg, 0.85 mmol), and DIEA (0.23 mL, 2.27 mmol). The mixture was stirred at room temperature for 1 h. After the reaction was complete, compound KH06 was purified by reverse-phase preparative chromatography. LCMS (ESI, m / z): 483.3 [M+1]. 1H NMR(400MHz,DMSO)δ8.63(s,1H),7.79-7.65(m,3H),6.38(s,1H),3.75(m,2H),3.72 -3.43(m,5H),3.18-3.14(m,1H),3.06–2.82(m,3H),2.28-2.21(m,7H),2.11(s,1H).

[0189] Example 7 Synthesis of Compound KH07

[0190] Compound KH07-2: To a solution of compound KH07-1a (600 mg, 4.21 mmol) in DMF (12 mL) were added compound KH07-1 (983 mg, 4.63 mmol) and cesium carbonate (1.646 g, 5.05 mmol), and the mixture was allowed to react at 100°C for 2 h. After completion of the reaction, the reaction system was quenched with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was then purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain compound KH07-2. LCMS (ESI, m / z): 319.2 [M+1] + . 1 H NMR (400MHz, DMSO) δ8.20(d,J=4.9Hz,1H),6.50(d,J=4.9Hz,1H),3.69(br s,2H),3.51(br s,2H),3.36(s,2H),3.15(d,J=9.5Hz,2H),2.93(br s,2H),2.56–2.50(m,2H),1.38(s,9H),1.19-1.14(m,3H).

[0191] Compound KH07-3: To a solution of compound KH07-2 (200 mg, 0.63 mmol) in EA (4 mL) was added a solution of hydrogen chloride in ethyl acetate (2 mL), and the mixture was reacted at 60°C for 1 h. After the reaction was complete, the mixture was concentrated under vacuum to obtain compound KH07-3. LCMS (ESI, m / z): 219.2 [M+1] + . 1 H NMR (400MHz, DMSO) δ9.60 (d, J=32.3Hz, 2H), 8.30 (d, J=5.7Hz, 1H), 6.78 (d, J= 5.6Hz,1H),3.82-3.78(m,2H),3.69-3.63(m,2H),3.45–3.37(m,2H),3.13(br s, 4H), 2.69 (q, J = 7.5Hz, 2H), 1.20 (t, J = 7.5Hz, 3H).

[0192] Compound KH07: To a solution of compound KH01-3 (80 mg, 0.33 mmol) in DMF (3 mL) were added KH07-3 (103 mg, 0.40 mmol), HATU (191 mg, 0.50 mmol), and DIEA (0.22 mL, 1.33 mmol), and the mixture was stirred at room temperature for 1 h. After the reaction was complete, compound KH07 was purified by reverse-phase preparative chromatography. LCMS (ESI, m / z): 447.2 [M+1] + . 1 H NMR (400MHz, DMSO) δ8.48(d,J=1.8Hz,1H),8.23(s,1H),7.79-7.52(m,2H),7.47(d,J=2.0Hz,1H),6.61(d,J=4.7Hz,1H),3.78-3.25(m,8H),2.91(br s,2H),2.60(d,J=6.9Hz,2H),2.05(br s,1H),1.19(s,3H),1.10–0.84(m,4H).

[0193] Example 8 Synthesis of Compound KH08

[0194] Compound KH08-2: To a solution of compound KH08-1 (677 mg, 3.00 mmol) in DMF (14 mL) were added MeI (639 mg, 4.50 mmol) and cesium carbonate (1.955 g, 6.00 mmol) and allowed to react at room temperature for 3 h. After completion of the reaction, the reaction system was quenched with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound KH08-2. LCMS (ESI, m / z): 240.1 [M+1] + . 1 H NMR (400MHz, DMSO) δ9.05 (dd, J = 2.4, 0.8 Hz, 1H), 8.64 (dd, J = 2.4, 0.4 Hz, 1H), 3.92 (s, 3H).

[0195] Compound KH08-3: To a solution of compound KH08-2 (600 mg, 2.50 mmol) in 1,4-dioxane (12 mL) were added compound KH08-2a (0.9 mL, 2.75 mmol) and bistriphenylphosphine palladium dichloride (176 mg, 0.25 mmol), and the mixture was reacted at 100°C for 12 h. After completion of the reaction, the mixture was concentrated under reduced pressure to obtain a crude product, which was then purified by silica gel column chromatography (petroleum ether:ethyl acetate = 3:1) to obtain compound KH08-3. LCMS (ESI, m / z): 289.0 [M+1] + . 1 H NMR (400MHz, DMSO) δ9.20–9.13 (m, 1H), 8.58 (d, J = 1.6Hz, 1H), 8.12-8.05 (m, 2H), 3.86 (s, 3H).

[0196] Compound KH08-4: To a solution of compound KH08-3 (200 mg, 0.69 mmol) in methanol (8 mL) were added lithium hydroxide monohydrate (88 mg, 2.08 mmol) and water (4 mL), and the mixture was stirred at 60°C for 1 h. After the reaction was complete, the pH was adjusted to 5 with dilute hydrochloric acid, and the mixture was extracted with ethyl acetate. The mixture was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound KH08-4. LCMS (ESI, m / z): 275.0 [M+1]. + . 1 H NMR (400MHz, DMSO) δ 13.74 (s, 1H), 9.12 (s, 1H), 8.50 (s, 1H), 8.05 (t, J = 4.9Hz, 2H).

[0197] Compound KH08: To a solution of compound KH08-4 (130 mg, 0.47 mmol) in DMF (3 mL) were added KH07-3 (121 mg, 0.47 mmol), HATU (271 mg, 0.71 mmol), and DIEA (0.31 mL, 1.90 mmol), and the mixture was stirred at room temperature for 1 h. After the reaction was complete, compound KH08 was purified by reverse-phase preparative chromatography. LCMS (ESI, m / z): 475.2 [M+1] + . 1 H NMR (400MHz, DMSO) δ9.09(d,J=1.2Hz,1H),8.39(s,1H),8.20(d,J=4.8Hz,1H),8.15-7.62(m,2H),6.50(d,J=5.0Hz,1H),3.93–3.43(m,6H),3.36(br s,1H),3.16–2.86(m,3H),2.54(d,J=7.6Hz,2H),1.18(br s,3H).

[0198] Example 9 Synthesis of Compound KH09

[0199] Compound KH09-2: To a solution of compound KH09-1 (5 g, 33.61 mmol) and iron acetylacetonate (2.370 g, 6.70 mmol) in tetrahydrofuran (30 mL) and NMP (5 mL) was added cyclopropylmagnesium bromide (67 mL, 67.0 mmol) at 0°C and allowed to react at room temperature for 1 h. After completion, the reaction was quenched with saturated ammonium chloride solution, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was then purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain compound KH09-2. LCMS (ESI, m / z): 155.2 [M+1] + .

[0200] Compound KH09-3: To a solution of compound KH09-2 (500 mg, 3.23 mmol) in DMF (10 mL) were added compound KH09-2a (412 mg, 1.94 mmol) and cesium carbonate (759 mg, 2.33 mmol), and the mixture was allowed to react at 100°C for 2 h. After completion of the reaction, the reaction system was quenched with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was then purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain compound KH09-3. LCMS (ESI, m / z): 331.2 [M+1] + . 1H NMR (400MHz, DMSO) δ8.09(d,J=5.0Hz,1H),6.53(d,J=5.0Hz,1H),3.64(d,J=5.0Hz,2H),3.49(br s,2H),3.32–3.27(m,2H),3.16-3.12(m,2H),2.90(br s,2H),1.92–1.85(m,1H),1.38(s,9H),1.00–0.90(m,4H).

[0201] Compound KH09-4: To a solution of compound KH09-3 (240 mg, 0.73 mmol) in ethyl acetate (12 mL) was added hydrogen chloride in ethyl acetate (6 mL), and the mixture was allowed to react at 60°C for 1 h. After the reaction was complete, the mixture was concentrated under reduced pressure to obtain compound KH09-4. LCMS (ESI, m / z): 231.1 [M+1] + .

[0202] Compound KH09: To a solution of compound KH08-4 (110 mg, 0.40 mmol) in DMF (3 mL) were added KH09-4 (108 mg, 0.40 mmol), HATU (229 mg, 0.60 mmol), and DIEA (0.27 mL, 1.60 mmol), and the mixture was stirred at room temperature for 1 h. After the reaction was complete, compound KH09 was purified by reverse-phase preparative chromatography. LCMS (ESI, m / z): 487.2 [M+1] + . 1 H NMR(400MHz,DMSO)δ9.09(s,1H),8.39(s,1H),8.13–7.80(m,3H),6.53(d,J=4.9Hz,1H ),3.84–3.42(m,6H),3.29–3.18(m,1H),3.09–2.84(m,3H),1.92-1.87(m,1H),0.95(br s,4H).

[0203] Example 10 Synthesis of Compound KH10

[0204] Compound KH10-2: To a solution of compound KH10-1 (5 g, 22.17 mmol) in DMF (50 mL) were added iodomethane (4.72 g, 33.25 mmol) and cesium carbonate (14.446 g, 44.34 mmol) and allowed to react at room temperature for 2 h. After completion, the reaction was quenched with water and extracted with ethyl acetate. The mixture was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was then purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain compound KH10-2. LCMS (ESI, m / z): 239.9 [M+1] + . 1 H NMR (400MHz, DMSO) δ9.04(s,1H),8.63(s,1H),3.92(s,3H).

