Orexin receptor modulator and preparation method and application thereof

Abstract

The invention discloses an orexin receptor modulator as well as a preparation method and application thereof, and particularly discloses an orexin receptor antagonist shown in the following formula. The orexin receptor antagonist provided by the invention can be used for treating nervous system related diseases. # imgabs0 #

Description

[0001] This application claims the priority of Chinese Patent Application No. 2024101188562 with a filing date of January 29, 2024. This application incorporates the entire text of the above-mentioned Chinese patent application by reference. Technical Field

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

[0003] Orexin, also known as hypocretin and orexigenic peptide, includes orexin A and orexin B (or hypocretin-1 and hypocretin-2), which is a neuropeptide secreted by the hypothalamus. Its main physiological functions are as follows: 1. Regulating food intake, orexin can activate neurons that regulate eating, significantly promote eating, 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, prolong wakefulness time, and blocking the action of orexin can promote sleep; 4. Participating in endocrine regulation, orexin has an obvious effect on the endocrine of pituitary hormones; 5. Being related to 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 the mechanism of drug addiction, etc.

[0004] Orexin produces physiological effects by acting on orexin receptors (OXR). Orexin receptors are a type of G-protein coupled receptor, and there are two types, namely OX1 receptor and OX2 receptor. Among them, the OX1 receptor selectively binds to orexin A, while the OX2 receptor can bind to orexin A and orexin B. The OX1 receptor and OX2 receptor are almost only present in the brain tissue and are selectively expressed in the brain. Among them, the OX1 receptor is highly expressed in the locus coeruleus. The locus coeruleus is the origin nucleus of noradrenergic neurons, while the OX2 receptor is highly expressed in the tuberomammillary nucleus. The tuberomammillary nucleus is the origin nucleus of histaminergic neurons. The expression of both the OX1 receptor and OX2 receptor can be seen in the raphe nucleus. The raphe nucleus is the origin nucleus of serotonergic neurons; the expression of both the OX1 receptor and OX2 receptor can also be seen in the ventral tegmental area. The ventral tegmental area is the origin nucleus of dopaminergic neurons.

[0005] Thus, orexin receptors are of important pathological significance and are associated with a variety of diseases, such as sleep disorders, depression, anxiety, panic disorder, obsessive-compulsive disorder, affective neuropathy, depressive neuropathy, anxiety neuropathy, mood disorder, panic attack disorder, behavioral disorder, emotional disorder, post-traumatic stress disorder, sexual dysfunction, psychosis, schizophrenia, manic-depression, mental confusion, dementia, drug dependence, addiction, cognitive impairment, Alzheimer's disease, Parkinson's disease, movement disorder, eating disorder, headache, migraine, pain, digestive system diseases, epilepsy, inflammation, cardiovascular diseases, diabetes, metabolic diseases, immune-related diseases, endocrine-related diseases, and hypertension, etc.

[0006] Currently, there are already multiple drugs in the clinical stage or on the market, such as Suvoraxant of Merck & Co., Lemborexant of Eisai Co., Ltd., etc., and 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 such structures exhibit good activity, selectivity, brain exposure, brain-to-blood ratio (the ratio of drug concentration in the brain to drug concentration in the plasma, abbreviated as B / P), low toxicity and side effects, long half-life and other effects.

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

[0009]

[0010] 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 heterocyclic group, C5-10 aryl, C5-10 heteroaryl, and the C3-8 cycloalkyl, C3-8 heterocyclic group, C5-10 aryl, C5-10 heteroaryl are optionally substituted by 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;

[0011] R4 is selected from H, deuterium, halogen, hydroxyl, 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 heterocyclic group, C6-10 aryl and C5-10 heteroaryl, and the C3-8 cycloalkyl, C3-8 heterocyclic group, C6-10 aryl and C5-10 heteroaryl are optionally substituted by 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;

[0012] R5-R 12 、R e 、R d each independently is selected from hydrogen, deuterium, halogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 deuterated alkyl;

[0013] X1 and X2 independently are selected from CH or N;

[0014] The heteroatoms in the C3-8 heterocyclic group and C5-10 heteroaryl are one, two or three of N, O and S, and the number of heteroatoms is 1, 2 or 3.

[0015] In some embodiments, the structure of the compound is as follows:

[0016]

[0017] Ra, Rb, and Rc each independently are 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 heterocyclic group, C5-10 aryl, C5-10 heteroaryl, and the C3-8 cycloalkyl, C3-8 heterocyclic group, C5-10 aryl, C5-10 heteroaryl are optionally substituted by 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;

[0018] R4 is selected from H, deuterium, halogen, hydroxyl, 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 heterocyclic group, and the C3-8 cycloalkyl and C3-8 heterocyclic group are optionally substituted by 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;

[0019] R5-R 12 、R e 、R d each independently is selected from hydrogen, deuterium, halogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 deuterated alkyl;

[0020] X1 and X2 are selected from C or N.

[0021] In some embodiments, the compound of the present invention has the structures shown in Formula Ia or Ib:

[0022]

[0023] R1, R2 and R3 each independently are 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 heterocyclic group, C5-10 aryl, C5-10 heteroaryl, and the C3-8 cycloalkyl, C3-8 heterocyclic group, C5-10 aryl and C5-10 heteroaryl are optionally substituted by 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;

[0024] The definitions of other substituents are as described above.

[0025] In some embodiments, the compound of the present invention has the structures shown in Formula IIIa or IIIb:

[0026]

[0027] 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, C3-8 cycloalkyl, C3-8 heterocyclic group, C5-10 aryl, C5-10 heteroaryl, and the C3-8 cycloalkyl, C3-8 heterocyclic group, 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, or C1-6 hydroxyalkoxy;

[0028] The definitions of other substituents are as described above.

[0029] In some other embodiments, the compounds of the present invention have the structures shown in Formula IIa or IIb:

[0030]

[0031] Wherein, the definitions of the substituents are as described above.

[0032] In some embodiments, in the compounds, stereoisomers, or pharmaceutically acceptable salts thereof of the present invention, 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, C3-8 cycloalkyl.

[0033] In some embodiments, in the compounds, stereoisomers, or pharmaceutically acceptable salts thereof of the present invention, 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, C3-8 cycloalkyl.

[0034] In some embodiments, in the compounds, stereoisomers, or pharmaceutically acceptable salts thereof of the present invention, 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.

[0035] In some embodiments, in the compounds, stereoisomers, or pharmaceutically acceptable salts thereof of the present invention, R1 and R3 are independently selected from methyl, deuterated methyl, hydroxymethyl, and R2 is hydrogen.

[0036] In some embodiments, in the compounds, stereoisomers or pharmaceutically acceptable salts thereof of the present invention, 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, C1-6 hydroxyalkoxy.

[0037] In some embodiments, in the compounds, stereoisomers or pharmaceutically acceptable salts thereof of the present invention, 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, C1-3 alkyl.

[0038] In some embodiments, in the compounds, stereoisomers or pharmaceutically acceptable salts thereof of the present invention, R4 is selected from fluorine, trifluoromethyl, cyclopropyl, and the cyclopropyl is optionally substituted with halogen or methyl.

[0039] In some embodiments, in the compounds, stereoisomers or pharmaceutically acceptable salts thereof of the present invention, R5-R 12 are each independently selected from hydrogen, deuterium or methyl.

[0040] In some embodiments, in the compounds, stereoisomers or pharmaceutically acceptable salts thereof of the present invention, R4 is hydrogen.

[0041] In some embodiments, in the compounds, stereoisomers or pharmaceutically acceptable salts thereof of the present invention, R1 and R3 are each independently selected from hydrogen, C1-6 alkyl, C1-6 deuterated alkyl and C1-6 hydroxyalkyl.

[0042] In some embodiments, in the compounds, stereoisomers or pharmaceutically acceptable salts thereof of the present invention, R4 is H, C1-6 haloalkyl or C3-8 cycloalkyl.

[0043] In some embodiments, in the compounds, stereoisomers or pharmaceutically acceptable salts thereof of the present invention, R4 is H, trifluoromethyl or cyclopropyl.

[0044] In some embodiments, in the compounds, stereoisomers or pharmaceutically acceptable salts thereof of the present invention, R1 and R3 are each independently selected from hydrogen, C1-3 alkyl and C1-3 deuterated alkyl.

[0045] In some embodiments, in the compounds, stereoisomers or pharmaceutically acceptable salts thereof of the present invention, R2 is hydrogen or halogen.

[0046] In some embodiments, in the compounds, their stereoisomers or pharmaceutically acceptable salts of the present invention, R4 is hydrogen, C1-3 alkyl or C1-3 haloalkyl.

[0047] In some embodiments, in the compounds, their stereoisomers or pharmaceutically acceptable salts of the present invention, R5-R 12 are each independently hydrogen.

[0048] In some embodiments, in the compounds, their stereoisomers or pharmaceutically acceptable salts of the present invention, R1 and R3 are each independently selected from C1-3 alkyl and C1-3 deuterated alkyl.

[0049] In some embodiments, in the compounds, their stereoisomers or pharmaceutically acceptable salts of the present invention, R1 and R3 are independently C1-3 deuterated alkyl.

[0050] In some embodiments, in the compounds, their stereoisomers or pharmaceutically acceptable salts of the present invention, R4 is hydrogen or C1-3 haloalkyl.

[0051] In some embodiments, in the compounds, their stereoisomers or pharmaceutically acceptable salts of the present invention, R1 and R3 are each independently selected from hydrogen, methyl and deuterated methyl.

[0052] In some embodiments, in the compounds, their stereoisomers or pharmaceutically acceptable salts of the present invention, R1 and R3 are independently methyl or deuterated methyl.

[0053] In some embodiments, in the compounds, their stereoisomers or pharmaceutically acceptable salts of the present invention, R1 and R3 are deuterated methyl.

[0054] In some embodiments, in the compounds, their stereoisomers or pharmaceutically acceptable salts of the present invention, R1 and R3 are independently H, -CH3, -CHD2, -CH2D, -CD3.

[0055] In some embodiments, in the compounds, their stereoisomers or pharmaceutically acceptable salts of the present invention, R1 and R3 are independently H, -CH3 or -CD3.

[0056] In some embodiments, in the compounds, their stereoisomers or pharmaceutically acceptable salts of the present invention, R1 and R3 are -CD3.

[0057] In some embodiments, in the compounds, their stereoisomers or pharmaceutically acceptable salts of the present invention, R1 and R3 are independently -CH3 or -CD3.

[0058] In some embodiments, in the compounds, their stereoisomers or pharmaceutically acceptable salts of the present invention, R4 is hydrogen or trifluoromethyl.

[0059] In some embodiments, in the compounds, their stereoisomers or pharmaceutically acceptable salts of the present invention, R2 is hydrogen or fluorine.

[0060] In some embodiments, in the compounds, their stereoisomers or pharmaceutically acceptable salts of the present invention, R2 is hydrogen.

[0061] In some embodiments, in the compounds, their stereoisomers or pharmaceutically acceptable salts of the present invention, R1 and R3 are independently C1-3 alkyl, R2 is halogen, and R4 is hydrogen.

[0062] In some embodiments, in the compounds, their stereoisomers or pharmaceutically acceptable salts of the present invention, R1 and R3 are methyl.

[0063] In some embodiments, in the compounds, their stereoisomers or pharmaceutically acceptable salts of the present invention, R2 is fluorine.

[0064] In some embodiments, in the compounds, their stereoisomers or pharmaceutically acceptable salts of the present invention, R4 is H, -F, -CF3,

[0065] In some embodiments, in the compounds, their stereoisomers or pharmaceutically acceptable salts of the present invention, R c is H, -F, -Cl, -CH3, -CH2CH3, -CD3, -CF3, or -OCH3.

[0066] In some embodiments, in the compounds, their stereoisomers or pharmaceutically acceptable salts of the present invention, R1 is H, -CH3, -CH2CH3, -CD3, -CF3,

[0067] In some embodiments, in the compounds, their stereoisomers or pharmaceutically acceptable salts of the present invention, R2 is H, -Cl, -F, -CF3 or -OCH3.

[0068] In some embodiments, in the compounds, their stereoisomers or pharmaceutically acceptable salts of the present invention, R3 is H, -CH3, -CD3 or

[0069] On the other hand, the present invention provides a compound having the structure as described below, its stereoisomers or its pharmaceutically acceptable salts:

[0070]

[0071]

[0072]

[0073] On the other hand, the present invention provides a pharmaceutical composition comprising the above compound, its stereoisomers or its pharmaceutically acceptable salts, and one or more pharmaceutically acceptable carriers or excipients.

[0074] On the other hand, the present invention provides the use of the above compound, its stereoisomers or its pharmaceutically acceptable salts, or the above pharmaceutical composition in the preparation of an orexin receptor antagonist; preferably in the preparation of an OX2 receptor antagonist.

[0075] On the other hand, the present invention provides the use of the above compound, its stereoisomers or its pharmaceutically acceptable salts, or the above 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, more preferably severe depression, primary and secondary insomnia or depression accompanied by insomnia.

[0076] On the other hand, the present invention provides the use of the above compound, its stereoisomers or its pharmaceutically acceptable salts, or the above pharmaceutical composition in the preparation of a drug for treating diseases related to orexin receptors; the diseases are preferably nervous system diseases.

[0077] In some embodiments, the nervous system diseases are insomnia, depression or anxiety, drug addiction, preferably severe depression, primary and secondary insomnia or depression accompanied by insomnia.

[0078] On the other hand, the present invention provides a method for preparing a compound of formula I, which comprises the following steps:

[0079]

[0080] It further comprises the following steps:

[0081]

[0082] It further comprises the following steps:

[0083]

[0084] Alternatively, the present invention provides an intermediate having the following structure:

[0085]

[0086]

[0087] Among them, each substituent is defined as described above.

