19-Nor C3,3-disubstituted C21-azaspiro-substituted steroids and methods of using the same

Abstract

19-Nor C3,3-disubstituted C21-azaspiro-substituted steroids of the present invention and methods of using the same. In particular, the present invention relates to compounds represented by general formula (I), methods for preparing the same, pharmaceutical compositions containing the compounds, and prevention and / or treatment of various CNS-related disorders of the compounds of the present invention as GABA A R positive allosteric regulators, for prevention and / or treatment in various CNS-related disorders, such as treatment of sleep disorders, mood disorders, insomnia, anxiety, depression, traumatic brain injury (TBI), stress and epilepsy. Among them, each substituent in general formula (I) has the same definition as in the specification. TIFF2025519406000134.tif35170

Description

Technical Field

[0001] The present disclosure relates to 19-nor-C3,3-disubstituted C21-azacyclo-substituted steroids and methods for their preparation, and their use in the field of GABA A receptor-related diseases. Specifically, it relates to the compounds of formula (I) and their pharmaceutically acceptable salts.

Background Art

[0002] Depression is a common type of mental disorder, with continuous and long-term mood depression as its main clinical feature. It is the most important type of modern people's mental disorders. Although it is not uncommon to experience feelings of sadness from time to time, in the majority of people, these emotions are usually short-lived and disappear after a few days. When it appears as a depressive disorder, the patient's symptoms interfere with daily life and normal functions. Depression is the main cause of the disorder and can cause multiple symptoms. Not only is there a mood drop, but the disease condition can also lead to changes in endocrine and immune functions later, thus increasing the susceptibility to physical diseases. In the worst case, depression can lead to suicide. Depression can be classified into major depressive disorder (MDD), persistent depressive disorder (also called 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 it is predicted that this number will increase to 248.9 million prevalent cases at a growth rate of 11.6% by 2027. In 2018, it is estimated that there were the most prevalent cases in Asia (130.7 million cases) and the fewest in the Oceania region (1.5 million cases).

[0004] PPD is one of the most common neurobiological complications of childbirth, occurring in 13% of women postpartum, and in some women it may begin as early as the late pregnancy. About 5-10% of severe cases are the main cause of maternal death. Therefore, considering the potential destructive consequences of PPD not only for the patient but also for her child and family, the unmet needs in this area are particularly high.

[0005] Neuroactive steroids (NAS) are the most effective regulators of neuronal excitability, and neurosteroids mainly affect the function of the central nervous system (CNS) through allosteric regulation of the GABA A receptor (GABA A R). It has been proven that the GABA receptor, which contains GABA A , GABA B , GABA C , usually correlates with mood disorders, and the GABA A and GABA B receptors. The GABA A receptor is a pentameric chloride ion channel receptor, mainly composed of two α subunits (α1-α6), two β subunits (β1-β3) and one additional subunit (γ1-γ3, δ, ε, π or θ). After the GABA receptor on the neuronal cell membrane binds to GABA, it causes the opening of the chloride ion channel (chloride ions flow into the membrane), hyperpolarizes the neuronal cell membrane, and causes neuronal inhibition. The unique subunit composition determines the biological, physical and pharmacological characteristics of the channel, as well as its location at synaptic or extrasynaptic sites. A decrease in GABA levels, a decrease in GABA synthetase expression, a change in GABA A R subunit expression, and a decrease in the number of GABAergic interneurons are observed in the plasma, cerebrospinal fluid or cortical tissue of MDD patients. It has been confirmed that perinatal GABA levels are relatively low in women at risk of developing PPD, and GABA levels are negatively correlated with the depression score. GABA A R positive allosteric regulators are GABA of GABA A R positive allosteric regulators are GABA of GABA AIt can promote the binding to the receptor and enhance the inhibitory effect of GABA.

[0006] 19-Nor C3,3-disubstituted C21-azaspiro-substituted steroids, as improved steroids, have a relatively good effect of regulating cerebral excitation and can be used for the prevention and treatment of depression and other CNS-related diseases. The compounds, compositions and methods described herein relate to this purpose.

Summary of the Invention

[0007] In one embodiment of the present disclosure, there is provided a compound represented by formula (I) and a pharmaceutically acceptable salt thereof. TIFF2025519406000002.tif35170 Among them, (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 simultaneously selected from C atoms. R1 is H, C 1-6 alkyl group, halogenated C 1-6 alkyl group, C 3-6 cycloalkyl group, C 3-6 cycloalkyl C 1-3 alkyl group, C 1-6 alkoxy C 1-3 alkyl group, halogenated C 1-6 alkoxy C 1-3 alkyl group, 6- to 10-membered aryl group, or 5- to 10-membered heteroaryl group, and the above 6- to 10-membered aryl group and 5- to 10-membered heteroaryl group are optionally substituted by one or more halogens, C 1-6 alkyl group, halogenated C 1-6 alkyl group, C 1-6 alkoxy group, halogenated C 1-6 alkoxy group, -(C=O)NH2, -NH2, or cyano group. R2 is H, halogen, C 1-6 alkyl group, or C 1-6 alkoxy C 1-3 alkyl group. R3 is H, C 1-6an alkyl group, or C 1-6 an alkoxy C 1-3 selected from alkyl groups.

[0008] Or (2) X and Y are simultaneously selected from C atoms, and X and Y, together with the atoms to which they are attached, form ring A, said ring A is selected from TIFF2025519406000003.tif17170, wherein A1, A2, A3, A4 are each independently selected from CR4 or an N atom, R1 is H, halogenated C 1-6 an alkyl group, C 3-6 a cycloalkyl group, C 3-6 cycloalkyl C 1-3 an alkyl group, C 1-6 an alkoxy C 1-3 an alkyl group, halogenated C 1-6 an alkoxy C 1-3 an alkyl group, a 6- to 10-membered aryl group, or a 5- to 10-membered heteroaryl group, and said 6- to 10-membered aryl group and 5- to 10-membered heteroaryl group may optionally be substituted by one or more halogens, C 1-6 an alkyl group, halogenated C 1-6 an alkyl group, C 1-6 an alkoxy group, halogenated C 1-6 an alkoxy group, -(C=O)NH2, -NH2, or a cyano group. R2 is H, a halogen, C 1-6 an alkyl group, or C 1-6 an alkoxy C 1-3 an alkyl group. R3 is H, C 1-6 an alkyl group, or C 1-6 an alkoxy C 1-3 an alkyl group. Each R4 is independently H, a halogen, C 1-6 an alkyl group, C 1-6 an alkoxy group, C 1-6 a halogenated alkoxy group, C 1-6 an alkoxy C 1-3 an alkyl group, or halogenated C1-6 alkoxy C 1-3 is selected from an alkyl group.

[0009] In another embodiment of the present disclosure, there is provided a compound represented by formula (IA) or (IB), or a pharmaceutically acceptable salt thereof, TIFF2025519406000004.tif35170 among which, (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 simultaneously selected from C atoms, R1 is H, C 1-6 an alkyl group, halogenated C 1-6 an alkyl group, C 3-6 a cycloalkyl group, C 3-6 cycloalkyl C 1-3 an alkyl group, C 1-6 alkoxy C 1-3 an alkyl group, halogenated C 1-6 alkoxy C 1-3 an alkyl group, a 6- to 10-membered aryl group, or a 5- to 10-membered heteroaryl group, and the 6- to 10-membered aryl group and the 5- to 10-membered heteroaryl group are optionally substituted by one or more halogens, C 1-6 an alkyl group, halogenated C 1-6 an alkyl group, C 1-6 an alkoxy group, halogenated C 1-6 an alkoxy group, -(C=O)NH2, -NH2, or a cyano group. R2 is H, a halogen, C 1-6 an alkyl group, or C 1-6 alkoxy C 1-3 is selected from an alkyl group, R3 is H, C 1-6 an alkyl group, or C 1-6 alkoxy C 1-3 is selected from an alkyl group.

[0010] or (2) X and Y are simultaneously selected from C atoms, and X and Y together with the atoms to which they are attached form ring A, wherein ring A is Selected from 17170 of TIFF2025519406000005.tif, Among them, A1, A2, A3, and A4 are each independently selected from CR4 or an N atom, R1 is H, halogenated C 1-6 alkyl group, C 3-6 cycloalkyl group, C 3-6 cycloalkyl C 1-3 alkyl group, C 1-6 alkoxy C 1-3 alkyl group, halogenated C 1-6 alkoxy C 1-3 alkyl group, 6- to 10-membered aryl group, or 5- to 10-membered heteroaryl group, and the 6- to 10-membered aryl group and 5- to 10-membered heteroaryl group are optionally substituted by one or more halogens, C 1-6 alkyl group, halogenated C 1-6 alkyl group, C 1-6 alkoxy group, halogenated C 1-6 alkoxy group, -(C=O)NH2, -NH2, or a cyano group may be substituted, R2 is H, halogen, C 1-6 alkyl group, or C 1-6 alkoxy C 1-3 alkyl group, R3 is H, C 1-6 alkyl group, or C 1-6 alkoxy C 1-3 alkyl group, Each R4 is independently H, halogen, C 1-6 alkyl group, C 1-6 alkoxy group, C 1-6 halogenated alkoxy group, C 1-6 alkoxy C 1-3 alkyl group, or halogenated C 1-6 alkoxy C 1-3 alkyl group.

[0011] 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, (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 selected from C atoms, R1 is H, C 1-3 alkyl group, halogenated C 1-3 alkyl group, C 3-6 cycloalkyl group, C 3-6 cycloalkyl C 1-3 alkyl group, C 1-6 alkoxy C 1-3 alkyl group, halogenated C 1-6 alkoxy C 1-3 alkyl group, 6- to 10-membered aryl group, or 5- to 10-membered heteroaryl group, and the above 6- to 10-membered aryl group and 5- to 10-membered heteroaryl group are optionally substituted by one or more halogens, C 1-3 alkyl group, halogenated C 1-3 alkyl group, C 1-3 alkoxy group, halogenated C 1-3 alkoxy group, -(C=O)NH2, -NH2, or cyano group may be substituted, R1 is more preferably H, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, an s-butyl group, a t-butyl group, a fluoromethyl group, a chloromethyl group, a difluoromethyl group, a dichloromethyl group, a trifluoromethyl group, a trichloromethyl group, a 2,2-difluoroethyl group, a 2,2-dichloroethyl group, a 2,2,2-trifluoroethyl group, a 2,2,2-trichloroethyl group, a pentafluoroethyl group, a pentachloroethyl group, a cyclopentyl group, a cyclohexyl group, a cyclopropylmethyl group, a cyclopropylethyl group, a cyclobutylmethyl group, a cyclobutylethyl group, a cyclopentylmethyl group, a cyclopentylethyl group, a cyclohexylmethyl group, a cyclohexylethyl group, a methoxymethyl group, an ethoxymethyl group, a methoxyethyl group, an ethoxyethyl group, a trifluoromethoxymethyl group, a trifluoromethoxyethyl group, a phenyl group, a naphthyl group, a pyrrolyl group, a furanyl group, a thienyl group, an imidazolyl group, a pyrazolyl group, an oxazolyl group, an isoxazolyl group, a thiazolyl group, an isothiazolyl group, a pyridyl group, a pyridazinyl group, a pyrimidinyl group, a pyrazinyl group, an indolyl group, a benzopyrazolyl group, an isoindolyl group, an indazolyl group, a benzotriazolyl group, a benzothienyl group, an isobenzothienyl group, a benzofuranyl group, a benzoisofuranyl group, a benzodioxole group, or a benzimidazolyl group, and the phenyl group, naphthyl group, pyrrolyl group, furanyl group, thienyl group, imidazolyl group, pyrazolyl group, oxazolyl group, isoxazolyl group, thiazolyl group, isothiazolyl group, pyridyl group, pyridazinyl group, pyrimidinyl group, pyrazinyl group, indolyl group, benzopyrazolyl group, isoindolyl group, indazolyl group, benzotriazolyl group, benzothienyl group, isobenzothienyl group, benzofuranyl group, benzoisofuranyl group, benzodioxole group, or benzimidazolyl group is optionally substituted with one or more F, Cl, Br, I, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, a fluoromethyl group, a chloromethyl group, a difluoromethyl group, a dichloromethyl group, a trifluoromethyl group, a trichloromethyl group, a 2,2-difluoroethyl group, a 2,2-dichloroethyl group, a 2,2,2-trifluoroethyl group, 2,2,substituted by a 2-trichloroethyl group, a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group, a trifluoromethoxy group, a trichloromethoxy group, a 2,2-difluoroethoxy group, a 2,2-dichloroethoxy group, a 2,2,2-trifluoroethoxy group, a 2,2,2-trichloroethoxy group, -(C=O)NH2, -NH2, or a cyano group, R1 is more preferably selected from a methyl group, an ethyl group, a cyclopentyl group, a cyclohexyl group, a cyclopropylmethyl group, a 2,2,2-trifluoroethyl group, a methoxyethyl group, a trifluoromethoxyethyl group, a phenyl group, an oxazolyl group, a thiazolyl group, a pyridyl group, a benzodioxole group, a benzopyrazolyl group, or an indolyl group, and the phenyl group, oxazolyl group, thiazolyl group, pyridyl group, benzodioxole group, benzopyrazolyl group, indolyl group are optionally substituted by one or more F, Cl, Br, I, a methyl group, an ethyl group, a difluoromethyl group, a trichloromethyl group, a methoxy group, a trifluoromethoxy group, a 2,2,2-trifluoroethoxy group, -(C=O)NH2, -NH2, or a cyano group, R2 is selected from H, F, Cl, Br, I, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, a methoxymethyl group, or an ethoxymethyl group, R3 is selected from H, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, a methoxymethyl group, or an ethoxymethyl group, or (2) X and Y are both C atoms, and X and Y, together with the atoms to which they are attached, form ring A, The above ring A is selected from TIFF2025519406000006.tif39170, R1 is H, halogenated C 1-3 alkyl group, C 3-6 cycloalkyl C 1-3 alkyl group, C 1-6 alkoxy C 1-3 alkyl group, halogenated C 1-6 alkoxy C 1-3Selected from an alkyl group, a 6- to 10-membered aryl group, or a 5- to 10-membered heteroaryl group, and the 6- to 10-membered aryl group and the 5- to 10-membered heteroaryl group are optionally substituted with one or more halogens, C 1-3 alkyl group, halogenated C 1-3 alkyl group, C 1-3 alkoxy group, halogenated C 1-3 may be substituted by an alkoxy group, -(C=O)NH2, -NH2, or a cyano group, R1 is more preferably H, fluoromethyl group, chloromethyl group, difluoromethyl group, dichloromethyl group, trifluoromethyl group, trichloromethyl group, 2,2-difluoroethyl group, 2,2-dichloroethyl group, 2,2,2-trifluoroethyl group, 2,2,2-trichloroethyl group, pentafluoroethyl group, pentachloroethyl group, cyclopropylmethyl group, cyclopropylethyl group, cyclobutylmethyl group, cyclobutylethyl group, cyclopentylmethyl group, cyclopentylethyl group, cyclohexylmethyl group, cyclohexylethyl group, methoxymethyl group, ethoxymethyl group, methoxyethyl group, ethoxyethyl group, trifluoromethoxymethyl group, trifluoromethoxyethyl group, phenyl group, naphthyl group, pyrrolyl group, furanyl group, thienyl group, imidazolyl group, pyrazolyl group, oxazolyl group, isoxazolyl group, thiazolyl group, isothiazolyl group, pyridyl group, pyridazinyl group, pyrimidinyl group, pyrazinyl group, indolyl group, benzopyrazolyl group, isoindolyl group, indazolyl group, benzotriazolyl group, benzothienyl group, isobenzothienyl group, benzofuranyl group, benzoisofuranyl group, benzodioxole group, or benzimidazolyl group, and the phenyl group, naphthyl group, pyrrolyl group, furanyl group, thienyl group, imidazolyl group, pyrazolyl group, oxazolyl group, isoxazolyl group, thiazolyl group, isothiazolyl group, pyridyl group, pyridazinyl group, pyrimidinyl group, pyrazinyl group, indolyl group, benzopyrazolyl group, isoindolyl group, indazolyl group, benzotriazolyl group, benzothienyl group, isobenzothienyl group, benzofuranyl group, benzoisofuranyl group, benzodioxole group, or benzimidazolyl group is optionally substituted by one or more of F, Cl, Br, I, methyl group, ethyl group, n-propyl group, isopropyl group, fluoromethyl group, chloromethyl group, difluoromethyl group, dichloromethyl group, trifluoromethyl group, trichloromethyl group, methoxy group, ethoxy group, n-propoxy group, isopropoxy group, trifluoromethoxy group, trichloromethoxy group, -(C=O)NH2, -NH2, or cyano group, R1 is more preferably selected from a cyclopropylmethyl group, a 2,2,2-trifluoroethyl group, a methoxyethyl group, a trifluoromethoxyethyl group, a phenyl group, an oxazolyl group, a thiazolyl group, a pyridyl group, a benzodioxole group, a benzopyrazolyl group, or an indolyl group, and the phenyl group, oxazolyl group, thiazolyl group, pyridyl group, benzodioxole group, benzopyrazolyl group, indolyl group are optionally substituted by one or more of F, Cl, Br, I, a methyl group, an ethyl group, a trifluoromethyl group, a methoxy group, a trifluoromethoxy group, -(C=O)NH2, -NH2, or a cyano group. R2 is selected from H, F, Cl, Br, I, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, a methoxymethyl group, or an ethoxymethyl group. R3 is selected from H, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, a methoxymethyl group, or an ethoxymethyl group. Each R4 is independently selected from H, F, Cl, Br, I, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group, a fluoromethoxy group, a chloromethoxy group, a difluoromethoxy group, a dichloromethoxy group, a trifluoromethoxy group, a trichloromethoxy group, a 2,2-difluoroethoxy group, a 2,2-dichloroethoxy group, a 2,2,2-trifluoroethoxy group, a 2,2,2-trichloroethoxy group, a methoxymethyl group, an ethoxymethyl group, a methoxyethyl group, a fluoromethoxymethyl group, a chloromethoxymethyl group, a difluoromethoxymethyl group, a dichloromethoxymethyl group, a trifluoromethoxymethyl group, a trichloromethoxymethyl group, a 2,2-difluoroethoxymethyl group, a 2,2-dichloroethoxymethyl group, a 2,2,2-trifluoroethoxymethyl group, a 2,2,2-trichloroethoxymethyl group, a fluoromethoxyethyl group, a chloromethoxyethyl group, a difluoromethoxyethyl group, a dichloromethoxyethyl group, a trifluoromethoxyethyl group, a trichloromethoxyethyl group, a 2,2-difluoroethoxyethyl group, a 2,2-dichloroethoxyethyl group, a 2,2,2-trifluoroethoxyethyl group, or a 2,2,2-trichloroethoxyethyl group.

[0012] In another embodiment of the present disclosure, there is provided a compound represented by formula (IIA), (IIB), (IIC), (IID), and a pharmaceutically acceptable salt thereof, TIFF2025519406000007.tif66170 among which, A1, A2, A3, A4 are each independently selected from CR4 or an N atom, R1 is H, C 1-6 alkyl group, halogenated C 1-6 alkyl group, C 3-6 cycloalkyl group, C 3-6 cycloalkyl C 1-3 alkyl group, C 1-6 alkoxy C 1-3 alkyl group, halogenated C 1-6 alkoxy C 1-3 alkyl group, 6- to 10-membered aryl group, or 5- to 10-membered heteroaryl group, and the 6- to 10-membered aryl group and 5- to 10-membered heteroaryl group may be optionally substituted by one or more halogens, C 1-6 alkyl group, halogenated C 1-6 alkyl group, C 1-6 alkoxy group, halogenated C 1-6 alkoxy group, -(C=O)NH2, -NH2, or cyano group, R2 is H, halogen, C 1-6 alkyl group, or C 1-6 alkoxy C 1-3 alkyl group, R3 is H, C 1-6 alkyl group, or C 1-6 alkoxy C 1-3 alkyl group, each R4 is independently H, halogen, C 1-6 alkyl group, C 1-6 alkoxy group, C 1-6 halogenated alkoxy group, C 1-6 alkoxy C 1-3 alkyl group, or halogenated C 1-6 alkoxy C 1-3 alkyl group.