[0205] Compound KH10-3: To a solution of compound KH10-2 (4.44 g, 18.53 mmol) in dioxane (50 mL) were added compound KH10-2a (7.628 g, 20.39 mmol) and Pd(PPh3)Cl2 (650 mg, 0.93 mmol), and the mixture was allowed to react at 100°C for 12 h. After completion of the reaction, the mixture was quenched with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was then purified by silica gel column chromatography (petroleum ether:ethyl acetate = 3:1) to obtain compound KH10-3. LCMS (ESI, m / z): 288.9 [M+1] + . 1 H NMR (400MHz, DMSO) δ9.17 (d, J = 1.1 Hz, 1H), 8.58 (d, J = 1.5 Hz, 1H), 8.07 (dd, J = 10.1, 3.1 Hz, 2H), 3.86 (s, 3H).

[0206] Compound KH10-4: To a solution of compound KH10-3 (4.89 g, 16.97 mmol) in methanol (40 mL) and water (10 mL) was added lithium hydroxide (812 mg, 33.93 mmol) and the mixture was allowed to react at room temperature for 12 h. After the reaction was complete, the reaction mixture was adjusted to pH = 5 by adding aqueous hydrochloric acid. The mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound KH10-4. LCMS (ESI, m / z): 274.9 [M+1]. + .

[0207] Compound KH10-5: To a solution of compound KH10-4 (2 g, 7.29 mmol) in DMF (20 mL) were added compound KH10-4a (1.548 g, 7.29 mmol), HATU (3.328 g, 8.75 mmol), and DIEA (2.54 mL, 14.59 mmol) and allowed to react at room temperature for 1 h. After completion, the reaction was quenched with water and extracted with ethyl acetate. The mixture was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was then purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:1) to obtain compound KH10-5. LCMS (ESI, m / z): 469.1 [M+1]. + .

[0208] Compound KH10-6: To a solution of compound KH10-5 (1 g, 2.13 mmol) in ethyl acetate (10 mL) was added ethyl acetate (20 mL) and the mixture was allowed to react at room temperature for 12 h. After the reaction was complete, the mixture was concentrated under vacuum to obtain compound KH10-6. LCMS (ESI, m / z): 369.0 [M+1] + .

[0209] Compound KH10: To a solution of compound KH10-6 (150 mg, 0.41 mmol) in isopropanol (10 mL) were added compound KH10-6a (48 mg, 0.27 mmol) and DIEA (0.16 mL, 0.95 mmol). The mixture was reacted at 90°C for 12 h. After the reaction was complete, the mixture was filtered to obtain compound KH10. LCMS (ESI, m / z): 509.1 [M+1] + . 1 H NMR (400MHz, CD3OD_SPE) δ8.97 (s, 1H), 8.23 ​​(d, J = 1.7Hz, 1H), 7.96-7.67 (m, 2H), 3.8 9-3.81(m,2H),3.78-3.56(m,4H),3.52-3.42(m,1H),3.16–3.00(m,3H),2.40(s,6H).

[0210] Example 11 Synthesis of Compound KH11

[0211] Compound KH11-2: To a solution of compound KH11-1 (1 g, 4.96 mmol) in THF:NMP = 10:1 (10 mL / 1 mL) was added Fe(acac)3 (175 mg, 0.49 mmol) at room temperature. The reaction system was cooled to 0°C, and methylmagnesium bromide (4 mL, 12.41 mmol) was added. The reaction was allowed to react at 0°C for 0.5 h. After the reaction was complete, the reaction solution was returned to room temperature and quenched with saturated aqueous ammonium chloride. The mixture was extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was then purified by silica gel column chromatography (petroleum ether:ethyl acetate = 4:1) to obtain compound KH11-2. LCMS (ESI, m / z): 161.0 [M+1] + . 1 H NMR (400MHz, DMSO) δ2.43 (d, J=2.7Hz, 6H).

[0212] Compound KH11: To a solution of compound KH10-6 (241 mg, 0.65 mmol) in isopropanol (4 mL) were added compound KH11-2 (70 mg, 0.44 mmol) and DIEA (0.27 mL, 1.53 mmol), and the mixture was stirred at 90°C overnight. After the reaction was complete, compound KH11 was purified by reverse-phase preparative chromatography. LCMS (ESI, m / z): 493.1 [M+1] + . 1 H NMR (400MHz, DMSO) δ9.09 (d, J = 1.3Hz, 1H), 8.38 (s, 1H), 8.11-7.62 (m, 2H), 3.73 (dd, J=11.4,7.6Hz,2H),3.63-3.45(m,4H),3.33(s,1H),3.11–2.86(m,3H),2.27(s,6H).

[0213] Example 12 Synthesis of Compound KH12

[0214] Compound KH12-2: To a solution of compound KH12-1 (2 g, 9.4 mmol) in isopropanol (20 mL) were added compound KH12-1a (2.015 g, 14.1 mmol) and DIEA (2.435 g, 18.8 mmol), and the mixture was allowed to react at 90°C for 2 h. After completion of the reaction, the mixture was quenched with water and extracted with ethyl acetate. The mixture was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was then purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain compound KH12-2. LCMS (ESI, m / z): 319.1 [M+1]. + .1 H NMR(400MHz,DMSO)δ6.38(s,1H),3.73–3.63(m,2H),3.58–3.47(m,2H),3.38–3.36(m,1H) ,3.14(dd,J=11.1,3.7Hz,2H),2.99–2.87(m,2H),2.51(s,1H),2.21(s,6H),1.39(s,9H).

[0215] Compound KH12-3: To a solution of compound KH12-2 (1 g, 3.13 mmol) in acetonitrile (10 mL) was added NBS (837 mg, 4.7 mmol) and the mixture was allowed to react at room temperature for 2 h. After completion, the reaction was quenched with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was then purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain compound KH12-3. LCMS (ESI, m / z): 399.1 [M+1] + . 1 H NMR (400MHz, DMSO) δ3.74–3.60(m,2H),3.58–3.43(m,2H),3.33–3.29(m,1H),3.14(dd ,J=11.2,4.0Hz,2H),2.97–2.88(m,2H),2.54–2.48(m,1H),2.38(s,6H),1.39(s,9H).

[0216] Compound KH12-4: To a solution of compound KH12-3 (467 mg, 1.18 mmol) in DMSO (5 mL) were added compound KH12-3a (597 mg, 2.35 mmol), Pd(Pcy3)2Cl2 (87 mg, 0.12 mmol), and potassium acetate (404 mg, 4.11 mmol), and the mixture was reacted at 135°C for 6 h. After completion of the reaction, the mixture was quenched with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound KH12-4. LCMS (ESI, m / z): 445.3 [M+1]. + .

[0217] Compound KH12-5: To a solution of compound KH12-4 (916 mg, 2.06 mmol) in THF (10 mL) was added hydrogen peroxide (4.67 g, 41.23 mmol) and the mixture was allowed to react at 0°C for 2.5 h. After completion, the reaction was quenched with sodium sulfite. The organic phase was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was then purified by silica gel column chromatography (petroleum ether:ethyl acetate = 2:1) to obtain compound KH12-5. LCMS (ESI, m / z): 335.7 [M+1]. + . 1 H NMR(400MHz,DMSO)δ7.90(s,1H),3.65–3.56(m,2H),3.53–3.46(m,2H),3.30– 3.25(m,2H),3.15–3.10(m,2H),2.94–2.86(m,2H),2.22(s,6H),1.39(s,9H).

[0218] Compound KH12-6: To a solution of compound KH12-5 (170 mg, 0.51 mmol) in acetonitrile (2 mL) were added iodomethane (181 mg, 1.27 mmol) and potassium carbonate (211 mg, 1.53 mmol) and allowed to react at room temperature for 4 h. After completion, the reaction was quenched with water, and the organic phase was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was then purified by silica gel column chromatography (petroleum ether:ethyl acetate = 2:1) to obtain compound KH12-6. LCMS (ESI, m / z): 349.3 [M+1]. + . 1 H NMR(400MHz,DMSO)δ3.63(d,J=6.9Hz,2H),3.59(s,3H),3.50(d,J=5.1Hz,2H),3.33–3 .29(m,2H),3.13(dd,J=11.1,4.1Hz,2H),2.99–2.83(m,2H),2.25(s,6H),1.39(s,9H).

[0219] Compound KH12-7: To a solution of compound KH12-6 (150 mg, 0.41 mmol) in ethyl acetate (2 mL) was added hydrochloric acid in ethyl acetate (5 mL) and the mixture was allowed to react at room temperature for 1 h. After the reaction was complete, the mixture was concentrated under vacuum to obtain compound KH12-7. LCMS (ESI, m / z): 249.2 [M+1] + .

[0220] Compound KH12: To a solution of compound KH12-7 (150 mg, 0.6 mmol) in acetonitrile (2 mL) were added compound KH10-4 (110 mg, 0.4 mmol), TCFH (135 mg, 0.5 mmol), and NMI (115 mg, 1.4 mmol). The mixture was allowed to react at room temperature for 1 h. After the reaction was complete, compound KH12 was purified by reverse-phase preparative chromatography. LCMS (ESI, m / z): 505.1 [M+1] + . 1 H NMR(400MHz,DMSO)δ9.09(s,1H),8.39(s,1H),8.17-7.83(m,2H),3.62(s, 3H),3.59–3.44(m,5H),3.39-3.32(m,2H),3.12-3.07(m,3H),2.30(s,6H).