[0088] On the other hand, the present invention provides a method for preparing a compound of formula II, which comprises the following steps:

[0089]

[0090] It further comprises the following steps:

[0091]

[0092] It further comprises the following steps:

[0093]

[0094] Alternatively, the present invention provides the following intermediates:

[0095]

[0096]

[0097] Among them, each substituent is defined as described above.

[0098] Term Explanation

[0099] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0100] In the present invention, an alkyl group refers to a saturated aliphatic hydrocarbon group, which is a straight-chain 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 isomers thereof, etc.

[0101] More preferably, it is a lower alkyl group containing 1 to 6 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, etc.

[0102] The alkyl group can be substituted or unsubstituted. When substituted, the substituent can be substituted at any available connection point. 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 group. In the present invention, methyl, ethyl, isopropyl, tert-butyl, haloalkyl, deuterated alkyl, alkoxy-substituted alkyl and hydroxy-substituted alkyl are preferred; the hydroxy-substituted alkyl can be 2-hydroxyisopropyl or 1-hydroxyethyl.

[0103] In the present invention, the cycloalkyl group refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent. 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.

[0104] Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, etc.; polycyclic cycloalkyl groups include spirocycloalkyl, fused cycloalkyl and bridged cycloalkyl.

[0105] In the present invention, the spirocycloalkyl group refers to a polycyclic group in which a 5- to 20-membered monocyclic ring shares a carbon atom (referred to as a spiro atom). It can contain one or more double bonds, but none of the rings 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 spiro atoms shared between rings, the spirocycloalkyl group is divided into monospirocycloalkyl, dispirocycloalkyl or polyspirocycloalkyl, preferably monospirocycloalkyl and dispirocycloalkyl. More preferably, it is 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered or 5-membered / 6-membered monospirocycloalkyl. Non-limiting examples of spirocycloalkyl groups include:

[0106]

[0107] It also includes spirocycloalkyl groups in which a monospirocycloalkyl group shares a spiro atom with a heterocycloalkyl group. Non-limiting examples include:

[0108]

[0109] In the present invention, a fused cycloalkyl group refers to a fully carbon polycyclic group having 5 to 20 ring atoms, wherein each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, and one or more rings may contain one or more double bonds, but no ring has a fully conjugated π-electron system. Preferably, it has 6 to 14 ring atoms, more preferably 7 to 10 ring atoms. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl groups, preferably bicyclic or tricyclic, more preferably 5-membered / 5-membered or 5-membered / 6-membered bicyclic alkyl groups. Non-limiting examples of the fused cycloalkyl group include:

[0110]

[0111] In the present invention, a bridged cycloalkyl group refers to a fully carbon polycyclic group having 5 to 20 ring atoms, wherein any two rings share two non-directly connected carbon atoms, and it may contain one or more double bonds, but no ring has a fully conjugated π-electron system. Preferably, it has 6 to 14 ring atoms, more preferably 7 to 10 ring atoms. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of the bridged cycloalkyl group include:

[0112]

[0113] The cycloalkyl ring may be fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring connected to the parent structure is a cycloalkyl group. Non-limiting examples include indanyl, tetrahydronaphthyl, benzocycloheptyl, etc. The cycloalkyl group may be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more of the following groups, which are 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 group.

[0114] In the present invention, a 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) mheteroatoms (where m is an integer from 0 to 2), but excluding ring moieties of -O-O-, -O-S- or -S-S-, and the remaining ring atoms are carbon. Preferably it contains 3 to 12 ring atoms, where 1 to 4 are heteroatoms; more preferably it contains 3 to 10 ring atoms; still more preferably it contains 3 to 8 ring atoms. Non-limiting examples of monocyclic heterocyclic groups include pyrrolidinyl, pyrrolidinone group, piperidin-2-one group, 3,4-dihydropyridin-2(1H)-one group, 4,5-dihydropyridazin-3(2H)-one group, azetidinyl, oxetanyl, oxanyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, etc.; preferably pyrrolidinyl, pyrrolidinone group, piperidin-2-one group, 3,4-dihydropyridin-2(1H)-one group, 4,5-dihydropyridazin-3(2H)-one group, azetidinyl, oxetanyl, dihydropyrrolyl, tetrahydrofuranyl, pyrazolidinyl, morpholinyl, piperazinyl and pyranyl; more preferably dihydropyrrolyl, pyrrolidinyl, pyrrolidinone group, piperidin-2-one group, 3,4-dihydropyridin-2(1H)-one group, 4,5-dihydropyridazin-3(2H)-one group, azetidinyl, oxetanyl, oxanyl, morpholinyl, piperidinyl, piperazinyl,

[0115] pyranyl. Polycyclic heterocyclic groups include spiro, fused and bridged heterocyclic groups; the spiro, fused and bridged heterocyclic groups involved are optionally connected to other groups by a single bond, or further fused to other cycloalkyl groups, heterocyclic groups, aryl groups and heteroaryl groups through any two or more atoms on the ring.

[0116] In the present invention, a spiroheterocyclic group refers to a polycyclic heterocyclic group with a single atom (referred to as a spiro atom) shared between 5- to 20-membered monocyclic rings, where one or more ring atoms are heteroatoms selected from nitrogen, oxygen or S(O) m (where m is an integer from 0 to 2), 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. Preferably it is 6 to 14-membered, more preferably 7 to 10-membered. According to the number of spiro atoms shared between rings, the spiroheterocyclic group is divided into a monospiroheterocyclic group, a bispiroheterocyclic group or a multispiroheterocyclic group, preferably a monospiroheterocyclic group and a bispiroheterocyclic group. More preferably it is a 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered or 5-membered / 6-membered monospiroheterocyclic group. Non-limiting examples of spiroheterocyclic groups include:

[0117]

[0118] In the present invention, the fused heterocyclic group refers to a polycyclic heterocyclic group having 5 to 20 members, wherein each ring in the system shares an adjacent pair of atoms with other rings in the system, and one or more rings may contain one or more double bonds, but none of the rings has a completely conjugated π-electron system, and one or more ring atoms are heteroatoms selected from nitrogen, oxygen or S(O) m (where m is an integer from 0 to 2), and the remaining ring atoms are carbon. It is preferably 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 the fused heterocyclic group include:

[0119]

[0120] In the present invention, the bridged heterocyclic group refers to a polycyclic heterocyclic group having 5 to 14 members, wherein any two rings share two non-directly connected atoms, and it may contain one or more double bonds, but none of the rings has a completely conjugated π-electron system, and one or more ring atoms are heteroatoms selected from nitrogen, oxygen or S(O) m (where m is an integer from 0 to 2), and the remaining ring atoms are carbon. It is preferably 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 bridged heterocyclic groups, preferably bicyclic, tricyclic or tetracyclic, and more preferably bicyclic or tricyclic. Non-limiting examples of the bridged heterocyclic group include:

[0121]

[0122] The heterocyclic group ring may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring connected to the parent structure is the heterocyclic group, and non-limiting examples thereof include:

[0123]

[0124] The heterocyclic group may be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more of the following groups, which are 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 group.

[0125] In the present invention, the aryl group refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (i.e., rings sharing adjacent carbon atom pairs) group having a conjugated π-electron system, preferably 6 to 10 members, more preferably 6 to 8 members, such as phenyl and naphthyl, and preferably phenyl. The aryl ring may be fused to a heteroaryl, heterocyclic or cycloalkyl ring, wherein the ring connected to the parent structure is the aryl ring, and non-limiting examples thereof include:

[0126]

[0127] The aryl group may be substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, which are 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 group.

[0128] In the present invention, the heteroaryl group refers to a heteroaromatic system containing 1 to 4 heteroatoms and 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. The heteroaryl group is preferably 5 to 10-membered, more preferably 5 to 8-membered, and most preferably 5-membered or 6-membered, such as pyrazinyl, pyridazinyl, imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, isoxazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, oxadiazole, pyrazinyl, etc., and preferably pyrimidinyl, pyrazolyl, oxazolyl, isoxazolyl, oxadiazole, pyridine. The heteroaryl ring may be fused to an aryl, heterocyclic or cycloalkyl ring, and the ring connected to the parent structure is the heteroaryl ring. Non-limiting examples thereof include:

[0129]

[0130] The heteroaryl group may be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, which are 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 group.

[0131] In the present invention, the alkoxy group refers to -O-(alkyl) and -O-(unsubstituted cycloalkyl), wherein the alkyl group is defined as 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 the alkoxy group include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy. The alkoxy group may be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, which are 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 group;

[0132] Non-limiting examples of the alkoxy group also include: propan-2-oxy, etc.

[0133] In the present invention, haloalkyl refers to an alkyl group substituted by one or more halogen atoms, wherein the alkyl group is as defined above. Non-limiting examples of haloalkyl include: trifluoromethyl, trifluoroethyl;

[0134] Non-limiting examples of haloalkyl also include: difluoromethyl, 1,1,2,2-tetrafluoroethyl, perfluoroethyl, etc.

[0135] In the present invention, haloalkoxy refers to an alkoxy group substituted by one or more halogen atoms, wherein the alkoxy group is as defined above;

[0136] The haloalkoxy group can be fully halogenated or partially halogenated, and the number of halogen atoms can be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, etc.; the halogen is preferably F, Cl, Br, I; for example, it can be trifluoromethoxy, difluoromethoxy, 1,1,2,2-tetrafluoroethoxy, perfluoroethoxy, etc.

[0137] In the present invention, hydroxyalkyl refers to an alkyl group substituted by a hydroxy group, wherein the alkyl group is as defined above.

[0138] In the present invention, alkenyl refers to an alkenyl group, also known as an olefinic group, preferably an alkenyl group containing 2 to 8 carbon atoms, more preferably an alkenyl group containing 2 to 6 carbon atoms, still more 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 include: vinyl, propenyl. Wherein the alkenyl group can be further substituted by other relevant groups, for example: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate group.

[0139] In the present invention, alkynyl refers to an alkynyl group, also known as an alkynic group, referring 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, still more preferably an alkynyl group containing 2 to 4 carbon atoms, and most preferably an alkynyl group containing 2 to 3 carbon atoms. Wherein the alkynyl group can be further substituted by other relevant groups, for example: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate group.

[0140] In the present invention, hydroxy refers to the -OH group.

[0141] In the present invention, halogen refers to fluorine, chlorine, bromine or iodine.

[0142] In the present invention, amino refers to -NH2.

[0143] In the present invention, cyano refers to -CN.

[0144] In the present invention, nitro refers to -NO2.

[0145] In the present invention, carboxyl refers to -C(O)OH.

[0146] Any hydrogen atom in the present invention can be replaced by its isotope deuterium, and any hydrogen atom in the exemplified compounds involved in the present invention can also be replaced by a deuterium atom.

[0147] In the present invention, unless otherwise specified, according to the technology described in the present invention or the technology known in the art that is immediately disclosed, the substituents on the cyclic group (for example, aryl, heteroaryl, fused ring, saturated or unsaturated cycloalkyl or heterocycloalkyl) are intended to mean 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 is the same or different. For example, the cyclic group means that any substitutable position of ring A is substituted by one or more Rc. Another example, the cyclic group includes the following non-limiting examples: And when there is more than one Rc substitution on the benzene ring, each Rc can be the same or different. In some embodiments, the cyclic group includes the following non-limiting examples: And when there is more than one Rc substitution on the ring, each Rc can be the same or different.

[0148] In the present invention, "optionally" or "optionally" means that the subsequent described event or circumstance can but does not have to occur. For example, "a heterocyclic group optionally substituted by an alkyl group" means that the alkyl group can but does not have to be present, and this description includes the case where the heterocyclic group is substituted by an alkyl group and the case where the heterocyclic group is not substituted by an alkyl group.

[0149] In the present invention, "substituted" means that one or more hydrogen atoms in the group, preferably up to 5, more preferably 1 to 3 hydrogen atoms, are independently replaced by the 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) the possible or impossible substitutions without much effort. For example, an amino group or a hydroxyl group with a free hydrogen may be unstable when combined with a carbon atom having an unsaturated (such as olefinic) bond.

[0150] The compounds of this patent application include their isotopic derivatives. The term "isotopic derivative" refers to a compound that differs structurally 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-isotopes) replacing carbon atoms are within the scope of this patent application. Such compounds can be used, for example, as analytical tools or probes in biological assays, or can be used as in vivo diagnostic imaging tracers for diseases, or as tracers for pharmacodynamic, pharmacokinetic, or receptor studies. The various deuterated forms of the compounds of this patent application mean that each available hydrogen atom attached to a carbon atom can be independently replaced by a deuterium atom. Those skilled in the art can refer to relevant literature to synthesize deuterated forms of the compounds. Commercially available deuterated starting materials can be used in the preparation of deuterated compounds, or they can be synthesized using conventional techniques with deuterated reagents, including but not limited to deuterated borane, tetrahydrofuran solution of trideuterated borane, deuterated lithium aluminum hydride, deuterated iodoethane, and deuterated iodomethane, etc. Deuterated compounds usually retain activities comparable to those of the undeuterated compounds, and when deuteration occurs at certain specific sites, better metabolic stability can be achieved, thus obtaining certain therapeutic advantages.

[0151] The compounds of this patent application can exist in specific stereoisomeric forms. The term "stereoisomer" refers to isomers that have 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, diastereoisomers, (D)- and (L)-isomers, tautomers, atropisomers, conformational isomers, and their mixtures (such as racemates, mixtures of diastereoisomers). The substituents in the compounds of this patent application can have additional asymmetric atoms. All 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 certain compound of this patent application can be prepared by asymmetric synthesis or chiral auxiliaries, or, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), form diastereoisomeric salts with appropriate optically active acids or bases, and then perform diastereoisomer separation by conventional methods well-known in the art to obtain the pure isomer. In addition, the separation of enantiomers and diastereoisomers is usually accomplished by chromatography.