[0013] In another embodiment of the present disclosure, there is provided a compound represented by formula (IIA-1), (IIA-2), (IIB-1), (IIB-2), (IIC-1), (IIC-2), (IID-1), (IID-2), and a pharmaceutically acceptable salt thereof. TIFF2025519406000008.tif148170, among which A1, A2, A3, and A4 are each independently selected from CR4 or an N atom. R1 is H, C 1-6 alkyl group, halogenated C 1-6 alkyl group, C 3-6 cycloalkyl group, C 3-6 cycloalkyl C 1-3 alkyl group, C 1-6 alkoxy C 1-3 alkyl group, halogenated C 1-6 alkoxy C 1-3 alkyl group, 6- to 10-membered aryl group, or 5- to 10-membered heteroaryl group, and the 6- to 10-membered aryl group and 5- to 10-membered heteroaryl group may be optionally substituted by one or more halogens, C 1-6 alkyl group, halogenated C 1-6 alkyl group, C 1-6 alkoxy group, halogenated C 1-6 alkoxy group, -(C=O)NH2, -NH2, or cyano group. R2 is H, halogen, C 1-6 alkyl group, or C 1-6 alkoxy C 1-3 alkyl group. R3 is H, C 1-6 alkyl group, or C 1-6 alkoxy C 1-3 alkyl group. Each R4 is independently H, halogen, C 1-6 alkyl group, C 1-6 alkoxy group, C 1-6 halogenated alkoxy group, C 1-6 alkoxy C 1-3 alkyl group, or halogenated C 1-6 alkoxy C 1-3It is selected from an alkyl group.

[0014] In some aspects 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 H, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, an s-butyl group, a t-butyl group, a fluoromethyl group, a chloromethyl group, a difluoromethyl group, a dichloromethyl group, a trifluoromethyl group, a trichloromethyl group, a 2,2-difluoroethyl group, a 2,2-dichloroethyl group, a 2,2,2-trifluoroethyl group, 2,2,2-trichloroethyl group, pentafluoroethyl group, pentachloroethyl group, cyclopentyl group, cyclohexyl group, cyclopropylmethyl group, cyclopropylethyl group, cyclobutylmethyl group, cyclobutylethyl group, cyclopentylmethyl group, cyclopentylethyl group, cyclohexylmethyl group, cyclohexylethyl group, methoxymethyl group, ethoxymethyl group, methoxyethyl group, ethoxyethyl group, trifluoromethoxymethyl group, trifluoromethoxyethyl group, phenyl group, naphthyl group, pyrrolyl group, furanyl group, thienyl group, imidazolyl group, pyrazolyl group, oxazolyl group, isoxazolyl group, thiazolyl group, isothiazolyl group, pyridyl group, pyridazinyl group, pyrimidinyl group, pyrazinyl group, indolyl group, benzopyrazolyl group, isoindolyl group, indazolyl group, benzotriazolyl group, benzothienyl group, isobenzothienyl group, benzofuranyl group, benzisofuranyl group, benzodioxole group, or benzimidazolyl group, and the phenyl group, naphthyl group, pyrrolyl group, furanyl group, thienyl group, imidazolyl group, pyrazolyl group, oxazolyl group, isoxazolyl group, thiazolyl group, isothiazolyl group, pyridyl group, pyridazinyl group, pyrimidinyl group, pyrazinyl group, indolyl group, benzopyrazolyl group, isoindolyl group, indazolyl group, benzotriazolyl group, benzothienyl group, isobenzothienyl group, benzofuranyl group, benzisofuranyl group, benzodioxole group, or benzimidazolyl group is optionally substituted by one or more of F, Cl, Br, I, methyl group, ethyl group, n-propyl group, isopropyl group, fluoromethyl group, chloromethyl group, difluoromethyl group, dichloromethyl group, trifluoromethyl group, trichloromethyl group, 2,2-difluoroethyl group, 2,2-dichloroethyl group, 2,2,2-trifluoroethyl group, 2,2,2-trichloroethyl group, methoxy group, ethoxy group, n-propoxy group, isopropoxy group, trifluoromethoxy group, trichloromethoxy group, 2,2-difluoroethoxy group, 2,2-dichloroethoxy group, 2,2,2-trifluoroethoxy group, 2,2,2-trichloroethoxy group, -(C=O)NH2, -NH2, or cyano group, and the other variables are as defined in the present disclosure.,

[0015] 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 a pharmaceutically acceptable salt thereof, R1 is selected from H, a methyl group, an ethyl group, a cyclopropylmethyl group, a 2,2,2-trifluoroethyl group, a methoxyethyl group, a trifluoromethoxyethyl group, a phenyl group, an oxazolyl group, a thiazolyl group, a pyridyl group, a benzodioxole group, a benzopyrazolyl group, or an indolyl group, and the phenyl group, oxazolyl group, thiazolyl group, pyridyl group, benzodioxole group, benzopyrazolyl group, indolyl group are optionally substituted by one or more F, Cl, Br, I, a methyl group, an ethyl group, a trifluoromethyl group, a methoxy group, a trifluoromethoxy group, or a cyano group, and the other variables are as defined in the present disclosure.

[0016] 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 a pharmaceutically acceptable salt thereof, R1 is selected from H, a methyl group, an ethyl group, a tert-butyl group, a cyclopropylmethyl group, a 2,2,2-trifluoroethyl group, a cyclopentyl group, a cyclohexyl group, a methoxymethyl group, an ethoxymethyl group, a methoxyethyl group, an ethoxyethyl group, a trifluoromethoxymethyl group, a trifluoromethoxyethyl group, selected from TIFF2025519406000009.tif74170, the above TIFF2025519406000010.tif74170 is optionally substituted with one or more of F, Cl, Br, I, methyl group, ethyl group, n-propyl group, isopropyl group, fluoromethyl group, chloromethyl group, difluoromethyl group, dichloromethyl group, trifluoromethyl group, trichloromethyl group, 2,2-difluoroethyl group, 2,2-dichloroethyl group, 2,2,2-trifluoroethyl group, 2,2,2-trichloroethyl group, methoxy group, ethoxy group, n-propoxy group, isopropoxy group, fluoromethoxy group, chloromethoxy group, difluoromethoxy group, dichloromethoxy group, trifluoromethoxy group, trichloromethoxy group, 2,2-difluoroethoxy group, 2,2-dichloroethoxy group, 2,2,2-trifluoroethoxy group, 2,2,2-trichloroethoxy group, -(C=O)NH2, -NH2, or cyano group, and the other variables are as defined in the present disclosure.

[0017] 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 a pharmaceutically acceptable salt thereof, R1 is H, methyl group, ethyl group, cyclopropylmethyl group, 2,2,2-trifluoroethyl group, methoxyethyl group, trifluoromethoxyethyl group, selected from TIFF2025519406000011.tif74170, as described above TIFF2025519406000012.tif74170 is optionally substituted with one or more of F, Cl, Br, I, methyl group, ethyl group, trifluoromethyl group, methoxy group, trifluoromethoxy group, or cyano group, and the other variables are as defined in the present disclosure.

[0018] 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 a pharmaceutically acceptable salt thereof, R2 is selected from H, F, Cl, Br, I, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, a methoxymethyl group, or an ethoxymethyl group, and the other variables are as defined in the present disclosure.

[0019] 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 a pharmaceutically acceptable salt thereof, R2 is selected from H or a methyl group, preferably H, and the other variables are as defined in the present disclosure.

[0020] 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 a pharmaceutically acceptable salt thereof, R3 is selected from H, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, a methoxymethyl group, or an ethoxymethyl group, preferably a methyl group, and the other variables are as defined in the present disclosure.

[0021] In some embodiments of the present disclosure, in the compounds represented by formula (IIA), (IIA-1), (IIA-2), or a pharmaceutically acceptable salt thereof, R1 is selected from a phenyl group, an m-fluorophenyl group, an m-chlorophenyl group, an m-bromophenyl group, an m-iodophenyl group, an m-methoxyphenyl group, or an m-ethoxyphenyl group, and the other variables are as defined in the present disclosure.

[0022] 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 a phenyl group, an m-fluorophenyl group, or an m-methoxyphenyl group, and the other variables are as defined in the present disclosure.

[0023] 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, a cyclopropylmethyl group, a 2,2,2-trifluoroethyl group, a methoxyethyl group, a trifluoromethoxyethyl group, a phenyl group, an oxazolyl group, a thiazolyl group, a pyridyl group, a benzodioxole group, a benzopyrazolyl group, an indolyl group, and the above phenyl group, oxazolyl group, thiazolyl group, pyridyl group, benzodioxole group, benzopyrazolyl group, indolyl group is optionally substituted by one or more F, Cl, Br, I, a methyl group, an ethyl group, a trifluoromethyl group, a methoxy group, a trifluoromethoxy group, or a cyano group, and the other variables are as defined in the present disclosure.

[0024] 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 H, a cyclopropylmethyl group, a 2,2,2-trifluoroethyl group, a methoxyethyl group, a trifluoromethoxyethyl group, TIFF2025519406000013.tif74170 selected from, the above TIFF2025519406000014.tif74170 is optionally substituted by one or more F, Cl, Br, I, a methyl group, an ethyl group, a trifluoromethyl group, a methoxy group, a trifluoromethoxy group, or a cyano group, and the other variables are as defined in the present disclosure.

[0025] In some embodiments of the present disclosure, in the compounds represented by formula (IID), (IID-1), (IID-2), or a pharmaceutically acceptable salt thereof, R2 is selected from H, F, Cl, Br, I, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, a methoxymethyl group, or an ethoxymethyl group, and the other variables are as defined in the present disclosure.

[0026] In some embodiments of the present disclosure, in the compounds represented by formula (IID), (IID-1), (IID-2), or a pharmaceutically acceptable salt thereof, R3 is selected from H, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, a methoxymethyl group, or an ethoxymethyl group, and the other variables are as defined in the present disclosure.

[0027] In some embodiments of the present disclosure, in the compounds represented by formula (IID), (IID-1), (IID-2), or a pharmaceutically acceptable salt thereof, each R4 is independently selected from H, F, Cl, Br, I, methyl group, ethyl group, n-propyl group, isopropyl group, methoxy group, ethoxy group, n-propoxy group, isopropoxy group, fluoromethoxy group, chloromethoxy group, difluoromethoxy group, dichloromethoxy group, trifluoromethoxy group, trichloromethoxy group, 2,2-difluoroethoxy group, 2,2-dichloroethoxy group, 2,2,2-trifluoroethoxy group, 2,2,2-trichloroethoxy group, methoxymethyl group, ethoxymethyl group, methoxyethyl group, fluoromethoxymethyl group, chloromethoxymethyl group, difluoromethoxymethyl group, dichloromethoxymethyl group, trifluoromethoxymethyl group, trichloromethoxymethyl group, 2,2-difluoroethoxymethyl group, 2,2-dichloroethoxymethyl group, 2,2,2-trifluoroethoxymethyl group, 2,2,2-trichloroethoxymethyl group, fluoromethoxyethyl group, chloromethoxyethyl group, difluoromethoxyethyl group, dichloromethoxyethyl group, trifluoromethoxyethyl group, trichloromethoxyethyl group, 2,2-difluoroethoxyethyl group, 2,2-dichloroethoxyethyl group, 2,2,2-trifluoroethoxyethyl group, or 2,2,2-trichloroethoxyethyl group, and the other variables are as defined in the present disclosure.

[0028] In one embodiment of the present disclosure, in the compounds represented by formula (IIA), (IIA-1), (IIA-2), or a pharmaceutically acceptable salt thereof, R1 is C 1-6 alkyl group, C 3-6 cycloalkyl group, C 1-6 alkoxyC 1-3 alkyl group, C 1-6 halogenated alkoxyC 1-3 alkyl group, 6- to 10-membered aryl group, or 5- to 10-membered heteroaryl group, and the above 6- to 10-membered aryl group and 5- to 10-membered heteroaryl group are optionally substituted with 1, 2, 3, 4, 5 halogens, C 1-6 alkyl group, C 1-6An alkyl halide group, C 1-6 An alkoxy group, C 1-6 May be substituted by a halogenated alkoxy group, -(C=O)NH2, -NH2, or a cyano group, R2 is H, a halogen, C 1-6 An alkyl group, or C 1-6 An alkoxy C 1-3 Selected from alkyl groups, R3 is H, C 1-6 An alkyl group, or C 1-6 An alkoxy C 1-3 Selected from alkyl groups.

[0029] In some embodiments of the present disclosure, in the compounds represented by formula (IIA), (IIA-1), (IIA-2), or a pharmaceutically acceptable salt thereof, R1 is a tert-butyl group (t-butyl group), a cyclopropylmethyl group, a cyclopentyl group, a cyclohexyl group, a methoxymethyl group, an ethoxymethyl group, a methoxyethyl group, an ethoxyethyl group, a trifluoromethoxymethyl group, a trifluoromethoxyethyl group, Selected from TIFF2025519406000015.tif10170, and the above TIFF2025519406000016.tif10170 is optionally substituted by 1, 2, 3, 4, 5 F, Cl, Br, I, methyl group, ethyl group, n-propyl group, isopropyl group, fluoromethyl group, chloromethyl group, difluoromethyl group, dichloromethyl group, trifluoromethyl group, trichloromethyl group, 2,2-difluoroethyl group, 2,2-dichloroethyl group, 2,2,2-trifluoroethyl group, 2,2,2-trichloroethyl group, methoxy group, ethoxy group, n-propoxy group, isopropoxy group, fluoromethoxy group, chloromethoxy group, difluoromethoxy group, dichloromethoxy group, trifluoromethoxy group, trichloromethoxy group, 2,2-difluoroethoxy group, 2,2-dichloroethoxy group, 2,2,2-trifluoroethoxy group, 2,2,2-trichloroethoxy group, -(C=O)NH2, -NH2, or a cyano group. The other variables are as defined in the present disclosure.

[0030] In some aspects of the present disclosure, in the compounds represented by formula (IIA), (IIA-1), (IIA-2), or a pharmaceutically acceptable salt thereof, R1 is selected from 23170 of TIFF2025519406000017.tif, R 4a R 4b R 4c R 4d R 4e are each independently selected from H, F, Cl, Br, I, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, a fluoromethyl group, a chloromethyl group, a difluoromethyl group, a dichloromethyl group, a trifluoromethyl group, a trichloromethyl group, a 2,2-difluoroethyl group, a 2,2-dichloroethyl group, a 2,2,2-trifluoroethyl group, a 2,2,2-trichloroethyl group, a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group, a fluoromethoxy group, a chloromethoxy group, a difluoromethoxy group, a dichloromethoxy group, a trifluoromethoxy group, a trichloromethoxy group, a 2,2-difluoroethoxy group, a 2,2-dichloroethoxy group, a 2,2,2-trifluoroethoxy group, a 2,2,2-trichloroethoxy group, -(C=O)NH2, -NH2, or a cyano group. The other variables are as defined in the present disclosure.

[0031] In some aspects of the present disclosure, in the compounds represented by formula (IIA), (IIA-1), (IIA-2), or a pharmaceutically acceptable salt thereof, R2 is selected from H, F, Cl, Br, I, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, a methoxymethyl group, or an ethoxymethyl group, preferably H or a methyl group, and the other variables are as defined in the present disclosure.

[0032] In some aspects of the present disclosure, in the compounds represented by formula (IIA), (IIA-1), (IIA-2), or a pharmaceutically acceptable salt thereof, R3 is selected from H, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, a methoxymethyl group, or an ethoxymethyl group, preferably a methyl group, and the other variables are as defined in the present disclosure.

[0033] In some embodiments of the present disclosure, the compounds represented by formula (IIA), (IIA-1), (IIA-2), or a pharmaceutically acceptable salt thereof, wherein, R1 is selected from TIFF2025519406000018.tif23170, R 4a 、R 4b 、R 4c 、R 4d 、R 4e are each independently selected from H, F, Cl, Br, I, methyl group, ethyl group, n-propyl group, isopropyl group, fluoromethyl group, chloromethyl group, difluoromethyl group, dichloromethyl group, trifluoromethyl group, trichloromethyl group, 2,2-difluoroethyl group, 2,2-dichloroethyl group, 2,2,2-trifluoroethyl group, 2,2,2-trichloroethyl group, methoxy group, ethoxy group, n-propoxy group, isopropoxy group, fluoromethoxy group, chloromethoxy group, difluoromethoxy group, dichloromethoxy group, trifluoromethoxy group, trichloromethoxy group, 2,2-difluoroethoxy group, 2,2-dichloroethoxy group, 2,2,2-trifluoroethoxy group, 2,2,2-trichloroethoxy group, -(C=O)NH2, -NH2, or cyano group, R2 is selected from H, F, Cl, Br, I, methyl group, ethyl group, n-propyl group, isopropyl group, methoxymethyl group, or ethoxymethyl group, preferably H or methyl group, R3 is selected from H, methyl group, ethyl group, n-propyl group, isopropyl group, methoxymethyl group, or ethoxymethyl group, preferably methyl group.

[0034] In some embodiments of the present disclosure, the compounds represented by formula (IIA), (IIA-1), (IIA-2), or a pharmaceutically acceptable salt thereof, wherein, R1 is selected from TIFF2025519406000019.tif23170, R 4a 、R4b , R 4c , R 4d R is independently selected from H, F, Cl, Br, I, methyl group, ethyl group, n-propyl group, isopropyl group, fluoromethyl group, chloromethyl group, difluoromethyl group, dichloromethyl group, trifluoromethyl group, trichloromethyl group, 2,2-difluoroethyl group, 2,2-dichloroethyl group, 2,2,2-trifluoroethyl group, 2,2,2-trichloroethyl group, methoxy group, ethoxy group, n-propoxy group, isopropoxy group, fluoromethoxy group, chloromethoxy group, difluoromethoxy group, dichloromethoxy group, trifluoromethoxy group, trichloromethoxy group, 2,2-difluoroethoxy group, 2,2-dichloroethoxy group, 2,2,2-trifluoroethoxy group, 2,2,2-trichloroethoxy group, -(C=O)NH2, -NH2, or cyano group, R2 is selected from H, F, Cl, Br, I, methyl group, ethyl group, n-propyl group, isopropyl group, methoxymethyl group, or ethoxymethyl group, preferably H or methyl group, R3 is selected from H, methyl group, ethyl group, n-propyl group, isopropyl group, methoxymethyl group, or ethoxymethyl group, preferably methyl group.

[0035] In another embodiment of the present disclosure, there is provided a compound shown below, or a pharmaceutically acceptable salt thereof: TIFF2025519406000020.tif247170TIFF2025519406000021.tif241170TIFF2025519406000022.tif128170

[0036] The present disclosure further provides a pharmaceutical composition comprising any one of the above-mentioned compounds or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. The above pharmaceutical composition can be prepared into various pharmaceutically acceptable dosage forms, such as tablets, capsules, oral liquids, granules, injections, etc. The above pharmaceutical composition can be administered by oral or parenteral means (such as intravenous, subcutaneous or topical, etc.). The dosage can be appropriately adjusted according to the patient's age, gender and disease type, and the usual daily dosage is about 1 to 200 mg.

[0037] The present disclosure also provides the use of the above compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition in the preparation of a drug that is a GABA A receptor modulator.

[0038] The present disclosure further provides the use of the above compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the preparation for treating CNS-related diseases. Among them, the above CNS-related diseases include sleep disorders (such as insomnia), mood disorders (such as depression (such as major depressive disorder (MDD)), mania, mood-cycling disorder (such as mild depression), bipolar disorder (such as type I and / or type II), anxiety disorders (such as generalized anxiety disorder (GAD), social anxiety disorder), stress, post-traumatic stress disorder (PTSD), obsessive-compulsive disorder (such as obsessive-compulsive disorder (OCD))), schizophrenia spectrum disorders (such as schizophrenia, schizoaffective disorder), spastic disorders (such as epilepsy (such as status epilepticus (SE)), epileptic seizures), memory and / or cognitive disorders (such as attention disorders (such as attention deficit hyperactivity disorder (ADHD))), dementia (such as Alzheimer's disease, Lewy body dementia, vascular dementia), movement disorders (such as Huntington's disease, Parkinson's disease, essential tremor), personality disorders (such as antisocial personality disorder, obsessive-compulsive personality disorder), autism spectrum disorder (ASD) (such as autism, idiopathic autism, such as synaptophathy, such as Rett syndrome, fragile X syndrome, Angelman syndrome), pain (such as neuropathic pain, injury-related pain syndrome, acute pain, chronic pain), traumatic brain injury (TBI), vascular diseases (such as stroke, ischemia, vascular malformation), substance use disorders and / or withdrawal syndromes (such as addiction to opioid preparations, cocaine and / or alcohol), and tinnitus, including but not limited to these.

[0039] 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 drug for treating depression. The above depression is selected from mild depression, major depressive disorder (MDD), persistent depressive disorder (PDD), psychotic depression, postpartum depression (PPD) or seasonal affective disorder. Definitions and explanations

[0040] Unless otherwise indicated, the following terms and phrases used in this specification shall have the following meanings. A particular term or phrase, when not specially defined, should not be considered uncertain or ambiguous but should be understood in its ordinary meaning. When a trade name appears in this specification, it is intended to refer to the corresponding product or its active ingredient.

[0041] As used in this disclosure, "pharmaceutically acceptable" 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 response, or other problems or complications, and commensurate with a reasonable benefit / risk ratio.

