Steroid compounds, methods of production, and use thereof

Abstract

The present invention relates to steroid compounds, methods for producing them, and their uses. Specifically, the present invention provides a compound represented by general formula (I), its stereoisomer or pharmaceutically acceptable salt thereof, a method for producing the same, a pharmaceutical composition containing the compound, and its use as a GABAa receptor modulator for treating CNS-related diseases. [Formula 1] JPEG2026516023000135.jpg39170

Description

[Technical Field]

[0001] This application claims priority to Chinese patent application 202310527779.1, filed on 11 May 2023; Chinese patent application 202311387436.6, filed on 25 October 2023; and Chinese patent application 202410117316.2, filed on 29 January 2024. The full text of the above Chinese patent applications is incorporated herein by reference.

[0002] This invention belongs to the pharmaceutical field and specifically relates to steroid compounds, methods for producing them, and their use. [Background technology]

[0003] GABAa receptors are ligand-gated ion channel receptors primarily located at the apical end of the postsynaptic membrane of neurons, capable of inducing fast inhibitory postsynaptic potentials (IPSPs). GABAa receptors are hybrid pentameric proteins composed of three homologous subunits (α1-α6, β1-β4, γ1-γ3, δ, ε, θ, π, and ρ1-ρ3). Each subunit consists of a relatively large N-terminus, four hydrophobic transmembrane domains, one cyclic intracellular domain (containing phosphorylation sites for tyrosine kinase, protein kinase A, and protein kinase C), and a relatively short C-terminus. Most GABAaA subunits form heteropentamers with combinations of two α, two β, and one γ(δ). Different subunit components influence the physiological and pharmacological functions of the resulting GABAaA. In mammalian brains, α1-β1-γ2 is the main structural type of GABAAR, and α2-β3-γ2 and α3-β3-γ2 are also commonly found. The β subunit of GABAAR contains a GABA-recognition site, and when it binds to GABA, the receptor is activated, and the internal Cl - The channel opens, Cl -These molecules selectively enter the cell. The cell membrane of the postsynaptic neuron becomes hyperpolarized, which inhibits electrical discharge and generates a postsynaptic inhibitory potential (IPSP). This inhibitory effect generated in the postsynaptic membrane reduces the excitability of the nerve cell.

[0004] GABAAR membrane endocytosis and recycling are known to occur via their β and γ subunits, and are achieved through binding to the clathrin adapter protein AP2. Phosphorylation of the Tyr and Ser sites in the binding sequence affects AP2 binding, modulates receptor internalization, and influences the inhibitory efficiency of GABAergic activity. Impairment of the inhibitory function of the GABA / GABAAR system may lead to an increased risk of neurological disorders.

[0005] Depression is a common neuropsychiatric disorder characterized by pathological changes in mood, primarily low mood. It is estimated that about 5% of adults worldwide suffer from this disorder. Its features include persistent sadness and a loss of interest or pleasure in activities that were previously considered fulfilling and enjoyable. Depression is a leading cause of disability worldwide and contributes significantly to the global disease burden.

[0006] Research suggests that both synaptic and extrasynaptic GABAa receptors may be involved in the development of depression, and that different subunits of the GABAa receptor play different roles in its development. Although research findings on changes in hippocampal GABAa receptor expression during the development of depression are inconsistent, activating GABAa receptors yields antidepressant and anxiolytic effects. Activating hippocampal GABAa receptors in rats reduces Glu levels, increases GABA levels, and exerts antidepressant effects. This suggests that regulating Glu and GABA levels may be one of the antidepressant pathways of the GABAa receptor. Furthermore, studies using patch-clamp electrophysiology have shown that GABAa receptors can suppress total cell current mediated by Glu ion channel receptors, indicating that GABAa receptors also modulate the function of Glu ion channel receptors. Therefore, GABAa receptor activation has an antidepressant effect, and its antidepressant pathway is closely related to the Glu-mediated and GABA-mediated systems.

[0007] However, with little innovation in the discovery and development of depression treatments over the past 20 years, the development of GABAa receptor modulators aims to change patients' expectations by altering treatment regimens for mesenteric depression (MDD). Currently, overseas pharmaceutical companies, including Sage Therapeutics and Marinus, are focusing their efforts on the development of GABAa receptor modulators.

[0008] Currently under development are several GABAa-targeted neurosteroid drugs, including Alfaxalone, Alfadolone, Ganaxolone, Allopregnanolone, and Sage-217. Of these, Alfaxalone, Alfadolone, Ganaxolone, and Allopregnanolone have all clinically demonstrated significant therapeutic effects as neurosteroid GABAa ligands. Unfortunately, however, due to their strong lipophilicity and rapid metabolism in the liver, these drugs have very low oral bioavailability and can only be administered by injection. Sage-217, an oral GABAa receptor-positive allosteric modulator from Sage Therapeutics, received Breakthrough Drug designation from the US FDA in its clinical development program for consistently, rapidly, and sustainably reducing symptoms of depression (including anxiety and insomnia), while demonstrating acceptable tolerability and safety. However, further research has revealed that Sage-217 still has many problems. For example, the high lipophilicity of its steroid skeleton results in low solubility, and the inability to chlorinate it further reduces its solubility, a problem that remains unresolved. In clinical applications, higher doses are required to achieve the desired effect, increasing costs and reducing patient compliance. Furthermore, due to its poor absorption, the drug must be taken with food in clinical regimens. Most critically, it has serious side effects. The FDA has issued a black box warning for the drug regarding "excessive sedation." Patients cannot drive or operate heavy machinery for 12 hours after taking the drug. Therefore, the drug can only be taken with dinner and cannot be used for more than 14 days. This issue may limit its approval under the MDD (Medical Developmental Disease) program.

[0009] Therefore, there is an urgent need to develop novel steroid compounds that can function as safe, long-term-use brain excitability modulators for the prevention and treatment of CNS-related diseases. These compounds should have improved drug discovery potential, a low metabolic rate, high in vivo exposure, maintain moderate lipophilicity to ensure penetration of the blood-brain barrier, and reduce maximum antagonistic activity against the target, thereby mitigating adverse reactions. [Overview of the project]

Problems to be Solved by the Invention

[0010] The technical problem to be solved by the present invention is to provide a GABAa receptor regulator having a completely new structure, specifically, to provide a steroid compound, a method for producing the same, a pharmaceutical composition thereof and its use, and the compound has a good positive regulatory effect on the GABAa receptor (for example, improved E max and / or EC 50 ), and / or improved pharmacokinetic properties (for example, longer half-life t 1 / 2 , larger exposure amount AUC and higher maximum blood drug concentration C max ), and / or improved safety margin (for example, having a wider safe dosage range or a lower possibility of side effects at the same dosage), and / or improved safety (for example, having lower toxicity and / or fewer side effects), and / or improved medicinal efficacy (for example, significant anti-epileptic effect and / or significant antidepressant effect).

Means for Solving the Problems

[0011] An object of the present invention is to provide a compound represented by the general formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof,

Chemical Formula

[0012] In one preferred embodiment, X is hydrogen, C 1-6 Alkyl alkyl group, C 6-10 A 5-10 membered heteroaryl group containing an aryl group or 1-4 heteroatoms selected from N, O, and S, wherein the above C 1-6 Alkyl alkyl group, C 6-10 An aryl group or a 5-10 membered heteroaryl group containing 1-4 heteroatoms selected from N, O, and S may optionally have one or more additional R groups. A Substituted with, preferably, X is hydrogen, C 6-10 A 5-10 membered heteroaryl group containing an aryl group or 1-4 heteroatoms selected from N, O, and S, wherein the above C 6-10 An aryl group or a 5-10 membered heteroaryl group containing 1-4 heteroatoms selected from N, O, and S may optionally have one or more additional R groups. A It will be replaced by this.

[0013] In one preferred embodiment, the above R A These are halogen, -CN, and -NR aa R bb -C(=O)R aa , -C(=O)OR aa -C(=O)NR aa R bb -S(=O)2R aa -S(=O)2NR aa R bb -S(=O)(=NR aa )R bb ,-P(=O)R aa R bb , C 1-6 Alkyl alkyl group, C 1-6 Haloalkyl group, C 1-6 Alkoxy group, C 3-8 The group is a cycloalkyl group or a 3- to 8-membered heterocyclyl group, preferably a halogen, -CN, or -S(=O)2R aa -S(=O)2NR aaR bb -S(=O)(=NR aa )R bb ,-P(=O)R aa R bb , C 1-6 Alkyl alkyl group, C 1-6 Haloalkyl group or C 1-6 An alkoxy group, more preferably a halogen, -CN, or -S(=O)2R aa -S(=O)2NR aa R bb -S(=O)(=NR aa )R bb ,-P(=O)R aa R bb , C 1-3 Alkyl alkyl group, C 1-3 Haloalkyl group or C 1-3 The group is an alkoxy group, and more preferably fluorine, chlorine, -CN, methyl group, trifluoromethyl group, methoxy group, -SO2CH3, -SO2NH2, -SCH3(=O)(=NH), -SCH3(=O)(=NCH3), or -P(=O)(CH3)2.

[0014] In one preferred embodiment, the above R aa , R bb and R cc These are, independently, hydrogen or C 1-6 It is an alkyl group, preferably hydrogen or C 1-3 It is an alkyl group, more preferably a hydrogen or methyl group.

[0015] In one preferred embodiment, L is -(CH2) n1 -,-(CH2) n1 C(O)(CH2) n2 -,-(CH2) n1 S(O)2(CH2) n2 -,-(CH2) n1 C(O)NH(CH2) n2 -,-(CH2) n1 C(O)(CH2) n2 NH-, -(CH2) n1 NHC(O)(CH2) n2 - or - (CH2) n1NHS(O)2(CH2) n2 -and preferably -C(O)(CH2) n2 -, -C(O)NH(CH2) n2 -, -C(O)(CH2) n2 NH-, -(CH2) n1 NHC(O)- or -(CH2) n1 It is NHS(O)2-, and more preferably -C(O)(CH2) n2 - or -C(O)(CH2) n2 It is NH-.

[0016] In one preferred embodiment, the above R x and R y These are, independently, hydrogen, deuterium, halogen, hydroxyl group, and C 1-6 Alkyl alkyl group, C 1-6 Haloalkyl group, C 1-6 Alkoxy group or C 3-8 It is a cycloalkyl group, preferably hydrogen, deuterium, halogen, hydroxyl group, or C 1-6 It is an alkyl group, and more preferably, hydrogen.

[0017] In one preferred embodiment, R1, R2, and R5 are each independently hydrogen, deuterium, halogen, hydroxyl group, and C 1-6 Alkyl alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 Haloalkyl group, C 1-6 Alkoxy group, -(CH2) n3 Ure dd ,-(CH2) n3 SR dd or -(CH2) n3 C(O)R dd Preferably, hydrogen, deuterium, C 1-3 Alkyl alkyl group, C 2-4 Alkenyl group, C 2-4 An alkynyl group, more preferably hydrogen or C 1-3 It is an alkyl group, and more preferably a hydrogen or methyl group.

[0018] In one preferred embodiment, R3, R3', R6, and R6' are each independently hydrogen, deuterium, or C 1-6 It is an alkyl group, preferably hydrogen, deuterium, or C 1-3 It is an alkyl group, more preferably hydrogen or C 1-3 It is an alkyl group, and more preferably a hydrogen or methyl group.

[0019] In one preferred embodiment, R4 and R4' are each independently hydrogen or C 1-6 It is an alkyl group, preferably hydrogen or C 1-3 It is an alkyl group, more preferably a hydrogen or methyl group, and R4 and R4' are not simultaneously hydrogen. In one preferred embodiment, the above R dd and R ee Each of them is independently C 1-6 Alkyl alkyl group or C 1-6 It is a haloalkyl group, preferably C 1-3 It is an alkyl group.

[0020] In one preferred embodiment, n is selected from 0, 1, 2, 3, or 4, and is preferably 0, 1, or 2.

[0021] In one preferred embodiment, the above m is selected from 0, 1, 2, 3, or 4, and is preferably 0, 1, or 2.

[0022] In one preferred embodiment, n1 is selected from 0, 1, or 2, and is preferably 0 or 1.

[0023] In one preferred embodiment, n2 is selected from 0, 1, or 2, preferably 0 or 1, and more preferably 1.

[0024] In one preferred embodiment, n3 is selected from 0, 1, or 2, and is preferably 0 or 1.

[0025] In one preferred embodiment, the above general formula (I) has a structure represented by general formula (II), [ka] In the formula, X, L, R1, R2, R3, R x , R y n and m are as described above.

[0026] In one preferred embodiment, the above general formula (I) further has a structure represented by general formula (III), [ka] In the formula, X, L, R1, R2, R x , R y n and m are as described above.

[0027] In one preferred embodiment, the above general formula (I) has a structure represented by general formula (IV), [ka] During the ceremony, Z is -(CH2) n4 - or -NH(CH2) n4 -and preferably -(CH2) n4 -and, moreover, -CH2-, R1 is hydrogen, deuterium, halogen, hydroxyl group, C 1-6 Alkyl alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 Haloalkyl group, C 1-6 Alkoxy group, -(CH2) n3 Ure dd ,-(CH2) n3 SR dd or -(CH2) n3 C(O)R dd And preferably, C 1-6 It is an alkyl group, more preferably C 1-3 It is an alkyl group, and more preferably a methyl group, R2 is hydrogen, deuterium, halogen, hydroxyl group, C 1-6 Alkyl alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 Haloalkyl group, C 1-6 Alkoxy group, -(CH2) n3 Ure dd ,-(CH2) n3 SR dd or -(CH2) n3 C(O)R dd Preferably, hydrogen or C 1-6 It is an alkyl group, more preferably hydrogen or C 1-3 It is an alkyl group, and more preferably a hydrogen or methyl group. R dd C 1-6 Alkyl alkyl group or C 1-6 It is a haloalkyl group, preferably C 1-3 It is an alkyl group, n4 is 0, 1, or 2, preferably 0 or 1. X, R x , R y n and m are as described above.

[0028] In one preferred embodiment, the above general formula (I) further has a structure represented by general formula (V) or general formula (VA), [ka] During the ceremony, X is hydrogen or optionally one or more R A A 5-10 membered heteroaryl group comprising 1-4 heteroatoms selected from N, O, and S substituted with R, preferably hydrogen or optionally one or more R A A 5-10 membered heteroaryl group containing 1-4 nitrogen atoms substituted with, R A These are halogens, hydroxyl groups, -CN, and -NR aa R bb -C(=O)R aa , -C(=O)OR aa-OC(=O)R aa , -OC(=O)OR aa -C(=O)NR aa R bb , -N(R aa )C(=O)R bb -OC(=O)NR aa R bb , -N(R aa )C(=O)OR bb , -N(R cc )C(=O)NR aa R bb , -SR aa -S(=O)R aa -S(=O)2R aa -S(=O)2OR aa -OS(=O)2R aa -S(=O)2NR aa R bb -S(=O)(=NR aa )R bb , -N(R aa )S(=O)2R bb ,-P(=O)R aa R bb , C 1-6 Alkyl alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 Haloalkyl group, C 1-6 Alkoxy group, C 1-6 Haloalkoxy group, C 3-8 The group is a cycloalkyl group or a 3- to 8-membered heterocyclyl group, preferably a halogen, -CN, or -S(=O)2R aa -S(=O)2NR aa R bb -S(=O)(=NR aa )R bb ,-P(=O)R aa R bb , C 1-6 Alkyl alkyl group, C 1-6 Haloalkyl group or C 1-6 An alkoxy group, more preferably a halogen, -CN, or -S(=O)2R aa -S(=O)2NR aa R bb -S(=O)(=NR aa )R bb,-P(=O)R aa R bb , C 1-3 Alkyl alkyl group, C 1-3 Haloalkyl group or C 1-3 It is an alkoxy group, more preferably fluorine, chlorine, -CN, methyl group, trifluoromethyl group, methoxy group, -SO2CH3, -SO2NH2, -SCH3(=O)(=NH), -SCH3(=O)(=NCH3), or -P(=O)(CH3)2. R aa , R bb and R cc These are hydrogen and C, respectively, independently. 1-6 Alkyl alkyl group or C 1-6 It is a haloalkyl group, preferably hydrogen or C 1-6 It is an alkyl group, more preferably hydrogen or C 1-3 It is an alkyl group, and more preferably a hydrogen or methyl group.

[0029] In one preferred embodiment, X in the above general formulas (Ia), (I), (II), (III), and (IV) is hydrogen or one of the following groups: [ka] And, Preferably, [ka] And, R A These are halogens, hydroxyl groups, -CN, and -NR aa R bb -C(=O)R aa , -C(=O)OR aa -OC(=O)R aa , -OC(=O)OR aa -C(=O)NR aa R bb , -N(R aa )C(=O)R bb -OC(=O)NR aa R bb , -N(R aa )C(=O)ORbb , -N(R cc )C(=O)NR aa R bb , -SR aa -S(=O)R aa -S(=O)2R aa -S(=O)2OR aa -OS(=O)2R aa -S(=O)2NR aa R bb -S(=O)(=NR aa )R bb , -N(R aa )S(=O)2R bb ,-P(=O)R aa R bb , C 1-6 Alkyl alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 Haloalkyl group, C 1-6 Alkoxy group, C 1-6 Haloalkoxy group, C 3-8 The group is a cycloalkyl group or a 3- to 8-membered heterocyclyl group, preferably a halogen, -CN, or -S(=O)2R aa -S(=O)2NR aa R bb -S(=O)(=NR aa )R bb ,-P(=O)R aa R bb , C 1-6 Alkyl alkyl group, C 1-6 Haloalkyl group or C 1-6 An alkoxy group, more preferably a halogen, -CN, or -S(=O)2R aa -S(=O)2NR aa R bb -S(=O)(=NR aa )R bb ,-P(=O)R aa R bb , C 1-3 Alkyl alkyl group, C 1-3 Haloalkyl group or C 1-3It is an alkoxy group, more preferably fluorine, chlorine, -CN, methyl group, trifluoromethyl group, methoxy group, -SO2CH3, -SO2NH2, -SCH3(=O)(=NH), -SCH3(=O)(=NCH3), or -P(=O)(CH3)2. R aa , R bb and R cc These are hydrogen and C, respectively, independently. 1-6 Alkyl alkyl group or C 1-6 It is a haloalkyl group, preferably hydrogen or C 1-6 It is an alkyl group, more preferably hydrogen or C 1-3 It is an alkyl group, and more preferably a hydrogen or methyl group. o is selected from 0, 1, 2, 3 or 4, preferably 0, 1 or 2, and more preferably 0 or 1.

[0030] In one preferred embodiment of the present invention, general formula (I) further has a structure represented by general formula (VI), [ka] During the ceremony, R1 is hydrogen, deuterium, halogen, hydroxyl group, C 1-6 Alkyl alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 Haloalkyl group or C 1-6 It is an alkoxy group, preferably hydrogen, deuterium, or C 1-6 It is an alkyl group, more preferably hydrogen, deuterium, or C 1-3 It is an alkyl group, more preferably hydrogen, deuterium, or a methyl group. X is hydrogen or optionally one or more R A A 5-10 membered heteroaryl group comprising 1-4 heteroatoms selected from N, O, and S substituted with R, preferably hydrogen or optionally one or more R A A 5-10 membered heteroaryl group containing 1-4 nitrogen atoms substituted with, more preferably, [ka] And, R A These are halogens, hydroxyl groups, cyano groups, and C 1-6 Alkyl alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 Haloalkyl group, C 1-6 Alkoxy group or C 1-6 It is a haloalkoxy group, preferably a cyano group, C 1-6 Alkyl alkyl group or C 1-6 It is a haloalkyl group, more preferably a cyano group, C 1-3 Alkyl alkyl group or C 1-3 It is a haloalkyl group, more preferably a cyano group, a methyl group, or a trifluoromethyl group. o is selected from 0, 1, or 2, and is preferably 0 or 1.

[0031] In one preferred embodiment of the present invention, general formula (VI) further has a structure represented by general formula (VIa) or (VIb), [ka] During the ceremony, X is hydrogen or optionally one or more R A A 5-10 membered heteroaryl group comprising 1-4 heteroatoms selected from N, O, and S substituted with R, preferably hydrogen or optionally one or more R A A 5-10 membered heteroaryl group containing 1-4 nitrogen atoms substituted with, more preferably, [ka] And, R A These are halogens, hydroxyl groups, cyano groups, and C 1-6 Alkyl alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 Haloalkyl group, C 1-6 Alkoxy group or C 1-6It is a haloalkoxy group, preferably a cyano group, C 1-6 Alkyl alkyl group or C 1-6 It is a haloalkyl group, more preferably a cyano group, C 1-3 Alkyl alkyl group or C 1-3 It is a haloalkyl group, more preferably a cyano group, a methyl group, or a trifluoromethyl group. o is selected from 0, 1, or 2, and is preferably 0 or 1.

[0032] In one preferred embodiment of the present invention, general formula (I) further has a structure represented by general formula (VII), [ka] During the ceremony, R1 is hydrogen, deuterium, halogen, hydroxyl group, C 1-6 Alkyl alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 Haloalkyl group or C 1-6 It is an alkoxy group, preferably hydrogen, deuterium, or C 1-6 It is an alkyl group, more preferably hydrogen, deuterium, or C 1-3 It is an alkyl group, more preferably hydrogen, deuterium, or a methyl group. X is optionally one or more R A A 5-10 membered heteroaryl group comprising 1-4 heteroatoms selected from N, O, and S substituted with R, preferably one or more R optionally. A A 5-10 membered heteroaryl group containing 1-4 nitrogen atoms substituted with, more preferably, [ka] And, R A These are halogens, hydroxyl groups, cyano groups, and C 1-6 Alkyl alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 Haloalkyl group, C 1-6 Alkoxy group or C1-6 is a haloalkoxy group, preferably a cyano group or C 1-6 is an alkyl group, more preferably a cyano group or C 1-3 is an alkyl group, still more preferably a cyano group or a methyl group, o is selected from 0, 1 or 2, preferably 0 or 1.

[0033] In one preferred embodiment of the present invention, general formula (VII) further has a structure represented by general formula (VIIa) or (VIIb),

Chemical formula

Chemical formula

[0034] In one preferred embodiment of the present invention, general formula (I) further has a structure represented by general formula (VIII),

Chemical formula

Chemical formula

[0035] In one preferred embodiment of the present invention, the general formula (VIII) further has a structure represented by the general formula (VIII-A) or (VIII-B),

Chemical formula

[0036] In one preferred embodiment of the present invention, the above compound is [ka] [ka] [ka] They are selected from among them.

[0037] The present invention further provides a pharmaceutical composition comprising a therapeutically effective amount of a compound represented by each of the above general formulas, a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier, diluent, or excipient.