[0221] Example 13 Synthesis of Compound KH13

[0222] Compound KH13: To a solution of compound KH10-4 (14.06 g, 51.27 mmol) in DMF (200 mL) were added compound KH06-3 (15 g, 56.40 mmol), HATU (23.38 g, 61.53 mmol), and DIEA (25 mL, 153.82 mmol) and allowed to react at room temperature for 1 h. After the reaction was complete, the mixture was extracted with water and ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. Petroleum ether was then added to the crude product for slurrying, and the mixture was filtered to obtain compound KH13. LCMS (ESI, m / z): 475.2 [M+1]. + . 1 H NMR(400MHz,DMSO)δ9.09(d,J=1.0Hz,1H),8.39(s,1H),8.13–7.81(m,2H),6.4 4(s,1H),3.88-3.72(m,2H),3.67-3.37(m,5H),3.04-2.89(m,3H),2.25(s,6H).

[0223] Example 14 Synthesis of Compound KH14

[0224] Compound KH14: To a solution of compound KH01-3 (250 mg, 1.01 mmol) in DMF (4 mL) were added KH06-3 (312 mg, 1.21 mmol), HATU (579 mg, 1.52 mmol), and DIEA (0.74 mL, 4.06 mmol). The mixture was stirred at room temperature for 1 h. After the reaction was complete, compound KH14 was purified by reverse-phase preparative chromatography. LCMS (ESI, m / z): 447.2 [M+1]. + . 1 H NMR (400MHz, DMSO) δ8.47(d,J=2.1Hz,1H),7.89-7.69(m,2H),7.46(d,J=2.1Hz,1H),6.37(s,1H),3.86–3.66(m ,2H),3.64–3.33(m,5H),3.04–2.83(m,3H),2.22(s,6H),2.08–2.01(m,1H),1.07(d,J=6.9Hz,2H),0.88(s,2H).

[0225] Example 15 Synthesis of Compound KH15

[0226] Compound KH15-8: To a solution of compound KH15-8a (3.00 g, 18.4 mmol, 1 eq) in THF (30 mL) were added NMP (2.19 g, 22.0 mmol, 2.15 mL, 1.2 eq) and FeCl3 (59.7 mg, 368 μmol, 21.3 μL, 0.02 eq). CD3MgI (1 M, 18.4 mL, 1 eq) was added dropwise at -60°C. After the addition was complete, the system was stirred at 20°C for 12 hours. TLC (petroleum ether / ethyl acetate = 2 / 1, compound KH15-8a Rf = 0.40, new spot Rf = 0.25) showed that the starting material had essentially disappeared, and the desired product had formed. After the reaction was complete, water (50 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (50 mL x 2). The organic layers were combined, washed with saturated brine (50 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 20 / 1 to 3 / 1) to obtain the target compound KH15-8. LCMS (ESI, m / z) = 146.1 [M+1] + . 1 HNMR: DMSO-d6, 400MHz δ7.32(s,1H),2.41(s,3H).

[0227] Compound KH15: To a solution of compound KH10-6 (80.0 mg, 217 μmol, 1 eq) in 1,4-dioxane (2 mL) were added compound KH15-8 (31.6 mg, 217 μmol, 1 eq) and Cs2CO3 (176 mg, 542 μmol, 2.5 eq). The system was purged with nitrogen three times after addition. Stirring was continued at 110°C under nitrogen for 12 hours. LCMS (EW30597-215-P1A) showed that the starting material had essentially disappeared, and the target product had formed. After completion of the reaction, 10 mL of water was added to the reaction mixture, followed by extraction with ethyl acetate (20 mL x 2). The organic layers were combined, washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to yield the crude product. The crude product was isolated by preparative HPLC to yield the target compound KH15. LCMS (ESI, m / z) = 478.1 [M+1] + . 1 HNMR: 400MHz, CDCl3δ8.87(s,1H),7.85-8.00(m,2H),7.35-7.65(m,1H),6.27-6.34 (m,1H),3.62-4.17(m,5H),3.41-3.60(m,2H),2.87-3.21(m,3H),2.22-2.38(m,3H).

[0228] Example 16 Synthesis of Compound KH16

[0229] Compound KH16-1b: To a solution of compound KH16-1a (2.00 g, 10.9 mmol, 1.25 mL, 1 eq) in tetrahydrofuran (40 mL) were added FeCl₃ (70.7 mg, 436 μmol, 25.2 μL, 0.04 eq) and NMP (2.59 g, 26.1 mmol, 2.54 mL, 2.4 eq). CD₃MgI (1 M, 21.8 mL, 2 eq) was added dropwise at -60°C. After the addition was complete, the mixture was stirred at -60°C for 1 h. TLC (petroleum ether:ethyl acetate = 5:1, compound KH16-1a Rf / = 0.50, new spot Rf = 0.40) and LCMS showed that the starting material had essentially disappeared, and the desired product had formed. The reaction mixture was quenched with water (50 mL) and extracted with ethyl acetate (80 mL x 2). The organic layers were combined, washed with saturated brine (50 ml), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 1 / 0 to 0 / 1) to obtain the target compound KH16-1b. LCMS (ESI, m / z) = 166.0 [M+1] + .

[0230] Compound KH16-1c: To a solution of compound KH16-1b (1.10 g, 6.63 mmol, 1 eq) in tetrahydrofuran (40 mL) were added NMP (788 mg, 7.95 mmol, 772 μL, 1.2 eq) and FeCl₃ (21.4 mg, 132 μmol, 7.68 μL, 0.02 eq). CD₃MgI (1 M, 6.63 mL, 1 eq) was then added dropwise at -60°C. After the addition was complete, the reaction mixture was stirred at -60°C for 1 h. TLC (petroleum ether:ethyl acetate = 5:1, compound KH16-1b Rf = 0.40, new spot Rf = 0.25) showed that the starting material had essentially disappeared, and the desired product had formed. The reaction mixture was quenched with water (50 mL) and extracted with ethyl acetate (80 mL x 2). The organic layers were combined, washed with saturated brine (50 ml), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 1 / 0 to 0 / 1) to obtain the target compound KH16-1c. LCMS (ESI, m / z) = 149.0 [M+1] + .

[0231] Compound KH16: To a solution of compound KH10-6 (80.0 mg, 217 μmol, 1 eq) in 1,4-dioxane (2 mL) were added compound KH16-1c (48.4 mg, 325 μmol, 1.5 eq) and Cs2CO3 (176 mg, 542 μmol, 2.5 eq). The system was purged with nitrogen three times. Under nitrogen, the mixture was stirred at 110°C for 12 hours. LCMS showed that the starting material had essentially disappeared, and the target product had formed. 10 mL of water was added to the reaction mixture, and ethyl acetate (20 mL x 2) was added for extraction. The organic layers were combined, washed with saturated brine (10 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was isolated by HPLC to obtain the target compound KH16. LCMS (ESI, m / z) = 481.2 [M+1]+. 1 H NMR(400MHz,DMSO-d6)δ9.09(s,1H),8.39(s,1H),8.08–7.83(m,2H),6.38(s,1H) ,3.87–3.70(m,2H),3.54(d,J=29.5Hz,4H),3.40–3.35(m,1H),3.06–2.85(m,3H).

[0232] Example 17 Synthesis of Compound KH17

[0233] Compound KH17: To a solution of compound KH17-1 (40 mg, 1 eq) in DMF (3 mL) were added HATU (103 mg, 2 eq), DIEA (174 mg, 10 eq), and compound KH17-2 (90 mg, 2 eq) in sequence. After addition, the mixture was stirred at room temperature overnight. After the reaction was complete, water (30 mL) was added for dilution, followed by extraction with ethyl acetate (30 mL x 2). The organic phase was collected. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography to obtain KH17. LCMS (ESI, m / z): 498.3 [M+1]. + .

[0234] Example 18 Synthesis of Compound KH18

[0235] Compound KH18: To a solution of compound KH18-1 (114 mg, 1 eq) in DMF (10 mL) were added HATU (272 mg, 2 eq), DIEA (460 mg, 10 eq), and compound KH18-2 (238 mg, 2 eq) in sequence. After addition, the mixture was stirred at room temperature overnight. After the reaction was complete, water (30 mL) was added for dilution, followed by extraction with ethyl acetate (50 mL x 2). The organic phase was collected. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography to obtain KH18. LCMS (ESI, m / z): 518.2 [M+1] + .

[0236] Example 19 Synthesis of Compound KH19

[0237] Compound KH19: To a solution of compound KH19-1 (130 mg, 1 eq) in DCM (10 mL) were added HATU (329 mg, 2 eq), DIEA (169 mg, 3 eq), and compound KH19-2 (288 mg, 2 eq) in sequence. After addition, the mixture was stirred at room temperature overnight. After the reaction was complete, water (200 mL) was added for dilution, followed by extraction with dichloromethane (100 mL). The organic phase was collected. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography to obtain KH19. LCMS (ESI, m / z): 501.2 [M+1] + .

[0238] Example 20 Synthesis of Compound KH2O

[0239] Compound KH20: To a solution of compound KH20-1 (53 mg, 1 eq) in DMF (6 mL) were added compound KH20-2 (124 mg, 2 eq), HATU (142 mg, 2 eq), and DIEA (241 mg, 10 eq). After addition, the mixture was stirred at room temperature overnight. After the reaction was complete, water (30 mL) was added for dilution, followed by extraction with ethyl acetate (30 mL x 2). The organic phase was collected. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography to obtain KH20. LCMS (ESI, m / z): 483.3 [M+1]. + .

[0240] Example 21 Synthesis of Compound KH21

[0241] Compound KH21: To a solution of compound KH21-1 (40 mg, 1 eq) in DCM (5 mL) were added KH21-2 (119 mg, 2 eq), HATU (136 mg, 2 eq), and DIEA (70 mg, 3 eq) in sequence. After addition, the mixture was stirred at room temperature overnight. After the reaction was complete, water (50 mL) was added for dilution, followed by extraction with dichloromethane (100 mL). The organic phase was collected. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography to obtain KH21. LCMS (ESI, m / z): 425.1 [M+1]. + .