[0042] As used in this disclosure, "pharmaceutically acceptable salts" refers to salts of the compounds according to this disclosure, which are prepared from acids and bases that are relatively non-toxic to the compounds found in this disclosure and having specific substituents. When a relatively basic functional group is included in the compounds according to this disclosure, acid addition salts can be obtained by contacting a sufficient amount of an acid with the neutral form of such compounds in a pure solution or a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts, organic acid salts, salts of amino acids (such as arginine), and salts of organic acids such as glucuronic acid. Since some specific compounds according to this disclosure contain basic functional groups, they can be converted into any acid addition salt.

[0043] Some compounds of this disclosure can have asymmetric carbon atoms (optical centers) or double bonds. Racemates, diastereomers, geometric isomers, and individual isomers are all included within the scope of this disclosure.

[0044] The compounds according to the present disclosure may be in the form of specific geometric or stereoisomers. The present disclosure intends that 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 mixtures enriched in enantiomers or diastereomers, are included within the scope of the present disclosure. Substituents such as alkyl groups may have other asymmetric carbon atoms. All such isomers and mixtures thereof are included within the scope of the present disclosure.

[0045] The pharmaceutically acceptable salts according to the present disclosure can be synthesized from the parent compounds containing acid groups or bases by conventional chemical methods. In general situations, the methods for preparing salts are as follows: prepared by reacting these compounds in the form of free acids or free bases with a stoichiometrically appropriate base or acid in water or an organic solvent or a mixture of both.

[0046] The term "pharmaceutically acceptable carrier" refers to a representative carrier of any formulation or carrier medium 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 toxicity and side effects on the host or patient, including, but not limited to, binders, fillers, lubricants, disintegrants, wetting agents, dispersants, solubilizers, suspending agents, etc.

[0047] The present disclosure intends to include all isotopes of the atoms present in the compounds according to the present disclosure. Isotopes include atoms with the same number of protons but different mass numbers. As common examples and without limitation, isotopes of hydrogen include deuterium and tritium. Isotopes of carbon include 13 C and 14 C. The isotope-labeled compounds of the present disclosure can generally be prepared by using appropriate isotope-labeled reagents in place of unlabeled reagents for further use by conventional techniques known to those skilled in the art or by methods similar to those described herein.

[0048] "Optionally substituted by one or more... " means that the group is either unsubstituted or at least one and at most five hydrogen atoms in the group, for example, 1, 2, 3, 4, or 5 hydrogen atoms, are independently replaced by the corresponding number (1, 2, 3, 4, 5) of substituents. For example, "the above-mentioned 6- to 10-membered aryl group and 5- to 10-membered heteroaryl group are optionally substituted by one or more halogens, C 1-6 alkyl group, halogenated C 1-6 alkyl group, C 1-6 alkoxy group, halogenated C 1-6 alkoxy group, -(C=O)NH2, -NH2, or cyano group" means that the 6- to 10-membered aryl group and 5- to 10-membered heteroaryl group are either unsubstituted or 1, 2, 3, 4, or 5 hydrogen atoms in the 6- to 10-membered aryl group and 5- to 10-membered heteroaryl group are independently replaced by the corresponding number (1, 2, 3, 4, 5) of halogens, C 1-6 alkyl group, halogenated C 1-6 alkyl group, C 1-6 alkoxy group, halogenated C 1-6 alkoxy group, -(C=O)NH2, -NH2, or cyano group.

[0049] Unless otherwise specified, the term "alkyl group" is used to represent a straight-chain or branched-chain saturated hydrocarbon group, which may be monosubstituted (e.g., -CH2F) or polysubstituted (e.g., -CF3), and may be monovalent (e.g., methyl group), divalent (e.g., methylene group), or polyvalent (e.g., methine group). For example, C1-C6 indicates 1 to 6 carbons, C 1-6is selected from C1, C2, C3, C4, C5, C6, and examples of the alkyl group include a methyl group (Me), an ethyl group (Et), a propyl group (e.g., n-propyl group and isopropyl group), a butyl group (e.g., n-butyl group, isobutyl group, s-butyl group, t-butyl group), a pentyl group (e.g., n-pentyl group, isoamyl group, neopentyl group, 1-ethylpropyl group), a hexyl group (e.g., n-hexyl group, isohexyl group, 1,1-dimethylbutyl group, 2,2-dimethylbutyl group, 3,3-dimethylbutyl group, and 2-ethylbutyl group), and the like.

[0050] Unless otherwise specified, the term "halo" or "halogen" by itself or as part of another substituent refers to a fluorine, chlorine, bromine, or iodine atom.

[0051] Unless otherwise specified, "haloalkyl group" is for representing a mono-halogenated / poly-halogenated straight-chain or branched-chain alkyl group. Typical haloalkyl groups are C 1-6 include haloalkyl groups, for example, C1, C2, C3, C4, C5, C6 haloalkyl groups. For example, examples of C1-C6 haloalkyl groups include, but are not limited to, fluoromethyl group, chloromethyl group, difluoromethyl group, dichloromethyl group, trifluoromethyl group, trichloromethyl group, 2,2-difluoroethyl group, 2,2-dichloroethyl group, 2,2,2-trifluoroethyl group, 2,2,2-trichloroethyl group, pentafluoroethyl group, and pentachloroethyl group.

[0052] Unless otherwise specified, "alkoxy group" represents the above alkyl group (including cycloalkyl group or haloalkyl group) having a specific number of carbon atoms linked by an oxygen bridge. Typical alkoxy groups are C 1-6It includes an alkoxy group, for example, a C1, C2, C3, C4, C5, C6 alkoxy group, a C3, C4, C5, C6 cycloalkoxy group, and a C1, C2, C3, C4, C5, C6 haloalkoxy group. Examples of alkoxy groups include, but are not limited to, methoxy group, ethoxy group, n-propoxy group, isopropoxy group, n-butoxy group, sec-butoxy group, tert-butoxy group, n-pentoxy group, S-pentyloxy group, hexyloxy group, 2-ethylbutoxy group. Examples of cycloalkoxy groups include, but are not limited to, cyclopropoxy group, cyclobutoxy group, cyclopentyloxy group, cyclohexyloxy group. Examples of haloalkoxy groups include, but are not limited to, fluoromethoxy group, chloromethoxy group, difluoromethoxy group, dichloromethoxy group, trifluoromethoxy group, trichloromethoxy group, 2,2-difluoroethoxy group, 2,2-dichloroethoxy group, 2,2,2-trifluoroethoxy group, 2,2,2-trichloroethoxy group, pentafluoroethoxy group, pentachloroethoxy group.

[0053] Unless otherwise specified, the term "cycloalkyl group" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, which may be mono- or polysubstituted and may be monovalent, divalent or polyvalent. Examples of these cycloalkyl groups include, but are not limited to, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, etc.

[0054] Unless otherwise specified, the term "aryl group" refers to a 6- to 10-membered all-carbon monocyclic or fused polycyclic (i.e., rings sharing adjacent carbon atom pairs) group having a conjugated π electron system, such as phenyl group and naphthyl group, preferably phenyl group.

[0055] Unless otherwise specified, "heteroaryl group" refers to a group of a 5- to 10-membered monocyclic or bicyclic 4n+2 aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms provided in an aromatic ring system (for example, having 6 or 10 π electrons shared in a cyclic arrangement), wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5- to 10-membered heteroaryl group"). In a heteroaryl group containing one or more nitrogen atoms, the bonding point may be a carbon or nitrogen atom as long as the valence is acceptable. The heteroaryl bicyclic system may contain one or more heteroatoms in one or two rings. "Heteroaryl group" includes a ring system in which the above heteroaryl ring is condensed with one or more carbocyclic groups or heterocyclic groups, wherein the connection point is on the heteroaryl ring, and in such a case, the number of ring members continues to represent the number of ring members in the heteroaryl ring system.

[0056] Exemplary 5-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyrrolyl, furanyl, and thienyl groups. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl groups. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl, and thiadiazolyl groups. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to, tetrazolyl groups. Exemplary 6-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyridyl groups. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, but are not limited to, pyridazinyl, pyrimidinyl, and pyrazinyl groups. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to, triazinyl and tetrazinyl groups, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include, but are not limited to, azacycloheptatrienyl, oxacycloheptatrienyl, and thiacycloheptatrienyl groups. Exemplary 5,6-fused bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothienyl, isobenzothienyl, benzofuryl, benzisofuryl, benzodioxolyl, benzimidazolyl, benzoxazolyl, benzoisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzisothiazolyl, benzothiadiazolyl, indenazinyl, and purinyl groups. Exemplary 6,6-fused bicyclic heteroaryl groups include, but are not limited to, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl groups.

[0057] Compounds are named using artificial or ChemDraw® software, and commercially available compounds adopt the supplier's catalog name.

Mode for Carrying Out the Invention

[0058] Hereinafter, the present disclosure will be further described in conjunction with specific examples and test examples, but the scope of the present disclosure is not limited in any form.

[0059] Example 1 TIFF2025519406000023.tif28170Synthesis route: TIFF2025519406000024.tif134170

[0060] 1. Add M1 (200 g, 734 mmol, 1.00 eq) and HBr (5.96 g, 35.4 mmol, 4.00 mL, 0.048 eq) to THF (1400 mL), then add Pd / C (10.0 g, 9.43 mmol, 0.013 eq). Place the system at 25°C and stir with H2 (1.00 MPa) for 24 hours. After filtering and concentrating the system, pulverize the solid, add 600 mL of acetone to dissolve it, filter to obtain a white crude product, and separate and purify the crude product by column chromatography (dichloromethane / methanol (10:1 to 5:1)) to obtain M2 (180 g, white solid).

[0061] 2. Add M2 (100 g, 364 mmol, 1.00 eq) to 1 L of toluene, then add bis(methylaluminum)(2,6-di-tert-butyl-4-anisole) (525 g, 1.09 mol, 571 mL, 3.00 eq). Place the system at -60°C and stir for 1 hour, then add bromomethylmagnesium (3 M, 364 mL, 3.00 eq) at -60°C, place the system at -60°C and stir for 3 hours, then add saturated NH4Cl (500 mL), filter, wash the filter cake with ethyl acetate (200 mL × 2), combine the organic phases, then wash with saturated brine (100 mL), dry over anhydrous sodium sulfate, filter, concentrate the organic phase under reduced pressure, and separate and purify by column chromatography (dichloromethane / methanol (100:1 to 10:1)) to obtain M3 (46 g, white solid, 98 g of M2 recovered).

[0062] 3. Ethyltriphenylphosphonium bromide (102 g, 275 mmol, 4.00 eq) was added to THF (120 mL) at 0 °C, then t-BuOK (30.9 g, 275 mmol, 4.00 eq) was added to THF (200 mL), then the system was set at 60 °C and stirred for 1 hour. Then M3 (20.0 g, 68.9 mmol, 1.00 eq) was dissolved in THF (120 mL), then this was added to the system, and the mixture was stirred at 60 °C for 13 hours. An NH4Cl solution (150 mL) was added to the system under ice bath conditions to quench it, then ethyl acetate (150 mL × 2) was added for extraction. The organic phases were combined, then washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure and purified by column chromatography (dichloromethane / methanol (100:1 to 3:1)) to obtain M4 (18.3 g, 60.6 mmol, yield: 88.0%).

[0063] 4. M4 (18.3 g, 60.6 mmol, 1.00 eq) was dissolved in THF (180 mL), then BH3Me2S (10.0 M, 30.3 mL, 5.00 eq) was added under the condition of 0 °C. The system was set at 25 °C and stirred for 3 hours. Then 3.00 M NaOH (100 mL) and H2O2 (86.5 g, 763 mmol, 73.3 mL, 12.6 eq) were added dropwise at 0 °C, and the system was set at 25 °C and reacted for 4 hours. The system was filtered, then the filtrate was quenched with a Na2SO3 solution (60.0 mL × 2), extracted with ethyl acetate (150 mL × 2), the organic phases were combined, then washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure and purified by column chromatography (dichloromethane / methanol (100:1 to 3:1)) to obtain M5 (13.0 g, 40.6 mmol, yield: 66.9%).

[0064] 5. M5 (13.0 g, 40.6 mmol, 1.00 eq) was dissolved in dichloromethane (130 mL), and then PCC (17.5 g, 81.1 mmol, 2.00 eq) was added under the condition of 0 °C. The system was placed at 25 °C and stirred for 3 hours. The system was filtered, and then the filtrate was quenched with a Na2SO3 solution (100 mL), extracted with dichloromethane (100 mL × 2). The organic phases were combined, then washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, the organic phase was concentrated under reduced pressure, and separated and purified by column chromatography (dichloromethane / methanol (100:1 to 3:1)) to obtain M6 (9.03 g, 28.3 mmol, yield: 69.9%).

[0065] 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), HBr (927 mg, 5.50 mmol, 622 μL, 0.190 eq) were added under the condition of 0 °C. Then the system was placed at 25 °C and stirred for 12 hours. The system was quenched with a NaHCO3 solution (50 mL), extracted with ethyl acetate (50.0 mL × 2). The organic phases were combined, then washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, the organic phase was concentrated under reduced pressure, and separated and purified by column chromatography (dichloromethane / methanol (100:1 to 1:1)) to obtain a white solid M7 (7.1 g, 17.8 mmol, yield 63.0%). 1 1H NMR (400 MHz, CDCl3) δ 3.99 - 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).

[0066] 7. 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) were added to HCl (12 M, 1 mL, 1.95 eq) and H2O (30 mL), and the mixture was stirred at 25 °C for 5 h. The system was filtered and concentrated to obtain 1-2, a yellow solid of the crude product (1.20 g).

[0067] 8. 1-2 (200 mg, 1.10 mmol, 1.00 eq), Et3N (111 mg, 1.10 mmol, 152 μL, 1.00 eq) were added to toluene (10.0 mL) at room temperature, then DPPA (302 mg, 1.10 mmol, 237 μL, 1.00 eq) was added. The system was stirred at 90 °C for 1 h, quenched with water (20 mL), extracted with ethyl acetate (30.0 mL), the organic phases were combined, then washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure. It was separated and purified by column chromatography (dichloromethane / methanol (100:1 - 10:1)) to obtain 1-3, a white solid (90 mg, 0.483 mmol, yield: 44%). MS (ESI) m / z = 180.2.

[0068] 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), then the system was stirred at 30 °C for 19 h, quenched with water (150 mL), extracted with ethyl acetate (80.0 mL × 2), the organic phases were combined, then washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure. Then the crude product was separated and purified by pre-HPLC (column: YMC Triart 30×150mm×7μm, mobile phase: [water(HCl)-ACN], B%: 30% - 90%, 40 min) to obtain Compound 1 (110 mg, 208 μmol, yield: 27.6%). MS (ESI) m / z = 478.5 [M - 17]+ , 1 1H NMR (400 MHz, CDCl3) δ 7.79 - 7.63 (m, 2H), 7.53 (s, 1H), 7.30 (br d, J = 6.52 Hz, 1H), 6.85 (br d, J = 1.64 Hz, 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).

[0069] Example 2 Synthesis route of TIFF2025519406000025.tif28170: TIFF2025519406000026.tif34170

[0070] 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) (for the preparation method of 2-1, refer to the preparation method of 1-3) were added to THF (10 mL). Then the system was placed at 50 °C and stirred for 16 h. The system was quenched with water (30 mL), extracted with ethyl acetate (40.0 mL × 2), the organic phases were combined, 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 separated by SFC (column: DAICEL CHIRALCEL OD (250 mm × 30 mm, 10 μm), mobile phase: [0.1% NH3H2O ETOH], B%: 60% - 60%, min) to obtain the crude product. The crude product was separated and purified by column chromatography (dichloromethane / methanol (100 / 0 - 95 / 5)) to obtain white solid 2 (70.0 mg, 141 μmol, yield: 22.8%). MS (ESI) m / z = 479.5 [M + H] + , 11H NMR (400 MHz, DMSO-d6) δ 9.11 (d, J = 2.12 Hz, 1H), 8.45 - 8.48 (m, 1H), 8.22 - 8.27 (m, 2H), 7.52 (dd, J = 8.38, 4.63 Hz, 1H), 4.69 - 4.76 (m, 1H), 4.54 - 4.62 (m, 1H), 4.25 (s, 1H), 2.77 (br t, J = 8.82 Hz, 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).

[0071] Example 3 TIFF2025519406000027.tif31170Synthesis route: TIFF2025519406000028.tif34170

[0072] 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) (for the preparation method of 3-1, refer to the preparation method of 1-3) were added to THF (20 mL). Then the system was placed at 50 °C and stirred for 6 h. The system was quenched with water (10 mL), extracted with 2-methyltetrahydrofuran (10.0 mL × 2), the organic phases were combined, 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 separated 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 yellow liquid of the crude product. The crude product was separated and 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] + , 11H NMR (400 MHz, CDCl3) δ 7.99 - 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, 2H), 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).

[0073] Example 4 TIFF2025519406000029.tif27170Synthesis route: TIFF2025519406000030.tif33170

[0074] 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) (for the preparation method of 4-1, refer to the preparation method of 1-3) were added to THF (20 mL). Then the system was placed at 50 °C and stirred for 6 hours. The system was quenched with water (100 mL), extracted with 2-methyltetrahydrofuran (20.0 mL × 2), the organic phases were combined, 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 separated by SFC (column: DAICEL CHIRALCEL OJ (250 mm × 30 mm, 10 μm), mobile phase: [0.1% NH3H2O ETOH], B%: 35% - 35%, min) to obtain a yellow liquid of the crude product. The crude product was separated and purified by pre-HPLC (column: Phenomenex luna C18 250×50 mm×10 μm, mobile phase: [water (HCl)-ACN], B%: 30% - 70%, 20 min) to obtain yellow solid 4. Then it was purified by SFC (EB6914-18-P1S2, RT = 2.589 min) (column: DAICEL CHIRALPAK IC (250 mm × 30 mm, 10 μm), mobile phase: [0.1%NH3H2O ETOH], B%: 50% - 50%, min) to obtain white solid 4 (80 mg, 161 μmol, yield: 57.8%). MS (ESI) m / z = 478.4 [M-OH] + , 1 1H NMR (400 MHz, CDCl3) δ 7.99 - 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).

[0075] Example 5 TIFF2025519406000031.tif 28170 Synthesis route: TIFF2025519406000032.tif 33170

[0076] 1. Add 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) (for the preparation method of 5-1, refer to the preparation method of 1-3) to THF (15 mL). Then place the system at 50 °C and stir for 14 hours. Quench the system with water (50 mL), extract with ethyl acetate (50.0 mL × 2). Combine the organic phases, then wash with saturated brine (50 mL), dry over anhydrous sodium sulfate, filter, concentrate the organic phase under reduced pressure. Purify the crude product by SFC (column: DAICEL CHIRALCEL OJ (250 mm × 30 mm, 10 μm), mobile phase: [0.1% NH3H2O ETOH], B%: 45% - 45%, min) to obtain yellow solid 5 (81 mg, 152 μmol, yield: 36.3%). MS (ESI) m / z = 508 [M+1] + , 1 1H NMR (400 MHz, DMSO-d6) δ 8.14 (s, 1H), 7.43 - 7.54 (m, 2H), 7.37 (t, J = 8.32 Hz, 1H), 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 = 8.76 Hz, 1H), 2.01 - 2.15 (m, 2H), 1.82 - 1.14 (m, 21H), 0.59 (s, 3H).

[0077] Example 6 TIFF2025519406000033.tif 31170 Synthesis route: TIFF2025519406000034.tif 36170

[0078] 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) (for the preparation method of 6-1, refer to the preparation method of 1-3) were added to THF (50 mL). Then, the system was placed at 50 °C and stirred for 16 hours. The system was quenched with water (50 mL), extracted with 2-methyltetrahydrofuran (50.0 mL × 2). The organic phases were combined, then washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure. After grinding the crude product, it was dissolved in MTBE (10 mL), placed at 25 °C and stirred for 1 hour. After filtration, the white solid 6 (200 mg, 478 μmol, yield: 14.8%) of the filter cake was obtained. MS (ESI) m / z = 416.3 [M+1] + , 1 1H NMR (400 MHz, DMSO-d6) δ 7.88 - 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).

[0079] Example 7 TIFF2025519406000035.tif31170Synthesis route: TIFF2025519406000036.tif35170

[0080] 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) (for the preparation method of 7-1, refer to the preparation method of 1-3) were added to THF (50 mL). Then the system was placed at 50 °C and stirred for 12 h. The system was quenched with water (20 mL), extracted with ethyl acetate (20.0 mL × 2), the organic phases were combined, then washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure. It was separated and purified by column chromatography (dichloromethane / methanol (100:1 to 10:1)) to obtain 7 (100 mg, 221 μmol, yield: 25.5%). MS (ESI) m / z = 430.5 [M+1] + , 1 1H NMR (400 MHz, CDCl3) δ 7.43 (s, 1H), 4.66 - 4.26 (m, 2H), 3.85 (q, J = 7.2 Hz, 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).

