19-norc3, 3-disubstituted c21-azacyclo-substituted steroids and methods of use thereof

Abstract

The present invention relates to 19-norC3, 3-disubstituted C21-azacyclo-substituted steroids and methods of use thereof. Particularly, the invention relates to a compound as shown in a general formula (I), a preparation method of the compound, a pharmaceutical composition containing the compound, and application of the compound as a GABAAR positive allosteric modulator in prevention and / or treatment of various CNS-related diseases, such as CNS-related diseases, CNS-related diseases, CNS-related diseases, CNS-related diseases, CNS-related diseases, CNS-related diseases, CNS-related diseases and CNS-related diseases. , for example, the treatment of sleep disorders, mood disorders, insomnia, anxiety, depression, traumatic brain injury (TBI), stress, epilepsy, and the like. Wherein each substituent in the general formula (I) is as defined in the specification.

Description

19-Nor C3,3-disubstituted C21-nitrogen heterocyclic steroids and methods of use thereof Technical Field

[0001] The present invention relates to a class of 19-nor C3,3-disubstituted C21-nitrogen heterocyclic steroids and their preparation methods, and their application in combination with GABA. A The invention relates to the application in the field of receptor-related diseases, and specifically relates to the compound represented by formula (I) and pharmaceutically acceptable salts thereof. Background Art

[0002] Depression is a common mental illness characterized by a persistent and prolonged period of low mood. It is the most important type of mental illness in modern people. Although it is not uncommon to experience occasional feelings of sadness, in most people these emotions are usually short-lived and disappear after a few days. When manifesting as a depressive disorder, the patient's symptoms can interfere with daily life and normal functioning. Depression is a major cause of disability and can cause a variety of symptoms. Not only is there low mood, but the condition can also lead to changes in endocrine and immune function, which can increase susceptibility to physical illness. In the worst cases, depression can lead to suicide. Depression can be divided into major depressive disorder (MDD), persistent depressive disorder (also known as dysthymia, PDD), psychotic depression, postpartum depression (PPD), and seasonal affective disorder (SAD).

[0003] In 2018, there were 223.1 million prevalent cases of MDD worldwide, and this number is projected to increase to 248.9 million prevalent cases by 2027, a growth rate of 11.6%. In 2018, the highest number of prevalent cases was estimated to be in Asia (130.7 million cases), while the lowest was in Oceania (1.5 million cases).

[0004] PPD is one of the most common neurobiological complications of childbirth, occurring in 13% of women postpartum, some of whom may begin as early as late pregnancy. Severe cases occur in approximately 5-10% of patients and are a leading cause of maternal mortality. Therefore, the unmet need for PPD is particularly high, given its potentially devastating consequences not only for patients but also for their children and families.

[0005] Neuroactive steroids (NAS) are the most potent modulators of neuronal excitability and have been shown to act primarily through GABA A GABA receptors A R) to affect the function of the central nervous system (CNS). GABA receptors include: GABA A , GABA B , GABA C , usually GABA A and GABA BReceptors associated with mood disorders, GABA A The GABA receptor is a pentameric chloride channel receptor that is mainly composed of two α subunits (α1-α6), two β subunits (β1-β3) and one additional subunit (γ1-γ3, δ, ε, π or θ). A After the receptor binds to GABA, it causes the chloride ion channel to open (chloride ions flow into the membrane), causing the neuronal cell membrane to hyperpolarize and causing neuronal inhibition. The unique subunit composition determines the biophysical and pharmacological characteristics of the channel and affects its location at the synapse or extrasynapse. The GABA level in the plasma, cerebrospinal fluid or cortical tissue of MDD patients is reduced, the expression of GABA synthase is reduced, and GABA A Altered expression of R subunits and a decrease in the number of GABAergic interneurons. Low perinatal GABA levels have been demonstrated in women at risk for PPD, and GABA levels are negatively correlated with depression scores. A R positive allosteric modulators can promote the A Receptor binding, enhancing the inhibitory effect of GABA.

[0006] 19-nor C3,3-disubstituted C21-nitrogen heterocyclic steroids are improved steroids with better brain excitation regulating effects and can be used to prevent and treat depression and other CNS-related diseases. The compounds, compositions and methods described herein relate to this purpose.

[0007] Summary of the Invention

[0008] In one embodiment of the present disclosure, provided are compounds represented by formula (I) and pharmaceutically acceptable salts thereof:

[0009] in,

[0010] (1) X is independently selected from C atoms, Y is independently selected from N atoms, or X is independently selected from N atoms, Y is independently selected from C atoms, or X and Y are both selected from C atoms;

[0011] R1 is selected from H, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 3-6 Cycloalkyl, C 3-6 Cycloalkyl C 1-3 Alkyl, C 1-6 Alkoxy C 1-3 Alkyl, halogenated C 1-6 Alkoxy C 1-3 alkyl, 6-10 membered aryl, or 5-10 membered heteroaryl, wherein the 6-10 membered aryl and 5-10 membered heteroaryl may be optionally substituted with one or more halogen, C 1-6 Alkyl, halogenated C1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 substituted by alkoxy, -(C=O)NH2, -NH2, or cyano;

[0012] R2 is selected from H, halogen, C 1-6 Alkyl, or C 1-6 Alkoxy C 1-3 alkyl;

[0013] R3 is selected from H, C 1-6 Alkyl, or C 1-6 Alkoxy C 1-3 alkyl.

[0014] or

[0015] (2) X and Y are both selected from C atoms, and X and Y together with the atoms to which they are attached form a ring A;

[0016] The ring A is selected from

[0017] wherein A1, A2, A3, and A4 are each independently selected from CR4 or N atom;

[0018] R1 is selected from H, halogenated C 1-6 Alkyl, C 3-6 Cycloalkyl, C 3-6 Cycloalkyl C 1-3 Alkyl, C 1-6 Alkoxy C 1-3 Alkyl, halogenated C 1-6 Alkoxy C 1-3 alkyl, 6-10 membered aryl, or 5-10 membered heteroaryl, wherein the 6-10 membered aryl and 5-10 membered heteroaryl may be optionally substituted with one or more halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, -(C=O)NH2,

[0019] -NH2, or cyano substituted;

[0020] R2 is selected from H, halogen, C 1-6 Alkyl, or C 1-6 Alkoxy C 1-3 alkyl;

[0021] R3 is selected from H, C 1-6 Alkyl, or C 1-6 Alkoxy C 1-3 alkyl;

[0022] Each R4 is independently selected from H, halogen, C1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Alkoxy C 1-3 Alkyl or halogenated C 1-6 Alkoxy C 1-3 alkyl.

[0023] In another embodiment of the present disclosure, provided are compounds represented by formula (IA) or (IB), or pharmaceutically acceptable salts thereof:

[0024] in,

[0025] (1) X is independently selected from C atoms, Y is independently selected from N atoms, or X is independently selected from N atoms, Y is independently selected from C atoms, or X and Y are both selected from C atoms;

[0026] R1 is selected from H, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 3-6 Cycloalkyl, C 3-6 Cycloalkyl C 1-3 Alkyl, C 1-6 Alkoxy C 1-3 Alkyl, halogenated C 1-6 Alkoxy C 1-3 alkyl, 6-10 membered aryl, or 5-10 membered heteroaryl, wherein the 6-10 membered aryl and 5-10 membered heteroaryl may be optionally substituted with one or more halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 substituted by alkoxy, -(C=O)NH2, -NH2, or cyano;

[0027] R2 is selected from H, halogen, C 1-6 Alkyl, or C 1-6 Alkoxy C 1-3 alkyl;

[0028] R3 is selected from H, C 1-6 Alkyl, or C 1-6 Alkoxy C 1-3 alkyl.

[0029] or

[0030] (2) X and Y are both selected from C atoms, and X and Y together with the atoms to which they are attached form a ring A;

[0031] The ring A is selected from

[0032] wherein A1, A2, A3, and A4 are each independently selected from CR4 or N atom;

[0033] R1 is selected from H, halogenated C 1-6 Alkyl, C 3-6 Cycloalkyl, C 3-6 Cycloalkyl C 1-3 Alkyl, C 1-6 Alkoxy C 1-3 Alkyl, halogenated C 1-6 Alkoxy C 1-3 alkyl, 6-10 membered aryl, or 5-10 membered heteroaryl, wherein the 6-10 membered aryl and 5-10 membered heteroaryl may be optionally substituted with one or more halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 substituted by alkoxy, -(C=O)NH2, -NH2, or cyano;

[0034] R2 is selected from H, halogen, C 1-6 Alkyl, or C 1-6 Alkoxy C 1-3 alkyl;

[0035] R3 is selected from H, C 1-6 Alkyl, or C 1-6 Alkoxy C 1-3 alkyl;

[0036] Each R4 is independently selected from H, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Alkoxy C 1-3 Alkyl or halogenated C 1-6 Alkoxy C 1-3 alkyl.

[0037] In some embodiments of the present disclosure, in the compound represented by formula (I), formula (IA) or formula (1B), or a pharmaceutically acceptable salt thereof,

[0038] (1) X is independently selected from C atoms, Y is independently selected from N atoms, X is independently selected from N atoms, Y is independently selected from C atoms, or both X and Y are C atoms;

[0039] R1 is selected from H, C 1-3 Alkyl, halogenated C 1-3 Alkyl, C 3-6 Cycloalkyl, C 3-6 Cycloalkyl C 1-3 Alkyl, C 1-6 Alkoxy C 1-3 Alkyl, halogenated C1-6 Alkoxy C 1-3 alkyl, 6-10 membered aryl, or 5-10 membered heteroaryl, wherein the 6-10 membered aryl and 5-10 membered heteroaryl may be optionally substituted with one or more halogen, C 1-3 Alkyl, halogenated C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 substituted by alkoxy, -(C=O)NH2, -NH2, or cyano;

[0040] R1 is further preferably selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl, fluoromethyl, chloromethyl, difluoromethyl, dichloromethyl, trifluoromethyl, trichloromethyl, 2,2-difluoroethyl, 2,2-dichloroethyl, 2,2,2-trifluoroethyl, 2,2,2-trichloroethyl, pentafluoroethyl, pentachloroethyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclobutylethyl, cyclopentylmethyl, cyclopentylethyl, cyclo hexylmethyl, cyclohexylethyl, methoxymethyl, ethoxymethyl, methoxyethyl, ethoxyethyl, trifluoromethoxymethyl, trifluoromethoxyethyl, phenyl, naphthyl, pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, benzopyrazolyl, isoindolyl, indazolyl, benzotriazolyl, benzothienyl, isobenzothienyl, benzofuranyl, benzoisofuranyl, benzodioxadiazole phenyl, naphthyl, pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, benzopyrazolyl, isoindolyl, indazolyl, benzotriazolyl, benzothienyl, isobenzothienyl, benzofuranyl, benzoisofuranyl, benzodioxolyl, or benzimidazolyl; the phenyl, naphthyl, pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, benzopyrazolyl, isoindolyl, indazolyl, benzotriazolyl, benzothienyl, isobenzothienyl, benzofuranyl, benzoisofuranyl, benzodioxolyl, or benzimidazolyl is optionally replaced by one or more F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl, substituted by propyl, fluoromethyl, chloromethyl, difluoromethyl, dichloromethyl, trifluoromethyl, trichloromethyl, 2,2-difluoroethyl, 2,2-dichloroethyl, 2,2,2-trifluoroethyl, 2,2,2-trichloroethyl, methoxy, ethoxy, n-propoxy, isopropoxy, trifluoromethoxy, trichloromethoxy, 2,2-difluoroethoxy, 2,2-dichloroethoxy, 2,2,2-trifluoroethoxy, 2,2,2-trichloroethoxy, -(C=O)NH2, -NH2, or cyano;

[0041] R1 is more preferably selected from methyl, ethyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, 2,2,2-trifluoroethyl, methoxyethyl, trifluoromethoxyethyl, phenyl, oxazolyl, thiazolyl, pyridyl, benzodioxolyl, benzopyrazolyl, or indolyl; said phenyl, oxazolyl, thiazolyl, pyridyl, benzodioxolyl, benzopyrazolyl, indolyl is optionally substituted with one or more F, Cl, Br, I, methyl, ethyl, difluoromethyl, trifluoromethyl, methoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, -(C=O)NH2, -NH2, or cyano;

[0042] R2 is selected from H, F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl, methoxymethyl, or ethoxymethyl;

[0043] R3 is selected from H, methyl, ethyl, n-propyl, isopropyl, methoxymethyl, or ethoxymethyl;

[0044] or

[0045] (2) X and Y are both C atoms, and X and Y together with the atoms to which they are attached form a ring A;

[0046] The ring A is selected from

[0047] R1 is selected from H, halogenated C 1-3 Alkyl, C 3-6 Cycloalkyl C 1-3 Alkyl, C 1-6 Alkoxy C 1-3 Alkyl, halogenated C 1-6 Alkoxy C 1-3 alkyl, 6-10 membered aryl, or 5-10 membered heteroaryl, wherein the 6-10 membered aryl and 5-10 membered heteroaryl may be optionally substituted with one or more halogen, C 1-3 Alkyl, halogenated C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 substituted by alkoxy, -(C=O)NH2, -NH2, or cyano;

[0048] R1 is further preferably selected from H, fluoromethyl, chloromethyl, difluoromethyl, dichloromethyl, trifluoromethyl, trichloromethyl, 2,2-difluoroethyl, 2,2-dichloroethyl, 2,2,2-trifluoroethyl, 2,2,2-trichloroethyl, pentafluoroethyl, pentachloroethyl, cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclobutylethyl, cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl, cyclohexylethyl, methoxymethyl, ethoxymethyl, methoxyethyl, ethoxyethyl, trifluoromethoxymethyl, trifluoromethoxyethyl, phenyl, naphthyl, pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, benzopyrazolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzotriazolyl, thienyl, benzofuranyl, benzisofuranyl, benzodioxolyl, or benzimidazolyl; the phenyl, naphthyl, pyrrolyl, furanyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, benzopyrazolyl, isoindolyl, indazolyl, benzotriazolyl, benzothienyl, isobenzothienyl, benzofuranyl, benzisofuranyl, benzodioxolyl, or benzimidazolyl being optionally substituted with one or more F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl, fluoromethyl, chloromethyl, difluoromethyl, dichloromethyl, trifluoromethyl, trichloromethyl, methoxy, ethoxy, n-propoxy, isopropoxy, trifluoromethoxy, trichloromethoxy, -(C=O)NH2, -NH2, or cyano;

[0049] R1 is more preferably selected from cyclopropylmethyl, 2,2,2-trifluoroethyl, methoxyethyl, trifluoromethoxyethyl, phenyl, oxazolyl, thiazolyl, pyridinyl, benzodioxolyl, benzopyrazolyl, or indolyl; said phenyl, oxazolyl, thiazolyl, pyridinyl, benzodioxolyl, benzopyrazolyl, indolyl is optionally substituted with one or more F, Cl, Br, I, methyl, ethyl, trifluoromethyl, methoxy, trifluoromethoxy, -(C=O)NH2, -NH2, or cyano;

[0050] R2 is selected from H, F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl, methoxymethyl, or ethoxymethyl;

[0051] R3 is selected from H, methyl, ethyl, n-propyl, isopropyl, methoxymethyl, or ethoxymethyl;

[0052] Each R4 is independently selected from H, F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, fluoromethoxy, chloromethoxy, difluoromethoxy, dichloromethoxy, trifluoromethoxy, trichloromethoxy, 2,2-difluoroethoxy, 2,2-dichloroethoxy, 2,2,2-trifluoroethoxy, 2,2,2-trichloroethoxy, methoxymethyl, ethoxymethyl, methoxyethyl, fluoromethoxymethyl, chloromethoxymethyl, difluoromethoxymethyl, dichloroethoxy, chloromethoxymethyl, trifluoromethoxymethyl, trichloromethoxymethyl, 2,2-difluoroethoxymethyl, 2,2-dichloroethoxymethyl, 2,2,2-trifluoroethoxymethyl, 2,2,2-trichloroethoxymethyl, fluoromethoxyethyl, chloromethoxyethyl, difluoromethoxyethyl, dichloromethoxyethyl, trifluoromethoxyethyl, trichloromethoxyethyl, 2,2-difluoroethoxyethyl, 2,2-dichloroethoxyethyl, 2,2,2-trifluoroethoxyethyl, or 2,2,2-trichloroethoxyethyl.

[0053] In another embodiment of the present disclosure, provided are compounds represented by formula (IIA), (IIB), (IIC), (IID), and pharmaceutically acceptable salts thereof:

[0054] in,

[0055] A1, A2, A3, A4 are each independently selected from CR4, or N atom;

[0056] R1 is selected from H, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 3-6 Cycloalkyl, C 3-6 Cycloalkyl C 1-3 Alkyl, C 1-6 Alkoxy C 1-3 Alkyl, halogenated C 1-6 Alkoxy C 1-3 alkyl, 6-10 membered aryl, or 5-10 membered heteroaryl, wherein the 6-10 membered aryl and 5-10 membered heteroaryl may be optionally substituted with one or more halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 substituted by alkoxy, -(C=O)NH2, -NH2, or cyano;

[0057] R2 is selected from H, halogen, C 1-6 Alkyl, or C 1-6 Alkoxy C 1-3 alkyl;

[0058] R3 is selected from H, C 1-6Alkyl, or C 1-6 Alkoxy C 1-3 alkyl;

[0059] Each R4 is independently selected from H, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Alkoxy C 1-3 Alkyl or halogenated C 1-6 Alkoxy C 1-3 alkyl.

[0060] In another embodiment of the present disclosure, provided are compounds represented by formula (IIA-1), (IIA-2), (IIB-1), (IIB-2), (IIC-1), (IIC-2), (IID-1), (IID-2), and pharmaceutically acceptable salts thereof:

[0061] in,

[0062] A1, A2, A3, A4 are each independently selected from CR4, or N atom;

[0063] R1 is selected from H, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 3-6 Cycloalkyl, C 3-6 Cycloalkyl C 1-3 Alkyl, C 1-6 Alkoxy C 1-3 Alkyl, halogenated C 1-6 Alkoxy C 1-3 alkyl, 6-10 membered aryl, or 5-10 membered heteroaryl, wherein the 6-10 membered aryl and 5-10 membered heteroaryl may be optionally substituted with one or more halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 substituted by alkoxy, -(C=O)NH2, -NH2, or cyano;

[0064] R2 is selected from H, halogen, C 1-6 Alkyl, or C 1-6 Alkoxy C 1-3 alkyl;

[0065] R3 is selected from H, C 1-6 Alkyl, or C 1-6 Alkoxy C 1-3 alkyl;

[0066] Each R4 is independently selected from H, halogen, C1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Alkoxy C 1-3 Alkyl or halogenated C 1-6 Alkoxy C 1-3 alkyl.

[0067] In some embodiments of the present disclosure, in the compounds represented by formula (IIA), (IIB), (IIC), (IIA-1), (IIA-2), (IIB-1), (IIB-2), (IIC-1), (IIC-2), or pharmaceutically acceptable salts thereof, R1 is selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl, fluoromethyl, chloromethyl, difluoromethyl, dichloromethyl, trifluoromethyl, trichloromethyl, 2,2-difluoroethyl, 2,2-dichloroethyl, 2,2,2-trifluoroethyl, 2,2,2-trichloroethyl, pentafluoroethyl, pentachloroethyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclobutylethyl, cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl, cyclohexylethyl, methoxymethyl, ethoxymethyl, methoxyethyl, ethoxyethyl, trifluoromethoxymethyl, trifluoromethoxyethyl, phenyl, naphthyl, pyrrolyl, furanyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, benzopyrazolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzodioxolyl, or benzimidazolyl; the phenyl, naphthyl, pyrrolyl, furanyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, benzopyrazolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzodioxolyl, or benzimidazolyl is optionally replaced by one or more F, Cl, Br , I, methyl, ethyl, n-propyl, isopropyl, fluoromethyl, chloromethyl, difluoromethyl, dichloromethyl, trifluoromethyl, trichloromethyl, 2,2-difluoroethyl, 2,2-dichloroethyl, 2,2,2-trifluoroethyl, 2,2,2-trichloroethyl, methoxy, ethoxy, n-propoxy, isopropoxy, trifluoromethoxy, trichloromethoxy, 2,2-difluoroethoxy, 2,2-dichloroethoxy, 2,2,2-trifluoroethoxy, 2,2,2-trichloroethoxy, -(C=O)NH2, -NH2, or cyano, and the other variables are as defined in the present disclosure.

[0068] In some embodiments of the present disclosure, in the compounds represented by formula (IIA), (IIB), (IIC), (IIA-1), (IIA-2), (IIB-1), (IIB-2), (IIC-1), (IIC-2), or pharmaceutically acceptable salts thereof, R1 is selected from H, methyl, ethyl, cyclopropylmethyl, 2,2,2-trifluoroethyl, methoxyethyl, trifluoromethoxyethyl, phenyl, oxazolyl, thiazolyl, pyridyl, benzodioxolyl, benzopyrazolyl, and indolyl; the phenyl, oxazolyl, thiazolyl, pyridyl, benzodioxolyl, benzopyrazolyl, and indolyl are optionally substituted with one or more F, Cl, Br, I, methyl, ethyl, trifluoromethyl, methoxy, trifluoromethoxy, or cyano groups, and other variables are as defined in the present disclosure.

[0069] In some embodiments of the present disclosure, in the compounds represented by formula (IIA), (IIB), (IIC), (IIA-1), (IIA-2), (IIB-1), (IIB-2), (IIC-1), (IIC-2), or pharmaceutically acceptable salts thereof, R1 is selected from H, methyl, ethyl, tert-butyl, cyclopropylmethyl, 2,2,2-trifluoroethyl, cyclopentyl, cyclohexyl, methoxymethyl, ethoxymethyl, methoxyethyl, ethoxyethyl, trifluoromethoxymethyl, trifluoromethoxyethyl, and optionally substituted with one or more F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl, fluoromethyl, chloromethyl, difluoromethyl, dichloromethyl, trifluoromethyl, trichloromethyl, 2,2-difluoroethyl, 2,2-dichloroethyl, 2,2,2-trifluoroethyl, 2,2,2-trichloroethyl, methoxy, ethoxy, n-propoxy, isopropoxy, fluoromethoxy, chloromethoxy, difluoromethoxy, dichloromethoxy, trifluoromethoxy, trichloromethoxy, 2,2-difluoroethoxy, 2,2-dichloroethoxy, 2,2,2-trifluoroethoxy, 2,2,2-trichloroethoxy, —(C═O)NH , —NH , or cyano, and other variables are as defined in the disclosure.