[0038] In some embodiments of the present invention, the pharmaceutical composition may be administered by any of the following methods: oral administration, spray inhalation, rectal administration, nasal administration, cheek administration, topical administration, parenteral administration such as injection or infusion into the subcutaneous, intravenous, intramuscular, intraperitoneal, intrathecal, ventricular, sternal, or intracranial cavity, or administration via an explanted reservoir. Of these, oral administration is preferred.

[0039] For oral administration, the compound of this application may be manufactured in any orally acceptable formulation form, including but not limited to tablets, capsules, aqueous solutions, or aqueous suspensions. The carrier used for tablets generally contains lactose and corn starch, and may also contain lubricants such as magnesium stearate. The diluent used for capsule formulations generally contains lactose and dried corn starch. Aqueous suspension formulations are typically used by mixing the active ingredient with a suitable emulsifier and suspension agent. Sweeteners, flavorings, or colorants may be further added to the above oral formulation forms as needed.

[0040] The present invention further provides the use of compounds represented by the above general formulas, their stereoisomers, their tautomers, or pharmaceutically acceptable salts thereof, or the above pharmaceutical compositions, in the manufacture of drugs.

[0041] The present invention further provides the use of compounds represented by the above general formulas, their stereoisomers, their tautomers, or pharmaceutically acceptable salts thereof, or the above pharmaceutical compositions, in the manufacture of GABAa receptor modulator drugs.

[0042] The present invention further provides the use of compounds represented by the above general formulas, their stereoisomers, their tautomers, or pharmaceutically acceptable salts thereof, or the above pharmaceutical compositions, in the manufacture of drugs for treating CNS-related diseases.

[0043] The present invention further provides for the use of compounds represented by the above general formulas, their stereoisomers, their tautomers, or pharmaceutically acceptable salts thereof, or the above pharmaceutical compositions, in the treatment of CNS-related diseases.

[0044] In some embodiments of the present invention, the above CNS-related diseases are selected from sleep disorders, mood disorders, premenstrual dysphoric disorder, schizophrenia spectrum disorders, spastic disorders, memory disorders and / or cognitive disorders, movement disorders, personality disorders, autism spectrum disorders, depression, postpartum depression, major depression, menopausal depression, anxiety disorders, premenstrual anxiety disorder, epilepsy, pain, traumatic brain injury, vascular diseases, substance use disorders and / or withdrawal syndromes or tinnitus.

[0045] In some embodiments of the present invention, the above CNS-related disease is depression.

[0046] In some embodiments of the present invention, the above CNS-related disease is postpartum depression.

[0047] In some embodiments of the present invention, the above CNS-related disease is major depression.

[0048] In some embodiments of the present invention, the above CNS-related disease is menopausal depression.

[0049] In some embodiments of the present invention, the above CNS-related disease is an anxiety disorder.

[0050] In some embodiments of the present invention, the above CNS-related disease is premenstrual dysphoric disorder.

[0051] In some embodiments of the present invention, the above CNS-related disease is epilepsy.

[0052] Detailed Description of the Present Invention Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0053] The compounds of the present invention may exist in the form of specific geometric isomers or stereoisomers. The present invention assumes that all such compounds include cis and trans isomers, (-)- and (+)- paired enantiomers, (R)- and (S)- enantiomers, diastereomers, (D)- isomers, (L)- isomers, and their racemic and other mixtures, such as enantiomer- or diastereomer-rich mixtures, all of which fall within the scope of the present invention. Substituents such as alkyl groups may include other chiral carbon atoms. All of these isomers and mixtures thereof are within the scope of the present invention. In some embodiments, preferred compounds are isomer compounds exhibiting superior biological activity. Purified or partially purified isomers and stereoisomers, or racemic or diastereomer mixtures of the compounds of the present invention are all within the scope of the present invention. Purification and separation of such substances can be achieved by standard techniques known in the art.

[0054] The term "alkyl group" refers to a linear or branched saturated aliphatic hydrocarbon group consisting of carbon and hydrogen atoms that are linked to the rest of the molecule by single bonds. An alkyl group may have 1 to 8 carbon atoms, i.e., a "C1-C8 alkyl group," for example, C1-C8 alkyl group. 1-4 Alkyl alkyl group, C 1-3 Alkyl alkyl group, C 1-2 Alkyl alkyl group, C3 alkyl group, C4 alkyl group, C 1-6 Alkyl alkyl group, C 3-6It is an alkyl group. Non-exclusive examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl, or 1,2-dimethylbutyl, or their isomers. The alkyl group may be optionally substituted or unsubstituted, and if substituted, the substituent may be substituted at any available linking point, and the substituent may be one or more, for example alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, alkylthio groups, halogens, mercapto groups, hydroxyl groups, nitro groups, amino groups, cyano groups, carboxyl groups, oxo groups, cycloalkyl groups, heterocyclyl groups, aryl groups, or heteroaryl groups.

[0055] The term "alkylene group" refers to an alkyl group in which one hydrogen atom is further substituted, for example, "C 1-8The term "alkylene group" refers to an alkylene group containing 1 to 8 carbon atoms, such as methylene, ethylene, propylene, butylene, pentylene, hexylene, 1-methylethylene, 2-methylethylene, methylpropylene, or ethylpropylene. The alkylene group may be optionally substituted or unsubstituted, and if substituted, the substituent may be substituted at any available linking point, and the substituent may be one or more, such as alkyl, alkenyl, alkynyl, alkoxy, alkylthio, halogen, mercapto, hydroxyl, nitro, amino, cyano, carboxy, oxo, cycloalkyl, heterocyclyl, aryl, or heteroaryl groups. A "methylene group" refers to -CH2-, an "ethylene group" refers to -(CH2)2-, a "propylene group" refers to -(CH2)3-, and a "butylene group" refers to -(CH2)4-, etc.

[0056] The term "cycloalkyl group" refers to saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituents, and cycloalkyl groups contain 3 to 20 carbon atoms, i.e., "C3-C20 20 It is a "cycloalkyl group," for example, C 3-18 Cycloalkyl groups, C 3-16 Cycloalkyl groups, C 3-12 Cycloalkyl groups, C 3-8 Cycloalkyl groups, C 3-6 Cycloalkyl groups, C 3-5 Cycloalkyl groups, C 3-4 Cycloalkyl groups, C 4-8 Cycloalkyl groups, C 4-6 Cycloalkyl groups, C 5-6 It is a cycloalkyl group, preferably C 3-8 Cycloalkyl groups, C 3-6 Cycloalkyl groups, C 3-5 Cycloalkyl groups, C 3-4These are cycloalkyl groups. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, and cyclooctyl groups, while polycyclic cycloalkyl groups include cycloalkyl groups of spiro rings, fused rings, and crosslinked rings. The above cycloalkyl groups may be optionally substituted or unsubstituted, and if substituted, there may be one or more substituents, such as alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, alkylthio groups, alkylamino groups, halogens, mercapto groups, hydroxyl groups, nitro groups, amino groups, cycloalkyl groups, heterocyclylalkyl groups, aryl groups, heteroaryl groups, cycloalkoxy groups, heterocyclylalkoxy groups, cycloalkylthio groups, heterocyclylalkylthio groups, oxo groups, carboxyl groups, or carboxylic acid ester groups.

[0057] The term "heterocyclyl group" refers to a saturated or unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, which contains 3 to 20 ring atoms, of which one or more ring atoms are nitrogen, oxygen, or S(O). mThe heteroatom is selected from (where m is an integer from 0 to 2), but does not contain the -OO-, -OS-, or -SS- ring portion, and the remaining ring atom is carbon. The term includes 3 to 20-membered heterocyclyl groups, for example, 3 to 18-membered heterocyclyl groups, 3 to 16-membered heterocyclyl groups, 3 to 12-membered heterocyclyl groups, 3 to 8-membered heterocyclyl groups, 3 to 6-membered heterocyclyl groups, 3 to 5-membered heterocyclyl groups, 3 to 4-membered heterocyclyl groups, 4 to 8-membered heterocyclyl groups, 4 to 6-membered heterocyclyl groups, and 5 to 6-membered heterocyclyl groups, preferably 3 to 8-membered heterocyclyl groups, 3 to 6-membered heterocyclyl groups, and 3 to 5-membered heterocyclyl groups. A 3- to 4-membered heterocyclyl group, a 4- to 8-membered heterocyclyl group, a 4- to 6-membered heterocyclyl group, a 5- to 6-membered heterocyclyl group, which optionally contain 1 to 4 heteroatoms, 1 to 3 heteroatoms, or 1 to 2 heteroatoms, of which the heteroatoms are optionally N, O, or S atoms, but do not contain the -OO-, -OS-, or -SS- ring portion, and particularly preferably a 3- to 8-membered heterocyclyl group containing 1 to 4 heteroatoms selected from N, O, and S. Non-limiting examples of monocyclic heterocyclyl groups include oxetanyl, thietanyl, pyrrolidinyl, imidazolidinyl, tetrahydrofuran, tetrahydrothienyl, tetrahydropyranyl, dihydroimidazolyl, dihydrofuryl, dihydropyrazolyl, piperidinyl, piperazinyl, morpholinyl, 1,3-dioxocyclopentyl, 2,2-difluoro-1,3-dioxocyclopentyl, or azepinyl groups. Non-limiting examples of polycyclic heterocyclyl groups include spiro-ring, fused-ring, and bridging-ring heterocyclyl groups, of which these spiro-ring, fused-ring, and bridging-ring heterocyclyl groups are optionally linked to other groups by single bonds, or further cyclically linked to other cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups by any two or more atoms on the ring.The heterocyclyl group may be optionally substituted or unsubstituted, and if substituted, the substituent may be substituted at any available linking point, and the substituent may be one or more, for example, alkyl group, alkenyl group, alkynyl group, alkoxy group, alkylthio group, halogen, mercapto group, hydroxyl group, nitro group, amino group, cyano group, carboxyl group, oxo group, cycloalkyl group, heterocyclyl group, aryl group or heteroaryl group.

[0058] The term "aryl group" refers to a 6-14 member all-carbon monocyclic or fused polycyclic group (i.e., a ring sharing adjacent carbon atom pairs) having a conjugated electron system, preferably 6-10 membered, such as a phenyl group or a naphthyl group. More preferably a phenyl group. The aryl group may be optionally substituted or unsubstituted, and if substituted, the substituent may be substituted at any available linking point, and the substituent may be one or more, such as alkyl, alkenyl, alkynyl, alkoxy, alkylthio, halogen, mercapto, hydroxyl, nitro, amino, cyano, carboxyl, oxo, cycloalkyl, heterocyclyl, aryl, or heteroaryl group. If the aryl group is substituted with a substituent, the substituent is not further substituted. The term "heteroaryl group" refers to a monocyclic or fused polycyclic heteroaromatic system containing 1 to 4 heteroatoms and 5 to 14 ring atoms, where the heteroatoms are selected from oxygen, sulfur, nitrogen, etc. The heteroaryl group is preferably a 5 to 14-membered heteroaryl group, more preferably a 5 to 10-membered heteroaryl group, such as a 5 to 6-membered heteroaryl group, a 5 to 6-membered heteroaryl cycloalkyl group, or a 5 to 6-membered heteroaryl C 6-10 Aryl group or C 6-10These are aryl 5-6 member heteroaryl groups, more preferably 5-6 member heteroaryl groups, 5-6 member heteroaryl 5-6 member heteroaryl groups, 5-6 member heteroaryl 5-6 member cycloalkyl groups, 5-6 member heteroaryl phenyl groups, or phenyl 5-6 member heteroaryl groups, and particularly preferably 5-10 member heteroaryl groups containing 1-4 heteroatoms selected from N, O, and S, for example pyrrolyl group, imidazolyl group, furanyl group, pyranyl group, thienyl group, thiazolyl group, thiadiazole group, pyrazolyl group, oxazolyl group, oxadiazole group, triazolyl group, tetrazolyl group, pyridine group, pyrimidinyl group, pyridadinyl group, pyrazinyl group, thienophenyl group, thienopyridine group, pyrazolophenyl group, pyrazolopyridine group, pyrazolocyclohexyl group, pyridothienyl group, pyridopyrrolyl group, benzothienyl group, indolyl group, 1763014960056_21 These include groups such as heteroaryl groups. The heteroaryl group may be optionally substituted or unsubstituted, and if substituted, the substituent may be substituted at any available linking point, and the substituent may be one or more, for example alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, alkylthio groups, halogens, mercapto groups, hydroxyl groups, nitro groups, amino groups, cyano groups, carboxyl groups, oxo groups, cycloalkyl groups, heterocyclyl groups, aryl groups, or heteroaryl groups. If the heteroaryl group is substituted with a substituent, the substituent is not further substituted.

[0059] In the heteroaryl or heterocyclyl groups described above, "hetero" means that one or more of the ring atoms are independently N, O, or S(O). m This indicates that the heteroatoms are selected from such heteroatoms (where m is an integer between 0 and 2), preferably 1 to 4 ring atoms are selected from N, O, or S, and preferably 1 to 3 ring atoms are selected from N, O, or S.

[0060] The term "alkoxy group" refers to -O-(alkyl group) or -O-(unsubstituted cycloalkyl group), the definitions of alkyl groups and cycloalkyl groups as described above. Non-exclusive examples of alkoxy groups include methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, and cyclohexyloxy groups. Alkoxy groups may be optionally substituted or unsubstituted, and if substituted, the substituent may be substituted at any available linking point, and the substituent may be one or more, such as alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, alkylthio groups, halogens, mercapto groups, hydroxyl groups, nitro groups, amino groups, cyano groups, carboxyl groups, oxo groups, cycloalkyl groups, heterocyclyl groups, aryl groups, or heteroaryl groups. If an alkoxy group is substituted with a substituent, the substituent is not further substituted.

[0061] The term "alkylthio group" refers to -S-(alkyl group) or -S-(unsubstituted cycloalkyl group), the definitions of alkyl groups and cycloalkyl groups as described above. Non-exclusive examples of alkylthio groups include methylthio group, ethylthio group, propylthio group, butylthio group, cyclopropylthio group, cyclobutylthio group, cyclopentylthio group, cyclohexylthio group, etc. Alkylthio groups may be optionally substituted or unsubstituted, and if substituted, the substituent may be substituted at any available linking point, and the substituent may be one or more, for example alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, alkylthio groups, halogens, mercapto groups, hydroxyl groups, nitro groups, amino groups, cyano groups, carboxyl groups, oxo groups, cycloalkyl groups, heterocyclyl groups, aryl groups, or heteroaryl groups. If the alkylthio group is substituted with a substituent, the substituent is not further substituted.

[0062] The term "alkylamino group" refers to -NH-(alkyl group or unsubstituted cycloalkyl group) or -N-(alkyl group or unsubstituted cycloalkyl group)(alkyl group or unsubstituted cycloalkyl group), where the definitions of alkyl group and cycloalkyl group are as described above. Non-limiting examples of alkylamino groups include methylamine group, ethylamino group, propylamino group, butylamino group, cyclopropylamino group, cyclobutylamino group, cyclopentylamino group, cyclohexylamino group, etc. Alkylamino groups may be optionally substituted or unsubstituted, and if substituted, the substituent may be substituted at any available linking point, and the substituent may be one or more, for example alkyl group, alkenyl group, alkynyl group, alkoxy group, alkylthio group, halogen, mercapto group, hydroxyl group, nitro group, amino group, cyano group, carboxyl group, oxo group, cycloalkyl group, heterocyclyl group, aryl group, or heteroaryl group. If the alkylamino group is substituted with a substituent, the substituent is not further substituted. The terms "halo," "halogen," or "halogenated" should be understood to refer to fluorine (F), chlorine (Cl), bromine (Br), or iodine (I) atoms, and preferably fluorine, chlorine, or bromine atoms.

[0063] The term "haloalkyl group" refers to an alkyl group substituted with one or more halogens, where the alkyl group is as defined above. Non-limiting examples of halomethyl groups include fluoromethyl, chloromethyl, bromomethyl, iodomethyl, difluoromethyl, chlorofluoromethyl, dichloromethyl, bromofluoromethyl, trifluoromethyl, chlorodifluoromethyl, dichlorofluoromethyl, trichloromethyl, bromodifluoromethyl, bromochlorofluoromethyl, and dibromofluoromethyl groups, with fluoromethyl, difluoromethyl, and trifluoromethyl groups being preferred. Non-limiting examples of haloethyl groups include 2-fluoroethyl group, 2-chloroethyl group, 2-bromoethyl group, 2,2-difluoroethyl group, 2-chloro-2-fluoroethyl group, 2,2-dichloroethyl group, 2-bromo-2-fluoroethyl group, 2,2,2-trifluoroethyl group, 2-chloro-2,2-difluoroethyl group, 2,2,2-dichloro-2-fluoroethyl group, 2,2,2-trichloroethyl group, 2-bromo-2,2-difluoroethyl group, and 2-bromo-2-chloro-2-fluoroethyl group. The group contains ethyl group, 2-bromo-2,2-dichloroethyl group, 1,1,2,2-tetrafluoroethyl group, pentafluoroethyl group, 1-chloro-1,2,2,2-tetrafluoroethyl group, 2-chloro-1,1,2,2-tetrafluoroethyl group, 1,2-dichloro-1,2,2-trifluoroethyl group, 2-bromo-1,1,2,2-tetrafluoroethyl group, and preferably 2-fluoroethyl group, 2-chloroethyl group, 2-bromoethyl group, and 2,2-difluoroethyl group.

[0064] The term "haloalkoxy group" refers to an alkoxy group substituted with one or more halogens, where the alkoxy group is as defined above. Non-limiting examples of halomethoxy groups include fluoromethoxy, chloromethoxy, bromomethoxy, iodomethoxy, difluoromethoxy, chlorofluoromethoxy, dichloromethoxy, bromofluoromethoxy, trifluoromethoxy, chlorodifluoromethoxy, dichlorofluoromethoxy, trichloromethoxy, bromodifluoromethoxy, bromochlorofluoromethoxy, and dibromofluoromethoxy, with fluoromethoxy, difluoromethoxy, and trifluoromethoxy being preferred. Non-limiting examples of haloethoxy groups include 2-fluoroethoxy group, 2-chloroethoxy group, 2-bromoethoxy group, 2,2-difluoroethoxy group, 2-chloro-2-fluoroethoxy group, 2,2-dichloroethoxy group, 2-bromo-2-fluoroethoxy group, 2,2,2-trifluoroethoxy group, 2-chloro-2,2-difluoroethoxy group, 2,2-dichloro-2-fluoroethoxy group, 2,2,2-trichloroethoxy group, 2-bromo-2,2-difluoroethoxy group, and 2-bromo-2-chloro-2-fluorinated group. The material contains a roethoxy group, a 2-bromo-2,2-dichloroethoxy group, a 1,1,2,2-tetrafluoroethoxy group, a pentafluoroethoxy group, a 1-chloro-1,2,2,2-tetrafluoroethoxy group, a 2-chloro-1,1,2,2-tetrafluoroethoxy group, a 1,2-dichloro-1,2,2-trifluoroethoxy group, a 2-bromo-1,1,2,2-tetrafluoroethoxy group, and preferably a 2-fluoroethoxy group, a 2-chloroethoxy group, a 2-bromoethoxy group, and a 2,2-difluoroethoxy group.

[0065] The term "alkenyl group" refers to the alkyl group defined above, consisting of at least two carbon atoms and at least one carbon-carbon double bond, and an "alkenyl group" can have 2 to 6 carbon atoms, for example, a vinyl group, a 1-propenyl group, a 2-propenyl group, a 1-, 2-, or 3-butenyl group, etc. An alkenyl group may be substituted or unsubstituted, and if substituted, the substituent may be one or more, for example, an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, an alkylthio group, an alkylamino group, a halogen, a mercapto group, a hydroxyl group, a nitro group, an amino group, a cycloalkyl group, a heterocyclylalkyl group, an aryl group, a heteroaryl group, a cycloalkoxy group, a heterocyclylalkoxy group, a cycloalkylthio group, a heterocyclylalkylthio group, etc.

[0066] The term "alkynyl group" refers to the alkyl group defined above, which consists of at least two carbon atoms and at least one carbon-carbon triple bond. An "alkynyl group" can have 2 to 6 carbon atoms, of which the alkynyl group may be further substituted with other related groups, such as alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, alkylthio groups, alkylamino groups, halogens, mercapto groups, hydroxyl groups, nitro groups, amino groups, cycloalkyl groups, heterocyclylalkyl groups, aryl groups, heteroaryl groups, cycloalkoxy groups, heterocyclylalkoxy groups, cycloalkylthio groups, heterocyclylalkylthio groups, carboxyl groups, or carboxylic acid ester groups.

[0067] The term "hydroxyl group" refers to the -OH group.

[0068] The term "amino group" refers to -NH2.

[0069] The term "cyano group" refers to -CN.

[0070] The term "nitro group" refers to -NO2.

[0071] The term "carboxyl group" refers to -C(O)OH.

[0072] The term "oxo group" refers to the oxygen atom (=O).

[0073] The terms “contains,” “includes,” “possesses,” “contains,” or “related to,” and other variations thereof herein, are inclusive or open and do not exclude other elements or method steps not mentioned. Those skilled in the art should understand that the above terms, such as “contains,” encompass the meaning of “consisting of.”

[0074] The term "one or more (species)" or similar expression "at least one (species)" can mean, for example, one, two, three, four, five, six, seven, eight, nine, ten (species) or more (species).

[0075] Where the lower and upper limits of a numerical range are disclosed, any numerical values ​​that fall within that range and any ranges that are included will be specifically disclosed. In particular, the range of possible values ​​disclosed herein should be understood to mean all values ​​and ranges that fall within a broader range.

[0076] In this specification, "Z" and "-Z-" both represent the same specific group and can be used interchangeably.

[0077] As used herein, the expression m~n refers to a range from m to n, a subscope consisting of each point value within that range, and each point value. For example, "C2~C8" or "C 2-8 The expression "C3~C8" should be understood to encompass the range of 2 to 8 carbon atoms, and any subscope and point values ​​within that range, such as C2~C5, C3~C4, C2~C6, C3~C6, C4~C6, C4~C7, C4~C8, etc., as well as C2, C3, C4, C5, C6, C7, C8, etc. For example, "C3~C 10 " or "C 3-10The expression "" should also be understood in a similar manner, for example, any subscope and each point value included therein, for example, C3~C9, C6~C9, C6~C8, C6~C7, C7~C 10 C7~C9, C7~C8, C8~C9, etc., C3, C4, C5, C6, C7, C8, C9, C 10 This could include things like "C1~C6" or "C 1-6 The expression "1 to 6 carbon atoms" should be understood to encompass the range of 1 to 6 carbon atoms, and any subscope and point values ​​within that range, such as C2 to C5, C3 to C4, C1 to C2, C1 to C3, C1 to C4, C1 to C5, C1 to C6, etc., as well as C1, C2, C3, C4, C5, C6, etc. Similarly, the expression "3 to 10 members" should be understood to encompass any subscope and point values ​​within that range, such as 3 to 5 members, 3 to 6 members, 3 to 7 members, 3 to 8 members, 4 to 5 members, 4 to 6 members, 4 to 7 members, 4 to 8 members, 5 to 7 members, 5 to 8 members, 6 to 7 members, 6 to 8 members, 9 to 10 members, etc., as well as 3, 4, 5, 6, 7, 8, 9, 10 members, etc. Other similar expressions in this specification should be understood in a similar manner.