[0081] Example 8 TIFF2025519406000037.tif28170Synthesis route: TIFF2025519406000038.tif62170

[0082] 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). The system was placed at 70 °C and stirred for 6 hours. CH3ONa (7.29 g, 135 mmol, 3.00 eq) was added to the system, and then the system was placed at 70 °C and stirred for 13 hours. HCl (1 M, 80.0 mL) was used to adjust the pH to ~1, and then extraction was performed using ethyl acetate (70.0 mL × 2). The organic phases were combined, then washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, the organic phase was concentrated under reduced pressure, and separation and purification were carried out by column chromatography (using dichloromethane / methanol (0 - 7%)), to obtain a pale yellow solid 8-3 (560 mg, 3.13 mmol, yield: 6.95%). MS (ESI) m / z = 179.0 [M+1] + It was.

[0083] 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). Then the system was placed at 50 °C and stirred for 18 hours. The system was quenched with water (40 mL), extracted with ethyl acetate (50.0 mL × 2), the organic phases were combined, then washed with saturated brine (60 mL), dried over anhydrous sodium sulfate, filtered, the organic phase was concentrated under reduced pressure, and separation and purification were carried out by column chromatography (using dichloromethane / methanol (0 - 7%)), to obtain a white solid 8 (200 mg, 400 μmol, yield: 39.8%). MS (ESI) m / z = 496.2 [M+1] + , 11H NMR (400 MHz, DMSO-d6) δ 8.60 (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 = 8.8 Hz, 1H), 2.18 - 1.93 (m, 2H), 1.82 - 1.54 (m, 7H), 1.44 - 0.95 (m, 17H), 0.59 (s, 3H).

[0084] Example 9 TIFF2025519406000039.tif28170Synthesis route: TIFF2025519406000040.tif33170

[0085] 1. Add 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) (for the preparation method of 9-1, refer to the preparation method of 8-3) to THF (15 mL). Then place the system at 50 °C and stir for 16 hours. Quench the system with water (100 mL), extract with ethyl acetate (50.0 mL × 2), combine the organic phases, then wash with saturated brine (100 mL), dry over anhydrous sodium sulfate, filter, concentrate the organic phase under reduced pressure, and purify by column chromatography (dichloromethane / methanol (100 / 0 - 90 / 10)) to obtain white solid 9 (200 mg, 404 μmol, yield: 47.9%). MS (ESI) m / z = 496.8 [M+1] + , 11H NMR (400 MHz, DMSO-d6) δ 8.49 (s, 1H), 7.71 - 7.77 (m, 2H), 7.38 (t, J = 8.88 Hz, 2H), 4.73 - 4.81 (m, 1H), 4.58 (d, J = 18.4 Hz, 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).

[0086] Example 10 TIFF2025519406000041.tif28170Synthesis route: TIFF2025519406000042.tif36170

[0087] 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) (for the preparation method of 10-1, refer to the preparation method of 8-3) were added to THF (10.0 mL). Then the system was placed at 50 °C and stirred for 18 h. The system was quenched with water (20 mL), extracted with ethyl acetate (40.0 mL × 2), the organic phases were combined, then washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, the organic phase was concentrated under reduced pressure, separated and purified by column chromatography (dichloromethane / methanol (0 - 5%)), and then further purified by pre-HPLC (column: Welch Xtimate C18 150×30 mm×5 μm, mobile phase: water (NH4HCO3)-ACN, B%: 0% - 90%, 14 min) to obtain white solid 10 (80.0 mg, 175 μmol, yield: 27.1%). MS (ESI) m / z = 455.3 [M+1] + , 11H NMR (400 MHz, DMSO-d6) δ 8.02 (s, 1H), 4.76 - 4.57 (m, 1H), 4.55 - 4.37 (m, 1H), 3.43 (br d, J = 7.2 Hz, 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).

[0088] Example 11 TIFF2025519406000043.tif28170Synthesis route: TIFF2025519406000044.tif62170

[0089] 1. Add 1,11 - 2 (2.30 g, 21.9 mmol, 2.38 mL, 1.00 eq) to toluene (30.0 mL), then cool the system to 5 °C and add 11 - 1 (3.00 g, 21.9 mmol, 2.50 mL, 1.00 eq). Then warm the system to 25 °C and stir for 12 hours. Concentrate the system to obtain a colorless oil 11 - 3 (5.05 g, 20.8 mmol, yield: 95%). 1 1H NMR (400 MHz, CDCl3) δ 8.09 (s, 1H), 7.20 (td, J = 2.0, 11.2 Hz, 1H), 7.14 - 7.05 (m, 1H), 6.92 (dd, J = 1.2, 8.4 Hz, 1H), 6.68 - 6.54 (m, 1H), 6.14 (br s, 1H), 4.39 (t, J = 5.2 Hz, 1H), 3.43 - 3.32 (m, 8H).

[0090] 2. HCl (12.0 M, 3.00 mL, 4.36 eq) was added to H2O (20.0 mL), then it was added dropwise to 11-3 (2.00 g, 8.26 mmol, 1.00 eq). The system was placed at 25 °C and stirred for 10 h. The system was quenched with water (20 mL), extracted with ethyl acetate (10.0 mL × 2), the organic phases were combined, then washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, the organic phase was concentrated under reduced pressure, and separated by column chromatography (petroleum ether / ethyl acetate (100 / 1 - 1 / 1)) to obtain white solid 11-4 (900 mg, 5.05 mmol, yield: 61.2%). 1 1H NMR (400 MHz, CDCl3) δ 10.40 (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 = 2.8 Hz, 1H).

[0091] 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), then the system was placed at 50 °C and stirred for 12 h. The system was quenched with water (20 mL), extracted with ethyl acetate (20.0 mL × 2), the organic phases were combined, then washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, the organic phase was concentrated under reduced pressure, and purified by separation by column chromatography (dichloromethane / methanol (100 / 1 - 3 / 1)) to obtain off-white solid 11 (200 mg, 0.401 mmol, yield: 44.1%), MS (ESI) m / z = 495.5 [M + 1] + , 11H NMR (400 MHz, CDCl3) δ 7.47 (td, J = 1.6, 10.4 Hz, 1H), 7.42 - 7.32 (m, 2H), 6.99 - 6.88 (m, 1H), 6.63 (d, J = 3.2 Hz, 1H), 6.37 (d, J = 3.2 Hz, 1H), 4.59 (d, J = 18.4 Hz, 1H), 4.35 (d, J = 18.4 Hz, 1H), 2.62 (s, 1H), 2.29 - 2.09 (m, 2H), 1.94 - 1.02 (m, 25H), 0.69 (s, 3H).

[0092] Example 12 TIFF2025519406000045.tif30170Synthesis route: TIFF2025519406000046.tif59170

[0093] 1. Add 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) to MeOH (50.0 mL), then add AcOH (14.0 mL) under the condition of 25 °C. Place the system at 25 °C and stir for 16 h. Concentrate the system to obtain a crude product, and purify it by column chromatography (dichloromethane / methanol (100 / 1 - 1 / 1)) to obtain white solid 12-2 (2.26 g, 12.1 mmol, yield: 17.0%). 1 1H NMR (400 MHz, CDCl3) δ 7.09 (br s, 1H), 4.31 - 3.73 (m, 1H), 2.44 (br d, J = 7.2 Hz, 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).

[0094] 2. 12-2 (1.00 g, 5.37 mmol, 1.00 eq) was added to i-PrOH (10.0 mL), then TMSNCO (1.24 g, 10.7 mmol, 1.43 mL, 2.00 eq) was added. The system was placed at 25 °C and stirred for 2 hours. The system was concentrated to obtain white solid 12-3 (1.19 g, 5.19 mmol, yield: 96.7%). 1 1H NMR (400 MHz, CDCl3) δ 6.90 - 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 = 4.4 Hz, 2H).

[0095] 3. 12-3 (500 mg, 2.18 mmol, 1.00 eq) and HCl / EtOAc (4.00 M, 545 μL, 1.00 eq) were placed at 25 °C and stirred for 1 hour. The system was concentrated to obtain 12-4 (350 mg, crude product). 1 1H NMR (400 MHz, DMSO-d6) δ 10.55 - 9.74 (m, 2H), 6.93 (br s, 1H), 6.73 - 6.51 (m, 1H), 3.47 (d, J = 7.2 Hz, 2H), 1.13 - 0.87 (m, 1H), 0.50 - 0.43 (m, 2H), 0.36 - 0.26 (m, 2H).

[0096] 4. 12-4 (350 mg, 2.71 mmol, 1.00 eq) was added to EtOH (4.00 mL), then CH(OCH3)3 (718 mg, 6.77 mmol, 742 μL, 2.50 eq) was added. The system was placed at 25 °C and stirred 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 white solid 12-5 (160 mg, 1.15 mmol, yield: 42.4%). 11H NMR (400 MHz, DMSO-d6) δ 11.46 (br s, 1H), 7.79 (s, 1H), 3.49 (d, J = 6.8 Hz, 2H), 1.20 - 0.91 (m, 1H), 0.60 - -0.21 (m, 4H).

[0097] 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), then the system was placed at 50 °C and stirred for 12 h. The system was quenched with water (20 mL), extracted with ethyl acetate (20.0 mL × 2), the organic phases were combined, then washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, the organic phase was concentrated under reduced pressure, and purified by column chromatography (dichloromethane / methanol (100 / 1 - 10 / 1)) to obtain white solid 12 (300 mg, 0.655 mmol, yield: 65.1%). MS (ESI) m / z = 456.5 [M + 1] + , 1 1H NMR (400 MHz, CDCl3) δ 7.44 (s, 1H), 4.58 - 4.47 (m, 1H), 4.42 - 4.31 (m, 1H), 3.67 (d, J = 7.2 Hz, 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 = 5.2 Hz, 2H).

[0098] Example 13 TIFF2025519406000047.tif30170Synthesis route: TIFF2025519406000048.tif35170

[0099] 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 Bide) were added to THF (10.0 mL). Then the system was placed at 50 °C and stirred for 16 h. The system was quenched with water (20 mL) and extracted with ethyl acetate (20.0 mL × 3). The organic phases were combined, then washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure. After separation and purification by column chromatography (dichloromethane / methanol 10:1), a pale yellow solid 13 (88 mg, 0.166 mmol, yield: 34.8%) was obtained. MS (ESI) m / z = 527.2 [M + 1] + , 1 1H NMR (400 MHz, DMSO-d6) δ 7.71 - 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).

[0100] Example 14 TIFF2025519406000049.tif32170 Synthesis route: TIFF2025519406000050.tif99170

[0101] 1. 14-1 (7.00 g, 39.9 mmol, 1.00 eq), (Boc)2O (8.71 g, 39.9 mmol, 9.16 mL, 1.00 eq) were added to MeOH (100 mL). Then BnNCO (1.37 g, 10.3 mmol, 1.25 mL, 1.10 eq) was added, and then the mixture was stirred at 25 °C for 12 h. The system was concentrated to obtain a crude product, which was separated and purified by column chromatography (petroleum ether / ethyl acetate (100 / 1 - 1 / 1)). After that, a white solid 14-2 (5.00 g, 23.3 mmol, yield: 58.5%) was obtained. 11H NMR (400 MHz, CDCl3) δ 6.35 (br s, 1H), 4.62 - 3.79 (m, 1H), 3.52 - 3.32 (m, 2H), 1.48 (br s, 9H).

[0102] 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 then the mixture was stirred at 60 °C for 12 h. The system was quenched with citric acid (30 mL), extracted with ethyl acetate (20 mL), the organic phases were combined, then washed with saturated brine (20 mL) of citric acid, dried over anhydrous sodium sulfate, filtered, the organic phase was concentrated under reduced pressure, and purified by column chromatography (petroleum ether / ethyl acetate (100 / 1 - 1 / 1)) to obtain a colorless oily liquid 14-3 (3.3 g, crude product).

[0103] 3. 14-3 (3.33 g, 9.59 mmol, 1.00 eq) was added to a 40 mL sealed tube, HCl / EtOAc (4.00 M, 2.40 mL, 1.00 eq) was added, the system was placed at 25 °C and stirred for 1 h, concentrated to obtain a colorless oily liquid 14-4 (2.8 g, crude product). 1 1H NMR (400 MHz, DMSO-d6) δ 7.68 (br s, 1H), 7.40 - 7.13 (m, 5H), 6.38 - 5.98 (m, 2H), 4.38 - 4.15 (m, 4H).

[0104] 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, then 10 mL of ethanol was further added, CH(OEt)3 (3.00 g, 28.3 mmol, 3.10 mL, 2.50 eq) was added, the system was placed at 25 °C and stirred for 5 h, the system was concentrated to obtain a crude product, and purified by column chromatography (petroleum ether / ethyl acetate (100 / 1 - 1 / 1)) to obtain a white solid 14-5 (1.30 g, 5.05 mmol, yield: 44.6%).1 1H NMR (400 MHz, DMSO-d6) δ 8.20 (s, 1H), 7.53 - 7.14 (m, 5H), 4.83 (s, 2H), 4.68 - 4.52 (m, 2H).

[0105] 5. 14-5 (800 mg, 3.11 mmol, 1.00 eq) was placed in a 100 mL hydrogenation flask equipped with an N2 balloon, then 5 mL of tetrahydrofuran and 15 mL of ethanol were further added, and then Pd / C (10.0 mg, 9.43 μmol, 0.001 eq) and Pd(OH)2 (10.0 mg, 7.12 μmol, 0.001 eq) were added. The system was placed at 25 °C under a H2 (50 Psi) pressure and stirred for 12 hours. The system was concentrated to obtain a crude product. The crude product was subjected to Pre-HPLC (column: Welch Xtimate C18 150×30 mm×5 μm, mobile phase: [water (HCl)-ACN], B%: 0% - 24%, 36 min) to obtain a white solid 14-6 (170 mg, 1.02 mmol, yield: 21.2%). 1 1H NMR (400 MHz, DMSO-d6) δ 11.80 (br s, 1H), 7.95 (d, J = 0.8 Hz, 1H), 4.52 (q, J = 9.2 Hz, 2H).

[0106] 6. After dissolving 14-6 (100 mg, 598 μmol, 1.00 eq) in 10 mL of tetrahydrofuran, it was 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 placed at 50 °C and stirred for 12 hours. The system was quenched with water (20 mL), extracted with ethyl acetate (20 mL). After combining the organic phases, they were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure and purified 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%). 11H NMR (400 MHz, DMSO-d6) δ 7.97 (s, 1H), 4.67 - 4.55 (m, 3H), 4.54 - 4.46 (m, 1H), 4.26 (s, 1H), 2.72 (br t, J = 8.8 Hz, 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).

[0107] Example 15 TIFF2025519406000051.tif32170Synthesis route: TIFF2025519406000052.tif101170

[0108] 1. 15-1 (10.0 g, 72.9 mmol, 1.00 eq) was dissolved in HCl (150 mL), the system was cooled to 0 °C, then NaNO2 (5.53 g, 80.2 mmol, 1.10 eq) and H2O (150 mL) were added to the system, the system was placed at 0 °C and stirred for 30 minutes, then SnCl2·2H2O (49.4 g, 219 mmol, 3.00 eq) and HCl (300 mL) were added to the system, the system was placed at 0 °C and stirred for 24 hours, the system was filtered, the filter cake was washed with H2O (200 mL) and dried, and then a black-brown solid 15-2 (8.40 g, 44.5 mmol, yield: 61.1%, HCl) was obtained. 1 1H NMR (400 MHz, DMSO-d6) δ 10.22 - 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).

[0109] 2. Dissolve 15-2 (5.00 g, 26.5 mmol, 1.00 eq, HCl) in ACN (45.0 mL), then add DIEA (3.43 g, 26.5 mmol, 4.62 mL, 1.00 eq) under room temperature conditions, adjust the pH of the system to about 8, add (Boc)₂O (5.79 g, 26.5 mmol, 6.09 mL, 1.00 eq), place the system at 25 °C and stir for 16 hours, concentrate the system to obtain a crude product, and purify the crude product with (Ethyl acetate:Petroleum ether = 0~10%) to obtain a black-brown solid 15-3 (4.56 g, 18.1 mmol, yield: 68.2%). 1 The ¹H NMR (400 MHz, DMSO-d₆) δ was 8.78 - 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).

[0110] 3. Dissolve 15-3 (4.56 g, 18.1 mmol, 1.00 eq) and DMAP (22.1 mg, 181 μmol, 0.01 eq) in pyridine (50.0 mL), then add benzyl isocyanate (2.65 g, 19.9 mmol, 2.43 mL, 1.10 eq), place the system at 60 °C and stir for 16 hours, quench the system with citric acid (200 mL), extract with ethyl acetate (200 mL), combine the organic phases, then wash with citric acid (300 mL) and saturated brine (200 mL), dry over anhydrous sodium sulfate, filter, concentrate the organic phase under reduced pressure to obtain a crude product, and purify by column chromatography (THF:Dichloromethane = 0~10%) to obtain a yellow solid 15-4 (5.00 g, 12.7 mmol, yield: 70.0%). 11H NMR (400 MHz, 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 = 5.6 Hz, 2H), 1.46 - 1.26 (m, 9H).

[0111] 4. 15-4 (2.00 g, 5.19 mmol, 1.00 eq) was added to HCl / dioxane (15.0 mL), then the system was placed at 25 °C and stirred for 24 h, and the system was concentrated to obtain a green solid 15-5 (2.00 g, crude), MS (ESI) m / z = 286.0 [M+1] + .

[0112] 5. 15-5 (2.00 g, 7.01 mmol, 1.00 eq) was added to EtOH (20.0 mL), then trimethoxymethane (1.86 g, 17.5 mmol, 1.92 mL, 2.50 eq) was added, the system was placed at 40 °C and stirred for 16 h, the system was concentrated to obtain a crude product, and the crude product was subjected to 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 1H NMR (400 MHz, 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).

[0113] 6. 15-6 (100 mg, 339 μmol, 1.00 eq) was added to EtOH (6.00 mL) and THF (2.00 mL), 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 placed at 25 °C and stirred for 16 hours, then the system was placed at 60 °C and stirred for 16 hours. The system was concentrated to obtain a crude product, and then pre-HPLC (column: Welch Xtimate C18 150×30 mm×5 μm, mobile phase: [water (HCl)-ACN], B%: 0% - 90%, 36 min) was used to obtain white solid 15-7 (60 mg, 284 μmol, yield: 83.8%). MS (ESI) m / z = 205.9 [M+1] + It was.

[0114] 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), then the system was placed at 50 °C and stirred for 16 hours. The system was quenched with water (20 mL), extracted with ethyl acetate (20.0 mL×2), the organic phases were combined, 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 and purified by column chromatography (with dichloromethane / methanol (0 - 10%)) to obtain white solid 15 (40 mg, 76.7 μmol, yield: 24.6%). MS (ESI) m / z = 522.2 [M+1] + , 11H NMR (400 MHz, DMSO-d6) δ 8.09 (s, 1H), 7.44 - 7.30 (m, 2H), 6.99 (d, J = 8.4 Hz, 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 = 7.2 Hz, 3H), 1.13 - 1.01 (m, 8H), 0.58 (s, 3H).

[0115] Example 16 TIFF2025519406000053.tif32170Synthesis route: TIFF2025519406000054.tif73170

[0116] 1. Add 1,16-1 (2.00 g, 8.75 mmol, 1.00 eq, HCl) to a round-bottom flask, add H2O (20.0 mL) under ice bath conditions, then add 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). Place the system at 25 °C and stir for 2 hours. Concentrate the system to obtain a yellow solid 16-2 (2.4 g) of the crude product, which was directly used in the next step of the reaction. 1 1H NMR (400 MHz, DMSO-d6) δ 12.56 - 12.34 (m, 1H), 11.36 (s, 1H), 7.39 (t, J = 8.0 Hz, 1H), 7.16 (s, 1H), 7.10 - 7.03 (m, 2H), 6.85 (br d, J = 8.0 Hz, 1H). 2. Add 16-2 (500 mg, 2.01 mmol, 1.00 eq) to a round-bottom flask, then add toluene (25.0 mL) and TEA (203.9 mg, 2.01 mmol, 280 μL, 1.00 eq). Place the system at 25 °C and stir for 0.5 h. Then add DPPA (554 mg, 2.01 mmol, 437 μL, 1.00 eq). Next, place the system at 90 °C and stir for 16 h. Quench the system with water (20 mL), extract with ethyl acetate (20.0 mL × 2). Combine the organic phases, then wash with saturated brine (100 mL), dry over anhydrous sodium sulfate, filter, concentrate the organic phase under reduced pressure, and purify by column chromatography (separated with dichloromethane / methanol (0 - 10%)) to obtain yellow solid 16-3 (290 mg, 1.18 mmol, yield: 58.7%). MS (ESI) m / z = 445.9 [M+1] + , 1 1H NMR (400 MHz, DMSO-d6) δ = 12.13 (br s, 1H), 8.19 (s, 1H), 7.96 - 7.93 (m, 2H), 7.60 (t, J = 8.8 Hz, 1H), 7.22 (br d, J = 8.4 Hz, 1H).