[0070] In some embodiments of the present disclosure, in the compounds represented by formula (IIA), (IIB), (IIC), (IIA-1), (IIA-2), (IIB-1), (IIB-2), (IIC-1), (IIC-2), or pharmaceutically acceptable salts thereof, R1 is selected from H, methyl, ethyl, cyclopropylmethyl, 2,2,2-trifluoroethyl, methoxyethyl, trifluoromethoxyethyl, described Optionally substituted with one or more F, Cl, Br, I, methyl, ethyl, trifluoromethyl, methoxy, trifluoromethoxy, or cyano, with the other variables being as defined in the disclosure.

[0071] In some embodiments of the present disclosure, in the compounds represented by Formula (IIA), (IIB), (IIC), (IIA-1), (IIA-2), (IIB-1), (IIB-2), (IIC-1), (IIC-2), or pharmaceutically acceptable salts thereof, R2 is selected from H, F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl, methoxymethyl, or ethoxymethyl, and other variables are as defined in the present disclosure.

[0072] In some embodiments of the present disclosure, in the compounds represented by Formula (IIA), (IIB), (IIC), (IIA-1), (IIA-2), (IIB-1), (IIB-2), (IIC-1), (IIC-2), or pharmaceutically acceptable salts thereof, R2 is selected from H or methyl, preferably H; other variables are as defined in the present disclosure.

[0073] In some embodiments of the present disclosure, in the compounds represented by formula (IIA), (IIB), (IIC), (IIA-1), (IIA-2), (IIB-1), (IIB-2), (IIC-1), (IIC-2), or pharmaceutically acceptable salts thereof, R3 is selected from H, methyl, ethyl, n-propyl, isopropyl, methoxymethyl, or ethoxymethyl, preferably methyl; other variables are as defined in the present disclosure.

[0074] In some embodiments of the present disclosure, in the compounds represented by formula (IIA), (IIA-1), (IIA-2), or pharmaceutically acceptable salts thereof, R1 is selected from phenyl, m-fluorophenyl, m-chlorophenyl, m-bromophenyl, m-iodophenyl, m-methoxyphenyl, or m-ethoxyphenyl, and other variables are as defined in the present disclosure.

[0075] In some embodiments of the present disclosure, in the compounds represented by formula (IIA), (IIA-1), (IIA-2), or pharmaceutically acceptable salts thereof, R1 is selected from phenyl, m-fluorophenyl, or m-methoxyphenyl, and other variables are as defined in the present disclosure.

[0076] In some embodiments of the present disclosure, in the compounds represented by formula (IID), (IID-1), (IID-2), or pharmaceutically acceptable salts thereof, R1 is selected from H, cyclopropylmethyl, 2,2,2-trifluoroethyl, methoxyethyl, trifluoromethoxyethyl, phenyl, oxazolyl, thiazolyl, pyridinyl, benzodioxolane, benzopyrazolyl, and indolyl; the phenyl, oxazolyl, thiazolyl, pyridinyl, benzodioxolane, benzopyrazolyl, and indolyl are optionally substituted with one or more F, Cl, Br, I, methyl, ethyl, trifluoromethyl, methoxy, trifluoromethoxy, or cyano groups, and other variables are as defined in the present disclosure.

[0077] In some embodiments of the present disclosure, in the compound represented by formula (IID), (IID-1), (IID-2), or a pharmaceutically acceptable salt thereof, R1 is selected from H, cyclopropylmethyl, 2,2,2-trifluoroethyl, methoxyethyl, trifluoromethoxyethyl, described Optionally substituted with one or more F, Cl, Br, I, methyl, ethyl, trifluoromethyl, methoxy, trifluoromethoxy, or cyano, with the other variables being as defined in the disclosure.

[0078] In some embodiments of the present disclosure, in the compounds represented by formula (IID), (IID-1), (IID-2), or pharmaceutically acceptable salts thereof, R2 is selected from H, F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl, methoxymethyl, or ethoxymethyl, and other variables are as defined in the present disclosure.

[0079] In some embodiments of the present disclosure, in the compounds represented by formula (IID), (IID-1), (IID-2), or pharmaceutically acceptable salts thereof, R3 is selected from H, methyl, ethyl, n-propyl, isopropyl, methoxymethyl, or ethoxymethyl, and other variables are as defined in the present disclosure.

[0080] In some embodiments of the present disclosure, in the compounds represented by formula (IID), (IID-1), (IID-2), or pharmaceutically acceptable salts thereof, each R4 is independently selected from H, F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, fluoromethoxy, chloromethoxy, difluoromethoxy, dichloromethoxy, trifluoromethoxy, trichloromethoxy, 2,2-difluoroethoxy, 2,2-dichloroethoxy, 2,2,2-trifluoroethoxy, 2,2,2-trichloroethoxy, methoxymethyl, ethoxymethyl, methoxyethyl, fluoromethoxy In some embodiments, the present invention comprises methyl, chloromethoxymethyl, difluoromethoxymethyl, dichloromethoxymethyl, trifluoromethoxymethyl, trichloromethoxymethyl, 2,2-difluoroethoxymethyl, 2,2-dichloroethoxymethyl, 2,2,2-trifluoroethoxymethyl, 2,2,2-trichloroethoxymethyl, fluoromethoxyethyl, chloromethoxyethyl, difluoromethoxyethyl, dichloromethoxyethyl, trifluoromethoxyethyl, trichloromethoxyethyl, 2,2-difluoroethoxyethyl, 2,2-dichloroethoxyethyl, 2,2,2-trifluoroethoxyethyl, or 2,2,2-trichloroethoxyethyl, and other variables are as defined in the present disclosure.

[0081] In one embodiment of the present disclosure, the compounds represented by formula (IIA), (IIA-1), (IIA-2), and pharmaceutically acceptable salts thereof,

[0082] R1 is selected from C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy C 1-3 Alkyl, C 1-6 Halogenated alkoxy C 1-3 alkyl, 6-10 membered aryl, or 5-10 membered heteroaryl, wherein the 6-10 membered aryl and 5-10 membered heteroaryl may be optionally substituted by 1, 2, 3, 4, 5 halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 substituted by a haloalkoxy group, -(C=O)NH2, -NH2, or a cyano group;

[0083] R2 is selected from H, halogen, C 1-6 Alkyl, or C 1-6 Alkoxy C 1-3 alkyl;

[0084] R3 is selected from H, C 1-6 Alkyl, or C 1-6 Alkoxy C 1-3 alkyl.

[0085] In some embodiments of the present disclosure, in the compound represented by formula (IIA), (IIA-1), (IIA-2), or a pharmaceutically acceptable salt thereof, R1 is selected from tert-butyl (t-butyl), cyclopentyl, cyclohexyl, methoxymethyl, ethoxymethyl, methoxyethyl, ethoxyethyl, trifluoromethoxymethyl, trifluoromethoxyethyl, described and optionally substituted with 1, 2, 3, 4, or 5 F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl, fluoromethyl, chloromethyl, difluoromethyl, dichloromethyl, trifluoromethyl, trichloromethyl, 2,2-difluoroethyl, 2,2-dichloroethyl, 2,2,2-trifluoroethyl, 2,2,2-trichloroethyl, methoxy, ethoxy, n-propoxy, isopropoxy, fluoromethoxy, chloromethoxy, difluoromethoxy, dichloromethoxy, trifluoromethoxy, trichloromethoxy, 2,2-difluoroethoxy, 2,2-dichloroethoxy, 2,2,2-trifluoroethoxy, 2,2,2-trichloroethoxy, -(C=O)NH2, -NH2, or cyano. Other variables are as defined in the disclosure.

[0086] In some embodiments of the present disclosure, in the compound represented by formula (IIA), (IIA-1), (IIA-2), or a pharmaceutically acceptable salt thereof, R1 is selected from

[0087] R 4a 、R 4b 、R 4c 、R 4d 、R 4e Each is independently selected from H, F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl, fluoromethyl, chloromethyl, difluoromethyl, dichloromethyl, trifluoromethyl, trichloromethyl, 2,2-difluoroethyl, 2,2-dichloroethyl, 2,2,2-trifluoroethyl, 2,2,2-trichloroethyl, methoxy, ethoxy, n-propoxy, isopropoxy, fluoromethoxy, chloromethoxy, difluoromethoxy, dichloromethoxy, trifluoromethoxy, trichloromethoxy, 2,2-difluoroethoxy, 2,2-dichloroethoxy, 2,2,2-trifluoroethoxy, 2,2,2-trichloroethoxy, -(C=O)NH2, -NH2, or cyano. Other variables are as defined in the present disclosure.

[0088] In some embodiments of the present disclosure, in the compounds represented by formula (IIA), (IIA-1), (IIA-2), or pharmaceutically acceptable salts thereof, R2 is selected from H, F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl, methoxymethyl, or ethoxymethyl, preferably H or methyl; other variables are as defined in the present disclosure.

[0089] In some embodiments of the present disclosure, in the compounds represented by formula (IIA), (IIA-1), (IIA-2), or pharmaceutically acceptable salts thereof, R3 is selected from H, methyl, ethyl, n-propyl, isopropyl, methoxymethyl, or ethoxymethyl, preferably methyl; other variables are as defined in the present disclosure.

[0090] In some embodiments of the present disclosure, the compound represented by formula (IIA), (IIA-1), (IIA-2), or a pharmaceutically acceptable salt thereof,

[0091] in,

[0092] R1 is selected from

[0093] R 4a 、R 4b 、R 4c 、R 4d 、R 4e each independently selected from H, F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl, fluoromethyl, chloromethyl, difluoromethyl, dichloromethyl, trifluoromethyl, trichloromethyl, 2,2-difluoroethyl, 2,2-dichloroethyl, 2,2,2-trifluoroethyl, 2,2,2-trichloroethyl, methoxy, ethoxy, n-propoxy, isopropoxy, fluoromethoxy, chloromethoxy, difluoromethoxy, dichloromethoxy, trifluoromethoxy, trichloromethoxy, 2,2-difluoroethoxy, 2,2-dichloroethoxy, 2,2,2-trifluoroethoxy, 2,2,2-trichloroethoxy, -(C=O)NH2, -NH2, or cyano;

[0094] R2 is selected from H, F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl, methoxymethyl, or ethoxymethyl; preferably H or methyl;

[0095] R3 is selected from H, methyl, ethyl, n-propyl, isopropyl, methoxymethyl, or ethoxymethyl; preferably methyl.

[0096] In some embodiments of the present disclosure, the compound represented by formula (IIA), (IIA-1), (IIA-2), or a pharmaceutically acceptable salt thereof,

[0097] in,

[0098] R1 is selected from

[0099] R 4a 、R 4b 、R 4c 、R 4deach independently selected from H, F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl, fluoromethyl, chloromethyl, difluoromethyl, dichloromethyl, trifluoromethyl, trichloromethyl, 2,2-difluoroethyl, 2,2-dichloroethyl, 2,2,2-trifluoroethyl, 2,2,2-trichloroethyl, methoxy, ethoxy, n-propoxy, isopropoxy, fluoromethoxy, chloromethoxy, difluoromethoxy, dichloromethoxy, trifluoromethoxy, trichloromethoxy, 2,2-difluoroethoxy, 2,2-dichloroethoxy, 2,2,2-trifluoroethoxy, 2,2,2-trichloroethoxy, -(C=O)NH2, -NH2, or cyano;

[0100] R2 is selected from H, F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl, methoxymethyl, or ethoxymethyl; preferably H or methyl;

[0101] R3 is selected from H, methyl, ethyl, n-propyl, isopropyl, methoxymethyl, or ethoxymethyl; preferably methyl.

[0102] In another embodiment of the present disclosure, there is provided a compound as shown below, or a pharmaceutically acceptable salt thereof:

[0103] The present disclosure also provides a pharmaceutical composition comprising any one of the above compounds or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. The pharmaceutical composition can be prepared into various pharmaceutically acceptable dosage forms, such as tablets, capsules, oral liquids, granules, injections, etc. The pharmaceutical composition can be administered orally or parenterally (such as intravenously, subcutaneously or topically). The dosage can be appropriately adjusted according to the patient's age, sex, and disease type, and the general daily dose is about 1-200 mg.

[0104] The present disclosure also provides the above-mentioned compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition for preparing GABA A Application of receptor modulator drugs.

[0105] The present disclosure further provides the use of the above-mentioned compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the preparation of a medicament for treating CNS-related diseases. Wherein the CNS-related diseases include but are not limited to sleep disorders (e.g., insomnia), mood disorders (e.g., depression (e.g., major depressive disorder (MDD)), mania, dysthymia (e.g., mild depression), bipolar disorder (e.g., type I and / or type II), anxiety disorders (e.g., generalized anxiety disorder (GAD), social anxiety disorder), stress, post-traumatic stress disorder (PTSD), obsessive-compulsive disorder (e.g., obsessive-compulsive disorder (OCD)), schizophrenia spectrum disorders (e.g., schizophrenia, schizoaffective disorder), convulsive disorders (e.g., epilepsy (e.g., status epilepticus (SE)), epileptic seizures), memory and / or cognitive disorders (e.g., attention disorders (e.g., attention deficit hyperactivity disorder (ADHD)), dementia, Dementia (e.g., Alzheimer's disease, Lewy body dementia, vascular dementia), movement disorders (e.g., Huntington's disease, Parkinson's disease, essential tremor), personality disorders (e.g., antisocial personality disorder, obsessive-compulsive personality disorder), autism spectrum disorders (ASD) (e.g., autism, monoetiological autism, such as synaptophathy, such as Rett syndrome, fragile X syndrome, Angelman syndrome), pain (e.g., neuropathic pain, injury-related pain syndrome, acute pain, chronic pain), traumatic brain injury (TBI), vascular disease (e.g., stroke, ischemia, vascular malformation), substance abuse disorders and / or withdrawal syndromes (e.g., addiction to opiates, cocaine, and / or alcohol), and tinnitus.

[0106] The present disclosure further provides the use of any one of the above compounds, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the preparation of a medicament for treating depression. The depression is selected from mild depression, major depressive disorder (MDD), persistent depressive disorder (PDD), psychotic depression, postpartum depression (PPD), or seasonal affective disorder.

[0107] Definition and Description

[0108] Unless otherwise indicated, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase should not be construed as indefinite or unclear unless specifically defined, but rather should be understood in accordance with its ordinary meaning. When a trade name appears in this document, it is intended to refer to the corresponding commercial product or its active ingredient.

[0109] The term "pharmaceutically acceptable" as used herein refers to compounds, compositions and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions or other problems or complications, and are commensurate with a reasonable benefit / risk ratio.

[0110] The "pharmaceutically acceptable salts" mentioned in the present disclosure refer to salts of the compounds of the present disclosure, which are prepared from compounds with specific substituents discovered in the present disclosure and relatively non-toxic acids and bases. When the compounds of the present disclosure contain relatively basic functional groups, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of acid in a pure solution or a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts, organic acid salts; also include salts of amino acids (such as arginine, etc.), and salts of organic acids such as glucuronic acid. Certain specific compounds of the present disclosure contain basic functional groups and can be converted into any acid addition salt.

[0111] Certain compounds of the present disclosure may have asymmetric carbon atoms (optical centers) or double bonds. Racemates, diastereomers, geometric isomers and individual isomers are all included within the scope of the present disclosure.

[0112] The compounds of the present disclosure may exist in specific geometric or stereoisomeric forms. The present disclosure contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic mixtures and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the present disclosure. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All of these isomers and their mixtures are included within the scope of the present disclosure.

[0113] The pharmaceutically acceptable salts of the present invention can be synthesized from parent compounds containing acid radicals or bases by conventional chemical methods. Generally, the salts are prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of an appropriate base or acid in water or an organic solvent or a mixture of the two.

[0114] The term "pharmaceutically acceptable carrier" refers to any preparation or carrier medium representative of a carrier that can deliver an effective amount of the active substance of the present disclosure, does not interfere with the biological activity of the active substance, and has no toxic side effects on the host or patient, including but not limited to: binders, fillers, lubricants, disintegrants, wetting agents, dispersants, solubilizers, suspending agents, etc.

[0115] The present disclosure is intended to include all isotopes of atoms present in the compounds of the present disclosure. Isotopes include those atoms having the same atomic number but different mass numbers. As a general example and without limitation, isotopes of hydrogen include deuterium and tritium. Isotopes of carbon include 13 C and 14 C. Isotopically labeled compounds of the present disclosure can generally be prepared by conventional techniques known to those skilled in the art or by methods analogous to those described herein, using an appropriate isotopically labeled reagent in place of the non-labeled reagent otherwise employed.

[0116] "Optionally substituted with one or more..." means that the group is not substituted, or at least one and up to five hydrogen atoms, such as 1, 2, 3, 4, 5 hydrogen atoms in the group are independently substituted with the corresponding number (1, 2, 3, 4, 5) of substituents. For example: "The 6-10 membered aryl and 5-10 membered heteroaryl may be optionally substituted with one or more halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 "Alkoxy, -(C=O)NH2, -NH2, or cyano" means that the 6-10 membered aryl and 5-10 membered heteroaryl are not substituted, or 1, 2, 3, 4, 5 hydrogen atoms in the 6-10 membered aryl and 5-10 membered heteroaryl are independently replaced by the corresponding number (1, 2, 3, 4, 5) of halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 It is substituted by an alkoxy group, -(C=O)NH2, -NH2, or a cyano group.

[0117] Unless otherwise specified, the term "alkyl" is used to refer to a straight or branched saturated hydrocarbon group, which may be monosubstituted (such as -CH2F) or polysubstituted (such as -CF3), and may be monovalent (such as methyl), divalent (such as methylene) or polyvalent (such as methine). For example, C1-C6 means 1 to 6 carbon atoms, C 1-6 Selected from C1, C2, C3, C4, C5, C6; examples of alkyl include methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, s-butyl, t-butyl), pentyl (e.g., n-pentyl, isopentyl, neopentyl, 1-ethylpropyl), hexyl (e.g., n-hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl and 2-ethylbutyl), etc.

[0118]

[0046] The terms "halo" or "halogen," by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom.

[0119] Unless otherwise specified, "haloalkyl" is used to refer to a monohalogenated / polyhalogenated straight or branched chain alkyl group. Typical haloalkyl groups include C 1-6 Haloalkyl, for example: C1, C2, C3, C4, C5, C6 haloalkyl. For example, examples of C1-C6 haloalkyl include, but are not limited to: fluoromethyl, chloromethyl, difluoromethyl, dichloromethyl, trifluoromethyl, trichloromethyl, 2,2-difluoroethyl, 2,2-dichloroethyl, 2,2,2-trifluoroethyl, 2,2,2-trichloroethyl, pentafluoroethyl, and pentachloroethyl.

[0120] Unless otherwise specified, "alkoxy" represents an alkyl group (including cycloalkyl or haloalkyl) as defined above with the specified number of carbon atoms attached through an oxygen bridge. Typical alkoxy groups include C 1-6 Alkoxy groups, such as C1, C2, C3, C4, C5, and C6 alkoxy groups, C3, C4, C5, and C6 cycloalkoxy groups, and C1, C2, C3, C4, C5, and C6 haloalkoxy groups. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, S-pentoxy, hexoxy, and 2-ethylbutoxy groups. Examples of cycloalkoxy groups include, but are not limited to, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, and cyclohexyloxy groups. Examples of haloalkoxy groups include, but are not limited to, fluoromethoxy, chloromethoxy, difluoromethoxy, dichloromethoxy, trifluoromethoxy, trichloromethoxy, 2,2-difluoroethoxy, 2,2-dichloroethoxy, 2,2,2-trifluoroethoxy, 2,2,2-trichloroethoxy, pentafluoroethoxy, and pentachloroethoxy.

[0121] Unless otherwise specified, "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent, which may be monosubstituted or polysubstituted and may be monovalent, divalent, or polyvalent. Examples of such cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

[0122] Unless otherwise specified, "aryl" refers to a 6- to 10-membered all-carbon monocyclic or fused polycyclic (ie, rings which share adjacent pairs of carbon atoms) group having a conjugated pi electron system, such as phenyl and naphthyl, with phenyl being preferred.

[0123] Unless otherwise specified, "heteroaryl" refers to a group of a 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 π electrons shared in a cyclic arrangement) having ring carbon atoms and 1-4 ring heteroatoms provided in an aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-10 membered heteroaryl"). In heteroaryl groups containing one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom as valence permits. Heteroaryl bicyclic ring systems can include one or more heteroatoms in one or both rings. "Heteroaryl" includes ring systems in which the above-mentioned heteroaryl rings are fused to one or more carbocyclyl or heterocyclyl groups, wherein the point of attachment is on the heteroaryl ring, and in such cases, the number of ring members continues to represent the number of ring members in the heteroaryl ring system.

[0124] Exemplary 5-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyrrolyl, furanyl, and thienyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to, tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyridinyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, but are not limited to, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include, but are not limited to, azepine, oxepinyl, and thiepine. Exemplary 5,6-bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzisofuranyl, benzodioxolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzisothiazolyl, benzothiadiazolyl, indanyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

[0125] Compounds are manually or Software naming, commercially available compounds use supplier catalog names. DETAILED DESCRIPTION

[0126] The present disclosure is further described below with reference to specific embodiments and test examples, but they do not limit the scope of the present disclosure in any form.

[0127] Example 1

[0128] Synthesis route:

[0129] 1. M1 (200 g, 734 mmol, 1.00 eq) and HBr (5.96 g, 35.4 mmol, 4.00 mL, 0.048 eq) were added to THF (1400 mL) and then Pd / C (10.0 g, 9.43 mmol, 0.013 eq) was added. The system was placed at 25 ° C and stirred under H2 (1.00 MPa) for 24 hours. After filtering and concentrating the system, the solid was crushed and dissolved in 600 mL of acetone. After filtration, a white crude product was obtained. The crude product was separated and purified by column chromatography (dichloromethane / methanol (10:1-5:1) to obtain M2 (180 g, white solid).