[0078] The different expressions used herein, such as "X is selected from A, B, or C," "X is selected from A, B, and C," "X is A, B, or C," and "X is A, B, and C," all have the same meaning, that is, X may be one or more of A, B, or C.

[0079] The term "-(CY1Y2)" used in this specification n The expression "-" indicates that each of the Y1 or Y2 connected to C may be the same or different, that is, each of the Y1 may be a different group, each of the Y2 may be a different group, each of the Y1 may be the same group, and each of the Y2 may be the same group.

[0080] The terms “optionally” or “optionally” refer to whether the event or situation described thereafter may or may not occur, and such description includes cases in which the event or situation described may or may not occur. For example, “optionally alkyl-substituted cycloalkyl group” means that an alkyl group may be present, but is not necessarily so, and such description includes cases in which the cycloalkyl group is substituted with an alkyl group and cases in which the cycloalkyl group is not substituted with an alkyl group.

[0081] The terms “substitution” and “substituted” refer to the substitution of one or more (e.g., one, two, three, or four) hydrogen atoms on a designated atom with a hydrogen atom selected from the indicated group, provided that the substitution does not exceed the normal valence of the designated atom in its current state and that the substitution forms a stable compound. A combination of substituents and / or variables is permitted only if such a combination forms a stable compound. Where it is stated that a substituent is absent, it should be understood that the substituent may be one or more hydrogen atoms, provided that the structure allows the compound to be stable. Where it is stated that each carbon atom in a group may be optionally substituted with a heteroatom, the condition is that the substitution does not exceed the normal valence of all atoms in the group in its current state and that a stable compound is formed.

[0082] Where a substituent is described as "optionally substituted," the substituent may be unsubstituted or substituted. Where an atom or group is described as being optionally substituted with one or more of the substituent list, one or more hydrogens on that atom or group may be replaced with independently selected, optional substituents. When the substituent is oxo (i.e., =O), it means that two hydrogen atoms are replaced. Unless otherwise specified, as used herein, the linkage point of a substituent may be any suitable position on the substituent.

[0083] If the substituent's bond penetrates a bond connecting two atoms within the ring, such substituent may be bonded to any of the ring-constituting atoms within the substituteable ring.

[0084] When any variable (e.g., R) and labeled variables (e.g., R1, R2, R3, R4, R5, R6, R7, etc.) appear one or more times in the composition or structure of a compound, the definition in each case is independent for each occurrence. For example, if a group is substituted with 0, 1, 2, 3, or 4 R substituents, the group may be optionally substituted with up to 4 R substituents, and all choices of R substituents in each case are independent of each other.

[0085] The term "pharmaceutically acceptable" refers to a substance that, within the bounds of normal medical judgment, is suitable for use in contact with a patient's tissue without causing inappropriate toxicity, irritation, or allergic reactions, has a reasonable cost-benefit ratio, and can be effectively used for its intended purpose.

[0086] The term "pharmaceutically acceptable salt" refers to a salt of the compound of the present invention, which is safe and effective when used in the body of a mammal and possesses the desired biological activity.

[0087] The term "pharmaceutical composition" refers to a composition comprising one or more compounds described in this invention or their physiologically / pharmaceutically acceptable salts, and other components such as physiologically / pharmaceutically acceptable carriers or excipients. The purpose of the pharmaceutical composition is to facilitate administration to the body, contribute to the absorption of the active ingredient, and further exert biological activity.

[0088] The term "pharmaceutically acceptable carrier" refers to a substance that does not have an apparent irritant effect on an organism and does not impair the biological activity and performance of the active compound. "pharmaceutically acceptable carriers" include, but are not limited to, flow enhancers, sweeteners, diluents, preservatives, dyes / colorants, flavorings, surfactants, wetting agents, dispersants, disintegrants, stabilizers, solvents, or emulsifiers.

[0089] Terms such as "administer" or "give" refer to methods that enable a compound or composition to be delivered to a desired site of action. These methods include, but are not limited to, oral or parenteral administration (including intraventricular, intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular injection or infusion), topical, or rectal administration. In particular, injection or oral administration.

[0090] As used herein, the term “treatment” includes, and is further extended to include, alleviating, reducing, or improving a disease or symptom, preventing other symptoms, improving or preventing underlying metabolic factors of a symptom, suppressing a disease or symptom, for example, preventing the progression of a disease or symptom, reducing a disease or symptom, promoting the relief of a disease or symptom, or ceasing the signs of a disease or symptom. “Treatment” further includes achieving therapeutic and / or preventive benefits. Therapeutic benefit means the eradication or improvement of the medical condition being treated. Furthermore, therapeutic benefit may be achieved by eradicating or improving one or more physiological signs associated with an underlying disease, and improvement in the patient’s condition may be observed even though the patient may still have the underlying disease. Preventive benefit means the patient using the composition to prevent the risk of a particular disease, or the patient taking one or more physiological symptoms of a disease when the disease manifests, even though the disease has not yet been diagnosed.

[0091] The terms “active ingredient,” “therapeutic agent,” “active substance,” or “activator” refer to chemical substances that can effectively treat or prevent a target disorder, disease, or condition. The term “neuropsychiatric disorders” refers to a general term encompassing neurological and / or psychiatric disorders.

[0092] With respect to drugs, drug units, or active ingredients, the terms “effective dose,” “therapeutic effective dose,” or “preventive effective dose” refer to a dose of the drug or medication sufficient to achieve the desired effect with tolerable side effects. The effective dose is determined by the individual, depending on the individual’s age and general condition, and also on the specific active substance. A suitable effective dose for an individual can be determined by a person skilled in the art through ordinary testing.

[0093] As used herein, “individual” includes humans and non-human animals. An exemplary human individual includes a human individual suffering from a disease (e.g., a disease described herein) (referred to as a patient) or a healthy individual. “Non-human animals” in this invention include all vertebrates, e.g., non-mammals (e.g., birds, amphibians, reptiles), and mammals, e.g., non-human primates, livestock and / or domesticated animals (e.g., sheep, dogs, cats, cattle, pigs, etc.).

[0094] The following detailed description of the invention is intended to illustrate non-limiting embodiments, enabling those skilled in the art to better understand the technical concept, principle, and practical applications of the invention, thereby allowing the invention to be modified and implemented in many ways to best suit the requirements of a particular use. [Effects of the Invention]

[0095] Beneficial effects The compounds of the present invention exhibit better binding ability to GABAa receptors, possess anti-neuropsychiatric activity, and simultaneously have better drug discovery potential, a lower metabolic rate, and moderate lipophilicity, ensuring penetration of the blood-brain barrier, having therapeutic or preventive effects on neuropsychiatric disorders, and exhibiting better patient compliance in clinical settings.

[0096] In some embodiments, the compounds of the present invention have a favorable positive regulatory effect on GABAa receptors (e.g., improved E max and / or EC 50(has). In some embodiments, the compounds of the present invention have improved safety (e.g., lower toxicity and / or fewer side effects). In some embodiments, the compounds of the present invention have an improved safety margin (e.g., a wider safe dose range or a lower likelihood of side effects at the same dose). In some embodiments, the compounds of the present invention have improved pharmacokinetic properties (e.g., a longer half-life t 1 / 2 , higher exposure AUC and higher maximum blood drug concentration C max (Having [the above characteristics]). In some embodiments, the compounds of the present invention have improved pharmacokinetic effects (e.g., significant antiepileptic effect and / or significant antidepressant effect). In some embodiments, the compounds of the present invention also have better drug potential, such as good patient compliance and / or less tolerance development.

[0097] Specifically, according to the results of the in vitro GABAa receptor cell activity test described herein, the compound of the present invention was found to be an effective GABAa receptor-positive modulator with excellent positive regulatory activity. Because the compound has a low Emax (i.e., a low upper limit of action at high concentrations), it suggests the possibility of fewer side effects in vivo. Furthermore, EC 50Combined with a low half-life (i.e., a lower dose at which action is required), this suggests the potential for a broader therapeutic range. In vivo pharmacokinetic studies using a PTZ-induced mouse epilepsy model showed that the compounds of the present invention can extend the survival rate of PTZ-induced seizure mice, exhibit a protective effect against acute seizures in mice, and some compounds still show partial protective effects even at extremely low doses. Furthermore, some compounds can significantly prolong the latency period and seizure frequency of clonic and generalized tonic-clonic seizures, demonstrating a significant antiepileptic effect. In vivo pharmacokinetic studies on forced swimming and sugar water preference in mice showed that the compounds of the present invention significantly shortened the immobility time of C57 mice in forced swimming experiments and significantly improved sugar water preference in C57 mice in sugar water preference experiments, demonstrating a significant antidepressant effect. In vivo pharmacokinetic studies in mice showed that the compounds of the present invention exhibit a longer half-life. 1 / 2 , higher exposure AUC and higher maximum blood drug concentration C max It was found to possess and exhibit good metabolic properties. Based on the results of acute toxicity experiments and adverse event observations in mice, the compound of the present invention was found to have a higher maximum tolerated dose (MTD), superior safety, and fewer side effects, and is worthy of further clinical development. [Modes for carrying out the invention]

[0098] The embodiments of the present invention will be described in detail below with reference to examples, but as those skilled in the art will understand, the following examples are merely illustrative and should not be considered to limit the scope of the present invention. Unless specific conditions are specified in the examples, the procedures should be carried out under general conditions or conditions recommended by the manufacturer. All reagents or equipment whose manufacturers are not specified are commercially available products. Unless otherwise specified, the proportions or percentages used herein are by weight. [Examples]

[0099] The structure of the compounds of the present invention is determined by nuclear magnetic resonance (NMR) and / or liquid chromatography-mass spectrometry (LC-MS).

[0100] The NMR chemical shift (δ) is expressed in parts per million (ppm). NMR measurements were performed using an AVANCE III600 nuclear magnetic spectrometer, with deuterated dimethyl sulfoxide (DMSO-d6), deuterated methanol (CD3OD), and deuterated chloroform (CDCl3) as the measurement solvents, and tetramethylsilane (TMS) as the internal standard.

[0101] For liquid chromatography-mass spectrometry (LC-MS) measurements, a Shimadzu LCMS2020 mass spectrometer is used. For HPLC measurements, a Shimadzu LC20A liquid chromatograph is used. For thin-layer chromatography, Yantai Jiangyou silica gel plates are used. For TLC, plates with a specification of 0.2 mm ± 0.03 mm are used, and for separated and purified products from thin-layer chromatography, plates with a specification of 0.4 mm to 0.5 mm are used.

[0102] Example 1 1-((2S,3S,5R,8R,9R,10S,13S,14S,15R,17S)-3-hydroxy-2,3,13,15-tetramethylhexadecahydro-1H-cyclopentadiene[a]phenanthrene-17-yl)ethane-1-one [ka]

[0103] Synthesis scheme: [ka]

[0104] Step 1: Preparation of (2S,5R,8R,9R,10S,13S,14S,17S)-17-hydroxy-2,13-dimethylhexadecahydro-3H-cyclopentadiene[a]phenanthrene-3-one [ka] (2S,8R,9S,10R,13S,14S,17S)-17-hydroxy-2,13-dimethyl-1,2,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-3H-cyclopentadiene[a]phenanthrene-3-one (5.00 g, 17.3 mmol) was dissolved in pyridine (60.0 mL) solution, 10% wet palladium-carbon (340 mg) was added, hydrogen was substituted, and the mixture was reacted with stirring at room temperature for 16 hours. The reaction mixture was filtered, the organic phase was concentrated, and the crude product (6.60 g, yield: 100%) was obtained and used directly in the next reaction.

[0105] Step 2: Preparation of (2S,5R,8R,9R,10S,13S,14S)-2,13-dimethyltetradecahydro-3H-cyclopentadiene[a]phenanthrene-3,17(2H)-dione [ka] (2S,5R,8R,9R,10S,13S,14S,17S)-17-hydroxy-2,13-dimethylhexadecahydro-3H-cyclopentadiene[a]phenanthrene-3-one (6.60 g, 22.7 mmol) was dissolved in dichloromethane (87.0 mL), and DMP (14.5 g, 34.1 mmol) was added. The mixture was reacted at room temperature for 2 hours with stirring. The reaction mixture was filtered, the organic phase was concentrated, and the crude product was obtained. It was separated by column chromatography and purified using (petroleum ether / ethyl acetate: 50 / 1~3 / 1) to obtain (2S,5R,8R,9R,10S,13S,14S)-2,13-dimethyltetradecahydro-3H-cyclopentadiene[a]phenanthrene-3,17(2H)-dione (5.50 g, yield: 84.0%). 1H NMR (400 MHz, CDCl3) δ 2.62 (t, J = 13.6Hz, 1H), 2.51~2.44 (m, 1H), 2.39~2.30 (m, 1H), 2.25~1.16 (m, 19H), 0.99 (d, J = 6.4Hz, 3H), 0.91 (s, 3H).

[0106] Step 3: Preparation of (2S,3S,5R,8R,9R,10S,13S,14S)-3-hydroxy-2,3,13-trimethylhexadecahydro-17H-cyclopentadiene[a]phenanthrene-17-one [ka] (2S,5R,8R,9R,10S,13S,14S)-2,13-dimethyltetradecahydro-3H-cyclopentadiene[a]phenanthrene-3,17(2H)-dione (5.50 g, 18.9 mmol) was dissolved in dry toluene (200 mL) solution, the system was purged with nitrogen gas, and cooled to -78°C. 0.4 M bismethylaluminum (2,6-di-tert-butyl-4-anisole) solution (142 mL, 56.8 mmol) was gradually added, and the reaction system was stirred at -78°C for 30 minutes. 3.0 M methylmagnesium bromide (20 mL, 60.0 mmol) was gradually added dropwise, and the reaction system was stirred at -78°C for 3 hours. TLC demonstrated complete reaction, the reaction was quenched with saturated ammonium chloride, extracted with ethyl acetate, the organic phase was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The mixture was filtered, concentrated and dried, and the crude product was separated by column chromatography (washed with petroleum ether:ethyl acetate = 2:1) to obtain (2S,3S,5R,8R,9R,10S,13S,14S)-3-hydroxy-2,3,13-trimethylhexadecahydro-17H-cyclopentadiene[a]phenanthrene-17-one (4.90 g, yield: 84.0%). 1H NMR (400 MHz, CDCl3) δ 2.47~2.40 (m, 1H), 2.13~2.03 (m, 1H), 1.96~1.88 (m, 1H), 1.83~1.03 (m, 23H), 0.88~0.86 (m, 6H).

[0107] Step 4: Preparation of (2S,3S,5R,8R,9R,10S,13S,14S)-2,3,13-trimethyl-17-((trimethylsilyl)oxy)-2,3,4,5,6,7,8,9,10,11,12,13,14,15-tetradecahydro-1H-cyclopentadiene[a]phenanthrene-3-ol [ka] 32.2 mL, 64.4 mmol of 2.0 M lithium diisopropylamide was added to a dry 100 mL round-bottom flask, the system was purged with nitrogen gas, and cooled to -78°C. (2S,3S,5R,8R,9R,10S,13S,14S)-3-hydroxy-2,3,13-trimethylhexadecahydro-17H-cyclopentadiene[a]phenanthrene-17-one (4.90 g, 16.1 mmol) was dissolved in 35 mL of anhydrous tetrahydrofuran and gradually added dropwise to the reaction system, continuing to react with stirring for 1 hour. Trimethylchlorosilane (3.50 mL, 40.3 mmol) was added to the reaction system, and the reaction mixture was reacted at -78°C for 2 hours, followed by stirring at 0°C for 15 minutes. TLC demonstrated complete reaction, the reaction was quenched with saturated ammonium chloride, extracted with ethyl acetate, the organic phase was washed with water and saturated brine, and dried over anhydrous sodium sulfate. Filtered and concentrated and dried to obtain the crude product (2S,3S,5R,8R,9R,10S,13S,14S)-2,3,13-trimethyl-17-((trimethylsilyl)oxy)-2,3,4,5,6,7,8,9,10,11,12,13,14,15-tetradecahydro-1H-cyclopentadiene[a]phenanthrene-3-ol (6.06 g, yield: 100% crude), which was used directly in the next reaction.

[0108] Step 5: Preparation of (2S,3S,5R,8R,9R,10S,13S,14S)-3-hydroxy-2,3,13-trimethyl-1,2,3,4,5,6,7,8,9,10,11,12,13,14-tetradecahydro-17H-cyclopentadiene[a]phenanthrene-17-one [ka] (2S,3S,5R,8R,9R,10S,13S,14S)-2,3,13-trimethyl-17-((trimethylsilyl)oxy)-2,3,4,5,6,7,8,9,10,11,12,13,14,15-tetradecahydro-1H-cyclopentadiene[a]phenanthrene-3-ol (6.06 g, 16.1 mmol) was dissolved in anhydrous dichloromethane (120 mL) and anhydrous acetonitrile (40.0 mL), purged with nitrogen gas, and palladium acetate (3.50 g, 9.17 mmol) was added. The mixture was reacted overnight at room temperature with stirring. The reaction mixture was filtered, the organic phase was concentrated, and the crude product was obtained. This was then separated by column chromatography and purified (petroleum ether / ethyl acetate: 50 / 1~5 / 1) to obtain (2S,3S,5R,8R,9R,10S,13S,14S)-3-hydroxy-2,3,13-trimethyl-1,2,3,4,5,6,7,8,9,10,11,12,13,14-tetradecahydro-17H-cyclopentadiene[a]phenanthrene-17-one (2.20 g, yield: 45.0%). 1 H NMR (400 MHz, CDCl3) δ 7.52 (dd, J = 6.0, 1.1 Hz, 1H), 6.02 (dd, J = 6.0, 3.2 Hz, 1H), 2.37~2.33 (m, 1H), 1.91~1.21 (m, 17H), 1.15~1.10 (m, 4H), 1.07 (s, 3H), 0.87 (d, J = 6.7 Hz, 3H).

[0109] Step 6: Preparation of (2S,3S,5R,8R,9R,10S,13S,14S,15R)-3-hydroxy-2,3,13,15-tetramethylhexadecahydro-17H-cyclopentadiene[a]phenanthrene-17-one [ka] 3.0 M methylmagnesium bromide (9.69 mL, 29.1 mmol) was added to a dry 100 mL round-bottom flask, the system was purged with nitrogen gas, and cooled to 0°C. Copper iodide (4.16 g, 21.8 mmol) was added to the reaction system, and the reaction was carried out at 0°C for 1 hour with stirring. (2S,3S,5R,8R,9R,10S,13S,14S)-3-hydroxy-2,3,13-trimethyl-1,2,3,4,5,6,7,8,9,10,11,12,13,14-tetradecahydro-17H-cyclopentadiene[a]phenanthrene-17-one (2.20 g, 7.27 mmol) was dissolved in 25 mL of anhydrous tetrahydrofuran and gradually added dropwise to the reaction system, continuing to react with stirring for 2 hours. Complete reaction was shown by TLC, the reaction was quenched with saturated ammonium chloride, extracted with ethyl acetate, the organic phase was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The mixture was filtered, concentrated and dried, and the crude product was separated by column chromatography (washed with petroleum ether:ethyl acetate = 3:1) to obtain (2S,3S,5R,8R,9R,10S,13S,14S,15R)-3-hydroxy-2,3,13,15-tetramethylhexadecahydro-17H-cyclopentadiene[a]phenanthrene-17-one (1.50 g, yield: 65.0%). 1 H NMR (400 MHz, CDCl3) δ 2.50~2.40 (m, 2H), 2.24 (d, J = 17.6 Hz, 1H), 1.91~1.09 (m, 25H), 1.03 (s, 3H), 0.87 (d, J = 6.7 Hz, 3H).

[0110] Step 7: Preparation of (2S,3S,5R,8R,9R,10S,13S,14S,15R,17S)-3-hydroxy-2,3,13,15-tetramethylhexadecahydro-1H-cyclopentadiene[a]phenanthrene-17-carbonitrile [ka] Potassium tert-butoxide (5.29 g, 47.2 mmol) and tert-butyl alcohol (30.0 mL) were added to a dry 100 mL round-bottom flask, and the system was purged with nitrogen gas. (2S,3S,5R,8R,9R,10S,13S,14S,15R)-3-hydroxy-2,3,13,15-tetramethylhexadecahydro-17H-cyclopentadiene[a]phenanthrene-17-one (1.50 g, 4.71 mmol) was dissolved in 15 mL of ethylene glycol dimethyl ether and gradually added dropwise to the reaction system, and the reaction was carried out with stirring for 30 minutes. p-toluenesulfonylmethyl isocyanide (1.84 g, 9.46 mmol) was dissolved in 15 mL of ethylene glycol dimethyl ether and gradually added dropwise to the reaction system, and the reaction was carried out overnight with stirring at room temperature. TLC confirmed complete reaction, and the reaction was quenched by adding water (50 mL). The aqueous phase was extracted with ethyl acetate (50 mL x 2), the organic phase was combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. This was separated by column chromatography and purified (petroleum ether / ethyl acetate: 50 / 1~3 / 1) to obtain (2S,3S,5R,8R,9R,10S,13S,14S,15R,17S)-3-hydroxy-2,3,13,15-tetramethylhexadecahydro-1H-cyclopentadiene[a]phenanthrene-17-carbonitrile (0.95 g, yield: 61.3%). 1H NMR (400 MHz, CDCl3) δ 2.51~2.48 (m, 1H), 2.26~2.21 (m, 1H), 1.89~1.21 (m, 18H), 1.16~1.09 (m, 6H), 1.06 (s, 3H), 1.00 (d, J = 7.4 Hz, 3H), 0.87 (d, J = 6.7 Hz, 3H).