[0117] 3. Add 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) to THF (20 mL). Then place the system at 50 °C and stir for 16 h. Quench the system with water (20 mL), extract with ethyl acetate (20.0 mL × 2). Combine the organic phases, then wash with saturated brine (20 mL), dry over anhydrous sodium sulfate, filter, concentrate the organic phase under reduced pressure, and purify by column chromatography (separated with dichloromethane / methanol (0 - 10%)) to obtain yellow solid 16 (230 mg, 0.403 mmol, yield: 52.1%). MS (ESI) m / z = 544.2 [M-H2O] + , 11H NMR (400 MHz, DMSO-d6) δ = 8.21 (s, 1H), 7.99 - 7.86 (m, 2H), 7.62 (t, J = 8.4 Hz, 1H), 7.25 (br d, J = 8.0 Hz, 1H), 4.78 - 4.53 (m, 2H), 4.26 (s, 1H), 2.76 (br t, J = 8.8 Hz, 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= 10.0 Hz, 2H), 0.59 (s, 3H).

[0118] Example 17 TIFF2025519406000055.tif28170Synthesis route: TIFF2025519406000056.tif68170

[0119] The same method as in Example 1 was adopted to synthesize Compound M7.

[0120] 1. 17-1 (1.00 g, 5.69 mmol, 1.00 eq) was weighed into a 40 mL sealed tube, 10 mL of H2O and HCl (12.0 M, 925 μL, 1.95 eq) were added at room temperature, glyoxylic acid (632 mg, 8.54 mmol, 475 μL, 1.50 eq) was added at room temperature, stirred at room temperature for 12 h, the system was lyophilized to obtain a black-brown solid, 10 mL of acetonitrile was added to make it into a pulp, then filtered, and the filter cake was concentrated and dried to obtain 17-2 (1.07 g, 5.48 mmol, yield: 96.3%). 1 1H NMR (400 MHz, DMSO-d6) δ = 11.52 (br s, 1H), 7.96 (d, J = 2.4 Hz, 1H), 7.65 (dd, J= 2.8, 9.2 Hz, 1H), 7.17 (s, 1H), 6.90 (d, J= 9.2 Hz, 1H), 3.83 (s, 3H).

[0121] 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, then 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 layer with brine (20.0 mL), dry over Na2SO4, filter and concentrate to obtain the crude product. Purify by column chromatography (petroleum ether / ethyl acetate = 100 / 1 - 1 / 1) to obtain a dark brown solid 17 - 3 (100 mg, 520 μmol, yield: 20.3%). 1 1H NMR (400 MHz, DMSO - d6) δ = 12.00 (br s, 1H), 10.26 (s, 1H), 8.61 (d, J = 2.8 Hz, 1H), 8.16 - 8.10 (m, 2H), 7.84 (d, J = 2.8 Hz, 1H), 7.61 (s, 1H), 7.44 - 7.33 (m, 1H), 6.93 (d, J = 8.8 Hz, 1H), 6.73 (d, J = 8.8 Hz, 1H), 3.87 (s, 3H).

[0122] 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). Then the system was placed at 30 °C and stirred for 19 h. The system was quenched with water (5 mL), extracted with ethyl acetate (10.0 mL × 2), the organic phases were combined, then washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure. Subsequently, the crude product was separated and purified by pre-HPLC (column: YMC Triart 30 × 150 mm × 7 μm, mobile phase: [water (HCl)-ACN], B%: 44% - 84%, 36 min) to obtain compound 17 (100 mg, 194 μmol, yield: 31.1%). MS (ESI) m / z = 509.1 [M+H] + , 1 1H NMR (400 MHz, DMSO-d6). δ = 8.61 (d, J = 2.4 Hz, 1H), 8.22 - 8.04 (m, 2H), 6.95 (d, J = 8.8 Hz, 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).

[0123] Example 18 TIFF2025519406000057.tif28170Synthesis route: TIFF2025519406000058.tif35170

[0124] 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) (for the preparation method of 18-1, refer to the preparation method of 17-3) were added to THF (10 mL). Then the system was placed at 50 °C and stirred for 16 h. The system was quenched with water (30 mL), extracted with ethyl acetate (40.0 mL × 2), the organic phases were combined, 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 separated by SFC (column: DAICEL CHIRALCEL OD (250 mm × 30 mm, 10 μm), mobile phase: [0.1% NH3H2O ETOH], B%: 60% - 60%, min) to obtain the crude product. The crude product was separated and purified by column chromatography (dichloromethane / methanol (100 / 0 - 95 / 5)) to obtain white solid compound 18 (150 mg, 298.1 μmol, yield: 47.39%). MS (ESI) m / z = 478.3 [M - H2O + H] + , 1 1H NMR (400 MHz, 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 = 8.68 Hz, 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).

[0125] Example 19 TIFF2025519406000059.tif28170Synthesis route: TIFF2025519406000060.tif35170

[0126] 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) (for the preparation method of 19-1, refer to the preparation method of 17-3) were added to THF (10 mL). Then, the system was placed at 50 °C and stirred for 16 h. The system was quenched with water (30 mL) and extracted with ethyl acetate (40.0 mL × 2). The organic phases were combined, 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 separated by SFC (column: DAICEL CHIRALCEL OD (250 mm × 30 mm, 10 μm, mobile phase: [0.1% NH3H2O ETOH], B%: 60% - 60%, min) to obtain the crude product. The crude product was separated and purified by column chromatography (dichloromethane / methanol (100 / 0 - 95 / 5)) to obtain the white solid compound 19 (135 mg, 259 μmol, yield: 58.8%). MS (ESI) m / z = 503.1 [M - H2O + H] + , 1 1H NMR (400 MHz, 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 = 8.0 Hz, 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 = 9.6 Hz, 7H), 1.30 - 1.16 (m, 4H), 1.12 (s, 4H), 1.06 (br d, J = 10.8 Hz, 2H), 0.60 (s, 3H).

[0127] Example 20 TIFF2025519406000061.tif28170 Synthesis route: TIFF2025519406000062.tif35170

[0128] 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) (for the preparation method of 20-1, refer to the preparation method of 17-3) were added to THF (10 mL). Then, the system was placed at 50 °C and stirred for 16 h. The system was quenched with water (30 mL), extracted with ethyl acetate (40.0 mL × 2), the organic phases were combined, then washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered, the organic phase was concentrated under reduced pressure, and the crude product was separated by SFC (column: DAICEL CHIRALCEL OD (250 mm × 30 mm, 10 μm), mobile phase: [0.1% NH3H2O ETOH], B%: 60% - 60%, min) to obtain the crude product. The crude product was separated and purified by column chromatography (dichloromethane / methanol (100 / 0 - 95 / 5)) to obtain the white solid compound 20 (60 mg, 120.82 μmol, yield: 28.81%). MS (ESI) m / z = 497.3 [M + H] + , 1 1H NMR (400 MHz, DMSO-d6) δ = 8.18 (s, 1H), 8.12 (q, J = 8.4 Hz, 1H), 7.89 (dd, J = 8.0, 2.0 Hz, 1H), 7.08 (dd, J = 8.00, 2.40 Hz, 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 = 8.8 Hz, 3H), 0.59 (s, 3H).

[0129] Example 21 TIFF2025519406000063.tif 28170 Synthesis Route: TIFF2025519406000064.tif 35170

[0130] 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) (for the preparation method of 21-1, refer to the preparation method of 17-3) were added to THF (10 mL). Then the system was placed at 50 °C and stirred for 16 h. The system was quenched with water (30 mL), extracted with ethyl acetate (40.0 mL × 2), the organic phases were combined, 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 separated by SFC (column: DAICEL CHIRALCEL OD (250 mm × 30 mm, 10 μm), mobile phase: [0.1% NH3H2O ETOH], B%: 60% - 60%, min) to obtain the crude product. The crude product was separated and purified by column chromatography (dichloromethane / methanol (100 / 0 - 95 / 5)) to obtain the white solid compound 21 (155 mg, 304 μmol, yield: 27.3%). MS (ESI) m / z = 497.3 [M + H] + , 1 1H NMR (400 MHz, DMSO-d6) δ = 8.33 - 8.27 (m, 2H), 7.89 - 7.83 (m, 1H), 7.57 (d, J = 1.6 Hz, 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).

[0131] Example 22 TIFF2025519406000065.tif 28170 Synthesis Route: TIFF2025519406000066.tif 35170

[0132] 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) (for the preparation method of 22-1, refer to the preparation method of 17-3) were added to THF (10 mL). Then, the system was placed at 50 °C and stirred for 16 hours. The system was quenched with water (30 mL), extracted with ethyl acetate (40.0 mL × 2), the organic phases were combined, 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 separated by SFC (column: DAICEL CHIRALCEL OD (250 mm × 30 mm, 10 μm), mobile phase: [0.1% NH3H2O ETOH], B%: 60% - 60%, min) to obtain the crude product. The crude product was separated and purified by column chromatography (dichloromethane / methanol (100 / 0 - 95 / 5)) to obtain the white solid compound 22 (25 mg, 50.8 μmol, yield: 5.59%). MS (ESI) m / z = 475.3 [M - H2O + H] + , 1 1H NMR (400 MHz, DMSO-d6) δ = 8.06 (s, 1H), 7.9 - 7.14 (m, 1H), 7.09 - 6.97 (m, 2H), 6.41 (td, J = 2.0, 7.2 Hz, 1H), 5.28 (s, 2H), 4.72 - 4.48 (m, 2H), 4.27 (s, 1H), 2.75 (br t, J = 8.8 Hz, 1H), 2.19 - 1.99 (m, 2H), 1.78 - 1.09 (m, 24H), 0.59 (s, 3H).

[0133] Example 23 TIFF2025519406000067.tif28170 Synthetic route: TIFF2025519406000068.tif35170

[0134] 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) (for the preparation method of 23-1, refer to the preparation method of 17-3) were added to THF (10 mL). Then, the system was placed at 50 °C and stirred for 16 h. The system was quenched with water (30 mL), extracted with ethyl acetate (40.0 mL × 2), the organic phases were combined, then washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered, the organic phase was concentrated under reduced pressure, and the crude product was separated by SFC (column: DAICEL CHIRALCEL OD (250 mm × 30 mm, 10 μm), mobile phase: [0.1% NH3H2O ETOH], B%: 60% - 60%, min) to obtain the crude product. The crude product was separated and purified by column chromatography (dichloromethane / methanol (100 / 0 - 95 / 5)) to obtain the white solid compound 23 (130 mg, 251 μmol, yield: 41.2%). MS (ESI) m / z = 479.2 [M - H2O + H] + , 1 1H NMR (400 MHz, DMSO-d6) δ = 9.03 (s, 1H), 8.51 (d, J = 2.4 Hz, 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 = 8.8 Hz, 1H), 2.15 - 2.04 (m, 2H), 1.76 - 1.23 (m, 22H), 1.05 (br d, J = 11.2 Hz, 2H), 0.60 (s, 3H).

[0135] Example 24 TIFF2025519406000069.tif28170 Synthesis route: TIFF2025519406000070.tif35170

[0136] 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) (for the preparation method of 24-1, refer to the preparation method of 17-3) were added to THF (5 mL). Then the system was placed at 50 °C and stirred for 16 hours. The system was quenched with water (30 mL), extracted with ethyl acetate (40.0 mL × 2), the organic phases were combined, then washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered, the organic phase was concentrated under reduced pressure, and the crude product was separated by SFC (column: DAICEL CHIRALCEL OD (250 mm × 30 mm, 10 μm), mobile phase: [0.1% NH3H2O ETOH], B%: 60% - 60%, min) to obtain the crude product. The crude product was separated and purified by column chromatography (dichloromethane / methanol (100 / 0 - 95 / 5)) to obtain the white solid compound 24 (95 mg, 183.1 μmol, yield: 72.2%). MS (ESI) m / z = 496.3 [M - H2O + H] + , 1 1H NMR (400 MHz, DMSO-d6). δ = 8.16 (s, 1H), 7.48 (br dd, J = 5.2, 9.2 Hz, 2H), 7.40 - 7.26 (m, 1H), 4.76 - 4.48 (m, 2H), 4.27 (s, 1H), 2.74 (br d, J = 9.2 Hz, 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).

[0137] Example 25 TIFF2025519406000071.tif28170Synthesis route: TIFF2025519406000072.tif35170

[0138] 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) (for the preparation method of 25-1, refer to the preparation method of 17-3) were added to THF (5 mL). Then the system was placed at 50 °C and stirred for 16 h. The system was quenched with water (30 mL), extracted with ethyl acetate (40.0 mL × 2), the organic phases were combined, 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 separated by SFC (column: DAICEL CHIRALCEL OD (250 mm × 30 mm, 10 μm), mobile phase: [0.1% NH3H2O ETOH], B%: 60% - 60%, min) to obtain the crude product. The crude product was separated and purified by column chromatography (dichloromethane / methanol (100 / 0 - 95 / 5)) to obtain the white solid compound 25 (80 mg, 184.1 μmol, yield: 58.4%), MS (ESI) m / z = 514.0 [M+H] + , MS (ESI) m / z = 496.3 [M - H2O + H] + , 1 1H NMR (400 MHz, DMSO-d6) δ = 8.13 (s, 1H), 7.65 - 7.57 (m, 1H), 7.55 - 7.48 (m, 1H), 7.24 (br t, J = 7.6 Hz, 1H), 4.73 - 4.51 (m, 2H), 4.27 (s, 1H), 2.76 (br t, J = 8.4 Hz, 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).

[0139] Example 26 TIFF2025519406000073.tif28170 Synthetic route: TIFF2025519406000074.tif35170

[0140] 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) (for the preparation method of 26-1, refer to the preparation method of 17-3) were added to THF (5 mL). Then the system was placed at 50 °C and stirred for 16 h. The system was quenched with water (30 mL), extracted with ethyl acetate (40.0 mL × 2), the organic phases were combined, then washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered, the organic phase was concentrated under reduced pressure, and the crude product was separated by SFC (column: DAICEL CHIRALCEL OD (250 mm × 30 mm, 10 μm), mobile phase: [0.1% NH3H2O ETOH], B%: 60% - 60%, min) to obtain the crude product. The crude product was separated and purified by column chromatography (dichloromethane / methanol (100 / 0 - 95 / 5)) to obtain the white solid compound 26 (70 mg, 133 μmol, yield: 32.8%). MS (ESI) m / z = 513.2 [M+H] + , 1 1H NMR (400 MHz, DMSO-d6) δ = 8.48 (d, J = 5.6 Hz, 1H), 8.17 - 8.16 (m, 1H), 8.02 (d, J = 1.6 Hz, 1H), 7.46 (dd, J = 2.0, 5.4 Hz, 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).

[0141] Example 27 TIFF2025519406000075.tif28170Synthetic route: TIFF2025519406000076.tif35170

[0142] 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) (for the preparation method of 27-1, refer to the preparation method of 17-3) were added to THF (10 mL). Then the system was placed at 50 °C and stirred for 16 h. The system was quenched with water (30 mL), extracted with ethyl acetate (40.0 mL × 2), the organic phases were combined, 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 separated by SFC (column: DAICEL CHIRALCEL OD (250 mm × 30 mm, 10 μm), mobile phase: [0.1% NH3H2O ETOH], B%: 60% - 60%, min) to obtain the crude product. The crude product was separated and purified by column chromatography (dichloromethane / methanol (100 / 0 - 95 / 5)) to obtain the white solid compound 27 (45 mg, 87.18 μmol, yield: 17.19%). MS (ESI) m / z = 496.3 [M - H2O + H] + , 1 1H NMR (400 MHz, 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 = 8.8 Hz, 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).

[0143] Example 28 TIFF2025519406000077.tif28170 Synthesis route: TIFF2025519406000078.tif35170

[0144] 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) (for the preparation method of 28-1, refer to the preparation method of 17-3) were added to THF (10 mL). Then the system was placed at 50 °C and stirred for 16 h. The system was quenched with water (30 mL), extracted with ethyl acetate (40.0 mL × 2), the organic phases were combined, then washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered, the organic phase was concentrated under reduced pressure, and the crude product was separated by SFC (column: DAICEL CHIRALCEL OD (250 mm × 30 mm, 10 μm), mobile phase: [0.1% NH3H2O ETOH], B%: 60% - 60%, min) to obtain the crude product. The crude product was separated and purified by column chromatography (dichloromethane / methanol (100 / 0 - 95 / 5)) to obtain the white solid compound 28 (95 mg, 182.56 μmol, yield 72.55%). MS (ESI) m / z = 496.3 [M - H2O + H] + , 1 1H NMR (400 MHz, DMSO-d6) δ = 8.23 (s, 1H), 7.61 (dd, J = 2.4, 9.0 Hz, 2H), 7.14 (br t, J = 2.4 Hz, 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).

[0145] Example 29 TIFF2025519406000079.tif32170 Synthetic route: TIFF2025519406000080.tif67170

[0146] 1. Weighed 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, added 50 mL of MeOH at room temperature, then added NaBH3CN (14.9 g, 237 mmol, 2.00 eq), and then added AcOH (28.1 g, 468 mmol, 26.7 mL, 3.94 eq) under the condition of 0 °C. Reacted with stirring at room temperature for 12 hours, added NaHCO3 (50.0 mL) under the condition of 0 - 10 °C, then added 300 mL of DCM for extraction. Extracted the aqueous phase with DCM (50.0 mL × 2), then washed the organic phase with 10 mL of brine, then added anhydrous Na2SO4 for drying and concentration to obtain a crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 100 / 1 - 1 = 1 / 1) to obtain a pale yellow oily liquid 29-2 (9.38 g, 46.8 mmol, yield: 39.4%). 1 1H NMR (400 MHz, 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).

[0147] 2. Weighed 29-2 (1.00 g, 4.99 mmol, 1.00 eq) into a 40 mL sealed tube, added 40 mL of i-PrOH (10.0 mL), TMSNCO (1.73 g, 14.98 mmol, 1.99 mL, 3 eq), stirred at room temperature for 12 h, concentrated the system to obtain a crude product. The crude product was 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 1H NMR (400 MHz, CDCl3) δ = 6.22 (br s, 1H), 4.61 (quin, J = 8.4 Hz, 3H), 1.89 - 1.49 (m, 8H), 1.43 - 1.40 (m, 9H).

[0148] 3. 3,29-3 (1.00 g, 4.11 mmol, 1.00 eq) was weighed into a 100 mL round-bottom flask, HCl / dioxane (4.00 M, 1.03 mL, 1.00 eq) was added, and the mixture was stirred at room temperature for 2 h. The system was concentrated to obtain a crude product, and the crude product was purified by column chromatography (petroleum ether / ethyl acetate = 100 / 1 - 1 / 1) to obtain yellow solid 29-4 (588 mg, yield: 100%). 1 1H NMR (400 MHz, 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).

[0149] 4. 29-4 (700 mg, 4.89 mmol, 1.00 eq) was weighed into a 40 mL sealed tube, EtOH (7 mL) and CH(OMe)3 (1.30 g, 12.2 mmol, 1.34 mL, 2.50 eq) were added at room temperature, and the mixture was stirred at room temperature for 12 h. The system was concentrated to obtain a crude product, and the crude product was purified by column chromatography (petroleum ether / ethyl acetate = 100 / 1 - 10 / 1) to obtain white solid 29-5 (200 mg, 1.27 mmol, yield: 25.9%). 1 1H NMR (400 MHz, 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 = 4.4 Hz, 2H).

[0150] 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), then the system was placed at 50 °C and stirred for 16 h. The system was quenched with water (30 mL), extracted with ethyl acetate (40.0 mL × 2), the organic phases were combined, then washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered, the organic phase was concentrated under reduced pressure, and the crude product was separated by SFC (column: DAICEL CHIRALCEL OD (250 mm × 30 mm, 10 μm), mobile phase: [0.1% NH3H2O ETOH], B%: 60% - 60%, min) to obtain the crude product. The crude product was separated and purified by column chromatography (dichloromethane / methanol (100 / 0 - 95 / 5)) to obtain the white solid compound 29 (150 mg, 312 μmol, yield: 47.8%). MS (ESI) m / z = 470.5 [M + H] + , 1 1H NMR (400 MHz, DMSO-d6) δ = 7.80 (s, 1H), 4.65 - 4.36 (m, 3H), 4.24 (s, 1H), 2.70 (br t, J = 8.8 Hz, 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).