[0152] The structure 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 absolute configuration of the compounds involved in the present application is concerned, the absolute configuration can be confirmed by conventional technical means in the art. For example, in single crystal X-ray diffraction (SXRD), the grown single crystal is used to collect diffraction intensity data with a Bruker D8 venture diffractometer, the light source is CuKα radiation, and the scanning mode: Scanning. After collecting the relevant data, the crystal structure is further analyzed by the direct method (Shelxs97) to confirm the absolute configuration.

[0153] In the chemical structure of the compounds 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 or contain both and configurations at the same time. Unless otherwise specified, in the present invention, the wedge solid line bond and the wedge dashed line bond represent the cis-trans isomerism of the stereocenter. For example, the wedge dashed line bond in represents that the two substituents Rd and Re are cis, that is, Rd and Re are on the same side of the plane.

[0154] The compounds of this patent application can exist in different tautomeric forms, and all such forms are included within the scope of this patent application. The term "tautomer" or "tautomeric form" refers to structural isomers that exist in equilibrium and are easily convertible from one isomeric form to another. It includes all possible tautomers, that is, existing in the form of a single isomer or a mixture in any proportion of the said tautomers. 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 the compounds does not exclude any tautomer.

[0155] 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 the pharmaceutical composition is to facilitate the administration to an organism, facilitate the absorption of the active ingredient and thus exert its biological activity.

[0156] In the present invention, a pharmaceutically acceptable salt refers to a salt of the compound of the present invention, which has safety and effectiveness when used in mammals and has the due biological activity.

[0157] For a drug or a pharmacological active agent, the term "therapeutically effective amount" refers to the 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 on the specific active substance. In a particular case, the appropriate therapeutically effective amount can be determined by those skilled in the art according to conventional tests.

[0158] As used herein, the term "pharmaceutically acceptable" means that these compounds, materials, compositions and / or dosage forms are, within the scope of reasonable medical judgment, suitable for contact with the tissues of a patient without excessive toxicity, irritation, allergic response or other problems or complications, have a reasonable benefit / risk ratio, and are effective for their intended use.

[0159] As used herein, the singular forms "a", "an" and "the" include plural references and vice versa, unless the context clearly indicates otherwise.

[0160] In the present invention, "a plurality of" means two or more than two, for example, it can be an integer number such as two, three, four, five, six, seven, eight, etc.

[0161] When the term "about" is applied to parameters 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 the parameter is not critical, numbers are usually given for illustrative purposes only and not for limitation. Description of the Drawings

[0162] Figure 1 Change rate of NREM sleep latency in male SD rats in Example 30.

[0163] Figure 2 Change rate of REM sleep latency in male SD rats in Example 30.

[0164] Figure 3 Change rate of wake duration in SD rats 2 h after administration in Example 30.

[0165] Figure 4 Change rate of wake duration in SD rats 6 h after administration in Example 30.

[0166] Figure 5 Change rate of NREM duration (non-rapid eye movement sleep duration) in SD rats 2 h after administration in Example 30.

[0167] Figure 6Change rate of NREM duration in SD rats 6 hours after drug administration in Example 30.

[0168] Figure 7 Change rate of REM duration in SD rats 2 hours after drug administration in Example 30.

[0169] Figure 8 Change rate of REM duration in SD rats 6 hours after drug administration in Example 30.

[0170] Figure 9 Change rate of NREM sleep latency in male SD rats in Example 31.

[0171] Figure 10 Change rate of REM sleep latency in male SD rats in Example 31.

[0172] Figure 11 Change rate of wake duration in SD rats 2 hours after drug administration in Example 31.

[0173] Figure 12 Change rate of wake duration in SD rats 6 hours after drug administration in Example 31.

[0174] Figure 13 Change rate of NREM duration in SD rats 2 hours after drug administration in Example 31.

[0175] Figure 14 Change rate of NREM duration in SD rats 6 hours after drug administration in Example 31.

[0176] Figure 15 Change rate of REM duration in SD rats 2 hours after drug administration in Example 31.

[0177] Figure 16 Change rate of REM duration in SD rats 6 hours after drug administration in Example 31.

[0178] Figure 17 Change rate of NREM sleep latency in SD rats in Example 35.

[0179] Figure 18 Change rate of wake duration in SD rats 6 hours after drug administration in Example 35.

[0180] Figure 19 Change rate of NREM duration in SD rats 6 h after drug administration in Example 35. Detailed implementation manners

[0181] The abbreviations in this article have the following meanings:

[0182]

[0183]

[0184] Unless otherwise specified, the reaction temperature is room temperature (20 °C to 30 °C).

[0185] The compound structures described in the following examples are confirmed by nuclear magnetic resonance hydrogen spectrum ( 1 1H-NMR) or mass spectrometry (MS).

[0186] Synthesis of compound KH01 in Example 1

[0187]

[0188] Compound KH01-1: To a toluene (15 mL) solution of compound 1 (1.5 g, 5.99 mmol), add 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), and react at 100 °C for 2 h. After the reaction is complete, wait for the reaction solution to return to room temperature, add water, extract the organic phase with ethyl acetate, wash with saturated brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure in vacuo to obtain a crude product; then purify the crude product 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 1H NMR (400 MHz, DMSO) δ 8.40 (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).

[0189] 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 bis(triphenylphosphine)palladium(II) dichloride (155 mg, 0.213 mmol), and the mixture was reacted at 100 °C for 12 h. After the reaction was complete, 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 (400 MHz, DMSO) δ 8.56 (d, J = 2.1 Hz, 1H), 7.94 (d, J = 3.0 Hz, 1H), 7.86 (d, J = 3.1 Hz, 1H), 7.65 (d, J = 2.1 Hz, 1H), 3.79 (s, 3H), 2.12–2.05 (m, 1H), 1.10–1.07 (m, 2H), 0.89–0.87 (m, 2H).

[0190] 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 the mixture was reacted at 60 °C for 1 h. After the reaction was complete, 1 M hydrochloric acid (6 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (30 mL × 2). The organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated by rotary evaporation to obtain compound KH01-3. LCMS (ESI, m / z): 247.0 [M+1] + .

[0191] 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 the mixture was 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 (20 mL × 2). The organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5 / 1 - 2 / 1) to obtain KH01-5. 1 H NMR (400 MHz, CDCl3) δ 8.50 (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).

[0192] Compound KH01-6: To a solution of compound KH01-5 (630 mg, 1.76 mmol) in ethyl acetate (5 mL) was added 1 M hydrochloric acid in ethyl acetate solution (17.6 mL, 17.6 mmol), and the reaction was carried out at room temperature for 12 h. After the reaction was complete, it was concentrated under reduced pressure to obtain KH01-6. LCMS (ESI, m / z): 259.0 [M+1] + 。

[0193] 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 the reaction was carried out at room temperature overnight. After the reaction was complete, it was purified by reverse preparative chromatography to obtain compound KH01. LCMS (ESI, m / z): 487.0 [M+1] + 。 1 1H NMR (400 MHz, DMSO-d6) δ 8.74–8.64 (m, 2H), 8.48 (d, J = 1.9 Hz, 1H), 7.88–7.78 (m, 2H), 7.47 (d, J = 2.1 Hz, 1H), 3.93–3.51 (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).

[0194] Synthesis of Compound KH02 in Example 2

[0195]

[0196] Compound KH02-2: To a solution of compound KH02-1 (400 mg, 1.89 mmol) in DMF (8 mL) were added compound 1 (416 mg, 2.29 mmol) and cesium carbonate (680 mg, 2.09 mmol), and the reaction was carried out at 100 °C for 12 h. After the reaction was complete, after the reaction solution was cooled to room temperature, water was added, and the organic phase was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure in vacuo to obtain a crude product; then the crude product was 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] + 。

[0197] Compound KH02-3: To a solution of compound KH02-2 (700 mg, 1.96 mmol) in EA (35 mL) was added ethyl acetate solution of hydrogen chloride (17.5 mL), and the reaction was carried out at room temperature for 12 h. After the reaction was complete, it was concentrated under reduced pressure in vacuo to obtain compound KH02-3. LCMS (ESI, m / z): 259.1 [M+1] + .

[0198] Compound KH02: To a solution of compound KH02-3 (218 mg, 0.74 mmol) in DMF (4 mL) was 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, it was purified by reverse-phase preparative chromatography to obtain compound KH02. LCMS (ESI, m / z): 487.1 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.66 (d, J = 24.8 Hz, 1H), 8.48 (d, J = 2.0 Hz, 1H), 7.78 - 7.66 (m, 2H), 7.47 (d, J = 1.9 Hz, 1H), 7.01 (d, J = 4.7 Hz, 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 = 7.1 Hz, 2H), 0.88 (s, 2H).

[0199] Synthesis of Compound KH03 in Example 3

[0200]

[0201] 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 the reaction was carried out at 100 °C for 16 h. After the reaction was complete, the reaction was quenched by adding water (50 mL), extracted with ethyl acetate (50 mL x 2), the organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated, and the obtained crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5 / 1 - 1 / 1) to obtain KH03-2. 11H NMR (400 MHz, CDCl3) δ 7.03 (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).

[0202] Compound KH03-3: Compound KH03-2 (400 mg, 1.1 mmol) was dissolved in tetrahydrofuran (5 mL), cooled to 0 °C, and LiAlH4 (83 mg, 2.2 mmol) was added. The reaction was carried out at 0 °C for 1 h. After the reaction was complete, the reaction was quenched by adding water (0.4 mL), anhydrous sodium sulfate was added and stirred for 10 mins, filtered and concentrated by rotary evaporation to obtain compound KH03-3. LCMS (ESI, m / z): 335.2 [M+1] + 。

[0203] 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 solution (7.48 mL, 7.48 mmol). The reaction was carried out at room temperature for 12 h. After the reaction was complete, it was filtered to obtain compound KH03-4. LCMS (ESI, m / z): 235.1 [M+1] + 。

[0204] 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). The reaction was carried out at room temperature overnight. After the reaction was complete, it was purified by reverse preparative chromatography to obtain compound KH03. LCMS (ESI, m / z): 463.3 [M+1] + 。 1 1H NMR (400 MHz, DMSO-d6) δ 8.47 (d, J = 1.5 Hz, 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).

[0205] Synthesis of Compound KH04 in Example 4

[0206]

[0207] The synthesis method of compound KH04-1 is shown in compound KH03-2.

[0208] Compound KH04-2: To a solution of compound KH04-1 (500 mg, 1.44 mmol) in THF (10 mL) was added methylmagnesium bromide (2 mL, 5.74 mmol) at -30 °C, and the mixture was stirred at room temperature overnight. After the reaction was complete, the reaction system was quenched by adding saturated aqueous ammonium chloride solution, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure in vacuo to obtain the 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 (400 MHz, DMSO-d6) δ 8.29 (d, J = 5.1 Hz, 1H), 6.83 (d, J = 5.1 Hz, 1H), 5.14 (s, 1H), 3.69 (br s, 2H), 3.52 (br s, 2H), 3.33 (s, 2H), 3.16 (d, J = 9.6 Hz, 2H), 2.94 (s, 2H), 1.38 (d, J = 5.9 Hz, 15H).

[0209] 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 solution (12 mL), and the mixture was reacted at 60 °C for 1 h. After the reaction was complete, it was concentrated under reduced pressure in vacuo to obtain compound KH04-3. LCMS (ESI, m / z): 249.1 [M+1] + .

[0210] Compound KH04: To a solution of compound KH04-3 (209 mg, 0.73 mmol) in DMF (3 mL) was 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, it was purified by reverse-phase preparative chromatography to obtain compound KH04. LCMS (ESI, m / z): 477.0 [M+1] + . 11H NMR (400 MHz, DMSO-d6) δ 8.47 (d, J = 2.0 Hz, 1H), 8.30 (s, 1H), 7.89 (m, J = 57.8, 54.4 Hz, 2H), 7.47 (d, J = 2.1 Hz, 1H), 6.86 (d, J = 5.2 Hz, 1H), 3.887 - 3.58 (m, 4H), 3.34 (m, J = 11.6, 4.0 Hz, 3H), 3.10–2.85 (m, 3H), 2.06 (br s, 1H), 1.38 (s, 6H), 1.07 (d, J = 7.5 Hz, 2H), 0.89 (br s, 2H).

[0211] Synthesis of Compound KH05 in Example 5

[0212]

[0213] Compound KH05-2: To a toluene (10 mL) solution of compound KH05-1 (1 g, 4.02 mmol) was 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), and the reaction was carried out at 100 °C for 2 h. After the reaction was complete, the reaction solution was allowed to return to room temperature, diluted with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure in vacuo 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] + 。 1 1H NMR (400 MHz, CDCl3) δ 8.48 (d, J = 2.4 Hz, 1H), 8.18 (d, J = 2.4 Hz, 1H), 6.69 (m, J = 17.6, 11.0 Hz, 1H), 5.89 (d, J = 17.6 Hz, 1H), 5.49 (d, J = 11.0 Hz, 1H), 3.97 (s, 3H).