[0242] Example 22 Synthesis of Compound KH22

[0243] Compound KH22: To a solution of compound KH22-1 (60 mg, 1 eq) in DMF (6 mL) were added HATU (161 mg, 2 eq), DIEA (273 mg, 10 eq), and KH22-2 (140 mg, 2 eq) in sequence. After addition, the mixture was stirred at room temperature overnight. After the reaction was complete, water (20 mL) was added for dilution, followed by extraction with ethyl acetate (30 mL x 2). The organic phase was collected. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography to obtain KH22. LCMS (ESI, m / z): 484.2 [M+1]. + .

[0244] Example 23 Synthesis of Compound KH25

[0245] Compound 25-b: To a solution of compound 25-4 (1 g, 5.45 mmol) in THF (10 mL) was added Fe(acac)3 (192 mg, 0.55 mmol) at room temperature. The reaction system was cooled to 0°C, and deuterated methylmagnesium iodide (1.0 M) (13.6 mL, 13.63 mmol) was added. The mixture was allowed to react at 0°C for 1 h. After completion, the reaction was quenched with saturated aqueous ammonium chloride (50 mL) and extracted with ethyl acetate (50 mL × 3). The organic phase was washed with saturated brine (50 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was then purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain a colorless oil (580 mg, 71.6% yield). LCMS (ESI, m / z): 149.2 [M+H]. + . 1 H NMR (400MHz, DMSO-d6) δ7.33 (s, 1H).

[0246] Compound 25-a: To a reaction flask, add 25-0 (5.71 g, 26.4 mmol) and 1,4-dioxane (80 mL), followed by 2-(tri-n-butylstannyl)thiazole (9.9 g, 26.4 mmol), bistriphenylphosphine palladium dichloride (1.85 g, 2.6 mmol), and tri(tetrahydrofuran-2-yl)phosphine (1.25 g, 5.4 mmol). Under nitrogen, heat to 110°C and stir for 16 hours. Cool the reaction mixture to room temperature, and evaporate the solvent under reduced pressure to obtain the crude product. Purify the product on a silica gel column using petroleum ether-methyl tert-butyl ether (100:0-60:40) as eluent. Collect the eluate and evaporate the solvent under reduced pressure to obtain 25-a as a colorless oil (4.2 g, yield: 68%). LCMS purity:95.50% MS Calculated:220.0; MS Found:221.3[M+H] + .

[0247] Compound 25-1: Dissolve 25-a (2.00 g, 9.1 mmol) in a mixture of methanol (18 mL) and water (9 mL). Add NaOH (726 mg, 18.2 mmol) to the reaction flask and stir at room temperature under nitrogen for 1 hour. After completion of the reaction, adjust the pH to 5 by adding 2 mol / L hydrochloric acid. Filter and wash the filter cake with a small amount of water. The filtrate is purified by C18 reverse-phase column [eluent: water-acetonitrile (100:0-95:5)]. The eluate is collected, the acetonitrile is evaporated under reduced pressure, and the mixture is mixed with the filter cake and lyophilized to obtain a pale yellow solid 25-1 (2.3 g, yield: 100%). LCMS (ESI, m / z): purity: 100%; MS calculated: 206.2; MS found: 207.1 [M+H] + .

[0248] Compound 25-2: To a solution of compound 25-1 (100 mg, 0.49 mmol) in DMF (3 mL) were added DIEA (0.24 mL, 1.45 mmol), HATU (188 mg, 0.73 mmol), and compound a (123 mg, 0.58 mmol) at room temperature and allowed to react for 2 h. After completion of the reaction, the reaction mixture was extracted with water (10 mL) and ethyl acetate (15 mL x 3). The organic phase was washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was then purified by silica gel column chromatography (ethyl acetate) to obtain a yellow oil (120 mg, yield 61.7%). LCMS (ESI, m / z): 401.1 [M+H] + .

[0249] Compound 25-3: To a solution of compound 25-2 (120 mg, 0.30 mmol) in ethyl acetate (2 mL) was added ethyl acetate (2 M) (2 mL) and the mixture was allowed to react at room temperature overnight. After the reaction was complete, the mixture was concentrated under vacuum to obtain a crude white solid (90 mg). LCMS (ESI, m / z): 301.0 [M+H] + .

[0250] Compound KH25: Compound 25-b (41 mg, 0.27 mmol) and DIEA (0.12 mL, 0.75 mmol) were added to a solution of compound 25-3 (75 mg, 0.25 mmol) in isopropanol (2 mL), and the mixture was allowed to react at 90°C overnight. After the reaction was complete, the reaction solution was concentrated under reduced pressure to obtain the crude product, which was purified by reverse-phase preparative chromatography to afford a white solid compound (35.06 mg, 34.0% yield). LCMS (ESI, m / z): 413.2 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ8.70–8.65(m,1H),7.94–7.76(m,3H),7.58–7.52(m,1H),6.3 8(s,1H),3.77–3.73(m,1H),3.60–3.48(m,3H),3.43–3.34(m,3H),3.04–2.89(m,3H).

[0251] Example 24 Synthesis of Compound KH26

[0252] Compound KH26: Compound 26-b (90 mg, 0.413 mmol), HATU (188 mg, 0.496 mmol), and DIEA (160 mg, 1.24 mmol) were added to a solution of compound 25-3 (94 mg, 0.454 mmol) in DMF (2 mL) and reacted at room temperature. After completion, the reaction solution was diluted with water (20 mL) and extracted with ethyl acetate (15 mL x 3). The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. Prep-HPLC analysis yielded a white solid (42.04 mg, 25.0%). LCMS (ESI, m / z): 407.1 [M+H] + . 1 H NMR (400MHz, DMSO) δ8.67(m,J=4.8,1.6Hz,1H),7.85(m,J=7.7,1.6Hz,3H),7.55(m,J=7.7,4.8 Hz, 1H), 6.38 (s, 1H), 3.75 (m, J = 11.5, 7.6Hz, 2H), 3.55 (s, 5H), 3.06–2.83 (m, 3H), 2.22 (s, 6H).

[0253] Example 25 Synthesis of Compound KH27

[0254] Compound KH27: Compound 27-b (53 mg, 0.33 mmol) and diisopropylethylamine (0.16 mL, 1.00 mmol) were added to a solution of compound KH25-3 (100 mg, 0.33 mmol) in isopropanol (3 mL). The mixture was reacted at 90°C overnight. After completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by reverse phase preparative chromatography (FA) to obtain a pink solid compound (23.19 mg, 16.4% yield). LCMS (ESI, m / z): 425.3 [M+1]. + . 1H NMR(400MHz,DMSO-d6)δ8.67(s,1H),7.97–7.70(m,3H),7.55(s,1H),3.80–3.6 6(m,2H),3.59–3.45(m,3H),3.35–3.27(m,2H),3.05–2.84(m,3H),2.27(s,6H).

[0255] Example 26 Synthesis of Compound KH28

[0256] Synthesis of Compound 28-1: To a reaction flask, add 28-0 (646 mg, 4.45 mmol), N,N-dimethylformamide (20 mL), compound a (942 mg, 4.45 mmol), and cesium carbonate (2.89 g, 8.9 mmol) in sequence. Under nitrogen, stir in an oil bath at 100°C overnight. After completion, cool to room temperature, add water until clear, and extract with ethyl acetate (50 mL x 3). The combined organic phases are washed twice with saturated ammonium chloride, dried over anhydrous magnesium sulfate, and the solvent is evaporated under reduced pressure to obtain the crude product. Purification is performed on a silica gel column using petroleum ether-methyl tert-butyl ether (100:0-40:60) as eluent. The eluate is collected and the solvent is evaporated under reduced pressure to obtain 28-1 (1.2 g, yield: 83%) as a yellow solid. LCMS (ESI, m / z) purity: 100.00%; MS Calculated: 322.1; MS Found: 323.0[M+H] + .

[0257] Synthesis of compound 28-2: 28-1 (700 mg, 2.17 mmol) and dichloromethane (5 mL) were added to a reaction flask. After sufficient dissolution, dioxane hydrochloride (60 mL) was added and the mixture was stirred at room temperature under nitrogen for 1 hour. After completion of the reaction, the solvent was evaporated under reduced pressure to obtain the crude product 28-2 as a brown solid (650 mg, yield: 100%). LCMS (ESI, m / z) purity: 100%; MS calculated: 222.2; MS found: 223.4 [M+H] + .

[0258] Synthesis of Compound KH28: In a reaction flask, 28-2 (482 mg, 2.17 mmol) was dissolved in N,N-dimethylformamide (6 mL). 25-1 (447 mg, 2.17 mmol), DIPEA (1122 mg, 8.70 mmol), and HATU (1.24 g, 3.25 mmol) were added sequentially. The mixture was stirred at room temperature under nitrogen for 2 hours. After completion, the reaction mixture was added with water and extracted with ethyl acetate (40 mL x 5). The organic phases were combined, washed twice with saturated ammonium chloride, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain a crude product. The product was purified on a silica gel column using dichloromethane-methanol (100:0-15:85) as eluent. The eluate was collected and the solvent was evaporated under reduced pressure to obtain a crude product with a purity of 90%. The crude product was purified via a C18 reverse-phase column [eluent: water-acetonitrile (100:0-40:60)]. The eluate was collected, the acetonitrile was evaporated under reduced pressure, and the mixture was mixed with the filter cake and lyophilized to obtain KH28 (582 mg, yield: 65%). LCMS (ESI, m / z): purity: 100.00%; MS calculated: 410.2; MS found: 411.0 [M+H] + . 1 H NMR (400MHz, CD3OD) δ: 8.66 (dd, J=5.2, 1.6Hz, 1H), 8.08 (d, J=2.0Hz, 1H), 7.83-7.81 (m, 2H), 7.62 (s, 1H), 7.51 (dd, J=8.0, 5.2Hz, 1H), 3 .93-3.89(m,1H),3.85-3.80(m,1H),3.73-3.63(m,4H),3.48-3.40(m,1H),3.16-3.12(m,1H),3.10-3.03(m,2H),2.36(d,J=2.8Hz,3H).