[0111] Step 8: Preparation of 1-((2S,3S,5R,8R,9R,10S,13S,14S,15R,17S)-3-hydroxy-2,3,13,15-tetramethylhexadecahydro-1H-cyclopentadiene[a]phenanthrene-17-yl)ethane-1-one [ka] (2S,3S,5R,8R,9R,10S,13S,14S,15R,17S)-3-hydroxy-2,3,13,15-tetramethylhexadecahydro-1H-cyclopentadiene[a]phenanthrene-17-carbonitrile (950 mg, 2.88 mmol) was dissolved in dry tetrahydrofuran solution (100 mL), the system was purged with nitrogen gas, and 3.0 M methylmagnesium bromide (28.5 mL, 85.5 mmol) was gradually added dropwise, and the reaction system was stirred at 80°C for 7 hours. Complete reaction was shown by TLC, the reaction was quenched with saturated ammonium chloride, extracted with ethyl acetate, the organic phase was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solution was filtered, concentrated and dried, and the crude product was separated by column chromatography (washed with petroleum ether:ethyl acetate = 4:1) to obtain 1-((2S,3S,5R,8R,9R,10S,13S,14S,15R,17S)-3-hydroxy-2,3,13,15-tetramethylhexadecahydro-1H-cyclopentadiene[a]phenanthrene-17-yl)ethane-1-one (540 mg, yield: 54.0%). 1H NMR (400 MHz, CDCl3) δ 2.49 (dd, J = 10.4, 8.6 Hz, 1H), 2.20~2.13 (m, 1H), 2.11 (s, 3H), 2.09~2.00 (m, 1H), 1.96~1.91 (m, 1H), 1.86~1.21 (m, 16H), 1.15~1.02 (m, 6H), 0.96 (d, J = 7.2 Hz, 3H), 0.87 (d, J = 6.7 Hz, 3H), 0.77 (s, 3H).

[0112] Example 2 1-(2-((2S,3S,5R,8R,9R,10S,13S,14S,15R,17S)-3-hydroxy-2,3,13,15-tetramethylhexadecahydro-1H-cyclopentadiene[a]phenanthrene-17-yl)-2-oxoethyl)-1H-pyrazole-4-carbonitrile [ka]

[0113] Synthesis scheme: [ka]

[0114] Step 1: Preparation of 2-bromo-1-((2S,3S,5R,8R,9R,10S,13S,14S,15R,17S)-3-hydroxy-2,3,13,15-tetramethylhexadecahydro-1H-cyclopentadiene[a]phenanthrene-17-yl)ethane-1-one [ka] 1-((2S,3S,5R,8R,9R,10S,13S,14S,15R,17S)-3-hydroxy-2,3,13,15-tetramethylhexadecahydro-1H-cyclopentadiene[a]phenanthrene-17-yl)ethane-1-one (150 mg, 0.43 mmol) was dissolved in methanol (5 mL), one drop of hydrogen bromide was added, and liquid bromine (75.6 mg, 0.48 mmol) was further added. The mixture was reacted at room temperature for 3 hours with stirring. Water (20.0 mL) was added, the aqueous phase was extracted with ethyl acetate (20.0 mL x 2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product (150 mg, crude product), which was used directly in the next reaction.

[0115] Step 2: Preparation of 1-(2-((2S,3S,5R,8R,9R,10S,13S,14S,15R,17S)-3-hydroxy-2,3,13,15-tetramethylhexadecahydro-1H-cyclopentadiene[a]phenanthrene-17-yl)-2-oxoethyl)-1H-pyrazole-4-carbonitrile [ka] 2-Bromo-1-((2S,3S,5R,8R,9R,10S,13S,14S,15R,17S)-3-hydroxy-2,3,13,15-tetramethylhexadecahydro-1H-cyclopentadiene[a]phenanthrene-17-yl)ethane-1-one (150 mg, 0.35 mmol), 1H-pyrazole-4-carbonitrile (48.0 mg, 0.52 mmol), and potassium carbonate (72.5 mg, 0.52 mmol) are mixed with anhydrous tetrahydrofuran (5.00 mL) and N,N-dimethylformamide (1.00 mL). The mixture was dissolved in (mL), reacted overnight at room temperature with stirring, filtered, and the filtrate was concentrated. The crude product was separated by high-performance liquid chromatography to obtain 1-(2-((2S,3S,5R,8R,9R,10S,13S,14S,15R,17S)-3-hydroxy-2,3,13,15-tetramethylhexadecahydro-1H-cyclopentadiene[a]phenanthren-17-yl)-2-oxoethyl)-1H-pyrazole-4-carbonitrile (51.0 mg, yield: 33.0%). 1 H NMR (400 MHz, CDCl3) δ 7.86 (s, 1H), 7.81 (s, 1H), 5.03~4.88 (m, 2H), 2.55 (dd, J = 10.2, 8.4 Hz, 1H), 2.27~2.10 (m, 2H), 2.03~1.81 (m, 5H), 1.75~1.25 (m, 11H), 1.17~1.03 (m, 7H), 0.98 (d, J = 7.0 Hz, 3H), 0.87 (d, J = 6.7 Hz, 3H), 0.83 (s, 3H). 13 C NMR (101 MHz, CDCl3) δ 201.98, 142.38, 136.01, 113.23, 93.17, 74.11, 61.69, 61.40, 57.43, 45.52, 43.08, 41.29, 41.22, 39.41, 39.26, 35.94, 35.09, 34.09, 33.53, 31.32, 30.25, 26.09, 25.21, 20.47, 18.25, 16.81, 15.13. LC-MS m / z (ESI): 420.25 [M+H-18] + .

[0116] Example 3 1-(2-((2S,3S,5R,8R,9R,10S,13S,14S,15R,17S)-3-hydroxy-2,3,13,15-tetramethylhexadecahydro-1H-cyclopentadiene[a]phenanthrene-17-yl)-2-oxoethyl)-1H-pyrazole-3-carbonitrile [ka]

[0117] Synthesis scheme [ka] The synthesis method was the same as in Example 2, except that 1H-pyrazole-4-carbonitride in the second step was replaced with 1H-pyrazole-3-carbonitride. 1 H NMR (400 MHz, CDCl3) δ 7.48 (d, J = 2.4 Hz, 1H), 6.73 (d, J = 2.4 Hz, 1H), 5.04~4.90 (m, 2H), 2.55 (dd, J = 10.3, 8.3 Hz, 1H), 2.26~2.09 (m, 2H), 2.00~1.95 (m, 1H), 1.90~1.81 (m, 3H), 1.76~1.23 (m, 12H), 1.18~1.03 (m, 7H), 0.98 (d, J = 7.1 Hz, 3H), 0.88 (d, J = 6.7 Hz, 3H), 0.83 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 202.16, 132.19, 125.17, 113.89, 111.96, 74.12, 62.08, 61.36, 57.42, 45.52, 43.09, 41.26, 41.22, 39.41, 39.26, 35.96, 35.10, 34.09, 33.54, 31.33, 30.25, 26.09, 25.22, 20.45, 18.25, 16.80, 15.12. LC-MS m / z (ESI): 420.20 [M+H-18] + .

[0118] Example 4 1-((2S,3S,5R,8R,9R,10S,13S,14S,15R,17S)-3-hydroxy-2,3,13,15-tetramethylhexadecahydro-1H-cyclopentadiene[a]phenanthrene-17-yl)-2-(3-(trifluoromethyl)-1H-pyrazole-1-yl)ethane-1-one [ka]

[0119] Synthesis scheme [ka] The synthesis method was the same as in Example 2, except that 1H-pyrazole-4-carbonitride in the second step was replaced with 3-(trifluoromethyl)-1H-pyrazole. 1H NMR (400 MHz, CDCl3) δ 7.47 (dt, J = 2.0, 1.0 Hz, 1H), 6.59 (d, J = 2.4 Hz, 1H), 4.97 (d, J = 4.6 Hz, 2H), 2.54 (dd, J = 10.5, 8.1 Hz, 1H), 2.29~2.10 (m, 2H), 1.97 (m, 1H), 1.92~1.05 (m, 20H), 0.98 (d, J = 7.0 Hz, 3H), 0.88 (d, J = 6.7 Hz, 3H), 0.84 (s, 3H). 13 C NMR (101 MHz, CDCl3) δ 202.58, 142.57 (q, J C-F = 38.0 Hz), 132.26, 122.71 (q, J C-F = 145.0 Hz), 105.01, 74.12, 61.87, 61.29, 57.36, 45.34, 43.10, 41.24, 41.21, 39.41, 39.26, 35.96, 35.10, 34.09, 33.60, 31.34, 30.24, 26.09, 25.20, 20.42, 18.26, 16.75, 15.12. MS m / z (ESI): 479.2 [MH] - .

[0120] Example 5 1-(2-((2S,3S,5R,8R,9R,10S,13S,14S,15R,17S)-3-hydroxy-2,3,13,15-tetramethylhexadecahydro-1H-cyclopentadiene[a]phenanthrene-17-yl)-2-oxoethyl)-1H-pyrazole-3,5-dicarbonitric [ka]

[0121] Synthesis scheme [ka] The synthesis method was the same as in Example 2, except that 1H-pyrazole-4-carbonitrile in the second step was replaced with 1H-pyrazole-3,5-dicarbonitrile. 1 H NMR (400 MHz, CDCl3) δ 7.21 (s, 1H), 5.16 (d, J = 1.6 Hz, 2H), 2.61~2.57 (m, 1H), 2.28~2.17 (m, 2H), 2.02~1.85 (m, 4H), 1.77~1.07 (m, 19H), 0.99 (d, J = 6.8 Hz, 3H), 0.88~0.86 (m, 6H). 13 C NMR (101 MHz, CDCl3) δ 200.10, 125.91, 118.36, 118.13, 111.80, 108.72, 74.13, 61.95, 61.33, 57.51, 45.86, 43.08, 41.21, 39.42, 39.25, 35.94, 35.08, 34.08, 33.57, 31.31, 30.30, 26.09, 25.23, 20.48, 18.23, 16.66, 15.12. MS m / z (ESI): 461.15 [MH] - .

[0122] Example 6 1-((2S,3S,5R,8R,9R,10S,13S,14S,15R,17S)-3-hydroxy-2,3,13,15-tetramethylhexadecahydro-1H-cyclopentadiene[a]phenanthrene-17-yl)-2-(1H-1,2,4-triazole-1-yl)ethane-1-one [ka]

[0123] Synthesis scheme [ka] The synthesis method was the same as in Example 2, except that 1H-pyrazole-4-carbonitrile in the second step was replaced with 1H-1,2,4-triazole. 1 H NMR (400 MHz, CDCl3) δ 8.14 (s, 1H), 7.96 (s, 1H), 5.04~4.91 (m, 2H), 2.59~2.55 (m, 1H), 2.26~2.13 (m, 2H), 2.00~1.84 (m, 4H), 1.76~1.04 (m, 19H), 0.98 (d, J = 6.8 Hz, 3H), 0.87 (d, J = 6.8 Hz, 3H), 0.84 (s, 3H). 13 C NMR (101 MHz, CDCl3) δ 201.99, 151.82, 144.53, 74.11, 61.38, 58.76, 57.42, 45.47, 43.10, 41.27, 41.22, 39.42, 39.27, 35.96, 35.10, 34.10, 33.56, 31.33, 30.25, 26.09, 25.22, 20.45, 18.26, 16.80, 15.13. MS m / z (ESI): 414.40 [M+H] + .

[0124] Example 7 1-((2S,3S,5R,8R,9R,10S,13S,14S,15R,17S)-3-hydroxy-2,3,13,15-tetramethylhexadecahydro-1H-cyclopentadiene[a]phenanthrene-17-yl)-2-(2H-1,2,3-triazole-2-yl)ethane-1-one [ka]

[0125] Example 8 1-((2S,3S,5R,8R,9R,10S,13S,14S,15R,17S)-3-hydroxy-2,3,13,15-tetramethylhexadecahydro-1H-cyclopentadiene[a]phenanthrene-17-yl)-2-(1H-1,2,3-triazole-1-yl)ethane-1-one [ka]

[0126] Synthesis scheme [ka] The synthesis method was the same as in Example 2, except that 1H-pyrazole-4-carbonitrile in the second step was replaced with 1H-1,2,3-triazole, and finally, the compounds were separated by column chromatography to obtain Product 1 (Compound 7) and Product 2 (Compound 8).

[0127] Compound 7: 1 H NMR (400 MHz, CDCl3) δ 7.69 (s, 2H), 5.24 (d, J = 1.2 Hz, 2H), 2.52 (dd, J = 10.5, 8.1 Hz, 1H), 2.26~2.07 (m, 2H), 2.05~1.96 (m, 1H), 1.92~1.27 (m, 17H), 1.12 (s, 3H), 0.97 (d, J = 7.1 Hz, 3H), 0.89~0.85 (m, 6H). 13 C NMR (101 MHz, CDCl3) δ 202.61, 135.03, 74.13, 63.87, 60.88, 57.37, 45.34, 43.11, 41.23, 41.14, 39.41, 39.28, 35.96, 35.12, 34.11, 33.63, 31.35, 30.26, 26.10, 25.21, 18.25, 16.71, 15.12. MS m / z (ESI): 414.3 [M+H] + .

[0128] Compound 8: 1 H NMR (400 MHz, CDCl3) δ 7.76 (d, J = 1.0 Hz, 1H), 7.65 (d, J = 1.1 Hz, 1H), 5.29~5.11 (m, 2H), 2.60 (dd, J = 10.5, 8.1 Hz, 1H), 2.31~2.12 (m, 2H), 2.07~1.97 (m, 1H), 1.93~1.83 (m , 3H), 1.79~1.12 (m, 16H), 0.98 (d, J = 7.0 Hz, 3H), 0.88 (d, J = 6.8 Hz, 3H), 0.84 (s, 3H). 13 C NMR (101 MHz, CDCl3) δ 201.69, 134.01, 125.04, 74.14, 61.46, 58.89, 57.40, 45.52, 43.08, 41.25, 41.21, 39.41, 39.26, 35.96, 35.09, 34.09, 33.56, 31.33, 30.26, 26.08, 25.21, 20.42, 18.26, 16.79, 15.11. MS m / z (ESI): 396.2 [M+H-H2O] + .

[0129] Example 9 1-((2S,3S,5R,8R,9R,10S,13S,14S,15R,17S)-3-hydroxy-2,3,13,15-tetramethylhexadecahydro-1H-cyclopentadiene[a]phenanthrene-17-yl)-2-(2H-tetrazole-2-yl)ethane-1-one [ka]

[0130] Example 10 1-((2S,3S,5R,8R,9R,10S,13S,14S,15R,17S)-3-hydroxy-2,3,13,15-tetramethylhexadecahydro-1H-cyclopentadiene[a]phenanthrene-17-yl)-2-(1H-tetrazole-1-yl)ethane-1-one [ka]

[0131] Synthesis scheme [ka] The synthesis method was the same as in Example 2, except that 1H-pyrazole-4-carbonitrile in the second step was replaced with 1H-tetrazole, and finally, the compounds were separated by column chromatography to obtain Product 1 (Compound 9) and Product 2 (Compound 10).

[0132] Compound 9: 1 H NMR (400 MHz, CDCl3) δ 8.57 (s, 1H), 5.45 (s, 2H), 2.66~2.56 (m, 1H), 2.28~2.15 (m, 2H), 2.03~1.11 (m, 23H), 0.98 (d, J = 6.8 Hz, 3H), 0.91~0.86 (m, 6H). 13 C NMR (101 MHz, CDCl3) δ 200.10, 153.22, 74.12, 61.42, 61.34, 57.43, 45.58, 43.11, 41.23, 41.19, 39.42, 39.27, 35.96, 35.10, 34.10, 33.57, 31.33, 30.28, 26.09, 25.22, 20.45, 18.23, 16.73, 15.11. MS m / z (ESI): 413.15 [MH] - .

[0133] Compound 10: 1H NMR (400 MHz, CDCl3) δ 8.74 (s, 1H), 5.33~5.17 (m, 2H), 2.67~2.60 (m, 1H), 2.29~2.16 (m, 2H), 2.00~1.08 (m, 23H), 0.99 (d, J = 6.8 Hz, 3H), 0.88 (d, J = 6.4 Hz, 3H), 0.84 (s, 3H). 13 C NMR (101 MHz, CDCl3) δ 200.07, 143.63, 74.11, 61.70, 57.46, 56.74, 45.71, 43.07, 41.31, 41.21, 39.42, 39.26, 35.94, 35.08, 34.08, 33.55, 31.31, 30.28, 26.07, 25.20, 20.48,18.24, 16.83, 15.10. MS m / z (ESI): 413.15 [MH] - .

[0134] Example 11 1-((2S,3S,5R,8R,9R,10S,13S,14S,15R,17S)-3-hydroxy-2,3,13,15-tetramethylhexadecahydro-1H-cyclopentadiene[a]phenanthrene-17-yl)-2-(5-methyl-2H-tetrazole-2-yl)ethane-1-one [ka]

[0135] Example 12 1-((2S,3S,5R,8R,9R,10S,13S,14S,15R,17S)-3-hydroxy-2,3,13,15-tetramethylhexadecahydro-1H-cyclopentadiene[a]phenanthrene-17-yl)-2-(5-methyl-1H-tetrazole-1-yl)ethane-1-one [ka]

[0136] Synthesis scheme [ka] The synthesis method was the same as in Example 2, except that 1H-pyrazole-4-carbonitrile in the second step was replaced with 5-methyl-1H-tetrazole, and finally, the compounds were separated by column chromatography to obtain Product 1 (Compound 11) and Product 2 (Compound 12).

[0137] Compound 11: 1 H NMR (400 MHz, CDCl3) δ 5.35 (s, 2H), 2.57 (s, 3H), 2.30~2.12 (m, 2H), 2.00 (m, 1H)1.95~1.05 (m,23 H), 0.98 (d, J = 6.9 Hz, 3H), 0.92~0.84 (m, 6H). 13 C NMR (101 MHz, CDCl3) δ 200.42, 163.38, 77.34, 77.02, 76.71, 74.13, 61.27, 57.39, 45.51, 43.09, 41.22, 39.41, 35.95, 35.09, 34.09, 33.56, 31.32, 30.26, 26.09, 25.20, 20.44, 18.24, 16.73, 15.11, 10.94. MS m / z (ESI): 429.3 [M+H] + .

[0138] Compound 12: 1 H NMR (400 MHz, CDCl3) δ 5.19~5.02 (m, 2H), 2.61 (dd, J = 10.4, 8.0 Hz, 1H), 2.47 (s, 3H), 2.33~2.12 (m, 2H), 2.07~1.96 (m, 1H), 1.94~1.81 (m, 3H), 1.78~1.06 (m, 19H), 0.99 (d, J = 7.0 Hz, 3H), 0.93~0.81 (m, 6H). 13 C NMR (101 MHz, CDCl3) δ 200.60, 152.42, 74.11, 61.41, 57.46, 56.08, 46.35, 43.72, 41.19, 39.85, 39.24, 35.93, 35.07, 34.08, 33.51, 31.30, 30.70, 30.27, 26.89, 25.23, 20.48, 18.23, 16.84, 15.12, 8.91. MS m / z (ESI): 429.3 [M+H] + .

[0139] Example 13 2-((1,3,4-thiadiazole-2-yl)amino)-1-((2S,3S,5R,8R,9R,10S,13S,14S,15R,17S)-3-hydroxy-2,3,13,15-tetramethylhexadecahydro-1H-cyclopentadiene[a]phenanthrene-17-yl)ethane-1-one [ka]

[0140] Synthesis scheme [ka] The synthesis method was the same as in Example 2, except that 1H-pyrazole-4-carbonitrile in the second step was replaced with 1,3,4-thiadiazole-2-amino. 1 H NMR (400 MHz, CDCl3) δ 8.45 (s, 1H), 7.66 (s, 1H), 4.78 (s, 2H), 2.57 (dd, J = 10.5, 8.0 Hz, 1H), 2.29~1.20 (m, 17H), 1.10 (d, J = 9.5 Hz, 6H), 0.97 (d, J = 7.0 Hz, 3H), 0.87 (dd, J = 6.8, 3.1 Hz, 3H), 0.84 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 203.75, 161.72, 133.15, 74.14, 60.91, 57.43, 57.34, 45.22, 43.15, 41.27, 41.01, 39.42, 39.30, 39.28, 35.98, 35.15, 34.13, 33.50, 31.38, 30.24, 26.13, 25.27, 20.39, 18.29, 16.61, 16.46, 15.12. MS m / z (ESI): 446.2 [M+H] + .

[0141] Example 14 1-(2-((2S,3S,5R,8R,9R,10S,13S,14S,15R,17S)-3-hydroxy-2,13,15-trimethylhexadecahydro-1H-cyclopentadiene[a]phenanthrene-17-yl)-2-oxoethyl)-1H-pyrazole-4-carbonitrile [ka]

[0142] Synthesis scheme [ka]

[0143] Step 1: Preparation of (2S,3S,5R,8R,9R,10S,13S,14S)-3-hydroxy-2,13-dimethylhexadecahydro-17H-cyclopenta[a]phenanthrene-17-one [ka] (2S,5R,8R,9R,10S,13S,14S)-2,13-dimethyltetradecahydro-3H-cyclopentadiene[a]phenanthrene-3,17(2H)-dione (20.0 g, 69.4 mmol) was dissolved in tetrahydrofuran (1000 mL), cooled to -70°C, and then lithium tri-tert-butoxyaluminum hydride (31.4 g, 123.5 mmol) dissolved in tetrahydrofuran (400 mL) was added. mmol) was added, the temperature was raised to -50°C, and the reaction was allowed to proceed for 3 hours. The reaction was then quenched with aqueous ammonium chloride solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered and concentrated, and then the (2S,3S,5R,8R,9R,10S,13S,14S)-3-hydroxy-2,13-dimethylhexadecahydro-17H-cyclopenta[a]phenanthrene-17-one product (9.0 g, yield 45%) was obtained by column chromatography (DCM / EA = 0-30%). 1 H NMR (400 MHz, CDCl3) δ 3.20~3.14 (m, 1H), 2.61~2.34 (m, 2H), 2.10~0.92 (m, 24H), 0.86 (s, 3H).