[0151] Example 30 TIFF2025519406000081.tif32170 Synthesis route: TIFF2025519406000082.tif34170

[0152] 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) (for the preparation method of 30-1, refer to the preparation method of 29-5) were added to THF (10 mL). Then the system was placed at 50 °C and stirred for 16 hours. The system was quenched with water (30 mL), extracted with ethyl acetate (40.0 mL × 2), the organic phases were combined, 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 separated by SFC (column: DAICEL CHIRALCEL OD (250 mm × 30 mm, 10 μm), mobile phase: [0.1% NH3H2O ETOH], B%: 60% - 60%, min) to obtain the crude product. The crude product was separated and purified by column chromatography (dichloromethane / methanol (100 / 0 - 95 / 5)) to obtain the white solid compound 30 (40 mg, 82.8 μmol, yield: 13.8%). MS (ESI) m / z = 484.3 [M + H] + , 1 1H NMR (400 MHz, DMSO-d6) δ = 7.79 (s, 1H), 4.61 - 4.37 (m, 2H), 4.24 (s, 1H), 3.86 (br t, J = 11.6 Hz, 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).

[0153] Example 31 TIFF2025519406000083.tif32170 Synthesis route: TIFF2025519406000084.tif95170

[0154] 1. Phthalic anhydride (10.0 g, 67.51 mmol, 1.00 eq) was weighed into a 1 L three-necked reaction flask, 200 mL of toluene was added, 31-1 (8.92 g, 67.51 mmol, 1.00 eq) was weighed and added to the system, and the mixture was stirred at 120 °C for 2.5 h. The filtration cake obtained by concentrating the system was pulped with 100 mL of petroleum ether to obtain white solid 31-2 (17.1 g, 60.64 mmol, yield: 89.82%). 1 1H NMR (400 MHz, CDCl3) δ = 7.97 - 7.63 (m, 4H), 6.56 (br s, 1H), 1.44 (br s, 9H).

[0155] 2. 2-Bromoethyl methyl ether (5.30 g, 38.13 mmol, 3.58 mL, 2.0 eq), 31-2 (5.00 g, 19.06 mmol, 1.00 eq) were weighed into a 250 mL three-necked reaction flask, then 100 mL of acetonitrile was added to the system. Benzyl(triethyl)ammonium chloride (1.74 g, 7.63 mmol, 0.4 eq) and K2CO3 (7.90 g, 57.19 mmol, 3.0 eq) were added at room temperature, and the mixture was stirred at 55 °C for 12 h. The system was quenched with water (100 mL), extracted with ethyl acetate (100.0 mL × 2), the organic phases were combined, 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 subjected to column chromatography (petroleum ether / ethyl acetate = 100 / 1 - 3 / 1) to obtain the product white solid 31-3 (4.7 g, 14.67 mmol, yield: 76.96%). 1 1H NMR (400 MHz, 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).

[0156] 3. Weighed 31-3 (4.7 g, 14.67 mmol, 1 eq) into a 100 mL round-bottom reaction flask, added HCl / EtOAc (4 M, 3.67 mL, 1 eq), stirred at room temperature for 2 h, concentrated, and obtained 31-4 (4.07 g, crude product). 1 1H NMR (400 MHz, DMSO-d6) δ = 7.85 (s, 4H), 3.44 (t, J = 5.6 Hz, 2H), 3.17 (s, 3H), 3.07 (t, J = 5.6 Hz, 2H).

[0157] 4. Weighed 31-4 (3.07 g, 13.94 mmol, 1 eq) into a 40 mL sealed tube, added 30 mL of isopropanol, added trimethylsilyl isocyanate (4.82 g, 41.82 mmol, 5.56 mL, 3 eq), stirred at room temperature for 12 h, concentrated the system, and obtained white solid 31-5 (4.8 g, crude product). 1 1H NMR (400 MHz, DMSO-d6) δ = 7.90 (br d, J = 6.0 Hz, 4H), 6.84 - 6.21 (m, 2H), 3.70 (s, 2H), 3.46 - 3.37 (m, 2H), 3.00 (br s, 3H).

[0158] 5. Added 50 mL of ethanol to a 100 mL three-necked flask, weighed 31-5 (4.80 g, 18.2 mmol, 1.00 eq) and added it to the system, weighed hydrazine hydrate (1.86 g, 36.47 mmol, 1.81 mL, 98% purity, 2 eq) and added it to the system, stirred at 70 °C for 2 h, washed the system with 1 M HCl (10 mL), then used EtOAc (10 mL × 2) to leave the aqueous phase, and freeze-dried to obtain yellow solid 31-6 (199 mg, crude product). 1 1H NMR (400 MHz, DMSO-d6) δ = 10.80 - 8.87 (m, 1H), 7.10 - 6.51 (m, 1H), 3.70 (br t, J = 5.6 Hz, 2H), 3.51 (br t, J = 5.6 Hz, 2H), 3.28 (s, 3H).

[0159] 6. Weighed 6,31-6 (120 mg, 901.25 μmol, 1 eq) into a 40 mL sealed tube, added 5 mL of ethanol to the system, weighed trimethoxymethane (239 mg, 2.25 mmol, 247 μL, 2.5 eq) and added it to the system. Using Pre HPLC (column: Phenomenex C18 75×30 mm×3 μm, mobile phase: [water (HCl)-ACN], B%: 0% - 24%, 36 min), obtained a colorless oily substance 31-7 (50 mg, 349.30 μmol, yield: 38.76%). 1 1H NMR (400 MHz, 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).

[0160] 7. Added 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) to THF (5 mL), then placed the system at 50 °C and stirred for 12 h. Quenched the system with water (5 mL), extracted with ethyl acetate (10.0 mL×2), combined the organic phases, then washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated the organic phase under reduced pressure, separated the crude product by SFC (column: DAICEL CHIRALCEL OD (250 mm×30 mm, 10 μm), mobile phase: [0.1% NH3H2O ETOH], B%: 60% - 60%, min) to obtain the crude product, and purified the crude product by column chromatography (dichloromethane / methanol (100 / 0 - 95 / 5)) to obtain a white solid compound 31 (105 mg, 222.74 μmol, yield: 63.77%), MS (ESI) m / z = 460.5 [M + H] + , 11H NMR (400 MHz, 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).

[0161] Example 32 TIFF2025519406000085.tif32170 Synthesis route: TIFF2025519406000086.tif57170

[0162] 1. Weighed 32-1 (20.0 g, 235 mmol, 1.00 eq) into a 250 mL round-bottom flask, added 100 mL of DMF, weighed 4-methoxybenzyl chloride (18.4 g, 117 mmol, 16.0 mL, 0.50 eq), weighed K2CO3 (48.7 g, 353 mmol, 1.50 eq), stirred at room temperature for 3 h, adjusted the pH of the system to pH = 5, extracted the system with 100 mL of ethyl acetate, washed the aqueous phase with 200 mL of ethyl acetate, combined the organic phases, then washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated the organic phase under reduced pressure to obtain a crude product, and purified the crude product by column chromatography (petroleum ether / ethyl acetate = 100 / 0 - 50 / 50) to obtain white solid 32-2 (6.20 g, 28.91 mmol, yield: 24.60%). 1 1H NMR (400 MHz, DMSO-d6) δ = 11.67 (br s, 1H), 7.92 (s, 1H), 7.24 (d, J = 8.8 Hz, 2H), 6.94 - 6.89 (m, 2H), 4.66 (s, 2H), 3.74 (s, 3H).

[0163] 2. Weighed 32-2 (1.00 g, 4.87 mmol, 1.00 eq) into a 100 mL three-necked reaction flask, protected it with nitrogen gas, added dioxane (50 mL), weighed 2-bromothiazole (799 mg, 4.87 mmol, 439 μL, 1.00 eq), and successively weighed Cs2CO3 (3.18 g, 9.75 mmol, 2.00 eq), CuI (464 mg, 2.44 mmol, 0.50 eq), and KI (647 mg, 3.90 mmol, 0.80 eq) into the system. Stirred the mixture at 100 °C for 12 h, concentrated the system, washed the filter cake with 30 mL of ethyl acetate and concentrated it. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 100 / 0 - 60 / 40) to obtain white solid 32-3 (170 mg, 590 μmol, yield: 12.1%). 1 1H NMR (400 MHz, DMSO-d6) δ = 8.45 (s, 1H), 7.60 (d, J = 3.6 Hz, 1H), 7.51 (d, J = 3.6 Hz, 1H), 7.33 (d, J = 8.4 Hz, 2H), 6.99 - 6.87 (m, 2H), 4.83 (s, 2H), 3.74 (s, 3H).

[0164] 3. Weighed 32-3 (170 mg, 590 μmol, 1.00 eq) into a 40 mL sealed tube, added 0.5 mL of water and 5 mL of acetonitrile to the system, weighed ammonium cerium(IV) nitrate (970 mg, 1.77 mmol, 882 μL, 3.00 eq), and stirred the mixture at room temperature for 12 h. Concentrated and filtered the system, then washed the filter cake with 10 mL of ethyl acetate, concentrated the filtrate to obtain the crude product. The crude product was purified by column prep-HPLC (column: Welch Xtimate C18 150×30 mm×5 μm, mobile phase: [water(NH4HCO3)-ACN], B%: 0% - 16%, 28 min) to obtain 32-4 (30 mg, 178.38 μmol, yield: 30.25%), MS (ESI) m / z = 169 [M+H] + , 11H NMR (400 MHz, DMSO-d6) δ = 7.85 - 7.77 (m, 1H), 7.37 (d, J = 3.6 Hz, 1H), 7.08 (d, J = 3.6 Hz, 1H), 6.86 (d, J = 8.8 Hz, 1H).

[0165] 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), then the system was placed at 50 °C and stirred for 12 h. The system was quenched with water (5 mL), extracted with ethyl acetate (10.0 mL × 2), the organic phases were combined, then washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, the organic phase was concentrated under reduced pressure, and the crude product was separated by SFC (column: DAICEL CHIRALCEL OD (250 mm × 30 mm, 10 μm), mobile phase: [0.1% NH3H2O ETOH], B%: 60% - 60%, min) to obtain the crude product. The crude product was separated and purified by column chromatography (dichloromethane / methanol (100 / 0 - 95 / 5)) to obtain white solid compound 32 (20 mg, 38.4 μmol, yield: 21.51%). MS (ESI) m / z = 485.1 [M + H]. + , 1 1H NMR (400 MHz, DMSO-d6) δ = 8.25 (s, 1H), 7.61 (d, J = 3.6 Hz, 1H), 7.51 (d, J = 3.6 Hz, 1H), 4.83 - 4.68 (m, 1H), 4.64 - 4.54 (m, 1H), 4.30 (s, 1H), 2.76 (br t, J = 8.8 Hz, 1H), 2.09 - 2.03 (m, 2H), 1.74 - 1.01 (m, 24H), 0.58 (s, 3H).

[0166] Example 33 TIFF2025519406000087.tif32170 Synthesis route: TIFF2025519406000088.tif68170

[0167] 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 it to the system under the condition of 0 °C. Keep the system at 0 °C and react for 0.5 h. Quench the system with an aqueous ammonium chloride solution (500 mL), extract with ethyl acetate (200 mL × 2), combine the organic phases, then wash with saturated brine (10 mL), dry over anhydrous sodium sulfate, filter, concentrate the organic phase under reduced pressure, and purify the crude product by Pre-HPLC (column: Phenomenex C18 75×30 mm×3 μm, mobile phase: [water (HCl)-ACN], B%: 36% - 76%, 36 min) to obtain a red solid 33-2 (150 mg, 451.10 μmol, yield: 14.28%). 1 1H NMR (400 MHz, CDCl3) δ = 2.54 (t, J = 8.8 Hz, 1H), 2.21 - 2.09 (m, 4H), 2.01 (td, J = 3.2, 12.0 Hz, 1H), 1.63 - 1.49 (m, 10H), 1.43 - 1.22 (m, 12H), 0.96 (dd, J = 5.6, 12.3 Hz, 1H), 0.82 - 0.79 (m, 1H), 0.76 (s, 3H), 0.61 (s, 3H).

[0168] 2. Weighed 33-2 (150 mg, 451.10 μmol, 1.00 eq) into a 40 mL sealed tube, protected the system with N2 gas, added 1.5 mL of methanol at room temperature, added 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) under the condition of 0 °C, then placed the system at room temperature and stirred for 12 hours. Quenched the system with an aqueous sodium bicarbonate solution (5 mL), extracted with ethyl acetate (5 mL × 2), combined the organic phases, then washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated the organic phase under reduced pressure, and purified the crude product by column chromatography (petroleum ether / ethyl acetate = 100 / 1 - 1 / 1) to obtain a white solid 33-3 (150 mg, 364.60 μmol, yield: 80.82%). 1 1H NMR (400 MHz, CDCl3) δ = 3.84 (d, J = 2.9 Hz, 2H), 2.75 (t, J = 8.8 Hz, 1H), 2.17 - 2.04 (m, 1H), 1.71 - 1.57 (m, 4H), 1.55 (br d, J = 3.2 Hz, 5H), 1.43 (br d, J = 2.4 Hz, 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, 12.1 Hz, 1H), 0.74 (br s, 1H), 0.68 (s, 3H), 0.56 (s, 3H).

[0169] 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), then the system was placed at 50 °C and stirred for 12 hours. The system was quenched with water (5 mL), extracted with ethyl acetate (10.0 mL × 2), the organic phases were combined, then washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, the organic phase was concentrated under reduced pressure, and the crude product was separated by SFC (column: DAICEL CHIRALCEL OD (250 mm × 30 mm, 10 μm), mobile phase: [0.1% NH3H2O ETOH], B%: 60% - 60%, min) to obtain the crude product. The crude product was separated and purified by column chromatography (dichloromethane / methanol (100 / 0 - 95 / 5)) to obtain the white solid compound 33 (20 mg, 38.93 μmol, yield: 16.02%). MS (ESI) m / z = 510.1 [M + H] + , 1 1H NMR (400 MHz, DMSO-d6) δ = 8.21 (s, 1H), 7.84 - 7.69 (m, 2H), 7.64 - 7.43 (m, 1H), 7.11 (br d, J = 2.0 Hz, 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).

[0170] Example 34 TIFF2025519406000089.tif30170Synthesis route: TIFF2025519406000090.tif33170

[0171] 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). Then the system was placed at 50 °C and stirred for 16 h. The system was quenched with water (20 mL) and extracted with ethyl acetate (10.0 mL × 2). The organic phases were combined, then 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 separated by SFC (column: DAICEL CHIRALCEL OD (250 mm × 30 mm, 10 μm), mobile phase: [0.1% NH3H2O ETOH], B%: 60% - 60%, min) to obtain the crude product. The crude product was separated and purified by column chromatography (dichloromethane / methanol (100 / 0 - 95 / 5)) to obtain the white solid compound 34 (63 mg, 122 μmol, yield: 22.8%). MS (ESI) m / z = 485.3 [M - H2O + H] + , 1 1H NMR (400 MHz, 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 = 8.8 Hz, 1H), 2.19 - 1.95 (m, 2H), 1.81 - 1.46 (m, 9H), 1.43 - 0.99 (m, 15H), 0.59 (s, 3H).

[0172] Example 35 TIFF2025519406000091.tif28170Synthesis route: TIFF2025519406000092.tif57170

[0173] The compound M7 was synthesized by adopting the same method as in Example 1.

[0174] 1. Compound 35-1 (1.03 g, 5.00 mmol, 0.80 eq) was added to a 100 mL three-necked flask (R1) filled with nitrogen gas. Dibromotetrafluoropyridine (1.10 g, 6.25 mmol, 1.00 eq) was added to the reaction system. Cs2CO3 (4.07 g, 12.5 mmol, 2.00 eq) was added to R1 at 25 °C. Potassium iodide (830.08 mg, 5.00 mmol, 0.80 eq) was added to R1. CuI (595.20 mg, 3.13 mmol, 0.50 eq) was added to R1 at 25 °C. 1,10-Phenanthroline (788 mg, 4.38 mmol, 0.70 eq) was added to R1 at 25 °C. Dioxane (20.0 mL) was added to R1 at 25 °C. R1 was stirred at 100 °C for 2 hours. Thin layer chromatography (petroleum ether / ethyl acetate = 1 / 3) indicated that compound 35-1 was consumed and a new spot appeared. Water (10 mL) was added to the mixture to quench it, and it was extracted with ethyl acetate (10 mL × 2). The combined organic phases were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 100 / 1 - 1 / 3) to obtain the yellow solid compound 35-2 (490 mg, 1.63 mmol, yield: 26.11%). 1 1H NMR (400 MHz, DMSO-d6) δ = 8.56 - 8.47 (m, 1H), 8.37 (s, 1H), 7.82 (dd, J = 2.4, 11.2 Hz, 1H), 7.32 (s, 2H), 7.29 - 7.22 (m, 1H), 6.94 (d, J = 8.8 Hz, 2H), 4.81 (s, 2H), 3.74 (s, 3H).

[0175] 2. Compound 35-2 (100 mg, 333.01 μmol, 1.00 eq) was added to a 40 mL sealed tube (R1), the temperature was controlled at 25 °C, acetonitrile (10 mL) was added to R1, the temperature was controlled at 25 °C, ammonium cerium(IV) nitrate (547.70 mg, 999.04 μmol, 497.91 μL, 3.00 eq) was added to R1, and the mixture was stirred at 60 °C for 12 h. The mixture was concentrated to obtain a crude product, and the crude product was purified by column chromatography to obtain white solid compound 35-3 (40 mg, 83.49 μmol, yield: 25.07%). 1 1H NMR (400 MHz, DMSO-d6) δ = 12.11 (br s, 1H), 8.51 (dd, J = 5.6, 9.1 Hz, 1H), 8.16 (s, 1H), 7.84 (dd, J = 2.4, 11.1 Hz, 1H), 7.24 (br t, J = 2.4 Hz, 1H).

[0176] 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), then the system was placed at 50 °C and stirred for 12 h. The system was quenched with water (5 mL), extracted with ethyl acetate (10.0 mL × 2), the organic phases were combined, then 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 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]. + , 11H NMR (400 MHz, DMSO-d6) δ = 8.53 (dd, J = 5.6, 9.2 Hz, 1H), 8.18 (s, 1H), 7.77 (dd, J = 2.4, 10.8 Hz, 1H), 7.28 (ddd, J = 2.4, 5.6, 8.4 Hz, 1H), 4.87 - 4.43 (m, 2H), 2.76 (br t, J = 8.8 Hz, 1H), 2.17 - 1.97 (m, 2H), 1.89 - 1.17 (m, 18H), 1.14 - 0.86 (m, 7H), 0.58 (s, 3H).

[0177] Example 36 TIFF2025519406000093.tif32170Synthesis route: TIFF2025519406000094.tif57170

[0178] 1. Compound 36-1 (5 g, 39.1 mmol, 1.00 eq) was placed in a 40 mL sealed tube (R1), the temperature was controlled at 25 °C, N2H4·H2O (20.0 g, 391 mmol, 19.4 mL, 10.0 eq) was added to R1, and R1 was stirred at 100 °C for 12 hours. The mixture was concentrated to obtain the crude product, a white solid compound 36-2 (2.10 g, 17.05 mmol, yield: 43.51%).

[0179] 2. Water (12.0 mL) was poured into a 250 mL round-bottom flask (R1), the temperature was controlled at 25 °C, hydrochloric acid (12 M, 1.00 mL, 2.79 eq) was added to R1, 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, glyoxylic acid (955 mg, 6.46 mmol, 718 μL, 1.50 eq) was added to R1 at 25 °C, the temperature was controlled at 25 °C, and R1 was stirred for 2 hours to obtain 36-3. The mixture was concentrated by lyophilization to obtain the yellow solid compound 36-3 (910 mg), MS (ESI) m / z = 180 [M+H]. +, 1H NMR (400 MHz, DMSO-d6) δ = 13.52 (br s, 1H), 8.34 (br d, J = 6.4 Hz, 1H), 7.70 (s, 1H), 7.52 - 7.00 (m, 2H), 2.59 (s, 3H).

[0180] 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, toluene (5.00 mL) was added to R1, and the mixture was stirred for 12 hours to obtain yellow solid compound 36-4 (30 mg, 170.29 μmol, yield: 3.05%) as a crude product, MS (ESI) m / z = 177 [M+H]. + , 1 1H NMR (400 MHz, DMSO-d6) δ = 12.62 (br s, 1H), 8.73 (d, J = 6.6 Hz, 1H), 8.45 (s, 1H), 8.33 - 8.17 (m, 2H), 2.74 (s, 3H).

[0181] 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), then the system was placed at 50 °C and stirred for 12 hours. The system was quenched with water (5 mL), extracted with ethyl acetate (10.0 mL × 2), the organic phases were combined, then 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 separated and purified by HPLC to obtain white solid compound 36 (15 mg, 30.17 μmol, yield: 27.12%), MS (ESI) m / z = 493 [M+H]. + , 11H NMR (400 MHz, DMSO-d6) δ = 8.75 (d, J = 7.2 Hz, 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 = 9.6 Hz, 2H), 1.83 - 1.18 (m, 18H), 1.14 - 0.85 (m, 7H), 0.59 (s, 3H).