[0130] 2. M2 (100 g, 364 mmol, 1.00 eq) was added to 1 L of toluene, and then methylaluminum bis(2,6-di-tert-butyl-4-anisole) (525 g, 1.09 mol, 571 mL, 3.00 eq) was added. The system was stirred at -60 ° C for 1 hour, and then bromomethylmagnesium (3 M, 364 mL, 3.00 eq) was added at -60 ° C. The system was stirred at -60 ° C for 3 hours, and then saturated NH4Cl (500 mL) was added and filtered. The filter cake was washed with ethyl acetate (200 mL × 2), and the organic phases were combined and then washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure. It was separated by column chromatography (dichloromethane / methanol (100:1-10:1) and purified to obtain M3 (46 g, white solid, recovered M2 98 g).

[0131] 3. Ethyltriphenylphosphonium bromide (102 g, 275 mmol, 4.00 eq) was added to THF (120 mL) at 0°C, followed by the addition of t-BuOK (30.9 g, 275 mmol, 4.00 eq) in THF (200 mL). The system was then stirred at 60°C for 1 hour. M3 (20.0 g, 68.9 mmol, 1.00 eq) was dissolved in THF (120 mL) and added to the system. The mixture was stirred at 60°C for 13 hours. NH4Cl solution (150 mL) was added to the system under ice bath conditions to quench the reaction. The mixture was then extracted with ethyl acetate (150 mL x 2). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The organic phase was separated by column chromatography (dichloromethane / methanol (100:1-3:1) to give M4 (18.3 g, 60.6 mmol, yield: 88.0%).

[0132] 4. M4 (18.3 g, 60.6 mmol, 1.00 eq) was dissolved in THF (180 mL), and then BH3·Me2S (10.0 M, 30.3 mL, 5.00 eq) was added at 0°C. The system was stirred at 25°C for 3 hours, and then 3.00 M NaOH (100 mL) and H2O2 (86.5 g, 763 mmol, 73.3 mL, 12.6 eq) were placed in the system at 25 ° C for 4 hours, the system was filtered and the filtrate was quenched with Na2SO3 solution (60.0 mL × 2), extracted with ethyl acetate (150 mL × 2), and the organic phases were combined and then washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure. It was separated by column chromatography (dichloromethane / methanol (100:1-3:1)) and purified to obtain M5 (13.0 g, 40.6 mmol, yield: 66.9%).

[0133] 5. M5 (13.0 g, 40.6 mmol, 1.00 eq) was dissolved in dichloromethane (130 mL) and PCC (17.5 g, 81.1 mmol, 2.00 eq) was added at 0°C. The system was stirred at 25°C for 3 hours. The system was filtered and the filtrate was quenched with Na2SO3 solution (100 mL). The mixture was extracted with dichloromethane (100 mL×2). The organic phases were combined and washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure. The mixture was separated by column chromatography (dichloromethane / methanol (100:1-3:1)) to give M6 (9.03 g, 28.3 mmol, yield: 69.9%).

[0134] 6. M6 (9.03 g, 28.3 mmol, 1.00 eq) was dissolved in MeOH (90.0 mL), and then Br2 (4.53 g, 28.3 mmol, 1.46 mL, 1.00 eq) and HBr (927 mg, 5.50 mmol, 622 μL, 0.190 eq) were added at 0°C. The system was then stirred at 25°C for 12 hours. The system was quenched with NaHCO3 solution (50 mL) and extracted with ethyl acetate (50.0 mL x 2). The organic phases were combined and washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure. The organic phase was separated and purified by column chromatography (dichloromethane / methanol (100:1-1:1) to give M7 (7.1 g, 17.8 mmol, yield: 63.0%) as a white solid. 1H NMR (400MHz, CDCl3) δ3.99-3.85(m,2H),2.92-2.69(m,1H),2.25-2.12(m,1H),1.98- 1.58(m,9H),1.53-1.28(m,11H),1.27-1.18(m,3H),1.15-1.03(m,3H),0.64(s,3H).

[0135] 7. Add 1-1 (1.00 g, 6.15 mmol, 1 eq, HCl) and glyoxylic acid (683.02 mg, 9.23 mmol, 513.55 μL, 1.5 eq) to HCl (12 M, 1 mL, 1.95 eq) and H2O (30 mL) and stir at 25 °C for 5 hours. Filter and concentrate the system to obtain a crude yellow solid 1-2 (1.20 g).

[0136] 8. 1-2 (200 mg, 1.10 mmol, 1.00 eq) and Et3N (111 mg, 1.10 mmol, 152 μL, 1.00 eq) were added to toluene (10.0 mL) at room temperature, and then DPPA (302 mg, 1.10 mmol, 237 μL, 1.00 eq) was added. The system was stirred at 90 ° C for 1 hour. The system was quenched with water (20 mL) and extracted with ethyl acetate (30.0 mL). The organic phases were combined and washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The organic phase was separated by column chromatography (dichloromethane / methanol (100:1-10:1) to give 1-3 as a white solid (90 mg, 0.483 mmol, yield: 44%). MS (ESI) m / z = 180.2.

[0137] 9. K2CO3 (1.04 g, 7.55 mmol, 10.0 eq), M7 (300 mg, 755 μmol, 1.00 eq) and 1-3 (541 mg, 3.02 mmol, 4.00 eq) were added to THF (18.0 mL), and the system was stirred at 30 ° C for 19 hours. The system was quenched with water (150 mL) and extracted with ethyl acetate (80.0 mL x 2). The organic phases were combined and washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure. The crude product was purified by pre-HPLC (column: YMC Triart 30*150mm*7um; mobile Phase: [water (HCl)-ACN]; B%: 30%-90%, 40 min) was separated and purified to obtain compound 1 (110 mg, 208 μmol, yield: 27.6%). MS (ESI) m / z = 478.5 [M-17] + ,1 H NMR (400MHz, CDCl3) δ7.79-7.63 (m, 2H) 7.53 (s, 1H) 7.30 (br d, J = 6.52Hz, 1H) 6.85 (br d,J=1.64Hz,1H)4.66-4.43(m,1H)4.40-4.22(m,1H)2.63-2.44(m,1H)2.40-1.90(m,2H)1.87-1.56(m, 6H)1.54-1.15(m,16H)1.12-0.93(m,3H)0.61(s,3H).

[0138] Example 2

[0139] Synthesis route:

[0140] 1. K2CO3 (852 mg, 6.17 mmol, 10.0 eq), M7 (294 mg, 740 μmol, 1.20 eq) and 2-1 (100 mg, 617 μmol, 1.00 eq) (the preparation method of 2-1 refers to the preparation method of 1-3) were added to THF (10 mL), and the system was stirred at 50 ° C for 16 hours. The system was quenched with water (30 mL) and extracted with ethyl acetate (40.0 mL×2). The organic phases were combined and then washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure. The crude product was purified by SFC (column: DAICEL CHIRALCEL OD (250 mm*30 mm, 10 μm); mobile phase: [0.1% NH3H2O ETOH]; B%: 60%-60%, min) to obtain a crude product, which was then purified by column chromatography (dichloromethane / methanol (100 / 0-95 / 5) to give a white solid 2 (70.0 mg, 141 μmol, yield: 22.8%). MS (ESI) m / z = 479.5 [M+H] + , 1 H NMR (400MHz, DMSO-d6) δ9.11 (d, J = 2.12Hz, 1H), 8.45-8.48 (m, 1H), 8.22-8.27 (m, 2H), 7. 52(dd,J=8.38,4.63Hz,1H),4.69-4.76(m,1H),4.54-4.62(m,1H),4.25(s,1H),2.77(br t,J=8.82Hz,1H),2.02-2.12(m,2H),1.56-1.78(m,7H),1.13-1.39(m,10H),0.97-1.12(m,7H),0.59(s,3H).

[0141] Example 3

[0142] Synthesis route:

[0143] 1. K2CO3 (386 mg, 2.79 mmol, 10.0 eq), M7 (111 mg, 279 μmol, 1.00 eq) and 3-1 (180 mg, 1.12 mmol, 4.00 eq) (the preparation method of 3-1 refers to the preparation method of 1-3) were added to THF (20 mL), and the system was stirred at 50 ° C for 6 hours. The system was quenched with water (10 mL) and extracted with 2-methyltetrahydrofuran (10.0 mL×2). The organic phases were combined and then washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure. The crude product was purified by SFC (column: DAICEL CHIRALCEL OJ (250 mm*30 mm, 10 μm); mobile phase: [0.1% NH3H2O ETOH]; B%: 40%-40%, min) to obtain a crude yellow liquid. The crude product was purified by column chromatography (dichloromethane / methanol (0-10%) to obtain a yellow solid 3 (100 mg, 202 μmol, yield: 72.2%). MS (ESI) m / z = 478.4 [M+H] + , 1 H NMR (400MHz, CDCl3) δ7.99-7.92(m,2H),7.63-7.58(m,1H),7.47-7.40(m,2H),7.25-7.20(m,1H),4.66-4.37(m,2 H),2.67-2.59(m,1H),2.28-2.11(m,2H),1.91-1.71(m,7H),1.70-1.61(m,2H),1.50-1.12(m,16H),0.61(s,3H).

[0144] Example 4

[0145] Synthesis route:

[0146] 1. K2CO3 (386 mg, 2.79 mmol, 10.0 eq), M7 (112 mg, 279 μmol, 1.00 eq) and 4-1 (200 mg, 1.12 mmol, 4.00 eq) (the preparation method of 4-1 refers to the preparation method of 1-3) were added to THF (20 mL), and the system was stirred at 50 ° C for 6 hours. The system was quenched with water (100 mL) and extracted with 2-methyltetrahydrofuran (20.0 mL×2). The organic phases were combined and then washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure. The crude product was purified by SFC (column: DAICEL CHIRALCEL OJ (250 mm*30 mm, 10 μm); mobile phase: [0.1% NH3H2O ETOH]; B%: 35%-35%, min) to give a crude yellow liquid. The crude product was purified by pre-HPLC (column: Phenomenex luna C18 250*50mm*10um; mobile phase: [water(HCl)-ACN]; B%: 30%-70%, 20 min) to give a yellow solid 4. The product was then purified by SFC (EB6914-18-P1S2, RT=2.589 min) (column: DAICEL CHIRALPAK IC (250mm*30mm, 10um); mobile phase: [0.1% NH3H2O ​​ETOH]; B%: 50%-50%, min) to give a white solid 4 (80 mg, 161 μmol, yield: 57.8%). MS (ESI) m / z=478.4 [M-OH] + , 1 H NMR (400MHz, CDCl3) δ7.99-7.87(m,2H),7.63-7.53(m,1H),7.17-7.06(m,2H),4.67-4.32(m,2H),2.72- 2.57(m,1H),2.30-2.09(m,2H),1.96-1.66(m,9H),1.52-1.39(m,14H),1.18-1.07(m,2H),0.61(s,3H).

[0147] Example 5

[0148] Synthesis route:

[0149] 1. K2CO3 (580 mg, 4.19 mmol, 10.0 eq), M7 (200 mg, 503 μmol, 1.2 eq) and 5-1 (80.2 mg, 0.419 mmol, 1.00 eq) (the preparation method of 5-1 refers to the preparation method of 1-3) were added to THF (15 mL), and the system was stirred at 50 ° C for 14 hours. The system was quenched with water (50 mL) and extracted with ethyl acetate (50.0 mL×2). The organic phases were combined and then washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure. The crude product was purified by SFC (column: DAICEL CHIRALCEL OJ (250 mm*30 mm, 10 μm); mobile phase: [0.1% NH3H2O ETOH]; B%: 45%-45%, min) to obtain a yellow solid 5 (81 mg, 152 μmol, yield: 36.3%). MS (ESI) m / z = 508 [M+1] + , 1 H NMR(400MHz,DMSO-d6)δ8.14(s,1H),7.43-7.54(m,2H),7.37(t,J=8.32Hz,1 H),6.77-6.88(m,1H),4.51-4.76(m,2H),4.25(s,1H),3.78(s,3H),2.76(br t,J=8.76Hz,1H),2.01-2.15(m,2H),1.82-1.14(m,21H),0.59(s,3H).

[0150] Example 6

[0151] Synthesis route:

[0152] 1. K2CO3 (4.46 g, 32.3 mmol, 1.0 eq), M7 (1.41 g, 3.55 mmol, 1.1 eq) and 6-1 (780 mg, 3.23 mmol, 1.00 eq) (the preparation method of 6-1 refers to the preparation method of 1-3) were added to THF (50 mL), and the system was stirred at 50 ° C for 16 hours. The system was quenched with water (50 mL) and extracted with 2-methyltetrahydrofuran (50.0 mL×2). The organic phases were combined and washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was ground and dissolved in MTBE (10 mL) and stirred at 25 ° C for 1 hour. After filtration, the filter cake obtained was a white solid 6 (200 mg, 478 μmol, yield: 14.8%). MS (ESI) m / z=416.3[M+1] + ,1 H NMR (400MHz, DMSO-d6) δ7.88-7.75(m,1H),4.59-4.41(m,2H),4.25-4.21(m,1H),3.31-3.28(m,3H),2.74-2.67(m,1H ),2.10-2.00(m,2H),1.80-1.42(m,9H),1.39-1.23(m,7H),1.20-1.06(m,6H),1.05-0.98(m,2H),0.62-0.48(m,3H).

[0153] Example 7

[0154] Synthesis route:

[0155] 1. K2CO3 (1.20 g, 8.66 mmol, 10.0 eq), M7 (378 mg, 0.952 mmol, 1.1 eq) and 7-1 (98 mg, 0.866 mmol, 1.00 eq) (the preparation method of 7-1 refers to the preparation method of 1-3) were added to THF (50 mL), and the system was stirred at 50 ° C for 12 hours. The system was quenched with water (20 mL) and extracted with ethyl acetate (20.0 mL×2). The organic phases were combined and washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The organic phase was separated and purified by column chromatography (dichloromethane / methanol (100:1-10:1) to obtain 7 (100 mg, 221 μmol, yield: 25.5%). MS (ESI) m / z=430.5[M+1] + , 1 H NMR (400MHz, CDCl3) δ7.43 (s, 1H), 4.66-4.26 (m, 2H), 3.85 (q, J = 7.2Hz, 2H), 2.73-2 .51(m,1H),2.29-2.07(m,3H),1.99-1.23(m,23H),1.17-1.02(m,4H),0.67(s,3H).

[0156] Example 8

[0157] Synthesis route:

[0158] 1. Trimethyl orthoformate (4.78 g, 45.0 mmol, 4.93 mL, 1.00 eq), 8-2 (5.00 g, 45.0 mmol, 4.31 mL, 1.00 eq), and 8-1 (4.05 g, 45.0 mmol, 1.00 eq) were added to MeOH (50.0 mL), and the system was stirred at 70 ° C for 6 hours. CH3ONa (7.29 g, 135 mmol, 3.00 eq) was added to the system and then stirred at 70 ° C for 13 hours. The pH was adjusted to ~1 using HCl (1M, 80.0 mL), and then extracted with ethyl acetate (70.0 mL × 2). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The organic phase was separated and purified by column chromatography (dichloromethane / methanol (0-7%) to give a light yellow solid 8-3 (560 mg, 3.13 mmol, yield: 6.95%). MS (ESI) m / z = 179.0 [M+1] + .

[0159] 2. K2CO3 (1.39 g, 10.0 mmol, 10.0 eq), M7 (399 mg, 1.00 mmol, 1.00 eq) and 8-3 (98 mg, 0.866 mmol, 1.00 eq) were added to THF (15 mL), and the system was stirred at 50°C for 18 hours. The system was quenched with water (40 mL) and extracted with ethyl acetate (50.0 mL×2). The organic phases were combined and washed with saturated brine (60 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The organic phase was separated and purified by column chromatography (dichloromethane / methanol (0-7%) to give a white solid 8 (200 mg, 400 μmol, yield: 39.8%). MS (ESI) m / z=496.2[M+1] + , 1 H NMR(400MHz,DMSO-d6)δ8.60(s,1H),7.86-7.43(m,3H),7.37-7.05(m,1H),4.94-4.48(m,2H),4.24(s,1H),2.76(br t,J=8.8Hz,1H),2.18-1.93(m,2H),1.82-1.54(m,7H),1.44-0.95(m,17H),0.59(s,3H).

[0160] Example 9

[0161] Synthesis route:

[0162] 1. K2CO3 (1.16 g, 8.42 mmol, 10.0 eq), M7 (400 mg, 1.01 mmol, 1.20 eq) and 9-1 (151 mg, 0.842 mmol, 1.00 eq) (9-1 preparation method refers to the preparation method of 8-3) were added to THF (15 mL), and then the system was stirred at 50 ° C for 16 hours. The system was quenched with water (100 mL) and extracted with ethyl acetate (50.0 mL × 2). The organic phases were combined and then washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The organic phase was separated and purified by column chromatography (dichloromethane / methanol (100 / 0-90 / 10) to give a white solid 9 (200 mg, 404 μmol, yield: 47.9%). MS (ESI) m / z = 496.8 [M+1] + , 1 H NMR (400MHz, DMSO-d6) δ8.49(s,1H),7.71-7.77(m,2H),7.38(t,J=8.88Hz,2H),4.73-4.81(m,1H),4.58(d,J=18.4Hz,1H) ,4.22-4.27(m,1H),2.75(s,1H),2.00-2.08(m,3H),1.57-1.77(m,8H),1.28-1.41(m,6H),0.93-1.12(m,9H),0.58(s,3H).

[0163] Example 10

[0164] Synthesis route:

[0165] 1. K2CO3 (894 mg, 6.47 mmol, 10.0 eq), M7 (257 mg, 0.647 mmol, 1.20 eq) and 10-1 (90.0 mg, 0.647 mmol, 1.00 eq) (the preparation method of 10-1 refers to the preparation method of 8-3) were added to THF (10.0 mL), and the system was stirred at 50 ° C for 18 hours. The system was quenched with water (20 mL) and extracted with ethyl acetate (40.0 mL×2). The organic phases were combined and then washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure. After separation by column chromatography (dichloromethane / methanol (0-5%), the product was purified by pre-HPLC (column: Welch Xtimate C18 150*30mm*5um; mobile Phase: water (NH4HCO3)-ACN; B%: 0%-90%, 14 min) was further purified to give a white solid 10 (80.0 mg, 175 μmol, yield: 27.1%). MS (ESI) m / z = 455.3 [M+1] + , 1 H NMR (400MHz, DMSO-d6) δ8.02(s,1H),4.76-4.57(m,1H),4.55-4.37(m,1H),3.43(br d,J=7.2Hz,2H),2.68(br s,1H),2.22-2.09(m,2H),1.82-1.08(m,26H),0.61-0.44(m,5H),0.38-0.28(m,2H).

[0166] Example 11

[0167] Synthesis route:

[0168] 1. Dissolve 11-2 (2.30 g, 21.9 mmol, 2.38 mL, 1.00 eq) in toluene (30.0 mL), then add 11-1 (3.00 g, 21.9 mmol, 2.50 mL, 1.00 eq) at 5 ° C., then stir the system at 25 ° C. for 12 hours, and concentrate the system to obtain a colorless oil 11-3 (5.05 g, 20.8 mmol, yield: 95%). 1H NMR (400MHz, CDCl3) δ8.09(s,1H),7.20(td,J=2.0,11.2Hz,1H),7.14-7.05(m,1H),6.92(dd,J=1.2,8.4Hz,1H),6.68-6.54(m,1H),6.14(br s,1H),4.39(t,J=5.2Hz,1H),3.43-3.32(m,8H).

[0169] 2. HCl (12.0 M, 3.00 mL, 4.36 eq) was added to H2O (20.0 mL) and then added dropwise to 11-3 (2.00 g, 8.26 mmol, 1.00 eq). The system was stirred at 25 ° C for 10 hours. The system was quenched with water (20 mL) and extracted with ethyl acetate (10.0 mL × 2). The organic phases were combined and then washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure. The organic phase was separated by column chromatography (petroleum ether / ethyl acetate (100 / 1-1 / 1) to give a white solid 11-4 (900 mg, 5.05 mmol, yield: 61.2%). 1 H NMR (400MHz, CDCl3) δ10.40 (br s, 1H), 7.49-7.32 (m, 3H), 7.02-6.92 (m, 1H), 6.59-6.52 (m, 1H), 6.45 (t, J = 2.8Hz, 1H).

[0170] 3. K2CO3 (1.26 g, 9.29 mmol, 10.0 eq), M7 (397 mg, 1.00 mmol, 1.10 eq) and 11-4 (162 mg, 0.909 mmol, 1.00 eq) were added to THF (10.0 mL), and the system was stirred at 50 ° C for 12 hours. The system was quenched with water (20 mL) and extracted with ethyl acetate (20.0 mL × 2). The organic phases were combined and washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The organic phase was separated and purified by column chromatography (dichloromethane / methanol (100 / 1-3 / 1) to give an off-white solid 11 (200 mg, 0.401 mmol, yield: 44.1%). MS (ESI) m / z = 495.5 [M+1] + , 1H NMR (400MHz, CDCl3) δ7.47(td,J=1.6,10.4Hz,1H),7.42-7.32(m,2H),6.99-6.88(m,1H),6.63(d,J=3.2Hz,1H),6.37(d,J=3 .2Hz,1H),4.59(d,J=18.4Hz,1H),4.35(d,J=18.4Hz,1H),2.62(s,1H),2.29-2.09(m,2H),1.94-1.02(m,25H),0.69(s,3H).