[0259] Example 27 Synthesis of Compound KH29

[0260] Synthesis of compound 29-1: In a single-necked flask, 29-0 (1 g, 4.97 mmol) and Fe(acac)3 (176 mg, 0.5 mmol) were added sequentially to a mixture of THF (15 mL) and NMP (1.5 mL). The mixture was then cooled to 0°C in ice water and slowly added with CD3MgI (12 mL, 12 mmol). Under nitrogen, the mixture was stirred at room temperature for 2 hours. After completion of the reaction, water was added and the mixture was extracted with MTBE (50 mL x 3). The organic phases were combined and the solvent was evaporated under reduced pressure to obtain the crude product. The crude product was purified on a silica gel column using petroleum ether-ethyl acetate (100:0-70:30) as eluent. The eluate was collected and the solvent was evaporated under reduced pressure to obtain 29-1 (570 mg, yield: 69%) as a colorless oil.

[0261] Synthesis of Compound 29-2: To a reaction flask, add 29-1 (570 mg, 3.43 mmol), 1,4-dioxane (12 mL), compound a (728 mg, 3.43 mmol), palladium acetate (77 mg, 0.34 mmol), BINAP (427 mg, 0.69 mmol), and cesium carbonate (2231 mg, 6.86 mmol) in sequence. Under nitrogen, stir the reaction in an oil bath at 100°C overnight. After completion, cool the reaction to room temperature, vacuum filter, collect the filtrate, and evaporate the solvent under reduced pressure to obtain the crude product. Purify the crude product on a silica gel column using petroleum ether-methyl tert-butyl ether (100:0-40:60) as eluent. Collect the eluate and evaporate the solvent under reduced pressure to obtain 29-2 (600 mg, 51% yield) as a white solid. LCMS (ESI, m / z) purity: 87.00%; MS Calculated: 342.2; MS Found: 343.8[M+H] + .

[0262] Synthesis of compound 29-3: 29-2 (140 mg, 0.41 mmol) and dichloromethane (1 mL) were added to a reaction flask. After sufficient dissolution, trifluoroacetic acid (4 mL) was added and the mixture was stirred at room temperature under nitrogen for 1 hour. After completion of the reaction, the solvent was evaporated under reduced pressure to obtain the crude product 29-3 as a yellow solid (90 mg, yield: 91%). LCMS (ESI, m / z) purity: 99.99%; MS calculated: 242.2; MS found: 243.3 [M+H] + .

[0263] Synthesis of compound KH29: In a reaction flask, 29-3 (90 mg, 0.37 mmol) was dissolved in N,N-dimethylformamide (2 mL). 25-1 (76 mg, 0.37 mmol), HATU (212 mg, 0.56 mmol), and DIPEA (120 mg, 0.93 mmol) were added sequentially. The reaction was stirred at room temperature under nitrogen for 1 hour. After completion, the reaction solution was poured into water and extracted with ethyl acetate (40 mL x 3). The combined organic phases were washed with saturated ammonium chloride, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain the crude product. Purification by preparative HPLC yielded KH29 (70 mg, yield: 44%). LCMS (ESI, m / z) purity: 99.44%, Rt = 1.939 min; MS Calculated: 430.2; MS Found: 431.2 [M+H] + .HPLC (method J) purity: 99.76%, Rt=8.521min.1 H NMR(400MHz, DMSO-d6)δ:8.67(dd,J=4.8,1.6Hz,1H),7.86-7.83(m,3H),7.55(dd,J 1=7.6,4.8Hz,1H),3.75-3.69(m,2H),3.53-3.51(m,4H),3.45-3.38(m,1H),3.03-2.99(m,1H),2.91(brs,2H).

[0264] Example 28 Synthesis of Compound KH30

[0265] Synthesis of Compound 30-1: 30-0 (2.5 g, 11.1 mmol) and methanol (50 mL) were added to a reaction flask and stirred until uniform. Thionyl chloride (2.64 g, 22.2 mmol) was then added dropwise. After complete addition, the oil bath was heated to 60°C and stirred for 2 hours. The mixture was cooled to room temperature and the solvent was evaporated under reduced pressure to obtain the crude product. The product was purified on a silica gel column using petroleum ether-methyl tert-butyl ether (100:0-30:70) as eluent. The eluate was collected and the solvent was evaporated under reduced pressure to obtain 30-1 (2.1 g, yield: 79%) as a yellow solid. LCMS (ESI, m / z) purity: 94%, Rt = 0.709 min; MS Calculated: 239.0; MS Found: 240.0 [M+H] + .

[0266] Synthesis of Compound 30-2: 30-1 (2.1 g, 8.78 mmol) and 1,4-dioxane (30 mL) were added to a reaction flask, followed by 2-(tri-n-butylstannyl)thiazole (3.6 g, 9.6 mmol), bistriphenylphosphine palladium dichloride (617 mg, 0.88 mmol), and tri(tetrahydrofuran-2-yl)phosphine (411 mg, 1.77 mmol). Under nitrogen, the temperature was raised to 110°C and stirred for 16 hours. The reaction mixture was cooled to room temperature and the solvent was evaporated under reduced pressure to obtain a crude product. The product was purified on a silica gel column [eluent: petroleum ether-methyl tert-butyl ether (100:0-50:50)]. The eluate was collected and the solvent was evaporated under reduced pressure to obtain 30-2 (2 g, yield: 79%) as a colorless oil. LCMS (ESI, m / z) purity: 65.91%, Rt=1.906min; MS Calculated: 288.0; MS Found: 288.9[M+H] + .

[0267] Synthesis of Compound 30-4: 30-2 (2.00 g, 6.9 mmol) was dissolved in a mixture of methanol (16 mL) and water (4 mL). NaOH (1.1 mg, 27.5 mmol) was added to the reaction flask and stirred at room temperature for 2 hours under nitrogen. After the reaction, the solvent was dried and the pH was adjusted to 4 by adding 2 mol / L hydrochloric acid. A large amount of white solid precipitated and was filtered. The filter cake was washed with a small amount of water and dried under vacuum to obtain a pale white solid 30-4 (2.0 g, yield: 100%). LCMS (ESI, m / z) purity: 100%, Rt = 0.499 min; MS Calculated: 274.00; MS Found: 275.1 [M+H] + .

[0268] Synthesis of Compound 30-6: 30-5 (250 mg, 1.76 mmol), 1,4-dioxane (10 mL), compound a (373 mg, 1.76 mmol), palladium acetate (40 mg, 0.17 mmol), 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (219 mg, 0.34 mmol), and cesium carbonate (1.14 g, 3.5 mmol) were added sequentially to a reaction flask. The mixture was stirred at 100°C under nitrogen for 16 hours. After completion of the reaction, the reaction mixture was filtered, and the filter cake was washed with methanol until the filtrate showed no UV fluorescence. The solvent was then evaporated under reduced pressure to obtain the crude product, which was then purified on a silica gel column using petroleum ether-methyl tert-butyl ether (100:0-40:60) as eluent. The eluate was collected and the solvent was evaporated under reduced pressure to obtain 30-6 as a yellow oil (350 mg, yield: 62%). LCMS (ESI, m / z) purity: 80%, Rt=0.940min; MS Calculated: 318.2; MS Found: 319.3[M+H] + .

[0269] Synthesis of Compound 30-7: 30-6 (210 mg, 0.96 mmol) and dichloromethane (2 mL) were added to a reaction flask. After sufficient dissolution, dioxane hydrochloride (10 mL) was added and the mixture was stirred under nitrogen for 1 hour. After completion of the reaction, the solvent was evaporated under reduced pressure to obtain the crude product 30-7 as a brown solid (200 mg, yield: 100%). The crude product was used directly in the next reaction. LCMS (ESI, m / z): purity: 100%, Rt = 0.530 min; MS Calculated: 218.1; MS Found: 219.3 [M+H] + .

[0270] Synthesis of Compound KH30: 30-7 (140 mg, 0.66 mmol), N,N-dimethylformamide (6 mL), 30-4 (127 mg, 0.46 mmol), 2-(7-azobenzotriazole)-tetramethyluronium hexafluorophosphate (320 mg, 0.84 mmol), and triethylamine (400 mg, 3.96 mmol) were added sequentially to a reaction flask. Under nitrogen protection, the reaction was stirred at room temperature for 1 hour. After completion of the reaction, the reaction solution was poured into water and extracted with ethyl acetate (50 mL x 4). The organic phases were combined, washed with saturated ammonium chloride, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain a crude product, which was purified by preparative HPLC to obtain KH30 (130.68 mg, yield: 59%). LCMS (ESI, m / z) purity: 99.42%, Rt=1.919min; MS Calculated: 474.1; MS Found: 475.0[M+H]+. 1 H NMR (400MHz, DMSO-d6) δ: 8.19 (d, J = 7.6Hz, 1H), 8.06 (d, J = 8.0Hz, 1H), 7.94-7.83 (m, 2 H), 6.38 (s, 1H), 3.78-3.74 (m, 2H), 3.56-3.37 (m, 5H), 3.07-2.93 (m, 3H), 2.22 (m, 6H).

[0271] Comparative Example 1 Synthesis of Compound A

[0272] Compound A was synthesized according to the method described in Example 476 of WO2012145581A1, and its structure is as follows.