[0182] Example 37 TIFF2025519406000095.tif32170Synthesis route: TIFF2025519406000096.tif35170

[0183] 1. K2CO3 (195.43 mg, 1.41 mmol, 10.0 eq), M7 (56.19 mg, 141.41 μmol, 1.00 eq), and 37-1 (the 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). Then the system was placed at 50 °C and stirred for 12 hours. The system was quenched with water (5 mL), extracted with ethyl acetate (10.0 mL × 2), the organic phases were combined, then washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure. After that, 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 1H NMR (400 MHz, DMSO-d6) δ = 8.66 (d, J = 5.6 Hz, 1H), 8.30 (d, J = 2.0 Hz, 1H), 8.10 (d, 1H), 7.67 (s, 1H), 6.66 (s, 1H), 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).

[0184] Example 38 TIFF2025519406000097.tif32170 Synthesis route: TIFF2025519406000098.tif82170

[0185] 1. Sodium hydride (2.69 g, 67.3 mmol, 60.0% purity, 1.50 eq) was dissolved in 25.0 mL of dimethylformamide, then placed in 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 mixture 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 then 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 - 20 °C. The reaction mixture was extracted with ethyl acetate (50.0 mL). Then the organic phase and the aqueous phase were separated. The aqueous phase was further extracted twice with ethyl acetate (30.0 mL). The organic phase was washed five times with water (50.0 mL) and then with saturated brine (100 mL), dried over an appropriate amount of anhydrous sodium sulfate, and 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 obtain colorless oily compound 38-2 (11.9 g, 38.3 mmol, yield: 85.3%).

[0186] 2. Compound 38-3 (989 mg, 4.82 mmol, 1.00 eq) was added to a 40.0 mL sealed tube (R1), degassed dioxane (20.0 mL) was added to R1 at room temperature, compound 38-2 (1.50 g, 4.82 mmol, 1.00 eq) was added to R1 at room temperature, cesium carbonate (3.14 g, 9.64 mmol, 2.00 eq) was added to R1 at room temperature, potassium iodide (640 mg, 3.86 mmol, 0.80 eq) was added to R1 at room temperature, 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 h, the reaction solution in R1 was filtered, ethyl acetate (20.0 mL) was added to R1 at room temperature, the organic and aqueous phases were separated, the aqueous phase was extracted twice more with ethyl acetate (20.0 mL), the organic phase was washed with saturated brine (20.0 mL), dried over an appropriate amount of anhydrous sodium sulfate, and finally the organic phase was filtered and concentrated to obtain a crude product. The 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 obtain compound 38-4 (952 mg, 2.45 mmol, yield 17.0%) as a yellow solid.

[0187] 3. Compound 38-4 (950 mg, 2.45 mmol, 1.00 eq) was added to a 50.0 mL single-neck flask (R1) protected by 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 h and at 40 °C for 12 h. Pd / C (52.1 mg, 48.9 μmol, 0.02 eq) was added to R1 at room temperature, and R1 was stirred at 25 °C for 1 h. The reaction solution was filtered, and the filtrate was concentrated to obtain compound 38-5 (185 mg, 620 μmol, yield: 25.4%) as a yellow solid.

[0188] 4. Compound 38-5 (185 mg, 620 μmol, 3.00 eq) was added to a 40.0 mL AK flask (R1), nitromethane (17.2 g, 282 mmol, 15.3 mL, 1365 eq) was added to R1 at room temperature, 1-(trifluoromethyl)-1,2-benziodoxol-3(1H)-one (65.3 mg, 207 μmol, 1.00 eq) was added to R1 at room temperature, and R1 was stirred at 100 °C for 16 h. The crude product obtained by concentrating the reaction solution was separated by conventional reverse phase to obtain a yellow solid compound 38-6 (25.0 mg, 60.1 μmol, yield: 88.0%).

[0189] 5. Compound 38-6 (25.0 mg, 68.3 μmol, 1.00 eq) was added to a 40.0 mL AK flask (R1), acetonitrile (10.0 mL) was added to R1 at room temperature, ammonium cerium(IV) nitrate (112 mg, 205 μmol, 102 μL, 3.00 eq) was added to R1 at room temperature, and R1 was stirred at 50 °C for 12 h. Ammonium cerium(IV) nitrate (112 mg, 205 μmol, 102 μL, 3.00 eq) was added to R1 at room temperature, and R1 was stirred at 60 °C for 10 h. Water (20.0 mL) was added to R1 at room temperature, the reaction solution was extracted with ethyl acetate (20.0 mL), then the organic phase and the aqueous phase were separated, the aqueous phase was extracted twice more with ethyl acetate (10.0 mL), the organic phase was washed with saturated brine (20.0 mL), further dried over an appropriate amount of anhydrous sodium sulfate, and finally the organic phase was filtered and concentrated to obtain a yellow solid compound 38-7 (20.0 mg, crude), MS (ESI) m / z = 247.0 [M+H] + It was as follows.

[0190] 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). Then the system was placed at 50 °C and stirred for 12 h. The system was quenched with water (5 mL), extracted with ethyl acetate (10.0 mL × 2), the organic phases were combined, then 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 separated and purified by HPLC to obtain a pale yellow solid compound 38 (8.2 mg, 13.7 μmol, yield: 15%). MS (ESI) m / z = 563.1 [M+H] + , 1 1H NMR (400 MHz, CHLOROFORM-d) δ = 8.33 (d, J = 5.6 Hz, 1H), 7.93 (dd, J = 1.6, 5.6 Hz, 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).

[0191] Example 39 TIFF2025519406000099.tif35170Synthesis route: TIFF2025519406000100.tif33170

[0192] 1. K2CO3 (483 mg, 3.49 mmol, 10.0 eq), M7 (139 mg, 349 μmol, 1.00 eq), and 39-1 (the preparation method refers to the preparation method of 35-3) (100 mg, 384 μmol, 1.10 eq) were added to THF (4.0 mL). Then the system was placed at 50 °C and stirred for 12 h. The system was quenched with water (5 mL), extracted with ethyl acetate (10.0 mL × 2), the organic phases were combined, then 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 separated and purified by HPLC to obtain the white solid compound 39 (136 mg, 222 μmol, yield: 63.1%), MS (ESI) m / z = 577.3 [M+H] + , 1 1H NMR (400 MHz, DMSO-d6) δ = 8.31 - 8.21 (m, 2H), 7.64 (dd, J = 1.6, 5.6 Hz, 1H), 7.42 (d, J = 1.6 Hz, 1H), 5.03 (q, J = 9.2 Hz, 2H), 4.80 - 4.53 (m, 2H), 2.77 (br t, J = 8.8 Hz, 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).

[0193] Example 40 TIFF2025519406000101.tif32170Synthesis route: TIFF2025519406000102.tif35170

[0194] 1. K2CO3 (509 mg, 3.68 mmol, 10.0 eq), M7 (146 mg, 368 μmol, 1.00 eq), and 40-1 (the 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). Then the system was placed at 50 °C and stirred for 12 h. The system was quenched with water (5 mL) and extracted with ethyl acetate (10.0 mL × 2). The organic phases were combined, then 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 separated and purified by HPLC to obtain a pale yellow solid compound 40 (65.4 mg, 129.1 μmol, yield: 35.1%). MS (ESI) m / z = 507.4 [M+H] + , 1 1H NMR (400 MHz, DMSO-d6) δ = 8.44 (s, 1H), 8.09 (s, 2H), 4.83 - 4.53 (m, 2H), 2.79 (br t, J = 8.8 Hz, 1H), 2.70 (s, 6H), 2.06 (br d, J = 9.6 Hz, 2H), 1.81 - 0.94 (m, 25H), 0.58 (s, 3H).

[0195] Example 41 TIFF2025519406000103.tif32170 Synthesis route: TIFF2025519406000104.tif32170

[0196] 1. K2CO3 (634 mg, 4.59 mmol, 10.0 eq), M7 (182 mg, 459 μmol, 1.00 eq), and 41-1 (the preparation method refers to the preparation method of 36-4) (100 mg, 505 μmol, 1.10 eq) were added to THF (4.0 mL). Then the system was placed at 50 °C and stirred for 12 hours. The system was quenched with water (5 mL), extracted with ethyl acetate (10.0 mL × 2), the organic phases were combined, then washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure. After that, the crude product was separated and purified by HPLC to obtain a pale yellow solid compound 41 (153 mg, 185.2 μmol, yield: 62.3%), and MS (ESI) m / z = 497.2 [M+H] + , 1 1H NMR (400 MHz, 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 = 7.2 Hz, 1H), 2.77 (br t, J = 8.8 Hz, 1H), 2.06 (br d, J = 9.6 Hz, 2H), 1.78 - 0.98 (m, 23H), 0.59 (s, 3H).

[0197] Example 42 TIFF2025519406000105.tif32170Synthesis route: TIFF2025519406000106.tif61170

[0198] 1. Under nitrogen gas protection, anhydrous tetrahydrofuran (15 mL) was added to a 100 mL three-necked flask (R1). Compound 42-1 (1 g, 3.16 mmol, 1.00 eq) was added to R1 at 25 °C, MeMgBr (3 M, 1.05 mL, 1.00 eq) was added to R1 at 0 °C, and R1 was stirred at 0 °C for 0.5 h. Saturated ammonium chloride (5 mL) was added to the mixture, and the mixture was filtered. The filter cake was washed with ethyl acetate (5 mL × 2). The filtrate and the organic layer were separated, washed with brine (10 mL), the organic phase was dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. The crude product was purified by high performance liquid chromatography to obtain a white compound 42-2 (165 mg, 496.21 μmol, yield: 15.70%).

[0199] 2. Compound 42-2 (165 mg, 496 μmol, 1.00 eq) was added to a 40 mL sealed tube (R1) filled with nitrogen gas. 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, and R1 was stirred at 25 °C for 5 h. Saturated sodium hydrogen carbonate (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 obtain a crude product. The crude product was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 100 / 1 - 1 / 1) to obtain a white solid compound 42-3 (140 mg, 340.29 μmol, yield: 68.58%). 11H NMR (400 MHz, CDCl3) δ = 4.05 - 3.74 (m, 2H), 2.82 (t, J = 8.8 Hz, 1H), 2.31 - 2.06 (m, 1H), 1.81 - 1.62 (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, 12.0 Hz, 1H), 0.82 (dd, J = 3.6, 11.6 Hz, 1H), 0.76 (s, 3H), 0.64 (s, 3H).

[0200] 3. K2CO3 (470.30 mg, 3.40 mmol, 10.0 eq), 42-3 (140 mg, 340.29 μmol, 1.00 eq), and 42-4 (61.30 mg, 340.29 μmol, 1.00 eq) were added to THF (4.0 mL), then the system was placed at 50 °C and stirred for 12 hours. The system was quenched with water (5 mL), extracted with ethyl acetate (10.0 mL × 2), the organic phases were combined, then 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 separated and purified by HPLC to obtain the pale yellow solid compound 42 (110 mg, 211.54 μmol, yield: 62.16%), MS (ESI) m / z = 511 [M+H]. + , 11H NMR (400 MHz, CDCl3) δ = 8.23 (d, J = 5.8 Hz, 1H), 7.88 (d, J = 5.6 Hz, 1H), 7.71 - 7.53 (m, 2H), 4.69 - 4.33 (m, 2H), 2.63 (t, J = 8.8 Hz, 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 = 2.1 Hz, 1H), 0.77 (s, 3H), 0.68 (s, 3H).

[0201] Example 43 TIFF2025519406000107.tif32170Synthesis route: TIFF2025519406000108.tif52170

[0202] 1. Compound 43-1 (255 mg, 1.24 mmol, 1.20 eq) was added to a 40.0 mL AK flask (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 the mixture was stirred at 80 °C for 2 hours. TLC (dichloromethane / methanol = 10 / 1) indicated that compound 43-1 had completely reacted and a new spot had formed. After filtering the reaction solution, the filtrate was concentrated to obtain a crude product as a white solid. The crude product was separated by conventional reverse phase to obtain compound 43-3 as a white solid (100 mg, 315 μmol, yield: 30.4%). 11H NMR (400 MHz, DMSO-d6) δ = 8.06 (s, 1H), 7.23 (d, J = 8.8 Hz, 2H), 6.91 (d, J = 8.8 Hz, 2H), 4.71 (s, 2H), 4.31 (t, J = 5.2 Hz, 2H), 3.99 (t, J = 5.2 Hz, 2H), 3.73 (s, 4H).

[0203] 2. Compound 43-3 (50.0 mg, 157 μmol, 1.00 eq) was placed in a 40.0 mL AK flask (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, ammonium cerium(IV) 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, R1 was stirred 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 was directly used in the next step.

[0204] 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), then the system was placed at 50 °C and stirred for 12 hours, the system was quenched with water (5 mL), extracted with ethyl acetate (10.0 mL × 2), the organic phases were combined, then washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure to obtain white solid compound 43 (160 mg, 309 μmol, yield: 60.9%), MS (ESI) m / z = 514.4 [M+H]. + , 11H NMR (400 MHz, 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).

[0205] Example 44 TIFF2025519406000109.tif32170Synthesis route: TIFF2025519406000110.tif29170

[0206] 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) (for the preparation method of 44-1, refer to 43-4) were added to THF (4 mL). Then the system was placed at 50 °C and stirred for 12 h. The system was quenched with water (5 mL), extracted with ethyl acetate (10.0 mL × 2), the organic phases were combined, then washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 0 - 10%) to obtain 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, and R2 was stirred at room temperature for 2 h. The mixture in R2 was filtered, and the filtered solid was concentrated to obtain a yellow solid compound 44 (144 mg, 270 μmol, yield: 60.7%). MS (ESI) m / z = 503.2 [M-OH+H]. + , 11H NMR (400 MHz, DMSO-d6) δ = 8.28 (s, 1H), 8.16 (s, 1H), 8.05 (td, J = 2.4, 10.5 Hz, 1H), 7.80 - 7.74 (m, 1H), 4.83 - 4.47 (m, 2H), 4.25 (br s, 1H), 2.77 (br t, J = 8.8 Hz, 1H), 2.12 - 2.01 (m, 2H), 1.78 - 1.01 (m, 24H), 0.59 (s, 3H).

[0207] Example 45 TIFF2025519406000111.tif32170Synthesis route: TIFF2025519406000112.tif52170

[0208] 1. Add compound 45-1 (2.00 g, 16.1 mmol, 1.00 eq, HCl) to a 500 mL single-neck flask (R1), add toluene (25.0 mL) to R1 at room temperature, add NaOH (6.42 g, 16.1 mmol, 1.00 eq) to R1 at room temperature, stir R1 at room temperature for 15 minutes. Dissolve benzyl chloroformate (2.63 g, 15.4 mmol, 2.20 mL, 0.96 eq) in toluene (10.0 mL), add R1 at -15°C, add NaOH (6.16 g, 15.4 mmol, 10.0% purity, 0.96 eq) to R1 at -15°C, and stir R1 at room temperature for 2 hours. Add chloroform (30.0 mL) to R1 at room temperature, separate the organic phase and the aqueous phase, extract the aqueous phase with chloroform (30.0 mL) three more times, wash the organic phase with saturated brine (100 mL), dry it with an appropriate amount of anhydrous sodium sulfate, and finally concentrate the organic phase by filtration to obtain a crude product. Purify the crude product (petroleum ether:ethyl acetate = 1:1, Rf = 0.49) by silica gel column chromatography (petroleum ether:ethyl acetate = 0 - 20%) to obtain a colorless oily compound 45-2 (1.46 g, 6.57 mmol, yield: 40.9%), MS (ESI) m / z = 223.1 [M+H]. + , 11H NMR (400 MHz, CHLOROFORM-d) δ = 7.27 (s, 5H), 5.06 (s, 2H), 0.99 (s, 9H).

[0209] 2. Compound 45-2 (960 mg, 4.32 mmol, 1.00 eq) was added to a 100 mL single-necked flask (R1), isopropanol (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, and 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 obtain compound 45-3 as a white solid (550 mg, 2.07 mmol, yield: 48.0%), MS (ESI) m / z = 265.9 [M+H]. + , 1 1H NMR (400 MHz, 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).

[0210] 3. Compound 45-3 (300 mg, 1.13 mmol, 1.00 eq) was added to a 50.0 mL single-necked flask (R1) under a hydrogen balloon (15.0 Psi) protection, 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, and R1 was stirred at room temperature for 12 hours. The reaction solution was filtered, and the filtrate was concentrated to obtain compound 45-4 as a white solid (145 mg, 1.11 mmol, yield: 97.8%). 11H NMR (400 MHz, DMSO-d6) δ = 6.19 - 5.62 (m, 2H), 4.35 (s, 2H), 1.31 (s, 9H).

[0211] 4. Compound 45-4 (95.0 mg, 724 μmol, 1.00 eq) was added to a 40.0 mL AK flask (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, and 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 as a white solid (110 mg, crude), MS (ESI) m / z = 142.3 [M+H]. + , 1 1H NMR (400 MHz, DMSO-d6) δ = 11.31 (br s, 1H), 7.69 (s, 1H), 1.44 (s, 9H).

[0212] 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), then the system was placed at 50 °C and stirred for 12 hours. The system was quenched with water (5 mL), extracted with ethyl acetate (10.0 mL × 2), the organic phases were combined, then washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (methanol:dichloromethane = 0 - 10%) to obtain compound 45 as a white solid (210 mg, 456 μmol, yield: 70.8%), MS (ESI) m / z = 458.3 [M +H]. + , 11H NMR (400 MHz, DMSO-d6) δ = 7.74 (s, 1H), 4.54 - 4.38 (m, 2H), 4.24 (s, 1H), 2.73 - 2.64 (m, 1H), 2.09 - 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).

[0213] Measurement of biological activity Test Example 1. Evaluation of intracellular and extracellular functional activities of cell synapses in vitro 1.1 Experimental materials TIFF2025519406000113.tif94170

[0214] 1.2 Experimental methods The α4β3δ-HEK-FlpIn-TRex stable cell line was cultured in DMEM + 10% FBS complete medium with Blasticidin 10 μg / mL, Zeocin 100 μg / mL, Hygromycin 100 μg / mL, and Puromycin 0.2 μg / mL as selective antibiotics. The α1β2γ2-CHO-TRex stable cell line was cultured in DMEM / F12 + 10% FBS complete medium with Blasticidin 10 μg / mL, Zeocin 100 μg / mL, Hygromycin 300 μg / mL, and Puromycin 1 μg / mL as selective antibiotics.

[0215] On the day before the patch-clamp experiment, the cells were seeded onto 12-mm cover glasses coated with polylysine and continuously cultured in 35-mm culture dishes. At the same time, tetracycline (1 μg / mL) was supplemented to induce the expression of GABA receptors. The composition of the extracellular solution was as follows (mM): 140 NaCl, 3 KCl, 1.5 MgCl2, 2 CaCl2, 10 HEPES, 10 Glucose. After thoroughly mixing, NaOH was added to adjust the pH to 7.4, and sucrose was added to adjust the osmotic pressure to 300 - 320 mOsm, and it was stored at 4°C. The composition of the electrode internal solution (mM): 145 KCl, 1 MgCl2, 5 EGTA, 10 HEPES, 5 MgATP. After thoroughly mixing, KOH was added to adjust the pH to 7.3, and sucrose was added to adjust the osmotic pressure to 290 - 300 mOsm. After filtering with a 0.22 μM filter, it can be used.

[0216] This experiment mainly applied the whole-cell patch-clamp recording method, clamped the membrane potential at -60 mV, applied a GABA (~1 μM)-activated receptor with an activation width in the range of EC10 - 20, formulated the test compound in 0.1% DMSO, performed perfusion for 30 s during GABA stimulation, and finally measured the positive allosteric regulatory effect of the test compound on α1β2γ2 or α4β3δ.

[0217] The experimental results at each concentration are shown as the fold increase in the GABA-induced current of the compound. First, the minimum concentration that increases the GABA-induced current of the compound was explored, and then the detection concentration was gradually increased in a three-fold manner until the activation effect of the compound reached above the EC 80 effect. The number of measured concentrations was at least 5, and it was carried out until a complete EC 50 curve and EC 50 value were obtained. All experiments were repeated on more than 3 cells, and data processing was performed using GraphPad prism software. The dose-dependent curve was fitted using the Hill equation, and finally the half-activation concentration EC 50 and E max were obtained. The results are shown in Table 1. TIFF2025519406000114.tif246170TIFF2025519406000115.tif58170

[0218] According to the results, it is shown that all of Compounds 1 to 45 have relatively good synaptic internal and external functional activities.