[0144] Step 2: Preparation of (2S,3S,5R,8R,9R,10S,13S,14S)-3-hydroxy-2,13-dimethyl-16-(phenylsulfinyl)hexadecahydro-17H-cyclopentadiene[a]phenanthrene-17-one [ka] (2S,3S,5R,8R,9R,10S,13S,14S)-3-hydroxy-2,13-dimethylhexadecahydro-17H-cyclopenta[a]phenanthrene-17-one (9.0 g, 31.0 mmol) was added to a potassium tert-butoxide (6.9 g, 61.6 mmol) solution dissolved in tetrahydrofuran (180 mL), stirred at room temperature for 10 minutes under nitrogen gas protection, and then methyl benzenesulfinate (9.6 g, 61.5 mmol) was added. mmol) was added, and the mixture was stirred at room temperature for 1 hour. The reaction was then quenched with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered and concentrated, and then the (2S,3S,5R,8R,9R,10S,13S,14S)-3-hydroxy-2,13-dimethyl-16-(phenylsulfinyl)hexadecahydro-17H-cyclopentadiene[a]phenanthrene-17-one product (7.8 g, yield 60%) was obtained by column chromatography (DCM / EA = 0-30%). MS m / z (ESI): 415 [M+H] +

[0145] Step 3: Preparation of (2S,3S,5R,8R,9R,10S,13S,14S)-3-hydroxy-2,13-dimethyl-1,2,3,4,5,6,7,8,9,10,11,12,13,14-tetradecahydro-17H-cyclopentadiene[a]phenanthrene-17-one [ka] (2S,3S,5R,8R,9R,10S,13S,14S)-3-hydroxy-2,13-dimethyl-16-(phenylsulfinyl)hexadecahydro-17H-cyclopentadiene[a]phenanthrene-17-one (7.8 g, 18.8 mmol) was dissolved in xylene (124 mL) and anhydrous sodium carbonate (29.0 g, 27.4 mmol) was added. After adding mmol), the mixture was stirred at 125°C for 24 hours, and after filtering out the sodium carbonate, it was concentrated and measured by column (DCM / EA = 0-30%) to obtain (2S,3S,5R,8R,9R,10S,13S,14S)-3-hydroxy-2,13-dimethyl-1,2,3,4,5,6,7,8,9,10,11,12,13,14-tetradecahydro-17H-cyclopentadiene[a]phenanthrene-17-one product (2.6 g, yield 48%). 1 H NMR (400 MHz, CDCl3) δ 7.53~7.51 (m, 1H), 6.04~6.01 (m, 1H), 3.22~3.16 (m, 1H), 2.38~2.34(m, 1H), 1.91~1.21(m, 18H), 1.07 (s, 3H), 0.97 (d, J = 6.4 Hz, 3H).

[0146] Step 4: Preparation of (2S,3S,5R,8R,9R,10S,13S,14S,15R)-3-hydroxy-2,13,15-trimethylhexadecahydro-17H-cyclopentadiene[a]phenanthrene-17-one [ka] In an ice bath, copper iodide (4.9 g, 25.7 mmol) was added to a solution of tetrahydrofuran in 3M methyl Grignard reagent (11.46 mL), stirred at 0°C for 1 hour, and (2S,3S,5R,8R,9R,10S,13S,14S)-3-hydroxy-2,13-dimethyl-1,2,3,4,5,6,7,8,9,10,11,12,13,14-tetradecahydro-17H-cyclopentadiene[a]phenanthrene-17-one (2.6 g, 9.02 mL) dissolved in tetrahydrofuran (32 mL). mmol) was added and stirred in an ice bath for 2 hours to allow the reaction to proceed completely. The reaction was then quenched with aqueous ammonium chloride solution, extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate and concentrated. The product (2S,3S,5R,8R,9R,10S,13S,14S,15R)-3-hydroxy-2,13,15-trimethylhexadecahydro-17H-cyclopentadiene[a]phenanthrene-17-one (2.3 g, yield 84%) was obtained by column (DCM / EA = 0-30%). 1 H NMR (400 MHz, CDCl3) δ 3.21~3.15(m, 1H), 2.50~2.38(m, 2H), 2.30~2.22(m,1H), 1.90~1.18(m,19H), 1.10 (d, J = 7.2 Hz, 3H), 1.03 (s, 3H), 0.97 (d, J = 6.4 Hz, 3H).

[0147] Step 5: Preparation of (2S,3S,5R,8R,9R,10S,13S,14S,15R,17S)-3-hydroxy-2,13,15-trimethylhexadecahydro-1H-cyclopentadiene[a]phenanthrene-17-carbonitrile [ka] Potassium tert-butoxide (8 g, 71.29 mmol) and tert-butyl alcohol (46 mL) were added to a dry 100 mL round-bottom flask, and the system was purged with nitrogen gas. (2S,3S,5R,8R,9R,10S,13S,14S,15R)-3-hydroxy-2,13,15-trimethylhexadecahydro-17H-cyclopentadiene[a]phenanthrene-17-one (2.3 g, 7.6 mmol) was dissolved in ethylene glycol dimethyl ether (12 mL) and gradually added dropwise to the reaction system, and the reaction was carried out with stirring for 30 minutes. p-toluenesulfonylmethyl isocyanide (2.8 g, 14.4 mmol) was dissolved in ethylene glycol dimethyl ether (12 mL) and gradually added dropwise to the reaction system, and the reaction was carried out at room temperature overnight with stirring. TLC confirmed complete reaction, water was added to quench the reaction, and after extraction with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, concentrated, and then (2S,3S,5R,8R,9R,10S,13S,14S,15R,17S)-3-hydroxy-2,13,15-trimethylhexadecahydro-1H-cyclopentadiene[a]phenanthrene-17-carbonitrile product (2.0 g, yield 84%) was obtained by column chromatography (DCM / EA = 0-30%). 1 H NMR (400 MHz, CDCl3) δ 3.21~3.15(m, 1H), 2.53~2.43(m, 1H), 2.27~2.20(m,2H), 1.89~1.12(m,20H), 1.06 (s, 3H), 1.01~0.96(m, 6H).

[0148] Step 6: Preparation of 1-((2S,3S,5R,8R,9R,10S,13S,14S,15R,17S)-3-hydroxy-2,13,15-trimethylhexadecahydro-1H-cyclopentadiene[a]phenanthrene-17-yl)ethane-1-one [ka] (2S,3S,5R,8R,9R,10S,13S,14S,15R,17S)-3-hydroxy-2,13,15-trimethylhexadecahydro-1H-cyclopentadiene[a]phenanthrene-17-carbonitrile (2.0 g, 6.3 mmol) was dissolved in dry tetrahydrofuran solution (250 mL), the system was purged with nitrogen gas, and 3.0 M methylmagnesium bromide (60 mL) was gradually added dropwise, and the reaction system was stirred at 80°C for 7 hours. TLC confirmed complete reaction, the reaction was quenched with saturated ammonium chloride, extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate. After concentration, column chromatography (DCM / EA = 0-30%) yielded 1-((2S,3S,5R,8R,9R,10S,13S,14S,15R,17S)-3-hydroxy-2,13,15-trimethylhexadecahydro-1H-cyclopentadiene[a]phenanthrene-17-yl)ethane-1-one product (1.3 g, yield 62%). 1 H NMR (400 MHz, CDCl3) δ 3.22~3.15(m, 1H), 2.51~2.46(m, 1H), 2.11(s, 3H), 2.05~1.03(m,22H), 0.98~0.95(m, 6H), 0.77 (s, 3H).

[0149] Step 7: Preparation of (2S,3S,5R,8R,9R,10S,13S,14S,15R,17S)-17-acetyl-2,13,15-trimethylhexadecahydro-1H-cyclopentadiene[a]phenanthrene-3-ylacetate [ka] 1-((2S,3S,5R,8R,9R,10S,13S,14S,15R,17S)-3-hydroxy-2,13,15-trimethylhexadecahydro-1H-cyclopentadiene[a]phenanthrene-17-yl)ethane-1-one (300 mg, 0.9 mmol) was dissolved in dichloromethane (20 mL), and DMAP (12 mg, 1.4 mmol), pyridine (1.2 mL), and acetic anhydride (0.8 mL) were added. The mixture was reacted at room temperature for 2 hours with stirring. After washing the reaction mixture with water, it was dried over anhydrous sodium sulfate, filtered the organic phase, and then concentrated to obtain (2S,3S,5R,8R,9R,10S,13S,14S,15R,17S)-17-acetyl-2,13,15-trimethylhexadecahydro-1H-cyclopentadiene[a]phenanthrene-3-yl acetate crude product (338 mg), which was used directly in the next step.

[0150] Step 8: Preparation of (2S,3S,5R,8R,9R,10S,13S,14S,15R,17S)-17-(2-bromoacetyl)-2,13,15-trimethylhexadecahydro-1H-cyclopentadiene[a]phenanthrene-3-ylacetate [ka] (2S,3S,5R,8R,9R,10S,13S,14S,15R,17S)-17-acetyl-2,13,15-trimethylhexadecahydro-1H-cyclopentadiene[a]phenanthrene-3-yl acetate (338 mg, 0.9 mmol) was dissolved in methanol (5.0 mL), one drop of hydrogen bromide was added, and liquid bromine (0.15 mL) was further added. The mixture was reacted at room temperature for 2 hours with stirring. The reaction was quenched with saturated sodium sulfite aqueous solution, extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate. After concentration, the mixture was obtained as (2S,3S,5R,8R,9R,10S,13S,14S,15R,17S)-17-(2-bromoacetyl)-2,13,15-trimethylhexadecahydro-1H-cyclopentadiene[a]phenanthrene-3-yl acetate crude product (408 mg), which was used directly in the next step.

[0151] Step 9: Preparation of (2S,3S,5R,8R,9R,10S,13S,14S,15R,17S)-17-(2-(4-cyano-1H-pyrazole-1-yl)acetyl)-2,13,15-trimethylhexadecahydro-1H-cyclopentadiene[a]phenanthrene-3-yl acetate [ka] (2S,3S,5R,8R,9R,10S,13S,14S,15R,17S)-17-(2-bromoacetyl)-2,13,15-trimethylhexadecahydro-1H-cyclopentadiene[a]phenanthrene-3-yl acetate (408 mg, 0.9 mmol), 1H-pyrazole-4-carbonitrile (120.0 mg, 1.3 mmol), and potassium carbonate (181.3 mg, 1.3 mmol) are mixed with anhydrous tetrahydrofuran (15.0 mL) and N,N-dimethylformamide (3.0 mL). The solution was dissolved in (mL), reacted overnight with stirring at room temperature, filtered, diluted with ethyl acetate, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product (2S,3S,5R,8R,9R,10S,13S,14S,15R,17S)-17-(2-(4-cyano-1H-pyrazole-1-yl)acetyl)-2,13,15-trimethylhexadecahydro-1H-cyclopentadiene[a]phenanthrene-3-yl acetate (418 mg), which was used directly in the next step.

[0152] Step 10: Preparation of 1-(2-((2S,3S,5R,8R,9R,10S,13S,14S,15R,17S)-3-hydroxy-2,13,15-trimethylhexadecahydro-1H-cyclopentadiene[a]phenanthrene-17-yl)-2-oxoethyl)-1H-pyrazole-4-carbonitrile [ka] (2S,3S,5R,8R,9R,10S,13S,14S,15R,17S)-17-(2-(4-cyano-1H-pyrazole-1-yl)acetyl)-2,13,15-trimethylhexadecahydro-1H-cyclopentadiene[a]phenanthrene-3-yl acetate crude product (418 mg, 0.9 mmol), potassium carbonate (373 mg, 2.7 mmol), methanol (10.0 The mixture was dissolved in (mL) and reacted with stirring at room temperature for 3 hours. The reaction mixture was filtered, the filtrate was concentrated, and the crude product was separated by high-performance liquid chromatography to obtain 1-(2-((2S,3S,5R,8R,9R,10S,13S,14S,15R,17S)-3-hydroxy-2,13,15-trimethylhexadecahydro-1H-cyclopentadiene[a]phenanthren-17-yl)-2-oxoethyl)-1H-pyrazole-4-carbonitrile (160 mg, yield: 42.0%). 1 H NMR (400 MHz, CDCl3) δ 7.86 (s, 1H), 7.81 (s, 1H), 5.03~4.88 (m, 2H), 3.22~3.16 (m, 1H), 2.58~2.53 (m, 1H), 2.26~2.11 (m, 2H), 2.00~1.80(m, 4H), 1.72~1.01 (m, 16H), 0.99~0.97 (m, 6H), 0.83 (s, 3H). 13 C NMR (101 MHz, CDCl3) δ 202.02, 142.40, 136.05, 113.25, 93.16, 77.15, 61.70, 61.40, 57.40, 45.54, 41.27, 40.98, 39.80, 39.47, 36.20, 36.04, 35.39, 33.65, 33.53, 31.28, 30.26, 26.15, 25.10, 18.57, 18.25, 16.81. MS m / z (ESI): 406 [M+H-18] + .

[0153] Example 15 1-((2S,3S,5R,8R,9R,10S,13S,14S,15R,17S)-3-hydroxy-2,13,15-trimethylhexadecahydro-1H-cyclopentadiene[a]phenanthrene17-yl)-2-(2H-1,2,3-triazole-2-yl)ethane-1-one [ka]

[0154] Example 16 1-((2S,3S,5R,8R,9R,10S,13S,14S,15R,17S)-3-hydroxy-2,13,15-trimethylhexadecahydro-1H-cyclopentadiene[a]phenanthrene-17-yl)-2-(1H-1,2,3-triazole-1-yl)ethane-1-one [ka] The synthesis method was the same as in Example 14, except that 1H-pyrazole-4-carbonitrile in step 9 was replaced with 1H-1,2,3-triazole, and finally, the compounds were separated by column chromatography to obtain Product 1 (compound 15) and Product 2 (compound 16).

[0155] Compound 15: 1 H NMR (400 MHz, CDCl3) δ 7.68 (s, 2H), 5.23 (s, 2H), 3.22~3.16 (m, 1H), 2.55~2.50 (m, 1H), 2.24~2.09 (m, 2H), 2.02~1.98 (m, 1H), 1.90~1.80(m, 3H), 1.72~1.01 (m, 16H), 0.98~0.96 (m, 6H), 0.87 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 202.63, 135.04, 77.20, 63.87, 60.90, 57.35, 45.36, 41.15, 41.00, 39.83, 39.48, 36.23, 36.08, 35.41, 33.66, 33.63, 31.31, 30.27, 26.18, 25.10, 18.58, 18.26, 16.72. MS m / z (ESI): 382 [M+H-18] + .

[0156] Compound 16: 1 H NMR (400 MHz, CDCl3) δ 7.76 (s, 1H), 7.65 (s, 1H), 5.28~5.12 (m, 2H), 3.23~3.16 (m, 1H), 2.62~2.58 (m, 1H), 2.27~2.12 (m, 2H), 2.04~1.98 (m, 1H), 1.92~1.80(m, 3H), 1.73~1.01 (m, 16H), 0.99~0.97 (m, 6H), 0.84 (s, 3H). 13 C NMR (101 MHz, CDCl3) δ 201.66, 133.99, 125.10, 77.18, 61.48, 58.94, 57.40, 45.55, 41.26, 40.99, 39.81, 39.49, 36.22, 36.06, 35.39, 33.67, 33.57, 31.30, 30.28, 26.16, 25.10, 18.57, 18.26, 16.82. MS m / z (ESI): 400 [M+H] + .

[0157] Example 17 1-((2S,3S,5R,8R,9R,10S,13S,14S,15R,17S)-3-hydroxy-2,13,15-trimethylhexadecahydro-1H-cyclopentadiene[a]phenanthrene-17-yl)-2-(2H-tetrazole-2-yl)ethane-1-one [ka]

[0158] Example 18 1-((2S,3S,5R,8R,9R,10S,13S,14S,15R,17S)-3-hydroxy-2,13,15-trimethylhexadecahydro-1H-cyclopentadiene[a]phenanthrene-17-yl)-2-(1H-tetrazole-1-yl)ethane-1-one [ka] The synthesis method was the same as in Example 14, except that 1H-pyrazole-4-carbonitrile in step 9 was replaced with 1H-tetrazole, and finally, the compounds were separated by column chromatography to obtain Product 1 (compound 17) and Product 2 (compound 18).

[0159] Compound 17: 1 H NMR (400 MHz, CDCl3) δ 8.57 (s, 1H), 5.45 (s, 2H), 3.23~3.16 (m, 1H), 2.62~2.57 (m, 1H), 2.27~2.14 (m, 2H), 2.04~1.99 (m, 1H), 1.92~1.81(m, 3H), 1.73~1.01 (m, 16H), 0.99~0.97 (m, 6H), 0.88 (s, 3H). 13 C NMR (101 MHz, CDCl3) δ 200.06, 153.23, 77.16, 61.42, 61.33, 57.39, 45.60, 41.19, 40.98, 39.80, 39.48, 36.21, 36.05, 35.39, 33.66, 33.54, 31.28, 30.28, 26.16, 25.09, 18.56, 18.23, 16.74. MS m / z (ESI): 401 [M+H] + .

[0160] Compound 18: 1 H NMR (400 MHz, CDCl3) δ 8.75 (s, 1H), 5.33~5.17 (m, 2H), 3.23~3.17 (m, 1H), 2.65~2.60 (m, 1H), 2.29~2.16 (m, 2H), 2.03~1.81(m, 4H), 1.74~1.06 (m, 16H), 1.01~0.97 (m, 6H), 0.84 (s, 3H). 13 C NMR (101 MHz, CDCl3) δ 200.06, 143.63, 77.14, 61.69, 57.43, 56.75, 45.73, 41.30, 40.96, 39.79, 39.47, 36.18, 36.01, 35.36, 33.65, 33.53, 31.26, 30.29, 26.14, 25.07, 18.56, 18.24, 16.85. MS m / z (ESI): 401 [M+H] + .

[0161] Example 19 1-(2-((2S,3S,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-2,3,13-trimethylhexadecahydro-1H-cyclopentadiene[a]phenanthrene-17-yl)-2-oxoethyl)-1H-pyrazole-4-carbonitrile [ka]

[0162] Synthesis scheme [ka]

[0163] Step 1: Preparation of (2S,3S,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-2,3,13-trimethylhexadecahydro-1H-cyclopentadiene[a]phenanthrene-17-carbonitrile [ka] Potassium tert-butoxide (4.06 g, 36.2 mmol) and tert-butyl alcohol (24.0 mL) were added to a dry 100 mL round-bottom flask, and the system was purged with nitrogen gas. (2S,3S,5R,8R,9R,10S,13S,14S)-3-hydroxy-2,3,13-trimethylhexadecahydro-17H-cyclopentadiene[a]phenanthrene-17-one (1.1 g, 3.62 mmol) was dissolved in 15 mL of ethylene glycol dimethyl ether and gradually added dropwise to the reaction system, and the reaction was carried out with stirring for 30 minutes. p-toluenesulfonylmethyl isocyanide (1.41 g, 7.24 mmol) was dissolved in 15 mL of ethylene glycol dimethyl ether and gradually added dropwise to the reaction system, and the reaction was carried out at room temperature overnight with stirring. TLC confirmed complete reaction, water (50 mL) was added to quench the reaction, the aqueous phase was extracted with ethyl acetate (50 mL x 2), the organic phase was combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was separated by column chromatography and purified (petroleum ether / ethyl acetate: 50 / 1~3 / 1) to obtain (2S,3S,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-2,3,13-trimethylhexadecahydro-1H-cyclopentadiene[a]phenanthrene-17-carbonitrile (0.65 g, yield: 57.1%).

[0164] Step 2: Preparation of 1-((2S,3S,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-2,3,13-trimethylhexadecahydro-1H-cyclopentadiene[a]phenanthrene-17-yl)ethane-1-one [ka] (2S,3S,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-2,3,13-trimethylhexadecahydro-1H-cyclopentadiene[a]phenanthrene 17-carbonitrile (650 mg, 2.06 mmol) was dissolved in dry tetrahydrofuran solution (75 mL), the system was purged with nitrogen gas, and 3.0 M methylmagnesium bromide (20 mL, 61.8 mmol) was gradually added dropwise, and the reaction system was stirred at 80°C for 7 hours. Complete reaction was shown by TLC, the reaction was quenched with saturated ammonium chloride, extracted with ethyl acetate, the organic phase was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The mixture was filtered, rotated dry, and the crude product was separated by column chromatography (washed with petroleum ether:ethyl acetate = 3:1) to obtain 1-((2S,3S,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-2,3,13-trimethylhexadecahydro-1H-cyclopentadiene[a]phenanthrene-17-yl)ethane-1-one (520 mg, yield: 76.0%).

[0165] Step 3: Preparation of 2-bromo-1-((2S,3S,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-2,3,13-trimethylhexadecahydro-1H-cyclopentadiene[a]phenanthrene-17-yl)ethane-1-one [ka] 1-((2S,3S,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-2,3,13-trimethylhexadecahydro-1H-cyclopentadiene[a]phenanthrene-17-yl)ethane-1-one (520 mg, 1.5 mmol) was dissolved in methanol (20 mL), one drop of hydrogen bromide was added, and liquid bromine (230 mg, 1.65 mmol) was further added. The mixture was reacted at room temperature for 3 hours with stirring. Water (50.0 mL) was added, the aqueous phase was extracted with ethyl acetate (50.0 mL x 2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product (520 mg crude product), which was used directly in the next reaction.

[0166] Step 4: Preparation of 1-(2-((2S,3S,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-2,3,13-trimethylhexadecahydro-1H-cyclopentadiene[a]phenanthrene-17-yl)-2-oxoethyl)-1H-pyrazole-4-carbonitrile [ka] 2-Bromo-1-((2S,3S,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-2,3,13-trimethylhexadecahydro-1H-cyclopentadiene[a]phenanthrene-17-yl)ethane-1-one (220 mg, 0.54 mmol), 1H-pyrazole-4-carbonitrile (74.7 mg, 0.81 mmol), and potassium carbonate (113 mg, 0.81 mmol) are mixed with anhydrous tetrahydrofuran (7.00 mL) and N,N-dimethylformamide (1.40 mL). The mixture was dissolved in (mL), reacted overnight at room temperature with stirring, filtered, and the filtrate was concentrated. The crude product was separated by high-performance liquid chromatography to obtain 1-(2-((2S,3S,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-2,3,13-trimethylhexadecahydro-1H-cyclopentadiene[a]phenanthrene-17-yl)-2-oxoethyl)-1H-pyrazole-4-carbonitrile (120 mg, yield: 52.6%). 1 H NMR (400 MHz, CDCl3) δ 7.86 (s, 1H), 7.81 (s, 1H), 5.06~4.79 (m, 2H), 2.60 (t, J = 8.8 Hz, 1H), 2.23~2.16 (m, 1H), 2.06~2.00 (m, 1H), 1.82 (d, J = 7.5 Hz, 2H), 1.78~1.68 (m, 4H), 1.65~1.53 (m, 6H), 1.52-1.37 (m, 6H), 1.35~1.18 (m, 6H), 0.87 (d, J = 6.7 Hz, 3H), 0.67 (s, 3H). 13 C NMR (101 MHz, CDCl3) δ 202.31, 142.58, 136.23, 113.42, 93.32, 74.34, 61.84, 61.31, 56.11, 45.63, 43.10, 41.86, 41.21, 39.37, 38.73, 36.15, 35.14, 34.21, 31.40, 26.26, 25.95, 24.51, 23.28, 20.64, 15.33, 14.00. MS m / z (ESI): 422.1 [MH] - .