[0214] Compound KH05-3: To a THF (5 mL) solution of compound KH05-2 (550 mg, 2.78 mmol) was added CF3-TMS (1.7 mL, 11.1 mmol) and sodium iodide (84 mg, 0.556 mmol), and the reaction was carried out at 70 °C for 4 h. After the reaction was complete, the reaction solution was concentrated under reduced pressure in vacuo to obtain a crude product, and the crude product 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] + 。 11H NMR (400 MHz, CDCl3) δ 8.40 (d, J = 2.3 Hz, 1H), 7.98 (d, J = 2.3 Hz, 1H), 3.96 (s, 3H), 2.79 - 2.73 (m, 1H), 2.04 - 1.92 (m, 1H), 1.77 - 1.65 (m, 1H).

[0215] Compound KH05 - 4: To a solution of compound KH05 - 3 (360 mg, 1.45 mmol) in 1,4 - dioxane (8 mL) was added compound KH05 - 3a (600 mg, 1.60 mmol) and bis(triphenylphosphine)palladium(II) dichloride (102 mg, 0.145 mmol), and the reaction was carried out at 100 °C for 12 h. After the reaction was complete, 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 give compound KH05 - 4. LCMS (ESI, m / z): 297.0 [M + 1] + 。 1 1H NMR (400 MHz, DMSO) δ 8.72 (d, J = 2.1 Hz, 1H), 7.98 (d, J = 3.2 Hz, 1H), 7.94 (d, J = 2.0 Hz, 1H), 7.92 (d, J = 3.2 Hz, 1H), 3.81 (s, 3H), 3.26 - 3.19 (m, 1H), 2.36 - 2.28 (m, 1H), 2.19 - 2.08 (m, 1H).

[0216] Compound KH05 - 5: To a solution of compound KH05 - 4 (336 mg, 1.14 mmol) in methanol (10 mL) was 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, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give compound KH05 - 5. LCMS (ESI, m / z): 282.9 [M + 1] + 。 1 1H NMR (400 MHz, DMSO) δ 13.46 (s, 1H), 8.67 (d, J = 2.0 Hz, 1H), 7.97 (d, J = 3.2 Hz, 1H), 7.91 (d, J = 3.2 Hz, 1H), 7.90 (d, J = 2.0 Hz, 1H), 3.24 - 3.17 (m, 1H), 2.34 - 2.28 (m, 1H), 2.17–2.07 (m, 1H).

[0217] Compound KH05-6: To a solution of compound KH05-5a (500 mg, 3.53 mmol) in 1,4-dioxane (17 mL) was 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), and the reaction was carried out overnight at 90 °C. After the reaction was complete, the reaction mixture was poured into water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure in vacuo 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 (400 MHz, DMSO) δ 6.27 (s, 1H), 6.05 (s, 1H), 3.52 (br s, 4H), 3.24 (br s, 2H), 3.13 (d, J = 9.9 Hz, 2H), 2.93 (s, 2H), 2.23 (s, 3H), 2.15 (s, 3H), 1.38 (s, 9H).

[0218] Compound KH05-7: To a solution of compound KH05-6 (643 mg, 2.03 mmol) in ethyl acetate (32 mL) was added a solution of hydrogen chloride in ethyl acetate (16 mL), and the reaction was carried out at 60 °C for 1 h. After the reaction was complete, it was concentrated under reduced pressure in vacuo to obtain compound KH05-7. LCMS (ESI, m / z): 218.2 [M+1] + 。

[0219] Compound KH05: To a solution of compound KH05-5 (138 mg, 0.5 mmol) in DMF (3 mL) was 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, it was purified by reverse-phase preparative chromatography to obtain compound KH05. LCMS (ESI, m / z): 482.0 [M+1] + 。 1 H NMR (400 MHz, DMSO) δ 8.62 (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).

[0220] Synthesis of Compound KH06 in Example 6

[0221]

[0222] Compound KH06-2: To a solution of Compound KH06-1 (300 mg, 2.10 mmol) in DMF (6 mL) was added Compound KH06-1a (494 mg, 2.32 mmol) and cesium carbonate (826 mg, 2.53 mmol), and the reaction was carried out at 100 °C for 2 h. After the reaction was complete, 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 in vacuo 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 1H NMR (400 MHz, DMSO) δ 6.38 (s, 1H), 3.67 (br s, 2H), 3.50 (br s, 2H), 3.35 (d, J = 12.5 Hz, 2H), 3.17 - 3.12 (m, 2H), 2.91 (s, 2H), 2.21 (s, 6H), 1.38 (s, 9H).

[0223] Compound KH06-3: To a solution of Compound KH06-2 (320 mg, 1.01 mmol) in ethyl acetate (16 mL) was added hydrogen chloride in ethyl acetate (8 mL), and the reaction was carried out at 60 °C for 1 h. After the reaction was complete, it was concentrated under reduced pressure in vacuo to obtain Compound KH06-3. LCMS (ESI, m / z): 219.2 [M+1] + . 1 1H NMR (400 MHz, DMSO) δ 9.65 (d, J = 50.5 Hz, 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).

[0224] Compound KH06: To a solution of compound KH06-3 (174 mg, 0.68 mmol) in DMF (3 mL) was added KH05-5 (160 mg, 0.57 mmol), HATU (324 mg, 0.85 mmol) and DIEA (0.23 mL, 2.27 mmol), and the mixture was stirred at room temperature for 1 h. After the reaction was complete, the product was purified by reversed-phase preparative chromatography to obtain compound KH06. LCMS (ESI, m / z): 483.3 [M+1]+. 1H NMR (400 MHz, DMSO) δ 8.63 (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).

[0225] Example 7 Synthesis of Compound KH07

[0226]

[0227] Compound KH07-2: To a solution of compound KH07-1a (600 mg, 4.21 mmol) in DMF (12 mL) was added compound KH07-1 (983 mg, 4.63 mmol) and cesium carbonate (1.646 g, 5.05 mmol), and the mixture was reacted at 100 °C for 2 h. After the reaction was complete, 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 in vacuo 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 1H NMR (400 MHz, DMSO) δ 8.20 (d, J = 4.9 Hz, 1H), 6.50 (d, J = 4.9 Hz, 1H), 3.69 (br s, 2H), 3.51 (br s, 2H), 3.36 (s, 2H), 3.15 (d, J = 9.5 Hz, 2H), 2.93 (br s, 2H), 2.56–2.50 (m, 2H), 1.38 (s, 9H), 1.19 - 1.14 (m, 3H).

[0228] Compound KH07-3: To a solution of compound KH07-2 (200 mg, 0.63 mmol) in EA (4 mL) was added hydrogen chloride in ethyl acetate solution (2 mL), and the mixture was reacted at 60 °C for 1 h. After the reaction was complete, it was concentrated under reduced pressure in vacuo to obtain compound KH07-3. LCMS (ESI, m / z): 219.2 [M+1]+ . 1 1H NMR (400 MHz, DMSO) δ 9.60 (d, J = 32.3 Hz, 2H), 8.30 (d, J = 5.7 Hz, 1H), 6.78 (d, J = 5.6 Hz, 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 = 7.5 Hz, 2H), 1.20 (t, J = 7.5 Hz, 3H).

[0229] Compound KH07: To a solution of compound KH01-3 (80 mg, 0.33 mmol) in DMF (3 mL) was 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, the product was purified by reverse-phase preparative chromatography to obtain compound KH07. LCMS (ESI, m / z): 447.2 [M+1] + . 1 1H NMR (400 MHz, DMSO) δ 8.48 (d, J = 1.8 Hz, 1H), 8.23 (s, 1H), 7.79 - 7.52 (m, 2H), 7.47 (d, J = 2.0 Hz, 1H), 6.61 (d, J = 4.7 Hz, 1H), 3.78 - 3.25 (m, 8H), 2.91 (br s, 2H), 2.60 (d, J = 6.9 Hz, 2H), 2.05 (br s, 1H), 1.19 (s, 3H), 1.10–0.84 (m, 4H).

[0230] Synthesis of Compound KH08 in Example 8

[0231]

[0232] Compound KH08-2: To a solution of compound KH08-1 (677 mg, 3.00 mmol) in DMF (14 mL) was added MeI (639 mg, 4.50 mmol) and cesium carbonate (1.955 g, 6.00 mmol), and the mixture was reacted at room temperature for 3 h. After the reaction was complete, 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 in vacuo to obtain compound KH08-2. LCMS (ESI, m / z): 240.1 [M+1] + . 11H NMR (400 MHz, DMSO) δ 9.05 (dd, J = 2.4, 0.8 Hz, 1H), 8.64 (dd, J = 2.4, 0.4 Hz, 1H), 3.92 (s, 3H).

[0233] Compound KH08-3: To a solution of compound KH08-2 (600 mg, 2.50 mmol) in 1,4-dioxane (12 mL) was added compound KH08-2a (0.9 mL, 2.75 mmol) and bis(triphenylphosphine)palladium(II) dichloride (176 mg, 0.25 mmol), and the mixture was reacted at 100 °C for 12 h. After the reaction was complete, 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 1H NMR (400 MHz, DMSO) δ 9.20–9.13 (m, 1H), 8.58 (d, J = 1.6 Hz, 1H), 8.12 - 8.05 (m, 2H), 3.86 (s, 3H).

[0234] Compound KH08-4: To a solution of compound KH08-3 (200 mg, 0.69 mmol) in methanol (8 mL) was 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, 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 1H NMR (400 MHz, DMSO) δ 13.74 (s, 1H), 9.12 (s, 1H), 8.50 (s, 1H), 8.05 (t, J = 4.9 Hz, 2H).

[0235] Compound KH08: To a solution of compound KH08-4 (130 mg, 0.47 mmol) in DMF (3 mL) was 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, the mixture was purified by reverse-phase preparative chromatography to obtain compound KH08. LCMS (ESI, m / z): 475.2 [M+1] + . 11H NMR (400 MHz, DMSO) δ 9.09 (d, J = 1.2 Hz, 1H), 8.39 (s, 1H), 8.20 (d, J = 4.8 Hz, 1H), 8.15 - 7.62 (m, 2H), 6.50 (d, J = 5.0 Hz, 1H), 3.93–3.43 (m, 6H), 3.36 (br s, 1H), 3.16–2.86 (m, 3H), 2.54 (d, J = 7.6 Hz, 2H), 1.18 (br s, 3H).

[0236] Synthesis of Compound KH09 in Example 9

[0237]

[0238] Compound KH09-2: At 0 °C, cyclopropylmagnesium bromide (67 mL, 67.0 mmol) was added to a solution of compound KH09-1 (5 g, 33.61 mmol) and iron(III) acetylacetonate (2.370 g, 6.70 mmol) in tetrahydrofuran (30 mL) and NMP (5 mL), and the reaction was carried out at room temperature for 1 h. After the reaction was complete, the reaction system 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 in vacuo 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] + .

[0239] 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 reaction was carried out at 100 °C for 2 h. After the reaction was complete, 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 in vacuo 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] + . 1 1H NMR (400 MHz, DMSO) δ 8.09 (d, J = 5.0 Hz, 1H), 6.53 (d, J = 5.0 Hz, 1H), 3.64 (d, J = 5.0 Hz, 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).

[0240] Compound KH09-4: To a solution of compound KH09-3 (240 mg, 0.73 mmol) in ethyl acetate (12 mL) was added a solution of hydrogen chloride in ethyl acetate (6 mL), and the mixture was reacted at 60 °C for 1 h. After the reaction was complete, it was concentrated under reduced pressure in vacuo to obtain compound KH09-4. LCMS (ESI, m / z): 231.1 [M+1] + 。

[0241] 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, it was purified by reverse-phase preparative chromatography to obtain compound KH09. LCMS (ESI, m / z): 487.2 [M+1] + 。 1 H NMR (400 MHz, DMSO) δ 9.09 (s, 1H), 8.39 (s, 1H), 8.13–7.80 (m, 3H), 6.53 (d, J = 4.9 Hz, 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).

[0242] Synthesis of Compound KH10 in Example 10

[0243]

[0244] Compound KH10-2: To a solution of compound KH10-1 (5 g, 22.17 mmol) in DMF (50 mL) were added methyl iodide (4.72 g, 33.25 mmol) and cesium carbonate (14.446 g, 44.34 mmol), and the mixture was reacted at room temperature for 2 h. After the reaction was complete, the reaction was quenched with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure in vacuo 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 (400 MHz, DMSO) δ 9.04 (s, 1H), 8.63 (s, 1H), 3.92 (s, 3H).

[0245] 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 reaction was carried out at 100 °C for 12 h. After the reaction was complete, the reaction was quenched with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure in vacuo 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 1H NMR (400 MHz, DMSO) δ 9.17 (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).

[0246] 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 reaction was carried out at room temperature for 12 h. After the reaction was complete, the reaction solution was adjusted to pH = 5 with aqueous hydrochloric acid, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure in vacuo to obtain compound KH10-4. LCMS (ESI, m / z): 274.9 [M+1] + 。

[0247] 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 the reaction was carried out at room temperature for 1 h. After the reaction was complete, the reaction was quenched with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure in vacuo 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] + 。

[0248] Compound KH10-6: To a solution of compound KH10-5 (1 g, 2.13 mmol) in ethyl acetate (10 mL) was added ethyl acetate solution of hydrogen chloride (20 mL), and the reaction was carried out at room temperature for 12 h. After the reaction was complete, the mixture was concentrated under reduced pressure in vacuo to obtain compound KH10-6. LCMS (ESI, m / z): 369.0 [M+1] + 。

[0249] Compound KH10: To a solution of compound KH10-6 (150 mg, 0.41 mmol) in isopropanol (10 mL) was added compound KH10-6a (48 mg, 0.27 mmol) and DIEA (0.16 mL, 0.95 mmol), and the reaction was carried out at 90 °C for 12 h. After the reaction was complete, the mixture was filtered by suction to obtain compound KH10. LCMS (ESI, m / z): 509.1 [M+1] + 。 1 H NMR (400 MHz, CD3OD_SPE) δ 8.97 (s, 1H), 8.23 (d, J = 1.7 Hz, 1H), 7.96 - 7.67 (m, 2H), 3.89 - 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).