[0171] Example 12

[0172] Synthesis route:

[0173] 1. 12-1 (5.00 g, 71.3 mmol, 5.33 mL, 1.00 eq), BocNHNH2 (9.43 g, 71.3 mmol, 1.00 eq) and NaBH3CN (8.97 g, 142.7 mmol, 2.00 eq) were added to MeOH (50.0 mL), and then AcOH (14.0 mL) was added at 25 ° C. The system was stirred at 25 ° C for 16 hours, and the system was concentrated to obtain a crude product. After purification by column chromatography (dichloromethane / methanol (100 / 1-1 / 1), a white solid 12-2 (2.26 g, 12.1 mmol, yield: 17.0%) was obtained. 1 H NMR(400MHz,CDCl3)δ7.09(br s,1H),4.31 -3.73(m,1H),2.44(br d,J=7.2Hz,2H),1.33-1.10(m,9H),0.79-0.52(m,1H),0.29-0.10(m,2H),0.00-0.21(m,2H).

[0174] 2. 12-2 (1.00 g, 5.37 mmol, 1.00 eq) was added to i-PrOH (10.0 mL), followed by TMSNCO (1.24 g, 10.7 mmol, 1.43 mL, 2.00 eq). The system was stirred at 25 ° C for 2 hours, and the system was concentrated to obtain a white solid 12-3 (1.19 g, 5.19 mmol, yield: 96.7%). 1H NMR (400MHz, CDCl3) δ6.90-6.51(m,1H),5.18(br s,2H),3.96-2.96(m,2H),1.48(s,8H),0.98-0.82(m,1H),0.57-0.45(m,2H),0.19(br d,J=4.4Hz,2H).

[0175] 3. 12-3 (500 mg, 2.18 mmol, 1.00 eq) and HCl / EtOAc (4.00 M, 545 μL, 1.00 eq) were stirred at 25 °C for 1 hour, and the system was concentrated to obtain 12-4 (350 mg, crude product). 1 H NMR(400MHz,DMSO-d6)δ10.55-9.74(m,2H),6.93(br s,1H),6.73-6.51(m,1H),3.47(d,J=7.2Hz,2H),1.13-0.87(m,1H),0.50-0.43(m,2H),0.36-0.26(m,2H).

[0176] 4. 12-4 (350 mg, 2.71 mmol, 1.00 eq) was added to EtOH (4.00 mL) and then CH(OCH3)3 (718 mg, 6.77 mmol, 742 μL, 2.50 eq) was added. The system was stirred at 25 ° C for 2 hours. The system was concentrated to obtain a crude product. The crude product was placed in isopropyl ether (5.00 mL) and stirred at 25 ° C for 30 minutes to obtain a white solid 12-5 (160 mg, 1.15 mmol, yield: 42.4%). 1 H NMR (400MHz, DMSO-d6) δ11.46 (br s, 1H), 7.79 (s, 1H), 3.49 (d, J = 6.8Hz, 2H), 1.20-0.91 (m, 1H), 0.60--0.21 (m, 4H).

[0177] 5. K2CO3 (695 mg, 5.03 mmol, 5.0 eq), M7 (399 mg, 1.01 mmol, 1.00 eq) and 12-5 (140 mg, 1.01 mmol, 1.00 eq) were added to THF (10.0 mL), and the system was stirred at 50 ° C for 12 hours. The system was quenched with water (20 mL) and extracted with ethyl acetate (20.0 mL×2). The organic phases were combined and washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The organic phase was separated and purified by column chromatography (dichloromethane / methanol (100 / 1-10 / 1) to give a white solid 12 (300 mg, 0.655 mmol, yield: 65.1%). MS (ESI) m / z=456.5[M+1] + , 1 H NMR (400MHz, CDCl3) δ7.44 (s, 1H), 4.58-4.47 (m, 1H), 4.42-4.31 (m, 1H), 3.67 (d, J = 7.2Hz, 2H), 2.67-2. 55(m,1H),2.28-2.06(m,2H),1.82-1.04(m,26H),0.67(s,3H),0.61-0.48(m,2H),0.38(q,J=5.2Hz,2H).

[0178] Example 13

[0179] Synthesis route:

[0180] 1. K2CO3 (657 mg, 4.76 mmol, 10.0 eq), M7 (208 mg, 0.523 mmol, 1.10 eq) and 13-1 (100 mg, 0.476 mmol, 1.00 eq) (purchased from Shanghai Bidex) were added to THF (10.0 mL), and the system was stirred at 50 ° C for 16 hours. The system was quenched with water (20 mL) and extracted with ethyl acetate (20.0 mL × 3). The organic phases were combined and washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The organic phase was separated and purified by column chromatography (dichloromethane / methanol 10:1) to give a light yellow solid 13 (88 mg, 0.166 mmol, yield: 34.8%). MS (ESI) m / z = 527.2 [M+1] + , 1H NMR (400MHz, DMSO-d6) δ7.71-7.39(m,5H),7.22-6.98(m,4H),5.06-4.61(m,2H),4.24(s,1H),2.23-2.04(m,3H),1.74-1.11(m,24H),0.61(s,3H).

[0181] Example 14

[0182] Synthesis route:

[0183] 1. 14-1 (7.00 g, 39.9 mmol, 1.00 eq) and (Boc)2O (8.71 g, 39.9 mmol, 9.16 mL, 1.00 eq) were added to MeOH (100 mL), and then BnNCO (1.37 g, 10.3 mmol, 1.25 mL, 1.10 eq) was added. The mixture was stirred at 25 ° C for 12 hours, and the system was concentrated to obtain a crude product. The crude product was separated by column chromatography (petroleum ether / ethyl acetate (100 / 1-1 / 1) and purified to obtain a white solid 14-2 (5.00 g, 23.3 mmol, yield: 58.5%). 1 H NMR (400MHz, CDCl3) δ6.35(br s,1H),4.62-3.79(m,1H),3.52-3.32(m,2H),1.48(br s,9H).

[0184] 2. 14-2 (2 g, 9.34 mmol, 1.00 eq) and DMAP (11.4 mg, 93.4 μmol, 0.01 eq) were added to pyridine (20 mL) and stirred at 60 ° C for 12 hours. The system was quenched with citric acid (30 mL) and extracted with ethyl acetate (20 mL). The organic phases were combined and washed with citric acid (30 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure. After purification by column chromatography (petroleum ether / ethyl acetate (100 / 1-1 / 1), 14-3 (3.3 g, crude product) was obtained.

[0185] 3. 14-3 (3.33 g, 9.59 mmol, 1.00 eq) was added to a 40 mL sealed tube, and HCl / EtOAc (4.00 M, 2.40 mL, 1.00 eq) was added. The system was stirred at 25 ° C for 1 hour and concentrated to obtain a colorless oily liquid 14-4 (2.8 g, crude product). 1H NMR (400MHz, DMSO-d6) δ7.68(br s,1H),7.40-7.13(m,5H),6.38-5.98(m,2H),4.38-4.15(m,4H).

[0186] 4. 14-4 (2.80 g, 11.3 mmol, 1.00 eq) was dissolved in EtOH (10.0 mL) and placed in a 40 mL sealed tube. 10 mL of ethanol was then added, followed by CH(OEt)3 (3.00 g, 28.3 mmol, 3.10 mL, 2.50 eq). The system was stirred at 25 ° C for 5 hours, and the system was concentrated to obtain a crude product, which was separated by column chromatography (petroleum ether / ethyl acetate (100 / 1-1 / 1) and purified to obtain a white solid 14-5 (1.30 g, 5.05 mmol, yield: 44.6%). 1 H NMR (400MHz, DMSO-d6) δ8.20(s,1H),7.53-7.14(m,5H),4.83(s,2H),4.68-4.52(m,2H).

[0187] 5. 14-5 (800 mg, 3.11 mmol, 1.00 eq) was added to a 100 mL hydrogenation bottle with N2 ball, and then 5 mL of tetrahydrofuran and 15 mL of ethanol were added, followed by the addition of Pd / C (10.0 mg, 9.43 μmol, 0.001 eq) and Pd(OH)2 (10.0 mg, 7.12 μmol, 0.001 eq). The system was placed under H2 (50 Psi) atmospheric pressure at 25 ° C. and stirred for 12 hours. The system was concentrated to obtain a crude product. The crude product was analyzed by Pre-HPLC (column: Welch Xtimate C18 150*30 mm*5 um; mobile phase: [water(HCl)-ACN]; B%: 0%-24%, 36 min) to give a white solid 14-6 (170 mg, 1.02 mmol, yield: 21.2%). 1 H NMR (400MHz, DMSO-d6) δ11.80 (br s, 1H), 7.95 (d, J = 0.8Hz, 1H), 4.52 (q, J = 9.2Hz, 2H).

[0188] 6. 14-6 (100 mg, 598 μmol, 1.00 eq) was dissolved in 10 mL of tetrahydrofuran and added to a 40 mL sealed tube. M7 (237 mg, 598 μmol, 1.00 eq) and K2CO3 (827 mg, 5.98 mmol, 10.0 eq) were added. The system was stirred at 50 ° C for 12 hours. The system was quenched with water (20 mL) and extracted with ethyl acetate (20 mL). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The organic phase was separated by column chromatography (petroleum ether / ethyl acetate (100 / 1-1 / 1) to obtain a white solid 14 (40.0 mg, 77.5 μmol, yield: 12.9%). 1 H NMR(400MHz,DMSO-d6)δ7.97(s,1H),4.67-4.55(m,3H),4.54-4.46(m,1H),4.26(s,1H),2.72(br t,J=8.8Hz,1H),2.10-2.02(m,2H),1.77-1.62(m,6H),1.37-1.22(m,9H),1.14-0.98(m,9H),0.56(s,3H).

[0189] Example 15

[0190] Synthesis route:

[0191] 1. Dissolve 15-1 (10.0 g, 72.9 mmol, 1.00 eq) in HCl (150 mL) and cool the system to 0°C. Then add NaNO2 (5.53 g, 80.2 mmol, 1.10 eq) and H2O (150 mL) to the system, stir the system at 0°C for 30 minutes, then add SnCl2·2H2O (49.4 g, 219 mmol, 3.00 eq) and HCl (300 mL) to the system, stir the system at 0°C for 24 hours, filter the system, wash the filter cake with H2O (200 mL), and dry it to obtain a dark brown solid 15-2 (8.40 g, 44.5 mmol, yield: 61.1%, HCl). 1 H NMR (400MHz, DMSO-d6) δ10.22-9.90(m,3H),6.90-6.79(m,1H),6.74-6.62(m,1H),6.53-6.40(m,1H),6.06-5.91(m,2H).

[0192] 2. 15-2 (5.00 g, 26.5 mmol, 1.00 eq, HCl) was dissolved in ACN (45.0 mL), and then DIEA (3.43 g, 26.5 mmol, 4.62 mL, 1.00 eq) was added at room temperature. The pH of the system was adjusted to about 8, (Boc)2O (5.79 g, 26.5 mmol, 6.09 mL, 1.00 eq) was added, and the system was stirred at 25 ° C for 16 hours. The system was concentrated to obtain a crude product, which was purified by using (Ethyl acetate: Petroleum ether = 0-10%) to obtain a dark brown solid 15-3 (4.56 g, 18.1 mmol, yield: 68.2%). 1 H NMR(400MHz,DMSO-d6)δ8.78-8.65(m,1H),7.39-7.23(m,1H),6.74-6.63(m,1H ),6.34-6.24(m,1H),6.16-6.08(m,1H),5.92-5.81(m,2H),1.48-1.33(m,9H).

[0193] 3. 15-3 (4.56 g, 18.1 mmol, 1.00 eq) and DMAP (22.1 mg, 181 μmol, 0.01 eq) were dissolved in pyridine (50.0 mL), and then benzyl isocyanate (2.65 g, 19.9 mmol, 2.43 mL, 1.10 eq) was added. The system was stirred at 60 ° C for 16 hours, and the system was quenched with citric acid (200 mL), extracted with ethyl acetate (200 mL), and the organic phases were combined and then washed with citric acid (300 mL) and saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and the crude organic phase was concentrated under reduced pressure. Purification by column chromatography (THF: Dichloromethane = 0-10%) gave a yellow solid 15-4 (5.00 g, 12.7 mmol, yield: 70.0%). 1 H NMR (400MHz, DMSO-d6) δ = 9.57 (s, 1H), 7.33-7.16 (m, 5H), 6.97-6.77 (m, 3H), 6.09-5.92 (m, 2H), 4.26 (brd, J = 5.6Hz, 2H), 1.46-1.26 (m, 9H).

[0194] 4. 15-4 (2.00 g, 5.19 mmol, 1.00 eq) was added to HCl / dioxane (15.0 mL) and the system was stirred at 25°C for 24 hours. The system was concentrated to give a green solid 15-5 (2.00 g, crude). MS (ESI) m / z = 286.0 [M+1] + .

[0195] 5. 15-5 (2.00 g, 7.01 mmol, 1.00 eq) was added to EtOH (20.0 mL) and then trimethoxymethane (1.86 g, 17.5 mmol, 1.92 mL, 2.50 eq) was added. The system was stirred at 40° C. for 16 hours. The system was concentrated to give a crude product. The crude product was purified by column chromatography (Ethyl acetate: Petroleum ether = 0-10%) to obtain a yellow solid 15-6 (990 mg, 2.73 mmol, yield: 38.9%). MS (ESI) m / z = 295.9 [M+1] + , 1 H NMR (400MHz, DMSO-d6) δ = 8.38-8.26 (m, 1H), 7.53-7.20 (m, 7H), 7.02-6.94 (m, 1H), 6.10-6.00 (m, 2H), 4.91-4.82 (m, 2H).

[0196] 6. 15-6 (100 mg, 339 μmol, 1.00 eq) was added to EtOH (6.00 mL) and THF (2.00 mL), and then Pd(OH)2 (23.8 mg, 16.9 μmol, 0.05 eq) and Pd / C (18.0 mg, 16.9 μmol, 10.0% purity, 0.05 eq) were added. The system was stirred at 25 ° C for 16 hours, and then the system was stirred at 60 ° C for 16 hours. The system was concentrated to obtain a crude product and then analyzed by pre-HPLC (column: Welch Xtimate C18 150*30mm*5um; mobile phase: [water(HCl)-ACN]; B%: 0%-90%, 36 min) to give a white solid 15-7 (60 mg, 284 μmol, yield: 83.8%), MS (ESI) m / z = 205.9 [M+1] + .

[0197] 7. K2CO3 (404 mg, 2.92 mmol, 10.0 eq), M7 (128 mg, 0.322 mmol, 1.10 eq) and 15-7 (60 mg, 0.292 mmol, 1.00 eq) were added to THF (6 mL), and the system was stirred at 50°C for 16 hours. The system was quenched with water (20 mL) and extracted with ethyl acetate (20.0 mL×2). The organic phases were combined and washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The organic phase was separated and purified by column chromatography (dichloromethane / methanol (0-10%) to give 15 (40 mg, 76.7 μmol, yield: 24.6%) as a white solid. MS (ESI) m / z=522.2 [M+1] + , 1 H NMR (400MHz, DMSO-d6) δ8.09 (s, 1H), 7.44-7.30 (m, 2H), 6.99 (d, J = 8.4Hz, 1H), 6.06 (s, 2H), 4.73-4.49 ( m,2H),4.28(s,1H),2.78-2.72(m,1H),2.13-2.03(m,2H),1.82-1.56(m,6H),1.43-1.26(m,7H),1.17(br t,J=7.2Hz,3H),1.13-1.01(m,8H),0.58(s,3H).

[0198] Example 16

[0199] Synthesis route:

[0200] 1. 16-1 (2.00 g, 8.75 mmol, 1.00 eq, HCl) was added to a round-bottom flask. H2O (20.0 mL) was added under ice bath conditions, followed by glyoxylic acid (1.94 g, 13.1 mmol, 1.46 mL, 50% purity, 1.50 eq) and HCl (12 M, 1.42 mL, 1.95 eq). The system was stirred at 25 ° C for 2 hours. The system was concentrated to obtain the crude product 16-2 (2.4 g) as a yellow solid, which was used directly in the next reaction. 1 H NMR (400MHz, DMSO-d6) δ12.56-12.34(m,1H),11.36(s,1H),7.39(t,J=8.0Hz,1H),7.16(s,1H),7.10-7.03(m,2H),6.85(br d,J=8.0Hz,1H).

[0201] 2. 16-2 (500 mg, 2.01 mmol, 1.00 eq) was added to a round-bottom flask, and toluene (25.0 mL) and TEA (203.9 mg, 2.01 mmol, 280 μL, 1.00 eq) were added. The system was stirred at 25 ° C for 0.5 hours, and then DPPA (554 mg, 2.01 mmol, 437 μL, 1.00 eq) was added. The system was then stirred at 90 ° C for 16 hours. The system was quenched with water (20 mL) and extracted with ethyl acetate (20.0 mL × 2). The organic phases were combined and washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The organic phase was separated and purified by column chromatography (dichloromethane / methanol (0-10%) to give a yellow solid 16-3 (290 mg, 1.18 mmol, yield: 58.7%). MS (ESI) m / z = 445.9 [M+1] + , 1 H NMR (400MHz, DMSO-d6) δ = 12.13 (br s, 1H), 8.19 (s, 1H), 7.96-7.93 (m, 2H), 7.60 (t, J = 8.8Hz, 1H), 7.22 (br d, J = 8.4Hz, 1H).

[0202] 3. K2CO3 (1.07 g, 7.75 mmol, 10.0 eq), M7 (339 mg, 0.853 mmol, 1.10 eq) and 16-3 (190 mg, 0.775 mmol, 1.00 eq) were added to THF (20 mL), and the system was stirred at 50 ° C for 16 hours. The system was quenched with water (20 mL) and extracted with ethyl acetate (20.0 mL × 2). The organic phases were combined and washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The organic phase was separated and purified by column chromatography (dichloromethane / methanol (0-10%) to give a yellow solid 16 (230 mg, 0.403 mmol, yield: 52.1%). MS (ESI) m / z = 544.2 [M-H2O] + , 1H NMR (400MHz, DMSO-d6) δ = 8.21 (s, 1H), 7.99-7.86 (m, 2H), 7.62 (t, J = 8.4Hz, 1H), 7.25 (br d, J = 8.0Hz, 1H), 4.78-4.53 (m, 2H), 4.26 (s, 1H), 2.76 (br t,J=8.8Hz,1H),2.14-2.02(m,2H),1.78-1.62(m,7H),1.55-1.28(m,7H),1.27-1.13(m,4H),1.11(s,4H),1.05(br d,J=10.0Hz,2H),0.59(s,3H).

[0203] Example 17

[0204] Synthesis route:

[0205] Compound M7 was synthesized using the same method as in Example 1.

[0206] 1. Weigh 17-1 (1.00 g, 5.69 mmol, 1.00 eq) into a 40 mL sealed tube, add 10 mL of H2O and HCl (12.0 M, 925 μL, 1.95 eq) at room temperature, add glyoxylic acid (632 mg, 8.54 mmol, 475 μL, 1.50 eq) at room temperature, stir at room temperature for 12 h, freeze-dry the system to obtain a dark brown solid, add 10 mL of acetonitrile to slurry, then filter, and concentrate the filter cake to obtain 17-2 (1.07 g, 5.48 mmol, yield: 96.3%). 1 H NMR (400MHz, DMSO-d6) δ = 11.52 (br s, 1H), 7.96 (d, J = 2.4Hz, 1H), 7.65 (dd, J = 2.8, 9.2Hz, 1H), 7.17 (s, 1H), 6.90 (d, J = 9.2Hz, 1H), 3.83 (s, 3H).

[0207] 2. Weigh 17-2 (500 mg, 2.56 mmol, 1.00 eq) into a 40 mL sealed tube, add 10 mL of toluene at room temperature, add DPPA (705 mg, 2.56 mmol, 555 μL, 1.00 eq) and TEA (259 mg, 2.56 mmol, 356 μL, 1.00 eq) at room temperature, stir at room temperature for 12 h, add water (10.0 mL) to quench the system, wash with ethyl acetate (10.0 mL × 2), wash the combined organic layers with brine (20.0 mL), dry over Na2SO4, filter, and concentrate to give the crude product. Purify by column chromatography (petroleum ether / ethyl acetate = 100 / 1–1 / 1) to give a dark brown solid 17-3 (100 mg, 520 umol, yield: 20.3%). 1 H NMR(400MHz,DMSO-d6)δ=12.00(br s,1H),10.26(s,1H),8.61(d,J=2.8Hz,1H),8.16-8.10(m,2H),7.84(d,J=2.8Hz,1H),7. 61(s,1H),7.44-7.33(m,1H),6.93(d,J=8.8Hz,1H),6.73(d,J=8.8Hz,1H),3.87(s,3H).

[0208] 3. K2CO3 (863 mg, 6.24 mmol, 10.0 eq)), M7 (297 mg, 749 μmol, 1.20 eq) and 17-3 (120 mg, 624 μmol, 1 eq) were added to THF (4.0 mL), and the system was stirred at 30 ° C for 19 hours. The system was quenched with water (5 mL) and extracted with ethyl acetate (10.0 mL × 2). The organic phases were combined and washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated and purified by pre-HPLC (column: YMC Triart 30*150mm*7um; mobile phase: [water(HCl)-ACN]; B%: 44%-84%, 36 min) to give compound 17 (100 mg, 194 μmol, yield: 31.1%). MS (ESI) m / z = 509.1 [M+H] + , 1H NMR (400MHz, DMSO-d6). δ = 8.61 (d, J = 2.4Hz, 1H), 8.22-8.04 (m, 2H), 6.95 (d, J = 8.8Hz, 1H), 4.76-4.48 (m, 2H), 3.87 (s, 3H) ,2.76(s,2H),2.12-2.03(m,2H),1.80-1.60(m,7H),1.44-1.40(m,1H),1.44-1.23(m,8H),1.18-0.97(m,8H),0.59(s,3H).