[0167] Example 20 1-((2S,3S,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-2,3,13-trimethylhexadecahydro-1H-cyclopentadiene[a]phenanthrene-17-yl)-2-(2H-tetrazole-2-yl)ethane-1-one [ka]

[0168] Example 21 1-((2S,3S,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-2,3,13-trimethylhexadecahydro-1H-cyclopentadiene[a]phenanthrene-17-yl)-2-(1H-tetrazole-1-yl)ethane-1-one [ka]

[0169] Synthesis scheme [ka] The synthesis method was the same as in Example 19, except that 1H-pyrazole-4-carbonitrile in the fourth step was replaced with 1H-tetrazole, and finally, the compounds were separated by column chromatography to obtain Product 1 (Compound 20) and Product 2 (Compound 21).

[0170] Product 1 (compound 20): 1 H NMR (400 MHz, CDCl3) δ 8.57 (s, 1H), 5.45 (s, 2H), 2.64 (t, J = 8.9 Hz, 1H), 2.28~2.14 (m, 1H), 2.08 (dt, J = 12.1, 3.4 Hz, 1H), 1.91~1.68 (m, 8H), 1.63~1.38 (m, 10H), 1.33~1.24 (m, 6H), 0.87 (d, J = 6.7 Hz, 3H), 0.71 (s, 3H). 13 C NMR (101 MHz, CDCl3) δ 200.38, 153.39, 74.34, 61.56, 61.25, 56.08, 45.69, 43.09, 41.85, 41.20, 39.27, 38.72, 36.15, 35.13, 34.20, 31.39, 26.25, 25.93, 24.50, 23.30, 20.61, 15.31, 13.92. MS m / z (ESI): 399.1 [MH] - .

[0171] Product 2 (compound 21): 1 H NMR (400 MHz, DMSO-d6) δ 9.31 (s, 1H), 5.69~5.44 (m, 2H), 4.06 (s, 1H), 2.81 (t, J = 8.9 Hz, 1H), 2.12~2.01 (m, 2H), 1.81~1.50 (m, 8H), 1.49~1.28 (m, 7H), 1.27~1.11 (m, 4H), 1.11~0.97 (m, 4H), 0.78 (d, J = 6.7 Hz, 3H), 0.60 (s, 3H). 13 C NMR (101 MHz, CDCl3) δ 202.45, 145.21, 72.00, 59.92, 56.81, 55.25, 44.63, 42.97, 41.31, 40.78, 38.23, 37.99, 35.43, 34.43, 33.69, 31.08, 25.95, 25.37, 23.97, 22.57, 20.11, 15.40, 13.38. MS m / z (ESI): 399.1 [MH] - .

[0172] Example 22 1-((2S,3S,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-2,3,13-trimethylhexadecahydro-1H-cyclopentadiene[a]phenanthrene-17-yl)-2-(1H-1,2,4-triazole-1-yl)ethane-1-one [ka]

[0173] Synthesis scheme [ka] The synthesis method was the same as in Example 19, except that 1H-pyrazole-4-carbonitrile in the fourth step was replaced with 1H-1,2,4-triazole. 1 H NMR (400 MHz, CDCl3) δ 8.14 (s, 1H), 7.95 (s, 1H), 5.04~4.91 (m, 2H), 2.62 (t, J = 8.6 Hz, 1H), 2.20 (q, J = 10.8, 10.0 Hz, 1H), 2.09~2.00 (m, 1H), 1.82~1.62 (m, 8H), 1.55~1.35 (m, 6H), 1.34~1.19 (m, 10H), 0.87 (d, J = 6.7 Hz, 3H), 0.68 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 202.26, 152.00, 74.31, 61.27, 58.89, 56.07, 45.55, 43.07, 41.83, 41.18, 39.31, 38.70, 36.13, 35.11, 34.18, 31.37, 29.88, 26.23, 25.92, 24.48, 23.27, 20.58, 15.30, 13.95. MS m / z (ESI): 400.2 [M+H] + .

[0174] Example 23 1-((2S,3S,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-2,3,13-trimethylhexadecahydro-1H-cyclopentadiene[a]phenanthrene-17-yl)-2-(5-methyl-2H-tetrazole-2-yl)ethane-1-one [ka]

[0175] Example 24 1-((2S,3S,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-2,3,13-trimethylhexadecahydro-1H-cyclopentadiene[a]phenanthrene-17-yl)-2-(5-methyl-1H-tetrazole-1-yl)ethane-1-one [ka]

[0176] Synthesis scheme [ka] The synthesis method was the same as in Example 19, except that 1H-pyrazole-4-carbonitrile in the fourth step was replaced with 5-methyl-1H-tetrazole, and finally, the compounds were separated by column chromatography to obtain Product 1 (Compound 23) and Product 2 (Compound 24).

[0177] Compound 23: 1 H NMR (400 MHz, CDCl3) δ 5.35 (s, 2H), 2.62 (t, J = 8.7 Hz, 1H), 2.56 (s, 3H), 2.28~2.14 (m, 1H), 2.07 (dt, J = 12.2, 3.4 Hz, 1H), 1.83~1.74 (m, 7H), 1.59~1.40 (m, 10H), 1.34~1.26 (m, 7H), 0.88 (d, J = 6.6 Hz, 3H), 0.71 (s, 3H). 13 C NMR (101 MHz, CDCl3) δ 200.69, 163.55, 74.30, 61.41, 61.18, 56.07, 45.61, 43.09, 41.84, 41.20, 39.25, 38.70, 36.14, 35.13, 34.18, 31.38, 26.24, 25.92, 24.49, 23.30, 20.61, 15.30, 13.90, 11.11. MS m / z (ESI): 413.1 [MH] - .

[0178] Compound 24: 1 H NMR (400 MHz, CDCl3) δ 5.10 (q, J = 18.1 Hz, 2H), 2.66 (t, J = 8.7 Hz, 1H), 2.47 (s, 3H), 2.24~2.19 (m, 1H), 2.07 (t, J = 12.0 Hz, 1H), 1.84~1.72 (m, 7H), 1.63~1.41 (m, 10H), 1.37~1.26 (m, 7H), 0.88 (d, J = 6.7 Hz, 3H), 0.68 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 200.47, 152.92, 74.29, 61.31, 56.18, 56.12, 45.77, 43.06, 41.83, 41.17, 39.42, 38.69, 36.12, 35.10, 34.17, 31.35, 26.22, 25.93, 24.48, 23.26, 20.63, 15.30, 14.02, 9.08. MS m / z (ESI): 415.1 [M+H] + .

[0179] Example 25 1-(2-((2S,3S,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-2,13-dimethylhexadecahydro-1H-cyclopentadiene[a]phenanthrene-17-yl)-2-oxoethyl)-1H-pyrazole-4-carbonitrile [ka]

[0180] Synthesis scheme [ka]

[0181] Step 1: Preparation of (2S,3S,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-2,13-dimethylhexadecahydro-1H-cyclopentadiene[a]phenanthrene-17-carbonitrile [ka] Potassium tert-butoxide (3.48 g, 34.4 mmol) and tert-butyl alcohol (20.0 mL) were added to a dry 100 mL round-bottom flask, and the system was purged with nitrogen gas. (2S,3S,5R,8R,9R,10S,13S,14S)-3-hydroxy-2,13-dimethylhexadecahydro-17H-cyclopenta[a]phenanthrene-17-one (1.00 g, 3.44 mmol) was dissolved in 10 mL of ethylene glycol dimethyl ether and gradually added dropwise to the reaction system, and the reaction was carried out with stirring for 30 minutes. p-toluenesulfonylmethyl isocyanide (1.21 g, 6.88 mmol) was dissolved in 10 mL of ethylene glycol dimethyl ether and gradually added dropwise to the reaction system, and the reaction was carried out at room temperature overnight with stirring. TLC confirmed complete reaction, water (50 mL) was added to quench the reaction, the aqueous phase was extracted with ethyl acetate (50 mL x 2), the organic phase was combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was separated by column chromatography and purified (petroleum ether / ethyl acetate: 50 / 1~3 / 1) to obtain (2S,3S,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-2,13-dimethylhexadecahydro-1H-cyclopentadiene[a]phenanthrene-17-carbonitrile (0.6 g, yield: 57.8%).

[0182] Step 2: Preparation of 1-((2S,3S,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-2,13-dimethylhexadecahydro-1H-cyclopentadiene[a]phenanthrene-17-yl)ethane-1-one [ka] (2S,3S,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-2,13-dimethylhexadecahydro-1H-cyclopentadiene[a]phenanthrene-17-carbonitrile (1.10 g, 3.65 mmol) was dissolved in dry tetrahydrofuran solution (124 mL), the system was purged with nitrogen gas, and 3.0 M methylmagnesium bromide (36.6 mL, 11.0 mmol) was gradually added dropwise, and the reaction system was stirred at 80°C for 7 hours. Complete reaction was shown by TLC, the reaction was quenched with saturated ammonium chloride, extracted with ethyl acetate, the organic phase was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The mixture was filtered, rotated dry, and the crude product was separated by column chromatography (washed with petroleum ether:ethyl acetate = 4:1) to obtain 1-((2S,3S,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-2,13-dimethylhexadecahydro-1H-cyclopentadiene[a]phenanthrene-17-yl)ethane-1-one (600 mg, yield: 51.8%).

[0183] Step 3: Preparation of (2S,3S,5R,8R,9R,10S,13S,14S,17S)-17-acetyl-2,13-dimethylhexadecahydro-1H-cyclopentadiene[a]phenanthrene-3-ylacetate [ka] 1-((2S,3S,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-2,13-dimethylhexadecahydro-1H-cyclopentadiene[a]phenanthrene-17-yl)ethane-1-one (500 mg, 1.57 mmol) was dissolved in dichloromethane (25.0 mL), and DMAP (20.0 mg, 2.36 mmol), pyridine (2.00 mL), and acetic anhydride (1.25 mL) were added. The mixture was reacted at room temperature for 2 hours with stirring. The reaction mixture was filtered, and the organic phase was concentrated to obtain (2S,3S,5R,8R,9R,10S,13S,14S,17S)-17-acetyl-2,13-dimethylhexadecahydro-1H-cyclopentadiene[a]phenanthrene-3-yl acetate crude product (566 mg, crude product).

[0184] Step 4: Preparation of (2S,3S,5R,8R,9R,10S,13S,14S,17S)-17-(2-bromoacetyl)-2,13-dimethylhexadecahydro-1H-cyclopentadiene[a]phenanthrene-3-ylacetate [ka] (2S,3S,5R,8R,9R,10S,13S,14S,17S)-17-acetyl-2,13-dimethylhexadecahydro-1H-cyclopentadiene[a]phenanthrene-3-yl acetate (566 mg, 1.57 mmol) was dissolved in methanol (6.00 mL), one drop of hydrogen bromide was added, and liquid bromine (0.25 mL, 4.88 mmol) was added. The mixture was reacted at room temperature for 3 hours with stirring. Water (20.0 mL) was added, the aqueous phase was extracted with ethyl acetate (20.0 mL x 2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product (680 mg, crude product), which was used directly in the next reaction.

[0185] Step 5: Preparation of (2S,3S,5R,8R,9R,10S,13S,14S,17S)-17-(2-(4-cyano-1H-pyrazole-1-yl)acetyl)-2,13-dimethylhexadecahydro-1H-cyclopentadiene[a]phenanthrene-3-yl acetate [ka] (2S,3S,5R,8R,9R,10S,13S,14S,17S)-17-(2-bromoacetyl)-2,13-dimethylhexadecahydro-1H-cyclopentadiene[a]phenanthrene-3-yl acetate (680 mg, crude product), 1H-pyrazole-4-carbonitrile (480.0 mg, 5.20 mmol) and potassium carbonate (725 mg, 5.20 mmol) are mixed with anhydrous tetrahydrofuran (10.0 The mixture was dissolved in (mL) and reacted overnight at room temperature with stirring. The reaction mixture was filtered, and the filtrate was concentrated to obtain (2S,3S,5R,8R,9R,10S,13S,14S,17S)-17-(2-(4-cyano-1H-pyrazole-1-yl)acetyl)-2,13-dimethylhexadecahydro-1H-cyclopentadiene[a]phenanthrene-3-yl acetate (600 mg, crude product).

[0186] Step 6: Preparation of 1-(2-((2S,3S,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-2,13-dimethylhexadecahydro-1H-cyclopentadiene[a]phenanthrene17-yl)-2-oxoethyl)-1H-pyrazole-4-carbonitrile [ka] (2S,3S,5R,8R,9R,10S,13S,14S,17S)-17-(2-(4-cyano-1H-pyrazole-1-yl)acetyl)-2,13-dimethylhexadecahydro-1H-cyclopentadiene[a]phenanthrene-3-yl acetate (600 mg, crude product), potassium carbonate (725 mg, 5.20 mmol) to methanol (10.00 mmol) The mixture was dissolved in (mL) and reacted with stirring at room temperature for 3 hours. The reaction mixture was filtered, the filtrate was concentrated, and the crude product was separated by high-performance liquid chromatography to obtain 1-(2-((2S,3S,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-2,13-dimethylhexadecahydro-1H-cyclopentadiene[a]phenanthrene17-yl)-2-oxoethyl)-1H-pyrazole-4-carbonitrile (172 mg, yield: 31.6%). 1 H NMR (400 MHz, CDCl3) δ 7.86 (s, 1H), 7.81 (s, 1H), 5.05~4.87 (m, 2H), 3.18 (dt, J = 10.3, 5.1 Hz, 1H), 2.61 (s, 1H), 2.26~2.14 (m, 1H), 2.09~1.97 (m, 2H), 1.90~1.01 (m, 20H), 0.98 (d, J = 6.3 Hz, 3H), 0.67 (s, 3H). 13 C NMR (101 MHz, CDCl3) δ 202.11, 142.39, 136.04, 113.23, 93.16, 77.20, 61.65, 61.11, 55.89, 45.46, 41.72, 40.80, 39.16, 39.07, 36.03, 35.92, 35.28, 33.66, 31.16, 26.16, 25.64, 24.33, 23.09, 18.59, 13.81. MS m / z (ESI): 392 [M+H-18] + .

[0187] Using a synthesis method similar to that of Examples 1 and 2, the following target compounds 26-68 were synthesized. [ka] [ka] [ka] [ka] [ka] [ka]

[0188] Biological testing and evaluation The present invention will be further described below in conjunction with test examples, but these test examples are not intended to limit the scope of the present invention.

[0189] The structure of compound Sage-217 is as follows: [ka] It is manufactured by referring to the manufacturing method of Example 20 of Patent CN105339381B.

[0190] Test Example 1: Positive regulatory effect of the compound of the present invention on GABAa receptors. 1. Experimental method: 1.1 Cell culture The cells used in this experiment were from a CHO cell line that stably expressed normal GABAa receptor function after transfection with human GABAa receptor α1, β2, and γ2 subunit cDNA. This cell line was constructed by B'sys GmbH. The cells were cultured in a medium containing the following components (purchased from Invitrogen): DMEM culture medium, 10% (v / v) inactivated fetal bovine serum, 5 μg / mL puromycin, 250 μg / mL hydroxymycin B, and 100 μg / mL zeocin. The cells were grown in a culture dish containing the above culture medium and cultured at 37°C in an incubator containing 5% CO2. 12–24 hours before the electrophysiological experiment, the cells were transferred to a circular glass plate placed in the culture dish and grown under the same culture medium and conditions as above. The cell density on each circular glass plate needed to meet the requirement that most cells were independently single.

[0191] 1.2 Electrophysiological Recording System In this experiment, total cellular currents were recorded using a manual patch-clamp system, a HEKA EPC10 USB signal amplifier, and a digital conversion system (purchased from HEKA Electronics, Germany). After removing a circular glass plate with CHO GABAa cells proliferating on its surface (see cell culture and required sections above) from the culture dish, it was placed in an electrophysiological recording groove under an inverted microscope. The groove was continuously perfused with extracellular fluid (approximately 1-2 mL per minute). In the experiment, the chloride ion current of the GABAa channel was recorded using the total cellular current recording technique. 1 μM GABA was used as an initial control to activate the chloride ion current of the GABAa channel in each cell (the reason for using a GABA concentration of 1 μM was that this concentration was the effective activation concentration between 10% and 20% obtained in the cells used in this experiment for the GABAa ion channel agonist GABA). Unless otherwise specified, all experiments were conducted at normal room temperature (~25°C), and only cells that met the standards for electrophysiological recording were used. In the experiment, cells were ruptured and sealed, and after entering a whole-cell state, were clamped to -80 mV. 1 μM GABA was applied to the cells via a drug perfusion system to induce a chloride ion current in the GABAa channel. The application time was approximately 4 seconds, and the magnitude of this current was used as the initial control value. Subsequently, the cells were perfused with the test concentration of the compound for 3 minutes and incubated. A mixed solution of 1 μM GABA and a corresponding test concentration of the compound was then applied to the cells to induce a current, thereby observing the enhancement effect of the test compound on the current induced by 1 μM GABA. Once the cell state was stable, the test compound was applied to the same cells from low to high concentrations. During the experiment, to avoid a decrease in current due to desensitization of the GABAa ion channel, the interval between applications of the test substance to the cells via the drug perfusion system was at least 180 seconds.

[0192] 2. Data Analysis The test data was analyzed using data analysis software provided by HEKA Patchmaster, Microsoft Excel, and Graphpad Prism.

[0193] 3. Experimental Results [Table 1-1] [Table 1-2] [1] A single concentration of 0.1 μM was selected. [2] The agonist ratio is the enhancement compared to the GABAa receptor current induced by 1 μM GABA, and is expressed as a percentage. [3] The compound tested as a positive modulator of the EC of the current of the GABAa receptor (chloride ion channel) induced by 1 μM GABA. 50 The (semi-maximal effective concentration) value was increased. [4] E max This represents the maximum enhancement compared to the GABAa receptor current induced by 1 μM GABA, and is expressed as a percentage. max And the concentration values ​​of the corresponding test compounds are, EC 50 Predicted from the fitting curve.

[0194] 4. Experimental Conclusion As can be seen from Table 1, the compounds of the examples of the present invention exhibited excellent positive regulatory effects on GABAa receptors. Among them, Examples 2, 9, and 20 showed lower E levels compared to Sage-217. max This indicates that it predicts potentially smaller side effects in vivo and lower EC 50 This, when combined with other factors, demonstrated the potential for a larger treatment window.

[0195] Test Example 2: In vivo drug efficacy experiment using a PTZ-induced mouse epilepsy model. 1. Test Method 1.1 Test animals Male C57 mice were purchased from Sibei Fu (Suzhou) Biotechnology Co., Ltd.

[0196] 1.2 Compounds awaiting measurement All compounds awaiting measurement were stored in a refrigerator at 4°C. The information on the test specimens is shown in the table below. [Table 2-A]

[0197] 1.3 Test equipment 1) 1 mL sterile disposable syringe with Kindly needle 2) 100-1000 μL pipette 3) Vortex-Genie2 Multifunctional Vortex Mixer 4) Digitally controlled ultrasonic cleaner 5) MSA Series Magnetic Stirrer 6) Sartorius SQP type electronic balance 7) Li Ping Precision Electronic Balance 8) The organic glass box and the side walls of the adjacent space are designed to block light (customizable).

[0198] 1.4 Grouping of test animals [Table 2-B] Note: (1) Vehicle: 5% DMSO + 5% HS-15 + 90% 20% hydroxypropyl β-cyclodextrin (10 mL / kg, po),

[0199] 1.5 Solvent preparation: 20% hydroxypropyl β-cyclodextrin 20.4082 g of hydroxypropyl-β-cyclodextrin (calculated with a purity of 98%) was precisely weighed and added to a 100 mL solvent bottle. 60 mL of redistilled water was also added, and the mixture was vortexed in a vortex mixer for 3-5 minutes. The mixture was then stirred in a magnetic stirrer for 1 hour to obtain a homogeneous and clear solution. After that, redistilled water was added to bring the volume to 100 mL, and the mixture was vortexed. Finally, the mixture was stirred magnetically for 10 minutes to obtain a homogeneous and clear solution.

[0200] 1.6 Preparation of compounds awaiting measurement 1) PTZ: Prepare a 120 mg / kg PTZ solution using physiological saline as the solvent (administered volume is 10 mL / kg), 2) Compounds awaiting measurement: Using Vehicle from 1.4 as the solvent, solutions of compounds awaiting measurement corresponding to 3 / 1 / 0.3 mg / kg were prepared (dosing volume: 10 mL / kg).

[0201] 1.7 Test Procedure a) One hour before the experiment, move the experimental animals to the control room to allow them to adapt to the environment. b) The mice were randomly divided into groups, labeled and weighed, with 10 mice per group. 60 minutes before PTZ administration, the compounds and vehicles awaiting measurement were administered orally to each group. c) Before the experimental observation, administer the PTZ solution subcutaneously and record this point as the start of the observation. d) Immediately after PTZ administration, the animals were placed in an observation box and observed for 30 minutes, and the appearance of each animal was recorded. I. Number of animal deaths, II. 1) Latency period of the first clonic seizure, 2) Latency period of the first generalized tonic-clonic seizure, 3) Number of clonic seizures, 4) Number of generalized tonic-clonic seizures. If no epileptic seizure occurred in the animal during the 30 min observation period, the latency period was recorded as 1800 s and the number of seizures was recorded as 0. • Clonic seizure: The animal experiences myoclonus throughout the body for more than 3 seconds, accompanied by falling. • Tonic seizure: The limbs are straightened and at a 90° angle to the body.

[0202] 2. Data Analysis All quantitative data were expressed as mean ± standard error (Mean ± SEM), and statistical analysis was performed on the data using Prism 8.0 statistical software.

[0203] 3. Experimental Results and Conclusions [Table 2-1] Conclusion: As can be seen from Table 2-1, compared to the blank group, all of the compounds in each example in this experiment extended the survival rate of PTZ-induced seizure mice and had a protective effect against acute epileptic seizures in mice. Of these, Examples 5, 6, 9, and 20, as well as Sage-217, still showed significant protective effects even at low doses (1 mpk), and Examples 5, 9, and 20 still showed some protective effects even at extremely low doses (0.3 mpk).

[0204] [Table 2-2] Conclusion: As can be seen from Table 2-2, compared to the blank group, all of the compounds in each example used in this experiment significantly prolonged the latency period of clonic seizures and generalized tonic-clonic seizures, and significantly reduced the number of seizures, demonstrating remarkable antiepileptic activity.

[0205] Test Example 3: In vivo efficacy experiment on forced swimming and sugar water preference in mice. 1. Purpose of the exam: The core of depression manifests as feelings of despair, helplessness, and a lack of pleasure. Forced swimming experiments are often used to evaluate despair-like behavior. In this experiment, animals are placed in an unpleasant environment from which they cannot escape (a water box). Initially, the animals exhibit active behavior (swimming or struggling), then become immobile, and the period of immobility gradually increases. A lack of pleasure means losing interest in things that were once considered enjoyable, and in rodents, this usually manifests as a decreased palatability for sweet things (sucrose). Therefore, the in vivo efficacy of the compounds in the embodiments of this invention in mice can be evaluated by forced swimming and sugar water palatability experiments.