[0250] Synthesis of Compound KH11 in Example 11

[0251]

[0252] Compound KH11-2: At room temperature, 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). The reaction system was cooled to 0 °C, and methylmagnesium bromide (4 mL, 12.41 mmol) was added, and the reaction was carried out at 0 °C for 0.5 h. After the reaction was complete, after the reaction solution was restored to room temperature, the reaction was quenched with saturated aqueous ammonium chloride solution, extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure in vacuo to obtain a crude product; then the crude product was 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 (do you mean 400 MHz, DMSO here?) δ 2.43 (d, J = 2.7 Hz, 6H).

[0253] Note: There might be a minor error in the original text where it says "H NMR(400MHz,CD3OD_SPE)δ8.97(s,1H),8.23(d,J=1.7Hz,1H),7.96-7.67(m,2H),3.89-3.81(m,2H),3.78-3.56(m,4H),3.52-3.42(m,1H),3.16–3.00(m,3H),2.40(s,6H)" and then later "H NMR(400MHz,DMSO)δ2.43(d,J=2.7Hz,6H)" without proper indication of the solvent change in the NMR notation. In the translation, I've tried to make the best sense of it, but it might be beneficial to double-check the original text for accuracy. Also, for the "H NMR(400MHz,DMSO)δ2.43(d,J=2.7Hz,6H)" part, I added a note asking if it was meant to be 400 MHz DMSO as it seems a bit inconsistent with the previous NMR notation.Compound KH11: To a solution of compound KH10-6 (241 mg, 0.65 mmol) in isopropanol (4 mL) was added compound KH11-2 (70 mg, 0.44 mmol) and DIEA (0.27 mL, 1.53 mmol), and the mixture was stirred overnight at 90 °C. After the reaction was complete, the product was purified by reverse-phase preparative chromatography to obtain compound KH11. LCMS (ESI, m / z): 493.1 [M+1] + . 1 H NMR (400 MHz, DMSO) δ 9.09 (d, J = 1.3 Hz, 1H), 8.38 (s, 1H), 8.11 - 7.62 (m, 2H), 3.73 (dd, J = 11.4, 7.6 Hz, 2H), 3.63 - 3.45 (m, 4H), 3.33 (s, 1H), 3.11–2.86 (m, 3H), 2.27 (s, 6H).

[0254] Synthesis of Compound KH12 in Example 12

[0255]

[0256] Compound KH12-2: To a solution of compound KH12-1 (2 g, 9.4 mmol) in isopropanol (20 mL) was added compound KH12-1a (2.015 g, 14.1 mmol) and DIEA (2.435 g, 18.8 mmol), and the mixture was reacted at 90 °C for 2 h. After the reaction was complete, the reaction was quenched with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure in vacuo 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 (400 MHz, DMSO) δ 6.38 (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, 3.7 Hz, 2H), 2.99–2.87 (m, 2H), 2.51 (s, 1H), 2.21 (s, 6H), 1.39 (s, 9H).

[0257] 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 reaction was carried out at room temperature for 2 h. After the reaction was complete, the reaction was quenched with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure in vacuo to obtain the 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 (400 MHz, DMSO) δ 3.74–3.60 (m, 2H), 3.58–3.43 (m, 2H), 3.33–3.29 (m, 1H), 3.14 (dd, J = 11.2, 4.0 Hz, 2H), 2.97–2.88 (m, 2H), 2.54–2.48 (m, 1H), 2.38 (s, 6H), 1.39 (s, 9H).

[0258] 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 reaction was carried out at 135 °C for 6 h. After the reaction was complete, the reaction was quenched with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure in vacuo to obtain compound KH12-4. LCMS (ESI, m / z): 445.3 [M+1] + 。

[0259] 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 reaction was carried out at 0 °C for 2.5 h. After the reaction was complete, 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 in vacuo to obtain the 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] + 。 11H NMR (400 MHz, DMSO) δ 7.90 (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).

[0260] Compound KH12-6: To a solution of compound KH12-5 (170 mg, 0.51 mmol) in acetonitrile (2 mL) were added methyl iodide (181 mg, 1.27 mmol) and potassium carbonate (211 mg, 1.53 mmol), and the mixture was reacted at room temperature for 4 h. After the reaction was complete, the reaction was quenched with water, and the organic phase was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure in vacuo 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 1H NMR (400 MHz, DMSO) δ 3.63 (d, J = 6.9 Hz, 2H), 3.59 (s, 3H), 3.50 (d, J = 5.1 Hz, 2H), 3.33–3.29 (m, 2H), 3.13 (dd, J = 11.1, 4.1 Hz, 2H), 2.99–2.83 (m, 2H), 2.25 (s, 6H), 1.39 (s, 9H).

[0261] 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 solution (5 mL), and the mixture was reacted at room temperature for 1 h. After the reaction was complete, the reaction mixture was concentrated under reduced pressure in vacuo to obtain compound KH12-7. LCMS (ESI, m / z): 249.2 [M+1] + .

[0262] 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), and the mixture was reacted at room temperature for 1 h. After the reaction was complete, the reaction mixture was purified by reverse-phase preparative chromatography to obtain compound KH12. LCMS (ESI, m / z): 505.1 [M+1] + . 11H NMR (400 MHz, DMSO) δ 9.09 (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).

[0263] Synthesis of Compound KH13 in Example 13

[0264]

[0265] Compound KH13: To a solution of compound KH10-4 (14.06 g, 51.27 mmol) in DMF (200 mL) was added compound KH06-3 (15 g, 56.40 mmol), HATU (23.38 g, 61.53 mmol) and DIEA (25 mL, 153.82 mmol), and the mixture was reacted at room temperature for 1 h. After the reaction was complete, water and ethyl acetate were added for extraction, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure in vacuo to obtain a crude product, and then petroleum ether was added to the crude product for pulping, and compound KH13 was obtained by filtration. LCMS (ESI, m / z): 475.2 [M+1] + 。 1 1H NMR (400 MHz, DMSO) δ 9.09 (d, J = 1.0 Hz, 1H), 8.39 (s, 1H), 8.13–7.81 (m, 2H), 6.44 (s, 1H), 3.88 - 3.72 (m, 2H), 3.67–3.37 (m, 5H), 3.04 - 2.89 (m, 3H), 2.25 (s, 6H).

[0266] Synthesis of Compound KH14 in Example 14

[0267]

[0268] Compound KH14: To a solution of compound KH01-3 (250 mg, 1.01 mmol) in DMF (4 mL) was added KH06-3 (312 mg, 1.21 mmol), HATU (579 mg, 1.52 mmol) and DIEA (0.74 mL, 4.06 mmol), and the mixture was stirred at room temperature for 1 h. After the reaction was complete, it was purified by reverse-phase preparative chromatography to obtain compound KH14. LCMS (ESI, m / z): 447.2 [M+1] + 。 11H NMR (400 MHz, DMSO) δ 8.47 (d, J = 2.1 Hz, 1H), 7.89 - 7.69 (m, 2H), 7.46 (d, J = 2.1 Hz, 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 = 6.9 Hz, 2H), 0.88 (s, 2H).

[0269] Synthesis of Compound KH15 in Example 15

[0270]

[0271] Compound KH15-8: To a solution of compound KH15-8a (3.00 g, 18.4 mmol, 1 eq) in THF (30 mL) was added NMP (2.19 g, 22.0 mmol, 2.15 mL, 1.2 eq), FeCl3 (59.7 mg, 368 μmol, 21.3 μL, 0.02 eq). After addition, CD3MgI (1 M, 18.4 mL, 1 eq) was added dropwise at -60 °C. After the addition was complete, the reaction system was stirred at 20 °C for 12 hours. TLC (petroleum ether / ethyl acetate = 2 / 1, Rf of compound KH15-8a = 0.40, Rf of the new spot = 0.25) showed that the starting material had almost disappeared and the target product was formed. After the reaction was completed, water (50 mL) was added to the reaction mixture, and then extracted with ethyl acetate (50 mL × 2). The organic layers were combined, 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 purified by column chromatography silica gel (petroleum ether / ethyl acetate = 20 / 1 - 3 / 1) to obtain the target compound KH15-8. LCMS (ESI, m / z) = 146.1 [M+1] + 。 1 1H NMR: DMSO-d6, 400 MHz δ 7.32 (s, 1H), 2.41 (s, 3H).

[0272] Compound KH15: To a solution of compound KH10-6 (80.0 mg, 217 μmol, 1 eq) in 1,4-dioxane (2 mL) was added compound KH15-8 (31.6 mg, 217 μmol, 1 eq) and Cs2CO3 (176 mg, 542 μmol, 2.5 eq). After addition, the system was purged with nitrogen three times. Under nitrogen protection, the mixture was stirred at 110 °C for 12 hours. LCMS (EW30597-215-P1A) showed that the starting materials had basically disappeared and the target product was formed. After the reaction was completed, 10 mL of water was added to the reaction mixture, and then extracted with ethyl acetate (20 mL × 2). The organic layers were combined, washed with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was separated by preparative high performance liquid chromatography to obtain the target compound KH15. LCMS (ESI, m / z) = 478.1 [M+1] + 。 1 1H NMR: 400 MHz, CDCl3 δ 8.87 (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).

[0273] Example 16 Synthesis of Compound KH16

[0274]

[0275] 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) was 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). After addition, CD3MgI (1 M, 21.8 mL, 2 eq) was added dropwise at -60 °C. After the addition was completed, the mixture was stirred at -60 °C for 1 h. TLC (petroleum ether:ethyl acetate = 5 / 1, Rf of compound KH16-1a = 0.50, Rf of the new spot = 0.40) and LCMS showed that the starting materials had basically disappeared and the target product was formed. The reaction mixture was quenched with water (50 mL), and then extracted with ethyl acetate (80 mL × 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 the crude product. The crude product was purified by column chromatography silica gel (petroleum ether / ethyl acetate = 1 / 0 - 0 / 1) to obtain the target compound KH16-1b. LCMS (ESI, m / z) = 166.0 [M+1] + 。

[0276] Compound KH16-1c: To a solution of compound KH16-1b (1.10 g, 6.63 mmol, 1 eq) in tetrahydrofuran (40 mL) was added NMP (788 mg, 7.95 mmol, 772 μL, 1.2 eq), followed by FeCl3 (21.4 mg, 132 μmol, 7.68 μL, 0.02 eq). Then, CD3MgI (1 M, 6.63 mL, 1 eq) was 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, Rf of compound KH16-1b = 0.40, Rf of new spot = 0.25) showed that the starting material had almost disappeared and the target product was formed. The reaction mixture was quenched with water (50 mL), and then extracted with ethyl acetate (80 mL × 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 the 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] + 。

[0277] Compound KH16: To a solution of compound KH10-6 (80.0 mg, 217 μmol, 1 eq) in 1,4-dioxane (2 mL) was added compound KH16-1c (48.4 mg, 325 μmol, 1.5 eq), Cs2CO3 (176 mg, 542 μmol, 2.5 eq), and the system was purged with nitrogen three times. Under nitrogen protection, the mixture was stirred at 110 °C for 12 h. LCMS showed that the starting material had almost disappeared and the target product was formed. 10 mL of water was added to the reaction mixture, and then extracted with ethyl acetate (20 mL × 2). The organic layers were combined, washed with saturated brine (10 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was separated by high performance liquid chromatography to obtain the target compound KH16. LCMS (ESI, m / z) = 481.2 [M+1]+. 1 H NMR (400 MHz, DMSO-d6) δ 9.09 (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 = 29.5 Hz, 4H), 3.40–3.35 (m, 1H), 3.06–2.85 (m, 3H).