[0273] Comparative Example 2 Synthesis of Compound B

[0274] Compound B was synthesized according to the method described in Example 237 of WO2012145581A1, and its structure is as follows.

[0275] Example 29 In vitro cell activity detection

[0276] 1. Cell Culture and Reagent Preparation

[0277] Experimental reagents and consumables

[0278] Cell line: Flp-In-CHO-OX1 / OX2

[0279] Complete medium: Ham's F-12K + 10% FBS + 1x Penicillin-Streptomycin (PS) + 600μg / ml Hygromycin B

[0280] Cell seeding medium: Ham's F-12K + 10% FBS

[0281] Assay buffer: 1X HBSS + 20mM HEPES

[0282] Detection kit: FLIPR Calcium 6 Assay Kit

[0283] 2. Experimental Methods

[0284] 2.1 IC of the test compound 50 Determination of value

[0285] 1) Culture the Flp-In-CHO-OX1 / OX2 stable pool cell line in complete medium at 37°C, 5% CO2, and maintain 70% to 90% confluency.

[0286] 2) After digestion with trypsin (TrypLE Express, ThermoFisher Scientific), the cells were resuspended in inoculation medium and seeded into 384-well cell culture plates (Corning, 3764) at a seeding density of 6500 cells per well in a 25 μL seeding volume at OX1 and 7000 cells per well in a 25 μL seeding volume at OX2. The plates were then incubated overnight at 37°C, 5% CO2.

[0287] 3) Freeze-thaw 20X Component A (calcium ion probe included in the kit, FLIPR Calcium 6 Assay Kit, Molecular Devices) to room temperature, dilute it to 2X working concentration with assay buffer containing 5 mM probenecid, and keep it at room temperature until use.

[0288] 4) Remove the cell culture plate and let it stand at room temperature for 10 minutes. Dilute fetal bovine serum (FBS, Gibco) to 0.03% using an Apricot (384-channel pipetting workstation) and assay buffer, leaving 20 μl of buffer in the 3764-well culture plate. Then, add 20 μl of 2X Component A containing 5 mM probenecid to each well. Centrifuge at 200 g for 3-5 seconds at room temperature and incubate at 37°C for 2 hours.

[0289] 5) Prepare 6x working solutions of the positive control compound and the test compound: dilute the compound 3-fold in DMSO over a 10-step gradient, starting at 1 mM for the positive control compound and 50 mM for the test compound. Transfer 240 nL of each diluted compound into a 384-well plate using an Echo 550. Add 40 μL of buffer, shake for 20 minutes, mix thoroughly, and incubate at room temperature until ready to use.

[0290] 6) Remove the cell culture plate and let it stand at room temperature for 10 minutes. Add 10 μL of the 6X positive control compound and the test compound working solution from step 5) to the corresponding experimental wells of the 384-well cell culture plate and incubate at room temperature for 30 minutes.

[0291] 7) Orexin A was diluted to 18 nM (6X) with assay buffer for orexin type 1 receptor, 50 μL was transferred to a 384-well plate (Corning, 3657), and the plate was incubated at room temperature. Orexin A was diluted to 12 nM (6X) with assay buffer for orexin type 2 receptor, 50 μL was transferred to a 384-well plate (Corning, 3657), and the plate was incubated at room temperature.

[0292] 8) Using FLIPR Tetra (Molecular Devices), add 10 μl of the Orexin A diluted in step 7) to each experimental well and collect data.

[0293] 2.2 Data Analysis

[0294] FLIPR Tetra collects fluorescence signal value / baseline value (ROB), takes the maximum ROB value, and calculates the percentage inhibition rate based on the readings of the negative control (0.1% DMSO) and the positive control (1,000 nM positive control Filorexant): Inhibition rate % = 100-(ROB sample -ROB Min ) / (ROB max -ROB Min )×100, and Prism8 was used to fit the percentage inhibition rate and the data of different compound concentrations to a nonlinear four-parameter logistic formula to calculate the IC50 value of the compound.

[0295] 2.3 Experimental Results

[0296] Table 1 OX2 / OX1 receptor antagonism of different compounds

[0297] Example 30 Animal Efficacy Study

[0298] Experimental purpose: To explore the effect of the test compound on the sleep of SD male rats using telemetry technology.

[0299] Experimental animals: SD rats (male, 5-6 weeks old, weighing approximately 300 g)

[0300] Dosing Information:

[0301] Table 2

[0302] Experimental methods: During the adaptation period, the animals were placed in a 12-hour light-dark alternating environment (lights on at 19:00; lights off at 07:00). On the day of the experiment, the animals were anesthetized with Zotai (ip, 20 mg / kg) combined with thiazine (ip, 8 mg / kg), and electrodes were surgically implanted. The animals recovered for 7 days after surgery. Three days before administration, the rats were given a vehicle by gavage 2 hours after lights off (9:00) every day to adapt to the administration, and the EEG and EMG signals were recorded 1 hour before and 6 hours after the administration of the vehicle on the day before administration. On the day of administration, 2 hours after lights off (9:00), each group of rats was given the corresponding drug by gavage, and the EEG and EMG signals were recorded from 1 hour before administration to 6 hours after administration, and the structural changes of wakefulness (Wake), rapid eye movement sleep (REM), and non-rapid eye movement sleep (NREM) after administration were analyzed (physiological indicators of time and latency). Among them,

[0303] NREM latency change rate (%) = (Dose NREM latency - Base NREM latency) / Base NREM latency × 100%.

[0304] REM latency change rate (%) = (Dose REM latency - Base REM latency) / Base REM latency × 100%

[0305] Awakening duration change rate % = (Dose awakening duration - Base awakening duration) / Base awakening duration × 100%

[0306] NREM sleep duration change rate (%) = (Dose NREM sleep duration - Base NREM sleep duration) / Base NREM sleep duration × 100%

[0307] REM sleep duration change rate (%) = (Dose REM sleep duration - Base REM sleep duration) / Base REM sleep duration × 100%

[0308] Data analysis: Raw data were collected using DSI system Ponemah software and analyzed using NeuroScore software. Experimental data are expressed as mean ± standard error (mean ± SEM) and statistically analyzed using Graph Pad Prism 8.0 software and one-way ANOVA with Dunnet post hoc test. *P or # P<0.05 indicates a significant difference, **P or ## P<0.01 indicates a very significant difference, ***P or ### P<0.001 indicates a very significant difference.

[0309] Experimental results:

[0310] 1) The effects of the control and drug groups on NREM and REM sleep latency in male SD rats are shown in Figures 1 and 2. As shown in Figure 1, the NREM latency change rate was significantly reduced in the groups administered with Example KH16, KH25, and KH27 compared to the negative control group. As shown in Figure 2, the REM latency change rate was significantly shortened in the groups administered with Example KH16, KH25, KH27, and KH30 compared to the negative control group.

[0311] 2) The effects of the control and drug groups on the wake duration index (Wake duration) of SD rats are shown in Figures 3 and 4. The results show that compared with the negative control group, the groups treated with Example KH16, KH25, KH27, and KH30 significantly reduced the wake duration of SD rats 2 hours after drug administration, and the group treated with Example KH27 compound was significantly superior to the other drug groups. Compared with the negative control group, each drug group significantly reduced the wake duration of SD rats 6 hours after drug administration.

[0312] 3) The effects of the control and drug groups on NREM duration (non-rapid eye movement) in SD rats are shown in Figures 5 and 6. The results show that compared to the negative control group, the groups treated with the Example KH16, KH25, and KH27 compounds significantly increased NREM duration in SD rats 2 hours after administration; the KH27 group was significantly superior to the other groups. Compared to the negative control group, the KH16, KH27, and KH30 groups all significantly increased NREM duration in SD rats 6 hours after administration.

[0313] 4) The effects of the control and drug groups on REM duration (rapid eye movement sleep) in SD rats are shown in Figures 7 and 8. The results show that compared with the negative control group, the REM duration of SD rats in each drug group at 2 hours and 6 hours after drug administration showed an increasing trend.

[0314] Example 31 Animal Efficacy Study

[0315] Experimental purpose: To explore the effect of the test compound on the sleep of SD male rats using telemetry technology.

[0316] Experimental animals: SD rats (male, 5-6 weeks old, weighing approximately 300 g)

[0317] Dosing Information:

[0318] Table 3

[0319] Experimental methods: During the adaptation period, the animals were placed in a 12-hour light-dark alternating environment (lights on at 19:00; lights off at 07:00). On the day of the experiment, the animals were anesthetized with Zotai (ip, 20 mg / kg) combined with thiazine (ip, 8 mg / kg), and electrodes were surgically implanted. The animals recovered for 7 days after surgery. Three days before administration, the rats were given a vehicle by gavage 2 hours after lights off (9:00) every day to adapt to the administration, and the EEG and EMG signals were recorded 1 hour before and 6 hours after the administration of the vehicle on the day before administration. On the day of administration, 2 hours after lights off (9:00), each group of rats was given the corresponding drug by gavage, and the EEG and EMG signals were recorded from 1 hour before administration to 6 hours after administration, and the structural changes of wakefulness (Wake), rapid eye movement sleep (REM), and non-rapid eye movement sleep (NREM) after administration were analyzed (physiological indicators of time and latency). Among them,

[0320] NREM latency change rate (%) = (Dose NREM latency - Base NREM latency) / Base NREM latency × 100%

[0321] REM latency change rate (%) = (Dose REM latency - Base REM latency) / Base REM latency × 100%

[0322] Awakening duration change rate % = (Dose awakening duration - Base awakening duration) / Base awakening duration × 100%

[0323] NREM sleep duration change rate (%) = (Dose NREM sleep duration - Base NREM sleep duration) / Base NREM sleep duration × 100%

[0324] REM sleep duration change rate (%) = (Dose REM sleep duration - Base REM sleep duration) / Base REM sleep duration × 100%

[0325] Data Analysis: Raw data were collected using DSI System Ponemah software and analyzed using NeuroScore software. Data are presented as mean ± standard error (SEM) and analyzed using Graph Pad Prism 8.0 software with one-way ANOVA and Dunnett's post hoc test. *P or #P < 0.05 indicates a significant difference, **P or ##P < 0.01 indicates a very significant difference, and ***P or ###P < 0.001 indicates an extremely significant difference.