[0219] Test Example 2. Evaluation of Liver Microsomal Metabolic Stability In Vitro 2.1 Preparation of Solutions 1) Preparation of test article working solution: Dilute the test article to 100 μM with acetonitrile. 2) Preparation of liver microsome working solution: Dilute liver microsomes to 0.56 mg / mL with 100 mM phosphate buffer. 3) Preparation of reduced nicotinamide adenine dinucleotide phosphate (NADPH) working solution: Weigh an appropriate amount of NADPH, dilute it to 20 mM with phosphate buffer, and further add an equal volume of 60 mM MgCl2 solution. 4) Preparation of stop solution: Dilute tolbutamide to 20 ng / mL with acetonitrile as the stop solution containing the internal standard.

[0220] 2.2 Incubation Process 1) Prepare adsorption-resistant EP tubes for incubation, label the species, test article / control article, time points (0, 5, 10, 20, 30, 60 min, Blank60, NCF60), etc. 2) Add 2 μL of the test article or control article working solution diluted to 100 μM with acetonitrile and 178 μL of the liver microsome working solution to each tube. Add 2 μL of acetonitrile instead of the test article to the Blank60 tube, place it in a water bath at 37°C for pre-incubation for about 10 min, and prepare three parallel samples for each. 3) After the pre-incubation is completed, except for 0 min and NCF60, add 20 μL of NADPH working solution to each tube to initiate the reaction. Add 20 μL of phosphate buffer (containing 30 mM MgCl2) to the NCF60 tube, and set the final concentration of the test article or control in the incubation system to 1 μM, the final concentration of liver microsomes to 0.5 mg / mL, the final concentration of NADPH to 1 mM, and the final concentration of MgCl2 to 3 mM. 4) First, add the 0 min sample to 600 μL of the stop solution, then add the NADPH working solution. After incubating each sample for the corresponding time, add 600 μL of the stop solution to stop the reaction. 5) After stopping the reaction of each sample, vortex for 30 s, then centrifuge at 13500 rpm for 10 min. Take 100 μL of the supernatant and put it into an EP tube, add 100 μL of Milli-Q water, vortex to mix evenly, and then analyze by LC-MS / MS. 6) Testosterone and dextromethorphan were used as positive controls under the same conditions to detect the stability and reliability of the system.

[0221] 2.3 Data analysis Estimate the half-life, liver microsome intrinsic clearance, and liver intrinsic clearance parameters of the test article from the remaining percentage of the test article, and show the results in Table 2. TIFF2025519406000116.tif246170TIFF2025519406000117.tif248170TIFF2025519406000118.tif16170

[0222] As shown in the above table, the compounds provided by the present disclosure often have relatively good stability in the liver microsomes of rats and humans, indicating good metabolic stability.

[0223] Test Example 3, Recovery Reflex Loss Test of SD Rats by Intravenous Injection of Compound 41 3.1 Test objective Detect the disappearance threshold of the righting reflex in SD rats by injection of Compound 41, and evaluate the sedative effect and therapeutic safety window of the compound.

[0224] 3.2 Test process Male SD rats weighed 180 - 200 g. After arriving at the animal breeding facility, the test animals were acclimated for 7 days and randomly grouped according to their body weight 1 day before the test. They were fasted for half a day without water deprivation before the test. Compound 41 was designed with a dose gradient of 0.8 times, and the doses were set at 23.5 mg / kg, 18.8 mg / kg, 15 mg / kg, 12 mg / kg, and 9.6 mg / kg. The situation of disappearance of the righting reflex within 4 hours after intraperitoneal injection of Compound 41 into the rats was observed. Criteria for judging the disappearance of the righting reflex in rats: After injection of Compound 41, if the rat in the supine position could not reverse within 30 s, it was considered positive for the disappearance of the righting reflex; otherwise, it was considered negative.

[0225] 3.3 Test results According to the test results, it is shown that at doses of 23.5 mg / kg, 18.8 mg / kg, 15 mg / kg, 12 mg / kg, and 9.6 mg / kg, the incidence rates of the righting reflex in rats were 80%, 50%, 30%, 0, and 0 respectively. Under the test conditions, the threshold dose for the disappearance of the righting reflex in SD rats by intraperitoneal injection of Compound 41 was 12 mg / kg, indicating that Compound 41 has a relatively wide therapeutic safety window.

[0226] Test Example 4, Righting Reflex Disappearance Test in SD Rats by Forced Oral Administration of Compound 41 4.1 Test purpose Detect the disappearance threshold of the righting reflex in SD rats by forced oral administration of Compound 41, and evaluate the sedative effect and therapeutic safety window of Compound 41.

[0227] 4.2 Test method Male SD rats weighed 180 - 200 g. After arriving at the animal breeding facility, the experimental animals were acclimatized for 7 days and randomly grouped according to their body weight 1 day before the experiment. They were fasted overnight without water deprivation before the test. Compound 41 was designed with a dose gradient of 0.8, and the doses were set at 39 mg / kg, 31.25 mg / kg, 25 mg / kg, 20 mg / kg, and 16 mg / kg, with 10 rats in each group. The disappearance status of the righting reflex within 4 hours after forced oral administration to the rats was observed. Criteria for judging the disappearance of the righting reflex in rats: After administration of the test compound, if a rat in the supine position could not reverse within 30 s, it was considered positive for the disappearance of the righting reflex; otherwise, it was considered negative.

[0228] 4.3 Test Results According to the results, at doses of 39 mg / kg, 31.25 mg / kg, 25 mg / kg, 20 mg / kg, and 16 mg / kg, the incidence rates of the righting reflex in rats were shown to be 100%, 90%, 50%, 0%, and 0% respectively. Under the experimental conditions, the threshold dose for the disappearance of the righting reflex in SD rats due to forced oral administration of Compound 41 was 20 mg / kg. The threshold dose for the disappearance of the righting reflex (20 mg / kg) when Compound 41 was forcibly administered orally to rats was 5.7 times the effective dose for anti - epileptic spasm (3.5 mg / kg), having a relatively wide therapeutic safety window.

[0229] Test Example 5, In - vivo Pharmacokinetic Study of Compound 41 in CD - 1 Mice 4.1 Test Animals and Solvent CD - 1 mice, male, weighing approximately 25 g, were randomly grouped with 3 mice in each group DMSO: 30% SBECD (10%:90%) 4.2 Test Methods The intravenous (IV) administration dose was 1 mg / kg, and the forced oral (IG) administration dose was 5 mg / kg. The animals were fasted 12 h before administration, allowed free access to water, and uniformly fed 3 h after administration. Approximately 0.15 mL of blood was collected at 5 min (intravenous), 15 min, 30 min, 1 h, 2 h, 4 h, 8 h, 12 h, and 24 h after administration, placed in heparinized EP tubes, centrifuged at 13,500 rpm for 10 min to separate the plasma. And the brain tissues of the mice were collected after cardiac perfusion at 30 min, 2 h, and 8 h. After pretreatment, analysis was performed by LC-MS / MS to measure the concentrations of the test substance in plasma and brain, and pharmacokinetic parameters were calculated.

[0230] 4.3 Test Results TIFF2025519406000119.tif43170TIFF2025519406000120.tif35170

[0231] According to the data in Table 3, after intravenous and forced oral administration of Compound 41 to CD-1 mice, both had relatively high plasma exposure (AUC) and relatively long half-lives, and the absolute bioavailability of forced oral administration could reach 109%, indicating that Compound 41 has good in vivo metabolic stability and high in vivo absorption level. According to the data in Table 4, Compound 41 is shown to have high access ability to the brain, high brain exposure, and relatively high brain concentration.

[0232] Test Example 6, In Vivo Pharmacokinetic Study of Compound 41 in SD Rats 5.1 Test Animals and Solvents SD rats, male, body weight was approximately 250 g, randomly grouped, with 3 rats in each group DMSO: 30% SBECD (10%: 90%) 5.2 Test Methods The intravenous administration dosage was 6.1 μmol / kg, and the forced oral administration dosage was 24.4 μmol / kg. The animals were fasted 12 h before administration, allowed to freely ingest water, and uniformly fed 3 h after administration. Approximately 0.3 mL of blood was collected at 5 min (intravenous), 15 min, 30 min, 1 h, 2 h, 3 h, 4 h, 6 h, 8 h, 12 h, and 24 h after administration, placed in heparinized EP tubes, centrifuged at 13500 rpm for 10 min, and plasma was separated. And the rat brain tissue was collected after heart perfusion at 30 min, 2 h, and 6 h. After pretreatment, analysis was performed by LC-MS / MS to measure the concentrations of the test substance in plasma and brain, and pharmacokinetic parameters were calculated.

[0233] 5.3 Test Results TIFF2025519406000121.tif43170TIFF2025519406000122.tif35170

[0234] According to the data in Table 5, after intravenous administration and forced oral administration of Compound 41 to SD rats, both had relatively high plasma exposure (AUC) and relatively long half-lives, and the absolute bioavailability of forced oral administration was shown to be 84%, indicating that Compound 41 has good in vivo metabolic stability and high in vivo absorption levels. According to the data in Table 5, Compound 41 is shown to have a high ability to access the brain, high brain exposure, and relatively high brain concentrations.

[0235] Test Example 7, Evaluation of the Anticonvulsant Effect of Compound 41 in SD Rats 6.1 Test Objectives SD rats were intraperitoneally injected with 50 mg / kg of pentetrazole (PTZ) to establish an SD rat epilepsy seizure animal model, and the anticonvulsant effect of Compound 41 was detected.

[0236] 6.2 Test Methods Male SD rats weighed 300 ± 10 g. After arriving at the animal breeding facility, the test animals were acclimated for 7 days and randomly grouped according to their body weight 1 day before dosing. They were fasted for half a day without water deprivation before the test. During the test, the animals were orally administered 3.5 mg / kg of Compound 41 in advance, and 2 hours after oral administration, a 50 mg / kg PTZ solution was intraperitoneally injected. The seizure convulsion behaviors of the rats within 1 hour after PTZ induction were observed respectively. The latency of clonic convulsion and the latency of tonic-clonic convulsion were detected.

[0237] 6.3 Test Results The behavioral raw data were finally presented as mean ± standard error (Mean ± S.E.M.). Statistical analysis was performed using One-way ANOVA Dunnett post hoc. P < 0.05 indicates a significant difference, P < 0.01 indicates a very significant difference, and P < 0.001 indicates an extremely significant difference.

[0238] From the results of the behavioral observation of seizure convulsions, within 1 hour after inducing seizure convulsion behavior by intraperitoneal injection of 50 mg / kg of PTZ, the latency of clonic convulsion behavior (2764.6 ± 1330.9 s) of the animals in the dosing group was significantly higher than that of the solvent control group (114.5 ± 36.9 s) (p < 0.001), and the latency of tonic-clonic convulsion behavior (3600 ± 0 s) of the animals in the dosing group was significantly higher than that of the solvent control group (115.8 ± 37.1 s) (P < 0.001).

Claims

1. A compound represented by formula (I), or a pharmaceutically acceptable salt thereof, Eventually, (1) X is independently selected from C atoms and Y is independently selected from N atoms, or X is independently selected from N atoms and Y is independently selected from C atoms, or X and Y are simultaneously selected from C atoms. R 1 is H, C 1-6 alkyl group, halogenated C 1-6 alkyl group, C 3-6 cycloalkyl group, C 3-6 cycloalkyl C 1-3 alkyl group, C 1-6 alkoxy C 1-3 alkyl group, halogenated C 1-6 alkoxy C 1-3 selected from an alkyl group, a 6- to 10-member aryl group, or a 5- to 10-member heteroaryl group, and the 6- to 10-member aryl group and the 5- to 10-member heteroaryl group are optionally substituted by one or more halogens, C 1-6 alkyl group, halogenated C 1-6 alkyl group, C 1-6 alkoxy group, halogenated C 1-6 alkoxy group, -(C=O)NH 2 , -NH 2 , or a cyano group, and may be substituted; R 2 H, halogen, C 1-6 Alkyl alkyl group, or C 1-6 Alkoxy C 1-3 Selected from alkyl groups, R 3 H, C 1-6 Alkyl alkyl group, or C 1-6 Alkoxy C 1-3 Selected from alkyl groups, Or (2) X and Y are simultaneously selected from C atoms, and X and Y, together with the atoms to which they are linked, form ring A. The aforementioned ring A is, Selected from, Among them, A 1 , A 2 , A 3 , A 4 Each of them independently performs CR 4 , or selected from N atoms, R 1 H, halogenated C 1-6 Alkyl alkyl group, C 3-6 Cycloalkyl groups, C 3-6 Cycloalkyl C 1-3 Alkyl alkyl group, C 1-6 Alkoxy C 1-3 Alkyl alkyl groups, C halogenated compounds 1-6 Alkoxy C 1-3 Selected from alkyl groups, 6-10 membered aryl groups, or 5-10 membered heteroaryl groups, the 6-10 membered aryl groups and 5-10 membered heteroaryl groups are optionally one or more halogens, C 1-6 Alkyl alkyl groups, C halogenated compounds 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, halogenated C 1-6 Alkoxy group, -(C=O)NH 2 , -NH 2 , or may be substituted with a cyano group, R 2 H, halogen, C 1-6 Alkyl alkyl group, or C 1-6 Alkoxy C 1-3 Selected from alkyl groups, R 3 H, C 1-6 Alkyl alkyl group, or C 1-6 Alkoxy C 1-3 Selected from alkyl groups, Each R 4 These are H, halogen, and C, respectively, independently. 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, C 1-6 Halide alkoxy group, C 1-6 Alkoxy C 1-3 Alkyl alkyl group, or halogenated C 1-6 Alkoxy C 1-3 Selected from alkyl groups, A compound, or a pharmaceutically acceptable salt thereof.

2. The aforementioned compound, or a pharmaceutically acceptable salt thereof, has the structure of formula (IA) or formula (IB), Among them, X, Y, ring A, R 1 , R 2 , R 3 , R 4 , A 1 , A 2 , A 3 and A 4 This is as defined in claim 1, The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

3. The aforementioned compound, or a pharmaceutically acceptable salt thereof, has the structure of formula (IIA), (IIB), or (IIC), Eventually, R 1 , R 2 and R 3 This is as defined in claim 1, The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

4. The aforementioned compound, or a pharmaceutically acceptable salt thereof, has the structure of formula (IIA-1), (IIA-2), (IIB-1), (IIB-2), (IIC-1), or (IIC-2), Eventually, R 1 , R 2 and R 3 This is as defined in claim 1, The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

5. R 1 H, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, s-butyl group, t-butyl group, fluoromethyl group, chloromethyl group, difluoromethyl group, dichloromethyl group, trifluoromethyl group, trichloromethyl group, 2,2-difluoroethyl group, 2,2-dichloroethyl group, 2,2,2-trifluoroethyl group, 2,2,2-trichloroethyl group, pentafluoroethyl group, pentachloroethyl group, cyclopentyl group, cyclohexyl group, cyclopropylmethyl group, cyclopropylethyl group, cyclo Butylmethyl group, cyclobutylethyl group, cyclopentylmethyl group, cyclopentylethyl group, cyclohexylmethyl group, cyclohexylethyl group, methoxymethyl group, ethoxymethyl group, methoxyethyl group, ethoxyethyl group, trifluoromethoxymethyl group, trifluoromethoxyethyl group, phenyl group, naphthyl group, pyrrolyl group, furanyl group, thienyl group, imidazolyl group, pyrazolyl group, oxazolyl group, isoxazolyl group, thiazolyl group, isothiazolyl group, pyridyl group, pyridadinyl group, pyrimidinyl group, pyrazinyl group, y A group selected from phenyl, naphthyl, pyrrolyl, furanyl, thienyl, imidazolyl, pyrazolyl, indolyl, benzotriazolyl, benzothienyl, benzofuranyl, benzoisofuranyl, benzodioxol, or benzimidazolyl, and the aforementioned phenyl, naphthyl, pyrrolyl, furanyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyridadinyl, pyrimidinyl, pyrazinyl, indolyl, benzopyrazolyl, isoindolyl Dylyl group, indazolyl group, benzotriazolyl group, benzothienyl group, isobenzothienyl group, benzofuranyl group, benzoisofuranyl group, benzodioxole group, or benzimidazolyl group may be optionally one or more F, Cl, Br, I, methyl group, ethyl group, n-propyl group, isopropyl group, fluoromethyl group, chloromethyl group, difluoromethyl group, dichloromethyl group, trifluoromethyl group, trichloromethyl group, 2,2-difluoroethyl group, 2,2,2-trifluoroethyl group, 2,2,2-Trichloroethyl group, methoxy group, ethoxy group, n-propoxy group, isopropoxy group, trifluoromethoxy group, trichloromethoxy group, 2,2-difluoroethoxy group, 2,2-dichloroethoxy group, 2,2,2-trifluoroethoxy group, 2,2,2-trichloroethoxy group, -(C=O)NH, 2 , -NH 2 , or substituted with a cyano group, R 2 This is selected from H, F, Cl, Br, I, methyl group, ethyl group, n-propyl group, isopropyl group, methoxymethyl group, or ethoxymethyl group. R 3 This is selected from H, methyl group, ethyl group, n-propyl group, isopropyl group, methoxymethyl group, or ethoxymethyl group. The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

6. R 1 H, methyl group, ethyl group, tert-butyl group, cyclopropylmethyl group, 2,2,2-trifluoroethyl group, cyclopentyl group, cyclohexyl group, methoxymethyl group, ethoxymethyl group, methoxyethyl group, ethoxyethyl group, trifluoromethoxymethyl group, trifluoromethoxyethyl group, Selected from, the above This can optionally include one or more F, Cl, Br, I, methyl group, ethyl group, n-propyl group, isopropyl group, fluoromethyl group, chloromethyl group, difluoromethyl group, dichloromethyl group, trifluoromethyl group, trichloromethyl group, 2,2-difluoroethyl group, 2,2-dichloroethyl group, 2,2,2-trifluoroethyl group, 2,2,2-trichloroethyl group, methoxy group, ethoxy group, n-propoxy group, isopropoxy group, fluoromethoxy group, chloromethoxy group, difluoromethoxy group, dichloromethoxy group, trifluoromethoxy group, trichloromethoxy group, 2,2-difluoroethoxy group, 2,2-dichloroethoxy group, 2,2,2-trifluoroethoxy group, 2,2,2-trichloroethoxy group, -(C=O)NH 2 , -NH 2 , or substituted with a cyano group, The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

7. R 1 teeth, Selected from, R 4a 、R 4b 、R 4c 、R 4d 、R 4e are each independently selected from H, F, Cl, Br, I, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, a fluoromethyl group, a chloromethyl group, a difluoromethyl group, a dichloromethyl group, a trifluoromethyl group, a trichloromethyl group, a 2,2-difluoroethyl group, a 2,2-dichloroethyl group, a 2,2,2-trifluoroethyl group, a 2,2,2-trichloroethyl group, a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group, a fluoromethoxy group, a chloromethoxy group, a difluoromethoxy group, a dichloromethoxy group, a trifluoromethoxy group, a trichloromethoxy group, a 2,2-difluoroethoxy group, a 2,2-dichloroethoxy group, a 2,2,2-trifluoroethoxy group, a 2,2,2-trichloroethoxy group, -(C=O)NH 2 、 -NH 2 、 or a cyano group, and R 2 H is, R 3 is a methyl group, The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

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

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

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

11. Use of the compound according to any one of claims 1 to 8 in the preparation of a drug for treating CNS-related diseases.

12. The aforementioned CNS-related disorders include sleep disorders, mood disorders, mania, dysthymia, bipolar disorder, anxiety disorders, stress, post-traumatic stress disorder (PTSD), obsessive-compulsive disorder, schizophrenia spectrum disorder, convulsive disorders, memory and / or cognitive impairment, dementia, motor disorders, personality disorders, autism, autism spectrum disorder (ASD), pain, traumatic brain injury (TBI), vascular diseases, substance abuse disorders and / or withdrawal syndromes, and tinnitus. The use described in claim 11.

13. The aforementioned CNS-related disorders include depression. The use described in claim 12.

14. The aforementioned depression includes mild depression, major depressive disorder, persistent depressive disorder, psychotic depression, postpartum depression, or seasonal affective disorder. The use described in claim 13.

15. The aforementioned CNS-related disorders include insomnia, bipolar I disorder, bipolar II disorder, generalized anxiety disorder (GAD), social anxiety disorder, schizophrenia, schizoaffective disorder, attention deficit disorder, Alzheimer's disease, Lewy body dementia, vascular dementia, Huntington's disease, Parkinson's disease, essential tremor, antisocial personality disorder, obsessive-compulsive personality disorder, autism, monoetogenic autism, synaptic dysfunction (synaptic dysfunction), Rett syndrome, fragile X syndrome, Angelman syndrome, neuropathic pain, injury-related pain syndrome, acute pain, chronic pain, stroke, ischemia, vascular malformations, and addiction to opioid preparations, cocaine, and / or alcohol. The use described in claim 12.

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