[0278] Example 17 Synthesis of Compound KH17

[0279]

[0280] Compound KH17: To a solution of compound KH17-1 (40 mg, 1 eq) in DMF (3 mL), HATU (103 mg, 2 eq), DIEA (174 mg, 10 eq), and compound KH17-2 (90 mg, 2 eq) were successively added. After the addition was complete, the mixture was stirred at room temperature overnight. After the reaction was complete, water (30 mL) was added for dilution, and then extraction was performed with ethyl acetate (30 mL × 2). The organic phase was collected, 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] + 。

[0281] Example 18 Synthesis of Compound KH18

[0282]

[0283] Compound KH18: To a solution of compound KH18-1 (114 mg, 1 eq) in DMF (10 mL), HATU (272 mg, 2 eq), DIEA (460 mg, 10 eq), and compound KH18-2 (238 mg, 2 eq) were successively added. After the addition was complete, the mixture was stirred at room temperature overnight. After the reaction was complete, water (30 mL) was added for dilution, and then extraction was performed with ethyl acetate (50 mL × 2). The organic phase was collected, 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] + 。

[0284] Example 19 Synthesis of Compound KH19

[0285]

[0286] Compound KH19: To a solution of compound KH19-1 (130 mg, 1 eq) in DCM (10 mL), HATU (329 mg, 2 eq), DIEA (169 mg, 3 eq), and compound KH19-2 (288 mg, 2 eq) were successively added. After the addition was complete, the mixture was stirred at room temperature overnight. After the reaction was complete, water (200 mL) was added for dilution, and then extraction was performed with dichloromethane (100 mL). The organic phase was collected, 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] + 。

[0287] Example 20 Synthesis of Compound KH20

[0288]

[0289] Compound KH20: To a solution of compound KH20-1 (53 mg, 1 eq) in DMF (6 mL), compound KH20-2 (124 mg, 2 eq), HATU (142 mg, 2 eq), and DIEA (241 mg, 10 eq) were successively added. After the addition was complete, the mixture was stirred at room temperature overnight. After the reaction was complete, water (30 mL) was added for dilution, and then extraction was performed with ethyl acetate (30 mL × 2). The organic phase was collected, 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] + 。

[0290] Example 21 Synthesis of Compound KH21

[0291]

[0292] Compound KH21: To a solution of compound KH21-1 (40 mg, 1 eq) in DCM (5 mL), KH21-2 (119 mg, 2 eq), HATU (136 mg, 2 eq), and DIEA (70 mg, 3 eq) were successively added. After the addition was complete, the mixture was stirred at room temperature overnight. After the reaction was complete, water (50 mL) was added for dilution, and then extraction was performed with dichloromethane (100 mL). The organic phase was collected, 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] + 。

[0293] Example 22 Synthesis of Compound KH22

[0294]

[0295] Compound KH22: To a solution of compound KH22-1 (60 mg, 1 eq) in DMF (6 mL), HATU (161 mg, 2 eq), DIEA (273 mg, 10 eq), and KH22-2 (140 mg, 2 eq) were successively added. After the addition was complete, the mixture was stirred at room temperature overnight. After the reaction was complete, water (20 mL) was added for dilution, and then extraction was performed with ethyl acetate (30 mL × 2). The organic phase was collected, 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] + 。

[0296] Example 23 Synthesis of Compound KH25

[0297]

[0298] Compound 25-b: To a solution of Compound 25-4 (1 g, 5.45 mmol) in THF (10 mL) at room temperature was added Fe(acac)3 (192 mg, 0.55 mmol). The reaction system was cooled to 0 °C, and deuterated methylmagnesium iodide (1.0 M) (13.6 mL, 13.63 mmol) was added. The reaction was carried out at 0 °C for 1 h. After the reaction was complete, the reaction was quenched with saturated aqueous ammonium chloride solution (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 and filtered. After concentration under reduced pressure, a crude product was obtained; the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain a colorless oil (580 mg, yield 71.6%). LCMS (ESI, m / z): 149.2 [M+H] + 。 1 H NMR (400 MHz, DMSO-d6) δ 7.33 (s, 1H).

[0299] Compound 25-a: In a reaction flask, 25-0 (5.71 g, 26.4 mmol) and 1,4-dioxane (80 mL) were added, and then 2-(tributylstannyl)thiazole (9.9 g, 26.4 mmol), bis(triphenylphosphine)palladium dichloride (1.85 g, 2.6 mmol) and tris(tetrahydrofuran-2-yl)phosphine (1.25 g, 5.4 mmol) were added in sequence. Under nitrogen protection, the temperature was raised to 110 °C and stirred for 16 h. The reaction solution was cooled to room temperature, and the solvent was removed under reduced pressure to obtain a crude product, which was purified by silica gel column [eluent: petroleum ether - methyl tert-butyl ether (100:0 - 60:40)]. The eluate was collected and the solvent was removed under reduced pressure to obtain a colorless oil 25-a (4.2 g, yield: 68%). LCMS purity: 95.50% MS Calculated: 220.0; MS Found: 221.3 [M+H] + 。

[0300] Compound 25-1: Dissolve 25-a (2.00 g, 9.1 mmol) in a mixed solution of methanol (18 mL) and water (9 mL). Add NaOH (726 mg, 18.2 mmol) to the reaction flask. Stir at room temperature for 1 hour under nitrogen protection. After the reaction is complete, adjust the pH to 5 with 2 mol / L hydrochloric acid. Filter, and wash the filter cake with a small amount of water. Purify the filtrate through a C18 reverse-phase column [eluent: water - acetonitrile (100:0 - 95:5)], collect the eluate, evaporate acetonitrile under reduced pressure, and then mix it with the filter cake and lyophilize 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] + .

[0301] Compound 25-2: Add DIEA (0.24 mL, 1.45 mmol), HATU (188 mg, 0.73 mmol), and compound a (123 mg, 0.58 mmol) to a solution of compound 25-1 (100 mg, 0.49 mmol) in DMF (3 mL) at room temperature, and react at room temperature for 2 h. After the reaction is complete, add water (10 mL) and ethyl acetate (15 mL × 3) to the reaction solution for extraction. Wash the organic phase with saturated brine (20 mL × 2), dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain a crude product; then purify the crude product 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] + .

[0302] Compound 25-3: Add ethyl acetate solution of hydrogen chloride in ethyl acetate (2 M) (2 mL) to a solution of compound 25-2 (120 mg, 0.30 mmol) in ethyl acetate (2 mL), and react at room temperature overnight. After the reaction is complete, concentrate under reduced pressure to obtain a crude white solid (90 mg). LCMS (ESI, m / z): 301.0 [M+H] + .

[0303] Compound KH25: Add compound 25-b (41 mg, 0.27 mmol) and DIEA (0.12 mL, 0.75 mmol) to a solution of compound 25-3 (75 mg, 0.25 mmol) in isopropanol (2 mL), and react at 90 °C overnight. After the reaction is complete, concentrate the reaction solution under reduced pressure to obtain a crude product; purify the crude product by preparative reverse-phase chromatography to obtain a white solid compound (35.06 mg, yield 34.0%). LCMS (ESI, m / z): 413.2 [M+H] + . 11H NMR (400 MHz, DMSO-d6) δ 8.70–8.65 (m, 1H), 7.94–7.76 (m, 3H), 7.58–7.52 (m, 1H), 6.38 (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).

[0304] Synthesis of Compound KH26 in Example 24

[0305]

[0306] Compound KH26: To a solution of compound 25-3 (94 mg, 0.454 mmol) in DMF (2 mL) was added compound 26-b (90 mg, 0.413 mmol), HATU (188 mg, 0.496 mmol) and DIEA (160 mg, 1.24 mmol), and the reaction was carried out at room temperature. After completion of the reaction, the reaction solution was diluted with water (20 mL), extracted with ethyl acetate (15 mL x 3), the organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by Prep-HPLC to obtain a white solid (42.04 mg, 25.0%). LCMS (ESI, m / z): 407.1 [M+H] + . 1 1H NMR (400 MHz, DMSO) δ 8.67 (m, J = 4.8, 1.6 Hz, 1H), 7.85 (m, J = 7.7, 1.6 Hz, 3H), 7.55 (m, J = 7.7, 4.8 Hz, 1H), 6.38 (s, 1H), 3.75 (m, J = 11.5, 7.6 Hz, 2H), 3.55 (s, 5H), 3.06–2.83 (m, 3H), 2.22 (s, 6H).

[0307] Synthesis of Compound KH27 in Example 25

[0308]

[0309] Compound KH27: To a solution of compound KH25-3 (100 mg, 0.33 mmol) in isopropanol (3 mL) was added compound 27-b (53 mg, 0.33 mmol) and diisopropylethylamine (0.16 mL, 1.00 mmol), and the reaction was carried out at 90 °C overnight. After the reaction was complete, 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, yield 16.4%). LCMS (ESI, m / z): 425.3 [M+1] + .1 1H NMR (400 MHz, DMSO-d6) δ 8.67 (s, 1H), 7.97–7.70 (m, 3H), 7.55 (s, 1H), 3.80–3.66 (m, 2H), 3.59–3.45 (m, 3H), 3.35–3.27 (m, 2H), 3.05–2.84 (m, 3H), 2.27 (s, 6H).

[0310] Synthesis of Compound KH28 in Example 26

[0311]

[0312] Synthesis of Compound 28-1: In a reaction flask, 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) were added successively. Under nitrogen protection, the reaction was stirred overnight in an oil bath at 100 °C. After the reaction was completed, it was cooled to room temperature, water was added until it became clear, and it was extracted with ethyl acetate (50 mL × 3). The organic phases were combined, washed twice with saturated ammonium chloride, dried over anhydrous magnesium sulfate, the solvent was removed under reduced pressure to obtain a crude product, which was purified by a silica gel column [eluent: petroleum ether - methyl tert-butyl ether (100:0 - 40:60)], the eluate was collected, and the solvent was removed under reduced pressure to obtain a yellow solid 28-1 (1.2 g, yield: 83%). LCMS (ESI, m / z) purity: 100.00%; MS Calculated: 322.1; MS Found: 323.0 [M + H] + .

[0313] Synthesis of Compound 28-2: In a reaction flask, 28-1 (700 mg, 2.17 mmol) and dichloromethane (5 mL) were added. After complete dissolution, dioxane hydrochloride (60 mL) was added. Under nitrogen protection, the reaction was stirred at room temperature for 1 hour. After the reaction was completed, the solvent of the reaction solution was removed under reduced pressure to obtain a crude product, a brown solid 28-2 (650 mg, yield: 100%). LCMS (ESI, m / z) purity: 100%; MS Calculated: 222.2; MS Found: 223.4 [M + H] + .

[0314] Synthesis of Compound KH28: In a reaction flask, 28-2 (482 mg, 2.17 mmol) was dissolved in N,N-dimethylformamide (6 mL). Subsequently, 25-1 (447 mg, 2.17 mmol), DIPEA (1122 mg, 8.70 mmol), and HATU (1.24 g, 3.25 mmol) were added successively. Under nitrogen protection, the reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, water was added to the reaction solution, and the mixture was extracted with ethyl acetate (40 mL × 5). The organic phases were combined, washed twice with saturated ammonium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography [eluent: dichloromethane-methanol (100:0 - 15:85)], the eluate was collected, and the solvent was removed under reduced pressure to obtain a crude product with a purity of 90%. The crude product was further purified by C18 reversed-phase column chromatography [eluent: water-acetonitrile (100:0 - 40:60)], the eluate was collected, the acetonitrile was removed under reduced pressure, and then it was mixed with the filter cake and freeze-dried 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 1H NMR (400 MHz, CD3OD) δ: 8.66 (dd, J = 5.2, 1.6 Hz, 1H), 8.08 (d, J = 2.0 Hz, 1H), 7.83 - 7.81 (m, 2H), 7.62 (s, 1H), 7.51 (dd, J = 8.0, 5.2 Hz, 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 = 2.8 Hz, 3H).

[0315] Synthesis of Compound KH29 in Example 27

[0316]

[0317] 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 successively added to a mixed solution of THF (15 mL) and NMP (1.5 mL). Then, after cooling to 0 °C in an ice bath, CD3MgI (12 mL, 12 mmol) was slowly added. Under nitrogen protection, the mixture was stirred at room temperature for 2 hours. After the reaction was completed, water was added, and the mixture was extracted with MTBE (50 mL × 3). The organic phases were combined, the solvent was removed under reduced pressure to obtain a crude product, which was purified by silica gel column [eluent: petroleum ether - ethyl acetate (100:0 - 70:30)]. The eluate was collected, the solvent was removed under reduced pressure to obtain colorless oil 29-1 (570 mg, yield: 69%).

[0318] Synthesis of Compound 29-2: In a reaction flask, 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) were successively added. Under nitrogen protection, the mixture was stirred in an oil bath at 100 °C overnight. After the reaction was completed, it was cooled to room temperature, filtered under vacuum, the filtrate was collected, the solvent was removed under reduced pressure to obtain a crude product, which was purified by silica gel column [eluent: petroleum ether - methyl tert-butyl ether (100:0 - 40:60)]. The eluate was collected, the solvent was removed under reduced pressure to obtain white solid 29-2 (600 mg, yield: 51%). LCMS (ESI, m / z) purity: 87.00%; MS Calculated: 342.2; MS Found: 343.8 [M+H] + 。

[0319] Synthesis of Compound 29-3: In a reaction flask, 29-2 (140 mg, 0.41 mmol) and dichloromethane (1 mL) were added. After complete dissolution, trifluoroacetic acid (4 mL) was added. Under nitrogen protection, the mixture was stirred at room temperature for 1 hour. After the reaction was completed, the solvent of the reaction solution was removed under reduced pressure to obtain a crude product, yellow solid 29-3 (90 mg, yield: 91%). LCMS (ESI, m / z) purity: 99.99%; MS Calculated: 242.2; MS Found: 243.3 [M+H] + 。

[0320] Synthesis of Compound KH29: In a reaction flask, 29-3 (90 mg, 0.37 mmol) was dissolved in N,N-dimethylformamide (2 mL). Subsequently, 25-1 (76 mg, 0.37 mmol), HATU (212 mg, 0.56 mmol), and DIPEA (120 mg, 0.93 mmol) were added successively. Under nitrogen protection, the reaction mixture was stirred at room temperature for 1 hour. After the reaction was completed, 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 removed under reduced pressure to obtain a crude product. The crude product was purified by preparative HPLC to obtain 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 = 8.521 min. 1 1H NMR (400 MHz, DMSO-d6) δ: 8.67 (dd, J = 4.8, 1.6 Hz, 1H), 7.86 - 7.83 (m, 3H), 7.55 (dd, J1 = 7.6, 4.8 Hz, 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).

[0321] Synthesis of Compound KH30 in Example 28

[0322]

[0323] Synthesis of Compound 30-1: In a reaction flask, 30-0 (2.5 g, 11.1 mmol) and methanol (50 mL) were added. After stirring evenly, thionyl chloride (2.64 g, 22.2 mmol) was added dropwise. After the addition was completed, the temperature was raised to 60 °C in an oil bath and stirred for 2 hours. The temperature was lowered to room temperature, and the solvent was removed under reduced pressure to obtain a crude product. The crude product was purified by silica gel column [eluent: petroleum ether - methyl tert-butyl ether (100:0 - 30:70)], the eluate was collected, and the solvent was removed under reduced pressure to obtain yellow solid 30-1 (2.1 g, yield: 79%). LCMS (ESI, m / z) purity: 94%, Rt = 0.709 min; MS Calculated: 239.0; MS Found: 240.0 [M+H] + .