[0326] Experimental results:

[0327] 1) The effects of the control and drug groups on NREM and REM sleep latency in male SD rats are shown in Figures 9 and 10. As shown in Figure 9, the NREM latency change rate was significantly reduced in the groups administered with Example KH27, KH28, and KH29 compared to the negative control group. As shown in Figure 10, the REM latency change rate was significantly shortened in the groups administered with Example KH27 and KH29 compared to the negative control group.

[0328] 2) The effects of the control and drug groups on the wake duration of SD rats are shown in Figures 11 and 12. As can be seen from the results, compared with the negative control group, the groups treated with the compounds of Examples KH27 and KH29 significantly reduced the wake duration of SD rats 2 hours and 6 hours after administration.

[0329] 3) The effects of the control and drug groups on NREM duration (non-rapid eye movement) in SD rats are shown in Figures 13 and 14. The results show that, compared with the negative control group, the group treated with the Example KH27 compound significantly increased NREM duration in SD rats 2 hours after administration. Compared with the negative control group, both the KH27 and KH29 groups significantly increased NREM duration in SD rats 6 hours after administration.

[0330] 4) The effects of the control and drug groups on REM duration in SD rats are shown in Figures 15 and 16. The results show that compared with the negative control group, both the KH27 and KH29 groups significantly increased NREM duration in SD rats 2 hours after drug administration. Compared with the negative control group, the KH27 group significantly increased NREM duration in SD rats 6 hours after drug administration.

[0331] Example 32 Metabolic stability in human hepatocytes

[0332] Experimental purpose: To study the metabolic stability of compounds in human hepatocytes

[0333] Experimental materials: Human hepatocyte suspension

[0334] Experimental operation: Frozen hepatocytes were taken out of the liquid nitrogen tank and revived, and the cell viability was calculated by trypan blue staining. The hepatocyte suspension was added to the preheated incubation plate, and then the test sample and control compound working solution were added. Mix well and immediately place it in the shaker in the incubator, and start the timer to start the reaction. The reaction was set to 0, 15, 30, 60 and 90 minutes incubation time points. The incubation conditions were 37°C, saturated humidity, and 5% CO2. In the reaction system, the final concentration of the test sample was 1μM, the final concentration of the control was 3μM, and the final concentration of the hepatocytes was 0.5×10 6 cells / mL. At the end of the incubation at the corresponding time point, the incubation plate was removed and an appropriate amount of cell suspension was taken into a sample plate containing a certain volume of stop solution (acetonitrile solution containing 200 ng / mL tolbutamide and labetal). After all sample plates were sealed, they were shaken on a shaker at 600 rpm for 10 minutes and then centrifuged at 3220 × g for 20 minutes. The supernatants of the test and control samples were diluted with ultrapure water at a ratio of 1:3. After all samples were mixed, they were analyzed by LC / MS / MS and the half-life (T 1 / 2 ), the results are shown in Table 4.

[0335] Table 4

[0336] Example 33 Pharmacokinetic Evaluation of Compound

[0337] Experimental purpose: To study the pharmacokinetics of the compound in SD rats - drug concentration in brain tissue

[0338] Experimental animals: SD rats (male, 6-8 weeks old, weight 247.48-255.52g)

[0339] Experimental Procedure: The pharmacokinetic profile of the compound following oral administration in rodents was tested using a standard protocol. A single oral dose of 1 mg / mL clear solution of the compound was administered to rats. The oral vehicle was a 20% aqueous HP-β-CD solution. Male Sprague-Dawley rats were administered a 5 mg / kg oral gavage dose. Whole brains were harvested 0.5, 2, and 4 hours after administration. Tissue samples were homogenized in methanol / 15 mM phosphate buffer (1:2 by volume) with a dilution factor of 6. Sample concentrations were quantified using LC-MS / MS analysis. The results are shown in Table 5.

[0340] Table 5

[0341] Example 34 Pharmacokinetic Evaluation of Compound

[0342] Experimental purpose: To study the pharmacokinetics of the compound in SD rats

[0343] Experimental animals: SD rats (male, 6-8 weeks old, weight 250.13-262.17 g)

[0344] Experimental Procedure: The pharmacokinetic characteristics of the compounds following oral administration were determined in rodents using a standard protocol. A 1 mg / mL clear solution of the compound was administered intravenously or orally to rats. The solvent was 10% DMSO / 80% PEG400 / 10% water. Male Sprague-Dawley rats were administered either intravenously at 1 mg / kg or orally by gavage at 5 mg / kg. Plasma was collected at 0.083 (IV only), 0.25, 0.5, 1, 2, 4, 8, and 24 hours after administration. LC-MS / MS was used to quantify plasma concentrations, and pharmacokinetic parameters such as clearance (Cl), peak concentration (Cmax), half-life (T1 / 2), time to peak concentration (Tmax), and area under the concentration-time curve (AUC0-last) were calculated. The results are shown in Table 6.

[0345] Table 6

[0346] Example 35 Animal Efficacy Study

[0347] Experimental purpose: To explore the effect of the test compound on the sleep of SD male rats using telemetry technology.

[0348] Experimental animals: SD rats (male, 5-6 weeks old, weighing approximately 300 g)

[0349] Dosing Information:

[0350] Table 7

[0351] Experimental Methods: During the acclimation period, animals were placed in a 12-hour light-dark cycle (lights on: 7:00 PM; lights off: 7:00 AM). On the day of the experiment, animals were anesthetized with Zota (ip, 20 mg / kg) combined with thiazine (ip, 8 mg / kg), and electrodes were surgically implanted. Postoperative recovery was allowed for 7 days. For 3 days prior to drug administration, rats were given vehicle by gavage daily, 2 hours after lights off (9:00 AM) for drug acclimation. On the day before drug administration, EEG and EMG signals were recorded 1 hour before and 6 hours after vehicle administration. On the day of drug administration, rats in each group were given the corresponding drug by gavage, 2 hours after lights off (9:00 AM). EEG and EMG signals were recorded from 1 hour before drug administration to 6 hours after drug administration. Changes in wake and non-rapid eye movement (NREM) sleep structure (including duration and latency) were analyzed.

[0352] Data Analysis: Raw data were collected using DSI System Ponemah software and analyzed using NeuroScore software. Data are presented as mean ± standard error (SEM) and analyzed using Graph Pad Prism 8.0 software with one-way ANOVA and Dunnett's post hoc test. *P or #P < 0.05 indicates a significant difference, **P or ##P < 0.01 indicates a very significant difference, and ***P or ###P < 0.001 indicates an extremely significant difference.

[0353] Experimental results:

[0354] 1) The effects of the control group and drug group on NREM sleep latency in SD male rats are shown in Figure 17. As shown in Figure 17, the NREM latency in the group administered with Example KH16 compound was significantly reduced compared with the negative control group.

[0355] 2) The effects of the control group and drug group on the wake duration index of SD rats are shown in Figure 18. From the results, it can be seen that compared with the negative control group, the Example KH16 compound-administered group significantly reduced the wake duration of SD rats 6 hours after administration.

[0356] 3) The effects of the control and drug groups on NREM duration (non-rapid eye movement sleep duration) in SD rats are shown in Figure 19. The results show that compared with the negative control group, the group administered with Example KH16 compound significantly increased NREM duration in SD rats 6 hours after administration.

[0357] The above results show that KH16 at a dose of 5 mg / kg has a sleep improvement effect on rats comparable to that of the positive control drug at a dose of 10 mg / kg.

Claims

1. A compound of the following formula, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that The compound structure is as follows: Ra, Rb and Rc are each independently selected from H, deuterium, halogen, amino, nitro, mercapto, cyano, carboxyl, C1-6 alkyl, C1-6 haloalkyl, C1-6 deuterated alkyl, C1-6 hydroxyalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkoxy, C3-8 cycloalkyl, C3-8 heterocyclyl, C5-10 aryl and C5-10 heteroaryl, said C3-8 cycloalkyl, C3-8 heterocyclyl, C5-10 aryl and C5-10 heteroaryl being optionally substituted with deuterium, halogen, amino, nitro, mercapto, cyano, carboxyl, C1-6 alkyl, C1-6 haloalkyl, C1-6 deuterated alkyl, C1-6 hydroxyalkyl, C1-6 alkoxy, C1-6 haloalkoxy or C1-6 hydroxyalkoxy; R4 is selected from H, deuterium, halogen, hydroxy, amino, nitro, sulfhydryl, cyano, carboxyl, C1-6 alkyl, C1-6 haloalkyl, C1-6 deuterated alkyl, C1-6 hydroxyalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkoxy, C3-8 cycloalkyl, C3-8 heterocyclyl, C6-10 aryl and C5-10 heteroaryl, wherein the C3-8 cycloalkyl, C3-8 heterocyclyl, C6-10 aryl and C5-10 heteroaryl are optionally substituted with deuterium, halogen, amino, nitro, sulfhydryl, cyano, carboxyl, C1-6 alkyl, C1-6 haloalkyl, C1-6 deuterated alkyl, C1-6 hydroxyalkyl, C1-6 alkoxy, C1-6 haloalkoxy or C1-6 hydroxyalkoxy; R5-R 12 , Re and Rd are each independently selected from hydrogen, deuterium, halogen, C1-6 alkyl, C1-6 haloalkyl and C1-6 deuterated alkyl; X1 and X2 are independently selected from CH and N; The heteroatoms in the C3-8 heterocyclic group and the C5-10 heteroaryl group are one, two or three of N, O and S, and the number of heteroatoms is 1, 2 or 3.