[0209] Example 18

[0210] Synthesis route:

[0211] 1. K2CO3 (870 mg, 6.29 mmol, 10.0 eq), M7 (300 mg, 755 μmol, 1.20 eq) and 18-1 (113 mg, 629 μmol, 1.00 eq) (the preparation method of 18-1 refers to the preparation method of 17-3) were added to THF (10 mL), and the system was stirred at 50 ° C for 16 hours. The system was quenched with water (30 mL) and extracted with ethyl acetate (40.0 mL×2). The organic phases were combined and washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure. The crude product was purified by SFC (column: DAICEL CHIRALCEL OD (250 mm*30 mm, 10 μm); mobile phase: [0.1% NH3H2O ETOH]; B%: 60%-60%, min) to obtain a crude product, which was then purified by column chromatography (dichloromethane / methanol (100 / 0-95 / 5) to give compound 18 (150 mg, 298.1 μmol, yield: 47.39%) as a white solid. MS (ESI) m / z = 478.3 [M-H2O+H] + , 1 H NMR (400MHz, DMSO-d6) δ = 8.13 (s, 1H), 7.58-7.50 (m, 1H), 7.49-7.38 (m, 2H), 7 .38-7.29(m,1H),4.72-4.65(m,1H),4.59-4.51(m,1H),4.26(s,1H),2.76(br t,J=8.68Hz,1H),2.14-2.02(m,2H),1.79-1.64(m,6H),1.61-1.44(m,2H),1.43-1.21(m,9H),1.17-1.02(m,7H),0.58(s,3H).

[0212] Example 19

[0213] Synthesis route:

[0214] 1. K2CO3 (609 mg, 4.41 mmol, 10.0 eq), M7 (193 mg, 485 μmol, 1.10 eq) and 19-1 (90 mg, 441 μmol, 1.00 eq) (the preparation method of 19-1 refers to the preparation method of 17-3) were added to THF (10 mL), and the system was stirred at 50 ° C for 16 hours. The system was quenched with water (30 mL) and extracted with ethyl acetate (40.0 mL×2). The organic phases were combined and washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by SFC (column: DAICEL CHIRALCEL OD (250 mm*30 mm, 10 μm); mobile phase: [0.1% NH3H2O The crude product was separated by column chromatography (dichloromethane / methanol (100 / 0-95 / 5) to obtain compound 19 (135 mg, 259 μmol, yield: 58.8%) as a white solid. MS (ESI) m / z = 503.1 [M-H2O+H] + , 1 H NMR (400MHz, DMSO-d6) δ=8.41-8.35(m,1H),8.19(s,1H),8.09-8.03(m,1H),8.11-8.03(m,1H),7.77-7.70(m,1H),7.55(t,J=8.0Hz,1H),7.46(br s,1H),4.76-4.55(m,2H),4.26(s,1H),2.82-2.72(m,1H),2.16-2.03(m,2H),1.80-1.62(m,7H),1.35(br d,J=9.6Hz,7H),1.30-1.16(m,4H),1.12(s,4H),1.06(br d, J = 10.8 Hz, 2H), 0.60 (s, 3H).

[0215] Example 20

[0216] Synthesis route:

[0217] 1. K2CO3 (580 mg, 4.2 mmol, 10.01 eq), M7 (200 mg, 503.29 μmol, 1.20 eq) and 20-1 (75.6 mg, 419.68 μmol, 1.00 eq) (the preparation method of 20-1 refers to the preparation method of 17-3) were added to THF (10 mL), and the system was stirred at 50 ° C for 16 hours. The system was quenched with water (30 mL) and extracted with ethyl acetate (40.0 mL×2). The organic phases were combined and then washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure. The crude product was purified by SFC (column: DAICEL CHIRALCEL OD (250 mm*30 mm, 10 μm); mobile phase: [0.1% NH3H2O ETOH]; B%: 60%-60%, min) to obtain a crude product, which was then purified by column chromatography (dichloromethane / methanol (100 / 0-95 / 5) to give compound 20 (60 mg, 120.82 μmol, yield: 28.81%) as a white solid. MS (ESI) m / z = 497.3 [M+H] + , 1 H NMR (400MHz, DMSO-d6) δ=8.18(s,1H),8.12(q,J=8.4Hz,1H),7.89(dd,J=8.0,2.0Hz,1H),7.08(dd,J=8.00,2.40Hz,1H),4.75-4.67 (m,1H),4.61-4.53(m,1H),4.25(s,1H),2.80-2.72(m,1H),2.13-2.04(m,2H),1.78-1.63(m,7H),1.63-1.45(m,3H),1.42-1.15(m, 11H), 1.05 (br d, J=8.8Hz, 3H), 0.59 (s, 3H).

[0218] Example 21

[0219] Synthesis route:

[0220] 1. K2CO3 (1.53 g, 11.1 mmol, 10.0 eq), M7 (485 mg, 1.22 mmol, 1.10 eq) and 21-1 (200 mg, 1.11 mmol, 1.00 eq) (the preparation method of 21-1 refers to the preparation method of 17-3) were added to THF (10 mL), and the system was stirred at 50 ° C for 16 hours. The system was quenched with water (30 mL) and extracted with ethyl acetate (40.0 mL×2). The organic phases were combined and washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure. The crude product was purified by SFC (column: DAICEL CHIRALCEL OD (250 mm*30 mm, 10 μm); mobile phase: [0.1% NH3H2O The crude product was separated by column chromatography (dichloromethane / methanol (100 / 0-95 / 5) to obtain a white solid compound 21 (155 mg, 304 μmol, yield: 27.3%). MS (ESI) m / z = 497.3 [M+H] + , 1 H NMR (400MHz, DMSO-d6) δ=8.33-8.27(m,2H),7.89-7.83(m,1H),7.57(d,J=1.6Hz,1H),4.77-4.56(m,2H) ,4.25(s,1H),2.81-2.73(m,1H),2.13-2.02(m,2H),1.78-1.59(m,7H),1.53-1.03(m,17H),0.59(s,3H).

[0221] Example 22

[0222] Synthesis route:

[0223] 1. K2CO3 (1.26 g, 9.08 mmol, 10.0 eq), M7 (200 mg, 503 μmol, 1.10 eq) and 22-1 (160 mg, 908 μmol, 1.00 eq) (the preparation method of 22-1 refers to the preparation method of 17-3) were added to THF (10 mL), and the system was stirred at 50 ° C for 16 hours. The system was quenched with water (30 mL) and extracted with ethyl acetate (40.0 mL×2). The organic phases were combined and then washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure. The crude product was purified by SFC (column: DAICEL CHIRALCEL OD (250 mm*30 mm, 10 μm); mobile phase: [0.1% NH3H2O ETOH]; B%: 60%-60%, min) to obtain a crude product, which was then purified by column chromatography (dichloromethane / methanol (100 / 0-95 / 5) to give compound 22 (25 mg, 50.8 μmol, yield: 5.59%) as a white solid. MS (ESI) m / z = 475.3 [M-H2O+H] + , 1 H NMR (400MHz, DMSO-d6) δ = 8.06 (s, 1H), 7.9-7.14 (m, 1H), 7.09-6.97 (m, 2H), 6.4 1(td,J=2.0,7.2Hz,1H),5.28(s,2H),4.72-4.48(m,2H),4.27(s,1H),2.75(br t,J=8.8Hz,1H),2.19-1.99(m,2H),1.78-1.09(m,24H),0.59(s,3H).

[0224] Example 23

[0225] Synthesis route:

[0226] 1. K2CO3 (844 mg, 6.11 mmol, 10.0 eq), M7 (267 mg, 671.7 μmol, 1.10 eq) and 23-1 (110 mg, 610.6 μmol, 1.00 eq) (the preparation method of 23-1 refers to the preparation method of 17-3) were added to THF (10 mL), and the system was stirred at 50 ° C for 16 hours. The system was quenched with water (30 mL) and extracted with ethyl acetate (40.0 mL×2). The organic phases were combined and washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure. The crude product was purified by SFC (column: DAICEL CHIRALCEL OD (250 mm*30 mm, 10 μm); mobile phase: [0.1% NH3H2O ETOH]; B%: 60%-60%, min) to obtain a crude product, which was then purified by column chromatography (dichloromethane / methanol (100 / 0-95 / 5) to give compound 23 (130 mg, 251 μmol, yield: 41.2%) as a white solid. MS (ESI) m / z = 479.2 [M-H2O+H] + , 1 H NMR (400MHz, DMSO-d6) δ = 9.03 (s, 1H), 8.51 (d, J = 2.4Hz, 1H), 8.28 (s, 1H), 8.21-8.12 (m, 1H), 4.78-4.56 (m, 2H), 4.26 (s, 1H), 2.78 (br t,J=8.8Hz,1H),2.15-2.04(m,2H),1.76-1.23(m,22H),1.05(br d,J=11.2Hz,2H),0.60(s,3H).

[0227] Example 24

[0228] Synthesis route:

[0229] 1. K2CO3 (350.53 mg, 2.54 mmol, 10.0 eq), M7 (100.8 mg, 256.63 μmol, 1.1 eq) and 24-1 (46 mg, 233.3 μmol, 1.0 eq) (the preparation method of 24-1 refers to the preparation method of 17-3) were added to THF (5 mL), and the system was stirred at 50 ° C for 16 hours. The system was quenched with water (30 mL) and extracted with ethyl acetate (40.0 mL×2). The organic phases were combined and washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure. The crude product was purified by SFC (column: DAICEL CHIRALCEL OD (250 mm*30 mm, 10 μm); mobile phase: [0.1% NH3H2O The crude product was separated by column chromatography (dichloromethane / methanol (100 / 0-95 / 5) to obtain a white solid compound 24 (95 mg, 183.1 μmol, yield: 72.2%). MS (ESI) m / z = 496.3 [M-H2O+H] + , 1 H NMR (400MHz, DMSO-d6). δ = 8.16 (s, 1H), 7.48 (br dd, J = 5.2, 9.2Hz, 2H), 7.40-7.26 (m, 1H), 4.76-4.48 (m, 2H), 4.27 (s, 1H), 2.74 (br d,J=9.2Hz,2H),2.15-2.01(m,2H),1.79-1.55(m,7H),1.49-1.21(m,8H),1.10(s,8H),0.57(s,3H).

[0230] Example 25

[0231] Synthesis route:

[0232] 1. K2CO3 (350.5 mg, 2.54 mmol, 10.0 eq), M7 (100.79 mg, 256.63 μmol, 1.0 eq) and 25-1 (50 mg, 253.63 μmol, 1.0 eq) (the preparation method of 25-1 refers to the preparation method of 17-3) were added to THF (5 mL), and the system was stirred at 50 ° C for 16 hours. The system was quenched with water (30 mL) and extracted with ethyl acetate (40.0 mL×2). The organic phases were combined and washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure. The crude product was purified by SFC (column: DAICEL CHIRALCEL OD (250 mm*30 mm, 10 μm); mobile phase: [0.1% NH3H2O ETOH]; B%: 60%-60%, min) to obtain a crude product, which was then purified by column chromatography (dichloromethane / methanol (100 / 0-95 / 5) to give compound 25 (80 mg, 184.1 μmol, yield: 58.4%) as a white solid. MS (ESI) m / z = 514.0 [M+H] + , MS(ESI)m / z=496.3[M-H2O+H] + , 1 H NMR (400MHz, DMSO-d6) δ = 8.13 (s, 1H), 7.65-7.57 (m, 1H), 7.55-7.48 (m, 1H), 7.24 (br t, J = 7.6Hz, 1H), 4.73-4.51 (m, 2H), 4.27 (s, 1H), 2.76 (br t,J=8.4Hz,1H),2.10-2.05(m,1H),2.12-2.04(m,1H),1.78-1.64(m,6H),1.81 -1.62(m,1H),1.42-1.23(m,9H),1.11(s,5H),1.08-0.99(m,3H),0.58(s,3H).

[0233] Example 26

[0234] Synthesis route:

[0235] 1. K2CO3 (562.4 mg, 4.07 mmol, 10.0 eq), M7 (178 mg, 447.6 μmol, 1.1 eq) and 26-1 (80 mg, 407 μmol, 1.0 eq) (the preparation method of 26-1 refers to the preparation method of 17-3) were added to THF (5 mL), and the system was stirred at 50 ° C for 16 hours. The system was quenched with water (30 mL) and extracted with ethyl acetate (40.0 mL×2). The organic phases were combined and then washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by SFC (column: DAICEL CHIRALCEL OD (250 mm*30 mm, 10 μm); mobile phase: [0.1% NH3H2O ETOH]; B%: 60%-60%, min) to obtain a crude product, which was then purified by column chromatography (dichloromethane / methanol (100 / 0-95 / 5) to give compound 26 (70 mg, 133 μmol, yield: 32.8%) as a white solid. MS (ESI) m / z = 513.2 [M+H] + , 1 H NMR (400MHz, DMSO-d6) δ = 8.48 (d, J = 5.6Hz, 1H), 8.17-8.16 (m, 1H), 8.02 (d, J = 1.6Hz, 1H), 7.46 (dd, J = 2.0, 5.4Hz, 1H), 4.73-4.54 (m,2H),4.42-4.37(m,1H),2.79-2.73(m,1H),2.11-2.04(m,2H),1.79-1.64(m,7H),1.41-1.23(m,9H),1.11(s,8H),0.58(s,3H).

[0236] Example 27

[0237] Synthesis route:

[0238] 1. K2CO3 (701 mg, 5.07 mmol, 10.0 eq), M7 (202 mg, 507 μmol, 1.1 eq) and 27-1 (100 mg, 507 μmol, 1.0 eq) (the preparation method of 27-1 refers to the preparation method of 17-3) were added to THF (10 mL), and the system was stirred at 50°C for 16 hours. The system was quenched with water (30 mL) and extracted with ethyl acetate (40.0 mL×2). The organic phases were combined and washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by SFC (column: DAICEL CHIRALCEL OD (250 mm*30 mm, 10 μm); mobile phase: [0.1% NH3H2O The crude product was separated by column chromatography (dichloromethane / methanol (100 / 0-95 / 5) to obtain a white solid compound 27 (45 mg, 87.18 μmol, yield: 17.19%). MS (ESI) m / z = 496.3 [M-H2O+H] + , 1 H NMR (400MHz, DMSO-d6)δ=8.18(s,1H),7.60-7.46(m,1H),7.45-7.31(m,2H),4.81-4.64(m,1H),4.61-4.52(m,1H),4.27(s,1H),2.76(br t,J=8.8Hz,1H),2.14-2.04(m,2H),1.78-1.57(m,7H),1.53-1.22(m,10H),1.11(s,5H),1.08-0.96(m,2H),0.58(s,3H).

[0239] Example 28

[0240] Synthesis route:

[0241] 1. K2CO3 (347.79 mg, 2.52 mmol, 10.0 eq), M7 (100 mg, 251.64 μmol, 1.1 eq) and 28-1 (49.61 mg, 251.64 μmol, 1.0 eq) (the preparation method of 28-1 refers to the preparation method of 17-3) were added to THF (10 mL), and the system was stirred at 50 ° C for 16 hours. The system was quenched with water (30 mL) and extracted with ethyl acetate (40.0 mL×2). The organic phases were combined and washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure. The crude product was purified by SFC (column: DAICEL CHIRALCEL OD (250 mm*30 mm, 10 μm); mobile phase: [0.1% NH3H2O ETOH]; B%: 60%-60%, min) to obtain a crude product, which was then purified by column chromatography (dichloromethane / methanol (100 / 0-95 / 5) to give compound 28 (95 mg, 182.56 μmol, yield: 72.55%) as a white solid. MS (ESI) m / z = 496.3 [M-H2O+H] + , 1 H NMR (400MHz, DMSO-d6) δ = 8.23 ​​(s, 1H), 7.61 (dd, J = 2.4, 9.0Hz, 2H), 7.14 (br t,J=2.4Hz,1H),4.81-4.46(m,2H),4.26(s,1H),2.76(s,1H),2.17-1.96(m,2H),1.84-1.19(m,17H),1.16-0.96(m,7H),0.59(s,3H).

[0242] Example 29

[0243] Synthesis route:

[0244] 1. Weigh 29-1 (10.0 g, 118 mmol, 10.5 mL, 1.00 eq) and Boc hydrazine (15.7 g, 118 mmol, 1.00 eq) into a 250 mL reaction flask, and add 50 mL of MeOH was then added with NaBH3CN (14.9 g, 237 mmol, 2.00 eq), and then AcOH (28.1 g, 468 mmol, 26.7 mL, 3.94 eq) was added at 0°C. The reaction was stirred at room temperature for 12 hours. NaHCO3 (50.0 mL) was added at 0-10°C, and then 300 mL of DCM was added for extraction. The aqueous phase was extracted with DCM (50.0 mL × 2), and then the organic phase was washed with 10 mL of brine and then dried and concentrated with anhydrous Na2SO4 to obtain a crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 100 / 1–1 = 1 / 1) to give a light oily liquid 29-2 (9.38 g, 46.8 mmol, yield: 39.4%). 1 H NMR (400MHz, CDCl3) δ=6.93-6.15(m,1H),4.91(br s,1H),3.45(br s,1H),1.63(br s,4H),1.46-1.31(m,12H).

[0245] 2. Weigh 29-2 (1.00 g, 4.99 mmol, 1.00 eq) into a 40 mL sealed tube, add 40 mL Li-PrOH (10.0 mL) and TMSNCO (1.73 g, 14.98 mmol, 1.99 mL, 3 eq) at room temperature, and stir at room temperature for 12 h. Concentrate the system to obtain a crude product, which is purified by column chromatography (petroleum ether / ethyl acetate = 100 / 1–1 = 1 / 1) to obtain a white solid 29-3 (1 g, 4.11 mmol, yield: 82.3%). 1 H NMR (400MHz, CDCl3) δ = 6.22 (br s, 1H), 4.61 (quin, J = 8.4Hz, 3H), 1.89-1.49 (m, 8H), 1.43-1.40 (m, 9H).

[0246] 3. Weigh 29-3 (1.00 g, 4.11 mmol, 1.00 eq) into a 100 mL round-bottom flask, add HCl / dioxane (4.00 M, 1.03 mL, 1.00 eq) and stir at room temperature for 2 h. Concentrate the system to obtain a crude product, which is purified by column chromatography (petroleum ether / ethyl acetate = 100 / 1–1 = 1 / 1) to obtain a yellow solid 29-4 (588 mg, yield: 100%). 1HNMR (400MHz, DMSO-d6)δ=6.53-6.51(m,1H),7.57-6.06(m,1H),4.44-4.28(m,1H),1.81-1.29(m,8H).

[0247] 4. Weigh 29-4 (700 mg, 4.89 mmol, 1.00 eq) into a 40 mL sealed tube, add EtOH (7 mL) and CH(OMe)3 (1.30 g, 12.2 mmol, 1.34 mL, 2.50 eq) at room temperature, and stir at room temperature for 12 h. Concentrate the system to obtain a crude product, which is purified by column chromatography (petroleum ether / ethyl acetate = 100 / 1-10 / 1) to obtain a white solid 29-5 (200 mg, 1.27 mmol, yield: 25.9%). 1 H NMR (400MHz, DMSO-d6) δ = 11.45 (br s, 1H), 7.77 (s, 1H), 4.61-4.00 (m, 1H), 1.95-1.82 (m, 2H), 1.80-1.66 (m, 4H), 1.56 (br d, J = 4.4Hz, 2H).

[0248] 5. K2CO3 (902 mg, 6.53 mmol, 10.0 eq), M7 (311 mg, 783 μmol, 1.1 eq) and 29-5 (100 mg, 652.82 μmol, 1.0 eq) were added to THF (10 mL), and the system was stirred at 50 ° C for 16 hours. The system was quenched with water (30 mL) and extracted with ethyl acetate (40.0 mL×2). The organic phases were combined and washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by SFC (column: DAICEL CHIRALCEL OD (250 mm*30 mm, 10 μm); mobile phase: [0.1% NH3H2O ETOH]; B%: 60%-60%, min) to obtain a crude product, which was then purified by column chromatography (dichloromethane / methanol (100 / 0-95 / 5) to give compound 29 (150 mg, 312 μmol, yield: 47.8%) as a white solid. MS (ESI) m / z = 470.5 [M+H] + , 1H NMR (400MHz, DMSO-d6) δ = 7.80 (s, 1H), 4.65-4.36 (m, 3H), 4.24 (s, 1H), 2.70 (br t,J=8.8Hz,1H),2.11-1.98(m,2H),1.96-1.83(m,2H),1.77-1.55(m,12H),1.47-1.20(m,10H),1.15-0.97(m,8H),0.56(s,3H).

[0249] Example 30

[0250] Synthesis route:

[0251] 1. K2CO3 (827 mg, 5.98 mmol, 10.0 eq), M7 (261 mg, 658 μmol, 1.1 eq) and 30-1 (100 mg, 598 μmol, 1.0 eq) (the preparation method of 30-1 refers to the preparation method of 29-5) were added to THF (10 mL), and the system was stirred at 50 ° C for 16 hours. The system was quenched with water (30 mL) and extracted with ethyl acetate (40.0 mL×2). The organic phases were combined and then washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure. The crude product was purified by SFC (column: DAICEL CHIRALCEL OD (250 mm*30 mm, 10 μm); mobile phase: [0.1% NH3H2O The crude product was separated by column chromatography (dichloromethane / methanol (100 / 0-95 / 5) to obtain a white solid compound 30 (40 mg, 82.8 μmol, yield: 13.8%). MS (ESI) m / z = 484.3 [M+H] + , 1 H NMR (400MHz, DMSO-d6) δ = 7.79 (s, 1H), 4.61-4.37 (m, 2H), 4.24 (s, 1H), 3.86 (br t,J=11.6Hz,1H),2.74-2.65(m,1H),2.12-1.98(m,2H),1.81-1.53(m,14H),1.46-0.99(m,20H),0.56(s,3H).

[0252] Example 31

[0253] Synthesis route:

[0254] 1. Weigh phthalic anhydride (10.0 g, 67.51 mmol, 1.00 eq) into a 1 L three-necked reaction flask, add 200 mL of toluene, weigh 31-1 (8.92 g, 67.51 mmol, 1.00 eq) and add it to the system. Stir at 120 ° C for 2.5 h. Concentrate the system to obtain a filter cake, and use 100 mL of petroleum ether to slurry to obtain a white solid 31-2 (17.1 g, 60.64 mmol, yield: 89.82%). 1 H NMR (400MHz, CDCl3) δ = 7.97-7.63 (m, 4H), 6.56 (br s, 1H), 1.44 (br s, 9H).