[0206] 2. Experimental materials 2.1 Test animals Female / male C57 mice were purchased from Sibei Fu (Suzhou) Biotechnology Co., Ltd.

[0207] 2.2 Compounds awaiting measurement All compounds awaiting measurement were stored in a refrigerator at 4°C. The information on the test specimens is shown in the table below. [Table 3-A]

[0208] 2.3 Test equipment [Table 3-B]

[0209] 2.4 Grouping of test animals [Table 3-C] Note: (1) Vehicle: 5% DMSO + 5% HS-15 + 90% 20% hydroxypropyl β-cyclodextrin (10 mL / kg, po).

[0210] 2.5 Preparation of test specimens When preparing the test specimens, a certain amount of sample was taken, a solvent was added, and then sonication was performed. Dilution of the test sample: A fixed volume of mother liquor was taken, and the desired volume of solvent was added by ratio dilution to dilute it. Labels were affixed to the prepared chemical solutions for future reference. Formula: Theoretical concentration (mg / mL) = Dose (mg / kg) / Volume of administration (mL / kg) Theoretical amount charged (mg) = [Preparation volume (mL) × Theoretical concentration of test sample (mg / mL) × Salt coefficient] / Purity

[0211] 2.6 Test Procedure Forced swimming: Animals were administered a solvent or drug for 1 hour according to the control group and the respective dose groups of the test drug. They were then placed in organic glass cylinders at 25°C and a water depth of 20 cm. The animals' swimming behavior in the water was recorded on video, and the immobile time of 2-6 minutes when the animals were floating in the water and stopped struggling was recorded and analyzed. Sugar water preference: D1: 1% sugar water was given to both sides; D2 / 3: drinking water was given to one side and 1% sugar water to the other side; D4: water deprivation and fasting; D5: sugar water preference value was detected. For detection, the mice were divided into experimental groups and administered the sugar water. After administration, they were given sugar water and drinking water weighed according to D2 / 3. The animals were allowed to drink freely for 2 hours in a dark environment, and the sugar water and drinking water were changed every hour during that time.

[0212] 3. Data Processing The experimental data is,

number

[0213] 4. Experimental Results and Conclusions [Table 3-1] [Table 3-2] As can be seen from the above results, compared to the blank group, the compound of Example 9 of the present invention significantly reduced the immobility time in the forced swimming experiment of C57 mice and significantly increased the sugar water preference value in the sugar water preference experiment of C57 mice, exhibiting a remarkable antidepressant effect and demonstrating certain advantages over Sage-217.

[0214] Test Example 4: In vivo pharmacokinetic experiment of the compound of the present invention in mice 1. Purpose of the exam: The compounds of the present invention were administered orally to male ICR mice, and the blood drug concentrations of the compounds in the mice were measured. The PK parameters were calculated, and the pharmacokinetics of the compounds of the present invention were evaluated.

[0215] 2. Test materials: (1) Test sample: Compound of the present invention example, prepared in-house. (2) Test animal: ICR mouse, SPF grade, male, Shanghai Lingcheng Biological Technology Co., Ltd. (3) Main testing equipment: [Table 4-A]

[0216] 3. Test plan: (1) Administration information: Preparation of the drug: The volume to be prepared was calculated according to the weight of the weighed drug, and 5% DMSO and 5% HS-15 were added in order. After the drug was completely dissolved, a 90% aqueous solution of 20% β-cyclodextrin was added and mixed thoroughly and uniformly as needed. Route of administration: Forced oral administration; oral dose was 10 mg / kg. Frequency and duration of administration: Single dose. (2) Test method: ICR mice were stratified by body weight and randomly divided into groups of 9 mice each. Each group was fasted overnight before the experiment. Forced oral administration was performed, and 50 μL of blood was collected from the retinal veins of the mice at 0, 0.167, 0.333, 0.5, 1, 2, 4, 6, 8, 12, and 24 hours. These samples were then placed in wet ice and allowed to stand for 4000 rpm. -1 The plasma was separated by centrifugation for 10 minutes and then frozen and stored in a -80°C refrigerator in preparation for measurement.

[0217] 4. Test results and analysis: High-performance liquid chromatography-tandem mass spectrometry (LC-MS / MS) was used to measure the concentration of plasma samples. Retention times of compounds and internal standards, chromatographic acquisition, and chromatographic integration were processed using the software Analyst (AB SCIEX), and data statistics were processed using Microsoft Office software. Plasma concentrations were measured using WinNonlin. TMThe data was processed using a non-compartment model of the pharmacokinetic software Version 6.3 (Pharsight, Mountain View, CA), and pharmacokinetic parameters were calculated using the linear log-trapezoid method. Specific results are shown in Table 4. [Table 4]

[0218] 5. Exam conclusions: As can be seen from the experimental results of mouse pharmacokinetics in the table, the compound of the present invention has a longer half-life t 1 / 2 , higher exposure AUC and higher maximum blood drug concentration C max These compounds exhibited favorable metabolic characteristics, and this result clearly reflected that compounds in this class with relatively low Emax values ​​exhibited superior in vivo efficacy compared to Sage-217, due to their longer half-lives and higher exposure levels.

[0219] Test Example 5: Acute toxicity experiment and observation of side effects of the compound of the present invention in mice. 1. Purpose of the Examination We will evaluate the acute toxicity expression in ICR mice after a single forced oral administration of the compound awaiting measurement, observe the recovery status of the ICR mice within 14 days after administration, and determine the maximum tolerated dose of the compound awaiting measurement.

[0220] 2. Test Method 2.1 Test animals Sixty-five male and sixty-five female ICR mice were purchased from Shanghai Jihui Laboratory Animal Husbandry Co., Ltd. The experimental animals underwent a 4-5 day acclimatization period before formal experiments began. The animals were housed in cages of five per cage at a room temperature of 23±2°C, with a 12 / 12-hour day-night cycle, and were given free access to food and water.

[0221] 2.2 Saving Samples All compounds awaiting measurement were stored in a refrigerator at 4°C. [Table 5-1]

[0222] 2.3 Test equipment 1 mL sterile disposable syringe with Kindly needle 100-1000 μL pipette Vortex-Genie2 Multifunctional Vortex Mixer Digitally controlled ultrasonic cleaner MSA Series Magnetic Stirrer Sartorius SQP type electronic balance Rihei Precision Electronic Balance

[0223] 2.4 Grouping of test animals [Table 5-2] Note: (1) Vehicle: 5% DMSO + 5% HS-15 + 90% 20% hydroxypropyl β-cyclodextrin (10 mL / kg, po).

[0224] 3. Test Procedure 3.1 Solvent preparation: 20% hydroxypropyl β-cyclodextrin 20.4082 g of hydroxypropyl-β-cyclodextrin (calculated with a purity of 98%) was precisely weighed and added to a 100 mL solvent bottle. 60 mL of redistilled water was also added, and the mixture was vortexed in a vortex mixer for 3-5 minutes. The mixture was then stirred in a magnetic stirrer for 1 hour to obtain a homogeneous and clear solution. After that, redistilled water was added to bring the volume to 100 mL, and the mixture was vortexed. Finally, the mixture was stirred magnetically for 10 minutes to obtain a homogeneous and clear solution.

[0225] 3.2 Preparation of compounds awaiting measurement Based on the vehicle in 2.4, a certain weight of the compound awaiting measurement was weighed, and first 5% DMSO liquid was added, vortexed and shaken until the drug was completely dissolved. Then, 5% HS-15 liquid was added, mixed again homogeneously, vortexed and shaken, and finally the remaining volume-proportional 20% hydroxypropyl β-cyclodextrin solution was added to form a clear, homogeneous solution of 2 mg / mL. Subsequently, the solution was gradient diluted according to the ratio to concentrations of 1, 0.5, and 0.25 mg / mL (administered volume of 10 mL / kg).

[0226] 3.3 Test Procedure a. After weighing the animals approximately 12-18 hours before the experiment, they were divided into groups and fasted overnight (water was not prohibited). b. The following day, the mice were weighed again by dividing them into groups, with 10 mice per group (5 males and 5 females / dose). Each group was then forcibly administered the compound and vehicle awaiting measurement, and the administration day was recorded as Day 1. c. Following the experimental procedure for acute toxicity testing, detailed observations were conducted at the side of the cage for each group at 0.5-1 hour and 4-8 hours after administration on Day 1, and daily observations were conducted at the side of the cage from Day 2 to Day 14. d. The observation time from Day 2 to Day 14 was from 9:00 to 12:00.

[0227] 4. Record Indicators (1) Record the clinical symptoms and mortality status of ICR mice in each group after administration, and determine the maximum tolerated dose. (2) After administration of ICR mice in each group, the status of symptom relief and recovery was recorded.

[0228] 5. Experimental Results (1) No deaths occurred in any group between 0.5 and 1 hour after administration. (2) 4-8 hours after administration, one male mouse and two female mice in the 20 mpk Sage-217 group died, and the surviving mice still showed prone symptoms. No deaths occurred in any of the dose groups in Examples 9 and 20. Of these, the 20 mpk group in Example 9 only experienced difficulty walking, and all of the following dose groups recovered to normal. (3) All remaining mice survived until Day 14.

[0229] Table 5-3 shows specific observation results for some doses on the first day, near the cage. [Table 5-3] a. The asterisk (*) indicates the severity of a single side effect, where * represents mild, ** represents moderate, and *** represents severe. b. The occurrence of prone position and decreased activity always coincided. c. Difficulty walking / prone position / loss of righting reflex can be understood as a sign that the side effects are gradually becoming more severe. d. Ataxia included difficulty walking and loss of balance.

[0230] 6. Experimental Conclusion Under these test conditions, ICR mice were administered a single forced oral dose of 2.5, 5, 10, and 20 mg / kg of Sage-217. Both male and female mice in the 20 mg / kg group experienced mortality, and the maximum tolerated dose (MTD) was 10 mg / kg. Observation of the mice near their cages revealed that ataxia worsened with increasing dose, with high doses accompanied by severe loss of righting reflexes. For Example 9, all animals were tolerable, the MTD was 20 mg / kg, and there was potential for further dose increases. The main adverse reaction at high doses was prone positioning and mild loss of righting reflexes in some mice. For Example 20, all animals were tolerable, the MTD was 20 mg / kg, and while ataxia worsening with increasing dose was the main symptom, there were no mouse deaths.

[0231] As can be seen from the above, the safety of the compounds in the examples of the present invention is significantly superior to that of Sage-217, and they reduce the side effects of GABAa agonists, making them valuable for further clinical development.

[0232] While embodiments for carrying out the present invention have already been described in detail, based on all the disclosed teachings, those skilled in the art can make various modifications and substitutions to the details of the technical proposal of the present invention, all of which fall within the scope of the protection of the present invention. The entire scope of the present invention is defined by the appended claims and any equivalents thereof.

Claims

1. A compound represented by general formula (I), its stereoisomer, or a pharmaceutically acceptable salt thereof, 【Chemistry 1】 During the ceremony, X is hydrogen, C 1-6 an alkyl group, C 2-6 an alkenyl group, C 2-6 an alkynyl group, C 1-6 an alkoxy group, C 3-8 a cycloalkyl group, a 3- to 8-membered heterocyclyl group, C 6-10 an aryl group or a 5- to 10-membered heteroaryl group, and in the formula, the C 1-6 alkyl group, C 2-6 alkenyl group, C 2-6 alkynyl group, C 1-6 alkoxy group, C 3-8 cycloalkyl group, 3- to 8-membered heterocyclyl group, C 6-10 aryl group or 5- to 10-membered heteroaryl group is optionally further substituted with one or more R A and R A is a halogen, hydroxyl group, -NO 2 -CN, -NR aa R bb , -C(=O)R aa , -C (=O) OR aa -OC(=O)R aa , -OC (=O) OR aa -C(=O)NR aa R bb , -N(R aa )C(=O)R bb -OC(=O)NR aa R bb , -N(R aa )C (=O)OR bb , -N(R cc )C(=O)NR aa R bb , -SR aa , -S(=O)R aa -S (=O) 2 R aa -S (=O) 2 Ure aa -OS (=O) 2 R aa -S (=O) 2 NR aa R bb -S (=O) (=NR aa )R bb , -N(R aa )S (=O) 2 R bb ,-P(=O)R aa R bb , C 1-6 Alkyl alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 Haloalkyl group, C 1-6 Alkoxy group, C 1-6 Haloalkoxy group, C 3-8 A cycloalkyl group or a 3- to 8-membered heterocyclyl group, wherein the C 1-6 Alkyl alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 Haloalkyl group, C 1-6 Alkoxy group, C 1-6 Haloalkoxy group, C 3-8 The cycloalkyl group or 3- to 8-membered heterocyclyl group may optionally be further: deuterium, halogen, hydroxyl group, amino group, mercapto group, nitro group, cyano group, C 1-6 Alkyl alkyl group, C 1-6 Haloalkyl group, C 1-6 Alkoxy group, C 1-6 Haloalkoxy group, C 1-6 Alkylthio group, C 1-6 Alkylamino group, C 3-8 Cycloalkyl group, 3-8 membered heterocyclyl group, C 6-10 Substituted with one or more substituents selected from aryl groups and 5- to 10-membered heteroaryl groups, R aa , R bb and R cc These are hydrogen and C, respectively, independently. 1-6 Alkyl alkyl group, C 1-6 Haloalkyl group, C 3-8 Cycloalkyl group, 3-8 membered heterocyclyl group, C 6-10 It is an aryl group or a 5-10 membered heteroaryl group, or R aa , R bb or R cc Any two of these, together with the atoms linked to them, form a 3- to 8-membered heterocyclyl group or a 5- to 10-membered heteroaryl ring. L is -(CH 2 ), -(CH n1 ), -(CH 2 ), -(CH n1 ), -(CH 2 ), -(CH n2 ), -(CH 2 ), -(CH n1 ), -(CH 2 ), -(CH n2 ), -(CH 2 ), -(CH n1 ), -(CH 2 ), -(CH n2 ), -(CH 2 ), -(CH n1 ), -(CH 2 ), -(CH n2 ), -(CH 2 ), -(CH n1 ), -(CH 2 ), -(CH n2 ), -(CH 2 ), -(CH n1 ), -(CH 2 ), -(CH n2 ), -(CH 2 ), -(CH n1 ), -(CH 2 ), -(CH 2 ), -(CH n2 ), -(CH 2 ), -(CH n1 ), -(CH 2 ), -(CH n2 ), -(CH 2 ), -(CH n1 ), -(CH<000012,), -(CH n2 ), -(CH 2 ), -(CH n1 ), -(CH[[ID=S3]] 2 ), -(CH<00001-5>), -(CH 2 ), -(CH n1 ), -(CH 2 ), -(CH 2 ), -(CH n2 ), and is R x and R y These are, independently, hydrogen, deuterium, halogen, hydroxyl group, amino group, mercapto group, nitro group, cyano group, and C 1-6 Alkyl alkyl group, C 1-6 Haloalkyl group, C 1-6 Alkoxy group, C 1-6 Haloalkoxy group, C 3-8 Cycloalkyl group, 3-8 membered heterocyclyl group, C 6-10 An aryl group or a 5-6 membered heteroaryl group, wherein the C 1-6 Alkyl alkyl group, C 1-6 Haloalkyl group, C 1-6 Alkoxy group, C 1-6 Haloalkoxy group, C 3-8 Cycloalkyl group, 3-8 membered heterocyclyl group, C 6-10 The aryl group or 5-6 membered heteroaryl group may optionally be further enriched with deuterium, halogen, hydroxyl group, amino group, mercapto group, nitro group, cyano group, or C 1-6 Alkyl alkyl group, C 1-6 Haloalkyl group, C 1-6 Alkoxy groups and C 1-6 Substituted with one or more substituents selected from haloalkoxy groups, R 1 , R 2 , R 3 , R 3 ', R 5 , R 6 and R 6 ' are, independently, hydrogen, deuterium, halogen, hydroxyl group, amino group, mercapto group, nitro group, cyano group, and C 1-6 Alkyl alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 Haloalkyl group, C 1-6 Alkoxy group, C 1-6 Haloalkoxy group, -(CH 2 ) n3 R dd ,-(CH 2 ) n3 Ure dd ,-(CH 2 ) n3 SR dd ,-(CH 2 ) n3 C(O)R dd ,-(CH 2 ) n3 C(O)OR dd ,-(CH 2 ) n3 S(O)R dd ,-(CH 2 ) n3 S(O) 2 R dd ,-(CH 2 ) n3 NR dd R ee ,-(CH 2 ) n3 C(O)NR dd R ee ,-(CH 2 ) n3 S(O)NR dd R ee ,-(CH 2 ) n3 NR dd C(O)R ee ,-(CH 2 ) n3 NR dd S(O)R ee or - (CH 2 ) n3 NR dd S(O) 2 R ee And, R dd and R ee These are hydrogen and C, respectively, independently. 1-6 Alkyl alkyl group, C 1-6 Haloalkyl group, C 3-8 Cycloalkyl group, 3-8 membered heterocyclyl group, C 6-10 It is an aryl group or a 5-10 membered heteroaryl group. R 4 and R 4 ' are, independently, hydrogen, halogen, hydroxyl group, amino group, mercapto group, nitro group, cyano group, and C 1-6 Alkyl alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 Haloalkyl group, C 1-6 Alkoxy group, C 1-6 Haloalkoxy group or C 3-8 It is a cycloalkyl group, and R 4 and R 4 'It does not simultaneously convert to hydrogen, n is an integer between 0 and 5. m is an integer between 0 and 5. n1 is an integer between 0 and 3. n2 is an integer between 0 and 3, and n3 is an integer between 0 and 3. A compound, its stereoisomer, or a pharmaceutically acceptable salt thereof.

2. One or more of the following conditions must be met: (1) X is hydrogen, C 1-6 Alkyl alkyl group, C 6-10 An aryl group or a 5- to 10-membered heteroaryl group, wherein the C 1-6 Alkyl alkyl group, C 6-10 The aryl group or 5-10 membered heteroaryl group may optionally be further further joined by one or more R groups. A Substituted with, preferably, X is hydrogen, C 6-10 An aryl group or a 5- to 10-membered heteroaryl group, wherein the C 6-10 The aryl group or 5-10 membered heteroaryl group may optionally be further further joined by one or more R groups. A Replaced by, (2) R A These are halogen, -CN, and -NR aa R bb , -C(=O)R aa , -C (=O) OR aa -C(=O)NR aa R bb -S (=O) 2 R aa -S (=O) 2 NR aa R bb -S (=O) (=NR aa )R bb ,-P(=O)R aa R bb , C 1-6 Alkyl alkyl group, C 1-6 Haloalkyl group, C 1-6 Alkoxy group, C 3-8 A cycloalkyl group or a 3- to 8-membered heterocyclyl group, preferably a halogen, -CN, or -S (=O) 2 R aa -S (=O) 2 NR aa R bb -S (=O) (=NR aa )R bb ,-P(=O)R aa R bb , C 1-6 Alkyl alkyl group, C 1-6 Haloalkyl group or C 1-6 An alkoxy group, more preferably a halogen, -CN, -S (=O) 2 R aa -S (=O) 2 NR aa R bb -S (=O) (=NR aa )R bb ,-P(=O)R aa R bb , C 1-3 Alkyl alkyl group, C 1-3 Haloalkyl group or C 1-3 The group is an alkoxy group, and more preferably fluorine, chlorine, -CN, methyl group, trifluoromethyl group, methoxy group, -SO 2 CH 3 , -SO 2 NH 2 ,-SCH 3 (=O)(=NH), -SCH 3 (=O)(=NCH) 3 ) or -P (=O) (CH 3 ) 2 And, (3) R aa , R bb and R cc These are, independently, hydrogen or C 1-6 It is an alkyl group, preferably hydrogen or C 1-3 It is an alkyl group, more preferably a hydrogen or methyl group, (4) L is - (CH 2 ) n1 -,-(CH 2 ) n1 C(O)(CH 2 ) n2 -,-(CH 2 ) n1 S(O) 2 (CH 2 ) n2 -,-(CH 2 ) n1 C(O)NH(CH) 2 ) n2 -,-(CH 2 ) n1 C(O)(CH 2 ) n2 NH-,-(CH 2 ) n1 NHC(O)(CH 2 ) n2 - or - (CH 2 ) n1 NHS(O) 2 (CH 2 ) n2 -and preferably -C(O)(CH 2 ) n2 -, -C(O)NH(CH 2 ) n2 -, -C(O)(CH 2 ) n2 NH-,-(CH 2 ) n1 NHC(O)- or -(CH 2 ) n1 NHS(O) 2 -and more preferably -C(O)(CH 2 ) n2 - or -C(O)(CH 2 ) n2 It is NH-, (5) R x and R y These are, independently, hydrogen, deuterium, halogen, hydroxyl group, and C 1-6 Alkyl alkyl group, C 1-6 Haloalkyl group, C 1-6 Alkoxy group or C 3-8 It is a cycloalkyl group, preferably hydrogen, deuterium, halogen, hydroxyl group, or C 1-6 It is an alkyl group, more preferably hydrogen, (6) R 1 , R 2 and R 5 These are, independently, hydrogen, deuterium, halogen, hydroxyl group, and C 1-6 Alkyl alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 Haloalkyl group, C 1-6 Alkoxy group, -(CH 2 ) n3 Ure dd ,-(CH 2 ) n3 SR dd or - (CH 2 ) n3 C(O)R dd Preferably, hydrogen, deuterium, C 1-3 Alkyl alkyl group, C 2-4 Alkenyl group or C 2-4 An alkynyl group, more preferably hydrogen or C 1-3 It is an alkyl group, and more preferably a hydrogen or methyl group. (7) R dd and R ee These are hydrogen and C, respectively, independently. 1-6 Alkyl alkyl group or C 1-6 It is a haloalkyl group, preferably hydrogen or C 1-3 It is an alkyl group, (8) R 3 , R 3 ', R 6 and R 6 ' are, respectively, hydrogen, deuterium, or C 1-6 It is an alkyl group, preferably hydrogen, deuterium, or C 1-3 It is an alkyl group, more preferably hydrogen or C 1-3 It is an alkyl group, and more preferably a hydrogen or methyl group. (9) R 4 and R 4 ' are each independently of hydrogen or C 1-6 It is an alkyl group, preferably hydrogen or C 1-3 It is an alkyl group, more preferably a hydrogen or methyl group, and R 4 and R 4 'It does not simultaneously convert to hydrogen, (10) n is selected from 0, 1, 2, 3 or 4, preferably 0, 1 or 2. (11) m is selected from 0, 1, 2, 3 or 4, preferably 0, 1 or 2. (12) n1 is selected from 0, 1 or 2, preferably 0 or 1. (13) n2 is selected from 0, 1 or 2, preferably 0 or 1. (14) n3 is selected from 0, 1 or 2, preferably 0 or 1. The compound described in feature 1, its stereoisomer, or a pharmaceutically acceptable salt thereof.