[0324] Synthesis of Compound 30-2 In a reaction flask, 30-1 (2.1 g, 8.78 mmol) and 1,4-dioxane (30 mL) were added. Subsequently, 2-(tributylstannyl)thiazole (3.6 g, 9.6 mmol), bis(triphenylphosphine)palladium dichloride (617 mg, 0.88 mmol), and tris(tetrahydrofuran-2-yl)phosphine (411 mg, 1.77 mmol) were added in sequence. Under nitrogen protection, the temperature was raised to 110 °C and stirred for 16 hours. The reaction solution was cooled to room temperature, and the solvent was removed under reduced pressure to obtain a crude product. The crude product was purified by silica gel column [eluent: petroleum ether-methyl tert-butyl ether (100:0 - 50:50)], the eluate was collected, and the solvent was removed under reduced pressure to obtain a colorless oil 30-2 (2 g, yield: 79%). LCMS (ESI, m / z) purity: 65.91%, Rt = 1.906 min; MS Calculated: 288.0; MS Found: 288.9 [M+H] + .

[0325] Synthesis of Compound 30-4 30-2 (2.00 g, 6.9 mmol) was dissolved in a mixed solution of methanol (16 mL) and water (4 mL). NaOH (1.1 mg, 27.5 mmol) was added to the reaction flask. Under nitrogen protection, it was stirred at room temperature for 2 hours. After the reaction was completed, the solvent was evaporated under reduced pressure, and 2 mol / L hydrochloric acid was added to adjust the pH value to 4. A large amount of white solid precipitated and was filtered. The filter cake was washed with a small amount of water and dried in vacuo 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] + .

[0326] Synthesis of Compound 30-6 In a reaction flask, 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'-binaphthalene-2,2'-bis(diphenylphosphine) (219 mg, 0.34 mmol), and cesium carbonate (1.14 g, 3.5 mmol) were added in sequence. Under nitrogen protection, the reaction was stirred at 100 °C for 16 hours. After the reaction was completed, the reaction solution was filtered, and the filter cake was washed with methanol until the filtrate had no ultraviolet fluorescence. The filtrate was evaporated under reduced pressure to remove the solvent, and the crude product was obtained. It was purified by silica gel column [eluent: petroleum ether - methyl tert-butyl ether (100:0 - 40:60)], the eluate was collected, and the solvent was evaporated under reduced pressure to obtain a yellow oil 30-6 (350 mg, yield: 62%). LCMS (ESI, m / z) purity: 80%, Rt = 0.940 min; MS Calculated: 318.2; MS Found: 319.3 [M+H] + 。

[0327] Synthesis of Compound 30-7 In a reaction flask, 30-6 (210 mg, 0.96 mmol) and dichloromethane (2 mL) were added. After being fully dissolved, dioxane hydrochloride (10 mL) was added. Under nitrogen protection, the reaction was stirred for 1 hour. After the reaction was completed, the reaction solution was evaporated under reduced pressure to remove the solvent, and the crude product, a brown solid 30-7 (200 mg, yield: 100%), was obtained. The crude product was directly used for the next reaction. LCMS (ESI, m / z) purity: 100%, Rt = 0.530 min; MS Calculated: 218.1; MS Found: 219.3 [M+H] + 。

[0328] Synthesis of Compound KH30 In a reaction flask, 30-7 (140 mg, 0.66 mmol), N,N-dimethylformamide (6 mL), 30-4 (127 mg, 0.46 mmol), 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (320 mg, 0.84 mmol), and triethylamine (400 mg, 3.96 mmol) were added in sequence. Under nitrogen protection, the reaction was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was poured into water, extracted with ethyl acetate (50 mL × 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 the crude product. It was purified by preparative HPLC to obtain KH30 (130.68 mg, yield: 59%). LCMS (ESI, m / z) purity: 99.42%, Rt = 1.919 min; MS Calculated: 474.1; MS Found: 475.0 [M+H]+. 11H NMR (400 MHz, DMSO-d6) δ: 8.19 (d, J = 7.6 Hz, 1H), 8.06 (d, J = 8.0 Hz, 1H), 7.94 - 7.83 (m, 2H), 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).

[0329] Synthesis of Compound A in Comparative Example 1

[0330] Compound A was synthesized according to the method described in Example 476 of WO2012145581A1, and its structure is as follows.

[0331]

[0332] Synthesis of Compound B in Comparative Example 2

[0333] Compound B was synthesized according to the method described in Example 237 of WO2012145581A1, and its structure is as follows.

[0334]

[0335] In vitro Cell Activity Detection in Example 29

[0336] 1. Cell Culture and Reagent Preparation

[0337] Experimental Reagents and Consumables

[0338]

[0339]

[0340] Cell Line: Flp-In-CHO-OX1 / OX2

[0341] Complete Medium: Ham's F-12K + 10% FBS + 1x Penicillin-Streptomycin (PS) + 600 μg / ml Hygromycin B Cell Seeding Medium: Ham's F-12K + 10% FBS

[0342] Experimental Buffer: 1X HBSS + 20 mM HEPES

[0343] Detection Kit: FLIPR Calcium 6 Assay Kit

[0344] 2. Experimental Method

[0345] 2.1 Determination of IC 50 Value of the Test Compound

[0346] 1) Culture the Flp-In-CHO-OX1 / OX2 stable pool cell line in complete medium at 37 °C in a 5% CO2 environment and maintain a confluence of 70% - 90%.

[0347] 2) After digestion with trypsin (TrypLE Express, ThermoFisher Scientific), resuspend the cells in seeding medium and seed them into a 384-well cell culture plate (Corning, 3764). The seeding density is 6500 cells per well for OX1 with a seeding volume of 25 μL, and 7000 cells per well for OX2 with a seeding volume of 25 μL. Then incubate overnight at 37 °C in 5% CO2.

[0348] 3) Thaw 20X Component A (the calcium probe provided in the kit, FLIPR Calcium 6 Assay Kit, Molecular Devices) to room temperature and dilute it to 2X working concentration containing 5 mM probenecid with assay buffer, and keep it at room temperature for use.

[0349] 4) Take out the cell culture plate and let it stand at room temperature for 10 minutes. Use Apricot (384-channel pipetting workstation) and assay buffer to dilute the concentration of fetal bovine serum (FBS, Gibco) to 0.03%. Finally, leave 20 μl of buffer in the 3764 culture plate, and then add 20 μl of 2X Component A containing 5 mM probenecid to each experimental well. After centrifuging at 200 g for 3 - 5 seconds at room temperature, incubate at 37 °C for 2 hours.

[0350] 5) Prepare 6x working solutions of positive control compounds and test compounds: Dilute the compounds with DMSO in 3-fold serial dilutions, with 10 concentration gradients. The starting concentration of the positive control compound is 1 mM, and the starting concentration of the test compound is 50 mM. Then use Echo550 to transfer 240 nL of each of the above gradient-diluted compounds to a 384-well working plate, add 40 μl of buffer, and then shake for 20 minutes, mix well and keep it at room temperature for use.

[0351] 6) Take out the cell culture plate and let it stand at room temperature for 10 minutes. Add 10 μL of the 6X working solutions of positive control compounds and test compounds in step 5) to the corresponding experimental wells of the 384-well cell culture plate, and incubate at room temperature for 30 minutes.

[0352] 7) Dilute Orexin A to 18 nM (6X) with the experimental buffer for orexin type 1 receptor, transfer 50 μL to a 384-well plate (Corning, 3657), and leave it at room temperature for use; dilute Orexin A to 12 nM (6X) with the experimental buffer for orexin type 2 receptor, transfer 50 μL to a 384-well plate (Corning, 3657), and leave it at room temperature for use.

[0353] 8) Using FLIPR Tetra (Molecular Devices), add 10 μl of the diluted Orexin A in step 7) to each experimental well and collect data.

[0354] 2.2 Data analysis

[0355] FLIPR Tetra collects the fluorescence signal value / baseline value (ROB), takes the maximum ROB value, and calculates the percentage inhibition rate data 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 ) x 100. Use Prism 8 to fit the percentage inhibition rate and the data of different concentrations of the compound to a non-linear four-parameter logistic formula to calculate the IC50 value of the compound.

[0356] 2.3 Experimental results

[0357] Table 1 Antagonistic effects of different compounds on OX2 / OX1 receptors

[0358]

[0359]

[0360] Example 30 Animal pharmacodynamic study

[0361] Experimental purpose: To explore the pharmacodynamic effects of the test compound on the sleep of male SD rats using telemetry technology.

[0362] Experimental animals: SD rats (male, 5 - 6 weeks old, body weight about 300 g)

[0363] Drug administration information:

[0364] Table 2

[0365]

[0366] Experimental method: During the adaptation period, the animals were placed in an environment with a 12-hour light-dark cycle (lights on at 19:00; lights off at 07:00). On the day of the experiment, the animals were anesthetized with Zoletil (i.p., 20 mg / kg) combined with xylazine (i.p., 8 mg / kg), and electrodes were surgically implanted. They were allowed to recover for 7 days after the surgery. Three days before drug administration, the rats were given the vehicle by gavage at 2 hours after lights off (9:00) every day for drug administration adaptation, and the electroencephalogram (EEG) and electromyogram (EMG) signals were recorded 1 hour before and 6 hours after vehicle administration on the day before drug administration. On the day of drug administration, the corresponding drugs were given to each group of rats by gavage at 2 hours after lights off (9:00), and the EEG and EMG signals were recorded from 1 hour before to 6 hours after drug administration to analyze the changes in the structure of wakefulness (Wake), rapid eye movement sleep (REM), and non-rapid eye movement sleep (NREM) (time and latency physiological indicators) after drug administration. Among them,

[0367] The change rate of NREM latency (%) = (Dose NREM latency - Base NREM latency) / Base NREM latency × 100%.

[0368] The change rate of REM latency (%) = (Dose REM latency - Base REM latency) / Base REM latency × 100%

[0369] The change rate of wakefulness duration (%) = (Dose wakefulness duration - Base wakefulness duration) / Base wakefulness duration × 100%

[0370] The change rate of NREM eye movement sleep duration (%) = (Dose NREM eye movement sleep duration - Base NREM eye movement sleep duration) / Base NREM eye movement sleep duration × 100%

[0371] The change rate of REM eye movement sleep duration (%) = (Dose REM eye movement sleep duration - Base REM eye movement sleep duration) / Base REM eye movement sleep duration × 100%

[0372] Data analysis: The original data were collected by the DSI system using Ponemah software and analyzed using NeuroScore software. The experimental data were expressed as mean ± standard error of the mean (Mean ± S.E.M.). Statistical analysis was performed using GraphPad Prism 8.0 software with One-way ANOVA, and Dunnet post hoc test was used. *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 an extremely significant difference.

[0373] Experimental results:

[0374] 1) The effects of the control group and the drug group on the NREM and REM sleep latencies of SD male rats are as shown in Figure 1 and 2 . As can be seen from Figure 1 , the change rate of NREM latency: compared with the negative control group, the change rates of NREM latency in the administration groups of compounds KH16, KH25, and KH27 were all significantly reduced. As can be seen from Figure 2 , the change rate of REM latency: compared with the negative control group, there were significant differences in the shortening of REM latency in the administration groups of compounds KH16, KH25, KH27, and KH30.

[0375] 2) The effects of the control group and the drug group on the wake duration index of SD rats are as shown in Figure 3 and 4 . As can be seen from the results, compared with the negative control group, the administration groups of compounds KH16, KH25, KH27, and KH30 significantly reduced the wake duration of SD rats 2 h after administration, and the administration group of compound KH27 was significantly better than other administration groups. Compared with the negative control group, all administration groups significantly reduced the wake duration of SD rats 6 h after administration.

[0376] 3) The effects of the control group and the drug group on the NREM duration (non-rapid eye movement sleep duration) of SD rats are as shown in Figure 5 and 6 . Among them. As can be seen from the results, compared with the negative control group, the administration groups of compounds KH16, KH25, and KH27 significantly increased the NREM duration of SD rats 2 h after administration; and the administration group of KH27 was significantly better than other administration groups. Compared with the negative control group, the administration groups of KH16, KH27, and KH30 all significantly increased the NREM duration of SD rats 6 h after administration.

[0377] 4) The effects of the control group and the drug group on the REM duration (rapid eye movement sleep duration) of SD rats are as shown in Figure 7 and 8 . Among them, as can be seen from the results, compared with the negative control group, the REM durations of SD rats 2 h and 6 h after administration in each administration group showed an increasing trend.

[0378] Animal pharmacodynamic study of Example 31

[0379] Experimental purpose: To explore the pharmacodynamic effects of the test compound on the sleep of SD male rats using telemetry technology.