[0255] 2. Weigh 2-bromoethyl methyl ether (5.30 g, 38.13 mmol, 3.58 mL, 2.0 eq) and 31-2 (5.00 g, 19.06 mmol, 1.00 eq) into a 250 mL three-necked reaction flask, then add 100 mL of acetonitrile to the system, add benzyl(triethyl)ammonium chloride (1.74 g, 7.63 mmol, 0.4 eq) and K2CO3 (7.90 g, 57.19 mmol, 3.0 eq) at room temperature, and stir at 55 °C for 12 h. The system was quenched with water (100 mL), extracted with ethyl acetate (100.0 mL × 2), and the organic phases were combined and washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 100 / 1–3 / 1) to give the product 31-3 as a white solid (4.7 g, 14.67 mmol, yield: 76.96%). 1 H NMR (400MHz, CDCl3) δ = 8.05-7.56 (m, 4H), 3.98-3.72 (m, 2H), 3.68-3.46 (m, 2H), 3.35-3.07 (m, 3H), 1.56-1.30 (m, 10H).

[0256] 3. Weigh 31-3 (4.7 g, 14.67 mmol, 1 eq) into a 100 mL round-bottom reaction flask, add HCl / EtOAc (4 M, 3.67 mL, 1 eq), stir at room temperature for 2 h, and concentrate to obtain 31-4 (4.07 g, crude product). 1 H NMR (400MHz, DMSO-d6) δ = 7.85 (s, 4H), 3.44 (t, J = 5.6Hz, 2H), 3.17 (s, 3H), 3.07 (t, J = 5.6Hz, 2H).

[0257] 4. Weigh 31-4 (3.07 g, 13.94 mmol, 1 eq) into a 40 mL sealed tube, add 30 mL of isopropanol, add trimethylsilyl isocyanate (4.82 g, 41.82 mmol, 5.56 mL, 3 eq), stir at room temperature for 12 h, and concentrate the system to obtain a white solid 31-5 (4.8 g, crude product). 1 H NMR (400MHz, DMSO-d6) δ = 7.90 (br d, J = 6.0Hz, 4H), 6.84-6.21 (m, 2H), 3.70 (s, 2H), 3.46-3.37 (m, 2H), 3.00 (br s, 3H).

[0258] 5. Add 50 mL of ethanol to a 100 mL three-necked flask, weigh 31-5 (4.80 g, 18.2 mmol, 1.00 eq) and add it to the system. Measure hydrazine hydrate (1.86 g, 36.47 mmol, 1.81 mL, 98% purity, 2 eq) and add it to the system. Stir at 70 ° C for 2 h. The system is washed with 1 M HCl (10 mL) and then with EtOAc (10 mL × 2). The aqueous phase is retained and lyophilized to obtain a yellow solid 31-6 (199 mg, crude product). 1 H NMR (400MHz, DMSO-d6) δ = 10.80-8.87 (m, 1H), 7.10-6.51 (m, 1H), 3.70 (br t, J = 5.6Hz, 2H), 3.51 (br t, J = 5.6Hz, 2H), 3.28 (s, 3H).

[0259] 6. Weigh 31-6 (120 mg, 901.25 μmol, 1 eq) into a 40 mL sealed tube. Add 5 mL of ethanol to the system. Measure trimethoxymethane (239 mg, 2.25 mmol, 247 μL, 2.5 eq). Use Pre HPLC (column: Phenomenex C18 75*30 mm*3 um; mobile phase: [water(HCl)-ACN]; B%: 0%-24%, 36 min) to obtain a colorless oil 31-7 (50 mg, 349.30 μmol, yield: 38.76%). 1 H NMR (400MHz, DMSO-d6)δ=11.83-11.33(m,1H),7.85(s,1H),3.70(br s,2H),3.65-3.54(m,2H),3.28(s,3H).

[0260] 7. K2CO3 (482.75 mg, 3.49 mmol, 10.0 eq), M7 (138.81 mg, 349.30 μmol, 1 eq) and 31-7 (50 mg, 349 μmol, 1.0 eq) were added to THF (5 mL), and the system was stirred at 50 ° C for 12 hours. The system was quenched with water (5 mL) and extracted with ethyl acetate (10.0 mL×2). The organic phases were combined and washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure. The crude product was purified by SFC (column: DAICEL CHIRALCEL OD (250 mm*30 mm, 10 μm); mobile phase: [0.1% NH3H2O ETOH]; B%: 60%-60%, min) to obtain a crude product, which was then purified by column chromatography (dichloromethane / methanol (100 / 0-95 / 5) to give compound 31 (105 mg, 222.74 μmol, yield: 63.77%) as a white solid. MS (ESI) m / z = 460.5 [M+H] + , 1 H NMR (400MHz, DMSO-d6).δ=7.82(s,1H),4.65-4.39(m,2H),3.83-3.75(m,2H),3.58-3.55(m ,2H),3.21(s,3H),2.74-2.70(m,1H),2.08-1.99(m,2H),1.72-1.06(m,25H),0.56(s,3H).

[0261] Example 32

[0262] Synthesis route:

[0263] 1. Weigh 32-1 (20.0 g, 235 mmol, 1.00 eq) into a 250 mL round-bottom flask, add 100 mL of DMF, weigh 4-methoxybenzyl chloride (18.4 g, 117 mmol, 16.0 mL, 0.50 eq), weigh K2CO3 (48.7 g, 353 mmol, 1.50 eq), stir at room temperature for 3 h, adjust the pH of the system to pH = 5, extract the system with 100 mL of ethyl acetate, wash the aqueous phase with 200 mL of ethyl acetate, combine the organic phases and then wash with saturated brine (100 mL), dry over anhydrous sodium sulfate, filter, and concentrate the organic phase under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 100 / 0-50 / 50) to obtain a white solid 32-2 (6.20 g, 28.91 mmol, yield: 24.60%). 1H NMR (400MHz, DMSO-d6) δ = 11.67 (br s, 1H), 7.92 (s, 1H), 7.24 (d, J = 8.8Hz, 2H), 6.94-6.89 (m, 2H), 4.66 (s, 2H), 3.74 (s, 3H).

[0264] 2. Weigh 32-2 (1.00 g, 4.87 mmol, 1.00 eq) into a 100 mL three-necked reaction flask, protect with nitrogen, add dioxane (50 mL), weigh 2-bromothiazole (799 mg, 4.87 mmol, 439 μL, 1.00 eq), weigh Cs2CO3 (3.18 g, 9.75 mmol, 2.00 eq), CuI (464 mg, 2.44 mmol, 0.50 eq), KI (647 mg, 3.90 mmol, 0.80 eq) into the system, stir at 100 ° C for 12 h, concentrate the system, wash the filter cake with 30 mL of ethyl acetate, and purify the crude product by column chromatography (petroleum ether / ethyl acetate = 100 / 0-60 / 40) to give a white solid 32-3 (170 mg, 590 μmol, yield: 12.1%). 1 H NMR (400MHz, DMSO-d6) δ = 8.45 (s, 1H), 7.60 (d, J = 3.6Hz, 1H), 7.51 (d, J = 3.6 Hz,1H),7.33(d,J=8.4Hz,2H),6.99-6.87(m,2H),4.83(s,2H),3.74(s,3H).

[0265] 3. 32-3 (170 mg, 590 μmol, 1.00 eq) was weighed into a 40 mL sealed tube. 0.5 mL of water and 5 mL of acetonitrile were added to the system. Cerium (IV) ammonium nitrate (970 mg, 1.77 mmol, 882 μL, 3.00 eq) was weighed and stirred at room temperature for 12 h. The system was concentrated and filtered, and the filter cake was washed with 10 mL of ethyl acetate. The filtrate was concentrated to obtain the crude product, which was purified by prep-HPLC (column: Welch Xtimate C18 150*30 mm*5 um; mobile phase: [water(NH4HCO3)-ACN]; B%: 0%-16%, 28 min) to give 32-4 (30 mg, 178.38 μmol, yield: 30.25%). MS (ESI) m / z = 169 [M+H] + , 1H NMR (400MHz, DMSO-d6) δ = 7.85-7.77 (m, 1H), 7.37 (d, J = 3.6Hz, 1H), 7.08 (d, J = 3.6Hz, 1H), 6.86 (d, J = 8.8Hz, 1H).

[0266] 4. K2CO3 (246.54 mg, 1.78 mmol, 10.0 eq), M7 (71 mg, 178.38 μmol, 1 eq) and 32-4 (30 mg, 178 μmol, 1.0 eq) were added to THF (4 mL), and the system was stirred at 50 ° C for 12 hours. The system was quenched with water (5 mL) and extracted with ethyl acetate (10.0 mL×2). The organic phases were combined and washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by SFC (column: DAICEL CHIRALCEL OD (250 mm*30 mm, 10 μm); mobile phase: [0.1% NH3H2O ETOH]; B%: 60%-60%, min) to obtain a crude product, which was then purified by column chromatography (dichloromethane / methanol (100 / 0-95 / 5) to give compound 32 (20 mg, 38.4 μmol, yield: 21.51%) as a white solid. MS (ESI) m / z = 485.1 [M+H] + , 1 H NMR (400MHz, DMSO-d6) δ = 8.25 (s, 1H), 7.61 (d, J = 3.6Hz, 1H), 7.51 (d, J = 3.6Hz, 1H), 4.83-4.68 (m, 1H), 4.64-4.54 (m, 1H), 4.30 (s, 1H), 2.76 (br t,J=8.8Hz,1H),2.09-2.03(m,2H),1.74-1.01(m,24H),0.58(s,3H).

[0267] Example 33

[0268] Synthesis route:

[0269] 1. Add 15 mL of THF to a 100 mL three-necked flask, protect the system with N2 gas, weigh 33-1 (1 g, 3.16 mmol, 1.00 eq), weigh MeMgBr (3 M, 1.05 mL, 1 eq) and add them to the system at 0°C. The system is placed at 0°C for 0.5 h, quenched with aqueous ammonium chloride (500 mL), extracted with ethyl acetate (200 mL × 2), and the organic phases are combined and washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product is purified by Pre-HPLC (column: Phenomenex C18 75*30 mm*3 um; mobile phase: [water (HCl)-ACN]; B%: 36%-76%, 36 min) to give a red solid 33-2 (150 mg, 451.10 μmol, yield: 14.28%). 1 H NMR (400MHz, CDCl3) δ = 2.54 (t, J = 8.8Hz, 1H), 2.21-2.09 (m, 4H), 2.01 (td, J = 3.2, 12.0Hz, 1H), 1.63-1.49 (m,10H),1.43-1.22(m,12H),0.96(dd,J=5.6,12.3Hz,1H),0.82-0.79(m,1H),0.76(s,3H),0.61(s,3H).

[0270] 2. Weigh 33-2 (150 mg, 451.10 μmol, 1.00 eq) into a 40 mL sealed tube. Protect the system with N2 gas. Add 1.5 mL of methanol at room temperature. Add HBr (14.75 mg, 87.51 μmol, 9.90 μL, 0.194 eq) and Br2 (72.09 mg, 451.10 μmol, 23.25 μL, 1 eq) at 0°C. Then stir the system at room temperature for 12 hours. Quench the system with aqueous sodium bicarbonate solution (5 mL) and extract with ethyl acetate (5 mL × 2). Combine the organic phases, wash with saturated brine (10 mL), dry over anhydrous sodium sulfate, filter, and concentrate the organic phase under reduced pressure. The crude product is purified by column chromatography (petroleum ether / ethyl acetate = 100 / 1–1 / 1) to give 33-3 (150 mg, 364.60 μmol, yield: 80.82%) as a white solid. 1H NMR (400MHz, CDCl3) δ = 3.84 (d, J = 2.9Hz, 2H), 2.75 (t, J = 8.8Hz, 1H), 2.17-2.04 (m, 1H), 1.71-1.57 (m, 4H), 1.55 (br d, J = 3.2Hz, 5H), 1.43 (br d,J=2.4Hz,3H),1.39(br s,5H),1.25-1.13(m,4H),1.12-1.04(m,2H),0.89(br dd,J=5.2,12.1Hz,1H),0.74(br s,1H),0.68(s,3H),0.56(s,3H).

[0271] 3. K2CO3 (335.93 mg, 2.43 mmol, 10.0 eq), 33-4 (43.55 mg, 243.06 μmol, 1 eq) and 33-3 (100 mg, 243.06 μmol, 1.0 eq) were added to THF (5 mL), and the system was stirred at 50 ° C for 12 hours. The system was quenched with water (5 mL) and extracted with ethyl acetate (10.0 mL×2). The organic phases were combined and washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by SFC (column: DAICEL CHIRALCEL OD (250 mm*30 mm, 10 μm); mobile phase: [0.1% NH3H2O The crude product was separated by column chromatography (dichloromethane / methanol (100 / 0-95 / 5) to obtain compound 33 as a white solid (20 mg, 38.93 μmol, yield: 16.02%). MS (ESI) m / z = 510.1 [M+H] + , 1 H NMR (400MHz, DMSO-d6) δ = 8.21 (s, 1H), 7.84-7.69 (m, 2H), 7.64-7.43 (m, 1H), 7.11 (br d,J=2.0Hz,1H),4.81-4.55(m,2H),3.88(s,1H),2.85-2.67(m,1H),2.22-1.90(m,2H),1.80-0.75(m,23H),0.74(s,3H),0.60(s,3H).

[0272] Example 34

[0273] Synthesis route:

[0274] 1. K2CO3 (742 mg, 5.37 mmol, 10.0 eq), M7 (100 mg, 537 μmol, 1 eq) and 34-1 (235 mg, 591 μmol, 1.1 eq) were added to THF (15 mL), and the system was stirred at 50 ° C for 16 hours. The system was quenched with water (20 mL) and extracted with ethyl acetate (10.0 mL×2). The organic phases were combined and washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by SFC (column: DAICEL CHIRALCEL OD (250 mm*30 mm, 10 μm); mobile phase: [0.1% NH3H2O The crude product was separated by column chromatography (dichloromethane / methanol (100 / 0-95 / 5) to obtain compound 34 (63 mg, 122 μmol, yield: 22.8%) as a white solid. MS (ESI) m / z = 485.3 [M-H2O+H] + , 1 H NMR (400MHz, DMSO-d6)δ=8.35-8.11(m,3H),7.81-7.60(m,2H),4.79-4.52(m,2H),4.26(s,1H),2.77(br t,J=8.8Hz,1H),2.19-1.95(m,2H),1.81-1.46(m,9H),1.43-0.99(m,15H),0.59(s,3H).

[0275] Example 35

[0276] Synthesis route:

[0277] Compound M7 was synthesized using the same method as in Example 1.

[0278] 1. Add compound 35-1 (1.03 g, 5.00 mmol, 0.80 eq) to a 100 mL three-necked flask (R1) with nitrogen, add dibromotetrafluoropyridine (1.10 g, 6.25 mmol, 1.00 eq), add Cs2CO3 (4.07 g, 12.5 mmol, 2.00 eq) to R1 at 25 ° C, add potassium iodide (830.08 mg, 5.00 mmol, 0.80 eq) to R1, add CuI (595.20 mg, 3.13 mmol, 0.50 eq) to R1 at 25 ° C, add 1,10-phenanthroline (788 mg, 4.38 mmol) to R1 at 25 ° C. l, 0.70eq) was added to R1; dioxane (20.0mL) was added to R1 at 25°C, and R1 was stirred at 100°C for 2 hours. Thin layer chromatography (petroleum ether / ethyl acetate = 1 / 3) showed that compound 35-1 was consumed and a new spot appeared; the mixture was quenched with water (10mL) and extracted with ethyl acetate (10mL×2). The combined organic phases were washed with brine (10ml), dried over Na2SO4, filtered and concentrated to obtain a crude product; the crude product was purified by silica gel (petroleum ether / ethyl acetate = 100 / 1–1 / 3) column chromatography to obtain a yellow solid compound 35-2 (490mg, 1.63mmol, yield: 26.11%). 1 H NMR (400MHz, DMSO-d6) δ=8.56-8.47(m,1H),8.37(s,1H),7.82(dd,J=2.4,11.2Hz,1 H),7.32(s,2H),7.29-7.22(m,1H),6.94(d,J=8.8Hz,2H),4.81(s,2H),3.74(s,3H).

[0279] 2. Compound 35-2 (100 mg, 333.01 μmol, 1.00 eq) was added to a 40 mL sealed tube (R1) and the temperature was controlled at 25°C. Acetonitrile (10 mL) was added to R1 and the temperature was controlled at 25°C. Cerium ammonium nitrate (547.70 mg, 999.04 μmol, 497.91 μL, 3.00 eq) was added to R1 and stirred at 60°C for 12 hours. The mixture was concentrated to obtain a crude product. The crude product was purified by column chromatography to obtain a white solid compound 35-3 (40 mg, 83.49 μmol, yield: 25.07%). 1 H NMR (400MHz, DMSO-d6) δ = 12.11 (br s, 1H), 8.51 (dd, J = 5.6, 9.1Hz, 1H), 8.16 (s, 1H), 7.84 (dd, J = 2.4, 11.1Hz, 1H), 7.24 (br t, J = 2.4Hz, 1H).

[0280] 3. K2CO3 (306 mg, 2.22 mmol, 10.0 eq), M7 (88.2 mg, 222 μmol, 1.00 eq) and 35-3 (40 mg, 222.05 μmol, 1.00 eq) were added to THF (4.0 mL), and the system was stirred at 50 ° C for 12 hours. The system was quenched with water (5 mL) and extracted with ethyl acetate (10.0 mL × 2). The organic phases were combined and washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated and purified by HPLC to obtain white solid compound 35 (30.0 mg, 60.23 μmol, yield: 27.12%). MS (ESI) m / z = 497 [M+H] + , 1 H NMR(400MHz, DMSO-d6)δ=8.53(dd,J=5.6,9.2Hz,1H),8.18(s,1H),7.77(dd,J= 2.4,10.8Hz,1H),7.28(ddd,J=2.4,5.6,8.4Hz,1H),4.87-4.43(m,2H),2.76(br t,J=8.8Hz,1H),2.17-1.97(m,2H),1.89-1.17(m,18H),1.14-0.86(m,7H),0.58(s,3H).

[0281] Example 36

[0282] Synthesis route:

[0283] 1. Compound 36-1 (5 g, 39.1 mmol, 1.00 eq) was placed in a 40 mL sealed tube (R1) and the temperature was controlled at 25°C. N2H4·H2O (20.0 g, 391 mmol, 19.4 mL, 10.0 eq) was added to R1. R1 was stirred at 100°C for 12 hours. The mixture was concentrated to give the crude product, compound 36-2 (2.10 g, 17.05 mmol, yield: 43.51%), as a white solid.

[0284] 2. Water (12.0 mL) was poured into a 250 mL round bottom flask (R1) and the temperature was controlled at 25°C. Hydrochloric acid (12 M, 1.00 mL, 2.79 eq) was added to R1 and the temperature was controlled at 25°C. Compound 36-2 (530 mg, 4.30 mmol, 1.00 eq) was added to R1 at 25°C. Oxalic acid (955 mg, 6.46 mmol, 718 μL, 1.50 eq) was added to R1 at 25°C and the temperature was controlled at 25°C. R1 was stirred for 2 hours to obtain 36-3. The mixture was concentrated by freeze drying to obtain yellow solid compound 36-3 (910 mg). MS (ESI) m / z = 180 [M+H] + , 1H NMR (400MHz, DMSO-d6) δ = 13.52 (br s, 1H), 8.34 (br d, J = 6.4Hz, 1H), 7.70 (s, 1H), 7.52-7.00 (m, 2H), 2.59 (s, 3H).

[0285] 3. Compound 36-3 (1.00 g, 5.58 mmol, 1.00 eq) was placed in a 40 mL sealed tube (R1), DPPA (1.54 g, 5.58 mmol, 1.20 mL, 1.00 eq) was added to R1, TEA (1.13 g, 11.2 mmol, 1.55 mL, 2.00 eq) was added to R1, and toluene (5.00 mL) was added to R1. The mixture was stirred for 12 hours to give the crude product as a yellow solid compound 36-4 (30 mg, 170.29 μmol, yield: 3.05%). MS (ESI) m / z = 177 [M+H] + , 1 H NMR (400MHz, DMSO-d6) δ = 12.62 (br s, 1H), 8.73 (d, J = 6.6Hz, 1H), 8.45 (s, 1H), 8.33-8.17 (m, 2H), 2.74 (s, 3H).

[0286] 4. K2CO3 (156.90 mg, 1.14 mmol, 10 eq), M7 (45.11 mg, 113.52 μmol, 1 eq) and 36-4 (20 mg, 113.52 μmol, 1.00 eq) were added to THF (4.0 mL), and the system was stirred at 50 °C for 12 hours. The system was quenched with water (5 mL) and extracted with ethyl acetate (10.0 mL × 2). The organic phases were combined and washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated and purified by HPLC to obtain compound 36 (15 mg, 30.17 μmol, yield: 27.12%) as a white solid. MS (ESI) m / z = 493 [M+H]+ , 1 H NMR (400MHz, DMSO-d6) δ = 8.75 (d, J = 7.2Hz, 1H), 8.45 (s, 1H), 8.33-8.11 (m, 2H), 4.92-4.46 (m, 2H), 2.83-2.69 (m, 4H), 2.06 (br d,J=9.6Hz,2H),1.83-1.18(m,18H),1.14-0.85(m,7H),0.59(s,3H).

[0287] Example 37

[0288] Synthesis route:

[0289] 1. K2CO3 (195.43 mg, 1.41 mmol, 10.0 eq), M7 (56.19 mg, 141.41 μmol, 1.00 eq) and 37-1 (preparation method refers to the preparation method of 36-4) (30 mg, 141.41 μmol, 1.00 eq) were added to THF (4.0 mL), and the system was stirred at 50 ° C for 12 hours. The system was quenched with water (5 mL) and extracted with ethyl acetate (10.0 mL × 2). The organic phases were combined and washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated and purified by HPLC to obtain white solid compound 37 (26 mg, 49.18 μmol, yield: 34.78%), MS (ESI) m / z = 529 [M+H] + , 1 H NMR(400MHz, DMSO-d6)δ=8.66(d,J=5.6Hz,1H),8.30(d,J=2.0Hz,1H),8.10(d,1H),7.67(s,1H),6.66(s,1 H),4.76-4.28(m,2H),2.73-2.54(m,1H),2.14(s,2H),1.89-1.62(m,9H),1.54-1.20(m,16H),0.69(s,3H).