2. The compound according to claim 1, its stereoisomer or pharmaceutically acceptable salt thereof, wherein: Ra, Rb and Rc are each independently selected from H, deuterium, halogen, amino, nitro, mercapto, cyano, carboxyl, C1-6 alkyl, C1-6 haloalkyl, C1-6 deuterated alkyl, C1-6 hydroxyalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkoxy, C3-8 cycloalkyl, C3-8 heterocyclyl, C5-10 aryl and C5-10 heteroaryl, said C3-8 cycloalkyl, C3-8 heterocyclyl, C5-10 aryl and C5-10 heteroaryl being optionally substituted with deuterium, halogen, amino, nitro, mercapto, cyano, carboxyl, C1-6 alkyl, C1-6 haloalkyl, C1-6 deuterated alkyl, C1-6 hydroxyalkyl, C1-6 alkoxy, C1-6 haloalkoxy or C1-6 hydroxyalkoxy; R4 is selected from H, deuterium, halogen, hydroxy, amino, nitro, sulfhydryl, cyano, carboxyl, C1-6 alkyl, C1-6 haloalkyl, C1-6 deuterated alkyl, C1-6 hydroxyalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkoxy, C3-8 cycloalkyl and C3-8 heterocyclyl, wherein the C3-8 cycloalkyl and C3-8 heterocyclyl are optionally substituted with deuterium, halogen, amino, nitro, sulfhydryl, cyano, carboxyl, C1-6 alkyl, C1-6 haloalkyl, C1-6 deuterated alkyl, C1-6 hydroxyalkyl, C1-6 alkoxy, C1-6 haloalkoxy or C1-6 hydroxyalkoxy; R5-R 12 , Re and Rd are each independently selected from hydrogen, deuterium, halogen, C1-6 alkyl, C1-6 haloalkyl and C1-6 deuterated alkyl; X1 and X2 are independently selected from CH and N.

3. The compound according to claim 2, its stereoisomer or pharmaceutically acceptable salt thereof, characterized in that The compound has a structure as shown in Formula Ia or Ib: R1, R2 and R3 are each independently selected from H, deuterium, halogen, amino, nitro, sulfhydryl, cyano, carboxyl, C1-6 alkyl, C1-6 haloalkyl, C1-6 deuterated alkyl, C1-6 hydroxyalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkoxy, C3-8 cycloalkyl, C3-8 heterocyclyl, C5-10 aryl and C5-10 heteroaryl, said C3-8 cycloalkyl, C3-8 heterocyclyl, C5-10 aryl and C5-10 heteroaryl being optionally substituted with deuterium, halogen, amino, nitro, sulfhydryl, cyano, carboxyl, C1-6 alkyl, C1-6 haloalkyl, C1-6 deuterated alkyl, C1-6 hydroxyalkyl, C1-6 alkoxy, C1-6 haloalkoxy or C1-6 hydroxyalkoxy; The other substituents are as defined in claim 2.

4. The compound according to claim 2, its stereoisomer or pharmaceutically acceptable salt thereof, characterized in that The compound has a structure as shown in Formula IIIa or IIIb: R1, R2 and R3 are each independently selected from H, deuterium, halogen, amino, nitro, sulfhydryl, cyano, carboxyl, C1-6 alkyl, C1-6 haloalkyl, C1-6 deuterated alkyl, C1-6 hydroxyalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkoxy, C3-8 cycloalkyl, C3-8 heterocyclyl, C5-10 aryl and C5-10 heteroaryl, said C3-8 cycloalkyl, C3-8 heterocyclyl, C5-10 aryl and C5-10 heteroaryl being optionally substituted with deuterium, halogen, amino, nitro, sulfhydryl, cyano, carboxyl, C1-6 alkyl, C1-6 haloalkyl, C1-6 deuterated alkyl, C1-6 hydroxyalkyl, C1-6 alkoxy, C1-6 haloalkoxy or C1-6 hydroxyalkoxy; The other substituents are as defined in claim 2.

5. The compound according to claim 3, its stereoisomer or pharmaceutically acceptable salt thereof, characterized in that The compound is shown in Formula IIa or IIb: The definition of the substituents is as described in claim 3.

6. The compound according to claim 3, its stereoisomer or pharmaceutically acceptable salt thereof, characterized in that: R1, R2 and R3 are each independently selected from H, deuterium, halogen, amino, nitro, mercapto, cyano, carboxyl, C1-6 alkyl, C1-6 haloalkyl, C1-6 deuterated alkyl, C1-6 hydroxyalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkoxy and C3-8 cycloalkyl; preferably, R1, R2 and R3 are independently selected from C1-3 alkyl, C1-3 haloalkyl, C1-3 deuterated alkyl, C1-3 hydroxyalkyl, C1-3 alkoxy, C1-3 haloalkoxy, C1-3 hydroxyalkoxy and C3-8 cycloalkyl. alkyl; preferably, R1 and R3 are independently selected from C1-3 alkyl, C1-3 deuterated alkyl, C1-3 haloalkyl, C1-3 hydroxyalkyl, C1-3 alkoxy and C1-3 haloalkoxy, and R2 is hydrogen; preferably, R1 and R3 are independently selected from methyl, deuterated methyl or hydroxymethyl, and R2 is hydrogen; preferably, R1, R2 and R3 are each independently selected from H, deuterium, halogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 deuterated alkyl, C1-6 hydroxyalkyl, C1-6 alkoxy, C1-6 haloalkoxy and C1-6 hydroxyalkoxy.

7. The compound according to claim 2, its stereoisomer or pharmaceutically acceptable salt thereof, characterized in that: R4 is selected from halogen, hydroxy, C1-3 alkyl, C1-3 haloalkyl, C1-3 deuterated alkyl, C1-3 hydroxyalkyl, C1-3 alkoxy, C1-3 haloalkoxy, C1-3 hydroxyalkoxy and C3-8 cycloalkyl, wherein the C3-8 cycloalkyl is optionally substituted by deuterium, halogen or C1-3 alkyl; preferably, R4 is selected from fluorine, trifluoromethyl or cyclopropyl, wherein the cyclopropyl is optionally substituted by halogen or methyl; preferably, R4 is hydrogen.

8. The compound according to claim 2, its stereoisomer or pharmaceutically acceptable salt thereof, characterized in that: R5-R 12 are each independently selected from hydrogen, deuterium and methyl.

9. The compound according to claim 3 or 5, its stereoisomer or pharmaceutically acceptable salt thereof, characterized in that: The compound satisfies one or more of the following conditions: (1) R1 and R3 are each independently selected from hydrogen, C1-6 alkyl, C1-6 deuterated alkyl and C1-6 hydroxyalkyl; (2) R2 is hydrogen or halogen; (3) R4 is H, C1-6 alkyl, C1-6 haloalkyl or C3-8 cycloalkyl; (4)R5-R 12 are each independently hydrogen.

10. The compound according to claim 9, its stereoisomer or pharmaceutically acceptable salt thereof, wherein: The compound satisfies one or both of the following conditions: (1) R1 and R3 are each independently selected from hydrogen, C1-3 alkyl and C1-3 deuterated alkyl; (2) R4 is hydrogen, C1-3 alkyl or C1-3 haloalkyl.

11. The compound according to claim 9, its stereoisomer or pharmaceutically acceptable salt thereof, characterized in that: The compound satisfies one or more of the following conditions: (1) R1 and R3 are each independently selected from hydrogen, methyl and deuterated methyl; (2) R2 is hydrogen or fluorine; (3) R4 is hydrogen or trifluoromethyl.

12. The compound according to claim 10, its stereoisomer or pharmaceutically acceptable salt thereof, characterized in that: R1 and R3 are each independently selected from C1-3 alkyl and C1-3 deuterated alkyl; preferably, R1 and R3 are each independently selected from methyl and deuterated methyl.

13. The compound according to claim 5, its stereoisomer or pharmaceutically acceptable salt thereof, characterized in that: The compound satisfies one or more of the following conditions: (1) R1 and R3 are C1-3 deuterated alkyl; (2) R2 is hydrogen; (3) R4 is hydrogen or C1-3 haloalkyl.

14. The compound according to claim 13, its stereoisomer or pharmaceutically acceptable salt thereof, characterized in that: R1 and R3 are deuterated methyl groups.

15. The compound according to claim 5, its stereoisomer or pharmaceutically acceptable salt thereof, characterized in that: R1 and R3 are independently C1-3 alkyl, R2 is halogen, and R4 is hydrogen; preferably, R1 and R3 are independently methyl; preferably, R2 is fluorine.

16. The compound according to claim 1, its stereoisomer or pharmaceutically acceptable salt thereof, characterized in that The compound is any of the following structures:

17. A pharmaceutical composition comprising a therapeutically effective dose of the compound according to any one of claims 1 to 16, its stereoisomers or pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable carriers or excipients.

18. Use of the compound according to any one of claims 1 to 16, its stereoisomer or pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 17 in the preparation of an orexin receptor antagonist; preferably in the preparation of an orexin-2 receptor antagonist.

19. Use of the compound according to any one of claims 1 to 16, its stereoisomer or pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 17 in the preparation of a medicament for treating a nervous system disease; the nervous system disease is preferably insomnia, depression or anxiety or drug addiction, more preferably major depressive disorder, primary and secondary insomnia, or depression associated with insomnia.

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