[0380] Experimental animals: SD rats (male, 5 - 6 weeks old, body weight about 300 g)

[0381] Drug administration information:

[0382] Table 3

[0383]

[0384] Experimental method: The animals were placed in an environment with a 12 - hour light - dark cycle during the adaptation period (lights on at 19:00; lights off at 07:00). On the day of the experiment, the animals were anesthetized with Zoletil (i.p., 20 mg / kg) combined with xylazine (i.p., 8 mg / kg), and electrodes were surgically implanted. After the operation, the animals were allowed to recover for 7 days. Three days before drug administration, the rats were given the vehicle by gavage at 2 hours after lights off (9:00) every day for drug administration adaptation, and the electroencephalogram (EEG) and electromyogram (EMG) signals were recorded 1 hour before and 6 hours after the administration of the vehicle on the day before drug administration. On the day of drug administration, the corresponding drugs were given to each group of rats by gavage at 2 hours after lights off (9:00), and the EEG and EMG signals were recorded from 1 hour before to 6 hours after drug administration. The changes in the structure of wakefulness (Wake), rapid - eye - movement sleep (REM), and non - rapid - eye - movement sleep (NREM) (time and latency physiological indices) were analyzed. Among them,

[0385] Percentage change rate of NREM latency = (Dose NREM latency - Base NREM latency) / Base NREM latency × 100%

[0386] Percentage change rate of REM latency = (Dose REM latency - Base REM latency) / Base REM latency × 100%

[0387] Percentage change rate of wakefulness duration = (Dose wakefulness duration - Base wakefulness duration) / Base wakefulness duration × 100%

[0388] Percentage change rate of NREM eye movement sleep duration = (Dose NREM eye movement sleep duration - Base NREM eye movement sleep duration) / Base NREM eye movement sleep duration × 100%

[0389] Percentage change rate of REM eye movement sleep duration = (Dose REM eye movement sleep duration - Base REM eye movement sleep duration) / Base REM eye movement sleep duration × 100%

[0390] Data analysis: The original data was collected by the DSI system's Ponemah software and analyzed using NeuroScore software. The experimental data was expressed as mean ± standard error (Mean ± S.E.M.). Statistical analysis was performed using GraphPad Prism 8.0 software with One-way ANOVA, and Dunnet post hoc test was used. *P or #P < 0.05 indicates significant difference, **P or ##P < 0.01 indicates very significant difference, ***P or P < 0.001 indicates extremely significant difference.

[0391] Experimental results:

[0392] 1) The effects of the control group and the drug group on the NREM and REM sleep latencies of SD male rats are shown in Figure 9 、 10 . As can be seen from Figure 9 , the change rate of NREM latency: compared with the negative control group, the change rates of NREM latency in the administration groups of Examples KH27, KH28, and KH29 compounds were all significantly reduced. As can be seen from Figure 10 , the change rate of REM latency: compared with the negative control group, the shortening of REM latency in the administration groups of Examples KH27 and KH29 compounds showed significant differences.

[0393] 2) The effects of the control group and the drug group on the wake duration index of SD rats are shown in Figure 11 、 12 . It can be seen from the results that compared with the negative control group, the administration groups of Examples KH27 and KH29 compounds significantly reduced the wake duration of SD rats at 2 h and 6 h after administration.

[0394] 3) The effects of the control group and the drug group on the NREM duration (non-rapid eye movement sleep duration) of SD rats are shown in Figure 13 、 14 . Among them. It can be seen from the results that compared with the negative control group, the administration group of Example KH27 compound significantly increased the NREM duration of SD rats at 2 h after administration. Compared with the negative control group, both the KH27 and KH29 administration groups significantly increased the NREM duration of SD rats at 6 h after administration.

[0395] 4) The effects of the control group and the drug group on the REM duration (rapid eye movement sleep duration) of SD rats are shown in Figure 15 、 16As shown, it can be seen from the results that compared with the negative control group, both the KH27 and KH29 administration groups significantly increased the NREM duration of SD rats 2 hours after administration. Compared with the negative control group, the KH27 administration group significantly increased the NREM duration of SD rats 6 hours after administration.

[0396] Example 3 Metabolism Stability in Human Hepatocytes

[0397] Experimental Purpose: To study the metabolic stability of the compound in human hepatocytes

[0398] Experimental Materials: Suspended human hepatocytes

[0399] Experimental Operation: Take out the cryopreserved hepatocytes from the liquid nitrogen tank and resuscitate them. Calculate the cell viability by trypan blue staining. Add the hepatocyte suspension to a pre-warmed incubation plate, then add the test article and the working solution of the control compound, mix well and immediately place it in the shaker in the incubator, and start the timer to start the reaction. Set the incubation time points of 0, 15, 30, 60, and 90 minutes for the reaction, and the incubation conditions are 37 °C, saturated humidity, and containing 5% CO2. In the reaction system, the final concentration of the test article is 1 μM, the final concentration of the reference substance is 3 μM, and the final concentration of the hepatocytes is 0.5×10 6 cells / mL. At the end of the incubation at the corresponding time points, take out the incubation plate, take an appropriate amount of the cell suspension into a sample plate containing a certain volume of the termination solution (an acetonitrile solution containing 200 ng / mL tolbutamide and labetalol). After sealing all the sample plates and shaking them on the shaker at 600 rpm for 10 minutes, centrifuge them at 3220×g for 20 minutes. Dilute the supernatant of the test article and the reference substance with ultrapure water at a ratio of 1:3. After mixing all the samples, analyze them by LC / MS / MS method and calculate the half-life (T 1 / 2 ), and the results are shown in Table 4.

[0400] Table 4

[0401] Compound ID T1 / 2 (min) Positive control (seltorexant) 24.0 KH16 42.3 KH25 52.1 KH26 88.7 KH28 91.9 KH29 49.3

[0402] Example 33 Pharmacokinetic Evaluation of the Compound

[0403] Experimental Purpose: To study the pharmacokinetics of the compound in SD rats - drug concentration in brain tissue

[0404] Experimental Animals: SD rats (male, 6 - 8 weeks old, body weight 247.48 - 255.52 g)

[0405] Experimental operation: The pharmacokinetic characteristics of the compound in rodents after oral administration were tested according to the standard protocol. In the experiment, the corresponding compound was prepared into a clear solution of 1 mg / mL, and the rats were given a single oral dose. The oral vehicle was an aqueous solution of 20% HP-β-CD. Male SD rats were used in this project. The drug was administered by oral gavage at a dose of 5 mg / kg. Whole brains were collected at 0.5, 2, and 4 hours after dosing. The tissue samples were homogenized with [methanol / 15 mM phosphate buffer (volume ratio, 1:2)], and the dilution factor was 6. Finally, the sample concentration was quantitatively analyzed by LC-MS / MS analysis method, and the results are shown in Table 5.

[0406] Table 5

[0407]

[0408]

[0409] Pharmacokinetic evaluation of the compound in Example 34

[0410] Experimental purpose: To study the pharmacokinetics of the compound in SD rats

[0411] Experimental animals: SD rats (male, 6 - 8 weeks old, body weight 250.13 - 262.17 g)

[0412] Experimental operation: The pharmacokinetic characteristics of the compound in rodents after oral administration were tested according to the standard protocol. In the experiment, the corresponding compound was prepared into a clear solution of 1 mg / mL, and the rats were given a single intravenous or oral dose. The vehicle was 10% DMSO / 80% PEG400 / 10% water. Male SD rats were used in this project. The dose was 1 mg / kg intravenously or 5 mg / kg by oral gavage. Plasma was collected at 0.083 (only intravenous), 0.25, 0.5, 1, 2, 4, 8, and 24 hours after dosing. Finally, the plasma drug concentration was quantitatively analyzed by LC-MS / MS analysis method, and the pharmacokinetic parameters such as clearance rate (Cl), peak concentration (Cmax), half-life (T1 / 2), time to peak concentration (Tmax), area under the plasma concentration-time curve (AUC0-last), etc. were calculated, and the results are shown in Table 6.

[0413] Table 6

[0414]

[0415] Animal efficacy study in Example 35

[0416] Experimental purpose: To explore the pharmacodynamic effect of the test compound on the sleep of male SD rats using telemetry technology.

[0417] Experimental animals: SD rats (male, 5 - 6 weeks old, body weight about 300 g)

[0418] Administration Information:

[0419] Table 7

[0420]

[0421] Experimental Method: During the adaptation period, the animals were placed in an environment with a 12-hour light-dark cycle (lights on at 19:00; lights off at 07:00). On the day of the experiment, the animals were anesthetized with Zoletil (i.p., 20 mg / kg) combined with xylazine (i.p., 8 mg / kg), and electrodes were surgically implanted. After the surgery, the animals were allowed to recover for 7 days. Three days before drug administration, the rats were given the vehicle by gavage at 2 hours after lights off (9:00) every day for drug administration adaptation, and the electroencephalogram (EEG) and electromyogram (EMG) signals were recorded 1 hour before and 6 hours after the administration of the vehicle on the day before drug administration. On the day of drug administration, the corresponding drugs were given to each group of rats by gavage at 2 hours after lights off (9:00), and the EEG and EMG signals were recorded from 1 hour before to 6 hours after drug administration. The changes in the structure of wakefulness (Wake) and non-rapid eye movement sleep (NREM) (time and latency physiological indices) after drug administration were analyzed.

[0422] Data Analysis: The raw data were collected by the DSI system Ponemah software and analyzed by the NeuroScore software. The experimental data were expressed as mean ± standard error of the mean (Mean ± S.E.M.). Statistical analysis was performed using GraphPad Prism 8.0 software and one-way ANOVA, and Dunnet post hoc test was used. *P or #P < 0.05 indicates significant difference, **P or ##P < 0.01 indicates very significant difference, and ***P or P < 0.001 indicates extremely significant difference.

[0423] Experimental Results:

[0424] 1) The effects of the control group and the drug group on the NREM sleep latency of male SD rats are as Figure 17 shown. As can be seen from Figure 17 , compared with the negative control group, the NREM latency in the administration group of the KH16 compound of the example was significantly reduced.

[0425] 2) The effects of the control group and the drug group on the wake duration index of SD rats are as Figure 18 shown. From the results, it can be seen that compared with the negative control group, the wake duration of SD rats 6 hours after drug administration in the administration group of the KH16 compound of the example was significantly reduced.

[0426] 3) The effects of the control group and the drug group on the NREM duration (non-rapid eye movement sleep duration) of SD rats are as Figure 19As shown. Among them. It can be seen from the results that, compared with the negative control group, the administration group of the compound KH16 significantly increased the NREM duration of SD rats 6 hours after administration.

[0427] The above results indicate that at a dosage of 5 mg / kg, KH16 has an equivalent effect on improving the sleep of rats as the positive control drug at a dosage of 10 mg / kg.

Claims

1. A compound of the following formula, its stereoisomers or its pharmaceutically acceptable salts, characterized in that The structure of the said compound 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 heterocyclic group, C5-10 aryl and C5-10 heteroaryl, and the said C3-8 cycloalkyl, C3-8 heterocyclic group, C5-10 aryl and C5-10 heteroaryl are optionally substituted by 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, 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 heterocyclic group, C6-10 aryl and C5-10 heteroaryl, and the said C3-8 cycloalkyl, C3-8 heterocyclic group, C6-10 aryl and C5-10 heteroaryl are optionally substituted by 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; 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 said C3-8 heterocyclic group and C5-10 heteroaryl are one, two or three of N, O and S, and the number of heteroatoms is 1, 2 or 3.

2. The compound, its stereoisomer or its pharmaceutically acceptable salt according to claim 1, characterized in that, 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 heterocyclic group, C5-10 aryl and C5-10 heteroaryl, and the said C3-8 cycloalkyl, C3-8 heterocyclic group, C5-10 aryl and C5-10 heteroaryl are optionally substituted by 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, hydroxyl, 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 and C3-8 heterocyclic group, and the C3-8 cycloalkyl and C3-8 heterocyclic group 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 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, stereoisomer or pharmaceutically acceptable salt thereof according to claim 2, characterized in that The compound has the structure shown in Formula Ia or Ib: 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, C3-8 cycloalkyl, C3-8 heterocyclic group, C5-10 aryl and C5-10 heteroaryl, and the C3-8 cycloalkyl, C3-8 heterocyclic group, 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 or C1-6 hydroxyalkoxy; The definitions of other substituents are as described in claim 2.

4. The compound, stereoisomer or pharmaceutically acceptable salt thereof according to claim 2, characterized in that The compound has the structure shown in Formula IIIa or IIIb: 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, C3-8 cycloalkyl, C3-8 heterocyclic group, C5-10 aryl and C5-10 heteroaryl, and the C3-8 cycloalkyl, C3-8 heterocyclic group, 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 or C1-6 hydroxyalkoxy; The definitions of other substituents are as described in claim 2.

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

6. The compound, stereoisomer or pharmaceutically acceptable salt thereof according to claim 3, 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; 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, stereoisomer or pharmaceutically acceptable salt thereof according to claim 2, 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, and the C3-8 cycloalkyl is optionally substituted with deuterium, halogen, or C1-3 alkyl; preferably, R4 is selected from fluorine, trifluoromethyl, or cyclopropyl, and the cyclopropyl is optionally substituted with halogen or methyl; preferably, R4 is hydrogen.

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

9. The compound, stereoisomer or pharmaceutically acceptable salt thereof according to claim 3 or 5, 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 Each is independently hydrogen.

10. The compound, stereoisomer or pharmaceutically acceptable salt thereof according to claim 9, characterized in that, The compound satisfies one or two 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, stereoisomer or pharmaceutically acceptable salt thereof according to claim 9, 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, stereoisomer or pharmaceutically acceptable salt thereof according to claim 10, 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, stereoisomer or pharmaceutically acceptable salt thereof according to claim 5, 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, stereoisomer or pharmaceutically acceptable salt thereof according to claim 13, characterized in that R1 and R3 are deuterated methyl.

15. The compound, stereoisomer or pharmaceutically acceptable salt thereof according to claim 5, 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, stereoisomer or pharmaceutically acceptable salt thereof according to claim 1, characterized in that The compound has any of the following structures:

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

18. Use of the compound, stereoisomer or pharmaceutically acceptable salt thereof according to any one of claims 1-16, 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, stereoisomer or pharmaceutically acceptable salt thereof according to any one of claims 1-16, or the pharmaceutical composition according to claim 17 in the preparation of a medicament for treating nervous system diseases; the nervous system diseases are preferably insomnia, depression or anxiety or drug addiction, more preferably major depressive disorder, primary and secondary insomnia or depression accompanied by insomnia.

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