[0290] Example 38

[0291] Synthesis route:

[0292] 1. Sodium hydride (2.69 g, 67.3 mmol, 60.0% purity, 1.50 eq) was dissolved in 25.0 mL of dimethylformamide and added to a 250 mL three-necked flask (R1) protected by a nitrogen balloon. Benzyl alcohol (4.85 g, 44.9 mmol, 4.65 mL, 1.00 eq) was added to R1 at room temperature; the reaction solution was stirred at room temperature for half an hour. Compound 38-1 (10.0 g, 44.9 mmol, 1.00 eq) was dissolved in 30.0 mL of dimethylformamide and added to R1 at 0°C. R1 was stirred at 0°C for half an hour. Saturated ammonium chloride (50.0 mL) was added to R1 at 10°C to 20°C. The reaction solution was extracted with ethyl acetate (50.0 mL). The organic phase and the aqueous phase were separated. The aqueous phase was extracted twice with ethyl acetate (30.0 mL). The organic phase was washed with water (50.0 mL) 5 times, then with saturated brine (100 mL), and then dried over anhydrous sodium sulfate. Finally, the organic phase was filtered and concentrated to obtain a crude product. The crude product (petroleum ether: ethyl acetate = 10:1, R f =0.48) was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0-10%) to give compound 38-2 (11.9 g, 38.3 mmol, yield: 85.3%) as a colorless oil.

[0293] 2. Add compound 38-3 (989 mg, 4.82 mmol, 1.00 eq) to a 40.0 mL sealed tube (R1), add degassed dioxane (20.0 mL) to R1 at room temperature, add compound 38-2 (1.50 g, 4.82 mmol, 1.00 eq) to R1 at room temperature, add cesium carbonate (3.14 g, 9.64 mmol, 2.00 eq) to R1 at room temperature, add potassium iodide (640 mg, 3.86 mmol, 0.80 eq) to R1 at room temperature, and add 1,10-phenanthroline. (608 mg, 3.37 mmol, 0.70 eq) was added to R1 at room temperature, cuprous iodide (459 mg, 2.41 mmol, 0.50 eq) was added to R1 at room temperature, R1 was stirred at 100 ° C for 2 hours, the reaction solution in R1 was filtered, ethyl acetate (20.0 mL) was added to R1 at room temperature, the organic phase and the aqueous phase were separated, the aqueous phase was extracted twice with ethyl acetate (20.0 mL), the organic phase was washed with saturated brine (20.0 mL), and then dried over anhydrous sodium sulfate. Finally, the organic phase was filtered and concentrated to obtain a crude product. Crude product (petroleum ether / ethyl acetate = 3 / 1, R f =0.28) was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0-10%) to give compound 38-4 (952 mg, 2.45 mmol, yield: 17.0%) as a yellow solid.

[0294] 3. Compound 38-4 (950 mg, 2.45 mmol, 1.00 eq) was added to a 50.0 mL single-necked flask (R1) under a hydrogen balloon (15.0 Psi). Tetrahydrofuran (20.0 mL) was added to R1 at room temperature. Pd / C (26.0 mg, 24.5 μmol, 0.01 eq) was added to R1 at room temperature. R1 was stirred at 25°C for 10 hours and then at 40°C for 12 hours. Pd / C (52.1 mg, 48.9 μmol, 0.02 eq) was added to R1 at room temperature. R1 was stirred at 25°C for 1 hour. The reaction mixture was filtered, and the filtrate was concentrated to afford compound 38-5 (185 mg, 620 μmol, yield: 25.4%) as a yellow solid.

[0295] 4. Compound 38-5 (185 mg, 620 μmol, 3.00 eq) was added to a 40.0 mL AK bottle (R1). Nitromethane (17.2 g, 282 mmol, 15.3 mL, 1365 eq) was added to R1 at room temperature. 1-(Trifluoromethyl)-1,2-benzidoxyl-3(1H)-one (65.3 mg, 207 μmol, 1.00 eq) was added to R1 at room temperature. R1 was stirred at 100°C for 16 hours. The reaction solution was concentrated to obtain a crude product, which was separated by conventional reverse phase separation to afford compound 38-6 (25.0 mg, 60.1 μmol, 29.1% yield, yield: 88.0%) as a yellow solid.

[0296] 5. Compound 38-6 (25.0 mg, 68.3 μmol, 1.00 eq) was added to a 40.0 ml AK bottle (R1). Acetonitrile (10.0 mL) was added to R1 at room temperature. Cerium ammonium nitrate (112 mg, 205 μmol, 102 μL, 3.00 eq) was added to R1 at room temperature. R1 was stirred at 50°C for 12 hours. Cerium ammonium nitrate (112 mg, 205 μmol, 102 μL, 3.00 eq) was added to R1 at room temperature. R1 was stirred at 60°C for 10 hours. Water (20.0 mL) was added to R1 at room temperature. The reaction solution was extracted with ethyl acetate (20.0 mL). The organic phase and the aqueous phase were separated. The aqueous phase was extracted twice with ethyl acetate (10.0 mL). The organic phase was washed with saturated brine (20.0 mL) and dried over anhydrous sodium sulfate. Finally, the organic phase was filtered and concentrated to obtain compound 38-7 (20.0 mg, crude) as a yellow solid. MS (ESI) m / z = 247.0 [M+H] + .

[0297] 6. K2CO3 (127 mg, 918 μmol, 10.0 eq), M7 (36.5 mg, 91.8 μmol, 1.00 eq) and 38-7 (20.0 mg, 81.3 μmol, 8.85 eq-1 eq) were added to THF (4.0 mL), and the system was stirred at 50 ° C for 12 hours. The system was quenched with water (5 mL) and extracted with ethyl acetate (10.0 mL × 2). The organic phases were combined and washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated and purified by HPLC to obtain light yellow solid compound 38 (8.2 mg, 13.7 μmol, yield: 15%), MS (ESI) m / z = 563.1 [M+H] + , 1 H NMR (400MHz, CHLOROFORM-d) δ = 8.33 (d, J = 5.6Hz, 1H), 7.93 (dd, J = 1.6, 5.6Hz, 1H), 7.81-7.59 (m, 2H), 4.72-4.29 (m ,2H),2.74-2.51(m,1H),2.25-2.05(m,2H),1.87-1.75(m,5H),1.55-1.39(m,7H),1.36-1.07(m,13H),0.69(s,3H).

[0298] Example 39

[0299] Synthesis route:

[0300] 1. K2CO3 (483 mg, 3.49 mmol, 10.0 eq), M7 (139 mg, 349 μmol, 1.00 eq) and 39-1 (preparation method refers to the preparation method of 35-3) (100 mg, 384 μmol, 1.10 eq) were added to THF (4.0 mL), and the system was stirred at 50 ° C for 12 hours. The system was quenched with water (5 mL) and extracted with ethyl acetate (10.0 mL × 2). The organic phases were combined and washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated and purified by HPLC to obtain white solid compound 39 (136 mg, 222 μmol, yield: 63.1%), MS (ESI) m / z = 577.3 [M+H] + , 1H NMR (400MHz, DMSO-d6) δ=8.31-8.21(m,2H),7.64(dd,J=1.6,5.6Hz,1H),7.42(d,J=1.6Hz,1H),5.03(q,J=9.2Hz,2H),4.80-4.53(m,2H),2.77(br t,J=8.8Hz,1H),2.16-2.01(m,2H),1.78-1.56(m,8H),1.47-1.22(m,10H),1.13-1.00(m,7H),0.59(s,3H).

[0301] Example 40

[0302] Synthesis route:

[0303] 1. K2CO3 (509 mg, 3.68 mmol, 10.0 eq), M7 (146 mg, 368 μmol, 1.00 eq) and 40-1 (preparation method refers to the preparation method of 36-4) (70.0 mg, 368 μmol, 1.00 eq) were added to THF (4.0 mL), and the system was stirred at 50 ° C for 12 hours. The system was quenched with water (5 mL) and extracted with ethyl acetate (10.0 mL×2). The organic phases were combined and washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated and purified by HPLC to obtain a light yellow solid compound 40 (65.4 mg, 129.1 μmol, yield: 35.1%), MS (ESI) m / z=507.4 [M+H] + , 1 H NMR (400MHz, DMSO-d6) δ = 8.44 (s, 1H), 8.09 (s, 2H), 4.83-4.53 (m, 2H), 2.79 (br t, J = 8.8Hz, 1H), 2.70 (s, 6H), 2.06 (br d,J=9.6Hz,2H),1.81-0.94(m,25H),0.58(s,3H).

[0304] Example 41

[0305] Synthesis route:

[0306] 1. K2CO3 (634 mg, 4.59 mmol, 10.0 eq), M7 (182 mg, 459 μmol, 1.00 eq) and 41-1 (preparation method refers to the preparation method of 36-4) (100 mg, 505 μmol, 1.10 eq) were added to THF (4.0 mL), and the system was stirred at 50 ° C for 12 hours. The system was quenched with water (5 mL) and extracted with ethyl acetate (10.0 mL×2). The organic phases were combined and washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated and purified by HPLC to obtain light yellow solid compound 41 (153 mg, 185.2 μmol, yield: 62.3%), MS (ESI) m / z=497.2 [M+H] + , 1 H NMR (400MHz, DMSO-d6) δ=8.35(s,1H),7.55(s,2H),4.84-4.49(m,2H),4.25(s,1H),4.03(q,J=7.2Hz,1H),2.77(br t,J=8.8Hz,1H),2.06(br d,J=9.6Hz,2H),1.78-0.98(m,23H),0.59(s,3H).

[0307] Example 42

[0308] Synthesis route:

[0309] 1. Under nitrogen, add anhydrous tetrahydrofuran (15 mL) to a 100 mL three-necked flask (R1). Add compound 42-1 (1 g, 3.16 mmol, 1.00 eq) to R1 at 25°C. Add MeMgBr (3 M, 1.05 mL, 1.00 eq) to R1 at 0°C. Stir R1 at 0°C for 0.5 h. Add saturated ammonium chloride (5 mL) to the mixture and filter. Wash the filter cake with ethyl acetate (5 mL x 2). Separate the organic layer from the filtrate, wash with brine (10 mL), dry the organic phase over anhydrous sodium sulfate, and concentrate to obtain the crude product. The crude product was purified by HPLC to obtain white compound 42-2 (165 mg, 496.21 μmol, yield: 15.70%).

[0310] 2. Compound 42-2 (165 mg, 496 μmol, 1.00 eq) was added to a 40 mL sealed tube (R1) filled with nitrogen, MeOH (1.50 mL) was added to R1 at 25 °C, HBr (16.23 mg, 96.27 μmol, 10.89 μL, 0.194 eq) was added to R1 at 0 °C, Br2 (79.30 mg, 496.21 μmol, 25.58 μL, 1.00 eq) was added to R1 at 0 °C, R1 was stirred at 25 °C for 5 hours, saturated sodium bicarbonate (5 mL) was added to the mixture to quench it, and the mixture was extracted with ethyl acetate (5 mL×2). The combined organic layers were washed with brine (5 mL), dried over Na2SO4, filtered and concentrated to give the crude product. The crude product was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 100 / 1–1 / 1) to obtain white solid compound 42-3 (140 mg, 340.29 μmol, yield: 68.58%) 1 H NMR (400MHz, CDCl3) δ = 4.05-3.74 (m, 2H), 2.82 (t, J = 8.8Hz, 1H), 2.31-2.06 (m, 1H), 1.81-1.6 2(m,4H),1.61-1.48(m,5H),1.47-1.40(m,2H),1.39-1.28(m,4H),1.27-1.11(m,9H),0.96(br dd,J=5.2,12.0Hz,1H),0.82(dd,J=3.6,11.6Hz,1H),0.76(s,3H),0.64(s,3H).

[0311] 3. K2CO3 (470.30 mg, 3.40 mmol, 10.0 eq), 42-3 (140 mg, 340.29 μmol, 1.00 eq) and 42-3 (61.30 mg, 340.29 μmol, 1.00 eq) were added to THF (4.0 mL), and the system was stirred at 50 ° C for 12 hours. The system was quenched with water (5 mL) and extracted with ethyl acetate (10.0 mL × 2). The organic phases were combined and washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated and purified by HPLC to obtain a light yellow solid compound 42 (110 mg, 211.54 μmol, yield 62.16%), MS (ESI) m / z = 511 [M+H] + , 1H NMR (400MHz, CDCl3) δ = 8.23 ​​(d, J = 5.8Hz, 1H), 7.88 (d, J = 5.6Hz, 1H), 7.71-7.5 3(m,2H),4.69-4.33(m,2H),2.63(t,J=8.8Hz,1H),2.33-2.15(m,1H),2.11(br d,J=11.4 Hz,1H),1.81-1.63(m,4H),1.55-1.39(m,6H),1.37-1.13(m,12H),1.05-0.95(m,1H),0.83(br d,J=2.1Hz,1H),0.77(s,3H),0.68(s,3H).

[0312] Example 43

[0313] Synthesis route:

[0314] 1. Compound 43-1 (255 mg, 1.24 mmol, 1.20 eq) was added to a 40.0 mL AK bottle (R1). Dimethyl sulfoxide (5.00 mL) was added to R1 at room temperature. Potassium carbonate (286 mg, 2.07 mmol, 2.00 eq) was added to R1 at room temperature. Compound 43-2 (200 mg, 1.04 mmol, 1.00 eq) was added to R1 at room temperature and stirred at 80° C. for 2 hours. TLC (dichloromethane / methanol = 10 / 1) showed that compound 43-1 was completely reacted and new spots were generated. After filtering the reaction solution, the filtrate was concentrated to obtain a crude white solid. The crude product was subjected to conventional reverse phase separation to obtain compound 43-3 (100 mg, 315 μmol, yield 30.4%) as a white solid. 1 H NMR (400MHz, DMSO-d6) δ = 8.06 (s, 1H), 7.23 (d, J = 8.8Hz, 2H), 6.91 (d, J = 8.8Hz ,2H),4.71(s,2H),4.31(t,J=5.2Hz,2H),3.99(t,J=5.2Hz,2H),3.73(s,4H).

[0315] 2. Compound 43-3 (50.0 mg, 157 μmol, 1.00 eq) was added to a 40.0 ml AK bottle (R1). Acetonitrile (0.50 ml) was added to R1 at room temperature. Potassium carbonate (286 mg, 2.07 mmol, 2.00 eq) was added to R1 at room temperature. Cerium ammonium nitrate (259 mg, 473 μmol, 236 μL, 3.00 eq) was added to R1 at room temperature. R1 was stirred at room temperature for 4 hours and then at 60°C for 12 hours. The reaction solution was concentrated to obtain crude product 43-4. MS (ESI) m / z = 198.1 [M+H] + , and the crude product is directly used in the next step.

[0316] 3. K2CO3 (701 mg, 5.07 mmol, 10.0 eq), M7 (202 mg, 507 μmol, 1 eq) and 43-4 (100 mg, 507 μmol, 1.0 eq) were added to THF (4 mL), and the system was stirred at 50 ° C for 12 hours. The system was quenched with water (5 mL) and extracted with ethyl acetate (10.0 mL × 2). The organic phases were combined and washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 43 (160 mg, 309 μmol, yield: 60.9%) as a white solid. MS (ESI) m / z = 514.4 [M+H] + , 1 H NMR (400MHz, CDCl3) δ = 7.46 (s, 1H), 4.55-4.33 (dd, 2H), 4.27-4.25 (d, 2H), 4.14-4.09 (m, 2H), 2.58-2.63 (m, 1H), 2.32-1.09 (m, 27H), 0.67 (s, 3H).

[0317] Example 44

[0318] Synthesis route:

[0319] 1. K2CO3 (615 mg, 4.45 mmol, 10.0 eq), M7 (177 mg, 445 μmol, 1.0 eq) and 44-1 (100 mg, 489.81 μmol, 1.1 eq) (44-1 preparation method refers to 43-4) were added to THF (4 mL), and then the system was stirred at 50 ° C for 12 hours. The system was quenched with water (5 mL) and extracted with ethyl acetate (10.0 mL × 2). The organic phases were combined and washed with saturated brine (10 mL) and dried over anhydrous sodium sulfate. The reaction mixture was filtered and the organic phase was concentrated under reduced pressure to give a crude product. The crude product was purified by silica gel column chromatography (dichloromethane:methanol=0-10%) to give a yellow solid. The yellow solid was transferred to a 50.0 mL single-necked flask (R2). 10.0 mL of methyl tert-butyl ether was added to R2. R2 was stirred at room temperature for 2 hours. The mixture in R2 was filtered and the filtered solid was concentrated to give compound 44 (144 mg, 270 μmol, yield: 60.7%) as a yellow solid. MS (ESI) m / z=503.2 [M-OH+H] + , 1 H NMR (400MHz, DMSO-d6) δ = 8.28 (s, 1H), 8.16 (s, 1H), 8.05 (td, J = 2.4, 10.5Hz, 1H), 7.80-7.74 (m, 1H), 4.83-4.47 (m, 2H), 4.25 (br s, 1H), 2.77 (br t,J=8.8Hz,1H),2.12-2.01(m,2H),1.78-1.01(m,24H),0.59(s,3H).

[0320] Example 45

[0321] Synthesis route:

[0322] 1. Compound 45-1 (2.00 g, 16.1 mmol, 1.00 eq, HCl) was added to a 500 mL single-necked flask (R1). Toluene (25.0 mL) was added to R1 at room temperature. NaOH (6.42 g, 16.1 mmol, 1.00 eq) was added to R1 at room temperature. R1 was stirred at room temperature for 15 minutes. Benzyl chloroformate (2.63 g, 15.4 mmol, 2.20 mL, 0.96 eq) was dissolved in toluene (10.0 mL) and added to R1 at -15°C. NaOH (6.16 g, 15.4 mmol, 10.0% purity, 0.96 eq) was added to R1 at -15°C. R1 was stirred at room temperature for 2 hours. Chloroform (30.0 mL) was added to R1 at room temperature, and the organic and aqueous phases were separated. The aqueous phase was then extracted three times with chloroform (30.0 mL). The organic phase was washed with saturated brine (100 mL) and dried over anhydrous sodium sulfate. Finally, the organic phase was filtered and concentrated to obtain the crude product. The crude product (petroleum ether:ethyl acetate = 1:1, Rf = 0.49) was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 0-20%) to obtain compound 45-2 (1.46 g, 6.57 mmol, yield: 40.9%) as a colorless oil. MS (ESI) m / z = 223.1 [M+H] + , 1 H NMR (400MHz, CHLOROFORM-d) δ = 7.27 (s, 5H), 5.06 (s, 2H), 0.99 (s, 9H).

[0323] 2. Compound 45-2 (960 mg, 4.32 mmol, 1.00 eq) was added to a 100 mL single-necked flask (R1). Isopropyl alcohol (20.0 mL) was added to R1 at room temperature. Trimethylsilyl isocyanate (498 mg, 4.32 mmol, 574 μL, 1.00 eq) was added to R1 at room temperature. R1 was stirred at room temperature for 6 hours. Trimethylsilyl isocyanate (249 mg, 2.16 mmol, 287 μL, 0.50 eq) was added to R1 at room temperature. R1 was stirred at room temperature for 18 hours. The reaction solution was directly concentrated to obtain a crude product. The crude product (dichloromethane:methanol=10:1) was purified by silica gel column chromatography (methanol:dichloromethane=0-10%) to give compound 45-3 (550 mg, 2.07 mmol, yield: 48.0%) as a white solid. MS (ESI) m / z=265.9 [M+H] + , 1H NMR (400MHz, DMSO-d6) δ = 9.27 (s, 1H), 7.47-7.20 (m, 5H), 5.94-5.70 (m, 2H), 5.30-4.81 (m, 2H), 1.32-1.22 (m, 9H).

[0324] 3. Compound 45-3 (300 mg, 1.13 mmol, 1.00 eq) was added to a 50.0 mL single-necked flask (R1) under the protection of a hydrogen balloon (15.0 Psi). Ethanol (15.0 mL) was added to R1 at room temperature. Pd / C (12.0 mg, 11.3 μmol, 10.0% purity, 0.01 eq) was added to R1 at room temperature. R1 was stirred at room temperature for 12 hours. The reaction solution was filtered and the filtrate was concentrated to obtain compound 45-4 (145 mg, 1.11 mmol, yield: 97.8%) as a white solid. 1 H NMR (400MHz, DMSO-d6) δ = 6.19-5.62 (m, 2H), 4.35 (s, 2H), 1.31 (s, 9H).

[0325] 4. Compound 45-4 (95.0 mg, 724 μmol, 1.00 eq) was added to a 40.0 mL AK bottle (R1). Ethanol (5.00 mL) was added to R1 at room temperature. Trimethyl orthoformate (192 mg, 1.81 mmol, 198 μL, 2.50 eq) was added to R1 at room temperature. p-Toluenesulfonic acid (12.5 mg, 72.4 μmol, 0.10 eq) was added to R1 at room temperature. R1 was stirred at 60°C for 12 hours. The reaction solution was concentrated to obtain a crude product. The crude product (petroleum ether:ethyl acetate = 1:1) was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 0-100%) to obtain compound 45-5 (110 mg, crude) as a white solid. MS (ESI) m / z = 142.3 [M+H] + , 1 H NMR (400MHz, DMSO-d6) δ = 11.31 (br s, 1H), 7.69 (s, 1H), 1.44 (s, 9H).

[0326] 5. K2CO3 (890 mg, 6.44 mmol, 10.0 eq), M7 (256 mg, 644 μmol, 1.0 eq) and 45-5 (100 mg, 708 μmol, 1.1 eq) were added to THF (4 mL), and the system was stirred at 50 ° C for 12 hours. The system was quenched with water (5 mL) and extracted with ethyl acetate (10.0 mL × 2). The organic phases were combined and washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product. The product was purified by silica gel column chromatography (methanol: dichloromethane = 0-10%) to give compound 45 (210 mg, 456 μmol, yield: 70.8%) as a white solid. MS (ESI) m / z = 458.3 [M+H] + , 1 H NMR (400MHz, DMSO-d6) δ = 7.74 (s, 1H), 4.54-4.38 (m, 2H), 4.24 (s, 1H), 2.73-2.64 (m, 1H), 2.0 9-2.00(m,2H),1.75-1.59(m,7H),1.45(s,9H),1.39-1.23(m,9H),1.10(s,8H),0.56(s,3H).