3. General formula (I) has the structure shown by general formula (II), 【Chemistry 2】 During the ceremony, X, L, R x , R y , R 1 , R 2 , R 3 n and m are as described in claim 1 or 2. A compound according to feature 1 or 2, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

4. General formula (I) has the structure shown by general formula (III), 【Transformation 3】 During the ceremony, X is hydrogen, C 1-6 Alkyl alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 Alkoxy group, C 3-8 Cycloalkyl group, 3-8 membered heterocyclyl group, C 6-10 An aryl group or a 5- to 10-membered heteroaryl group, wherein the C 1-6 Alkyl alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 Alkoxy group, C 3-8 Cycloalkyl group, 3-8 membered heterocyclyl group, C 6-10 The aryl group or 5-10 membered heteroaryl group may optionally be further further joined by one or more R groups. A Replaced by, R A is a halogen, hydroxyl group, -NO 2 -CN, -NR aa R bb , -C(=O)R aa , -C (=O) OR aa -OC(=O)R aa , -OC (=O) OR aa -C(=O)NR aa R bb , -N(R aa )C(=O)R bb -OC(=O)NR aa R bb , -N(R aa )C (=O)OR bb , -N(R cc )C(=O)NR aa R bb , -SR aa , -S(=O)R aa -S (=O) 2 R aa -S (=O) 2 Ure aa -OS (=O) 2 R aa -S (=O) 2 NR aa R bb -S (=O) (=NR aa )R bb , -N(R aa )S (=O) 2 R bb ,-P(=O)R aa R bb , C 1-6 Alkyl alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 Haloalkyl group, C 1-6 Alkoxy group, C 1-6 Haloalkoxy group, C 3-8 A cycloalkyl group or a 3- to 8-membered heterocyclyl group, wherein the C 1-6 Alkyl alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 Haloalkyl group, C 1-6 Alkoxy group, C 1-6 Haloalkoxy group, C 3-8 The cycloalkyl group or 3- to 8-membered heterocyclyl group may optionally be further: deuterium, halogen, hydroxyl group, amino group, mercapto group, nitro group, cyano group, C 1-6 Alkyl alkyl group, C 1-6 Haloalkyl group, C 1-6 Alkoxy group, C 1-6 Haloalkoxy group, C 1-6 Alkylthio group, C 1-6 Alkylamino group, C 3-8 Cycloalkyl group, 3-8 membered heterocyclyl group, C 6-10 Substituted with one or more substituents selected from aryl groups or 5- to 10-membered heteroaryl groups, R aa , R bb and R cc These are hydrogen and C, respectively, independently. 1-6 Alkyl alkyl group, C 1-6 Haloalkyl group, C 3-8 Cycloalkyl group, 3-8 membered heterocyclyl group, C 6-10 It is an aryl group or a 5-10 membered heteroaryl group, or R aa , R bb or R cc Any two of these, together with the atoms linked to them, form a 3- to 8-membered heterocyclyl group or a 5- to 10-membered heteroaryl ring. L is -(CH 2 ), -(CH n1 ), -(CH 2 ), -(CH n1 ), -(CH 2 ), -(CH n2 ), -(CH 2 ), -(CH n1 ), -(CH 2 ), -(CH n2 ), -(CH 2 ), -(CH n1 ), -(CH 2 ), -(CH n2 ), -(CH<00​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​ R x and R y These are, independently, hydrogen, deuterium, halogen, hydroxyl group, amino group, mercapto group, nitro group, cyano group, and C 1-6 Alkyl alkyl group, C 1-6 Haloalkyl group, C 1-6 Alkoxy group, C 1-6 Haloalkoxy group, C 3-8 Cycloalkyl group, 3-8 membered heterocyclyl group, C 6-10 An aryl group or a 5-6 membered heteroaryl group, wherein the C 1-6 Alkyl alkyl group, C 1-6 Haloalkyl group, C 1-6 Alkoxy group, C 1-6 Haloalkoxy group, C 3-8 Cycloalkyl group, 3-8 membered heterocyclyl group, C 6-10 The aryl group or 5-6 membered heteroaryl group may optionally be further enriched with deuterium, halogen, hydroxyl group, amino group, mercapto group, nitro group, cyano group, or C 1-6 Alkyl alkyl group, C 1-6 Haloalkyl group, C 1-6 Alkoxy group or C 1-6 Substituted with one or more substituents selected from haloalkoxy groups, R 1 and R 2 These are, independently, hydrogen, deuterium, halogen, hydroxyl group, amino group, mercapto group, nitro group, cyano group, and C 1-6 Alkyl alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 Haloalkyl group, C 1-6 Alkoxy group, C 1-6 Haloalkoxy group, -(CH 2 ) n3 R dd ,-(CH 2 ) n3 Ure dd ,-(CH 2 ) n3 SR dd ,-(CH 2 ) n3 C(O)R dd ,-(CH 2 ) n3 C(O)OR dd ,-(CH 2 ) n3 S(O)R dd ,-(CH 2 ) n3 S(O) 2 R dd ,-(CH 2 ) n3 NR dd R ee ,-(CH 2 ) n3 C(O)NR dd R ee ,-(CH 2 ) n3 S(O)NR dd R ee ,-(CH 2 ) n3 NR dd C(O)R ee ,-(CH 2 ) n3 NR dd S(O)R ee or - (CH 2 ) n3 NR dd S(O) 2 R ee And, R dd and R ee These are hydrogen and C, respectively, independently. 1-6 Alkyl alkyl group, C 1-6 Haloalkyl group, C 3-8 Cycloalkyl group, 3-8 membered heterocyclyl group, C 6-10 It is an aryl group or a 5-10 membered heteroaryl group. n is an integer between 0 and 5. m is an integer between 0 and 5. n1 is an integer between 0 and 3. n2 is an integer between 0 and 3, and n3 is an integer between 0 and 3. A compound according to any one of claims 1 to 3, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

5. One or more of the following conditions must be met: (1) X is hydrogen, C 1-6 Alkyl alkyl group, C 6-10 An aryl group or a 5- to 10-membered heteroaryl group, wherein the C 1-6 Alkyl alkyl group, C 6-10 The aryl group or 5-10 membered heteroaryl group may optionally be further further joined by one or more R groups. A Substituted with, preferably, X is hydrogen, C 6-10 An aryl group or a 5- to 10-membered heteroaryl group, wherein the C 6-10 The aryl group or 5-10 membered heteroaryl group may optionally be further further joined by one or more R groups. A Replaced by, (2) R A These are halogen, -CN, and -NR aa R bb , -C(=O)R aa , -C (=O) OR aa -C(=O)NR aa R bb -S (=O) 2 R aa -S (=O) 2 NR aa R bb -S (=O) (=NR aa )R bb ,-P(=O)R aa R bb , C 1-6 Alkyl alkyl group, C 1-6 Haloalkyl group, C 1-6 Alkoxy group, C 3-8 A cycloalkyl group or a 3- to 8-membered heterocyclyl group, preferably a halogen, -CN, or -S (=O) 2 R aa -S (=O) 2 NR aa R bb -S (=O) (=NR aa )R bb ,-P(=O)R aa R bb , C 1-6 Alkyl alkyl group, C 1-6 Haloalkyl group or C 1-6 An alkoxy group, more preferably a halogen, -CN, -S (=O) 2 R aa -S (=O) 2 NR aa R bb -S (=O) (=NR aa )R bb ,-P(=O)R aa R bb , C 1-3 Alkyl alkyl group, C 1-3 Haloalkyl group or C 1-3 The group is an alkoxy group, and more preferably fluorine, chlorine, -CN, methyl group, trifluoromethyl group, methoxy group, -SO 2 CH 3 , -SO 2 NH 2 ,-SCH 3 (=O)(=NH), -SCH 3 (=O)(=NCH) 3 ) or -P (=O) (CH 3 ) 2 And, (3) R aa , R bb and R cc These are, independently, hydrogen or C 1-6 It is an alkyl group, preferably hydrogen or C 1-3 It is an alkyl group, more preferably a hydrogen or methyl group, (4) L is - (CH 2 ) n1 -,-(CH 2 ) n1 C(O)(CH 2 ) n2 -,-(CH 2 ) n1 S(O) 2 (CH 2 ) n2 -,-(CH 2 ) n1 C(O)NH(CH) 2 ) n2 -,-(CH 2 ) n1 NHC(O)(CH 2 ) n2 - or - (CH 2 ) n1 NHS(O) 2 (CH 2 ) n2 -and preferably -C(O)(CH 2 ) n2 -, -C(O)NH(CH 2 ) n2 -,-(CH 2 ) n1 NHC(O)- or -(CH 2 ) n1 NHS(O) 2 -and more preferably -C(O)(CH 2 ) n2 -and, (5) R x and R y These are, independently, hydrogen, deuterium, halogen, hydroxyl group, and C 1-6 Alkyl alkyl group, C 1-6 Haloalkyl group, C 1-6 Alkoxy group or C 3-8 It is a cycloalkyl group, preferably hydrogen, deuterium, halogen, hydroxyl group, or C 1-6 It is an alkyl group, more preferably hydrogen, (6) R 1 and R 2 These are, independently, hydrogen, deuterium, halogen, hydroxyl group, and C 1-6 Alkyl alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 Haloalkyl group, C 1-6 Alkoxy group, -(CH 2 ) n3 Ure dd ,-(CH 2 ) n3 SR dd or - (CH 2 ) n3 C(O)R dd Preferably, hydrogen, deuterium, C 1-3 Alkyl alkyl group, C 2-4 Alkenyl group or C 2-4 An alkynyl group, more preferably hydrogen or C 1-3 It is an alkyl group, and more preferably a hydrogen or methyl group. (7) R dd and R ee Each of them is independently C 1-6 Alkyl alkyl group or C 1-6 It is a haloalkyl group, preferably C 1-3 It is an alkyl group, (8) n is selected from 0, 1, 2, 3 or 4, preferably 0, 1 or 2. (9) m is selected from 0, 1, 2, 3 or 4, preferably 0, 1 or 2. (10) n1 is selected from 0, 1 or 2, preferably 0 or 1. (11) n2 is selected from 0, 1 or 2, preferably 0 or 1. (12) n3 is selected from 0, 1 or 2, preferably 0 or 1. A compound according to any one of claims 1 to 4, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

6. General formula (I) has the structure shown by general formula (IV), 【Chemistry 4】 During the ceremony, Z is - (CH 2 ) n4 - or -NH (CH 2 ) n4 - and preferably - (CH 2 ) n4 -and moreover, -CH 2 -and, R 1 is hydrogen, deuterium, halogen, hydroxyl group, C 1-6 Alkyl alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 Haloalkyl group, C 1-6 Alkoxy group, -(CH 2 ) n3 Ure dd ,-(CH 2 ) n3 SR dd or - (CH 2 ) n3 C(O)R dd And preferably, C 1-6 It is an alkyl group, more preferably C 1-3 It is an alkyl group, and more preferably a methyl group, R 2 is hydrogen, deuterium, halogen, hydroxyl group, C 1-6 Alkyl alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 Haloalkyl group, C 1-6 Alkoxy group, -(CH 2 ) n3 Ure dd ,-(CH 2 ) n3 SR dd or - (CH 2 ) n3 C(O)R dd Preferably, hydrogen or C 1-6 It is an alkyl group, more preferably hydrogen or C 1-3 It is an alkyl group, and more preferably a hydrogen or methyl group. R dd C 1-6 Alkyl alkyl group or C 1-6 It is a haloalkyl group, preferably C 1-3 It is an alkyl group, n3 is 0, 1, or 2, preferably 0 or 1. n4 is 0, 1, or 2, preferably 0 or 1. X, R x , R y n and m are as described in any one of claims 1 to 5. A compound according to any one of claims 1 to 5, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

7. General formula (I) has a structure further represented by general formula (V), 【Transformation 5】 During the ceremony, X is hydrogen or optionally one or more R A A 5-10 member heteroaryl group substituted with, preferably hydrogen or optionally one or more R A A 5-10 membered heteroaryl group containing 1-4 nitrogen atoms substituted with, R A These are halogens, hydroxyl groups, -CN, and -NR aa R bb , -C(=O)R aa , -C (=O) OR aa -OC(=O)R aa , -OC (=O) OR aa -C(=O)NR aa R bb , -N(R aa )C(=O)R bb -OC(=O)NR aa R bb , -N(R aa )C (=O)OR bb , -N(R cc )C(=O)NR aa R bb , -SR aa , -S(=O)R aa -S (=O) 2 R aa -S (=O) 2 Ure aa -OS (=O) 2 R aa -S (=O) 2 NR aa R bb -S (=O) (=NR aa )R bb , -N(R aa )S (=O) 2 R bb ,-P(=O)R aa R bb , C 1-6 Alkyl alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 Haloalkyl group, C 1-6 Alkoxy group, C 1-6 Haloalkoxy group, C 3-8 A cycloalkyl group or a 3- to 8-membered heterocyclyl group, preferably a halogen, -CN, or -S (=O) 2 R aa -S (=O) 2 NR aa R bb -S (=O) (=NR aa )R bb ,-P(=O)R aa R bb , C 1-6 Alkyl alkyl group, C 1-6 Haloalkyl group or C 1-6 An alkoxy group, more preferably a halogen, -CN, -S (=O) 2 R aa -S (=O) 2 NR aa R bb -S (=O) (=NR aa )R bb ,-P(=O)R aa R bb , C 1-3 Alkyl alkyl group, C 1-3 Haloalkyl group or C 1-3 The group is an alkoxy group, and more preferably fluorine, chlorine, -CN, methyl group, trifluoromethyl group, methoxy group, -SO 2 CH 3 , -SO 2 NH 2 ,-SCH 3 (=O)(=NH), -SCH 3 (=O)(=NCH) 3 ) or -P (=O) (CH 3 ) 2 And, R aa , R bb and R cc These are hydrogen and C, respectively, independently. 1-6 Alkyl alkyl group or C 1-6 It is a haloalkyl group, preferably hydrogen or C 1-6 It is an alkyl group, more preferably hydrogen or C 1-3 It is an alkyl group, and more preferably a hydrogen or methyl group. A compound according to any one of claims 1 to 6, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

8. The aforementioned X is hydrogen or one of the following groups: 【Transformation 6】 Preferably, 【Transformation 7】 And, R A is halogen, a hydroxy group, -CN, -NR aa R bb , -C(=O)R aa , -C(=O)OR aa , -OC(=O)R aa , -OC(=O)OR aa , -C(=O)NR aa R bb , -N(R aa )(=O)R bb , -OC(=O)NR aa R bb , -N(R aa )(=O)OR bb , -N(R cc )(=O)NR aa R bb , -SR aa , -S(=O)R aa , -S(=O) 2 R aa , -S(=O) 2 OR aa , -OS(=O) 2 R aa , -S(=O) 2 NR aa R bb , -S(=O)(=NR aa )(=O)R bb , -N(R aa )(=O)S(=O) 2 R bb , -P(=O)R aa bb , C 1-6 alkyl group, C 2-6 alkenyl group, C 2-6 alkynyl group, C 1-6 haloalkyl group, C 1-6 alkoxy group, C 1-6 haloalkoxy group, C 3-8 cycloalkyl group or a 3- to 8-membered heterocyclyl group, preferably halogen, -CN, -S(=O) 2 R aa , -S(=O) 2 NR aa R bb , -S(=O)(=NR aa )(=O)R bb , -P(=O)R aa R​ bb , C 1-6 an alkyl group, C 1-6 a haloalkyl group or C 1-6 an alkoxy group, more preferably, halogen, -CN, -S(=O) 2 R aa , -S(=O) 2 NR aa R bb , -S(=O)(=NR aa )R bb , -P(=O)R aa R bb , C 1-3 an alkyl group, C 1-3 a haloalkyl group or C 1-3 an alkoxy group, even more preferably, fluorine, chlorine, -CN, a methyl group, a trifluoromethyl group, a methoxy group, -SO 2 CH 3 , -SO 2 NH 2 , -SCH 3 (=O)(=NH), -SCH 3 (=O)(=NCH 3 ) or -P(=O)(CH 3 ) 2 and R aa , R bb and R cc These are hydrogen and C, respectively, independently. 1-6 Alkyl alkyl group or C 1-6 It is a haloalkyl group, preferably hydrogen or C 1-6 It is an alkyl group, more preferably hydrogen or C 1-3 It is an alkyl group, and more preferably a hydrogen or methyl group. o is selected from 0, 1, 2, 3 or 4, preferably 0 or 1. A compound according to any one of claims 1 to 7, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

9. General formula (I) has the structure shown by general formula (VI), 【Transformation 8】 During the ceremony, R 1 is hydrogen, deuterium, halogen, hydroxyl group, C 1-6 Alkyl alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 Haloalkyl group or C 1-6 It is an alkoxy group, preferably hydrogen, deuterium, or C 1-6 It is an alkyl group, more preferably hydrogen, deuterium, or C 1-3 It is an alkyl group, more preferably hydrogen, deuterium, or a methyl group. X is hydrogen or optionally one or more R A A 5-10 member heteroaryl group substituted with, preferably hydrogen or optionally one or more R A A 5-10 membered heteroaryl group containing 1-4 nitrogen atoms substituted with, more preferably, 【Chemistry 9】 And, R A These are halogens, hydroxyl groups, cyano groups, and C 1-6 Alkyl alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 Haloalkyl group, C 1-6 Alkoxy group or C 1-6 It is a haloalkoxy group, preferably a cyano group, C 1-6 Alkyl alkyl group or C 1-6 It is a haloalkyl group, more preferably a cyano group, C 1-3 Alkyl alkyl group or C 1-3 It is a haloalkyl group, more preferably a cyano group, a methyl group, or a trifluoromethyl group. o is selected from 0, 1, or 2, preferably 0 or 1. A compound according to any one of claims 1 to 6, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

10. General formula (I) has the structure shown by general formula (VII), 【Chemistry 10】 During the ceremony, R 1 is hydrogen, deuterium, halogen, hydroxyl group, C 1-6 Alkyl alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 Haloalkyl group or C 1-6 It is an alkoxy group, preferably hydrogen, deuterium, or C 1-6 It is an alkyl group, more preferably hydrogen, deuterium, or C 1-3 It is an alkyl group, more preferably hydrogen, deuterium, or a methyl group. X is optionally one or more R A A 5-10 member heteroaryl group substituted with, preferably one or more R groups optionally. A A 5-10 membered heteroaryl group containing 1-4 nitrogen atoms substituted with, more preferably, 【Chemistry 11】 And, R A is a halogen, hydroxy group, cyano group, C 1-6 alkyl group, C 2-6 alkenyl group, C 2-6 alkynyl group, C 1-6 haloalkyl group, C 1-6 alkoxy group or C 1-6 haloalkoxy group, preferably a cyano group or C 1-6 alkyl group, more preferably a cyano group or C 1-3 alkyl group, still more preferably a cyano group or a methyl group, o is selected from 0, 1, or 2, preferably 0 or 1. A compound according to any one of claims 1 to 3, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

11. General formula (I) has the structure shown by general formula (VIII), 【Chemistry 12】 During the ceremony, R 1 is hydrogen, deuterium, or C 1-6 It is an alkyl group, preferably hydrogen, deuterium, or C 1-3 It is an alkyl group, more preferably a hydrogen or methyl group, R 3 is hydrogen, deuterium, or C 1-6 It is an alkyl group, preferably hydrogen, deuterium, or C 1-3 It is an alkyl group, more preferably a hydrogen or methyl group, R 4 C 1-6 It is an alkyl group, preferably C 1-3 It is an alkyl group, more preferably a methyl group, X is optionally one or more R A A 5-membered heteroaryl group containing 1 to 4 nitrogen atoms substituted with, preferably, 【Chemistry 13】 And, R A Halogen, -CN, C 1-6 Alkyl alkyl group, C 1-6 Haloalkyl group, C 1-6 Alkoxy group or C 3-8 It is a cycloalkyl group, preferably a halogen, -CN, C 1-3 Alkyl alkyl group, C 1-3 Haloalkyl group or C 1-3 It is an alkoxy group, more preferably fluorine, chlorine, -CN, methyl group, ethyl group, trifluoromethyl group or methoxy group, o is selected from 0, 1, or 2. A compound according to feature 1 or 2, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

12. General formula (I) has a structure represented by general formula (VIII-A) or (VIII-B), 【Chemistry 14】 During the ceremony, R 1 is hydrogen, deuterium, or C 1-6 It is an alkyl group, preferably hydrogen, deuterium, or C 1-3 It is an alkyl group, more preferably a hydrogen or methyl group, R 3 is hydrogen, deuterium, or C 1-6 It is an alkyl group, preferably hydrogen, deuterium, or C 1-3 It is an alkyl group, more preferably a hydrogen or methyl group, R 4 C 1-6 It is an alkyl group, preferably C 1-3 It is an alkyl group, more preferably a methyl group, R A Halogen, -CN, C 1-6 Alkyl alkyl group, C 1-6 Haloalkyl group, C 1-6 Alkoxy group or C 3-8 It is a cycloalkyl group, preferably a halogen, -CN, C 1-3 Alkyl alkyl group, C 1-3 Haloalkyl group or C 1-3 It is an alkoxy group, more preferably fluorine, chlorine, -CN, methyl group, ethyl group, trifluoromethyl group or methoxy group, o is selected from 0, 1, or 2. A compound according to any one of claims 1, 2, or 11, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. 【Request Item 13】 【Chemistry 15-1】 【Chemistry 15-2】 【Chemistry 15-3】 Selected from, The compound described in feature 1, its stereoisomer, or a pharmaceutically acceptable salt thereof.

14. A therapeutically effective amount comprising a compound according to any one of claims 1 to 13, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier, diluent, or excipient. Pharmaceutical composition.

15. In the production of a GABAa receptor modulator drug, the compound according to any one of claims 1 to 13, its stereoisomer or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 14, use.

16. Use of a compound according to any one of claims 1 to 13, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 14, in the manufacture of a drug for treating a CNS-related disorder, preferably the CNS-related disorder being a sleep disorder, mood disorder, premenstrual dysphoric disorder, schizophrenia spectrum disorder, spastic disorder, memory impairment and / or cognitive impairment, motor disorder, personality disorder, autism spectrum disorder, depression, postpartum depression, major depression, menopausal depression, anxiety disorder, premenstrual anxiety disorder, epilepsy, pain, traumatic brain injury, vascular disease, substance use disorder and / or withdrawal syndrome, or tinnitus, more preferably depression, postpartum depression, major depression, menopausal depression, anxiety disorder, premenstrual dysphoric disorder, or epilepsy. use.

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