[0327] Biological activity test

[0328] Experimental Example 1. Evaluation of the functional activity of synapses in vitro

[0329] 1.1 Experimental Materials

[0330] 1.2 Experimental methods

[0331] The α4β3δ-HEK-FlpIn-TRex stable cell line was cultured in DMEM / F12 medium supplemented with 10% FBS, supplemented with 10 μg / ml blasticidin, 100 μg / ml zeocin, 100 μg / ml hygromycin, and 0.2 μg / ml puromycin. The α1β2γ2-CHO-TRex stable cell line was cultured in DMEM / F12 medium supplemented with 10% FBS, supplemented with 10 μg / ml blasticidin, 100 μg / ml zeocin, 300 μg / ml hygromycin, and 1 μg / ml puromycin.

[0332] The day before the patch-clamp experiment, cells were seeded on poly-lysine-coated 12 mm coverslips and cultured in 35 mm culture dishes. Tetracycline (1 μg / ml) was supplemented to induce GABA receptor expression. The extracellular solution (mM) consisted of: 140% NaCl, 3% KCl, 1.5% MgCl₂, 2% CaCl₂, 10% HEPES, and 10% glucose. After thorough mixing, the pH was adjusted to 7.4 with NaOH, and the osmolarity was adjusted to 300–320 mOsm with sucrose. The solution was stored at 4°C. The electrode solution (mM) consisted of: 145% KCl, 1% MgCl₂, 5% EGTA, 10% HEPES, and 5% MgATP. After thorough mixing, the pH was adjusted to 7.3 with KOH, and the osmolarity was adjusted to 290–300 mOsm with sucrose. The solution was filtered through a 0.22 μM filter and ready for use.

[0333] This experiment mainly uses the whole-cell patch clamp recording method. The membrane potential is clamped at -60mV. GABA (~1μM) with an activation amplitude in the EC10-20 range is used to activate the receptor. The test compound is prepared in 0.1% DMSO. When GABA stimulation is given, it is first perfused for 30s. Finally, the positive allosteric regulatory effect of the test compound on α1β2γ2 or α4β3δ is detected.

[0334] The experimental results of each concentration are expressed as the multiple of the compound's increase in GABA-induced current. First, find the minimum concentration of the compound that can just enhance the GABA-induced current, and then gradually increase the test concentration by 3 times until the compound's activation effect reaches EC 80 The test concentrations should be at least 5, until the complete EC 50 Curve and EC 50 All experiments were repeated for 3 cells or more. Data processing was completed by GraphPad Prism software. The dose-dependent curve was fitted with the Hill equation, and the half-maximal activation concentration EC was finally obtained. 50 and E max The results are shown in Table 1.

[0335] Table 1 Functional activity results of compounds on intrasynaptic and extrasynaptic receptors

[0336] The results showed that compounds 1-45 all had good intra- and extra-synaptic functional activities.

[0337] Test Example 2: In vitro liver microsome stability evaluation

[0338] 2.1 Solution preparation

[0339] 1) Preparation of test sample working solution: dilute the test sample to 100 μM with acetonitrile;

[0340] 2) Preparation of liver microsome working solution: Dilute liver microsomes to 0.56 mg / mL with 100 mM phosphate buffer;

[0341] 3) Prepare the reduced nicotinamide adenine dinucleotide phosphate (NADPH) working solution: Weigh an appropriate amount of NADPH and dilute it to 20 mM with phosphate buffer. Then add an equal volume of 60 mM MgCl2 solution.

[0342] 4) Preparation of stop solution: dilute tolbutamide to 20 ng / mL with acetonitrile to serve as the stop solution containing the internal standard.

[0343] 2.2 Incubation process

[0344] 1) Prepare incubation anti-adsorption EP tubes and label them with species, test / control, time points (0, 5, 10, 20, 30, 60 min, Blank60, NCF60), etc.

[0345] 2) Add 2 μL of the test sample or control working solution diluted to 100 μM with acetonitrile and 178 μL of liver microsome working solution to each tube. Add 2 μL of acetonitrile to a Blank 60 tube instead of the test sample and pre-incubate in a 37°C water bath for approximately 10 minutes. Repeat for each sample in triplicate.

[0346] 3) After the preincubation, 20 μL of NADPH working solution was added to each tube except for 0 min and NCF60 to start the reaction. 20 μL of phosphate buffer (containing 30 mM MgCl2) was added to the NCF60 tube. The final concentration of the test or control in the incubation system was 1 μM, the final concentration of liver microsomes was 0.5 mg / mL, the final concentration of NADPH was 1 mM, and the final concentration of MgCl2 was 3 mM.

[0347] 4) For the 0 min sample, add 600 μL of stop solution first, then add NADPH working solution. After incubating each sample for the corresponding time, add 600 μL of stop solution to terminate the reaction;

[0348] 5) After terminating the reaction, each sample was vortexed for 30 seconds and then centrifuged at 13500 rpm for 10 minutes. 100 μL of the supernatant was taken and placed in an EP tube. 100 μL of Milli-Q water was added and vortexed to mix thoroughly before analysis by LC-MS / MS.

[0349] 6) Testosterone and dextromethorphan were used as positive controls under the same conditions to test the stability and reliability of the system.

[0350] 2.3 Data Analysis

[0351] The parameters of the half-life, liver microsomal intrinsic clearance, and liver intrinsic clearance of the test sample were calculated based on the remaining percentage of the test sample. The results are shown in Table 2.

[0352] Table 2 Half-life, liver microsomal intrinsic clearance, liver intrinsic clearance of the compounds

[0353] As shown in the table above, most of the compounds provided by the present disclosure have good stability in rat and human liver microsomes, indicating that they have good metabolic stability.

[0354] Test Example 3: Loss of righting reflex test in SD rats injected with compound 41

[0355] 3.1 Purpose of the test

[0356] The loss of righting reflex threshold of SD rats injected with compound 41 was tested to evaluate the sedative effect and therapeutic safety window of the compound.

[0357] 3.2 Experimental process

[0358] Male SD rats weighing 180-200g were acclimated to the animal facility for 7 days and randomly divided into groups based on body weight 1 day before the experiment. They were fasted for half a day before the experiment, but were not allowed to drink water. Compound 41 was administered in a 0.8-fold dose gradient, with the doses set at 23.5mg / kg, 18.8mg / kg, 15mg / kg, 12mg / kg, and 9.6mg / kg. The rats were observed for loss of righting reflex within 4 hours after intraperitoneal injection of compound 41. Criteria for determining loss of righting reflex in rats: After injection of compound 41, if the rat in the supine position failed to turn over within 30 seconds, it was considered positive for loss of righting reflex; otherwise, it was considered negative for loss of righting reflex.

[0359] 3.3 Test results

[0360] The test results showed that the incidence of righting reflex in rats was 80%, 50%, 30%, 0%, and 0% at doses of 23.5 mg / kg, 18.8 mg / kg, 15 mg / kg, 12 mg / kg, and 9.6 mg / kg, respectively. Under the experimental conditions, the threshold dose of compound 41 for the disappearance of the righting reflex in SD rats after intraperitoneal injection was 12 mg / kg, indicating that compound 41 has a wide therapeutic safety window.

[0361] Test Example 4: Loss of righting reflex test in SD rats after oral administration of compound 41

[0362] 4.1 Test Purpose

[0363] The loss of righting reflex threshold of SD rats was tested after oral administration of compound 41 to evaluate the sedative effect and therapeutic safety window of compound 41.

[0364] 4.2 Test methods

[0365] Male SD rats weighing 180-200 g were acclimated to the animal room facility for 7 days and randomly divided into groups according to body weight one day before the experiment. The rats were fasted overnight before the experiment, but were not allowed to drink water. Compound 41 was designed with a 0.8-fold dose gradient, with the dosage set at 39 mg / kg, 31.25 mg / kg, 25 mg / kg, 20 mg / kg, and 16 mg / kg, with 10 rats per group. The rats were observed for loss of righting reflex within 4 hours after oral administration. The criterion for loss of righting reflex in rats: After administration of the test compound, if the rat in the supine position fails to turn over within 30 seconds, it is considered to be positive for loss of righting reflex; otherwise, it is considered to be negative for loss of righting reflex.

[0366] 4.3 Test results

[0367] The results showed that the incidence of righting reflex in rats was 100%, 90%, 50%, 0%, and 0% at doses of 39 mg / kg, 31.25 mg / kg, 25 mg / kg, 20 mg / kg, and 16 mg / kg, respectively. Under these experimental conditions, the threshold dose for loss of righting reflex in SD rats administered with compound 41 by oral gavage was 20 mg / kg. The threshold for loss of righting reflex in rats administered with compound 41 by oral gavage (20 mg / kg) was 5.7 times the effective dose for anticonvulsant effects (3.5 mg / kg), indicating a wide therapeutic safety window.

[0368] Experimental Example 5: Pharmacokinetic Study of Compound 41 in CD-1 Mice

[0369] 4.1 Test Animals and Solvents

[0370] CD-1 mice, male, weighing approximately 25 g, were randomly divided into groups, 3 mice per group.

[0371] DMSO: 30% SBECD (10%: 90%)

[0372] 4.2 Test methods

[0373] The intravenous (IV) dose was 1 mg / kg, and the oral (IG) dose was 5 mg / kg. Animals were fasted for 12 hours prior to administration, with free access to water. They were fed uniformly 3 hours after administration. Approximately 0.15 mL of blood was collected from heparinized EP tubes at 5 minutes (intravenous), 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 8 hours, 12 hours, and 24 hours after administration. The blood was centrifuged at 13,500 rpm for 10 minutes to separate the plasma. Mouse brain tissue was then collected 30 minutes, 2 hours, and 8 hours after cardiac perfusion. After pretreatment, the samples were analyzed by LC-MS / MS to determine the concentrations of the analyte in plasma and brain, and pharmacokinetic parameters were calculated.

[0374] 4.3 Test results

[0375] Table 3 Pharmacokinetic parameters of compound 41 after intravenous (1 mg / kg) and oral gavage (5 mg / kg) administration in CD-1 mice

[0376] Table 4 Brain concentration of CD-1 mice after oral administration of compound 41 (5 mg / kg)

[0377] The data in Table 3 show that after intravenous and oral administration of compound 41 to CD-1 mice, there was a high plasma exposure (AUC), a long half-life, and an absolute bioavailability of up to 109% by oral administration, indicating that compound 41 has good metabolic stability in vivo and a high degree of in vivo absorption. The data in Table 4 show that compound 41 has a strong ability to enter the brain, a high brain exposure, and a high brain concentration.

[0378] Test Example 6: Pharmacokinetic study of compound 41 in SD rats

[0379] 5.1 Test Animals and Solvents

[0380] SD rats, male, weighing about 250 g, were randomly divided into groups, 3 in each group.

[0381] DMSO: 30% SBECD (10%: 90%)

[0382] 5.2 Test methods

[0383] The intravenous dose was 6.1 μmol / kg, and the oral dose was 24.4 μmol / kg. Animals were fasted for 12 hours before administration, with free access to water. They were fed uniformly 3 hours after administration. Approximately 0.3 mL of blood was collected from heparinized EP tubes at 5 minutes (intravenous), 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 12 hours, and 24 hours after administration. The blood was centrifuged at 13,500 rpm for 10 minutes to separate the plasma. Brain tissue was collected from rats at 30 minutes, 2 hours, and 6 hours after cardiac perfusion. After pretreatment, LC-MS / MS analysis was performed to determine the concentrations of the analyte in plasma and brain, and pharmacokinetic parameters were calculated.

[0384] 5.3 Test results

[0385] Table 5 Pharmacokinetic parameters of compound 41 after intravenous (6.1 μmol / kg) and oral gavage (24.4 μmol / kg) administration to SD rats

[0386] Table 6 Brain concentration of SD rats after oral administration of compound 41 (24.4 μmol / kg)

[0387] The data in Table 5 show that after intravenous and oral administration of compound 41 to SD rats, there was a high plasma exposure (AUC), a long half-life, and an absolute bioavailability of 84% by oral administration, indicating that compound 41 has good metabolic stability in vivo and a high degree of absorption in vivo. The data in Table 5 show that compound 41 has a strong ability to enter the brain, a high brain exposure, and a high brain concentration.

[0388] Test Example 7: Evaluation of the anticonvulsant effect of compound 41 in SD rats

[0389] 6.1 Test Purpose

[0390] SD rats were intraperitoneally injected with 50 mg / kg pentylenetetrazol (PTZ) to establish an epileptic convulsion animal model in SD rats, and the anticonvulsant effect of compound 41 was detected.

[0391] 6.2 Test method

[0392] Male Sprague-Dawley rats weighing 300 ± 10 g were acclimated to the animal facility for 7 days and randomly divided into groups based on body weight one day before dosing. They were fasted for half a day prior to the experiment, but were not allowed to drink water. For testing, the rats were orally administered 3.5 mg / kg of compound 41. Two hours after the oral administration, 50 mg / kg of PTZ solution was injected intraperitoneally. Seizure behavior was observed within one hour after PTZ induction. Latency to clonic and tonic seizures was measured.

[0393] 6.3 Test results

[0394] The behavioral raw data were finally expressed as mean ± standard error (Mean ± SEM) and statistically analyzed using One-way ANOVA Dunnett post hoc. P < 0.05 indicated a significant difference, P < 0.01 indicated a very significant difference, and P < 0.001 indicated an extremely significant difference.

[0395] The results of behavioral observations on epileptic seizures showed that within 1 hour after intraperitoneal injection of 50 mg / kg PTZ to induce epileptic seizures, the latency of clonic seizures in the drug-treated group (2764.6±1330.9s) was significantly higher than that in the solvent control group (114.5±36.9s) (P<0.001); the latency of tonic-clonic seizures in the drug-treated group (3600±0s) was significantly higher than that in the solvent control group (115.8±37.1s) (P<0.001).

Claims

1. A compound represented by formula (I), or a pharmaceutically acceptable salt thereof, in, (1) X is independently selected from C atoms, Y is independently selected from N atoms, or X is independently selected from N atoms, Y is independently selected from C atoms, or X and Y are both selected from C atoms; R1 is selected from H, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 3-6 Cycloalkyl, C 3-6 Cycloalkyl C 1-3 Alkyl, C 1-6 Alkoxy C 1-3 Alkyl, halogenated C 1-6 Alkoxy C 1-3 alkyl, 6-10 membered aryl, or 5-10 membered heteroaryl, wherein the 6-10 membered aryl and 5-10 membered heteroaryl may be optionally substituted with one or more halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 substituted by alkoxy, -(C=O)NH2, -NH2, or cyano; R2 is selected from H, halogen, C 1-6 Alkyl, or C 1-6 Alkoxy C 1-3 alkyl; R3 is selected from H, C 1-6 Alkyl, or C 1-6 Alkoxy C 1-3 alkyl; or (2) X and Y are both selected from C atoms, and X and Y together with the atoms to which they are attached form a ring A; The ring A is selected from wherein A1, A2, A3, and A4 are each independently selected from CR4 or N atom; R1 is selected from H, halogenated C 1-6 Alkyl, C 3-6 Cycloalkyl, C 3-6 Cycloalkyl C 1-3 Alkyl, C 1-6 Alkoxy C 1-3 Alkyl, halogenated C 1-6 Alkoxy C 1-3 alkyl, 6-10 membered aryl, or 5-10 membered heteroaryl, wherein the 6-10 membered aryl and 5-10 membered heteroaryl may be optionally substituted with one or more halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 substituted by alkoxy, -(C=O)NH2, -NH2, or cyano; R2 is selected from H, halogen, C 1-6 Alkyl, or C 1-6 Alkoxy C 1-3 alkyl; R3 is selected from H, C 1-6 Alkyl, or C 1-6 Alkoxy C 1-3 alkyl; Each R4 is independently selected from H, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Alkoxy C 1- 3 alkyl, or halogenated C 1-6 Alkoxy C 1-3 alkyl.

2. The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein the compound or pharmaceutically acceptable salt thereof has the structure of Formula (IA) or Formula (IB): in, X, Y, ring A, R1, R2, R3, R4, A1, A2, A3 and A4 are as defined in claim 1.

3. The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein the compound or pharmaceutically acceptable salt thereof has the structure of Formula (IIA), (IIB) or (IIC): in, R1, R2 and R3 are as defined in claim 1.

4. The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein the compound or pharmaceutically acceptable salt thereof has the structure of Formula (IIA-1), (IIA-2), (IIB-1), (IIB-2), (IIC-1) or (IIC-2): in, R1, R2 and R3 are as defined in claim 1.

5. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, in, R1 is selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl, fluoromethyl, chloromethyl, difluoromethyl, dichloromethyl, trifluoromethyl, trichloromethyl, 2,2-difluoroethyl, 2,2-dichloroethyl, 2,2,2-trifluoroethyl, 2,2,2-trichloroethyl, pentafluoroethyl, pentachloroethyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclobutylethyl, cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl yl, cyclohexylethyl, methoxymethyl, ethoxymethyl, methoxyethyl, ethoxyethyl, trifluoromethoxymethyl, trifluoromethoxyethyl, phenyl, naphthyl, pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, benzopyrazolyl, isoindolyl, indazolyl, benzotriazolyl, benzothienyl, isobenzothienyl, benzofuranyl, benzoisofuranyl, benzodioxolyl , or benzimidazolyl; the phenyl, naphthyl, pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, benzopyrazolyl, isoindolyl, indazolyl, benzotriazolyl, benzothienyl, isobenzothienyl, benzofuranyl, benzisofuranyl, benzodioxolyl, or benzimidazolyl is optionally replaced by one or more F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl substituted with 1,2-difluoroethyl, 2,2-dichloroethyl, 2,2,2-trifluoroethyl, 2,2,2-trichloroethyl, methoxy, ethoxy, n-propoxy, isopropoxy, trifluoromethoxy, trichloromethoxy, 2,2-difluoroethoxy, 2,2-dichloroethoxy, 2,2,2-trifluoroethoxy, 2,2,2-trichloroethoxy, -(C=O)NH2, -NH2, or cyano; R2 is selected from H, F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl, methoxymethyl, or ethoxymethyl; R3 is selected from H, methyl, ethyl, n-propyl, isopropyl, methoxymethyl, or ethoxymethyl.

6. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, in, R1 is selected from H, methyl, ethyl, tert-butyl, cyclopropylmethyl, 2,2,2-trifluoroethyl, cyclopentyl, cyclohexyl, methoxymethyl, ethoxymethyl, methoxyethyl, ethoxyethyl, trifluoromethoxymethyl, trifluoromethoxyethyl, described and optionally substituted with one or more F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl, fluoromethyl, chloromethyl, difluoromethyl, dichloromethyl, trifluoromethyl, trichloromethyl, 2,2-difluoroethyl, 2,2-dichloroethyl, 2,2,2-trifluoroethyl, 2,2,2-trichloroethyl, methoxy, ethoxy, n-propoxy, isopropoxy, fluoromethoxy, chloromethoxy, difluoromethoxy, dichloromethoxy, trifluoromethoxy, trichloromethoxy, 2,2-difluoroethoxy, 2,2-dichloroethoxy, 2,2,2-trifluoroethoxy, 2,2,2-trichloroethoxy, -(C=O)NH2, -NH2, or cyano.

7. The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, in, R1 is selected from R 4a 、R 4b 、R 4c 、R 4d 、R 4e each independently selected from H, F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl, fluoromethyl, chloromethyl, difluoromethyl, dichloromethyl, trifluoromethyl, trichloromethyl, 2,2-difluoroethyl, 2,2-dichloroethyl, 2,2,2-trifluoroethyl, 2,2,2-trichloroethyl, methoxy, ethoxy, n-propoxy, isopropoxy, fluoromethoxy, chloromethoxy, difluoromethoxy, dichloromethoxy, trifluoromethoxy, trichloromethoxy, 2,2-difluoroethoxy, 2,2-dichloroethoxy, 2,2,2-trifluoroethoxy, 2,2,2-trichloroethoxy, -(C=O)NH2, -NH2, or cyano; R2 is H; R3 is methyl.

8. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, selected from:

9. A pharmaceutical composition comprising the compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

10. Use of the compound according to any one of claims 1 to 8, a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 9 in the preparation of a GABAA receptor modulator.

11. Use of the compound according to any one of claims 1 to 8, a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 9 in the preparation of a medicament for treating CNS-related diseases.

12. The use according to claim 11, wherein the CNS-related diseases include: Sleep disorders, mood disorders, mania, dysthymic disorder, bipolar disorder, anxiety disorders, stress, post-traumatic stress disorder (PTSD), obsessive-compulsive disorder, schizophrenia spectrum disorder, convulsive disorders, memory and / or cognitive impairment, dementia, movement disorders, personality disorders, autism, autism spectrum disorder (ASD), pain, traumatic brain injury (TBI), vascular disease, substance abuse disorders and / or withdrawal syndrome, and tinnitus.

13. The use according to claim 12, wherein the CNS-related disease comprises depression.

14. The use according to claim 13, wherein the depression comprises mild depression, major depressive disorder, persistent depressive disorder, psychotic depression, postpartum depression or seasonal affective disorder.

15. The use according to claim 12, wherein the CNS-related diseases include insomnia, bipolar I disorder, bipolar II disorder, generalized anxiety disorder (GAD), social anxiety disorder, social anxiety disorder, schizophrenia, schizoaffective disorder, attention disorders, Alzheimer's dementia, dementia with Lewy bodies, vascular dementia, Huntington's disease, Parkinson's disease, essential tremor, antisocial personality disorder, obsessive-compulsive personality disorder, autism, monogenic autism, synaptophathy, Rett syndrome, fragile X syndrome, Angelman syndrome, neuropathic pain, injury-related pain syndrome, acute pain, chronic pain, stroke, ischemia, vascular malformation, and addiction to opioids, cocaine, and / or alcohol.

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